NEBOSH International Diploma in Occupational Health and Safety

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Version 1.2c (06/11/2012)

Element IB1: Principles of Chemical Control, Toxicology & Epidemiology

Learning outcomes.
On completion of this element, candidates should be able to:
1.
2.
3.
4.
5.

Outline the principles of control of chemicals.

Outline human anatomical systems and sensory organs.
Describe the main effects and routes of attack of chemicals on the human body.
Explain the health effects of chemicals used in the workplace.
Explain the principles of epidemiology and the principles of deriving and applying toxicological data to the identification of work-related Ill-health.

Relevant Standards

International Labour Standards, Chemical Safety Convention, C170, International Labour

Organisation, Geneva, 1990
International Labour Standards, Chemical Safety Recommendation, R177, International
Labour Organisation, Geneva, 1990.
ILO Asbestos, Convention (C162) and Recommendation (R172), International Labour Organisation, Geneva, 1986
International Labour Office, Safety in the Use of Chemicals at Work, an ILO Code of Practice, ILO, 1993.
The International Programme of Chemical Safety (IPCS), INCHEM Health and Safety
Guides (Series), World Health Organisation, 2005.
Globally Harmonised System of Classification and Labelling of Chemicals, Third revised
edition, 2009.
EC Caesar project

Minimum hours of tuition: 8 hours.

1.1 Principles of Control of Chemicals

Introduction
The International Labour Organisation (ILO) recognises that although significant progress has
been made in international chemicals management and regulations, serious incidents still occur
which have a negative impact on human health and the environment.
The International Programme on Chemical Safety (IPCS) was formed in 1980 to establish the
scientific basis for the safe use of chemicals and to strengthen national capabilities and capacities for chemical safety. It is collaboration between three United Nations bodies
1. World Health Organization
2. International Labour Organization
3. United Nations Environment Programme
The ILO Conventions and Recommendations in the Field of Chemical Safety Include:
Chemicals Convention, 1990 (No.170)
Chemicals Recommendation, 1990 (No. 177)
Prevention of Major Industrial Accidents Convention, 1993 (No.174)
Prevention of Major Industrial Accidents Recommendation, 1993 (No. 181)
Asbestos Convention, 1986 (No. 162)
Asbestos Recommendation, 1986 (No.172)
Working Environment (Air Pollution, Noise and Vibration) Convention, 1977 (No. 148)

Working Environment (Air Pollution, Noise and Vibration) Recommendation, 1977 (No. 156)
Radiation Protection Convention, 1960 (No. 115)
Benzene Recommendation, 1971 (No. 144)
Occupational Cancer Convention, 1974 (No.139)
Occupational Cancer Recommendation, 1974 (No.147)
Labour Inspection (Agriculture) Convention 1969 (No.129)
Labour Inspection (Agriculture) Recommendation, 1969 (No. 133)
To put the control of chemicals into perspective, this element begins with an overview of the principles aimed at controlling the use of chemicals in the workplace as contained within:
ILO Chemicals Convention (C170) and Recommendation (R177)
ILO Asbestos Convention (C162) and Recommendation (R172)
C170 - Chemicals Convention, 1990 (No. 170)
Convention concerning Safety in the use of Chemicals at Work (Entry into force: 04 Nov
1993)Adoption: Geneva, 77th ILC session (25 Jun 1990) - Status: Up-to-date instrument (Technical Convention).
The convention was convened having regard to the need for co-operation within the International
Programme on Chemical Safety.
The convention was intended to protect workers, the general public and the environment from the
harmful effects of chemicals. The convention states that it is essential to protect to reduce the incidence of chemically induced illness and injuries at work by:
evaluating all chemicals to determine their hazards
Provide employers with a mechanism to obtain from suppliers information about the chemicals
used so that an effective programme to protect workers from chemical hazards can be implemented.
To provide workers with information about chemicals at their workplace and appropriate preventive measures to participlate in protective programmes
Establishing principles for such programmes to ensure the safe use of chemicals.
The convention is arranged in seven parts and consists of twenty-seven articles.
Part 1 Scope and definitions
Articles 1and 2
Article 2 covers the definitions of terms used throughout the convention.
Chemicals means chemical elements and compounds, and mixtures thereof , whether natural or
synthetic. Hazardous chemical is defined as any chemical which has been classified in accordance with article 6.The term `use of chemicals at work covers activities where a worker may be
exposed to a chemical. Including Production, Handling, Storage, Transport, Disposal & treatment
, Release, Maintenance, repair and cleaning of equipment and containers for chemicals.
Part II General Principles
Articles 3-5
Part III Classification and related measures
Article 6 Classification systems
Article 7 Labelling and marking
Article 8 Chemical safety data sheets
Article 9 Responsibilities of suppliers
Part IV Responsibilities of employers
Article 10 Identification
Article 11 Transfer of chemicals
Article 12 Exposure
Article 13 Operational control
Article 14 Disposal
Article 15 Information and training

Article 16 Co-operation
Part V Duties of workers
Article 17
Part VI Rights of workers and their representatives
Article 18
Part VII Responsibility of Exporting states
Articles 19-27
It is recommended that candidates familiarise themselves with the requirements of this convention. The convention is available on the following link:
http://www.ilo.org/dyn/normlex/en/f?p=NORMLEXPUB:12100:1371090029550894::NO:12100:P1
2100_INSTRUMENT_ID:312315:NO
Article 8 on chemical safety data sheets is relevant to this unit.
Article 8 states that:
1. For hazardous chemicals, chemical safety data sheets containing detailed essential information regarding their identity, supplier, classification, hazards, safety precautions and emergency
procedures shall be provided to employers.
2. Criteria for the preparation of chemical safety data sheets shall be established by the competent authority, or by a body approved or recognised by the competent authority, in accordance
with national or international standards.
3. The chemical or common name used to identify the chemical on the chemical safety data
sheet shall be the same as that used on the label.
R177 - Chemicals Recommendation, 1990 (No. 177)
Recommendation concerning Safety in the use of Chemicals at WorkAdoption: Geneva, 77th ILC
session (25 Jun 1990) - Status: Up-to-date instrument (Technical Convention). The proposals
contained in this recommendation supplement the Chemicals Convention, 1990.
Articles 6 and 7 of the Recommendation regarding classification, state that:
6. The criteria for the classification of chemicals established pursuant to Article 6, paragraph 1, of
the Convention should be based upon the characteristics of chemicals including:
(a) toxic properties, including both acute and chronic health effects in all parts of the body;
(b) chemical or physical characteristics, including flammable, explosive, oxidising and dangerously reactive properties;
(c) corrosive and irritant properties;
(d) allergenic and sensitising effects;
(e) carcinogenic effects;
(f) teratogenic and mutagenic effects;
(g) effects on the reproductive system.
7. (1) As far as is reasonably practicable, the competent authority should compile and periodically
update a consolidated list of the chemical elements and compounds used at work, together with
relevant hazard information.
(2) For chemical elements and compounds not yet included in the consolidated list, the manufacturers or importers should, unless exempted, be required to transmit to the competent authority,
prior to use at work, and in a manner consistent with the protection of confidential information under Article 1, paragraph 2 (b), of the Convention, such information as is necessary for the maintenance of the list.
It is recommended that candidates familiarise themselves with the requirements of this recommendation. The recommendation is available on the following link:
http://www.ilo.org/dyn/normlex/en/f?p=1000:12100:0::NO::P12100_INSTRUMENT_ID:312515

1.2 ILO - Safety in the Use of Chemicals at Work an ILO Code of Practice
ILO - Safety in the use of Chemicals at Work an ILO Code of Practice
Overview
The code provides practical guidance on the implementation of the provisions of the Chemicals
Convention, 1990 (No. 170), and Recommendation, 1990 (No. 177). It is an ILO contribution to
the International Programme on Chemical Safety of UNEP, the ILO and the WHO (IPCS).
The code is the outcome of a PIACT Project. PIACT was explained in Unit A, and is an acronym
for the International Programme for the Improvement of Working Conditions and Environment.
The objective of the code is to provide guidance to those who have responsibilities for framing
provisions relating to the use of chemicals at work and offers guidelines to suppliers, employers,
and workers organisations. The code is not intended to replace national laws, regulations or accepted standards.
The code of practice is arranged as follows:
1. General provisions
2. General obligations, responsibilities and duties
3. Classification systems
4. Labelling and marking
5. Chemical safety data sheets
6. Operational control measures
7. Design and installation.
8. Work systems and practices
9. Personal protection
10. Information and training
11. Maintenance of engineering control measures
12. Monitoring in the workplace
13. Medical health surveillance
14. Emergency procedures and first aid
15. Investigation and reporting of accidents, occupational diseases and other incidents
Annex A: A possible approach for the protection of confidential information.
1.3 covers definitions of terms used throughout the code of practice. This list includes a definition
of the `competent authority'. Competent authority: A minister, government department or other
public authority with the power to issue regulations, orders or other instructions having the force
of law.
2: General obligations responsibilities and duties
The competent authority should:
formulate and state a coherent policy on safety in the use of chemicals at work, which forms
part of the national policy on occupational safety and health and the working environment required by the Occupational Safety and Health Convention, 1981 (No. 155).
review national measures and practice against international regulations, standards and systems, and with the measures and practice recommended by the code.
should formulate and implement the necessary measures including laws, standards and criteria
for safety in the use of chemicals at work to give effect to Convention No. 170 and Recommendation No. 177.
periodically review the stated policy and the existing measures to implement that policy.
ensure that compliance with laws and regulations concerning safety in the use of chemicals at
work is secured by an adequate and appropriate system of inspection.
have the power, if justified on safety and health grounds, to either:
prohibit or restrict the use of certain hazardous chemicals; or

(b) require advance notification and authorisation before such chemicals are used.
have powers to specify categories of workers who, for reasons of safety and health, are not allowed to use specified chemicals or are allowed to use them but only under conditions prescribed
in accordance with national laws or regulations.
establish:
a) systems and specific criteria appropriate for classifying chemicals.
b) systems and specific criteria for assessing the relevance of the information required to determine whether a chemical is hazardous;
c) requirements for marking and labelling chemicals.
d) criteria for the information contained in the chemical safety data sheets received by employers.
extend the application of classification systems taking into account harmonisation with internationally recognised systems.
require manufacturers and importers to provide it with information on specified criteria for assessing the hazards of chemical elements and compounds which are not yet included in the consolidated list compiled by the competent authority.
ensure that criteria are established on measures which provide for safety of workers.
Employers should:
Set out a written policy on arrangements on safety in the use of chemicals.
Ensure chemicals used at work are labelled or marked in accordance with the code and that
chemical safety data sheets are provided. Chemicals should not be used until all this information
has been obtained.
Maintain a record of hazardous chemicals.
Make an assessment of the risks arising from the use of chemicals.
Take appropriate measures to protect workers against the risk identified by the assessment.
Comply with appropriate standards , codes and guidelines in the use of chemicals.
Make adequate arrangements to deal with incidents and accidents.
Provide workers with necessary, appropriate and periodic instruction and training.
Provide health and safety measures to other establishments in other countries if they are part of
a multi-national enterprise without discrimintation.
Workers should:
take all reasonable steps to eliminate or minimise risk to themselves and to others.
take care of their own health and safety and that of other persons who may be affected by their
acts or omissions at work.
make proper use of all devices provided for their protection or the protection of others.
report forthwith to their supervisor any situation which they believe could present a risk, and
which they cannot properly deal with themselves.
Suppliers of chemicals (whether manufacturers, importers or distributors)
should ensure that:
such chemicals have been classified or their properties assessed;
such chemicals are marked to indicate their identity;
hazardous chemicals are labelled;
chemical safety data sheets for hazardous chemicals are prepared and provided to employers;
in accordance with the codes guidelines.
the properties of all chemicals are identified and assessed
all chemicals they supply are classified in accordance with systems and criteria approved or
recognised by the relevant competent authority.
ensure that revised labels and chemical safety data sheets are prepared and provided to employers.
confidential information not included in the chemical data sheet should disclose the information
in accordance with section 2.6.
4: Labelling and marking
The competent authority should establish requirements for the marking and labelling of chenmicals. Suppliers should ensure that chemicals are marked and hazardous substances labelled.

Employers should not use chemicals which have not been labelled or marked.
The purpose of labelling is to provide essential information on the classification, hazards and precautions to be observed and should cover both acute and chronic exposure.
Labelling requirements, which should be in conformity with national requirements, should cover:
the information to be given on the label, including as appropriate:
trade names;
identity of the chemical;
name, address and telephone number of the supplier;
hazard symbols;
nature of the special risks associated with the use of the chemical;
safety precautions;
identification of the batch;
the statement that a chemical safety data sheet giving additional information is
available from the employer;
the classification assigned under the system established by the competent
authority;
the legibility, durability and size of the label;
the uniformity of labels and symbols, including colours
5: Chemical safety data sheets
The competent authority should establish criteria for the preparation of chemical safety data
sheets for hazardous chemicals. Suppliers should ensure that safety data sheets are provided to
employers. Workers and their representatives have a right to chemical data sheets and information on them.
Information included on the safety data sheets as established by the competent authority should
include:
(a) chemical product and company identification
(b) information on ingredients (composition)
(c) hazard identification
(d) first-aid measures
(e) fire-fighting measures
(f) accidental release measures
(g) handling and storage
(h) exposure controls and personal protection
(i) physical and chemical properties
(j) stability and reactivity
(k) toxicological information
(l) ecological information
(m) disposal considerations
(n) transport information
(o)Regulatory information
(p) other information
It is recommended that candidates familiarise themselves with the requirements of this Code of
Practice. The Code of Practice is available on the following link:
http://www.ilo.org/wcmsp5/groups/public/@ed_protect/@protrav/@safework/documents/normativ
einstrument/wcms_107823.pdf

1.3 ILO Asbestos Convention (C162) and Recommendation (R172)

ILO Asbestos Convention (C162) and Recommendation (R172)
C162 - Asbestos Convention, 1986 (No. 162) Convention concerning Safety in the Use of

Asbestos (Entry into force: 16 Jun 1989)

Overview
This Convention is made up of six parts and thirty articles.
Part 1 Scope and Definitions
Articles 1 & 2
Article 1
The Convention applies to all activities involving exposure of workers to asbestos in the course of
work. Particular branches of economic activity or undertakings can be excluded by the competent
authority, having deciding upon the frequency duration and level of exposure and the type of work
and conditions of the workplace.
Article 2 covers definitions
asbestos means the fibrous form of mineral silicates belonging to rock-forming minerals of the
serpentine group, i.e. chrysotile (white asbestos), and of the amphibole group, i.e. actinolite,
amosite (brown asbestos, cummingtonite-grunerite), anthophyllite, crocidolite (blue asbestos),
tremolite, or any mixture containing one or more of these.
asbestos dust means airborne particles of asbestos or settled particles of asbestos which are
liable to become airborne in the working environment;
airborne asbestos dust means, for purposes of measurement, dust particles measured by gravimetric assessment or other equivalent method;
respirable asbestos fibres means asbestos fibres having a diameter of less than 3 micrometre
and a length-to-diameter ratio greater than 3:1. Only fibres of a length greater than 5 micrometre
shall be taken into account for purposes of measurement;
exposure to asbestos means exposure at work to airborne respirable asbestos fibres or asbestos
dust, whether originating from asbestos or from minerals, materials or products containing asbestos;
workers includes the members of production co-operatives.
workers' representatives means the workers' representatives recognised as such by national
law or practice, in conformity with the Workers' Representatives Convention, 1971.
Part II General Principles
Articles 3-8
Article 3 - National laws or regulations shall prescribe the measures to be taken for the prevention
and control of, and protection of workers against, health hazards due to occupational exposure to
asbestos. These shall be periodically reviewed in the light of technical progress and advances in
scientific knowledge.
Article 4 -The competent authority shall consult the most representative organisations of employers and workers concerned on the measures to be taken to give effect to the provisions of this
Convention.
Article 5 - the enforcement of laws and regulations shall be secured by an dequate and appropriate system of inspection.
Article 6 - Employers shall be made responsible for compliance with the prescribed measures,
,and shall cooperate whenever two or more employers undertake activities simultaneously at one
workplace. Employers shall prepare procedures for dealing with emergency situations in coopertion with the occupational safety and health services and after consulting with workers' represen-

tatives.
Article 7 -Workers shall comply with prescribed safety and hygiene procedures relating to occupational exposure to asbestos.
Article 8 - Employers and workers or their representatives shall co-operate as closely as possible
at all levels in the undertaking of the measures prescribed in the convention.
Part III Protective and Preventive Measures
Articles 9-19
Article 9 exposure to asbestos shall be prevented or controlled by one or more of the following
measures :
(a) making work in which exposure to asbestos may occur subject to regulations prescribing adequate engineering controls and work practices, including workplace hygiene;
(b) prescribing special rules and procedures, including authorisation, for the use of asbestos or of
certain types of asbestos or products containing asbestos or for certain work processes
Article 10 -Where necessary to protect the health of workers and technically practicable, national
laws or regulations shall provide for one or more of the following measures(a) replacement of asbestos or of certain types of asbestos or products containing asbestos by
other materials or products or the use of alternative technology, scientifically evaluated by the
competent authority as harmless or less harmful, whenever this is possible;
(b) total or partial prohibition of the use of asbestos or of certain types of asbestos or products
containing asbestos in certain work processes.
Article 11 - The use of crocidolite and products containing this fibre shall be prohibited.
Article 12 - Spraying of all forms of asbestos shall be prohibited.
Article 13 Employers shall notify the competent authority of certain types of work involving exposure to asbestos.
Article 14 producers, suppliers and manufacturers shall be responsible for adequate labeling of
containers and products that is easily understood by workers.
Article 15 - Limits of workers exposure to asbestos will be prescribed by the competent authority.
The exposure limits or other exposure criteria shall be fixed and periodically reviewed and updated In all workplaces where workers are exposed to asbestos, the employer shall take all appropriate measures to prevent or control the release of asbestos dust into the air, to ensure that
the exposure limits or other exposure criteria are complied with and also to reduce exposure to as
low a level as is reasonably practicable.
Article 16 - Each employer shall be made responsible for the establishment and implementation
of practical measures for the prevention and control of the exposure.
Article 17 Demolition of plants or structures containing friable asbestos insulation materials ,
and removal of asbestos from buildings or structures where asbestos is likely to become airborne
shall only be undertaken by contractors who are recognized by the competent authority as qualified to carry out such work. The employer or contractor shall be required before starting demolition work to draw up a work plan specifying the measures to be taken, including measures to(a) provide all necessary protection to the workers;
(b) limit the release of asbestos dust into the air; and
(c) provide for the disposal of waste containing asbestos in accordance with Article 19 of this
Convention.

Article 18 - The employer should provide appropriate clothing , which should not be worn outside
the workplace where workers personal clothing may become contaminated with asbestos dust.
The handling and cleaning of work and special protective clothing shall be carried out under controlled conditions. National laws shall prohibit the taking home of such clothing and personal protective equipment (PPE.The employer shall be responsible for cleaning, maintenance and storage of work clothing, special protective clothing and PPE. Facilities shall be provided by the employer for those workers exposed to asbestos to take a bath or shower at the workplace.
Article 19 - Employers shall dispose of waste containing asbestos in a manner that does not pose
a health risk to the workers concerned, including those handling asbestos waste, or to the population in the vicinity of the enterprise. Appropriate measures shall be taken by the competent authority and by employers to prevent pollution of the general environment by asbestos dust released from the workplace.
Part IV Surveillance of the Working Environment and Workers Health
Articles 20 & 21
Article 20 - the employer shall measure the concentrations of airborne asbestos dust in workplaces, and shall monitor the exposure of workers to asbestos at intervals and using methods
specified by the competent authority. The competent authority shall prescribe the period of time
for which the records of monitoring of the working environment and the exposure of workers to
asbestos shall be kept. Employers, representatives and inspection services shall have access to
these records.
Article 21 - Workers who are or have been exposed to asbestos shall be provided, with such
medical examinations as are necessary to supervise their health in relation to the occupational
hazard, and to diagnose occupational diseases caused by exposure to asbestos. The monitoring
shall not incur a cost to the worker and be free of charge and take place in working hours. Workers shall be informed of their medical examinations and receive individual advice concerning their
health in relation to their work. If it is medically inadvisable for a worker to continue to be exposed
to asbestos then efforts shall be made to provide those workers with another means of maintaining their income. A system of notification of occupational disease caused by asbestos shall be
developed by the competent authority.
Part V Information and Education
Article 22 - . The competent authority shall:
make appropriate arrangements to promote the dissemination of information and the education
of all concerned with regard to health hazards due to exposure to asbestos and to methods of
prevention and control.
ensure that employers have established written policies and procedures on measures for the
education and periodic training of workers on asbestos hazards and methods of prevention and
control.
The employer shall:
ensure that all workers exposed or likely to be exposed to asbestos are informed about the
health hazards related to their work, instructed in preventive measures and correct work practices
and receive continuing training in these fields.
Part VI Final Provisions
Articles 23-30
It is recommended that candidates familiarise themselves with the requirements of this convention. The convention is available on the following link:
http://www.ilo.org/dyn/normlex/en/f?p=1000:12100:0::NO::P12100_INSTRUMENT_ID:312307
R172 - Asbestos Recommendation, 1986 (No. 172) Recommendation concerning Safety in

the Use of Asbestos

This recommenation supplements the Asbestos Convention, 1986 and is arranged in five parts.
I Scope and Definitions
II General Principles
III Protective and Preventive Measures
IV Surveillance of the Working Environment and Workers Health
V Information and Education
I Scope and definitions
The recommendation states that `the provisions of the Asbestos Convention, 1986, and of this
Recommendation should be applied to all activities involving a risk of exposure of workers to asbestos in the course of work. Measures should be taken, in accordance with national law and
practice, to afford to self-employed persons protection analogous to that provided for in the Asbestos Convention, 1986, and in this Recommendation. Employment of young persons of less
than 18 years of age in activities involving a risk of occupational exposure to asbestos should receive special attention, as required by the competent authority'.
Definitions contained in this recommendation are those which have been included in the convention. However, the recommendation goes on to list activities involving a risk of occupational exposure to asbestos including (a) mining and milling of minerals containing asbestos;
(b) manufacture of materials or products containing asbestos;
(c) use or application of products containing asbestos;
(d) stripping, repair or maintenance of products containing asbestos;
(e) demolition or repair of plant or structure containing asbestos;
(f) transportation, storage and handling of asbestos or materials containing asbestos;
(g) other activities involving a risk of exposure to airborne asbestos dust.
It is recommended that candidates familiarise themselves with the requirements of this recommendation. The recommendation is available on the following link:
http://www.ilo.org/dyn/normlex/en/f?p=1000:12100:0::NO::P12100_INSTRUMENT_ID:312510

1.4 Summary Presentation - ILO Activities in the Field of Chemical Safety

ILO Activities in the Field of Chemical Safety
Safe Work
ILO
Geneva
Presentation Structure
Introduction
ILO OSH information systems
Chemical Safety at Work ILO approach
Key activities and major products
Inter-agency (international) cooperation
Conclusion
Introduction
} Direct relationship between magnitude of environmental pollution and world of work can be
seen from major accidents

} Release of chemicals have been identified as the cause of long-term environmental damage
} Damage highest in agricultural, chemical and energy sectors
} ILO standard setting and technical assistance in chemical safety 1919
} First binding instrument developed in 1921 (white lead)
} Not only conventions but also COPs, Guides etc.
} ILO list of occupational diseases diseases from exposure to chemicals
ILO OSH Information Systems
} ILO active not only in chemical safety
} Website provides information on all instruments free of charge
} Specific information on chemical safety can be assessed
} Ongoing programme of uploading all documents free of charge on the website
Chemical Safety at Work
} ILO approach
} Historical background
} Activities and products
} Difficulties in chemical safety
} ILO response
-Chemicals convention (No 170),1990
-GHS
-International chemical safety cards
-ILO chemicals control toolkit
ILO Involvement in Chemical Safety
} White lead convention (No.13), 1921
} UNEP/ILO/WHO IPCS, 1980
} Chemicals Convention (No.170), 1990
} Prevention of Major Industrial Accidents Convention (No.174) , 1993
} UNCED and follow-up
ILO Activities and Products
} A series of programmes were started after Bhopal disaster in 1984
} Technical cooperation projects (India etc).
} Conventions (170 and 174)
} Codes of practice (Chemicals, Major industrial accidents, asbestos)
} Major hazard control: manual
} Training manuals: chemicals and agrochemicals
} Encyclopaedia on OHS
} International chemical safety cards (IPCS)
} CIS information centres (>100 national and collaborating centres)
Difficulties in chemical safety
} Each chemical has a different hazard
} Users usually cannot analyze hazards
} Safe handling cannot be ensured without safety information
} Information flow should be from suppliers (manufacturers, importers, distributors) to employers
and then to the workforce
Means for providing information
} Labelling (concise information providing the intrinsic properties of the chemical on the
container)
} Chemical safety data sheets (comprehensive safety information for use on the shop floor
ILO Response
} Chemicals convention (No. 170), 1990

} Globally Harmonized System for the Classification and Labelling of Chemicals (GHS)
} International Chemical Safety Cards (ICSC)
} ILO Chemical Control Toolkit
Chemicals Convention, 1990 (No.170)
} Targeted and specific instrument
} Presupposes the existence of a system for assessing risks and setting limits
} No provisions on health surveillance, recording, notification and sanctions
} Instead, C170 provides a system for the sound management of chemicals
} Focussed on specific subject matter
Key elements of Chemicals Convention (No.170)
} National policy on chemical safety
} Classification systems
} Labelling and marking
} Chemical safety data sheets
} Responsibilities of suppliers
} Responsibilities of employers
} Duties and rights of workers
GHS-Globally Harmonised System
} Follow-up to the adoption of C170
} Development of a single, globally harmonised system to address classification of chemicals ,
labels and safety data
} Work undertaken under the IOMC, focal points being ILO, OECD and UN SCTDG
} 10 years to develop
IOMC, OECD & UN SCTDG
IOMC - The Inter-Organization Programme for the Sound Management of Chemicals was established in 1995 to strengthen cooperation and increase coordination in the field of chemical
safety
OECD -The Organisation for Economic Co-operation and Development is to promote policies
that will improve the economic and social well-being of people around the world.
UN SCTDG This stands for the UN Sub-Committee of Experts on the Transport of Dangerous Goods
Need for harmonisation
} National implementation and trade requires a harmonised system for hazard classification and
labelling
} Major systems were already in use:
-UN Transport Recommendations
-EU Directives on substances and preparations
-Canadian and US requirements for Workplace, Consumers and Pesticides
} Requirements were different under each system, for example:
-EU Class 1 cut off for acute toxicity was 25mg/kg (oral), whereas US systems was 50mg/kg
(oral)
-Hence all chemicals classified between 25 and 50 mg/kg were classified differently
-Labels were also different
Need for harmonisation continued..
} Adopted in December 2002
} Designed to cover all chemicals, including mixtures
} Provide for chemical hazard communication requirements for workplace, transport, consumers
and environment

} Truly harmonised and universal non-binding standard

} Progressive implementation of the GHS will have far reaching consequences
} Impact on national and international laws related to chemicals
} Facilitate trade in chemicals and ease global information exchange of hazards of toxic
chemicals and preventive measures
GHS Hazard classes
International chemical safety cards (ICSCs)
} Use at shop floor level by workers and OSH reps
} Use by employers when providing information and instructions to workers
} Special role in SMEs
} 1300 ICSCs available free in 16 languages
} 1.5 million downloads/year
International chemical safety cards (ICSCs)
} Information provided conforms to C170 and R174 on safety in the use of chemicals at work
} Not legally binding and should be seen as only an international reference to chemical safety
information
} User should verify compliance of cards with relevant national requirements
ILO Chemical Control Toolkit
} Scheme for Workplace Chemicals Control Kit designed for SMEs in developing countries
} Work undertaken by experts from ILO, IOHA , USA, South Africa, HSE
} Generic risk assessment based on GHS and task guidance sheets
} Aim is to provide simple and practical means to prevent/reduce risks of chemicals
Scope
} Many substances used at work contain chemicals
} Guidance should be provided to ensure safe handling
} Does not cover process generated dusts and fumes
} Based on the HSEs COSHH Essentials kit
Toolkit operation
Five stages :
Hazard classification
Scale of use
Ability to become airborne
Finding the control approach
Finding the task-specific control guidance sheet(s)
Stage 1: Hazard Classification
} Determination of the hazards presented by the chemicals (based on the GHS)
} 6 hazard groups (A-E inhalation, skin contact)
} Simple 3-step reference table allows hazard group to be assigned to the chemical
Stage 2: Scale of use
} Determines how much is used/handled
Stage 3: Ability to become airborne
} Physical form of chemical affects how likely it is to get into the air
} Solids 3 levels of dustiness (low-pellets, medium-crystalline, high powder)
} Liquids 3 levels of volatility
-High -Boiling point below 50oC
-Medium -Boiling point between 50oC and 150oC
-Low -Boiling point above 150oC

Stage 4: Selection of the control approach

} Stages 1-3 enable the choice of control approach to be made using table
} 4 control approaches possible
Stage 5: Find the task specific guidance sheet(s)
} General guidance sheet for each approach
} Development of a range of simple and practice task specific control guidance sheets is
planned
Inter-agency co-operation (IAC)
} Major part of ILOs input in chemical safety is through IAC
} IPCS (International Programme of Chemical Safety)
-UNEP (United Nations Environment Programme), WHO (World Health Organisation), ILO in
1980
-Development on internationally peer reviewed chemical risk assessments as well as harmonised methodologies
-setting of air and water quality guidelines
} IOMC
-ILO, WHO, UNEP, FAO, UNITAR, OECD, UNIDO in 1995
-Coordinates activities of the POs
-Work in 5 main areas:
-Risk assessment of chemicals
-GHS
-Risk reduction
-Information exchange
-Capacity building
Conclusion
} ILO has provided impetus for the development of legal and technical instruments
} Instruments based on scientific research, especially risk assessment and toxicology
} Transposing scientific work into regulatory mechanisms to prevent human and environmental
exposure to hazardous chemicals

2.0 Human Anatomical Systems & Sensory Organs

Anatomy and physiology are the two branches of science that help us to understand the human
body. These are defined as follows:
Anatomy deals with the structures and the relationships between them in the human body.
Physiology deals with the function of body parts.
To understand how the human body functions, it is important to consider both anatomy and
physiology together. The human body consists of 11 main systems.
These are:
1. Integumentary - the skin and structures derived from it, hair, nails, and sweat and oil glands.
2. Skeletal bones in the body, ligaments, joints and cartilages.
3. Muscular all the muscle tissue of the body including skeletal, visceral and cardiac.
4. Nervous brain, spinal cord, nerves and sense organs including eye and ear.
5. Endocrine all the glands that produce hormones.
6. Cardiovascular blood, heart and blood vessels
7. Lymphatic lymph, lymph vessels and structures or organs containing lymphatic tissue, such

as the spleen, thymus gland, lymph nodes and tonsils.

8. Respiratory - the lungs and the series of passageways leading in and out of them
9. Digestive a long tube and associated organs such as the salivary glands, stomach, liver and
gall bladder and pancreas.
10. Renal organs that produce, collect and eliminate urine.
11. Reproductive - organs that produce reproductive cells and organs that transport and store
reproductive cells.
However, this section will only be concerned with the respiratory, digestive, circulatory, nervous
and the special sensory organs (skin, eyes, ears, and nose), in line with the NEBOSH syllabus.

2.1 The Respiratory System

The whole of the body is controlled by the brain. It sends out messages in the form of electrical
impulses in two ways, which can be termed as voluntary or involuntary.
Voluntary messages are ones where we have to think to do something, such as writing.
In involuntary messages, things just seem to happen without any thought such as digestion, the
heart beating or respiration.
In the case of respiration, the brain sends these messages along the spinal cord telling us that
there is too much carbon dioxide in the body. The nerves that control respiration branch off and
can be found in muscles that actually make us breathe. These are termed intercostal muscles,
which are between the ribs and the diaphragm, a large dome shaped muscle that sits between
the bottom of the lungs and the stomach.
The diaphragm relaxes and domes upwards, and the intercostals relax and pull the ribs in and
down to make us exhale. When these muscles contract, we inhale. This process is called respiration.
When we inhale, we take in a mix of gases called air. The part of air that we need is oxygen.
There is about 21% of this in air. Blood cells travel along the capillaries until they become larger
and take the blood to the heart. The heart beats and this "oxygenated blood" is then carried to the
tissues. When the red cells have released their load of oxygen into the tissues, they pick up
waste products like carbon dioxide and then are returned to the heart in veins.
The heart beats and sends the "de-oxygenated" blood back to the lungs. The red cells release
the carbon dioxide into the lungs and we exhale. However, when we exhale, we breathe out
about 16% oxygen, therefore our body uses roughly 5% of the oxygen we take in.
Structure.
The respiratory system is an airway which has two main parts: the air passages (the upper respiratory tract) and the lungs. Air enters the nose and is cleansed of its larger impurities by the
coarse hairs of the nostrils. It is then warmed and moistened by the mucous membrane lining as
it passes through the nasal cavity.
It passes out of the nasal cavities into the pharynx. The pharynx is a muscular tube running from
the base of the skull down to the junction of the oesophagus and the larynx - "the back of the
throat". Air breathed in through the mouth (the buccal cavity) is drier, colder and less clean than
that breathed in by the nose.

Respiratory system.

The air then passes over the larynx (voice box), down the trachea which divides into two bronchi
(singular: bronchus).
Each bronchus branches into bronchioles, which are repeatedly branched into terminal bronchioles, which lead to an infundibulum of alveoli, very much like a bunch of grapes from which the
flesh has been removed.
The alveoli (or air sacs) form the delicate lining of the lungs, across which gas exchange between
the blood and the air takes place.
In order to protect the delicate tissue, the alveoli are covered by a thin film of moisture. To make
certain that inhaled air is moist and warm, all the airways are covered with wet, warm mucus.
The upper respiratory system is formed by the nasal cavities, pharynx and larynx. The lungs contain the bronchi, bronchioles, terminal bronchioles and the alveoli. These organs, with some of
the trachea, fill the major part of the thoracic cavity.
The left and the right lung are not quite the same. The right lung has three lobes or sections; the
left lung has two lobes.
The entrance to the larynx is protected by a muscular flap, the epiglottis, which closes during
swallowing. Loss of control of the epiglottis allows "aspiration" to occur.
The space between the lungs is called the mediastinum. It contains the heart, the great blood
vessels, oesophagus and thoracic duct.
A number of air sacs (alveoli) cluster together at the end of each terminal bronchiole to form an
infundibulum. The alveoli are lined with a single layer of epithelium, across which gases diffuse.
Each infundibulum is covered with a network of blood capillaries which have a single wall of epithelium. Thus, gases are able to pass to and from blood capillary vessels and alveoli.

Lungs and alveoli.

The great mass of lung tissue is elastic, porous and spongy in the healthy state. When disease of
the lung structure occurs, scar tissue usually forms. The lung loses its normal characteristics and
also its ability to function fully as a gas/blood exchange organ

2.2 The Digestive System

The digestive system
The overall function of the gastrointestinal tract is the control of ingested foodstuffs, which is dealt
with in four main stages:
Ingestion, via mastication and swallowing.
Digestion - treatment of foodstuff for absorption into the body.
Absorption of treated foodstuffs.
Excretion of food residues and desorbed wasted products.
The digestive system is the only way in which we can take in the energy that we need. It is a
process where large insoluble pieces of food are broken down into soluble substances, which are
small enough to be absorbed through the intestine wall and into the blood stream. Digestion involves physical and chemical actions.
Physical digestion involves chewing, churning and warming of the foods and chemical digestion
which uses enzymes to breakdown the foods.
When food enters the mouth, it is chewed and mixed with saliva which moistens the food, making

it easier to swallow and the enzyme it contains begins to change starches into sugar.
The tongue rolls the food into a bolus which is easily swallowed, and then it is pushed to the back
of the mouth and into the oesophagus.

Digestive System
The oesophagus.
The oesophagus is a muscular tube about 25 cm long, reaching from the pharynx to the stomach.
It is positioned behind the trachea and passes through the diaphragm.
Material does not "fall down" the oesophagus under gravity, but is carried down by a series of
peristaltic contractions which produce packages of material, each called a "bolus".
Muscular action provides the transporting mechanism throughout the remaining parts of the gastrointestinal tract.
The oesophagus is separated from the stomach by the cardiac sphincter, a ring of muscular fibres which prevent normal regurgitation of stomach contents back into the oesophagus.
During its passage through the oesophagus, slightly alkaline aqueous secretions are passed into
foodstuffs, as part of the digestive process.
Peristalsis (muscular action) then pushes the food into the stomach.
The Stomach.
The stomach is an enlarged section of the gastrointestinal tract which forms a receptacle for
foodstuffs passed from the oesophagus.
It is constructed of several muscle systems which enable foodstuff to be continually mixed while
the main digestive process takes place.
The digesting materials are held in the stomach by the pyloric sphincter.
The stomach holds 2.5 to 3.8 litres, but it is elastic and can contain much more.
It lies below the diaphragm, in front of the pancreas, with the spleen on the left side of the fundus
of the stomach. The bulk of the liver lies to the right of and behind the stomach (as viewed from
the side).
The stomach provides an acid medium for digestion. The acid secreted is hydrochloric acid, the
concentration of which gives a pH of about 1. Gentle movements in the stomach will churn the
food to a semi-liquid state called chime. The hydrochloric acid will kill germs and help the enzymes to work.
At given intervals, the pyloric sphincter will open to allow a little food to pass into the small intestine. Occasionally, the pyloric sphincter in infants fails to work correctly; this is known as pyloric
stenosis. This was once a fatal condition but now a simple operation can remedy the problem.
The warmth of the body will also melt the fats.
The Small Intestine.
The small intestine is the region in which the greater part of digestion takes place.
The small intestine is a muscular tube about 6m long, with an internal diameter approximately 3.5
cm, which extends from the pyloric sphincter of the stomach to the large intestine.
The first part of the small intestine is the duodenum, a horseshoe-shaped section, situated by the
digestive organs of the gall bladder and pancreas.
These organs supply digestive secretions for alkaline digestion in the small intestine. The pH of
the digestive juices ranges from 8.8 to 8.0.
The submucosa of the small intestine is thrown into many folds possessing numerous finger-like
projections called villi (singular - villus), whose walls are richly supplied with blood capillaries.
Absorption of the end-products of digestion occurs through the villi and into the underlying blood
vessels. From the villi, the blood capillaries converge to form the hepatic portal vein which delivers absorbed food to the liver. Non-nutrients such as toxic chemicals as well as nutrients may

pass into the body by this route.

Villi of the small intestine

Large Intestine.
The large intestine forms the final section of the gastrointestinal tract, from the small intestine to
the anus. It is about 1.5m long and about 6.3 cm in diameter, with a muscular structure similar to
that of the small intestine.
The large intestine takes no part in digestion or absorption of nutrients. The large intestine carries
mainly water and undigested materials such as fibre. Most of the water is filtered out in this region.
The large intestine acts as a storage place for waste matter and from time to time, this is discharged through the rectum.
Ionic salts, e.g. those of iron, are absorbed with the water. The pH of the large intestine will be
alkaline, about pH 8, following on from the small intestine.
Peritoneum.
The peritoneum is a serous membrane, which covers the abdominal and pelvic cavity. It has a
double-skinned structure, similar to the pleura in the thoracic cavity, but its structure is more
complex.

2.3 The Cardiovascular System

The cardiovascular system can also be termed the circulatory system. Its main functions are to
distribute oxygen and nutrients around the body, protect against disease and carry waste from
the cells.
In any fluid pipeline distribution system, there are three essential parts:
Motive power provided by pumps.
Pipes for carrying the fluid.
Valves for regulating the fluid flow.
In the human body, these functions are provided by the heart, the blood vessels and valves within
the heart, and blood vessels. To look at the workings of the cardiovascular system, it will be divided into the following five parts, heart, arteries, veins, capillaries and blood.
The Heart.
The heart is located in the thorax, centrally between the lungs and behind the base of the sternum, but with the apex pointing to the left, i.e. the longitudinal axis of the heart is not vertical.
Your heart is about the size of your own clenched fist, and weighs from 240 to 270 grams. The
heart is made almost entirely of a special type of muscle called cardiac muscle. The function of
the heart is to pump blood around the body.
The heart is divided by a septum into right and left sides, which in effect makes it two "pumps".
The right side of the heart is completely separated from the left, and blood does not flow between
them. Each side is divided into an upper and lower chamber: the atrium, which receives blood,
and the ventricle, which distributes blood. There are right and left atria (RA, LA) and right and left
ventricles (RV, LV).

The walls of the atria are thinner than those of the ventricles as they only pump blood to the
lungs, while the ventricles pump blood around the body.
Between the atrium and the ventricle of each side is an atrio-ventricular opening, guarded by the

tricuspid valve on the right and the bicuspid, or mitral, valve on the left side of the heart.
When the valves are closed, they seal off the atria from the ventricles. These valves only allow
blood to flow downwards.
The pulmonary and aortic valves control the blood-flow from the heart.
The blood vessels that take blood around the body are divided into three types. They are arteries,
veins and capillaries.
Arteries.
The arteries have a muscle coating and are slightly elastic to make carrying blood from the heart
easier. The blood is pumped into the main arteries, which branch down into smaller and narrower
tubes and carry blood to all parts of the body. The thinnest of the arteries are called arterioles,
and they link with even smaller blood vessels called capillaries.
Arteries are three-layered structures comprising:
(i) An outer protective coat of fibrous and connective tissue.
(ii) A middle muscular coat which exerts a steady pressure on the blood. When an artery is cut,
the muscular wall remains active, so blood continues to flow in spurts which coincide with the
pump of the heart and contraction and relaxation of the muscles of the artery walls.
(iii) The innermost lining of pavement epithelium is perfectly smooth, offering no resistance to the
flow of blood; but smooth as the coat is, adhesions do sometimes occur, particularly in later life,
with consequent narrowing of the arteries. This condition is known as arteriolosclerosis.
Veins.
Veins have the same three layers as arteries, but the middle muscular coat is thinner, less elastic,
less firm and more likely to collapse. This occurs when a vein is cut. The vessel tends to close,
stopping the flow of blood.
In addition, where blood in veins travels against gravity, such as in the limbs, there are pocket
valves in the lining epithelium. These pockets fill up if the blood attempts to flow back, bulging out
and blocking the vein against a back-flow. Oncoming blood forces the blood in the pockets forwards.
Capillaries.
In the capillaries, the process of exchange takes place where oxygen is given to the cells and
waste products returned into the blood.
The walls of the narrow blood capillaries are only one cell thick, which allows ease of access and
egress for materials at the molecular level.
The returning blood then enters small blood vessels called venules. The venules link up to form
larger and larger veins, which return blood to the heart.
The veins have a wider bore than arteries and, in many of them, there are small no return valves
that aid returning blood.
Blood.
The blood is a thick red liquid, composed of four parts, plasma, red cells, white cells and platelets.
When damaged blood comes into contact with the air or damage tissue it becomes sticky and
clots.
Plasma is the liquid part of the blood. It is a clear, pale yellow fluid consisting of 90% water. The
remaining 10% is made up of food, waste products, hormones, minerals and plasma proteins,
such as fibrinogen.
Red cells (red corpuscles or erythrocytes) - their main function is to carry oxygen from the lungs
into the tissues. They are made in the bone marrow, and are biconcaved in appearance.
White cells (white corpuscles or leucocytes) their main function is to protect the body from infection. Many of the white cells are made in the bone marrow, but some are made in the lymph

nodes. They are spherical in appearance.

2.4 Circulation of the Blood

In both the systemic and pulmonary circulations of the blood, blood vessels leaving the heart are
called arteries. They branch into named arteries to the organs, e.g. the right and left pulmonary
arteries from the main pulmonary artery.
Arteries branch into arterioles; and arterioles branch into blood capillaries, which supply substances to, and collect other material from, the cells.
Blood from capillaries flows into venules and then into veins. Venous blood collects in the superior and inferior vena cava and enters the right atrium of the heart.
The blood takes 15 to 26 seconds to travel around the systemic and pulmonary circulations together.

Systemic Circulation.
Oxygenated blood from the pulmonary circulation enters the left atrium, passes through the bicuspid valve to the left ventricle, and is pumped into the aorta which curves upwards over the
heart. It sends out offshoots to the chest, the upper limbs and the head.
It then curves round, descends through an opening in the diaphragm into the abdomen, finally
branching into the legs.
Blood leaves the aorta by various arteries, taking oxygenated blood, nutrients and secretions to
the organs and tissues. Arteries branch to become arterioles which, in turn, branch to become
blood capillaries, from which plasma and its inclusions diffuse into intercellular spaces and then
into individual cells.
Not all the blood plasma and waste fluids are returned to the blood capillaries; excess volume is
taken by the lymphatic vessels.
The plasma now returned to the blood is deoxygenated and contains carbon dioxide, sometimes
secretions necessary for other organs (e.g. hormones) and waste products.
The capillaries unite to become venules, venules become veins and blood flows from the organs
and systems, finally to enter the right atrium of the heart via the inferior and superior vena cava.
The systemic circulation has two ancillary subsystems:
1. Portal circulation.
2. Renal circulation.
Portal Circulation.
Organs normally only receive arterial blood, but the liver, besides receiving arterial blood in the
hepatic artery , direct from the abdominal aorta, receives venous blood via the portal vein, which
is formed from veins from the spleen, pancreas, stomach and small intestines.
The functions of the liver are concerned with some, or all, of the products of these organs, and
their proximity to the liver warrants direct routing.
The spleen supplies materials from the breakdown of red blood corpuscles; the pancreas sup-

plies insulin and probably glucagon for the control of blood sugar.
The stomach supplies body nutrients following digestion.
The veins leaving these four organs unite to become the portal vein, which also enters the liver
with the hepatic artery.
The blood in the portal vein is de-oxygenated, since its oxygen has been used in respiration in
the organs it has left.
With oxygen from the hepatic artery, the liver is able to release sufficient energy for its important
task and finally blood, now de-oxygenated but rich in the products and secretions of the liver,
leaves this organ via the hepatic vein enters the inferior vena cava and is returned to the right
auricle of the heart.
Renal Circulation.
This is important because it is the function of the kidneys to remove impurities from the blood.
The renal artery receives blood at high pressure from the aorta. The high blood pressure in the
renal artery is an important factor in the passing of nitrogenous waste and water into the kidneys.
Deoxygenated blood, which in every other respect is at its purest, leaves the kidney via the renal
vein and then moves on to the inferior vena cava.
Pulmonary Circulation.
Deoxygenated blood leaves the heart via the pulmonary artery. (Blood leaves the heart in arteries.)
In the systemic circulation, arteries contain oxygenated blood.
The pulmonary artery divides to carry blood to both lungs, where carbon dioxide and water vapour diffuse into the alveoli of the lungs.
Oxygen from the alveoli diffuses into blood capillaries, oxygenating the haemoglobin of the erythrocytes to oxyhaemoglobin.
Oxygenated blood is returned to the left ventricle of the heart by two pulmonary veins from each
lung.

2.5 The Nervous System

The nervous system can be divided into the central and peripheral nervous systems. The central
nervous system (CNS) consists of the brain and spinal cord. Its function is to process information
and initiate responses, and it is the site of mental activities.
The Peripheral nervous system (PNS) consists of receptors, nerves and ganglia which lie outside
of the CNS. Its function is to detect stimuli to transmit information to and from the CNS.
The PNS has two subdivisions:
The sensory division transmits action potentials from sensory organs to the CNS.
The motor division transmits action potentials from the CNS to effector organs such as the muscles and glands.
The peripheral nerves are to be found in all skin and muscle tissue on the distal plains of the
body. When stimulated they send messages to the brain via the CNS to tell the brain what to do.
As with all areas of the body the nervous system can be damaged.
The main areas of damage occur to the CNS in such conditions as unconsciousness, stroke and
compression of the brain and spinal injuries. These type of injuries can be life-threatening and
need immediate hospitalisation for comprehensive diagnosis and treatment.
Prognoses vary depending on the nature of the injury and subsequent trauma. Drugs are avail-

able to limit the level of trauma if given quickly enough, which prevent the secondary associated
problems

2.6 The Special Sensory Organs

The Special Sensory Organs.
The Integumentary System.
The skin is an organ in the body and has many functions.
It is made up of a number of different cell types which coordinate to produce a functional unit.
The skin forms the outer covering of the body and is continuous with the membrane lining which
covers the cavities within the body structure, and which have their openings at the body's outer
surface.
It protects the body, is a barrier against the entry of germs and, being almost waterproof, having a
partially permeable membrane, prevents unregulated water loss.
It is also sensitive to touch and pain, regulates the body temperature and makes melanin from
Vitamin D.
It is made up of two main layers, the epidermis and the dermis.

Epidermis.
The epidermis forms the tough outermost layer of skin that protects the more delicate tissues underneath.
It is composed of stratified (or layered) epithelium. Epithelium is defined as a coating or lining tissue. It is thickest in parts such as the palms of the hands which suffer harder wear, and thinnest
on the lips.
Within the epidermis, there are two cell zones:
The horny zone, which can be considered as a layer where flattened epithelial cells are changing into a dead proteinaceous substance called keratin, which forms the outermost layers of the
epidermis. It takes about forty days to completely replace the epidermis.
The germinal (or living) zone, which forms the deeper level in the epidermis, and consists of living cells which can reproduce and move to the horny zone. They do not, however, have a blood
supply as normal living tissue, but are nourished by lymph secretions which circulate between
them.
Dermis.
The dermis, or the true living skin, forms the inner part of the skin structure and is tough and elastic. It consists of mainly collagen fibres, which are interlaced with elastic fibres and is thicker than
the epidermis. The dermis contains:
Lymph vessels which form a network throughout the dermis and epidermis.
Sensory nerve endings which are sensitive to touch, pressure, pain and change in temperature.
Sweat glands and their ducts which produce dilute salt solution and aid cooling.
Hair roots and the arrectores pilorum (which are the involuntary muscles attached to the hair
follicles).
The sebaceous glands produce a greasy liquid called sebum which spreads over the surface of
the skin to keep it supple.
Capillary blood vessels set out at various intervals on the surface of the dermis. The flow of
blood through these areas is important in the control of heat transfer mechanisms.
Route of Attack on the skin.

The skin is the next vulnerable area, as it can be in contact with toxic substances, which may be
solid, liquid or gaseous, and in very high concentrations (i.e. in terms of quantity of substance to
skin area).
Fortunately, the epidermis has many layers of protection and does not allow solid or gaseous
substances to be absorbed (in general).
So only liquids provide a hazard.
If contact between the epidermis and a toxic substance does occur, a considerable amount of
contaminant can usually be removed before excessive absorption has taken place. Wearing normal clothing effectively reduces the area available for exposure to a toxic agent. However, the
skin of the hands, arms and legs usually has some breaks in its surface, and thus entry into the
body "by injection" is always a possibility.
Inflammation of the skin is much the same as for any other body organ; there are blood capillary
changes, there is increased permeability and there is migration of cells. Inflamed skin is painful,
sometimes itchy, often red and fissured, sometimes accompanied by exudate and shedding of
scales.
Chemicals attack the skin by pervasion or implantation, resulting in contact dermatitis, which may
take a number of forms:
Irritant Dermatitis: This is caused by corrosive irritants such as acids, alkalis, detergents, oils, metallic particles, solvents, oxidising and reducing agents and some biological agents (e.g. giant
hogweed). If the irritant is particularly aggressive, it can result in destruction of the skin.
Acute Irritant Dermatitis: Acute inflammation can be brought about by contact with acids and alkalis.

2.7 The Eye

The eye is situated in the orbital cavity (socket) and protected by the nose, cheek bones and
eyebrows. It is almost spherical in shape and is about 2.5cm in diameter.
The space between the eye and the orbital cavity is occupied by fatty tissue. The bony walls of
the orbit and the fatty tissue help to protect the eye from injury.
Structurally, the two eyes are separate but some of their activities coordinated so that they function as a pair. For example, three dimensional vision is impaired when only one eye is used.

Structure:
There are three layers of tissue in the walls of the eye. They are:
The outer fibrous layer: sclera and cornea.
The sclera is the white of the eye, forms the outermost layer of tissue and consists of a firm, fibrous membrane that maintains the shape of the eye and gives attachment to the extraocular or
extrinsic muscles.
The sclera continues to the front of the eye as a clear, transparent epithelial membrane called the
cornea. Light rays pass through the cornea to reach the retina.

The cornea is convex anteriorly and is involved in refracting or bending light rays to focus them
on the retina.
The middle vascular layer; choroids, ciliary body and iris.
Choroid: The choroid lines the inner surface of the clear. It is very rich in blood vessels and is a
deep chocolate brown in colour. Light enters the eye through the pupil, stimulates the nerve endings in the retina and then is absorbed by the choroids.
Ciliary body: This gives attachment to the suspensory ligament which, at the other end, is attached to the capsule enclosing the lens. Contraction and relaxation of the ciliary muscle changes
the thickness of the lens which bends, or refracts, light rays entering the eye to focus them on the
retina. The epithelial cells secrete aqueous fluid into the anterior segment of the eye, i.e. the
space between the lens and the cornea.
Iris: this is the visible coloured part of the eye and extends from the ciliary body, lying behind the
cornea in front of the lens. It is a circular body composed of pigment cells and two layers of muscle fibres, one circular and the other radiating.
Pupil: this lies in the centre of the iris. The pupil varies in size depending on the intensity of the
light. In bright light, the circular muscle fibres of the iris contract and constrict the pupil. In dim
light, the radiating muscle fibres contract, dilating the pupil.
Lens: this is a highly elastic circular biconvex transparent body, lying immediately behind the pupil. It is suspended from the ciliary body by the suspensory ligament and enclosed with a transparent capsule. Its thickness is controlled by the ciliary muscle through the suspensory ligament.
The lens bends light rays reflected by objects in front of the eye.
The inner nervous tissue layer: retina.
The retina is the innermost layer of the wall of the eye and lines about three quarters of the eyeball. It is an extremely delicate structure and is especially adapted to be stimulated by light rays.
It is composed of several layers of nerve cell bodies and their fibres, lying on a pigmented layer of
epithelial cells which attach it to the choroid.
The retina is the photosensitive part of the eye and the light-sensitive nerve cells are the rods and
cones.
Structures inside the eyeball are the lens, aqueous fluid (humour) and vitreous body.
Eyelids and Eyelashes: These protect the eye from injury.
The reflex closure of the lids occurs when the conjunctiva or eyelashes are touched, when an object comes close to the eye or when a bright light shines into the eye this is called the conjunctival or corneal reflex.
Blinking at about 3- to -7 second intervals spreads tears and meibomian secretions over the cornea, preventing drying.
Lacrimal apparatus.
The lacrimal glands are situated in the recesses in the frontal bones of each eye. Each gland is
approximately the size and shape of an almond, and is composed of secretory epithelial cells.
The glands secrete tears composed of water, mineral salts, antibodies, and lysozyme, a bactericidal enzyme.
Fluid from the tears and the secretion of the meibomian glands is spread over the cornea by
blinking. The functions of this mixture of fluids include :
washing away irritating materials. e.g. dust and grit;
the bacteriocidal enzyme lysozyme prevents microbial infection;
its oiliness delays evaporation and prevents drying of the conjunctiva;
nourishment of the cornea.
Route of entry into the body via the eye.

Another possible route of entry into the body is via the mucous membranes of the eye. Substances in the form of dust, mist, spray, fume or vapour may dissolve in the moist covering of the
eyelids and undergo absorption into the bloodstream (lachrymation).

2.8 The Ear

The ear consists of three parts, the outer ear, the middle ear and the inner ear.

The outer ear.

The outer part of the ear is called the pinna. The pinna is flexible and bends easily but the lobe at
the bottom is made of elastic cartilage.
Its presence on both sides of the head allows us to localise the source of sound from the front vs.
the back. Our ability to localise from side to side depends on the relative intensity and relative
phase of sound reaching the ear.
Cerumen (wax) is secreted by a gland in the wall of the ear canal and this protects the ear. The
wax lubricates the ear drum to keep it supple, the bitter taste helps keep insects away from the
ear, and dirt that enters the ear will stick to it.
The middle ear.
The middle ear is a cavity containing air with three small bones called ossicles. Because of their
shape they are known as the hammer (malleus), anvil (incus) and stirrup (stapes).
The ossicles are held in place by ligaments.
The ossicles link the tympanic membrane to the inner ear. The tympanic membrane consists of
three layers, with the outer layer continuous with the skin of the outer ear canal. The upper portion of the tympanic membrane is called the pars flaccida, while the lower portion is called the
pars tensa. The central portion of the pars tensa provides the active vibrating area in response to

sound. The tympanic membrane is a continually growing structure, which allows it to close if it
has a hole in it and to extrude a ventilation tube.
The sound waves that enter the pinna strike the ear drum. These vibrations are passed on into
the inner ear through the oval window.
The inner ear.
The inner ear consists of fluid filled tubes embedded in bone. It has two parts, the cochlea which
is concerned with hearing and the semi-circular canals which are concerned with balance.
The vibrations that are picked up in the middle ear are passed onto the cochlea, where the
movement of fluid (perilymph) makes hair cells move and stimulates impulses that are sent to the
brain.

2.9 The Nose

The nose has dual functions as a sensory organ and as a respiratory organ. It is made up of the
following structures:
Nasal cavity - consists of a large cavity, which is divided into two equal passages by a septum.
Lining of the nose - the nose is lined with a ciliated mucous membrane which contains mucussecreting goblet cells.
Anterior nares (nostrils) these are the openings from the exterior to the nasal cavity. Hairs are
present in this area.
Posterior nares these are the openings from the nasal cavity to the pharynx.
The nose functions to start the process by which inspired air is warmed, moistened and filtered

Filtering and Cleaning - the hairs at the anterior napes trap larger particles. Smaller particles such
as dust and microbes settle and adhere to the mucus.
Mucus protects the underlying epithelium from irritation and prevents drying.
With the beating of the cilia cells, the mucus is wafted towards the throat where it is swallowed or
expectorated.
Olfactory function of the nose The chemical particles which are given off by odorous substances are carried into the nose on inhalation.
The nerve endings, which are located in the roof of the nose, are stimulated by these chemical
substances.
The nerve impulses, which result from this stimulation are conveyed by the olfactory nerve to the
brain where the sensation of smell is perceived.
Sniffing concentrates these chemical particles more quickly into the roof of the nose which increases the number of cells stimulated, and the perception of smell is increased.
The sense of smell can be lost when the nasal mucosa are inflamed, therefore preventing the
odorous substances reaching the olfactory area of the nose.
Adaptation Perception of an odour quickly decreases and eventually ceases if an individual is
continuously exposed to it. This loss of perception is specific to the odour.

3.0 Main Routes of Attack on the Human Body.

Previously, we have already looked at the main routes of entry of harmful substances into the
human body i.e. inhalation, ingestion, skin pervasion and injection. We also identified target organs and target systems.
We will now add a little further to this by discussing the distinctions between inhalable and respirable dust, as this information will be needed in unit B5 (monitoring). In addition, we will further
look at the body's defensive responses.

3.1 Attacks on the Respiratory System

Route of Entry.
Aspiration is a term used to describe a route of entry which concerns the direct entry of solid or
liquid into the lungs. There are two ways by which it can happen.
Firstly, when substances that have been ingested are expelled in vomit and run down into the
respiratory tract.
Secondly, when substances are sucked directly into the lungs (things "going down the wrong
way"). A typical situation is when a liquid is being sucked into a pipette and the tip comes out of
the liquid. The suction back- pressure is released and causes a rush of liquid past the open epiglottis.
Aspiration can have serious consequences; toxic substances could exhibit an increase in their
relative hazard potential, e.g. if a hydrocarbon solvent has been ingested, it is not likely to be lethal; but if aspiration occurs during vomiting, entry into the respiratory system could produce a
lethal situation.
Inflammation of Respiratory Pathway.
The respiratory pathway is vulnerable to attack by many irritants and corrosives or any other substances which attack the skin. The terminology of the inflammatory processes follows the pathway of air into the lungs, viz.: rhinitis, laryngitis, trachetis, bronchitis and pneumonia.
In extreme cases, the effects of inflammation lead to swelling and exudation of fluids, resulting in
narrowing or even total blocking of the small conducting airways.
Exudation in the alveoli leads to interference with respiratory gas exchange, even to a fatal degree. Gases of low solubility will penetrate the respiratory pathway deep into the alveoli. Such
gases include sulphur dioxide, ozone, phosgene and oxides of nitrogen. The inflammation
caused results in fluid accumulating in the respiratory units (oedema). Other irritants include
metal fumes (metal fume fever) and polymer fumes (polymer fume fever).
Inhalation.
The lung is the most vulnerable part of the body, as it can readily absorb gases, soluble dust and
fumes. Nearly every molecule which comes in contact with the lining layer passes through without
much difficulty.
You should note that only material in the correct physical state is able to arrive at the absorbing
area. Added to the physical ability of the lining to absorb substances is the regularity of the
breathing cycle. Even small concentrations of a toxic agent in the atmosphere being inhaled can,

after a period, develop a build-up of toxicant in the body. This is another problem to be considered in connection with chronic toxicity. The lung also provides the largest area of epithelium for
the absorption process to occur.
When you are considering the risk of a material in terms of inhalation, the questions to be asked
are:
Is it gas?
Is it a liquid that will easily give off vapours?
If it is a solid, can respiratable dust be generated, or vapours?
If the answers are "yes", then you will be dealing with conditions which provide the greatest risk of
entry of substance into the lungs.

3.2 Respiratory Defence

Respiratory Defence.
The lungs are designed to allow gaseous transfer in and out of the body. The alveoli tissue is
very delicate and therefore vulnerable to physical damage.
Consequently, the alveoli are potentially at risk from a naturally dusty environment. In order to
protect the lungs, the body has developed special defence mechanisms, which can be divided
into two parts: physical filtration and biochemical clearance (or phagocytosis).
Physical Filtration.
Air is inhaled through the nose and because the airway is covered with moist hair, it is able to trap
any large particles. Mucus-forming cells in the nose and nasal sinuses bathe the hair, so that
trapped particles are washed out.
As the air passes through the nasal sinuses, it has to travel a tortuous path. You will recall that
particles in motion travel in a straight line, so when the bends occur, particles are likely to collide
with the sticky mucus lining and become trapped. They are then washed down into the pharynx,
where they are either swallowed or expectorated (coughed out). Where dust concentrations are
high, or have irritant characteristics, sneezing often occurs. This provides a protective mechanism
for removing unwanted solid material.
Air breathed in via the mouth, and containing particulate impurities, joins the partially-cleaned air
inhaled via the nose. This passes into the trachea, on into the bronchi, to the bronchioles and
then to the alveoli. The physical structure of the airway gradually changes to ever-narrowing diameters. Extensive branching also occurs, so the airway changes direction many times before it
reaches the alveoli.

Ciliary Escalator.
The extensive branching of the bronchus and bronchioles causes an increase in the total crosssectional area of the airway passages, and also of the surface area over which the air travels.
This has the combined effect of:
reducing the velocity of the flow rate, which allows some particles to sediment out of the airstream;
providing a greater surface area on which particles may be deposited by sedimentation or by
impaction at the bends.
The efficiency of the filtration system is best expressed in terms of the size of particulate matter
which is able to penetrate the system. Not all particulate matter has the same shape and dimensions, so values quoted may vary, depending upon the unifying system used.

As a generalisation, particulate matter is often assumed to have an "effective" spherical shape,

and the effective diameter is quoted. This is the system we will use in this course. If you ever
quote these values, they should be qualified as effective spherical diameter (ESD).
It has been shown that dust particles which can enter into the nose and nasal sinuses are about
100 m (ESD), and that particles below 10 m are able to pass through.
From the trachea to the terminal bronchioli, particle sizes down to about 7 m are removed. This
allows particles below 7 m to enter into the alveoli structure.
The range 7 m to about 0.5 m may be deposited in the alveoli. Below 0.5 m, the particles may
be returned to the outside environment by exhalation or they may be deposited in the alveoli by
diffusion. These particles are so small that they are not affected by gravitational forces, and they
are bounced about by collision with gaseous molecules.
The size range, 7 m to 0.5 m, is termed the respirable range, but remember that sizes below
0.5 m are still potentially hazardous, as deposition may occur.
You will appreciate the particle size range quoted above by considering the values given in Table
1.1.
Substance

ESDm

Table Salt

100

Human hair

50 (diameter CSA)

Smallest measure seen by eye Unaided

25-50

Cocoa

8-10

Rust (Fe203)

Clay dust

0.1-1.0

Table 1.1: Sizes of Some Common Particles

The dust above about 7 m in the lower respiratory airway having been filtered out and retained,
the solid deposits must now be removed. This is achieved by means of the ciliary escalator.
The ciliary escalator is formed by "hairy" or ciliated cells, which line the airway from the trachea to
the terminal bronchioles.
The cilia are in constant motion. Their coordinated movement has the ability to sweep particulate
matter, trapped by the sticky mucus exudate, up the airway. This sweeping action, which has
been described as having the appearance of a field of corn in the breeze, extends from the terminal bronchioli to the larynx.

The particulate matter removed may either be swallowed or expectorated. The ciliary escalator
takes about 24 hours to clear particulate matter from the airways.
Biochemical Clearance or Phagocytosis.
When particulate matter becomes deposited in the alveoli, it triggers a defensive mechanism
which involves the movement of granulocytes from the blood into the alveoli.
These amoeba-like cells are called phagocytes. They engulf foreign bodies in an effort to neutralise their harmful action. If the material is inert, the full phagocyte with its engulfed particles migrates away along lymphatic channels, to "retire" in a dormant area of the lung structure, away
from its functioning parts. This may be in a secluded lymph node (gland), or somewhere under
the pleural covering of the lungs. Some phagocytes move out of the alveoli and are cleared by

the ciliary escalator.

Unfortunately, certain dusts are not "inert" to the phagocytes and kill them. When this occurs,
normal body functions activated when tissue cells are damaged release substances which cause
inflammation and repair the injury by scar tissue formation. If the process occurs on the alveoli
surface, then scar tissue produces an "inelastic" structure and loss of lung function. As particulate
matter is released from dead phagocytes, others go "into battle" and consequently lose their lives.
This results in the formation of even more scar tissue.
The process can cause a progressive disease condition, or it may be halted by a process where
the particle becomes coated with an inert covering, called ferritin. If the phagocytes are killed in
one of the dormant areas of the lungs, then scarring occurs and the lung structure becomes stiffened. This causes breathing to become more arduous, and exerts stress upon the heart.

3.3 Inhalable and Respirable Dust.

Dust is generally understood to be an aerosol of solid particles, mechanically produced, with individual particle diameters of 0.1m upwards and can be a problem in almost any industry, from
bakeries to building sites. The hazards of dusts like lead, silica and cotton are well-known, but
there are many other substances which may be present in dust and are hazardous to health.
Particle size is critical in determining where particulates will settle in the lung. Larger particles will
settle in the bronchi and the bronchioles, and will not tend to penetrate to the smaller airways
found in the alveolar region. These are termed inspirable particles. Those smaller-sized particles
that can penetrate the gas exchange region of the lungs, the alveolus, are termed respirable particles.

Inspirable Particulate: Only part of the total quantity of dust that

is present in the worker's breathing zone is inhaled. This part is
designated as the `inspirable fraction' of dust and is governed by
the flow rates in the nose and mouth areas, as well as the airflow
around the head.
Respirable Particulates: Dust particles having a 50% cut point of
4 m m (ACGIH) or 5 m m (BMRC). These particles may be hazardous when deposited in the gas exchange region of the lungs.

Basic Structure of the

Respiratory System
Particle size is expressed as 'equivalent' or 'aerodynamic' diameter. This is equal to the diameter
of spherical particles of unit density that have the same falling velocity in air as the particle in
question.
Amongst inhaled particles, those with an equivalent diameter greater than approximately 20 microns (mm) will be trapped in the nose and upper airways.
Inhalable Dust is a new term used to describe dust that is hazardous when deposited anywhere
in the respiratory tree, including the nose and mouth. It has a 50% cut-point of 100 mm and includes the big and the small particles.
Particles in the region of 7 - 20 microns will penetrate to the bronchioles and are inspirable, while
particles in the size range 0.5 - 7 microns are respiratable.
Particles smaller than this will not settle out as their terminal velocity is so small that there is in-

sufficient time for them to be deposited in the alveolus and they are exhaled out again. This is
shown on the BMRC penetration curve below.

Figure 2.2. British Medical Research Council penetration curve for respirable particles
showing 50% cut point at 5mm.

Key Point:Inhalable dust is dust that is hazardous when deposited anywhere in the respiratory tree. Particles in the region
of 7 - 20 microns will penetrate to the bronchioles and are inspirable, while particles in the size range 0.5 - 7 microns are
respirable.

Cut Point: Describes the performance of cyclones and other particle size selective devices. For personal sampling, the 50% cut
point is the size of the dust that the device collects with 50% efficiency.
Airborne dust concentration
The concentration of dust to which a person is exposed is also critical to the impact on the health
of the person exposed. This is measured in the breathing zone of the worker, which is an imaginary hemisphere of approximately 30 cm, extending in front of their face and measured from the
midpoint of an imaginary line joining the ears (see diagram below).

Figure 2.3. The Breathing Zone

3.4 Video: The Respiratory System

http://www.sheilds-elearning.co.uk/file.php/4/videos/respiratory_system.flv

3.5 The Body's Defence Mechanisms.

Inhalation and Respiratory Defences.
Respiration not only facilitates the transport of oxygen into, and carbon dioxide out of, the lungs,
but it also allows the ingress of harmful agents such as chemicals, physically damaging dusts and
fibres, air of excessive temperature or dryness, and biological agents such as bacteria or viruses.
Some of the defence processes are readily identified:
Coughing results in the forceful ejection of inhaled substances.

Goblet cells in the conducting airways secrete mucus which, forming sputum, is expectorated or
swallowed; and the nose itself filters out the largest particles.
Before we attempt to study the respiratory defence mechanisms in detail, we need to return for a
moment to the respiratory tract (Figures 1.1 and 1.3).
Those parts of the respiratory pathway down to, and including, the terminal bronchioles are the
conducting airways; those beyond constitute the respiratory units, where gas exchange occurs.
Initial filtration of particles larger than 10 m takes place in the hairs in the nasal cavity.
Smaller particles and aerosols between 7 and 10 m are trapped in the mucus secreted by goblet
cells lining the conducting airways, and then transported upwards by the ciliary escalator to the
pharynx where they can be either swallowed or expectorated (see Figure 2.4).

Figure 2.4
Smaller particles and aerosols between 0.5 and 7 m pass into the respiratory units, where
deposition takes place in the respiratory bronchioles and alveoli. Here, they may be ingested as
foreign bodies by macrophages, large cells normally found in tissues which produce blood cells.
Macrophages may migrate back along the respiratory pathways to the ciliary escalators, ultimately to be swallowed or expectorated. It is also thought that some transport occurs through the
alveolar membrane and into the circulatory system.

3.6 The Body's Defence Mechanisms (cont'd).

We can summarise the deposition of aerosols and particles in the respiratory system as follows:

Above 10 m Nasal cavity

7-10 m Ciliary escalator
0.5-7 m Respiratory bronchioles and alveoli
Below 0.5 m most remain airborne and are exhaled.

Some diffuse and come into contact with the airway or alveolar membrane.

Once in the bloodstream, the toxic substance (e.g. benzene) may act upon the blood itself or be
carried around until it affects another organ, such as the liver, kidneys or bladder. Materials swallowed may be excreted unchanged in the faeces. Others may be acted upon by enzymes, acids,
and other processes in the gut, or be absorbed and pass via the portal vein to the liver. Here they
may be further acted upon and metabolised, or conjugated into a variety of soluble by products to
be excreted in the urine.

Some toxic materials, such as lead, are initially stored in the bones of the skeleton so the toxic
effects can be minimised by slowly allowing it to leach back into the bloodstream.

The various pathways which may be taken by toxic materials deposited in the conducting airways
and respiratory units are shown in Figure 2.5.

Substances which pass through the alveolar membrane enter directly into the pulmonary capillaries, or find their way into the tissue spaces of the lungs from which they are drained by the lymphatic system. Substances reaching the interstitial spaces are sometimes stored harmlessly prior
to draining into the lymphatic system (e.g. tin and iron compounds), or may result in damage or
set up disease processes (e.g. fibrosis or pneumoconiosis). Because the lymph glands act as filters for substances or micro-predators (such as phagocytes) which are being carried away by the
lymphatic system, they are often involved in lung disease. Many cancers of the lung, for example,
start in the lung's lymph glands.

Figure 2.5
Table 2.1 shows nine examples of input substances, their sites of contact in the respiratory pathways, together with their principal effects.
Input Substance
Site of Contact
Effect
1

Soluble irritant gases

(e.g. NH3)
Low solubility irritant
gases (NO2)

3 Sensitising metals (Cd)

Upper conducting airways

Lower conducting airways

and respiratory units
Conducting airways (depending on particle size)

4 Di-isocyanates (TDI)

Conducting airways

5 Cotton dust

Conducting airways

Inflammation

Inflammation

Immuno-pathological reaction
Immuno-pathological reaction (e.g. asthma)
Immuno-pathological reaction (e.g. byssinosis)

6 Fibrogenic dusts:
Silica

Asbestos

7 Radio-isotopes

8 Hardwood dusts

9 Cigarette smoke

Conducting airways and

respiratory units

Collagenous pneumoconiosis (silicosis)

Lower conducting airways

and respiratory units

Collagenous pneumoconiosis (asbestosis)

Conducting airways and

respiratory units
Upper conducting airways
and sinuses
Conducting airways and
respiratory units

Table 2.1:Substances, Site of Contact and Effect

Neoplasia (cancers)

Neoplasia (cancers)

Metaplasia of bronchial
lining (lung cancer)

3.7 Video: The Circulatory System

http://www.sheilds-elearning.co.uk/file.php/4/videos/respiratory_system.flv

3.8 The Body's Defence Mechanisms (cont'd).

Defensive Cells.
Defensive cells are very important in protecting the body against harmful inputs of all kinds.
Those associated with work and occupational illnesses make up only a small proportion of such
damaging inputs with which the body has to contend. Two examples will serve to illustrate the
types of defence cell which are important in occupational health and hygiene:
(a) Phagocytes, which play a central role in the prevention of lung diseases;
(b) Blood-borne defensive cells, which give rise to the immune response and the inflammatory
response.
Phagocytosis.

Figure 2.6
Stage 1: Chemotaxis - proximity of foreign body stimulates movement of phagocyte towards intruder.
Stage 2: Adhesion of foreign body to phagocyte. It is thought the immune response (qv) is the
basis for adhesion.
Stage 3: Ingestion of foreign body into the phagocytic cell, and
Stage 4: inclusion of the foreign body attracts a lysosome which discharges enzymes into the
phagosome, i.e. the mixture of enzymes and the foreign body.
Stage 5: Nitric oxide synthesising enzymes chemically digest the foreign body which may remain
in the phagocyte's cytoplasm; or the phagosome may be deposited in the surrounding tissue or
fluids and thence into the lymphatic system. Alternatively, the foreign body may remain as an indigestible inclusion while the phagocyte migrates to other tissue.
Harmful particles, micro-predators and other foreign bodies engulfed by phagocytes may thus be
rendered harmless.

3.9 The Body's Defence Mechanism (cont'd).

Fibrotic Response
This mechanism is a reaction to the inhalation and deposition of fibrogenic dust. The respiratory
defence system described as the process of phagocytosis, indicates how dust deposited in the
alveoli can cause the formation of inelastic scar tissue. The fibrous material prevents oxygen
transport across the lung lining into the blood stream, which significantly reduces lung efficiency.
Reduced lung function results in shortness of breath and possible heart strain in advanced cases.
Inflammatory Response
Inflammation is the reaction of tissue to a harmful agent which is insufficient to kill the tissue. It
can follow when a foreign body enters the body by way of inhalation, ingestion, absorption, pervasion, implantation, surface penetration, trauma, or energy transformation. Although inflammation is a defensive process of great importance, if called upon to act for too long, it can sometimes
result in disease.

Acute Inflammation.
Acute inflammation is the immediate defensive reaction of tissue to any injury and is typified by
the following sequence of events:
(i) Initially, the capillary vessels in the area of tissue affected briefly constrict.
(ii) Then the same blood vessels dilate, and the capillary walls become more permeable.
(iii) Protein-rich fluid (plasma) exudes from the capillaries into the surrounding tissue, causing
swelling (oedema).
(iv) Phagocytes migrate through the capillary walls towards the harmful input, where they ingest it
together with any damaged tissue.
(v) Tissue-dwelling macrophages join with the phagocytes and scavenge the affected area, which
is sometimes additionally bonded by fibrinogen (a protein associated with blood clotting).
Healing Process.
Towards the end of the inflammatory phase, cells called fibroblasts appear and secrete collagen.
This is a fibrous protein which cross-links with polysaccharides (sugars) to form a meshwork of
scar tissue which steadily builds up to repair the affected area. While this is going on, if the affected area is close to the skin, epidermal cells remove any final debris in the area and begin to
dismantle the scar tissue.
Chronic Inflammation.
Sometimes, excessive amounts of collagen are formed and in certain chronic inflammatory responses, macrophages die and other macrophages phagocytose their dead.
The combination of living and dead macrophages forms structures known as giant cells. Scarring
is a repair process by which gaps in tissue are made good.
In some types of chronic inflammation, however, this repair process becomes disordered. The
overgrowth of scar tissue, brought about by over-production of collagen, shrinks and contracts,
tearing and distorting the surrounding tissues. In the lungs, this results in the condition known as
emphysema and some types of pneumoconiosis result in extensive scarring and fibrosis.
Immune Response.
This term describes the mechanisms concerned with defence and preservation of normal body
integrity. In its classical form, a wide range of chemicals and micro-predators provoke an immune
response which involves the production of antibodies within the space of a few days. Whenever
next the antigen enters the body, it reacts with the residual antibody and the combination of antigen and antibody can be phagocytosed as detailed above.
In addition to the classical disposal of antigens, two other types of immune response are recognised:
(i) Surveillance.
Sometimes dividing cells give rise to mutant forms and any excess could result in the growth of
abnormal tissue (benign or malignant). Surveillance by immune response results in these mutants
being recognised as alien and destroyed.
(ii) Self-disposal.
Redundant blood and tissue cells need to be phagocytosed from the body, and the immune response ensures that redundant cells are recognised as distinct from functioning cells.

3.10 The Body's Defence Mechanisms (cont'd).

It is important to link the immune response with inflammatory responses, since the two can be
regarded as complementary stages in a continuous process.

The immune response can be regarded as the mechanism concerned with identifying and preparing any harmful inputs, or the resulting damaged tissues for the inflammatory process.
Harmful inputs which can provoke an immune response include:

micro-predators and chemicals;

energies which cause tissue damage;
psycho-social climates (to produce, for example, asthma).

Respiratory Inflammation.
The respiratory pathway is vulnerable to attack by many irritants and corrosives or any other substances which attack the skin. The terminology of the inflammatory processes follows the pathway of air into the lungs, via:

Rhinitis,
Laryngitis,
Tracheitis,
Bronchitis.

Pneumonia: In extreme cases, the effects of inflammation lead to swelling and exudation of fluids,
resulting in narrowing or even total blocking of the small conducting airways.
Exudation in the alveoli leads to interference with respiratory gas exchange, even to a fatal degree.
Gases of low solubility will penetrate the respiratory pathway deep into the alveoli. Such gases
include sulphur dioxide, ozone, phosgene and oxides of nitrogen.
The inflammation caused results in fluid accumulating in the respiratory units (oedema).
Other irritants include metal fumes (metal fume fever) and polymer fumes (polymer fume fever).
Inflammation of the Skin.
Inflammation of the skin is much the same as for any other body organ; there are blood capillary
changes, there is increased permeability and there is migration of cells.
Inflamed skin is painful, sometimes itchy, often red and fissured, sometimes accompanied by
exudate and shedding of scales.
Chemicals attack the skin by pervasion or implantation, resulting in contact dermatitis, which may
take a number of forms:
Irritant Dermatitis.
This is caused by corrosive irritants such as acids, alkalis, detergents, oils, metallic particles, solvents, oxidising and reducing agents and some biological agents (e.g. giant hogweed). If the irritant is particularly aggressive, it can result in destruction of the skin.
Acute Irritant Dermatitis.
This is brought about by contact with acids and alkalis, for example, which result in acute inflammation.
Cumulative Insult Dermatitis.
This typically develops after repeated exposure to weak irritants over a long period of time.
Allergic Contact Dermatitis.
Also known as Contact Sensitisation Dermatitis, it is associated with a wide range of substances.
Some metals, such as cobalt and nickel, produce allergic reactions. With nickel, for example, contact with its alloys or salts can result in a form of contact dermatitis which may also affect skin on
other parts of the body not directly exposed to the agent.

Once this sensitivity (to very small amounts) has developed, it is usually permanent.
It is almost impossible to give a list of materials known to cause sensitisation dermatitis.
Certainly it would be very long, but would include coal-tar products, explosives, photographic
chemicals, dyestuffs and intermediates, insecticides, oils, resins, alkyd resins and plasticisers.

3.11 Video: Occupational Dermatitis.

Occupational Dermatitis Video
http://www.sheilds-elearning.co.uk/file.php/4/videos/dermo2.flv

3.12 Routes of Attack on the Digestive System

Ingestion.
In terms of occupational hazards from toxins, the gastrointestinal tract is the least vulnerable area
of the body.
The possibility of solid or liquid toxicants being ingested is very limited. Even if accidental ingestion does occur, the substance must be soluble in the fluids secreted by the tract to enable absorption to take place.
For ingested materials encountered in an occupational setting to become hazardous, i.e. when
they are able to be absorbed across the walls of the gastrointestinal tract, their chemistry must be
complementary to aqueous media and to the pH changes which take place.
The limited toxic potential of ingested inorganic lead compounds could be explained in simple
terms on the basis of the reaction of lead ions in aqueous solution to pH changes.
In alkaline conditions, solubility would be limited; in acid conditions in the presence of high chloride ion concentration, again the solubility of ionic lead would be suppressed. Its ability to be involved in aqueous absorption would, therefore, be limited.

Page 1
The exchange of oxygen and carbon dioxide between air, blood and body tissues is known as
Multiple Choice (HP)
Answer 1:

Respiration

Response 1:

Correct

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Answer 2:

Inspiration

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Answer 3:

Expiration

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Answer 4:

Perspiration

Response 4:

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Page 2
The upper part of the respiratory tract consists of all of the following EXCEPT
Multiple Choice (HP)
Answer 1:

Lungs

Response 1:

Correct

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Answer 2:

Larynx

Response 2:

Incorrect try again

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Answer 3:

Pharynx

Response 3:

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Answer 4:

Two nasal passages

Response 4:

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Page 3
This protective structure helps to keep food and fluids out of the airways
Multiple Choice (HP)
Answer 1:

Epiglottis

Response 1:

Correct

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Answer 2:

Oesophagus

Response 2:

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Answer 3:

Larynx

Response 3:

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Answer 4:

Glottis

Response 4:

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Page 4
This structure warms, moistens and filters inhaled air

Multiple Choice (HP)

Answer 1:

Nose

Response 1:

Correct

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Answer 2:

Trachea

Response 2:

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Answer 3:

Lungs

Response 3:

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Answer 4:

Epiglottis

Response 4:

Incorrect try again

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3.13 Types of Injury and Preventative Measures

Injury through Contact with the Skin and Eyes.
The Skin.
The skin is extremely vulnerable, a simple fact not always appreciated by workmen who are required to work in processes where corrosive chemicals are used, and protective clothing is required to be worn. Two-thirds of all industrial injuries from chemicals are due to bodily contact
with liquids causing chemical burns.
Direct contact of corrosive liquids with the skin or eyes causes chemical reactions with the fatty
tissue of the skin, resulting in the evolution of heat and a breakdown of the various layers of skin.
This inflicts chemical burns of either first, second or third degree magnitude, depending on the
degree of penetration into the skin layers. Substantial third-degree burns can be very serious,
particularly if a large area of skin is affected by the chemical.
The immediate first aid treatment of any patient incurring chemical burns is to apply copious
quantities of water to the affected part, whether skin or eyes. If necessary and convenient, immerse the patient in cold water to dilute and wash away the corrosive and reduce heat in the affected area.
Eyes.
Gases, vapours, mists or aerosols may contact the cornea of the eye, and the irritant or corrosive
may cause eye damage. The greatest source of injury, however, is liquid splashing into the eye.
The immediate first aid treatment is continued irrigation of the eye with cold water until medical
aid is available. The irrigation may continue for 15/20 minutes. Thorough cleansing is essential
and speed is vital.
Protective factors: everyone required to work in areas where corrosive chemicals are used must
be issued with suitable PVC gloves or gauntlets, eye shields and other items of protective clothing considered necessary, as determined by the original protective clothing job assessment.
You will recall that the employer has a responsibility to supply, and the employee a duty to wear,
the prescribed protective clothing.

Injury through Inhalation.

The respiratory system is particularly vulnerable in corrosive and toxic atmospheres. Any chemical carried in gas, vapour, dust, fumes or aerosol will, on being inhaled, contaminate the nose,
throat and mouth and further down the respiratory tract, depending on the extent of the exposure.
The 'walls' of the air sacs (alveoli) are penetrated with ease by most chemicals, which can then
enter the bloodstream with poisonous effect. Remember that the inhaling rate of an adult is about
20 times each minute, and each inhalation takes in about litre of air.
You can therefore calculate the air intake of a worker in one eight-hour shift, and consider how
harmful the effect of even weak concentrations of corrosive materials would be.
The extent to which gases, vapours and mists cause problems on inhalation depends upon their
solubility and irritant properties. The effect varies considerably between the various chemicals:
Ammonia is highly soluble and irritant. The gas dissolves in the first moist tissues it contacts,
and produces intense irritation.
Chlorine has low solubility, and is an irritant only on reaching the lower respiratory areas. Thus,
one or two deep breaths at high concentration can be very harmful.
Gases of low solubility generally may not produce any immediate corrosive or irritating effect and
may be absorbed without any apparent danger. As concentration and exposure times increase,
'chemical pneumonia' may develop. Typical examples of low solubility gases are phosgene (carbonyl dichloride) and nitrogen oxides.
Protective factors include:
Design of plant should aim at the elimination of possible leakage.
Process control should aim at the elimination of vapours, fumes, mists and dusts.
Adequate ventilation and scrubbing systems should be provided.
Suitable respirators should be available in hazardous areas.
Injury through Ingestion.
Risk of injury by the accidental swallowing of chemicals is not usually considered serious in industrial processing, but it is a definite hazard in laboratory operations where careless pipetting of
chemicals can be dangerous, due to the possibility of swallowing materials and inhaling vapours.
Pipetting should be done using a bulb aspirator or other mechanical means.
The main hazard of chemical ingestion comes from lack of personal hygiene, e.g. failing to wash
the hands before eating meals, smoking or drinking, or from airborne dusts getting into the mouth
and being swallowed.
In the case of ingestion, a much higher concentration of chemical is usually required than for injury by inhalation. Ingested chemicals are absorbed in the digestive tract and pass through the
liver, where many deoxifying mechanisms operate.
Digestive disturbances and loss of appetite are early symptoms of chemical poisoning.
Protective factors include:
Full attention must be given to ventilating systems.
Breathing apparatus must be available.
Safe working systems for pipetting of materials in the laboratory must be established.
When working on experiments involving the use of toxic materials, the fume cupboard must be
correctly used.
Strict attention must be paid to personal hygiene at all times to avoid contamination of the
mouth when eating.
Injury through Contact with the Skin and Eyes

3.14 Injury through Absorption

As we have already seen, there can be an immediate and severe danger following skin contact
with chemical compounds such as chlorinated solvents, hydrocarbons, etc. This absorption into
the body system can result in serious internal organ damage.
The concentration of the chemical and the length of time it is on the skin are vital factors. Barrier
creams provide limited protection; but, once again, sensible hazard assessment and the issue of
the right protective equipment for the job are essential.
Protective factors: plant design and the elimination of hazards are the first prerequisites. Protective clothing is the second line of defence.
Preventing Personal Injury by Chemicals.
In addition to the protective factors mentioned earlier, the risk of personal injury from chemicals
may be controlled as follows:
Handling of Chemicals:
Safe working systems at receiving points for corrosive materials.
Tank car reception of acids and alkalis to be kept under review.
Adequate installation of emergency showers.
Cautionary notices to be conspicuous.
Manual handling to be reduced to a minimum, but where it is necessary to receive chemical corrosives in glass carboys (a glass bottle surrounded by protective packaging), care must be exercised in off-loading and general handling of them. Assessment of protective clothing should have
full regard for the potential hazard of the glass carboy breaking with consequent serious hazard.
Fortunately, this method of delivery is being replaced by tank car, but it still exists - particularly,
where only small quantities are required.
Fumes.
Fumes and dusts should be removed by suitable ventilation.
Safe Entry into Vessels.
Adequate precautions must be taken and full control exercised where workmen are required to
enter closed vessels for the purpose of cleaning and maintenance of vessels which have contained hazardous chemicals.
Permit-to-work systems are essential for this type of work, with the precautions clearly defined
and the relevant protective clothing and safety equipment clearly stipulated.
Adequate ventilation and the provision of a good air supply are high priorities.
Clothing.
A protective clothing entitlement must be assessed for all work where there is a danger of chemical contamination, based on the principle and standards of the individual protective clothing entitlement.
Procedures.
Emergency procedures must be established, and emergency showers and eye washing facilities
made available.
Training.
This should be given:
In relation to the nature of the materials being processed and the hazards involved, together
with preventative measures.
In first aid requirements and procedures.
Permit-to-work Systems.
Must be instituted for work involving the breaking of pipe lines conveying corrosive materials.

Valves on mains should be painted a distinctive colour to ensure easy identification.

Sampling Arrangements.
Arrangements for corrosive materials should be closely investigated, and safe working systems
devised and implemented.
Storage Facilities.
Facilities for chemicals in packages, bags, etc, should be thoroughly checked to avoid the possibility of moisturisation and cross-contamination of chemicals and potential chemical reaction.
Compressed Gas Cylinders.
These require very special care.
Spillages.
Require immediate treatment and cleaning up; contaminated articles should be carefully inspected and, if necessary, discarded.
The hygienist and safety practitioner, when studying the chemical environment, will obviously give
some time to the assessment of these factors.
The original assessment will commence with an Initial Hazard Assessment of the chemicals being
used to determine the potential hazard of the materials being processed. This will indicate the
type of training to be given and the protective clothing required

3.15 Examples of Corrosives and Irritants

Chrome.
Air contaminated with chromic acid mist, or with dust from chromates or dichromates, is the principal source of harmful exposure in industry.
(a) Chromium plating is carried out using an electrolyte containing about 50% chromic acid and,
during electrolysis, reddish-brown fumes of chromic acid are forced off in the form of mist by the
evolution of bubbles of hydrogen at the cathode.
(b) In anodising, a coating highly resistant to corrosion is formed on aluminium and its alloys
through the anodic oxidation of aluminium. Again, chromic acid is used as the solution in which
anodising is carried out, and the hydrogen liberated at the cathode carries significant quantities of
chromic acid mist into the atmosphere. It is this chromic acid, and any dissolved salts of chromium it contains, that are responsible for the dermatitis, ulceration and even lung cancer.
Dermatitis and Chrome Ulcers.
Lesions of the skin due to chromium salts have been known since 1827 when it was found as
chrome holes on the fingers of bichromate workers in Glasgow.
It has since been established that both chromates and bichromates of sodium and potassium,
together with chromic acid, may cause either dermatitis or localised ulceration.
Exposure to these substances occurs in chromium plating, French polishing, calico printing, photographic processing, litho-etching, chrome tanning and colour workers.
Typically, dermatitis develops on exposed parts of the body such as the hands, arms, chest or
face. Onset is often sudden, occurring sometimes after an exposure of several months and, in
severe cases, the face becomes intensely red and swollen, with the affected parts itching a great
deal and perhaps becoming painful. There is some evidence that fair-headed/skinned people are
particularly prone to chrome dermatitis, and their presence at chrome operations calls for particular care.
Chrome ulcers are thought to begin in abrasions in the skin and are most commonly found at the

foot of the finger-nail, the knuckle of the hand, or dorsum (top) of the foot. They are circular in
shape, up to one centimetre in diameter and look as if they are punched out, hence 'chrome hole'.
Some penetrate deeply, even to the bone and, although usually painless, they itch incessantly,
especially at night. In chromium plating and anodising, where chromic acid fumes are frequently
present, inhalation leads to perforation of the nasal septum. This effect has even been reported in
people spray painting anti-corrosive zinc chromate-based paints.
Cancer of the Lung.
The first reported case of cancer of the respiratory system in a chrome worker occurred in a 47year old man who had worked in the chromate industry in Scotland (1890).
Since then, it has been established that the incidence of lung cancer is about 3.6 times that of the
'normal' population, but with a latency period of about 25 years, this figure for risk may be an underestimate.
Preventive Measures.
Prevention of chrome-related diseases depends primarily on the removal of the dust or mist at
source by suitable ventilation equipment; cleanliness, supported by regular medical supervision,
and covering cuts and abrasions with suitable dressings.
Where contact with the arms or hands is likely, then workers should be supplied with adequate
protective equipment, including gloves, aprons and boots; but great care needs to be taken to
ensure that solutions cannot run down the arms or legs and into the protective clothing, or severe
ulceration may result.
Good hygiene is particularly important, and should be encouraged by the provision of ample
washing facilities backed up with good care of the hands, using barrier creams and lanolin-based
creams.

3.16 Examples of Dermatitic Hazards

The list of materials which can cause dermatitis is almost endless. In the occupational situation,
you must find out about the harmful effects of any substance that your workforce has to handle.
For the examination, some clear examples of materials which evoke a dermatitic response will
suffice.
Examples of Primary Cutaneous Irritants.
Greases.
Mineral oils.
Solvents, e.g. white spirit.
Chlorinated hydrocarbons.
Propanone (acetone).
Strong alkali and acids.
Cement.
Physical agents: heat, cold, radiation, friction.
Examples of Cutaneous Sensitisers.
Rubber additives.
Nickel compounds.
Hair dyes containing p-phenylenediamine.
Methanol solutions (formalin).
Wood dust: African (Iroko) teak.
Resins used in plastic manufacture.
Many modern chemicals are able to evoke both irritant and sensitising responses. Compounds of
chromium and arsenic can cause dermatitis, which may progress further to give ulceration of the

affected areas.
Control of Potential Dermatitic Situations.
The main aim in the control of potential dermatic situations is the limitation of exposure to a level
where the risk is eliminated, or reduced to a practical minimum.
For dusts and vapours, total enclosure with mechanical handling and exhaust ventilation systems
provides a safe place strategy. The exhausted materials should be rendered safe, and not indiscriminately vented into the atmosphere.
For liquids, pastes, or dustless solids, mechanical handling may be satisfactory.
When it is not possible to provide a safe place strategy, a safe person strategy must be adopted
and suitable protective equipment provided, e.g. gloves, impervious overalls with close-fitting collars and cuffs, wellington boots; and, in certain circumstances, half-mask respirators. Barrier
creams provide very limited protection where primary irritants are encountered, and are useless
against cutaneous sensitisers.
Where protective equipment is supplied, management is mainly responsible for its use and
should provide adequate supervision and the necessary incentives for workers to use the equipment when they are not supervised.
Personal hygiene should really only provide a 'back up' if a breakdown in safety control occurs;
but, in practice, it does provide a positive method of reducing the risk of contracting dermatitis.
Where there is a known risk from cutaneous sensitisers, 'patch testing' personnel before they are
exposed to potentially hazardous conditions is a commonly used practice. Patch testing involves
applying a small amount of various materials to the skin, often on the forearm, and checking to
see whether or not a positive reaction to the material occurs. Patch testing must only be carried
out by a professionally-trained person.
Problems resulting from occupational dermatitis should always be referred to a dermatologist with
adequate industrial experience in your particular industry.

3.17 Carcinogenesis.
Background.
A cancer is a growing mass of non-productive tissue that is relentlessly progressive, ending in the
death of the individual.
This tissue growth is termed a malignant tumour and can spread within the body via the bloodstream or the lymphatic system. This process, termed metastasis, leads to the formation of other
small tumours scattered widely throughout the body.
These new tumours can grow into nearby tissues and destroy them as a consequence, by a
process termed invasion. Metastasis and invasion are the two characteristics that distinguish malignant tumours from those classified as benign.
Descriptions of the important terms associated with carcinogenesis are as follows:
Tumour: a swelling related to the growth of diseased cells, which grows at the expense of other
healthy cells in its vicinity. There are basically two kinds: benign and malignant.
Benign tumours usually grow very slowly, remain localised and their cell structure is often similar
to the cells of origin.
Malignant tumours grow rapidly without restraint, spread into surrounding tissue and have their
own cell structure, unlike the cells of origin. The term cancer is used to describe the formation of

malignant tumours.
Carcinogen: an agent (either physical, chemical or viral) which has the ability to produce malignant tumours. In terms of occupational cancer, the carcinogenic agent will be physical and
chemical.
Occupational carcinogen: a carcinogen which induces cancer in a person as a result of their occupation. This is a definition given by the World Health Organisation and appears to be clear and
simple. Unfortunately, in practice the classification of a cancerous condition arising from occupation is far from simple.
Formation of Cancerous Cells.
It is generally accepted that cancerous cells are formed by the carcinogen attacking the mechanism which controls the reproduction of normal cells. The toxic action of carcinogens differs from
'ordinary' toxic action:
They upset the fundamental cell reactions within the cell structure, whereas ordinary toxic substances mainly upset the general metabolic processes which prevent cells from functioning normally.
They evoke irreversible effects which continue after exposure to the carcinogen has ceased. The
action of ordinary toxic agents usually stops when the exposure ceases, and recovery generally
follows.
The effects of a carcinogenic agent will not appear for many years after exposure. The period of
time is its latency period. Periods between 5 and 50 years are given for different agents. During
this time, there is little or no warning of the eventual tragic outcome. 'Ordinary' toxic agents can
evoke an acute response and also a chronic response.
The particular point made above highlights the importance of strict control in the use of carcinogenic substances. Once the symptoms have been diagnosed, the problem will often have
reached the point of no return.

3.18 Mode of Action of Chemical Carcinogens.

Carcinogens interact with the genetic material of the cell, the DNA, causing structural and functional alterations which cause the cell to grow in an uncontrolled manner.
This damage to the DNA may be repaired by enzymes that exist within the cell nucleus.
However, in cases where this repair is not carried out effectively, the cell is significantly altered
and acquires properties which were absent prior to the damage.
In some instances, these new properties may be passed on to daughter cells during cell division.
This hereditary transmission of new characteristics is an indication that the cell has been mutated, and the event that brings about this change is termed a 'mutation'.
The process of mutagenesis, therefore, is considered the first step in the process of carcinogenesis, and many short-term tests for carcinogenicity are based on the ability of a chemical to induce
mutations.
Generally, carcinogens and mutagens are categorised as such on the basis of human or, more
likely, animal data.
The International Agency for Research on Cancer (IARC) classifies substances as:

'Carcinogenic to humans' (human evidence)

'Probably carcinogenic to humans' (good animal evidence)
'Possibly carcinogenic to humans' (less good animal evidence)

No-threshold Concepts.

Later in this unit, we will consider dose-response relationships, which are based on the concept of
a minimum level of toxin exposure below which no harmful effect can be detected.
The assumption is that below this specific level, the degree of harm inflicted by the toxin is insignificant and will not cause lasting damage.
This threshold level for acute toxic effects can therefore be used to define workplace exposure
limits.
In the case of carcinogenic toxins, the situation is much more complex.
Theoretically, a single 'hit' or reaction of a compound or its metabolite on the crucial part of one
DNA molecule might be sufficient to initiate a cancerous change. Hence there is no threshold of
harm, and any level of exposure to a carcinogen has the potential to cause cancer.
In practice, however, the chances of one molecule reaching the target site are probably small for
most compounds and depend on a number of factors including potency, absorption, distribution
and metabolism.
The capacity of the particular cell to repair such damage will also be important.
You should therefore appreciate how the concept of a no-threshold level of harm for carcinogenic
substances differs significantly from the approach to exposure limits applied to other toxins, and
thus affects the assessment of risk and the setting of appropriate control standards.
Setting and Justifying Control Strategies for New Suspected Carcinogens.
In practice, there must be a threshold dose for a particular carcinogen, but is it difficult to determine in mammals in vivo because the critical biochemical changes at cellular level are impossible
to detect.
The results from animal carcinogenicity testing studies are particularly hard to assess.
It is difficult to show an increased frequency of tumours in a small population, such as those used
in animal cancer studies in which there may already be a significant incidence of some types of
tumour.
There is also a practical statistical limit which determines the frequency of occurrence of a cancer
which can be detected. Hence assessing cancer risk from carcinogenicity studies is very difficult.
As a result, those conducting and assessing the tests tend to err on the side of caution.
Another problem is the need to use high doses close to the maximum tolerated dose in carcinogenicity testing.
This approach is contentious since carcinogens may show dose-dependent metabolism, which
can distort interpretation of the carcinogenicity data for weak carcinogens tested at dose levels
much higher than occupationally expected.
Consequently, a compound may only be carcinogenic under the extreme dosing conditions of the
test.
Extrapolation between species is also a problem in risk assessment and the interpretation of toxicological data. The species or strain used in a particular carcinogenicity study may have a high
incidence of a specific type of tumour. The assessment of the significance of an increase in the
incidence of this tumour, and its relevance to man, can pose particular problems.
Therefore, risk assessment for carcinogenicity tends to be much more difficult than for any other
type of toxic effect. The incidence of a toxic effect may be measured under precise laboratory
conditions, but extrapolation to a real-life situation to give an estimate of risk involves many assumptions and gives rise to uncertainties.
The setting of control standards from these risk assessments is therefore often based on obscure
data, which may be without precise scientific foundation.
In practice, there is little alternative to extrapolation from scientific studies, since for new chemical
substances, human data is not available and toxic effects in man cannot be verified by direct ex-

perimentation.
Thus evaluation of human exposure from the limited data available tends to lead to a worst-case
estimation which, by definition, will tend to exaggerate the risk to human health.

3.19 Environmental and Non-occupational Cancers.

Another problem in setting standards for exposure to carcinogenic substances is the fact that the
long latent period between exposure to particular agents and the development of tumours in man
makes it difficult to establish in retrospect what has actually caused the cancer. Also, it is often
not possible to distinguish occupational and non-occupational cancers. Chemicals are often
thought to be a major factor in the causation of human cancer. However, carcinogenic chemicals
can be identified in food, the air, and the environment generally and are not just confined to the
workplace.
We shall look at the principal occupational carcinogens such as asbestos, arsenic, benzene,
chromium, nickel and mineral oils in a later study unit. Remember that exposure to several
chemicals can occur in one person's working lifetime, with possible carcinogenesis of a number
of tumours (e.g. lung, mesothelioma, head and neck). However, there are also more important
sources of non-occupational cancers.
The main offender in this category is the habit of cigarette smoking, the carcinogenic effects of
which are well known. An estimate of the risk of cancer attributable to various agents suggests
that the largest contribution comes from the effects of tobacco and from dietary habits. There is
no support for the common belief that most cancers could be prevented by controlling chemical
pollution of the air, food and water, or occupational exposure.
The incidence of most cancers is either steady or declining, with the exception of cancers which
are directly linked to smoking. If the increased use of chemicals either occupationally or environmentally is causing cancer, it is doing so to an extent that is not measurable in the overall statistics.
There is certainly no evidence of an epidemic of cancer caused by the increased use of synthetic
chemicals. Nevertheless, while cancers probably originate from a whole variety of circumstances,
exposure to chemicals does contribute to the generation of some cancers.
The effect of environmental and non-occupational cancers, therefore, is to provide a background
level against which any suspected occupational cancer must be distinguished and measured.
This adds a further complication to the difficulty of assessing the actual risk of occupational carcinogens and setting meaningful control standards in relation to the inherent cancer risk of the
population as a whole.

3.20 Summary.
In this element, we have considered the main routes and mechanisms of attack by toxic, corrosive and dermatitic substances, dusts and fibres. We looked at the various routes of entry and
absorption routes, including the respiratory system, the gastrointestinal tract and the skin.
Target organs and systems are important elements of our studies, so we have covered the significance of the bloodstream, the circulatory system, the lymphatic system, the liver, the urinary
system and the reproductive system in unit B1.
The body's defensive responses are obviously highly significant, and we have studied inhalation
and respiratory defences and defensive cells.

Finally, we have discussed carcinogenesis and mutagenesis, including the formation of cancerous cells, the no-threshold concepts and the influence of environmental and non-occupational
factors.
Class of Toxin

Target Organ/System Some Symptoms

damaged

Example

Hepatotoxins

Liver

Jaundice, liver
enlargement

Carbon tetrachloride

Nephrotoxins

Kidney

oedema, Proteinuria

Neurotoxins

Nervous system

Haematopoietic agents Blood or haematopoietic system

Halogenated
hydrocarbons
Narcosis, behavioural Mercury and
changes
compounds,
Chloroform, ether
Cyanosis, loss of
Carbon monoxide,
consciousness
cyanides

Lung toxins

Lungs

Cough, difficulty
breathing

Asbestos, siliceous
dust

Reproductive toxins

Reproductive organs, Sterility, birth defects, Lead and compounds

developing foetus

Cutaneous agents

Skin

Defatting, rashes,
irritation

Eye toxins

Eye

Conjunctivitis, corneal Acids, organic solvents

damage

Ketones, chlorinated
organic solvents

4.0 Health Effects of Chemicals Used in the Workplace

Classification of hazardous substances
In this section, we will give definitions of the physical forms - solids, liquids, dusts, fibres, mists,
gases, fumes and vapours.
Before we begin this section, it would be a good idea to establish some definitions for terms that
we will encounter throughout this unit.
Toxic
A Toxic substance is one that is capable of causing injury or damage to a living organism. A wide
variety of materials are considered as toxic; examples are sulphuric acid whose action is notably
corrosive; compounds of heavy metals which may act as systemic poisons; selenium compounds,
such as selenium dioxide and natural products such as the aflatoxins (naturally occurring mycotoxins that are produced by many species of Aspergillus, a fungus, most notably Aspergillus
flavus and Aspergillus parasiticus. Aflatoxins are among the most carcinogenic substances
known.)
Corrosive
A Corrosive material is one which causes damage to skin, eyes or other parts on the body on
contact. The technical definition is written in terms of
"... destruction, or irreversible damage to living tissue at the site of contact".
Often this damage is caused directly by the chemical, but the action of some corrosive materials
is a consequence of inflammation which they may cause. Concentrated acids are obvious exam-

ples of corrosive materials, but even dilute solutions of bases such as sodium or ammonium hydroxide may also be very corrosive, particularly in contact with the eyes.
Irritant
An Irritant is a chemical which may cause reversible inflammation on contact.
Harmful
This denotes a substance that may cause damage to health. It should be considered as similar to
toxic but less dangerous. It should still be treated and handled with caution.
Dermatitic
Dermatitis is an inflammation of the skin which may be brought about by repeated contact with
chemicals. A wide variety of chemicals may be responsible, especially those which can cause defatting of the skin, such as chlorinated solvents. Irritation, cracked skin and blisters are common
symptoms. Dermatitis may also arise if a person is susceptible to sensitisation, and is allergic to
butyl rubber, latex or other types of gloves designed to protect the skin from contact with chemicals.
Dermatitis may seem a comparatively minor problem compared to the other hazards posed by
chemicals, but should be regarded as a potentially serious condition and not ignored.
Sensitisation
A sensitiser is a chemical which may lead to the development of allergic reactions after repeated
exposure.
Carcinogenic
A Carcinogenic chemical is one which is believed to be capable of causing cancer, that is, acting
as a carcinogen.
A Carcinogen is a chemical known or believed to cause cancer in humans. The number of proven
carcinogens is comparatively small, but many more chemicals are suspected to be carcinogenic.
Mutagenic
A mutagenic agent or mutagen is one which is capable of causing mutations. It may also (but
does not necessarily) act as a carcinogen.
A mutation is a heritable change in genetic material - in other words, a change which can potentially be passed from parent to child. This change may occur in a gene or in a chromosome, and
may take the form of a chemical rearrangement, or a partial loss or gain of genetic material.
Asphyxiant
An asphyxiant is a material capable of reducing the level of oxygen in the body to dangerous levels. Most commonly, asphyxiants work by merely displaying air in an enclosed environment. This
reduces the concentration of oxygen below the normal level of around 19% which can lead to
breathing difficulties, unconsciousness or even death.
The danger is (in theory) posed by any gas which is potentially present at high levels in the environment.
Some asphyxiants act directly upon the oxygen-carrying ability of the blood. Carbon monoxide,
for example, binds strongly to the haemoglobin molecule, which is responsible for the transport of
oxygen around the body. This reduces the amount of haemoglobin which is free to transport oxygen, possibly to dangerous levels. Carbon monoxide is produced in potentially large amounts
when material is burnt with a limited supply of oxygen. It is generated at often substantial levels
when cigarettes are smoked.

4.1 Physical Nature of Airborne Contaminants

Airborne contaminants can be grouped under the general term of aerosol.

An aerosol is a scientific term that applies to any disperse system of liquid or solid particles suspended in air, so it applies to a wide range of particulate systems encountered occupationally.
Aerosols of interest to the occupational hygienist include (Note: 1 m = 1m/1,000,000):
Dusts: Solid particles made airborne by mechanical disintegration of bulk solid material, (i.e. cutting, crushing, grinding). Size 1 m - 1000 m
Spray: Large liquid droplets produced by mechanical disruption of bulk liquid, (i.e. spraying,
pouring and stirring). Size 10 m - 1000 m
Mist: Finer liquid droplets produced during condensation, (i.e. cooling of hot vapours). Size 0.01
m - 10 m
Fume: Small solid particles produced by condensation of vapours or gaseous combustion products, (i.e. cooling of combustion products from hot processes). Size 0.01 m - 1 m
Smoke: Very small solid or liquid particles of complex shape arising from incomplete combustion, (i.e. hot processes involving combustion). Size 0.01 m - 1 m
As well as size, particle shape is important in determining the effects of inhalation of airborne contaminants, since this affects the way that particles behave in air and also how they behave after
they have been deposited in the respiratory tract.
Particle shapes include:
Spherical - e.g. mists and sprays.
Isometric - (non-spherical but compact particles) e.g. dusts.
Platelets - (plate-shaped particles) e.g. certain dusts such as mica.
Fibres - (long, thin needle-shaped particles) e.g. asbestos and mineral fibre.
Since airborne contaminants occur in a wide range of shapes and dimensions, it is necessary to
employ simple indices of size in order to compare the aerodynamic properties of different aerosols.
A commonly-used index is the aerodynamic diameter, which is the diameter of a sphere of water
which has the same falling speed in air as the particle in question.
Since we are principally interested in how the aerosol particle behaves in air and also in the respiratory tract, this comparative index gives a useful indication of how different types of aerosol particle are likely to behave.
You will remember that in Unit B1 we made reference to the Effective Spherical Diameter (ESD)
(which is a similar index to the aerodynamic diameter in that it attempts to approximate the shape
of the aerosol particle to an equivalent sphere) in relation to filtration and deposition of airborne
particles in the various sections of the respiratory tract.

4.2 Video: [News bulletin] Toxic Gas

http://www.sheilds-elearning.co.uk/file.php/4/videos/NewsToxicGas.flv

4.3 Specific Workplace Examples of Hazardous Substances

In this section we shall be looking closely at specific workplace examples of hazardous substances including:

Isocyanates
Polycyclic Aromatic Hydrocarbons
Mineral Oils
Vinyl Chlorides
MbOCA (2,2 Dichloro-4,4 Methylene Dianiline).
Cement
Ammonia
Chromium
Wood dust
Nickel
Siliceous dust
Sulphuric Acid
Sodium Hydroxide
Solvents
Lead and compounds
Asbestos

4.4 Mercury
Elemental mercury is a member of the heavy metal group, with a density greater than lead.
It is unique in that it is a liquid at normal temperatures and pressures, a property used to advantage in the electrical industry where liquid contacts are required, or for measuring equipment such
as thermometers or barometers.
It is a relatively un-reactive metal, quite easily extracted from its main sulphide ores. For this reason, mercury, like lead, has been known for a considerable time. Its toxic potential was recognised by the Romans.
Mercury is able to form inorganic compounds, e.g. mercuric chloride (HgCl2) (corrosive sublimate), mercurous chloride (Hg2Cl2) (calomel), and organic compounds, e.g. diethyl mercury or
methyl mercury hydroxide.
In 18th and 19th century England, mercury was used in the production of felt, which was used in
the manufacturing of hats common of the time. People who worked in these hat factories were
exposed daily to trace amounts of the metal, which accumulated within their bodies over time,
causing some workers to develop dementia caused by mercury poisoning. "Mad as a Hatter" is a
colloquial phrase used in conversation to refer to a crazy person and it became popular as a way
to refer to someone who was perceived as insane.
Mode of Entry.
Elemental mercury liquid is not absorbed by the gastrointestinal tract or through the skin in normal circumstances.
Absorption of mercury metal vapour does occur readily following inhalation into the lungs. There
is vague evidence that the vapour is absorbed into the body following skin contact.
Liquid mercury does readily form mercury vapour in considerable concentrations at room temperatures, but the ability to vaporise is almost completely prevented by the formation of a dust or
moisture layer over the free surface of the liquid.
It is for this reason that many schools or electrical workshops have mercury vapour-free atmospheres, but have small lakes of mercury metal under benches or the floor.
The situation changes dramatically if the temperature is raised above normal ambient levels, and
vaporisation then becomes vigorous and potentially very hazardous.
When mercury liquid is used with surfaces open to the atmosphere, a layer of water should be

used to make a safety seal.

Target Organs.
The two main target organs for mercurial intoxication are the brain and kidneys. An acute response following inhalation of fumes or gases containing elemental mercury produces irritation
with a delayed cough and chest pains; often this proceeds to acute pneumonia. The eyes are
also affected by absorbed mercury vapour.
Chronic Effects and Diagnosis.
The vapour from mercury metal is absorbed into the blood following inhalation and becomes deposited mainly in the brain. The metal molecules become involved in metabolic reactions which
result in injury to the central nervous system (CNS).
Inorganic compounds of mercury can also affect the CNS but, in general, kidney damage occurs.
The excretion of protein in the urine is an indication of this condition.
Exposure to mercury vapour can result in a brownish discolouration developing in the lens of the
eyes. The condition does not appear to interfere with vision and it can occur without other symptoms of mercurial intoxication.
The initial signs of mercurial intoxication include general symptoms such as headaches and a
gradually developing sallow colour. Irritability and aggressiveness develop, as do tremors in the
hands, which have a marked effect on the ability to write. The tremors also occur on the eyelids,
lips and tongue. The tremor condition is aggravated by alcoholism. Gingivitis occurs, and in severe cases this results in teeth being lost. Gums become very sore and swollen, bleed easily and
may ulcerate.
The marked effects on the personality resulting from damage to the CNS can become extreme.
The expression 'Mad as a hatter' referred to an occupational condition resulting from the use of
hot acid solutions of mercuric nitrate in treating rabbit furs to produce felt for hats.
In extreme cases of chronic mercurial intoxication, loss of memory, hallucinations and considerable loss of intellectual capacity occurs.
Where organic mercury compounds have been absorbed into the body, the nervous condition
(tremor and reduced visual field) is more pronounced than the psychotic condition (erethism).
Where kidney damage has occurred, apart from excretion of protein, loss of albumin may result
as well. This can upset the normal fluid balance causing a more generalised kidney failure. When
the victim is removed from exposure, complete recovery from the adverse condition usually occurs.
One particular effect from mercury fulminate is the development of dermatitis. Swelling and itching of the affected area are the primary symptoms. This is followed by local oedema and pusforming pimples. If the powder becomes lodged in skin folds or cracks, painful necrotic ulcers
may develop. Inhalation of the dust causes extreme irritation of the eyes, nose and throat.
Occupations and Persons at Risk.
Risk from mercurial intoxication occurs in:
Mining and processing of mercury ores.
Manufacture of thermometers, barometers and electrical switchgear.
The use of mercury amalgams in dentistry and water-gliding.
Manufacture and use of mercury compounds, e.g. inorganic salts used in antifouling paints, or fur
felt treatments.

Organo-mercury compounds used as fungicides in seed dressing, e.g. ethyl or diethyl mercury.
Manufacture of detonators using mercury fulminate.

4.5 Benzene
Benzene has a molecular formula C6H6 and its structural formula provides the basic structure for
aromatic chemicals (Figure 4.1)

Figure 4.1 Molecular structure of Benzene

Benzene is a colourless, sweet-smelling, volatile liquid with a boiling temperature of 80C. It is
very harmful and is absorbed into the body following inhalation and/or skin contact.
Acute Effects.
Inhalation of the vapour in high concentration causes headaches and dizziness, and can act as a
stimulant.
These symptoms will soon be overtaken by narcosis which can progress to coma and death. The
vapour also causes considerable irritation to the eyes and mucous membranes of the nose, nasal
cavities and the mouth.
Chronic Effects.
Absorption of low concentration of benzene into the body over a long period of time results in severe anaemia. This results from the impairment of the blood-forming metabolism in the bone marrow. The condition can progress to aplastic anaemia as the terminal phase. It is now generally
accepted that leukaemia, the blood cancer, can result from absorption of benzene into the body
over long periods of time.
The homologues of benzene, toluene and the xylenes, produce the same acute chronic effects as
benzene, but their toxic action is very much less than benzene.
It is believed that as alkyl groups are added to the benzene ring structure, the carcinogenic risk
declines markedly.
One word of caution: you should be aware that the homologues of benzene invariably contain
small amounts of benzene as an impurity. This could lead to an enhanced toxic potential due to
the presence of these trace quantities.

4.6 Phenol
Phenol has a molecular formula C6H5OH and a structure related to benzene which is shown in
Figure 4.2.

Figure 4.2
Acute Effects.
The main effect following a high level of absorption occurs within the central nervous system. Collapse and coma follow rapidly after the body has been in contact with phenol solutions. Death often results following contact. Periods of between 30 minutes and several hours before death occurs have been recorded, depending upon concentration of the liquid and the area of body af-

fected.
In high concentrations, phenol solution can cause death if the body area contaminated exceeds
15-20%.
Where death is delayed or the absorption is not fatal, extensive damage occurs in the kidneys,
liver, pancreas and spleen. A pulmonary oedema could also occur following inhalation.
Chronic Effects.
Exposure to phenol, and absorption over long periods, especially of vapours or fumes, cause digestive disturbances, e.g. vomiting, excessive salivation or diarrhoea. Nervous disorders, e.g.
headache, dizziness and mental disturbances can also occur. Dermatitis often follows contact
with the skin. Liver and kidney failure following long exposure have been recorded as causes of
death.

4.7 Coal Tar Pitch Volatiles.

These are the vapours and fumes which are evolved from a liquid residue formed when coal is
heated and decomposed in the absence of air.
Coal tar pitch is the complex liquid mixture of mainly organic aromatic substances and ammoniacal liquors which remain after coal gas has been produced from coal. In more recent times, coke
ovens and patent fuels manufacture provide equivalent hazardous conditions.
Toxic Hazards.
The general presence of coal tar pitch volatiles is considered as a potential carcinogenic or cocarcinogenic risk to humans.
The level of concentration should be well below the working limit for possible 'simple toxic' concentrations of many substances contained within the vapours.
Associated Substances.
The following list comprises the better-known compounds derived from coal tar pitch:
Benzene.
Toluene.
Xylenes.
Napthalene.
Phenanthrene.
Anthracene.
Crude tar bases (Pyridine 0.1).
Crude tar acids (phenols, cresols, xylenols).
From the reactions during the decomposition of coal, aromatic polycyclic hydrocarbons will be
produced. It is very likely that these contribute to the carcinogenic potential of the coal tar pitch
volatiles.

4.8 Aliphatics.
Aliphatic halogen compounds are used extensively as solvents and reagents for manufacturing
processes.
Apart from their ability to cause dermatitis, and especially the particular condition termed
'chloracne' from compounds containing chlorine, they can cause carcinogenic responses in animals as well as in humans, e.g. vinyl chloride (see later). They can cause acute narcotic responses in high concentrations; they can be addictive, and can cause liver failure.

Target Organs.
Aliphatic organic compounds have a high affinity for fats, waxes and greases, hence their use as
solvents. When they are absorbed into the body, they will concentrate in areas of high body fat.
The two main target organs are the brain and the liver.
In the brain, they interfere with the central nervous system which results in a narcotic response.
In the liver, they cause toxic metabolic processes which can eventually lead to necrosis (breakdown) of liver tissue. As the liver is the main detoxification organ for harmful body substances,
any failure will result in rapid body damage, even premature death.
Examples.
Two classic examples of halogenated hydrocarbons which exemplify the above-stated problems
are trichloroethylene and tetrachloromethane (carbon tetrachloride).
Trichloroethylene (TCE).
This compound was officially listed as an animal carcinogen in July 1976 by the United States
National Cancer Institute, and therefore constitutes a potential risk to humans.
Since that time, research has not identified a definite link with human risk.
In the UK, the substance is still under review, but concern by the Health and Safety Executive
may be described as marginal.
The potential of TCE to trigger a narcotic response is accepted, and strict control over airborne
concentration should be maintained.
Where a gassing accident situation occurs, the result may be permanent brain damage or death.
In low concentration, the effects are mainly debilitating, i.e. headaches, drowsiness, fatigue and
loss of ability to concentrate.
The potential risk from TCE as a liver toxin generally results from low, and apparently harmless,
inhalation over many years. As a breakdown in the liver structure occurs, i.e. cirrhosis, liver functions are impaired. Stomach pains, vomiting and jaundice are typical symptoms.
Tetrachloromethane (CTC).
CTC (carbon tetrachloride) is cited as a substance with a carcinogenic risk for humans.
There is, however, some doubt as to the direct ability of CTC to evoke a carcinogenic response
on its own. Many references to CTC list the substance as a co-carcinogen, i.e. it has the ability to
assist another compound to evoke a carcinogenic response.
CTC has the ability to cause narcosis in the same way as TCE and the symptoms are similar.
As well as affecting the brain (CNS) and the liver, CTC causes injury to the kidneys. There is evidence to suggest that the kidneys are more vulnerable to attack than the liver.
CTC has been used in the past in portable fire extinguishers, a wax polish solvent and a general
degreasing agent. It is still used for certain chemical manufacturing processes, e.g. fluoroalkanes
used for aerosol propellants.
Other chlorinated hydrocarbons that may be encountered are 1,1-trichloroethane (genklene),
sym-tetrachloroethane, trichloromethane (chloroform), and tetrachloroethylene (perchloroethylene).

4.9 Isocyanates
Organic di-isocyanate compounds are used to make adhesives, synthetic rubber, polyurethane
paints and lacquers and quick-drying printing inks. Their most important application, however, is
in the manufacture of plastics, especially the flexible and rigid (poly) urethane foams.

A large number of di-isocyanates can be made, but only a few have important industrial applications:
Hexamethylene di-isocyanate (HDI) was the first to be used, but this aliphatic isocyanate is very
volatile and was found to cause significant respiratory problems, following which it was withdrawn
from use in Great Britain when a suitable alternative was found.
This was toluene di-isocyanate (TDI), an aromatic compound; but this, in turn, was eventually
found to be responsible for severe respiratory problems because of its irritant effect. However,
TDI is still widely used in the manufacture of flexible foams and paints; it presents a severe hazard to fire fighters.
A more recent introduction, with virtually no vapour hazard, is methane diphenyl isocyanate
(MDI).
Effects and Symptoms.
Of the commonly used isocyanates, both HDI and TDI act as irritants and allergens.
Irritant effects include rhinitis (inflammation of the mucous membrane of the nose), pharyngitis
(inflammation of the part of the throat immediately beyond the mouth), bronchitis, and, in cases of
excessive exposure, bronchiolitis obliterans.
In most cases, the symptoms and signs clear rapidly after the worker is removed from contact
with the isocyanate.
But in many of those who have shown a quick initial recovery, the symptoms have recurred, often
violently, after further contact with even very low concentrations of isocyanate (a condition known
as sensitisation).
Others are known to suffer from a chronic form of asthma, particularly in cold weather, and have
to depend on bronchodilator inhalations to ameliorate the symptoms.

4.10 Polycyclic Aromatic Hydrocarbons

Cancer of the skin is associated with processes where workers come in contact with substances
containing a group of chemicals called polycyclic aromatic hydrocarbons (PCH).
They have within their structure benzene rings, they are joined or fused together and they only
contain the atoms of carbon and hydrogen.
A well-known member of the series is benzo(a)pyrene (1,2-benzpyrene), the structure of which is
shown in Figure 4.3.

Figure 4.3
There are, however, many such compounds, and a large number have been listed as having carcinogenic potential. They will always be found together in mixtures having a varying level of concentration.
Recent evidence suggests that the carcinogenic potential of PCH is enhanced by a very small
concentration of extremely potent PCH containing atoms of sulphur in its structure.
Occupations or Processes at Risk.
The following is a list of processes or occupations where workers are at risk from PCH mixtures:
Coke ovens.
Patent fuel manufacture.
Distillation of coal tar.
Bitumen-felt production and uses (e.g. roofing).

Automatic lathe worker.

Lubrication of machinery.
Petroleum workers.
Road workers (laying tarmac).
Underground telephone electricity linesmen (making waterproof pitch joints).
Secondary exposure can occur from petrol or diesel engine exhaust fumes and the burning of
carbonaceous materials, e.g. coal, oil or domestic refuse, especially on rubbish tips.
The types of materials commonly associated with these processes are coal tar, pitch, asphalt,
creosote and mineral oils.
Effects and Symptoms.
The substances mentioned are all skin irritants. You will remember that oils and greases can
cause non-infective dermatitis; the same is true for coal tar, pitch or creosote.
Following long periods of exposure, the irritant effect develops into more serious conditions where
benign andmalignant growths may be formed.
The growths occur as small lumps with a wart-like appearance, hence the name 'tar wart'. In the
early stages of the growth, it is very likely to be of benign nature, but if it goes untreated, it will
eventually become malignant.
Where the wart-like growths develop after only short exposures, recovery from the condition is
likely to be complete, especially if exposure ceases.
Where the growths take a long time to develop, the progression to the malignant state is more
likely. Due to the latency period, the condition can develop long after exposure has ceased. With
the development of the malignant state, the wart becomes ulcerated.
Skin cancer is described as squamous celled carcinoma. This means that the disease is involved
with the cellular structure associated with the epithelium. In the skin, these cells are found in the
lower levels of the epidermis, between the dermis and the horny keratinised outer layer. This type
of skin cancer can occur all over the body, but is usually confined to the main regions of exposure.
Main Body Regions Associated with Skin Cancer.
The main regions where skin cancer develops are generally related to the type of occupation to
which the person belongs:
For shale oil workers, the growth commonly occurs on the arms, but cancer of the scrotum may
also develop.
For persons working in the cotton industry with mule spinners, cancer of the scrotum is the usual
site of the disease, as in the case of persons working on automatic lathes or involved with lubricating machinery.
Where carbonaceous mixtures and their fumes are involved, the condition can develop over a
wider region, e.g. someone on a patent fuel plant could develop skin cancer on the eyelids, face,
neck, arms, thighs, scrotum or behind the ears.

4.11 Mineral Oils

Cancer of the scrotum occurs mainly in workers who are exposed to mineral oils which, by the
nature of the process they operate, cause their clothes to become heavily contaminated over the
thigh region.
Wart-like lumps are produced, which develop into painful sores; if the condition is allowed to develop, the lesion will spread and cause objectionable odours from the decaying flesh around the

ulcerated condition.
Without medical intervention, tumours will spread to the testicle, spermatic chord and into the abdomen. For many, the condition has been fatal. During the time leading up to death, considerable
weight loss and pain can occur.
If early diagnosis of the condition is made, then, as with other skin cancers, recovery from the
condition becomes possible. Better still, the condition can be avoided if sufficient care is taken to
'design out' conditions that allow a worker to become saturated with oil.
When there is a possibility of oil contamination of the genital area, the workers must be made fully
aware of the potential risk, and be provided with special personal hygiene facilities, i.e. regular
use of clean working clothes and underwear, with special washing facilities.
To overcome possible reticence in reporting adverse genital conditions, compulsory medical inspections must be adopted as a back-up service.

4.12 Vinyl Chlorides

Occupationally, exposure to vinyl chloride is linked to angiosarcoma of the liver, the name given
to malignant tumours which form in the cells lining blood vessels. It is a very rare condition, which
can occur in any blood vessel, but as occupational diseases, only tumours of this type in the liver
are of any significance.
Vinyl chloride monomer (VCM) is a small unsaturated chlorinated ethene compound, CH2:CHCl
(chloroethyene) and is the basic monomer used for the production of polyvinylchloride polymers.
The main victims have all been exposed to high concentrations of the vapour when carrying out
cleaning operations in polymerisation vessels, but some workers were only concerned with other
manufacturing processes.
Entry into the body is believed to be by inhalation into the lungs, followed by absorption into the
blood. The absorbed vapours are then deposited in the liver where biochemical reactions involve
the material in liver metabolism. Experimental data on humans have found that very little of the
VCM inhaled is expired from the body.
There is no evidence of absorption into the body via skin contact.
Symptoms.
In its early stages, only minor liver function abnormalities are experienced. The condition is only
identified by exhaustive liver function tests. Liver enlargement can be detected and a high blood
pressure in the portal vein (portal hypertension) can occur. This can lead to leakage of fluid (oedema) into the abdominal cavity. Serious bleeding into the gastrointestinal tract from ruptured
blood vessels has also occurred in some cases.
The tumours eventually invade the whole liver and the victim dies. Secondary growths resulting
from the original growth form widely as the disease progresses. There is no known cure.
Due to the relatively few deaths from the disease, no accurate latency period for the disease has
been established; from reported cases, an average of about 15 years can be calculated, although
the range is from 4 to 28 years.
Occupations at Risk.
The main victims of this disease are workers on the polymerisation plants using VCM. One case
has been reported of a worker involved in the production of VCM, and three cases involved workers concerned with compounding and related processes.

There is no evidence that the polymerised material, polyvinylchloride (PVC), has any carcinogenic potential, except where there may be residues of VCM in the material. No VCM has been
detected in PVC which has been decomposed.
Other Harmful Effects of Vinyl Chloride.
Having discussed the carcinogenic properties of vinyl chloride, it is appropriate to review the other
harmful effects produced by this material:
Sclerotic skin changes: a marked hardening in the skin involving changes in the collagen fibres.
Osteoporosis: loss of calcium from the bones. It occurs in the bones of the fingers, hands and
wrists, but has also been reported in certain bones in the pelvic girdle.
Reynaud's Disease: a condition related to circulatory problems in the fingers. In this case, it is not
induced by vibration.
Thrombocytopenia: a reduction in the number of thrombocytes in the blood, which reduces the
ability of blood to form clots; extensive bleeding occurs in open wounds and excessive bruising is
caused by relatively light knocks to the body.
Fibrosis of the liver: mainly concerned with fibrotic changes in the portal vein.
Impaired liver function: identified by abnormal results from blood and urine tests.
Impaired lung function: associated with fibrotic changes in the delicate tissue sections of the lung.
It causes reduced efficiency in gaseous exchange.
Narcosis: caused by inhalation of high concentrations of vinyl chloride. Fat-soluble compounds
have the characteristic action of depressing the central nervous system and producing narcosis.
The level of the effect is related to the extent that the substance dissolves in brain tissue. Vinyl
chloride vapour was once considered as a human anaesthetic. Fortunately, there is no record of
its general use.

4.13 MbOCA (2,2 Dichloro-4,4 Methylene Dianiline).

MbOCA is used as a curing agent with isocyanate-containing polymers to make abrasionresistant urethane rubbers and moulded semi-rigid polyurethane foam articles with a hardened
skin.
These materials are used in a wide range of products such as wheels, rollers, conveyor pulleys,
cable connectors and seals, anti-vibration mounts, etc.
It is manufactured in the UK by the reaction of formaldehyde with o-chloroaniline; some is also
imported. When pure, MbOCA is a colourless crystalline solid. The commercial grades are yellow-brown and may contain small quantities of o-chloroaniline and polyamines. MbOCA and its
salts are classified as toxic, to be labelled with the risk phrases R45: 'May cause cancer' and
R22: 'Harmful if swallowed'.
Toxicity.
MbOCA has low acute toxicity when administered orally, but gives positive results in tests for
mutagenicity, so MbOCA or its metabolites may cause genetic damage in certain organisms.
In addition, long-term oral administration has been shown to produce an increase in the incidence
of tumours over those seen in controls. Also, long-term subcutaneous administration in rats resulted in liver and lung tumours. As a consequence, MbOCA is regarded as an animal carcinogen.
There is not enough information available to assess the human toxicity of MbOCA following either
acute or repeated exposure. An epidemiological study of exposed workers did not reveal any evidence of cancers attributable to MbOCA exposure. However, it could be argued that this study
was limited by lack of information on exposure levels and duration of exposure.

Carcinogenicity.
In view of the above comments, MbOCA is considered genotoxic and an animal carcinogen. The
mechanisms suggested for carcinogenicity seen in animal studies are related to metabolic processes in the human liver; related substances, which are known human carcinogens, are believed
to act by similar metabolic pathways.
Consequently, MbOCA is regarded as carcinogenic to humans. A no-effect level has not been
established, and skin absorption may account for a significant proportion of uptake. Due to these
uncertainties, a Workplace Exposure Limit (WEL) has been set, with skin designated as the potential absorption route.
This indicates the difficulty in interpreting toxicological data and extrapolating the findings to set
exposure standards for humans. The WEL set for MbOCA represents a compromise between
cautious interpretation of the available toxicological data and standards of exposure which industry can realistically achieve.

4.14 Corrosive and Irritant Hazards

The following are some of the corrosive and irritant substances which may be encountered in the
course of industrial processes:
Cement.
Acids.
Sulphuric acid (H2SO4); hydrochloric acid (HCl); nitric acid (HNO3); phosphoric acid (H3PO4).
Alkalis.
Sodium hydroxide (caustic soda) (NaOH); potassium hydroxide (caustic potash) (KOH).
Gases, Vapours.
Tetrachloromethane (CCl4): gives off an irritant vapour, with corrosive and toxic effect.
Monochloroacetic acid (CH2Cl.COOH): a corrosive acid which can cause serious chemical burns
when it comes into contact with the skin or eyes, and also emits harmful vapours.
Chlorine: a greenish yellow gas with a choking, irritating smell; it is very poisonous, even if inhaled in a very small quantity.
All corrosive chemicals can produce, under the correct conditions, damaging corrosive vapours.

4.15 Cement
Cement is widely used in construction. Anyone who uses cement (or anything containing cement,
such as mortar, plaster and concrete) or is responsible for managing its use should be aware that
it presents a hazard to health.
Health effects.
Cement can cause ill-health mainly by:
Skin contact;
Inhalation of dust; and
Manual handling.

Skin contact.
Contact with wet cement can cause both dermatitis and burns.
Dermatitis.
Skin affected by dermatitis feels itchy and sore, and looks red, scaly and cracked. Cement is capable of causing dermatitis by two mechanisms - irritancy and allergy.
Irritant dermatitis is caused by the physical properties of cement that irritate the skin mechanically. The fine particles of cement, often mixed with sand or other aggregates to make mortar or
concrete, can abrade the skin and cause irritation resulting in dermatitis. With treatment, irritant
dermatitis will usually clear up. But if exposure continues over a longer period, the condition will
get worse and the individual is then more susceptible to allergic dermatitis.
Allergic dermatitis is caused by sensitisation to the hexavalent chromium (chromate) present in
cement. The way this works is quite distinct from that of irritancy. Sensitisers penetrate the barrier
layer of the skin and cause an allergic reaction. Hexavalent chromium is known to be the most
common cause of allergic dermatitis in men.
Research has shown that between 5% and 10% of construction workers may be sensitised to
cement and that plasterers, concreters and bricklayers are particularly at risk. Once someone has
become sensitised to hexavalent chromium, any future exposure may trigger dermatitis. Some
skilled tradesmen have been forced to change their trade because of this. The longer the duration
of skin contact with a sensitiser, the more it will penetrate the skin and the greater the risk of sensitisation will become. Therefore, if cement is left on the skin throughout the working day, rather
than being washed off at intervals, the risk of contact sensitisation to hexavalent chromium will be
increased. Both irritant and allergic dermatitis can affect a person at the same time.
Wet cement can cause burns. The principal cause is thought to be the alkalinity of the wet cement. If wet cement becomes trapped against the skin, for example by kneeling in it or if cement
falls into a boot or glove, a serious burn or ulcer can rapidly develop. These often take months to
heal, and in extreme cases will need skin grafts or can even lead to amputation. Serious chemical
burns to the eyes can also be caused following a splash of cement.
Inhalation of dust.
High levels of dust can be produced when cement is handled, for example when emptying or disposing of bags. In the short term, exposure to high levels of cement dust irritates the nose and
throat. Scabbling or concrete cutting can also produce high levels of dust which may contain silica.
Manual handling.
Working with cement also poses risks such as sprains and strains, particularly to the back, arms
and shoulders from lifting and carrying cement bags, mixing mortar etc. More serious damage to
the back can be caused in the long term if workers are continually lifting heavy weights.
Skin contact.
You should first consider using elimination or substitution to prevent the possibility of contact with
cement. Otherwise, you should apply control measures which minimise contact with the skin either directly or indirectly from contaminated surfaces in the working environment. An important
way of controlling cement dermatitis is by washing the skin with warm water and soap, or other
skin cleanser, and drying the skin afterwards. Sinks should be large enough to wash the forearms
and have both hot and cold (or warm) running water. Soap and towels should be provided. Facilities for drying clothes and changing clothes should also be available.

Gloves may help to protect skin from cement, but they may not be suitable for all aspects of construction site work. Caution is advised when using gloves as cement trapped against the skin inside the glove can cause a cement burn. You should provide protective clothing, including overalls with long sleeves and long trousers.
Employers are required to arrange for employees to receive suitable health surveillance where
there is exposure to a substance known to be associated with skin disease and where there is a
reasonable likelihood that the disease may occur. This means you should provide health surveillance for workers who will be working with wet cement on a regular basis.
Health surveillance is needed to:
Protect individuals;
Identify as early as possible any indicators of skin changes related to exposure, so that steps can
be taken to treat their condition and to advise them about the future; and give early warning of
lapses in control.
Health surveillance must never be regarded as reducing the need to control exposure or to wash
cement off the skin.
Simple health surveillance will usually be sufficient. Skin inspections should be done at regular
intervals by a competent person, and the results recorded. Employers will probably need the help
of an occupational health nurse or doctor to devise a suitable health surveillance regime and they
will need to train a 'responsible person', for instance a supervisor, to carry out the skin inspections.
A responsible person is someone appointed by the employer who, following instruction from an
occupational health physician or nurse, is competent to recognise the signs and symptoms of
cement-related dermatitis. The responsible person should report any findings to the employer,
and will need to refer cases to a suitably-qualified person (e.g. an occupational health nurse).
The employer must keep health records containing the particulars set out in the Appendix to the
General COSHH Approved Code of Practice. Employers are also required to provide employees
with information, instruction and training on the nature of the risk to health, and the precautions to
be taken.
This should include characteristic signs and symptoms of dermatitis.
Employees should be encouraged to examine their own skin for any such signs and report them.
Reports should be made to the 'responsible person' or to the occupational health nurse.

4.16 Ammonia
Ammonia is a colourless gas with a pungent odour, readily soluble in water, with which it forms
ammonium hydroxide (NH4OH).
It is used as a refrigerant, in petrol refining, metallurgy, water purification, fertilisers, and in the
manufacture of many drugs and chemicals.
Ammonia Burns.
Burns, which may be severe and even fatal, may follow splashing of ammonia onto the skin.
If ammonia gets into the eyes, there is an immediate effect on the conjunctiva, causing severe
pain. Ulceration of the conjunctiva and cornea, scarring of the tissues and lenticular opacity may
interfere with vision, even causing blindness. Apparatus to irrigate the eyes with water must
therefore be installed wherever the hazard of splashing with ammonia exists, although goggles/face masks should always be worn. Irrigation must be promptly applied and continued for at
least an hour.
Effects and Symptoms.
One of the largest and best documented cases of ammonia poisoning occurred on 11th September, 1940 when 75 people were overcome in the cellars of the Wenlock Brewery, London, used
as an air-raid shelter. Debris from an explosion fell on the refrigeration plant, causing it to leak

ammonia gas.
Those farthest from the leak were the least affected, with smarting of the eyes and mouth, accompanied by pain on swallowing. All were hoarse and could hardly raise their voices above a
whisper, and there was a strong smell of ammonia on the breath. The lips, mouth and tongue
were reddened and raw; the conjunctiva and eye-lids were red and swollen.
The group with moderate exposure additionally complained of a feeling of tightness in the chest,
difficulty in swallowing, coughing and sometimes blood-stained sputum. Moist sounds were present in the lungs, and several developed ulcers in the buccal mucosa and cornea. Some developed oedema of the lungs (liquidity) within six hours and the overall fatality rate of this group was
22%.
Survivors rapidly recovered a semblance of normal health, although hoarseness only cleared up
over a number of weeks.
Preventive Measures:
All equipment containing ammonia should be tested and inspected regularly, and any necessary
repairs effected immediately.
Detectors should be fitted to operate at well below the occupational exposure limit (25 ppm LTEL,
8-hour TWA; 35 ppm STEL, 15 minutes), with control valves placed outside the building.
Gas-masks/canister respirators must be provided and stored in a readily accessible locality.
Employees must be instructed as to the dangers, and trained in how to avoid them.
Every workman engaged in repair or maintenance work must carry a gas-mask in case of an escape of gas.
No work should be attempted on ammonia plant without initiating a permit-to-work.
Some other gases having a high hazard potential are:
Sulphur dioxide (SO2)
Sulphur trioxide (SO3)
Nitrogen dioxide (NO2 and N2O4)
Nitrous oxide (N2O)
Nitric oxide (NO)
Chlorine (Cl2)
Phosgene (COCl2)

4.17 Chromium
Chrome.
Air contaminated with chromic acid mist, or with dust from chromates or dichromates, is the principal source of harmful exposure in industry.
Chromium plating is carried out using an electrolyte containing about 50% chromic acid and, during electrolysis, reddish-brown fumes of chromic acid are forced off in the form of mist by the evolution of bubbles of hydrogen at the cathode.
Anodising, a coating highly resistant to corrosion is formed on aluminium and its alloys through
the anodic oxidation of aluminium. Again, chromic acid is used as the solution in which anodising
is carried out, and the hydrogen liberated at the cathode carries significant quantities of chromic
acid mist into the atmosphere. It is this chromic acid, and any dissolved salts of chromium it contains, that are responsible for the dermatitis, ulceration and even lung cancer.
Dermatitis and Chrome Ulcers.
Lesions of the skin due to chromium salts have been known since 1827 when it was found as
chrome holes on the fingers of bichromate workers in Glasgow.
It has since been established that both chromates and bichromates of sodium and potassium,
together with chromic acid, may cause either dermatitis or localised ulceration.
Exposure to these substances occurs in chromium plating, French polishing, calico printing, pho-

tographic processing, litho-etching, chrome tanning and colour workers.

Typically, dermatitis develops on exposed parts of the body such as the hands, arms, chest or
face. Onset is often sudden, occurring sometimes after an exposure of several months and, in
severe cases, the face becomes intensely red and swollen, with the affected parts itching a great
deal and perhaps becoming painful. There is some evidence that fair-headed/skinned people are
particularly prone to chrome dermatitis, and their presence at chrome operations calls for particular care.
Chrome ulcers are thought to begin in abrasions in the skin and are most commonly found at the
foot of the finger-nail, the knuckle of the hand, or dorsum (top) of the foot. They are circular in
shape, up to one centimetre in diameter and look as if they are punched out, hence 'chrome hole'.
Some penetrate deeply, even to the bone and, although usually painless, they itch incessantly,
especially at night. In chromium plating and anodising, where chromic acid fumes are frequently
present, inhalation leads to perforation of the nasal septum. This effect has even been reported in
people spray painting anti-corrosive zinc chromate-based paints.
Cancer of the Lung.
The first reported case of cancer of the respiratory system in a chrome worker occurred in a 47year old man who had worked in the chromate industry in Scotland (1890).
Since then, it has been established that the incidence of lung cancer is about 3.6 times that of the
'normal' population, but with a latency period of about 25 years, this figure for risk may be an underestimate.
Preventive Measures.
Prevention of chrome-related diseases depends primarily on the removal of the dust or mist at
source by suitable ventilation equipment; cleanliness, supported by regular medical supervision,
and covering cuts and abrasions with suitable dressings.
Where contact with the arms or hands is likely, then workers should be supplied with adequate
protective equipment, including gloves, aprons and boots; but great care needs to be taken to
ensure that solutions cannot run down the arms or legs and into the protective clothing, or severe
ulceration may result.
Good hygiene is particularly important, and should be encouraged by the provision of ample
washing facilities backed up with good care of the hands, using barrier creams and lanolin-based
creams.

4.18 Wood Dust

Wood dust consists of tiny particles of wood produced during the processing and handling of
wood, chipboard, hardboard and other composite boards. The elimination or control of risks from
wood dust is required by the Health and Safety at Work etc Act 1974, the Dangerous Substances
and Explosive Atmospheres Regulations 2002 (DSEAR) and the Control of Substances Hazardous to Health (COSHH) Regulations 2002.
Activities likely to produce high dust levels include:
Machining operations, particularly sawing, routing and turning;
Sanding, by machine and by hand;
Using compressed airlines to blow dust off furniture and other articles before spraying;
Hand assembly of machined/sanded components;
Any operations involving composite boards, eg medium-density fibreboard (MDF);
The bagging of dust from dust extraction systems; and
Factory cleaning, especially if compressed airlines are used for blowing dust from surfaces etc.
What are the hazards?
Health.

The following health problems are among the effects associated with exposure to wood dust:
Skin disorders;
Obstruction in the nose, and rhinitis;
Asthma;
A rare type of nasal cancer.
Regulation 6(1) of the COSHH Regulations2,4 requires an assessment to be made (and normally
recorded) of risks to health associated with wood dust, together with any action needed to prevent or control those risks.
Regulation 7(1) goes on to say that exposure to wood dust should be prevented, or where this is
not reasonably practicable, adequately controlled.
Hardwood dust and softwood dust have been assigned maximum exposure limits (MELs) of 5
mg/m3 (8-hour time-weighted average) under the COSHH Regulations. Therefore exposure by
inhalation to wood dust should be reduced so far as is reasonably practicable and in any case
below the MEL. In COSHH, hardwood dust is defined as a carcinogen.
Regulations 7(3) and 7(5) specify additional requirements for the control of carcinogens.
Precautions.
If exposure to wood dust cannot be prevented altogether, then assess the risk to health from exposure to airborne dust by:
Finding out if exposure to dust is being adequately controlled in your workplace.
A dust lamp can be used to show up the dust and where it is coming from; where necessary carrying out dust sampling7 (your trade association should be able to give advice on organisations
which can do this) and determining whether workers will be exposed to airborne dust levels in
excess of the MEL.
Exposure to airborne dust may be adequately controlled by:
Using a process or method of work that reduces the generation of dust to a minimum;
Providing dust control equipment to all dust producing processes to stop the dust entering the
workroom atmosphere, eg local exhaust ventilation at woodworking machines; and
Making sure that plant and equipment is properly maintained.
Keep ventilation ducts free from blockages and repair broken or damaged ducts. Maintain filter
units and other plant equipment regularly in accordance with the manufacturer's recommendations and COSHH.
Where measures taken to reduce exposure to airborne dust are inadequate, then in addition suitable10 respiratory protective equipment must be provided and used. It should be selected from
equipment that carries the European Community mark of conformity (the CE mark) and be appropriate to adequately control the exposure to the substance creating the risk.
Provide other personal protective equipment, such as eye protection, overalls and gloves, where
necessary. Make sure it is suitable12 and kept in good order. Launder overalls and aprons regularly.
Provide good washing facilities with hot and cold water, soap and towels and encourage a high
standard of personal hygiene.
Provide vacuum cleaning equipment to remove dust from clothing, where this is a problem. Prevent the use of compressed airlines for this purpose.
Make sure workers are adequately informed, instructed, trained and supervised. This is essential
if they are to understand the precautions and their duties and responsibilities

4.19 Nickel
Nickel carbonyl, also known as tetracarbonylnickel, is the organonickel compound with the
chemical formula Ni(CO)4. This pale-yellow metal carbonyl is very volatile at room temperature

and highly toxic. Nickel Carbonyl can be used to nickel-coat steel and other metals and to make
very pure nickel. It is an intermediate in the Mond process for the purification of nickel and is a
reagent in organometallic chemistry.
Toxicology and safety considerations.
Ni(CO)4 is highly hazardous, much more so than implied by its CO content, reflecting the effects
of the nickel if it were released in the body. Nickel carbonyl may be fatal if absorbed through the
skin or more likely, inhaled due to its high volatility. Its LC50 for a 30-minute exposure has been
estimated at 3 ppm, and the concentration that is immediately fatal to humans would be 30 ppm.
Some subjects exposed to puffs up to 5 ppm described the odour as musty or sooty, but since the
compound is so exceedingly toxic its smell provides no reliable warning against a potentially fatal
exposure.
Historically, laboratories that used Ni(CO)4 would keep a canary in the lab as an indicator of
nickel carbonyl toxicity, due to the higher sensitivity of birds to this poison.
Human systemic effects by inhalation:
Somnolence,
Fever, and
Other pulmonary changes.
Vapours may cause:
Coughing,
Dyspnea (difficult breathing),
Irritation,
Congestion and oedema of the lungs,
Tachycardia (rapid pulse),
Cyanosis,
Headache,
Dizziness, and
Weakness.
Toxicity by inhalation is believed to be caused by both the nickel and carbon monoxide liberated
in the lungs. Chronic exposure may cause cancer of lungs or nasal sinuses.
Sensitisation dermatitis is fairly common. It is considered the most hazardous compound of nickel
in the workplace. It is lipid-soluble and can cross biological membranes (e.g., lung alveolus,
blood-brain barrier, placental barrier).
The vapours of Ni(CO)4 can autoignite.
Nickel carbonyl poisoning is characterised by a two-stage illness. The first consists of headaches
and chest pain lasting a few hours, usually followed by a short remission. The second phase is a
chemical pneumonitis which starts after typically 16 hours with symptoms of cough, breathlessness and extreme fatigue. These reach greatest severity after four days, possibly resulting in
death from cardiorespiratory or renal failure. Convalescence is often extremely protracted, often
complicated by exhaustion, depression and dyspnea on exertion. Permanent respiratory damage
is unusual. The carcinogenicity of Ni(CO)4 is a matter of debate.
Nickel carbonyl vapor decomposes quickly in air, lasting only about a minute.

4.20 Siliceous Dust

Inhaling finely divided crystalline silica dust in very small quantities over time can lead to silicosis,
bronchitis, or cancer, as the dust becomes lodged in the lungs and continuously irritates them,
reducing lung capacities. (In the body crystalline silica particles do not dissolve over clinically
relevant periods of time.) This effect can create an occupational hazard for people working with
sandblasting equipment, products that contain powdered crystalline silica and so on. Children,
asthmatics of any age, allergy sufferers, and the elderly (all of whom have reduced lung capacity)

can be affected in much less time. Amorphous silica, such as fumed silica is not associated with
development of silicosis, but may cause irreversible lung damage in some cases. Laws restricting
silica exposure with respect to the silicosis hazard specify that they are concerned only with silica
that is both crystalline and dust-forming.
Silicosis, also known as Potter's rot, is a form of occupational lung disease caused by inhalation
of crystalline silica dust, and is marked by inflammation and scarring in forms of nodular lesions in
the upper lobes of the lungs. It is a type of pneumoconiosis.
Silicosis (particularly the acute form) is characterized by shortness of breath, cough, fever, and
cyanosis (bluish skin). It may often be misdiagnosed as pulmonary edema (fluid in the lungs),
pneumonia, or tuberculosis.
The name silicosis (from the Latin silex, or flint) was originally used by Visconti in 1870. The recognition of respiratory problems from breathing in dust dates to ancient Greeks and Romans. Agricola, in the mid-16th century, wrote about lung problems from dust inhalation in miners. In 1713,
Bernardino Ramazzini noted asthmatic symptoms and sand-like substances in the lungs of stone
cutters. With industrialization, as opposed to hand tools, came increased production of dust. The
pneumatic hammer drill was introduced in 1897 and sandblasting was introduced in 1904, both
significantly contributing to the increased prevalence of silicosis.
Classification of silicosis is made according to the disease's severity (including radiographic pattern), onset, and rapidity of progression. These include:
Chronic simple silicosis
Usually resulting from long-term exposure (10 years or more) to relatively low concentrations of
silica dust and usually appearing 1030 years after first exposure. This is the most common type
of silicosis. Patients with this type of silicosis, especially early on, may not have obvious signs or
symptoms of disease, but abnormalities may be detected by x-ray. Chronic cough and exertional
dyspnea are common findings. Radiographically, chronic simple silicosis reveals a profusion of
small (<10 mm in diameter) opacities, typically rounded, and predominating in the upper lung
zones.
Accelerated silicosis
Silicosis that develops 510 years after first exposure to higher concentrations of silica dust.
Symptoms and x-ray findings are similar to chronic simple silicosis, but occur earlier and tend to
progress more rapidly. Patients with accelerated silicosis are at greater risk for complicated disease, including progressive massive fibrosis (PMF).
Complicated silicosis
Silicosis can become "complicated" by the development of severe scarring (progressive massive
fibrosis,or also known as conglomerate silicosis), where the small nodules gradually become confluent, reaching a size of 1 cm or greater. PMF is associated with more severe symptoms and
respiratory impairment than simple disease. Silicosis can also be complicated by other lung disease, such as tuberculosis, non-tuberculous mycobacterial infection, and fungal infection, certain
autoimmune diseases, and lung cancer. Complicated silicosis is more common with accelerated
silicosis than with the chronic variety.
Acute silicosis
Silicosis that develops a few weeks to 5 years after exposure to high concentrations of respirable
silica dust. This is also known as silicoproteinosis. Symptoms of acute silicosis include more rapid
onset of severe disabling shortness of breath, cough, weakness, and weight loss, often leading to
death. The x-ray usually reveals a diffuse alveolar filling with air bronchograms, described as a
ground-glass appearance, and similar to pneumonia, pulmonary edema, alveolar hemorrhage,
and alveolar cell lung cancer.
Signs and symptoms.

Because chronic silicosis is slow to develop, signs and symptoms may not appear until years after exposure. Signs and symptoms include:
Dyspnea (shortness of breath) exacerbated by exertion
Cough, often persistent and sometimes severe
Fatigue
Tachypnea (rapid breathing) which is often labored
Loss of appetite and weight loss
Chest pain
Fever
Gradual dark shallow rifts in nails eventually leading to cracks as protein fibres within nail beds
are destroyed.
In advanced cases, the following may also occur:
Cyanosis (blue skin).
Cor pulmonale (right ventricle heart disease).
Respiratory insufficiency.
Patients with silicosis are particularly susceptible to tuberculosis (TB) infection-known as silicotuberculosis. The reason for the increased risk-3 fold increased incidence-is not well understood. It
is thought that silica damages pulmonary macrophages, inhibiting their ability to kill mycobacteria.
Even workers with prolonged silica exposure, but without silicosis, are at an increased risk (3-10
fold) for TB.
Pulmonary complications of silicosis also include Chronic Bronchitis and airflow limitation (indistinguishable from that caused by smoking), non-tuberculous Mycobacterium infection, fungal lung
infection, compensatory emphysema, and pneumothorax. There are some data revealing an association between silicosis and certain autoimmune diseases, including nephritis, Scleroderma,
and Systemic Lupus Erythematosus, especially in acute or accelerated silicosis.
In 1996, the International Agency for Research on Cancer (IARC) reviewed the medical data and
classified crystalline silica as "carcinogenic to humans." The risk was best seen in cases with underlying silicosis, with relative risks for lung cancer of 2-4. Numerous subsequent studies have
been published confirming this risk. In 2006, it was concluded that "The silicosis-cancer association is now established, in agreement with other studies and meta-analysis."
Pathophysiology.
When small silica dust particles are inhaled, they can embed themselves deeply into the tiny alveolar sacs and ducts in the lungs, where oxygen and carbon dioxide gases are exchanged.
There, the lungs cannot clear out the dust by mucous or coughing.
Furthermore, the surface of silicon dust can generate silicon-based radicals that lead to the production of hydroxyl and oxygen radicals, as well as hydrogen peroxide, which can inflict damage
to the surrounding cells.
Diagnosis.
There are three key elements to the diagnosis of silicosis. First, the patient history should reveal
exposure to sufficient silica dust to cause this illness. Second, chest imaging (usually chest x-ray)
that reveals findings consistent with silicosis. Third, there are no underlying illnesses that are
more likely to be causing the abnormalities. Physical examination is usually unremarkable unless
there is complicated disease. Also, the examination findings are no specific for silicosis. Pulmonary function testing may reveal airflow limitation, restrictive defects, reduced diffusion capacity,
mixed defects, or may be normal (especially without complicated disease). Most cases of silicosis
do not require tissue biopsy for diagnosis, but this may be necessary in some cases, primarily to
exclude other conditions.
For uncomplicated silicosis, chest x-ray will confirm the presence of small (< 10 mm) nodules in
the lungs, especially in the upper lung zones. Using the ILO classification system, these are of
profusion 1/0 or greater and shape/size "p", "q", or "r". Lung zone involvement and profusion increases with disease progression. In advanced cases of silicosis, large opacity (> 1 cm) occurs
from coalescence of small opacities, particularly in the upper lung zones. With retraction of the
lung tissue, there is compensatory emphysema. Enlargement of the hilum is common with

chronic and accelerated silicosis. In about 5-10% of cases, the nodes will calcify circumferentially,
producing so-called "eggshell" calcification. This finding is not pathognomonic (diagnostic) of silicosis. In some cases, the pulmonary nodules may also become calcified.
A computed tomography or CT scan can also provide a mode detailed analysis of the lungs, and
can reveal cavitation due to concomitant mycobacterial infection.
Prevention.
The best way to prevent silicosis is to identify work-place activities that produce respirable crystalline silica dust and then to eliminate or control the dust ("primary prevention"). Water spray is often used where dust emanates. Dust can also be controlled through dry air filtering.
Following observations on industry workers in Lucknow (India), experiments on rats found that
jaggery (a traditional sugar) had a preventive action against silicosis.
Treatment.
Silicosis is an irreversible condition with no cure. Treatment options currently focus on alleviating
the symptoms and preventing complications.
These include:
Stopping further exposure to silica and other lung irritants, including tobacco smoking.
Cough suppressants.
Antibiotics for bacterial lung infection.
TB prophylaxis for those with positive tuberculin skin test or IGRA blood test.
Prolonged anti-tuberculosis (multi-drug regimen) for those with active TB.
Chest physiotherapy to help the bronchial drainage of mucus.
Oxygen administration to treat hypoxemia, if present.
Bronchodilators to facilitate breathing.
Lung transplantation to replace the damaged lung tissue is the most effective treatment, but is
associated with severe risks of its own.
For acute silicosis, Whole-lung lavage (see Bronchoalveolar lavage) may alleviate symptoms, but
does not decrease overall mortality.
Epidemiology.
Occupational silicosis.
Silicosis is the most common occupational lung disease worldwide, it occurs everywhere but is
especially common in developing countries. From 1991 to 1995, China reported more than
24,000 deaths due to silicosis each year. In the United States, it is estimated that one million-two
million workers have had occupational exposure to crystalline silica dust and 59,000 of these
workers will develop silicosis sometime in the course of their lives.
Although silicosis has been known for centuries, the industrialization of mining has led to an increase in silicosis cases. Pneumatic drilling in mines and less commonly, mining using explosives, would raise rock dust. In the United States, a 1930 epidemic of silicosis due to the construction of the Hawk's Nest Tunnel near Gauley Bridge, West Virginia caused the death of at
least 400 workers. Other accounts place the mortality figure at well over 1000 workers, primarily
African American transient workers from the southern United States. Workers who became ill
were fired and left the region, making an exact mortality account difficult. The Hawks Nest Tunnel
Disaster is known as "America's worst industrial disaster. The prevalence of silicosis led some
men to grow what is called a miner's mustache, in an attempt to intercept as much dust as possible.
Chronic simple silicosis has been reported to occur from environmental exposures to silica in regions with high silica soil content and frequent dust storms.
Because of work-exposure to silica dust, silicosis is an occupational hazard to mining, sandblasting, quarry, ceramics and foundry workers, as well as grinders, stone cutters, refractory brick
workers, tombstone workers, pottery workers, and others. Brief or casual exposure to low levels
of crystalline silica dust are said to not produce clinically significant lung disease.

4.21 Sulphuric Acid

Sulphuric acid is a strong mineral acid with the molecular formula H2SO4. Sulphuric acid is soluble in water at all concentrations.
Sulphuric acid has many applications, and is a central substance in the chemical industry. Principal uses include lead-acid batteries for cars and other vehicles, ore processing, fertiliser manufacturing, oil refining, wastewater processing, and chemical synthesis.
Laboratory hazards
The corrosive properties of sulphuric acid are accentuated by its highly exothermic reaction with
water. Burns from sulphuric acid are potentially more serious than those of comparable strong
acids (e.g. hydrochloric acid), as there is additional tissue damage due to dehydration and particularly secondary thermal damage due to the heat liberated by the reaction with water.
The danger is greater with more concentrated preparations of sulphuric acid, but even the normal
laboratory "dilute" grade (approximately 1 M, 10%) will char paper by dehydration if left in contact
for a sufficient time. Therefore, solutions equal to or stronger than 1.5 M are labeled "CORROSIVE", while solutions greater than 0.5 M but less than 1.5 M are labeled "IRRITANT". Fuming
sulphuric acid (oleum) is not recommended for use in schools as it is quite hazardous.
The standard first aid treatment for acid spills on the skin is, as for other corrosive agents, irrigation with large quantities of water. Washing is continued for at least ten to fifteen minutes to cool
the tissue surrounding the acid burn and to prevent secondary damage. Contaminated clothing is
removed immediately and the underlying skin washed thoroughly.
Preparation of the diluted acid can also be dangerous due to the heat released in the dilution
process. The concentrated acid is always added to water and not the other way round, to take
advantage of the relatively high heat capacity of water. Addition of water to concentrated sulphuric acid leads to the dispersal of a sulphuric acid aerosol or worse, an explosion. Preparation
of solutions greater than 6 M (35%) in concentration is most dangerous, as the heat produced
may be sufficient to boil the diluted acid: efficient mechanical stirring and external cooling (such
as an ice bath) are essential.
On a laboratory scale, sulphuric acid can be diluted by pouring concentrated acid onto crushed
ice made from de-ionised water. The ice melts in an endothermic process while dissolving the
acid. The amount of heat needed to melt the ice in this process is greater than the amount of heat
evolved by dissolving the acid so the solution remains cold. After all the ice has melted, further
dilution can take place using water.
Industrial hazards.
Although sulphuric acid is non-flammable, contact with metals in the event of a spillage can lead
to the liberation of hydrogen gas. The dispersal of acid aerosols and gaseous sulphur dioxide is
an additional hazard of fires involving sulfuric acid.
Sulphuric acid is not considered toxic besides its obvious corrosive hazard, and the main occupational risks are skin contact leading to burns and the inhalation of aerosols. Exposure to aerosols
at high concentrations leads to immediate and severe irritation of the eyes, respiratory tract and
mucous membranes: this ceases rapidly after exposure, although there is a risk of subsequent
pulmonary edema if tissue damage has been more severe. At lower concentrations, the most
commonly reported symptom of chronic exposure to sulphuric acid aerosols is erosion of the
teeth, found in virtually all studies: indications of possible chronic damage to the respiratory tract
are inconclusive as of 1997. There have been reports of sulphuric acid ingestion leading to vitamin B12 deficiency with subacute combined degeneration. The spinal cord is most often affected
in such cases, but the optic nerves may show demyelination, loss of axons and gliosis.
Legal restrictions.
International commerce of sulphuric acid is controlled under the United Nations Convention
Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances, 1988, which lists sulfuric

acid under Table II of the convention as a chemical frequently used in the illicit manufacture of
narcotic drugs or psychotropic substances.

4.22 Sodium Hydroxide

Sodium hydroxide (NaOH), also known as lye and caustic soda, is a caustic metallic base. It is
used in many industries, mostly as a strong chemical base in the manufacture of pulp and paper,
textiles, drinking water, soaps and detergents and as a drain cleaner.
Pure sodium hydroxide is a white solid available in pellets, flakes, granules, and as a 50% saturated solution. It is hygroscopic and readily absorbs water from the air, so it should be stored in
an airtight container. It is very soluble in water with liberation of heat. It also dissolves in ethanol
and methanol, though it exhibits lower solubility in these solvents than does potassium hydroxide.
Solid sodium hydroxide or solutions of sodium hydroxide may cause chemical burns, permanent
injury or scarring if it contacts unprotected human, or other animal, tissue. It may cause blindness
if it contacts with the eye. Protective equipment such as rubber gloves, safety clothing and eye
protection should always be used when handling the material or its solutions.
Dissolution of sodium hydroxide is highly exothermic, and the resulting heat may cause heat
burns or ignite flammables. It also produces heat when reacted with acids. Sodium hydroxide is
corrosive to some metals, e.g. aluminum, which produces flammable hydrogen gas on contact.
Sodium hydroxide is also mildly corrosive to glass, which can cause damage to glazing or freezing of ground glass joints.

4.23 Solvents
Solvents are chemical substances. In construction products, they act as carriers for surface coatings such as paints, varnishes, adhesives and pesticides.
The most common solvents found in construction are:
White spirit - in paints, varnishes and cleaning products.
Xylene - in paints, adhesives and pesticides.
Butanol - in natural and synthetic resins, paints and lacquers.
Many construction products contain mixtures of solvents. Exposure to solvents can have serious
effects on workers' health. If you use solvents or manage or supervise someone who does, or if
you are involved in the specification of solvent-based products for use in construction, you need
to be aware that exposure can be a health hazard and safe working practices must be used to
minimise the risk of exposure.
Solvents can make you ill by:
Breathing in vapours - paints, paint strippers and glues give off solvent vapours as they dry or
cure and these vapours may be harmful. Deliberate inhalation of solvent vapours (glue sniffing)
can kill.
Skin contact - some solvents can be absorbed through the skin. Repeated or prolonged skin contact with liquid solvents may cause dermatitis.
Eye contact - contact with liquid solvent and solvent vapour can cause irritation and inflammation.
Ingestion - solvents can be taken into the body on contaminated food, drink and cigarettes.
People have accidentally drunk solvents that have been kept in old, unlabelled drinks containers.
The main effects of solvents are irritation of the skin, eyes and lungs, headache, nausea, dizziness and light headedness.
Exposure can impair co-ordination and this can make people more prone to accidents such as

falling off ladders. People may lose concentration on important or difficult tasks and they may react more slowly to dangerous situations. The effect can vary from person to person and will generally be made worse by drinking alcohol.
Very high exposures can cause unconsciousness and even death, for instance where adhesives
are used in unventilated confined spaces, or where there are serious spillages. Other possible
effects on health vary according to which solvent people are exposed to. Anyone who has been
exposed to solvents and feels that their health has been affected should seek medical advice
Work with solvent-based construction products is subject to the Control of Substances Hazardous
to Health Regulations 2002 (COSHH), which require the health risk to be assessed and then prevented or controlled. Users will find information on the hazards on the containers but they should
also get information (often as 'Hazard Data Sheets') from manufacturers and suppliers. Users
then need to consider how those hazards can be prevented or controlled.
Designers or people who specify products for use in construction have a duty under regulation 13
of the Construction (Design and Management) Regulations (CDM) to avoid risks to the health and
safety of those carrying out construction work. Where it is not possible to avoid the risk, they
should specify the least hazardous products which perform to an acceptable standard. If solventbased products cannot be avoided, the designer or specifier should provide information about
safe use.
Precautions.
Preventing exposure.
First of all, consider whether the solvent-based products need to be used at all. Can they be replaced by an alternative, less hazardous material? For example, use a water-based formulation if
possible; these are widely available.
Controlling exposure.
If solvent-based products are used, make sure the work area is well ventilated. Open doors, windows, roof lights etc to increase ventilation and make sure that they are kept open. Local exhaust
(mechanical) ventilation may be necessary in some cases.
If possible, avoid spraying solvent-based products, as this causes more vapour to get into the air
than using a brush.
Store solvents in properly labelled, suitable containers. Use dispensers where possible to keep
evaporation to a minimum and reduce spillage. Keep lids on containers unless contents are being
poured or dipped etc. Use sealed containers for solvent waste.
Dispose of solvent-soaked rags in closed containers.
Train workers in how to minimise exposure and in how to deal with spillages.
Spillages can lead to very high exposures and greatly increased fire risk. The risks from spillages
and the precautions needed to deal with them should be considered in a risk assessment before
the work starts.
Fire.
Many solvents are flammable. Take precautions to avoid fire and explosion risks; in particular, do
not smoke in areas where solvents are used. Store products containing solvents in a secure and
well-ventilated area.
Personal protective equipment (PPE).
If exposure cannot be adequately controlled in any other way, workers should wear PPE. They
may need to wear one or more of the following:
Protective overalls.
Appropriate gloves that have been specially selected for use with solvents.
Face shields.
Respiratory protective equipment, where ventilation does not provide adequate control.
Half-mask respirators fitted with the appropriate filter may be sufficient in many instances, but

compressed airline breathing apparatus may be necessary where solvents are sprayed, or when
working in a confined space.
Those who need to wear PPE should be trained in its proper use and in its limitations. Store the
equipment in clean, dry conditions away from chemicals - a locker would be suitable. PPE should
be maintained and kept clean and fit for wear.
Hygiene.
Good personal hygiene is very important. Facilities for washing and changing should be provided
and workers should wash their hands before eating, drinking, smoking and going to the toilet.
Eating, drinking and smoking should take place away from the work area. You should not smoke
in areas where solvents are used - solvents passing through a cigarette can break down into
even more harmful substances.
Articles which become heavily contaminated with solvent should be removed immediately. Overalls and contaminated personal clothing should be laundered before being re-worn. It may be
necessary to air them in a safe place first, to let the solvent evaporate off. Laundering should only
be done by professional cleaners who have been told of the nature of the contamination.
Thinners should not be used to remove paint or grease from the skin, as this can cause the skin
to become dry and inflamed. Proper cleaning materials, e.g. soap or other cleanser, should be
provided and used.
First aid.
Anyone who appears to have been affected by solvents should be taken into the fresh air immediately and given appropriate first-aid treatment. Heavily- contaminated clothing should be removed as soon as possible. Wash solvent splashes off the skin with plenty of water and cover
any wounds with a suitable dressing. Splashes of solvent in the eye should be treated by washing
the eye with water for at least 10 minutes before the injured person is transferred to hospital.
A variety of chemicals are used to clean building facades, statues, etc. These may be acid-based,
e.g. hydrochloric acid (HCI), hydrofluoric acid (HF), phosphoric acid (H3PO4), nitric acid (HNO3)
or alkali-based, for example caustic soda (sodium hydroxide -NaOH) or caustic potash (potassium hydroxide - KOH). Information is available that gives health and safety guidance for anyone
who uses these materials or is responsible for managing or supervising their use.
Health effects.
Chemical cleaners can cause serious ill health mainly by:
skin contact: acids and alkalis cause burns which are often slow to heal; and
Inhaling fumes or mist: concentrated solutions of acids and alkalis may give off toxic and corrosive fumes. Spray application produces a mist which may also be toxic and corrosive.
Concentrated solutions from which the dilute working solutions are made up pose the greatest
risk, but even dilute solutions can cause serious injury. This is particularly true of HF where skin
contact with diluted solution can cause very serious and extremely painful burns which may not
be felt until up to 24 hours after contact.

4.24 Lead
Lead.
Elemental lead is one of the heavy metals, having a relatively high density of 11.34 kg m-3 (most
other metal densities are below 9 kg m-3).
It is not a reactive metal, especially under average conditions. Being fairly soft and having a low
melting temperature of 600C, as well as being a relatively easy metal to extract from its principal
ore, lead sulphide, lead has provided mankind with a useful material of construction since early

times. Some lead figures are believed to have been made as early as 3800 BCE and lead beads
have been found at Catalhuyuk in Turkey, dating back to 6400 BCE. The use of lead in plumbing
systems was well established by the time of the Roman Empire; the Latin name for lead, plumbum nigrum, literally 'black soft metal' has given the English language the word 'plumber'.
Lead compounds have been, and are still being, used as raw materials in manufacturing processes, and as a material of construction.
They can be roughly categorised into inorganic lead, e.g. lead oxide in lead/acid batteries, lead
chromate (chrome yellow) red lead (Pb2O4) used for pigments (although its use is being reduced
and banned by some countries), and organic lead, e.g. petrol antiknock agent, lead tetraethyl
(Pb(C2H5)4), another product which will eventually be discontinued.
Mode of Entry.
Lead metal in its massive solid state has virtually no ability to be absorbed into the body by any of
the three normal modes of entry.
As a fume or very finely divided dust, lead inhalation becomes a serious risk as a potential mode
of entry. In this form, however, lead metal will almost certainly have been changed to lead oxide,
so the absorption reactions will not be truly representative of lead metal itself. Absorption by skin
contact or via the gastrointestinal tract has no occupational risk.
For inorganic lead compounds, inhalation of dusts generally poses the most serious situation.
Absorption by skin contact and ingestion is limited.
For organic lead compounds, inhalation and skin contact form the main occupational mode of entry for absorption into the body. Ingestion poses only a minor risk. The best example of an organic
lead compound is lead tetraethyl. It is highly volatile at normal temperature and passes easily
through the skin following skin contact.
When lead compounds are absorbed into the body, the inorganic compounds produce different
symptoms from the organo-lead compounds.
An important point to note about the entry of the element lead into the metabolism of the body by
occupationally-induced situations is that lead is also a ubiquitous substance in the natural world.
The element enters into our bodies in small but regular doses from the food we eat and the water
we drink.
As lead has no known beneficial effect in the metabolic process, it is not required and so any additional absorption of the element lead resulting from occupation is an added body burden.
Target Organs.
The target organs associated with lead intoxication are:
Central nervous system.
Gastrointestinal tract.
Blood and blood-forming organs.
Exterior (straightening) muscles of the wrist or foot.
The gums.
Lead becomes incorporated in bone structure where it accumulates, giving it a site where it can
become a cumulative toxin.
Effects and Symptoms.
Intoxication by inorganic lead compounds leads to general symptoms related to the gastrointestinal tract, the nervous system and the blood.

Acute intoxication, resulting in general from inhalation of high concentrations of lead fume or dust,
produces nausea, vomiting and headaches. This is often followed by constipation and severe intermittent colic. During the attack of colic, the victim becomes very pale, feels cold and may sweat
freely. If the brain becomes affected, then dullness, restlessness, tremor convulsion or coma may
develop.
When exposure has occurred over long periods and chronic intoxication takes place, other clinical
symptoms develop. The classical symptoms are headaches, anaemia, palsy (muscle weakness),
the appearance of a blue line on the gums and, very rarely, encephalopathy (changes in the
nerve output of the brain).
(i) The headache is related to adverse effects on brain activity.
(ii) Anaemia results from the interference by leaded metabolic substance in the synthesis of haemoglobin.
(iii) Palsy results from the paralysis of the motor neurones that control muscles. The particular
muscles concerned are those liable to fatigue due to occupational activity. "Wrist drop" was a
characteristic symptom where the conditions had been allowed to proceed untreated. "Foot drop"
has also been recorded. With better hygiene control, these conditions hopefully belong to occupational disease history.
The famous blue line on the gums associated with lead intoxication results from soluble lead
compounds being precipitated from the general circulation as lead sulphide in the gum region below the lower front teeth. The sulphide is a black compound but appears blue in the gum tissue.
The condition results from the reaction of lead ions with sulphide ions generated by microorganisms in gum tissue. The blue line is not a direct measure of lead intoxication, only an indication of the absorption of lead into the body's metabolism.
The depth of colour produced is, however, an indication of the duration and severity of the exposure to which the victim has been subjected.
The incorporation of lead into the body metabolism causes certain biochemical abnormalities to
occur. These effects are related to the impairment of haemoglobin synthesis. The particular effects are outside the requirements of this course, but you should note they are used in the diagnosis of lead intoxication.
One point of note is that the presence of lead can cause a breakdown of haemoglobin structure.
It can therefore be classified as a weak haemolitic toxin.
The concentration of lead compounds in the blood as a measure of lead intoxication must be
used with extreme caution. Lead is stored in the body from natural and possibly occupational input; the blood lead level generally indicates the state of the balance between the body and the
leaded bone store.
However, it has been shown that the balance can be upset and, under certain circumstances,
massive amounts of lead can be discharged into general circulation from the bone store. A raised
body temperature can cause this situation to occur.
Absorption of lead tetraethyl, or tetraethyl lead (TEL), as it is more accurately described, is a very
hazardous situation. The material is highly toxic in low atmospheric concentrations, and inhalation
of the vapour can have fatal consequences.
Its absorption into the body mainly affects the central nervous system. It produces restlessness, a
raised level of excitement and talkativeness, muscular twitching and possible delusions, acute
and violent mania. These conditions are accompanied by a fall in body temperature and a drop in
normal blood pressure.
Where the level of intoxication is lower, headaches, vertigo, fatigue, a sense of physical weakness, and insomnia with disturbing dreams are classic symptoms.

Encephalopathy is also associated with absorption of organic lead compounds.

In all cases, the severity of the effects of lead in the body depends upon the difference between
the level of absorption and that of excretion. The ratio of these two factors goes a long way to determining whether certain individuals are affected or not by the lead in their body.
Occupations and Persons at Risk.
The following list covers commonly occurring situations:
Lead smelting.
Lead chemical manufacture.
Lead/acid battery manufacture.
Shipyards.
Petrol manufacture and handling.
Plumbers.
Painters.
Welders.

4.25 Asbestos
It is generally accepted that the type of asbestos classified as crocidolite (blue asbestos) is the
causative agent for mesothelioma. It belongs to a group of inorganic crystalline fibrous silicates
generally called asbestos.
Mesothelioma is the name given to malignant tumours that develop in the pleura and the peritoneum. It is a very rare disease in normal circumstances. Where there has been exposure to asbestos, however, the possibility of developing the disease is markedly increased.
Evidence from many studies indicates that not only are the workers directly involved with the material at risk, but also those who work in the vicinity of its use.
The problem also affects the localities around the area where the material is used, and a high incidence of the disease often occurs in areas 'down wind' from factories involved with asbestos
products. The families of asbestos workers are also at risk, as cases have been reported where
wives and children have succumbed to the disease.
The risk of mesothelioma from the other types of asbestos in general use, i.e. amosite (brown
asbestos) and chrysotile (white asbestos), is considerably reduced, but there is a risk.
Asbestos Types - Crocidolite( Blue) Chrysotile (White) Amosite (Brown)
The mode of entry into the body is generally by inhalation into the lungs. Mesothelioma of the
pleura occurs when the asbestos fibres have migrated through the lung structure into the pleura,
where they can remain undisturbed until they trigger off this sinister disease.
Mesothelioma of the peritoneum can result from fibres migrating through the gastrointestinal tract
to reside in the relative physiological calm of the peritoneum. The fibre may enter the gastrointestinal tract by simple ingestion, but the mechanism most likely is the swallowing of fibres removed
from the respiratory system by the cilia escalator after inhalation.
Tumour development in the peritoneum sometimes occurs from tumours which began in the
pleura.
Factors Involved in Tumour Formation.
The carcinogenic potential of asbestos substances is generally accepted as being related to the
physical size of the fibre and not its chemical composition.

The importance of size has been demonstrated experimentally on rats, where crocidolite fibres
which had been reduced to a non-fibrous dust did not evoke a carcinogenic response in the
pleura, compared with fibrous crocidolite which did evoke a response.
The evidence as to the precise size of fibre required to evoke the carcinogenic response is still
subject to considerable debate, although a general area of potential harm is agreed. Fibres having diameters greater than 0.2 m but less than 0.5 m have been given in research literature.
Fibre lengths in excess of 10 m or between the range 10 to 80 m have been put forward.
The aspect ratio, i.e. the ratio of fibre length to diameter, has been quoted as 10:1 and 5:1.
The general standard for defining risk fibres are those which have a length greater than 5 m and
a diameter less than 3 m, with an aspect ratio of 3:1. There is still some doubt about the validity
of these dimensional characteristics in determining risk.
An important question arising from the relationship between the physical dimension of crocidolite
fibres and their ability to evoke a carcinogenic response is: 'Can other fibrous materials evoke the
same response?'
The answer is unfortunately 'yes'. Aluminium silicate fibres and glass-fibres of equivalent dimension have induced pleural tumours in experimental animals.
The ability of crocidolite to migrate into the pleura and peritoneum and evoke a harmful response
is generally believed to be related to its ability to produce fine, straight fibres. They are able to
break up into the size range which can migrate fairly freely in body tissue and take with them their
potential for harm. When they cease their wandering and 'retire' to a quiet haven, they are then
able to concentrate their irritation in that particular area.
Amosite tends to produce less fine fibres than crocidolite; its potential for harm is therefore reduced.
Chrysotile forms curly fibres which tend to gather into bunches. These properties reduce its ability
to migrate through tissue, which considerably reduces its potential to evoke mesothelioma; but, if
finely milled, the curly fibres can be reduced to dimensions comparable with crocidolite fibres, so
the potential of white asbestos to evoke mesothelioma becomes dramatically increased. It is a
point which is not well publicised.
The exact mechanism by which the cell damage is caused is unknown. One tentative hypothesis
postulates that the potentially harmful size range of the fibres equates to that of viruses, but the
exact relationship has not been explained.
Symptoms:
Pleural Mesothelioma.
In the early stages of tumour growth, there is an increase in fluid around the lungs, which causes
breathlessness and a feeling of heaviness within the chest. It is often mistaken for a heart condition or the ageing process.
As tumour growth rate increases, the lungs and structures in the thoracic cavity become more
compressed until the effects are fatal. Pain usually only develops in the final stages of the disease, due to the effects upon the nerves in the walls of the thoracic cavity and in the spine. The
pain level is very difficult to control.
Peritoneal Mesothelioma.
The tumour development follows a similar course to that in the pleura. Initially, a general swelling
of the abdomen occurs which is often mistaken as 'middle-age' spread. As the tumour size increases, normal movement of the intestine is impeded and constipation follows. Pain is sometimes experienced when defecation takes place. Eventually, cramp pains cause the victim to seek
medical help.

In both cases, the medical diagnosis of the condition is of no value. The victim has, by this time,
long passed the point of no return. One glimmer of hope is that in a few cases, tumours have
spontaneously disappeared.
About six months after recognising there is something wrong with their bodies, the victims will
usually seek medical advice. Few live longer than about a year after consultation; many less.
It is not possible to define conditions or safety limits whereby this form of cancer can be prevented. There is little or no hope of recovery if the condition develops.
The condition occurs fairly readily where there is exposure to blue asbestos. It is likely to arise
from brown asbestos and may possibly arise from white asbestos.
The latency period of mesothelioma is not well-defined. Values ranging from 5 to 60 years are
quoted; the average is about 25 years. Exposure times have been as low as two months.
Except for laggers and insulators whose exposure ranges over the working lifetime, i.e. 25-50
years, the average exposure for victims in one epidemiological survey was about 10 years.
These facts are put forward as the basis of the argument that not only should blue asbestos be
banned from use, but the other forms as well. There are counter arguments of economics related
to employment in the asbestos industry, and the value of asbestos as an industrial and social material of construction.

4.26 CHIP
It is now time to look at these regulations in more detail, as well as the use of risk and safety
phrases and the application of safety data sheets in preventing ill-health arising from the use of
chemicals.
CHIP refers to the Chemicals (Hazard Information and Packaging for Supply) Regulations 2009,
which came into force on 6th April 2009. These regulations are also known as CHIP 4.
CHIP is the law that applies to suppliers of dangerous chemicals. It is intended to protect people
and the environment from the effects of those chemicals by requiring suppliers to provide information about the dangers, and to ensure that they are safely packaged.
CHIP requires the supplier of a dangerous chemical to:
identify the hazards (dangers) of the chemical, a process known as 'classification';
give information about the hazards to their customers; suppliers usually provide this information
on the package itself (e.g. a label); and
package the chemical safely.
NOTE: Safety data sheets (SDS) are no longer covered by the CHIP regulations. The laws that
require a SDS to be provided have been transferred to the European REACH regulation.
'Supply' means making a chemical available to another person. Manufacturers, importers, distributors, wholesalers and retailers are all examples of suppliers.
CHIP applies to most chemicals, but not all. The details of those to which it applies are set out in
the regulations. Some chemicals, such as cosmetics and medicines, are outside the scope and
have their own laws.
The CHIP Regulations have been amended because of the adoption of the European Regulation
on the Classification, Labelling and Packaging of Substances and Mixtures, known as the CLP
Regulation. The CLP Regulation is the European Union's adoption of the internationally-agreed
Global Harmonised System on the classification and labelling of chemicals, known as the 'GHS'.
CLP will be covered later in this unit.
The CLP Regulation was published on 31st December 2008 and entered into legal effect on 20th

January 2009

4.27 The New CHIP Regulations

The new CHIP 4 Regulations entered into force on 6 April 2009.
Although the CLP Regulation will be directly acting on Member States, without the need for transposition, the proposed amendments will allow CHIP to be aligned with the transitional period of
the CLP Regulation. This will ensure that the provisions of the CLP Regulation can be enforced in
Great Britain, both throughout the transitional period and beyond.
The CHIP 4 Regulations allow chemical suppliers to apply the requirements of the CLP Regulation (as an alternative to those in CHIP) in line with its transitional arrangements. These arrangements comprise a two-stage process whereby substances have to be reclassified and relabelled
by 1 December 2010, and mixtures (previously called preparations), by 1 June 2015. Substances
and mixtures already on the shelves on these dates can continue to be supplied until 1 December
2012 and 1 June 2017 respectively.
At the end of the transitional period, the CLP Regulation will eventually replace all existing European classification, labelling and packaging of chemicals legislation. The primary source for the
obligations under the CLP Regulation will be the Regulation itself, with the exception of the enforcement provisions set out in the CHIP 4 Regulations.
CHIP 4 provides for the enforcement of the CLP Regulation in Great Britain. Although the CLP
Regulation is directly acting on all EU Member States, it requires member states to appoint enforcing authorities to enforce its provisions and to introduce penalties for non-compliance.
The scope of the CLP Regulation is broadly the same as those parts of the Dangerous Substances Directive and Dangerous Preparations Directive it replaces, and the existing enforcing
authorities (mainly HSE and local authorities) for CHIP 4 will be the same as those for CHIP 3.
CHIP 4 also discharges the UK's obligation to appoint an enforcing authority to enforce the duties
in the CLP Regulation. The enforcing authorities (Health and Safety Executive, local authorities,
the Environment Agency and the Scottish Environment Protection Agency), penalties and sanctions remain the same. Northern Ireland implemented these provisions through regional legislation later in 2009.
CHIP 4 will also make a few minor editorial amendments, including arrangements to ensure that
the legislation keeps track of future changes to the CLP Regulation without the time-consuming
need to make new regulations.

4.28 Categories of Danger

CHIP 4 defines 23 categories of danger.
Carcinogens, mutagens and substances toxic for reproduction are subdivided into categories,
with Category 1 representing the most severe hazard.
In Health Effects Classification this includes the category of danger, the indication of danger (i.e.
very toxic, toxic, harmful, corrosive and irritant), the appropriate symbol and the symbol letter.You
should be aware that under the new CLP regulations as part of REACH, the symbols will change
slightly.
Hazard Symbols - Physicochemical
Symbol

Abbreviation

Hazard

Description of hazard

Explosive

Chemicals that
Explode

Oxidising

Chemicals that react

exothermically with
other chemicals.

F+

Extremely Flammable

Chemicals that have

an extremely low flash
point and boiling point,
and gases that catch
fire in contact with air.

Highly Flammable

Chemicals that may

catch fire in contact
with air, only need brief
contact with an ignition
source, have a very
low flash point or
evolve highly
flammable gases in
contact with water.

Abbreviation

Hazard

Description of hazard

T+

very toxic

Chemicals that at very

low levels cause
damage to health.

toxic

Chemicals that at low

levels cause damage
to health.

Hazard Symbols - Health

Symbol

Carc Cat 1

category 1
carcinogens

Chemicals that may

cause cancer or
increase its incidence

Carc Cat 2

category 2
carcinogens

Chemicals that may

cause cancer or
increase its incidence.

Carc Cat 3

category 3
carcinogens

Chemicals that may

cause cancer or
increase its incidence

Muta Cat 1

category 1 mutagens

Chemicals that induce

heritable genetic
defects or increase
their incidence.

Muta Cat 2

category 2 mutagens

Chemicals that induce

heritable genetic
defects or increase
their incidence.

Muta Cat 3

category 3 mutagens

Chemicals that induce

heritable genetic
defects or increase
their incidence

Repr Cat 1

category 1
reproductive toxins

Chemicals that
produce or increase
the incidence of nonheritable effects in
progeny and/or an
impairment in
reproductive functions
or capacity.

Repr Cat 2

category 2
reproductive toxins

Chemicals that
produce or increase
the incidence of nonheritable effects in
progeny and/or an
impairment in
reproductive functions
or capacity.

Repr Cat 3

category 3
reproductive toxins

Chemicals that
produce or increase
the incidence of nonheritable effects in
progeny and/or an
impairment in
reproductive functions
or capacity.

Xn

harmful

Chemicals that may

cause damage to
health

corrosive

Chemicals that may

destroy living tissue on
contact.

Xi

irritant

Chemicals that may

cause inflammation to
the skin or other
mucous membranes.

Abbreviation

Hazard

Description of hazard

dangerous for the

environment

Chemicals that may

present an immediate
or delayed danger to
one or more
components of the
environment

Hazard symbols - Environmental

Symbol

4.29 Summary of What You Need To Do - CHIP

4.30 REACH
REACH is a new European Union regulation concerning the Registration, Evaluation, Authorisation and restriction of CHemicals. It came into force on 1st June 2007 and replaces a number of
European Directives and Regulations with a single system.
Aims.
REACH has several aims:
To provide a high level of protection of human health and the environment from the use of
chemicals.
To make the people who place chemicals on the market (manufacturers and importers) responsible for understanding and managing the risks associated with their use.
To allow the free movement of substances on the EU market.
To enhance innovation in and the competitiveness of the EU chemicals industry.
To promote the use of alternative methods for the assessment of the hazardous properties of
substances e.g. quantitative structure-activity relationships (QSAR).
No data, no market.
A major part of REACH is the requirement for manufacturers or importers of substances to register them with a central European Chemicals Agency (ECHA). A registration package will be supported by a standard set of data on that substance. The amount of data required is proportionate
to the amount of substance manufactured or supplied.
If a manufacturer does not register their substances, then the data on them will not be available
and as a result, they will no longer be able to manufacture or supply them legally, i.e. no data, no
market.
Scope and exemptions.
REACH applies to substances manufactured or imported into the EU in quantities of 1 tonne per
year or more. Generally, it applies to all individual chemical substances on their own, in preparations or in articles (if the substance is intended to be released during normal and reasonably foreseeable conditions of use from an article).
Some substances are specifically excluded:
Radioactive substances.
Substances under customs supervision.
The transport of substances.
Non-isolated intermediates.
Waste.
Some naturally occurring low-hazard substances.
Some substances, covered by more specific legislation, have tailored provisions, including:
Human and veterinary medicines.
Food and foodstuff additives.
Plant protection products and biocides.
Other substances have tailored provisions within the REACH legislation, as long they are used in
specified conditions:
Isolated intermediates.
Substances used for research and development.
Pre-registration.
It is estimated that there are around 30,000 substances on the European market in quantities of 1

tonne or more per year. Registering all of these at once would be a huge task for both industry
and regulators. To overcome this, the registration of those substances already being manufactured or supplied is to take place in three phases. These phases are spread over 11 years. To
benefit from these phased-in deadlines, manufacturers or importers needed to pre-register their
substances from 1st June to 1st December 2008.
Registration.
Registration is a requirement on industry (manufacturers/importers) to collect and collate specified sets of information on the properties of those substances they manufacture or supply at or
above 1 tonne per year. This information is used to perform an assessment of the hazards and
risks that a substance may pose and how those risks can be controlled. This information and its
assessment is submitted to the European Chemicals Agency in Helsinki. Further information on
registration can be found on the ECHA website[13].
Joint registration and data sharing.
This is the principle that for any one substance, a single set of information on its intrinsic properties is produced that is shared by all those companies that manufacture or supply that substance.
Business specific (e.g. company name) and business sensitive (e.g. how it is used) information is
submitted separately by each company. The Companies will work together to get an agreement
on information sharing through a Substance Information Exchange Forum (SIEF). It is the responsibility of the businesses involved in the SIEF to work out the details of how the information
is shared. A role for national authorities in this aspect of REACH is not foreseen. Companies who
submit joint registrations via a SIEF benefit from a reduced registration fee.
Evaluation.
Dossiers submitted in support of registration will be subject to evaluation under REACH as follows:
Compliance checking: This is a check of the quality of the information submitted by industry. It
will be undertaken by the European Chemicals Agency (ECHA) in Helsinki and will be on a sample (at least 5%) of dossiers submitted at each tonnage level.
Dossier Evaluation: For substances registered at the highest tonnage levels (=100 tonnes/annum) a proposal is made by the registrant detailing those animal tests they consider are
required from the list of standard tests in Annexes IX and X of REACH. The ECHA will evaluate
these testing proposals to prevent unnecessary animal testing.
Substance evaluation: This is undertaken by national Competent Authorities on substances that
have been prioritised for potential regulatory action because of concerns about their hazardous
properties. A key regulatory outcome of evaluation could be the imposition of restrictions on the
manufacture, supply or use of a substance. Substance evaluation may also lead to a substance
being added to the priority list for authorisation, or a proposal to change the classification and labelling.
All dossiers will undergo an automated completeness check to ensure that all the relevant pieces
of information are present. This completeness check will not assess the quality or suitability of the
information. Further details on evaluation can also be found on the ECHA website.
Authorisation.
In order to place on the market or use substances with properties that are deemed to be of 'very
high concern', industry must apply for an authorisation. The European Chemicals Agency (ECHA)
in Helsinki will publish an initial list containing substances to be considered for the authorisation
process by 1 June 2009. A company wishing to market or use such a substance must submit an
application to the ECHA for an authorisation. Decisions on authorisation are made by the European Commission, taking advice from the ECHA and member states. Applicants will have to
demonstrate that risks associated with uses of these substances are adequately controlled or that
the benefits of their use outweigh the risks. Applicants must also analyse whether there are safer
suitable alternatives or technologies. If there are, then they must prepare substitution plans and if
not, then they should provide information on research and development activities if appropriate.
Restrictions.
If any substance poses a particular threat and it is deemed to require Community-wide action, it
can be restricted. Restrictions take many forms, from a total ban to not being allowed to supply it

to the general public. Restrictions can be applied to any substance, including those that do not
require registration. This part of REACH takes over the provisions of the Marketing & Use Directive.
Classification and labelling.
An important part of chemical safety is clear information about any hazardous properties of a
substance. The classification of different chemicals according to their characteristics (for example, those that are corrosive, or toxic to fish, etc.) currently follows an established system, which
is reflected in REACH. The CLP regulation deals with this and dovetails with REACH.
Substances of Very High Concern.
Some substances have hazards that have serious consequences, e.g. they cause cancer, or they
have other harmful properties and remain in the environment for a long time and gradually build
up in animals. These are 'substances of very high concern'. This category also includes substances shown to be of equivalent concern, such as "endocrine disruptors". One of the aims of
REACH is to control the use of such substances via authorisation and encourage industry to substitute these substances for safer ones.
Information in the supply chain.
The passage of information along the supply chain is a key feature of REACH. Users should be
able to understand what manufacturers and importers know about the dangers involved in using
chemicals and how to control risks. However, in order for suppliers to be able to assess these
risks, they need information from the users. REACH provides a framework in which information
can be passed both up and down supply chains.
REACH adopts and builds on the previous system for passing information - the Safety Data
Sheet (see section 1.5). This needs to accompany materials down through the supply chain, providing the information users require to ensure chemicals are safely managed. In time, it is intended that these safety data sheets will include information on safe handling and use.
Preparing for REACH.
REACH will impact most businesses in the UK in some way. It is important to understand what
your role is in REACH, and what you can do now to be sure you are prepared.
Compile an inventory.
An inventory of every chemical that comes into, is part of, or goes out of the business needs to be
compiled.
You need to know all the substances you use. For preparations, you need to find out what the
ingredients are. Keep a record of each one, and include essential information, for example the
name of the chemical and the percentage in any preparations. You can use this information to
determine the tonnage per year.
Additionally, you need to know whether you produce or import articles. If you do, establish if any
substance (which is intended to be released under normal or reasonably foreseeable conditions
of use) is present in these articles in quantities totalling over 1 tonne.
Once this inventory has been established, you can begin to understand what substances you rely
on, and consider the impact on your business should REACH influence the supply (or for registrants, the production or import) of a substance. Consider contingencies, for example alternative
supply routes, chemicals or processes, or supporting suppliers in their REACH obligations, etc.
Prioritise.
Every business using chemicals that are not exempt from REACH needs to understand how
valuable these substances are to them, and plan to make effective business decisions based on
this knowledge. Consider the importance of each substance to your business. Ask yourself the
following sorts of question:
For what is it used?
Are the uses to which you put chemicals going to be supported by their registrants?
How much of it do you use?
Are there any alternative substances or processes that could replace this?
Will your supplier/s maintain supply of important substances if REACH impacts the commercial

viability of doing so?

What will be the impact for you if the price increases or the supply drops, and what can you do
about it?
Do you want to share information back to registrants about the use to which you put chemicals,
or is this information so sensitive that you would prefer to compile risk assessments yourself, and
submit these directly to the European Chemicals Agency? What will this involve?
Identify any chemicals that may be 'substances of very high concern'.
Determine your role in relation to each substance on the inventory.
Build relationships.
You need to establish a relationship with your suppliers and any downstream users. You need to
know how REACH is going to affect your supply chain before you can decide what to do about it.
An appropriate person within your organisation needs to be designated as the main REACH contact and made the focus for communications with suppliers and customers.

4.31 Risk Phrases and Safety Phrases

Risk phrases are an important part of the classification and are assigned according to the particular criteria.
The risk phrase gives more information than the category of danger, and is more specific to the
particular chemical.
The Approved Supply List contains a section which lists 64 individual risk phrases and also gives
a further 57 combined risk phrases. Although the ASL is now being discontinued in line with new
REACH and CLP regulations, you may well come across these risk phrases for some time to
come, and it is a good idea to familiarise yourself with them.
R1 Explosive when dry
R2 Risk of explosion by shock, friction, fire or other sources of ignition
R3 Extreme risk of explosion by shock, friction, fire or other sources of ignition
R4 Forms very sensitive explosive metallic compounds
R5 Heating may cause an explosion
R6 Explosive with or without contact with air
R7 May cause fire
R8 Contact with combustible material may cause fire
R9 Explosive when mixed with combustible material
R10 Flammable
R11 Highly flammable
R12 Extremely flammable
R14 Reacts violently with water
R14/15 Reacts violently with water, liberating extremely flammable gases
R15 Contact with water liberates extremely flammable gases

R15/29 Contact with water liberates toxic, extremely flammable gases

R16 Explosive when mixed with oxidising substances
R17 Spontaneously flammable in air
R18 In use, may form flammable/explosive vapour-air mixture
R19 May form explosive peroxides
R20 Harmful by inhalation
R20/21 Harmful by inhalation and in contact with skin
R20/21/22 Harmful by inhalation, in contact with skin and if swallowed
R20/22 Harmful by inhalation and if swallowed
R21 Harmful in contact with skin
R21/22 Harmful in contact with skin and if swallowed
R22 Harmful if swallowed
R23 Toxic by inhalation
R23/24 Toxic by inhalation and in contact with skin
R23/24/25 Toxic by inhalation, in contact with skin and if swallowed
R23/25 Toxic by inhalation and if swallowed
R24 Toxic in contact with skin
R24/25 Toxic in contact with skin and if swallowed
R25 Toxic if swallowed
R26 Very toxic by inhalation
R26/27 Very toxic by inhalation and in contact with skin
R26/27/28 Very toxic by inhalation, in contact with skin and if swallowed
R26/28 Very toxic by inhalation and if swallowed
R27 Very toxic in contact with skin
R27/28 Very toxic in contact with skin and if swallowed
R28 Very toxic if swallowed
R29 Contact with water liberates toxic gas
R30 Can become highly flammable in use

R31 Contact with acids liberates toxic gas

R32 Contact with acids liberates very toxic gas
R33 Danger of cumulative effects
R34 Causes burns
R35 Causes severe burns
R36 Irritating to eyes
R36/37 Irritating to eyes and respiratory system
R36/37/38 Irritating to eyes, respiratory system and skin
R36/38 Irritating to eyes and skin
R37 Irritating to respiratory system
R37/38 Irritating to respiratory system and skin
R38 Irritating to skin
R39 Danger of very serious irreversible effects
R39/23 Toxic: danger of very serious irreversible effects through inhalation
R39/23/24 Toxic: danger of very serious irreversible effects through inhalation and in contact with
skin
R39/23/24/25 Toxic: danger of very serious irreversible effects through inhalation, in contact with
skin and if swallowed
R39/23/25 Toxic: danger of very serious irreversible effects through inhalation and if swallowed
R39/24 Toxic: danger of very serious irreversible effects in contact with skin
R39/24/25 Toxic: danger of very serious irreversible effects in contact with skin and if swallowed
R39/25 Toxic: danger of very serious irreversible effects if swallowed
R39/26 Very Toxic: danger of very serious irreversible effects through inhalation
R39/26/27 Very Toxic: danger of very serious irreversible effects through inhalation and in contact
with skin
R39/26/27/28 Very Toxic: danger of very serious irreversible effects through inhalation, in contact
with skin and if swallowed
R39/26/28 Very Toxic: danger of very serious irreversible effects through inhalation and if swallowed
R39/27 Very Toxic: danger of very serious irreversible effects in contact with skin

R39/27/28 Very Toxic: danger of very serious irreversible effects in contact with skin and if swallowed
R39/28 Very Toxic: danger of very serious irreversible effects if swallowed
R40 Limited evidence of a carcinogenic effect
R41 Risk of serious damage to eyes
R42 May cause sensitisation by inhalation
R43 May cause sensitisation by skin contact
R42/43 May cause sensitisation by inhalation and skin contact
R44 Risk of explosion if heated under confinement
R45 May cause cancer
R46 May cause heritable genetic damage
R48 Danger of serious damage to health by prolonged exposure
R48/20 Harmful: danger of serious damage to health by prolonged exposure through inhalation
R48/20/21 Harmful: danger of serious damage to health by prolonged exposure through inhalation and in contact with skin
R48/20/21/22 Harmful: danger of serious damage to health by prolonged exposure through inhalation, in contact with skin and if swallowed
R48/20/22 Harmful: danger of serious damage to health by prolonged exposure through inhalation and if swallowed
R48/21 Harmful: danger of serious damage to health by prolonged exposure in contact with skin
R48/21/22 Harmful: danger of serious damage to health by prolonged exposure in contact with
skin and if swallowed
R48/22 Harmful: danger of serious damage to health by prolonged exposure if swallowed
R48/23 Toxic: danger of serious damage to health by prolonged exposure through inhalation
R48/23/24 Toxic: danger of serious damage to health by prolonged exposure through inhalation
and in contact with skin
R48/23/24/25 Toxic: danger of serious damage to health by prolonged exposure through inhalation, in contact with skin and if swallowed
R48/23/25 Toxic: danger of serious damage to health by prolonged exposure through inhalation
and if swallowed
R48/24 Toxic: danger of serious damage to health by prolonged exposure in contact with skin
R48/24/25 Toxic: danger of serious damage to health by prolonged exposure in contact with skin
and if swallowed

R48/25 Toxic: danger of serious damage to health by prolonged exposure if swallowed

R49 May cause cancer by inhalation
R50 Very toxic to aquatic organisms
R50/53 Very toxic to aquatic organisms, may cause long-term adverse effects in the aquatic environment
R51 Toxic to aquatic organisms
R51/53 Toxic to aquatic organisms, may cause long-term adverse effects in the aquatic environment
R52 Harmful to aquatic organisms
R52/53 Harmful to aquatic organisms, may cause long-term adverse effects in the aquatic environment
R53 May cause long-term adverse effects in the aquatic environment
R54 Toxic to flora
R55 Toxic to fauna
R56 Toxic to soil organisms
R57 Toxic to bees
R58 May cause long-term adverse effects in the environment
R59 Dangerous for the ozone layer
R60 May impair fertility
R61 May cause harm to the unborn child
R62 Possible risk of impaired fertility
R63 Possible risk of harm to the unborn child
R64 May cause harm to breast-fed babies
R65 Harmful: may cause lung damage if swallowed
R66 Repeated exposure may cause skin dryness or cracking
R67 Vapours may cause drowsiness and dizziness
R68 Possible risk of irreversible effects
R68/20 Harmful: possible risk of irreversible effects through inhalation
R68/20/21 Harmful: possible risk of irreversible effects through inhalation and in contact with skin

R68/20/21/22 Harmful: possible risk of irreversible effects through inhalation, in contact with skin
and if swallowed
R68/20/22 Harmful: possible risk of irreversible effects through inhalation and if swallowed
R68/21 Harmful: possible risk of irreversible effects in contact with skin
R68/21/22 Harmful: possible risk of irreversible effects in contact with skin and if swallowed
R68/22 Harmful: possible risk of irreversible effects if swallowed
Safety Phrases
Safety Number Safety Phrase
S1 Keep locked up
S(1/2) Keep locked up and out of the reach of children
S2 Keep out of reach of children
S3 Keep in a cool place
S3/7 Keep container tightly closed in a cool place
S3/7/9 Keep container tightly closed in a cool, well-ventilated place
S3/9/14 Keep in a cool, well-ventilated place away from ... (incompatible materials to be indicated
by the manufacturer)
S3/9/14/49 Keep only in the original container in a cool, well-ventilated place away from ... (incompatible materials to be indicated by the manufacturer)
S3/9/49 Keep only in the original container in a cool, well-ventilated place
S3/14 Keep in a cool place away from ... (incompatible materials to be indicated by the manufacturer)
S4 Keep away from living quarters
S5 Keep contents under ... (appropriate liquid to be specified by the manufacturer)
S6 Keep under ... (inert gas to be specified by the manufacturer)
S7 Keep container tightly closed
S7/8 Keep container tightly closed and dry
S7/9 Keep container tightly closed and in a well-ventilated place
S7/47 Keep container tightly closed and at temperature not exceeding ... OC (to be specified by
the manufacturer)
S8 Keep container dry
S9 Keep container in a well-ventilated place
S12 Do not keep the container sealed
S13 Keep away from food, drink and animal feeding stuffs
S14 Keep away from ... (incompatible materials to be indicated by the manufacturer)
S15 Keep away from heat
S16 Keep away from sources of ignition - No smoking
S17 Keep away from combustible material
S18 Handle and open container with care
S20 When using do not eat or drink
S20/S21 When using do not eat, drink or smoke
S21 When using do not smoke
S22 Do not breathe dust
S23 Do not breathe gas/fumes/vapour/spray (appropriate wording to be specified by the manufacturer)
S24 Avoid contact with skin
S24/25 Avoid contact with skin and eyes
S25 Avoid contact with eyes
S26 In case of contact with eyes, rinse immediately with plenty of water and seek medical advice
S27 Take off immediately all contaminated clothing
S27/S28 After contact with skin, take off immediately all contaminated clothing, and wash imme-

diately with plenty of ... (to be specified by the manufacturer)

S28 After contact with skin, wash immediately with plenty of ... (to be specified by the manufacturer)
S29 Do not empty into drains
S29/35 Do not empty into drains; dispose of this material and its container in a safe way
S29/56 Do not empty into drains, dispose of this material and its container at hazardous or special waste collection point
S30 Never add water to this product
S33 Take precautionary measures against static discharges
S35 This material and its container must be disposed of in a safe way
S36 Wear suitable protective clothing
S36/37 Wear suitable protective clothing and gloves
S36/37/39 Wear suitable protective clothing, gloves and eye/face protection
S36/39 Wear suitable protective clothing and eye/face protection
S37 Wear suitable gloves
S37/39 Wear suitable gloves and eye/face protection
S38 In case of insufficient ventilation wear suitable respiratory equipment
S39 Wear eye/face protection
S40 To clean the floor and all objects contaminated by this material use ... (to be specified by the
manufacturer)
S41 In case of fire and/or explosion do not breathe fumes
S42 During fumigation/spraying wear suitable respiratory equipment (appropriate wording to be
specified by the manufacturer)
S43 In case of fire use ... (indicate in the space the precise type of fire-fighting equipment. If water increases the risk add - Never use water)
S45 In case of accident or if you feel unwell seek medical advice immediately (show the label
where possible)
S46 If swallowed, seek medical advice immediately and show this container or label
S47 Keep at temperature not exceeding ... OC (to be specified by the manufacturer)
S47/49 Keep only in the original container at temperature not exceeding ... OC (to be specified by
the manufacturer)
S48 Keep wet with ... (appropriate material to be specified by the manufacturer)
S49 Keep only in the original container
S50 Do not mix with ... (to be specified by the manufacturer)
S51 Use only in well-ventilated areas
S52 Not recommended for interior use on large surface areas
S53 Avoid exposure - obtain special instructions before use
S56 Dispose of this material and its container at hazardous or special waste collection point
S57 Use appropriate containment to avoid environmental contamination
S59 Refer to manufacturer/supplier for information on recovery/recycling
S60 This material and its container must be disposed of as hazardous waste
S61 Avoid release to the environment. Refer to special instructions/safety data sheet
S62 If swallowed, do not induce vomiting: seek medical advice immediately and show this container or label
S63 In case of accident by inhalation: remove casualty to fresh air and keep at rest
S64 In case of accident by inhalation: remove casualty to fresh air and keep at rest
Note that certain Safety Phrases, e.g. 10, 11, 19, etc. are no longer in use.

4.32 Toxicity, Flammability and Carcinogenic Properties.

Extremely Flammable F+ and Highly Flammable F
For the purposes of CHIP, a Flammable Liquid is one with a flash point of less than 37.8 C.
A Highly Flammable Liquid (F) is one with a flash point of less than 21 C

 A Highly Flammable solid is one that is spontaneously combustible in air at ambient temperature, readily ignites after brief contact with a flame or evolves highly flammable gases in contact
with water or moist air.
An Extremely Flammable Liquid (F+) is one with a flash point less than 0 C and a boiling point
of 35 C or less.
Carcinogens
Category 1 - substances known to be carcinogenic to humans.
Category 2 - substances that should be regarded as if they are carcinogenic to humans, for which
there is sufficient evidence, based on long-term animal studies and other relevant information, to
provide a strong presumption that human exposure may result in the development of cancer.
Category 3 - substances that cause concern owing to possible carcinogenic effects but for which
available information is not adequate to make satisfactory assessments.
Categories 1 and 2 carry the "toxic" (T) symbol and the Risk Phrase R45 (may cause cancer) or
R49 (may cause cancer by inhalation).
Category 3 carries the "harmful" (Xn) symbol and the Risk Phrase R40 (possible risk of irreversible effects).
Very Toxic (T+) and Toxic (T)
LCn - This abbreviation is used for the exposure concentration of a toxicant lethal to n% of a
test population e.g. LC50
LDn - This abbreviation is used for the dose of a toxicant lethal to n% of a test population.
Evident Toxicity- this concept is used to designate toxic effects after exposure to a substance
tested, which are so severe that exposure to the next highest fixed dose would probably lead to
death.
Very Toxic (T+)
Acute lethal effects:
R28 "Very Toxic if swallowed": LD50 oral, rat < or = 25mg/kg: less than 100% survival at 5mg/kg
oral, rat.
R27 "Very Toxic in contact with skin": LD50 dermal, rat or rabbit: < or = 50mg/kg.
R26 "Very Toxic by inhalation"; LC50 inhalation, rat, for aerosols or particulates < or =
0.25mg/litre/4h
Non-lethal irreversible effects after a single exposure:
R39 "Danger of very serious irreversible effects": Irreversible damage is likely to be caused by a
single exposure by an appropriate route, generally in the above dose ranges. In order to indicate
the route of exposure, combinations of Risk Phrases may be used e.g. R39/23 i.e. 'Danger of
very serious irreversible effects by inhalation'.
Toxic (T)
Acute lethal effects:
R25 "Toxic if swallowed"; LD50 oral, rat 25 < LD50 < or = 200mg/kg: At 5mg/kg, oral, rat less
than 100% survival but evident toxicity.
R24 "Toxic in contact with skin"; LD50 dermal, rat or rabbit: 50 < LD50 < or = 400mg/kg.
R23 "Toxic by inhalation"; LC50 inhalation, rat, for aerosols or particulates: 0.25 < LD50< or =
1mg/litre/4hr
Non-lethal irreversible effects after a single exposure:
R39 "Danger of very serious irreversible effects": Irreversible damage is likely to be caused by a
single exposure by an appropriate route, generally in the above dose ranges. In order to indicate
the route of exposure, combinations of Risk Phrases may be used e.g. R39/23 i.e. 'Danger of
very serious irreversible effects by inhalation'.
Severe effects after repeated or prolonged exposure:
R48 "Danger of serious damage to health by prolonged exposure": Serious damage is likely to be
caused by repeated or prolonged exposure by an appropriate route. "Toxic with R48" is used
when effects are observed at levels of the order of:
Oral, rat < or = 5mg/kg(bodyweight)/day
Dermal, rat or rabbit < or = 10mg/kg(bodyweight)/day

Inhalation, rat < or = 0.025mg/l, 6hr/day

In order to indicate the route of exposure, combinations of Risk Phrases may be used e.g. R48/23
i.e. "Danger of serious damage to health by prolonged exposure by inhalation

4.33 Safety Data Sheets.

Safety Data Sheets (SDS) have now been transferred from CHIP to the new REACH legislation.
Suppliers of substances are required, under REACH, to provide safety data sheets.
The purpose of the safety data sheet is to give information to users of the substance to enable
them to take the necessary measures to protect health and safety and the environment.
You need to provide a SDS if:
1. You supply a substance or a mixture (see definitions section below) that is either:
(a) classified as dangerous under Dangerous Substances Directive 67/548/EEC or Dangerous
Preparations Directive,1999/45/EC; or
(b) (b) persistent, bioaccumulative and toxic (PBT), or very persistent and very bioaccumulative
(vPvB) as defined in Annex XIII of REACH; or
(c) included in the European Chemicals Agency's 'Candidate List' of substances of very high concern (SVHC see 'definitions section below) for reasons other than (a) and (b) given here.
2. You are a supplier and your customer requests a SDS for a mixture that is not classified as
dangerous under Directive 1999/45/EC, but contains either:
(a) a substance posing human health or environmental hazards in an individual concentration of =
1 % by weight for non-gaseous mixtures or = 0.2 % by volume for gaseous mixtures; or
(b) a substance that is persistent, bioaccumulative and toxic, or very persistent and very bioaccumulative as defined in Annex XIII of REACH in an individual concentration of = 0.1 % by weight
for non-gaseous mixtures; or
(c) a substance on the 'Candidate List' of substances of very high concern (for reasons other than
those listed above), in an individual concentration of = 0.1 % by weight for non-gaseous mixtures;
or
(d) a substance for which there are Europe-wide workplace exposure limits, e.g. a substance that
has indicative occupational exposure limit value (IOELV).
3. Although not required by REACH, if you are a supplier to EU countries other than the UK, then
you may need to supply a SDS for mixtures that are not classified as dangerous but that contain
substances with national workplace exposure limit values in other EU countries. (You would need
to approach individual Member States for this information.)
You do not need to provide a SDS:
1. If you offer or sell dangerous substances or mixtures to the general public and you provide sufficient information to enable users to take the necessary measures as regards safety and the protection of human health and the environment, unless a SDS is requested by a downstream user
or distributor.
2. If the substances/mixtures are supplied in the UK and not classified as dangerous.
3. For certain products intended for the final user, e.g. medicinal products or cosmetics.
What information needs to be provided on a SDS?
The safety data sheet shall be dated and shall contain the following headings.
1. Identification of the substance/mixture and of the company/undertaking.
2. Hazards identification.
3. Composition/information on ingredients.
4. First-aid measures.
5. Fire-fighting measures.

6. Accidental release measures.

7. Handling and storage.
8. Exposure controls/personal protection.
9. Physical and chemical properties.
10. Stability and reactivity.
11. Toxicological information.
12. Ecological information.
13. Disposal considerations.
14. Transport information.
15. Regulatory information.
16. Other information.
Guidance on how to compile a SDS is detailed in Annex II of REACH.
REACH has introduced a few changes to the information required in a SDS. The main ones are:
Headings 2 and 3 swap around.
An email contact address should be included in section 1, for competent person(s) able to respond with appropriate advice.
A SDS should be supplied in an official language of the Member State(s) where the substance
or mixture is placed on the market (unless the relevant Competent Authority in the Member
State(s) concerned has indicated otherwise).
In addition, SDS for substances or mixtures containing substances that have been fully registered
under REACH will require:
Inclusion of registration numbers where appropriate (see also section on confidentiality provisions).
Inclusion of exposure scenarios including any risk management measures where required in an
annexe to the SDS. The information on the SDS should be consistent with the information in any
chemical safety assessment (CSA) for that substance, or a mixture if a CSA for the mixture is
available.
How and when should a SDS be provided?
A SDS should be provided to the recipient free of charge on paper or electronically, e.g. by postal
delivery, fax or email. A system that merely requires customers to download a SDS from a company's website or from a catalogue of SDS is not considered appropriate. A SDS should be provided either before, or at the time of, first delivery of the substance or mixture.
Where a customer re-orders substances or mixtures, then the supplier only has to provide the
SDS once (provided the sheet contents have not changed).
When should an SDS be updated?
The SDS needs to be updated:
1. as soon as new hazard information or information that may affect the risk management measures becomes available; or
2. once an Authorisation under REACH is granted or refused; or
3. once a restriction under REACH has been imposed.
The new dated version of the SDS, identified as 'Revision: date' shall be supplied to all customers
(of the substance/mixture in question) from the preceding 12 months.
Confidentiality provisions.
As a substance's registration number and the registrant's identity may be made publicly available
on the internet, some suppliers may be concerned that this will allow their customers to bypass
them in the supply chain.
A registrant can request for this information to be withheld from the internet (as long as this can
be justified), so suppliers of SDS may wish to discuss this issue with the registrant(s) in their supply chain(s).

Enforcement.
The SDS requirements in REACH became law on 1st June 2007. This means the changes detailed in this leaflet under 'What information needs to be provided on a SDS?' should already be
implemented now. However, as the requirements for SDS in REACH are similar to those they replace, enforcement of these new requirements in the UK is currently pragmatic. New prints of
SDS should conform to the new standards.
If new information on hazards or risk management measures becomes available, the SDS should
be updated without delay and the new format should be used. In addition, if new information has
been generated from the registration process (including the production of exposure scenarios)
the SDS should again be updated without delay in the new format. In other cases, suppliers
should seek to update their SDS as soon as is practicable.
Future of SDS
There is a new Regulation regarding the classification, labelling and packaging of substances and
mixtures, the "CLP Regulation" (Regulation (EC) No 1272/2008). The Regulation will be the
means by which the United Nations' Globally Harmonised System (GHS) of Classification and
Labelling of Chemicals will be implemented in the EU. This Regulation will change the way in
which hazard classification and labelling is expressed and will in turn lead to further changes to
SDS. If a substance or mixture is classified in accordance with the CLP Regulation before 1 December 2010, then that classification may be provided in the SDS along with the classification in
accordance with either Directive 67/548/EEC or 1999/45/EC.
More information is available at http://www.hse.gov.uk/ghs/eureg.htm. />

4.34 What is the GHS?

What is the GHS?
The GHS is an acronym for The Globally Harmonised System of Classification and Labelling of
Chemicals. The GHS is a system for standardising and harmonising the classification and labelling of chemicals. It is a logical and comprehensive approach to:
defining health, physical and environmental hazards of chemicals;
creating classification processes that use available data on chemicals for comparison with the
defined hazard criteria; and
communicating hazard information, as well as protective measures, on labels and Safety Data
Sheets (SDS).
GHS Document ("Purple Book") http://www.osha.gov/dsg/hazcom/ghs.html

Many countries already have regulatory systems in place for these types of requirements. These
systems may be similar in content and approach, but their differences are significant enough to
require multiple classifications, labels and safety data sheets for the same product when marketed in different countries or even in the same country when parts of the life cycle are covered
by different regulatory authorities. This leads to inconsistent protection for those potentially exposed to the chemicals, as well as creating extensive regulatory burdens on companies producing chemicals. For example, in the United States, there are requirements for classification and
labelling of chemicals for the Consumer Product Safety Commission, the Department of Transportation, the Environmental Protection Agency, and the Occupational Safety and Health Administration.

The GHS itself is not a regulation or a standard. The GHS Document (referred to as "The Purple
Book") establishes agreed hazard classification and communication provisions with explanatory
information on how to apply the system. The elements in the GHS supply a mechanism to meet
the basic requirement of any hazard communication system, which is to decide if the chemical
product produced and/or supplied is hazardous and to prepare a label and/or Safety Data Sheet
as appropriate. Regulatory authorities in countries adopting the GHS will thus take the agreed
criteria and provisions, and implement them through their own regulatory process and procedures
rather than simply incorporating the text of the GHS into their national requirements. The GHS
Document thus provides countries with the regulatory building blocks to develop or modify existing national programs that address classification of hazards and transmittal of information about
those hazards and associated protective measures. This helps to ensure the safe use of chemicals as they move through the product life cycle from "cradle to grave."
The Purpose and process of Classification of dangerouse chemicals with reference to
Chapter 1.3.2 of the Globally Harmonised System (GHS)
General Considerations on the GHS
Scope of the system
The GHS applies to pure substances and their dilute solutions and to mixtures.
One objective of the GHS is for it to be as simple and transparent with a clear distinction between
classes and categories in order to allow for self-classification as far as possible. For many hazard classes the criteria and semi-quantitative or qualitative and expert judgement is required to
interpret the data for classification purposes. Furthermore, for some classes of hazard (e.g. eye
irritation, explosives or self-reactive substances) a decision tree approach is provided to enhance
ease of use.
Concept of classification
The GHS uses the term Hazard Classification to indicate that only the intrinsic hazardous properties of substances or mixtures are considered.
Hazard classification incorporates only THREE steps:
(a) identification of relevant data regarding the hazards of a substance or mixture
(b) subsequent review of those data to ascertain the hazards associated with the substance or
mixture; and
(c) a decision on whether the substance or mixture will be classified as a hazardous substance or
mixture and the degree of hazard, where appropriate, by comparison of the data with agreed
hazard classification criteria.

4.35 Labelling
The European Commission proposed the European Regulation (EC) No 1272/2008 on the Classification, Labelling and Packaging of Substances and Mixtures (known as the CLP Regulation).
This was considered in detail during negotiations between Member States, the Council and the
European Parliament, between July 2007 and June 2008. The UK was represented by the HSE
throughout the negotiations.
The CLP Regulation was published in the European Union's Official Journal on 31st December
2008 and entered into legal effect on 20th January 2009, subject to a lengthy transitional period
(see below).
http://ec.europa.eu/enterprise/sectors/chemicals/documents/classification/index_en.htm#h2-clpregulation-(ec)-no-1272/2008
Transitional periods.

The Regulation provides a transition period to allow a gradual migration from the existing system
to the new regime. This transition period is up to 7 years (the Regulation will apply to the classification of substances from 1st December 2010, and to the classification of mixtures from 1st
June 2015). The transitional period will end on 1st June 2015 when the CLP Regulation enters
fully into force.
Over time, the CLP Regulation will replace the:
Dangerous Substances Directive (67/548/EEC)
Dangerous Preparations Directive (1999/45/EC)
Impact on the CHIP regulations and the proposed new CHIP 4.
These Directives have been implemented in the UK as CHIP 4, which will need to be adjusted
slightly to include the necessary enforcing regulations to deal with the CLP Regulation, and to
ensure that domestic law continues to be current with the changes at European level during the
transitional period.
http://guidance.echa.europa.eu/docs/guidance_document/clp_introductory_en.pdf
This pdf, although quite long, gives excellent guidance as to the application of CLP regulations
and the way in which they vary from the current, outgoing scheme.
This article from SHP by Douglas Leech, Technical Manager of the Chemicals Business Association, gives an in-depth assessment of the CLP regulations and is well worth the time taken to read
it.
"The dream of global harmonisation (GHS) of the classification, labelling and packaging (CLP) of
chemicals, originally conceived by the United Nations, came closer to fruition on 31st December
2008, when the European Union published Regulation (EC) 1272/2008, heralding the introduction
of European CLP1. While the long-term aims of these provisions are welcome - facilitating international trade, reducing costs, and improving the flow of information throughout the chemical
supply chain - the new provisions will involve significant changes and costs for industry over a
relatively short period of time.
The key dates in the process are: 1st December 2010, when substances must be reclassified and
labelled in line with the new global system; and 1st June 2015, when the same process will be
applied to mixtures (formerly called preparations).
Each element of the chemical supply chain - manufacturer, importer, downstream user, and distributor - has specific duties under the new provisions, as well as a responsibility to cooperate
with other suppliers in respect of the classification, labelling and packaging of substances.
The United Nations has been developing the new system since the Rio Earth Summit in 1992.
The Summit's Agenda 21 included the mandate to create 'a globally harmonised hazard classification and labelling system, including Safety Data Sheets and easily understood symbols'.
Under the GHS each hazard class and category is a 'building block'. The EU will implement the
vast majority of the available 'blocks' (77 out of 84) and has introduced harmonisation by making
the legislation a directly-acting Regulation, so EU member states do not have to pass domestic
legislation. Individual countries can simply select which 'blocks' they wish to implement.
Thus, the new system implies increased centralisation at EU level through directly-acting regulations and the operations of the European Chemicals Agency (ECHA). The latter is responsible for
developing methodologies, tools and technical guidance through REACH Implementation Projects (RIPs). For example, RIP 3.6 has been developing guidance on the classification and labelling under the proposed GHS-based Regulation, and the proposals were discussed at the 16th17th June meeting of the Competent Authority for REACH and Classification And Labelling (CA-

RACAL).
The EU claims it has designed the GHS-based Regulation to dovetail with other European
chemical legislation particularly REACH, which came into force in June 2007. The resulting system aims to provide one, global framework for identifying and describing chemical hazards. This
framework is complemented by a single system for communicating these hazards through symbols, labels and Safety Data Sheets.
The UK has consolidated all previous amendments to its Chemicals (Hazard Information and
Packaging for Supply) Regulations (CHIP) as well as introducing provisions to enforce the EU
CLP Regulation into CHIP 4 (Statutory Instrument 791/2009), which came into force on 6th April
2009. The UK CHIP Regulations will be repealed when the implementation of the CLP Regulation
is complete in June 2015.
Classification.
The classification hierarchy used by the new provisions is as follows: Explosive; Gases; Flammable; Other Flammable Materials; Oxidising Substances and Organic Residues; Toxic and Infectious Substances; Radioactive Materials; Corrosives; and Miscellaneous Dangerous Substances.
The Regulation also contains more than 7000 translated classifications in the form of Annex VI
table 3.1. This, along with table 3.2, replaces the list of substance classifications within the previous Directive's Annex I, the 'approved supply list'.
Annex VII of the CLP Regulation incorporates a 'translation' table, which can be used to convert
classifications under the current Dangerous Substances Directive to new classifications made by
applying the GHS criteria. If there is no direct equivalent, the least severe classification is assigned. The supplier has a duty to decide if a more severe classification is required.
The EU has said its intention is to help suppliers or importers of substances and mixtures comply
with their obligations under the new Regulation without having to reclassify, as long as the chemical has already been classified under the existing system. However, if a supplier or importer decides not to use the 'translation' table they must fully re-evaluate the substance or mixture using
the criteria in the Regulation.
The new CLP Regulation therefore creates a substance classification and labelling inventory that
will be populated by classifications determined by industry. Much of the information provided on
these classifications will be submitted as part of the suppliers' REACH registration for those substances placed on the market.
The classification of mixtures is a slightly more complex process owing to the fact that they can
contain numerous substances of different hazard classes. The regulation provides three alternative methods for the classifier to choose from:
* Test the mixture to determine classification; or
* Read across, as per Article 61; or
* Acute toxicity estimates (ATE), as per Annex I part 3.1.
The first option is usually impracticable owing to the sheer level of testing required, and the cost
of compliance. The tests are the same as those required for registration under REACH. The third
option, acute toxicity estimates, requires more information and is labour-intensive. It requires a
different skill set and the services of a toxicologist. This method is generally assumed to be an
accurate calculation method but, at present, the level of information and data available to guarantee an accurate calculation is not readily to hand. However, this process will become easier as
REACH gathers pace.
Labelling.
In labelling terms, the provisions introduce two 'signal words': Danger designates more serious
hazard categories; Warning is used for less severe hazard categories. The first stage of the label-

ling matrix is below:

Name, address, and telephone number of supplier;
Any relevant signal words;
Nominal quantity of substance or mixture in package;
Any relevant hazard statements;
Product identifiers (name, CAS number, etc.);
Any relevant precautionary statements;
Any relevant hazard pictograms;
Any supplementary information.
The regulation does not specify a label format, just a set of label elements that must be included.
With regard to substances and mixtures sold to the general public the existing provisions (i.e. in
the Dangerous Substances and Dangerous Preparations Regulations) for Tactile Warnings of
Danger (TDW) and Child-Resistant Closures and Fastenings (CRC/CRF) have been retained in
the new Regulation. The only change is to align the current applicable hazard classes to correspond with the new designations under CLP. Details of these requirements can be found in Article 35 and Annex II, Sections 3.1 & 3.2, of the Regulation.
Packaging.
The CLP Regulation retains the existing level of basic features with which packaging for supply to
the general public market should comply. First and foremost, it should be designed and constructed so that its contents cannot escape; the packaging must be compatible with the contents;
it must be able to withstand the stress and strains of handling; it should not attract the attention of
children; or mislead consumers.
In addition, its fastenings should not loosen during handling and it should be capable of being refastened repeatedly without leakage.
However, CLP also introduces special rules pertaining to the labelling of outer, inner and single
packaging (see Article 33). These rules allow for the removal of duplicate information when packages are labelled in accordance with both CLP and transport regulations. The rules are as follows:
Where a package consists of an outer and an inner packaging, together with any intermediate
packaging, and the outer packaging meets labelling provisions in accordance with the rules on
the transport of dangerous goods, the inner and any intermediate packaging shall be labelled in
accordance with the CLP Regulation. The outer packaging may also be labelled in accordance
with the Regulation. Where the hazard pictogram(s) required by this Regulation relate to the
same hazard, as in the rules for the transport of dangerous goods, the hazard pictogram(s) required by this Regulation need not appear on the outer packaging.
Where the outer packaging of a package is not required to meet labelling provisions in accordance with rules on the transport of dangerous goods, both the outer and any inner packaging,
including any intermediate packaging, shall be labelled in accordance with the CLP Regulation.
However, if the outer packaging permits the inner or intermediate packaging labelling to be clearly
seen, the outer packaging need not be labelled.
Single packages that meet the labelling provisions in accordance with the rules on the transport
of dangerous goods shall be labelled both in accordance with the latter and the CLP Regulation.
Where the hazard pictogram(s) required by the CLP Regulation relate to the same hazard, as in
rules on the transport of dangerous goods, the hazard pictogram(s) required by this Regulation
need not appear."
The article makes a very good point at its conclusion in that it recommends that businesses who
will be affected should investigate the implications of the new legislation in plenty of time. Those

who delay risk accruing substantial disadvantages when the regulations take full effect.

The physical characteristics of the label must include:

Secure fixing.
Clear and indelible printing.
Indication of danger symbols printed in black on an orange background and readily noticeable
from the rest of the label.
A minimum dimension that depends on the capacity of the package being labelled, i.e.
<3 litres 52 mm by 74 mm >500 litres 148 mm by 210 mm.
The aim is to ensure the packaging of chemical products is appropriate, secure and provides the
necessary information to safeguard the user.

4.36 Regionally Harmonised Classifications: Annex VI of the EU's CLP-Regulation (EC) No

1272/2008
What is contained within Annex VI of the EU's CLP-Regulation ?
Regionally harmonised classifications: Annex VI of the EU's CLP-Regulation (EC) No 1272/2008
This annex is arranged in three parts:
Part 1
Provides an introduction to the list of harmonised classification and labelling, including information
listed for each entry and related classifications and hazard statements in Table 3.1, subject to
certain considerations arising from translating the classifications listed in Annex I to Directive
67/548/EEC.
Part 2
Lays down general principles for preparing dossiers to propose and justify harmonised classification and labelling of substances at Community level.
Part 3
Lists hazardous substances for which harmonised classification and labelling have been established at Community level.
In Table 3.1 the classification and labelling are based on the criteria in Annex I to this Regulation.
In Table 3.2 classification and labelling are based on the criteria in Annex VI to Directive
67/548/EEC.

5.0 Principles of Epidemiology and the Principles of Deriving and Applying Toxicological
Data
Here we begin with a comprehensive review of the principles of toxicological investigation and
their use and limitation in recognising health hazards.
METHODS OF TOXICOLOGICAL TESTING.
Legal Requirements.
Regulations relating to the use of new substances in the UK require a range of physico-chemical,
toxicological and eco-toxicological studies.
The level of testing depends on the quantity of substance that is intended to be produced, but the
types of toxicological studies that are required are given below (and described in more detail
later):

Acute toxicity: -Oral - Inhalation - Cutaneous (skin).

Skin and eye irritancy.
Skin sensitisation: - Positive result indicates potential for contact dermatitis.
Subacute toxicity (28 days).
Mutagenicity (bacterial and non-bacterial):
To determine if the substance has the ability to cause genetic damage and the potential to induce
cancer.
Carcinogenicity:
If mutagenicity tests prove positive, the animal is subjected to lifetime exposure to the substance,
and at post-mortem an examination is carried out to detect tumours.
Teratogenicity:
To examine the effect of the substance on the development of the embryo and foetus to identify
gross anatomical abnormalities.
In addition to these tests, it may be necessary to repeat the studies using other species of animals and/or alternative routes of exposure.
Dose/Response Relationships.
Toxic substances have very different effects on organisms, including the minimum level at which
an effect is detectable; the sensitivity of the organism to small increases in dose; and the level at
which the harmful effect (most significantly, death) occurs.
Such factors are indicated in the dose-response relationship, which is a key concept in toxicology:
Dose is the amount per unit of body mass of toxic substance to which the organism is exposed.
Response is the resultant effect.
In order to define a dose-response relationship, we must specify the particular effect, i.e. death,
and also the conditions under which the effect is obtained, i.e. length of time of administration of
the dose.
If we consider a specific example we can see that

at low doses, no organisms will show a response, i.e. they all live;
at higher doses, all organisms show a response, i.e. they all die;
in between, there is a range of doses over which some organisms respond and others do
not.

This is shown in Figure 3.1.

The dose-response curve is S-shaped and the mid-point represents the dose which would cause
an effect (in this case death) in 50% of the organisms. It is designated as the LD50.
You should appreciate that LD50 is not an exact value, and in recent years there has been much
discussion as to its usefulness and necessity in toxicology. In 2001, the OECD abolished the requirement for the oral test. The LD50 values may vary for the same compound between different
groups of the same species of animal. The size of the sample used in testing varies; it can be as
many as one hundred or as few as twenty. During the discussions on the abolition of the LD50
test requirement, the OECD said that under its new system, the number of animal deaths could
be as few as three per test, implying that the total test population could be somewhere in the region of six.
This link gives access to an abstract of a study concerning the use of the Fixed Dose procedure
and its merits over the LD50 test.
http://dx.doi.org/10.1016/0278-6915(90)90117-6
However, the value is of use in comparing how toxic a substance is in relation to other sub-

stances. Table 3.1 gives examples of LD50 values for a variety of chemical substances.
Compound

LD50 (mg/kg)

Ethanol

10,000

DDT

100

Nicotine

Tetrodotoxin

0.1

Dioxin

0.001

Botulinus toxin

0.00001

Table 3.1
ED50 (effective dose for 50%) and TD50 (toxic dose for 50%) are related parameters which indicate the dose at which a biological response is likely.
Comparison of ED50 with LD50 gives an indication of the margin of safety between the dose
which causes the first identifiable effect and that which is fatal.
Testing for carcinogenic potential is more complex, since there is no simple dose-response relationship.
The toxicology of carcinogens is approached in a different way but still involves exposing laboratory animals (usually rats and mice) to the chemical by oral, inhalation or skin contact techniques.
There are also short-term predictive tests available which are considered to simulate potential
carcinogenicity in man. They are called short term, in contrast to the usual lifetime studies in rodents, which can take three to four years before a result is available.
Short term tests include:

Those for mutation (Ames test).

Tests for DNA damage.
Test for chromosomal damage.
Tests for cell transformation.

We will consider some of these tests in more detail later in this study unit.
Once a dose-response relationship has been demonstrated, there are a number of parameters
that can be derived from it.
If exposure is oral and lethality is used as the end point, LD50 can be determined as we have
seen previously. LD50 is defined as 'a statistically derived expression of a single dose of a material that can be expected to kill 50% of the animals'.
However, the S-shaped dose-response curve can be further analysed mathematically to determine doses that have a higher or lower probability of fatality.
The determination of LD90 from the dose response curve, for example (see Figure 3.1) enables
estimation of the dose that will kill the majority (i.e. 90%) of a sample of animals.
When the route of exposure is inhalation and lethality is used as the end point, it is the concentration of the airborne toxin that is of concern. Since the amount of toxin inhaled depends on the duration of exposure, there are two ways to express this data:
The lethal concentration can be determined for a specified duration of exposure. If the median
lethal concentration is determined, this is designated as LC50, which is defined as the statistically
derived expression of the concentration of airborne toxin that can be expected to kill 50% of ex-

posed animals in a specified time. As indicated above, the resulting dose-response relationship
can be used to estimate other corresponding parameters such as LC90.
The lethal time can be determined for exposure to a given concentration of airborne toxin. If the
median lethal time is determined, this is designated as LT50, which is defined as the statistically
derived expression of the exposure time necessary that can be expected to kill 50% of exposed
animals at a specified concentration of airborne substance.
With all these parameters, it is important to remember that they simply represent statistically determined doses, concentrations or times, derived experimentally in the manner described above.
Their use in comparing the 'toxicity' of different substances, and consequently their potential to
cause occupational ill-health must be qualified by a clear understanding of the limitations of the
method by which this statistical data is derived.
We made reference earlier to the concept of a dose below which no effect or response is measurable. This is termed the threshold dose and can be clearly demonstrated with responses such
as lethality. This concept of a threshold dose for the toxic effect is an important one, and implies
that there will be a dose at which the response does not occur in any member of the population.
This is shown in Figure 3.1 where the dose response curve shows no deviation from the x-axis
(% effect = 0) until log dose reaches a value of 5 units. The term for this is the 'no observed adverse effect level' or NOAEL. We have already discussed the converse of this with carcinogens,
where a threshold dose cannot be established and therefore it must be assumed that any exposure to carcinogenic substances has the possibility of an adverse effect.
The NOAEL is important for setting exposure limits such as workplace exposure standards, which
are designed to represent a level of exposure at which there is no evidence of harm. We will discuss the application of this type of toxicity data in establishing criteria for occupational exposure
limits in Unit B3.

5.1 Types of Toxicity Test.

Toxicity tests tend to share certain basic principles. They usually involve exposing experimental
animals to the test substance under controlled conditions.
For existing chemicals, toxicological information may also be obtained from epidemiological data
such as human exposure in the workplace, or humans and animals exposed in the general environment. So, for example, workplace exposure may be determined from the measurement of potentially toxic substances or their metabolites in human body fluids.
Similarly environmental exposure to pesticides may be determined in the field by measurement of
pesticide levels in wild birds.
The main types of toxicity tests are described below.
Acute Toxicity Tests.
These are designed to determine the effects which occur within a short period after dosing.
These tests can determine a dose-response relationship and the LD50 value.
The initial tests will involve increasing the dose to a sample of animals by successive orders of
magnitude (factors of 10) in order to establish the range of toxic effects.
Once this has been established, a study similar to that outlined in Table 3.2 can be carried out in
order to classify the substance. Note that the criterion used is 90% survival.
Test Dosage

Result

Action/Classification

5 mg/kg
< 90% survival > 90%
survival but toxicity > 90%
survival no toxicity

Very toxic Toxic Retest at

50 mg/kg

< 90% survival > 90%

survival but toxicity > 90%
survival no toxicity

Toxic, retest at 5 mg/kg

Harmful Retest at 500
mg/kg

< 90% survival or toxicity >

90% survival no toxicity

Harmful, retest at 50 mg/kg

Unclassified

50 mg/kg

500 mg/kg

Table 3.2: Investigation of Acute Oral Toxicity

If a large enough sample of animals is used at each dosage level, the LD50 value can be
determined from analysis of the data.
Subacute Toxicity Tests.
These involve exposing animals to a substance for a prolonged period of one or three months,
which enables toxic effects which have a slow onset to be detected.
This type of exposure provides information on the target organs affected by the substance, and
the major toxic effects. Such tests also allow measurement of the substance in blood and tissues
to be made.
The information gained can be used in the design of the next type of test, the chronic toxicity test.
Chronic Toxicity Tests.
These tests involve lifetime exposure of animals to the substance under study.
Similar measurements to those described for subacute toxicity tests can be made throughout the
study to identify the development of pathological changes, which can then be detected in a postmortem.
Other long-term changes in measurements such as food and water intake, body weight, and
behavioural changes can serve to indicate harmful effects.
These types of study are important in determining possible effects of long-term occupational
exposure, or environmental exposure to low levels of chemicals.
For all three types of toxicity test, the following parameters should also be considered:

Type of chemical under study (novel compound or in use for some time)
Selection of doses (quantity; single dose or repeated doses)
Species and strain of animal (extrapolation to human exposure)
Exposure route (comparable with likely occupational exposure route)
Method of exposure (physical and/or chemical properties of substance)
Experimental observations and measurements to be made (similarities with other compounds of known toxicity)

5.2 Uses and Limitations of Toxicological Testing.

So far, we have made general reference to various types of toxicity test designed to identify acute
or chronic effects. We now develop this further and examine three very different methods used to
examine substances for toxic effects.
(a) Mutagenicity testing aims to identify the potential to cause damage to genetic material. This, in
turn, indicates the possibility that the substance in question could possess mutagenic or carcino-

genic properties.
(b) Long-term toxicity tests involve lifetime studies on animals exposed to potentially toxic substances, and are able to provide a wealth of information on mode of action, dose effect relationships and target organs.
(c) Chemical analogy tests enable predictions to be made on possible mode of toxic activity
based on the chemical structure and properties of substances.
We shall examine each of these different test methods in turn to determine the methodology and
also the possible limitations in their use.
Mutagenicity Testing.
Mutagenesis occurs as a result of interaction between mutagenic agents (agents able to cause
mutations) and the genetic materials of organisms. Evolution of living species is based on spontaneous mutation followed by natural selection.
Mutations that give a natural advantage to a species survive to be promoted by natural selection,
whereas those that reduce the chances of survival are eliminated.
However, in recent years a growing number of toxic substances have been shown to possess
mutagenic properties, and the concern is the inability to predict the eventual effects of human exposure to these substances.
In addition, tests for mutagenicity are now more widely used because of their use as a rapid
screening method for carcinogenicity, because most mutagens have been found to be carcinogens. Furthermore, mutagenicity tests are useful in establishing the mode of action of carcinogens, since human tumours often display chromosomal abnormalities.
Gene Mutation.
DNA (deoxyribonucleic acid) consists of a long double helical chemical strand of ordered nucleic
acid bases.
The order and combination of the four different types of base provide a genetic code which contains unique information (in 'packets' called genes) to enable the synthesis of proteins and the
construction of living matter.
As well as holding the information necessary for the growth of organisms, this genetic information
can also be transmitted from one generation of cells to the next through self-replication. In this
way, species of organisms survive through reproduction.
Gene mutations involve additions or deletions of bases in the DNA molecules. In addition, a
mutagenic chemical, or part of it, may be incorporated into the DNA molecule.
In either case, these changes to the DNA molecule may cause the substitution of a new amino
acid or a different amino acid sequence in the synthesised protein molecule, thus leading to a
modification (possibly damaging) to the biological properties of the protein.
The most common test to detect genetic mutation is the Ames test. The basis of this test is to expose bacteria to the suspected mutagen and observe for detectable mutation. This is done by
using a special type of Salmonella typhimurium bacteria which has been genetically modified to
grow only in a medium containing histidine (a type of amino acid).
Normal bacteria, however, will multiply in a histidine-deficient medium.
Consequently, the test bacteria are incubated in a medium which contains insufficient histidine
and therefore no growth takes place.
If a mutagen is now added to the medium, it will cause a genetic change which reverses the
original genetic modification and now enables affected bacteria to multiply as normal in the histidine-deficient environment.
Hence the observation of appreciable growth indicates that reverse mutation has taken place,
and the substance in question does have mutagenic properties.
Since this test only involves the exposure of bacteria to the mutagen, it is termed an 'in vitro' test.

However, gene mutation tests can also be carried out 'in vivo' (in a host animal, usually a mouse)
by injecting the host with the mutagen and directly examining either micro-organisms or host cells
for evidence of genetic damage.
Chromosomal Effects.
The effect of a mutagen on a chromosome (an assembly of genes) may be great enough to be
visible microscopically, either as structural aberrations or changes in numbers.
Heritable Effects.
At present, there is no direct correlation between laboratory tests for heritable mutations and human experience. Nevertheless, if a substance has been shown to be mutagenic in a variety of
test systems, including heritable mutations in mammals, it must be considered as a mutagen in
humans unless there is convincing evidence to the contrary.
Long-term Animal Toxicity Studies.
Humans are more often exposed to chemicals at levels much lower than those that are acutely
fatal, but they are exposed over longer periods of time. To assess the nature of these toxic effects
under these more realistic situations, long-term toxicity studies on animals are conducted. The
key elements of such studies are outlined below.
Experimental Design.
Species and number:
Generally, two or more species should be used that metabolise the chemical in a way similar to
humans (often rats and dogs are used due to size, availability and the amount of toxicological
data already available on these animals).
Equal numbers of male and female animals should be used, with from 10 to 50 animals in each
dose group.
Route of administration:
The chemical should be administered by the likely route of exposure.
For most chemicals, the route will be oral, so the chemical will be incorporated into the diet or
drinking water.
For special circumstances such as industrial products, agricultural products and drugs, dermal
application or inhalation may be used.
Dose and duration:
Dosage will be set at three levels:

High enough to show signs of toxicity but not to kill.

Low enough to show no toxic effect.
Intermediate.

Duration is generally two years for rats and seven years or more for dogs.
Observations and Examinations.
Body weight and food consumption:
Decreased body weight gain is a simple but sensitive indicator of toxic effects.
Food consumption is also a useful indicator.
Appearance and behaviour: - both of these parameters, along with development of any abnormalities, should be noted.
Laboratory tests: - these include blood and urine sampling and testing.
Post-mortem examination:
All dead animals should be subjected to a full pathological examination, including weight and
analysis of major organs.

Correlation between general observations, clinical laboratory tests and post-mortem examination
for major organs and systems can provide valuable information on the effects and mechanism of
action of the chemical in question.
Evaluation:
The parameters of observations and examinations described above will provide information on
the toxicity of the chemical under test with respect to the target organs, the effects on these organs, and the dose-effect and dose-response relationships.
In addition, the NOAEL from long-term studies can be used to determine exposure limits or 'acceptable daily intakes' for humans, as we have discussed previously.

5.3 Chemical Analogy Studies.

One of the methods used to attempt to predict the possible toxic properties of a substance is to
assume that chemically related substances will show similarities in toxic properties. Whether this
is a true assumption will depend on the mechanism of action of the known toxicant and whether
the chemical analogue is able to act in a similar way.
The principal mechanisms of action, along with examples of the process or site of action and
types of toxicant, are outlined below.

Interference with receptors that transmit physical or chemical signals to cells:

Neurotransmitters (organophosphate pesticides)

Hormone receptors (halogenated aromatic hydrocarbons)
Enzymes (cyanides)
Transport proteins (carbon monoxide)

Interference with membrane function:

Membrane fluidity (organic solvents)

Mitochondrial membranes (organo-tin compounds)

Interference with cellular energy production:

Haemoglobin (carbon monoxide)

Electron transport inhibition (cyanides)

Covalent binding to biomolecules:

Lipids peroxidation (carbon tetrachloride)

Nucleic acids (mutagens)
You can see that some of the examples given above include ranges of chemically related toxic
substances that possess a similar mechanism of action due to their closely related chemical
structure. It also follows from this that by understanding the mechanism of action, it may be possible to predict other types of substance, of different structure but similar mechanism of action,
that could interact with metabolic processes in the same way as a particular toxicant.
Predictive studies of this type usually start by examining the physicochemical properties of the
substance to determine its vapour pressure, water and lipid solubility. This information gives clues
as to likely routes of exposure (inhalation, skin, or oral), likelihood of absorption and possible
routes of excretion of absorbed material. Then further predictive information can be obtained from

the structure of the substance (including structures of impurities), through the use of structure activity relationships and data on analogous substances referred to above.
Preliminary assessments of chemical carcinogens often begin with a close examination of chemical structure. Whilst chemicals that have structures similar to known carcinogens or mutagens are
not necessarily carcinogenic themselves, they will be assigned a high priority in any carcinogen
testing programme. In addition, there is evidence to show that certain chemical structures have
been shown to be correlated with carcenogenicity.

5.4 Epidemiology.
In this section, we are going to look at epidemiology (determining the cause having first observed
the effects) by examining the main methodologies of epidemiology, the sources of information
available, their application and limitations and also the use of epidemiological techniques in the
workplace.
HISTORICAL PERSPECTIVE.
You will remember that occupational health and hygiene are concerned with recognition, measurement, evaluation and control. Epidemiology is the science which forms the basis of the four
stages. At its crudest, epidemiology may be said to be the elucidation of the cause, having first
observed the effects. For example, if a number of workers on a particular process are suddenly
affected by dermatitis, i.e. the effect, it is likely that the cause is of occupational origin, possibly a
new raw material. However, the cause can often only be established in the light of current knowledge and understanding. John Snow (1813-1858) flew in the face of conventional wisdom when
he suggested that cholera was due to contaminated water rather than airborne miasmas.
A semblance of the cause-effect relationship in occupational disease has been recognised since
early times. Hippocrates, the father of medicine (born 460 BC), was probably among the first to
recognise lead as a cause of colic; and Pliny (23-79 AD) describes mercurialism in writing of the
diseases of slaves.
One of the greatest technical manuals ever written is De Re Metallica by Agricola, whose real
name was Georg Bauer (1494 - 1555), completed in 1530 but first published in Basle in 1556. He
described and illustrated in detail the techniques and methods used by German mining engineers
to win metallic ores, and also covered aspects of occupational diseases (he was a medical doctor
by profession). On miners in the Carpathian mountains, he comments:
On ventilation: 'If a shaft is very deep and no tunnel reaches to it, or no drift from another shaft
connects to it, or when a tunnel is of great length and no shaft reaches to it, then the air does not
replenish itself. In such a case, it (the air) weighs heavily upon them (the miners), causing them to
breathe with difficulty and extinguishing lamps. It is therefore necessary to install machines to enable the air to be renewed and for the miners to carry on their work.' (See Figure 4.1.)

Figure 4.1.
On accidents: 'The Burgomeister gives no-one permission to enter the mines after blasting until
the poisonous vapours are cleared.'
On diseases of the lung: 'If the dust has corrosive qualities, it eats away the lungs and implants
consumption in the body. In the mines of the Carpathian mountains, women are found who have
married seven husbands, all of whom this terrible consumption has carried off to a premature
death.'
To protect miners against the effects of the dust, Agricola advised purification of the air by ventilation and the use of loose veils over their faces.
Paracelsus (1493-1541) published the first monograph devoted entirely to the occupational dis-

eases of mine and smelter workers (Von der Bergsucht und Anderen Bergkrankheiten, 1567).
Although he makes correct clinical observations, he then unfortunately turns to unproven alchemical notions to explain them:
'The lung sickness comes through the power of the stars, in that their peculiar characteristics are
boiled out, which settle on the lungs in three different ways: in a mercurial manner like a sublimated smoke that coagulates, like a salt spirit, which passes from resolution to coagulation, and
thirdly, like a sulphur, which is precipitated on the walls by roasting.'
If Hippocrates is the father of medicine, then Bernardino Ramazzini (1633-1714) is the father of
occupational medicine. His De Morbis Artificum Diatriba (1700) contains accounts of the occupational diseases suffered by

miners of metals,
healers by inunction,
chemists,
potters,
tinsmiths,
glass-workers,
painters,
sulphur-workers,
blacksmiths,
workers with gypsum and lime,
apothecaries,
cleaners of privies and cesspits,
fullers,
oil pressers,
tanners,
cheese-makers,
tobacco-workers,
corpse-carriers,
midwives,
wet nurses,
vintners and brewers,
bakers and millers,
starch-makers,
sifters and measurers of grain,
stone-cutters,
launderers,
workers handling flax, jute and silk,
bathmen,
salt-makers,
workers who stand for long periods,
sedentary workers,
grooms,
porters,
athletes,
runners,
singers,
preachers,
farmers,
fishermen,
soldiers,
learner men,
priests and nuns,
printers,
scribes and notaries,

confectioners,
weavers,
coppersmiths,
carpenters,
grinders of metals,
brick-makers,
well-diggers,
sailors and rowers,
hunters and
soap-makers.

In short, most of the important occupations of the day. As a result of his investigations, he added
an important question to the Hippocratic art, urging physicians to ask of their patients, 'What is
your occupation?' He also 'urged physicians to leave their apothecary's shop, which is redolent
with cinnamon, and to visit the latrines where they may see the cause of ill-health.'

5.5 Statistics and Epidemiology.

Importance of Statistics
Few early writers produced statistics to support their accounts of occupational diseases, and it
was not until after the publication of his famous Essay on the Principle of Population (1798) that
Thomas Malthus (1766-1834) emphasised the importance of statistical techniques when he
claimed that food supply and birth rate increase in arithmetical and geometrical ratios respectively, so that poverty (through lack of food) is the inevitable result of increased population. Malthus' essay was also read by a young English scientist named Charles Darwin, who cited it as an
influence on his developing Theory of Evolution by Natural Selection.
William Farr (1807-1883) was appointed as compiler of statistics at the newly-formed General
Register Office (of births, marriages and deaths) in 1839, and by 1866 he was able to state, on
the basis of statistical analysis, that the curve of an epidemic (such as smallpox, typhoid or cholera) at first ascends rapidly then slopes more slowly to a maximum, to fall more rapidly than it
climbed (Farr's Law). The General Regiester Office has published occupational mortality data
every ten years since it was introduced by Farr in 1851.
Cholera.
Endemic in India for centuries, cholera became pandemic in Asia between 1816-1830 and
reached England in 1831. In the summer of 1854, cholera broke out in London, being particularly
severe in the poorly-drained slums around St. Giles and Soho. This gave John Snow the opportunity to carry out the first truly epidemiological investigation into the relationship between cause
and effect of a disease. The effect was obvious. After an incubation lasting about three days, victims suffered from severe diarrhoea and vomiting, accompanied by cramps in the legs and abdomen. The skin lost its elasticity due to dehydration, becoming cold and clammy, the heartbeat
became weakened and the pulse and voice very feeble. Before treatment with modern antibiotics,
patients would die after a few days and mortality rates were very high.
During the course of the epidemic, Snow plotted the household of every death in the area and his
'On the Mode of Communication of Cholera, 1855', includes the figures of his most famous field
study around the Broad Street pump. By plotting the incidence of deaths onto a map (Figure 4.2),
he was able to demonstrate that the nodal point was the Broad Street pump. This led to his initial
conclusion that it was the water from this pump which had been responsible for the outbreak.
Further investigation revealed that shortly before the epidemic, the Lambeth Water Company had
removed their waterworks to Thames Ditton, well above the tidal reaches of the Thames, and
hence the water was uncontaminated by London sewage.
The Southwark and Vauxhall Water Company, however, continued to supply water from the

Thames at London Bridge. He found there were 14 times more fatalities from cholera in people
drinking the Southwark supply than in those drinking the Thames Ditton supply.
He became absolutely convinced when he learned of the death of a Hampstead woman who sent
a carrier daily to collect water from the Broad Street pump, and died of cholera as a result. Her
niece, who had visited her for a day, also became the only victim of the disease in her district.
As Snow was proclaiming that dirty water was responsible for the epidemic, so a Parliamentary
enquiry was establishing the cause as stale air from the closely-packed tenements in the area,
thus proving that Miasmatic Theory was still prevalent amongst most eminent medical men of the
day.

Figure 4.2: Cholera Deaths Between 19 Aug and 30 Sept, 1854, as Plotted by John Snow
Plotting the Incidence of Legionnaires' Disease.
Environmental Health Officers investigating two outbreaks of Legionnaires' Disease around the
BBC's Bush House in 1987 and Leicester Square in 1988 used Snow's method of plotting the in-

cidence onto maps in an effort to identify the source of the infection.

The technique has also been used in the investigation of complaints arising from the use of pesticides and other agricultural chemicals. Some studies may take several years of intensive investigation to complete, consuming thousands of hours of work.

5.6 Sources of Epidemiological Data.

The first data used for the investigation of occupational causes of disease were population census figures and death registrations, the only information available for such purposes at the time.
These days, there is much more data available for the epidemiologist to use for studies and the
principal sources are given below.
National Records.
The main national records available for study are:
Death Certificates.
These provide a reasonably accurate and quantifiable measure of serious illness. However, problems occur with:
-the accuracy of the cause of death (this relies on the physician's decision)
-the occupation of the deceased (this may be the occupation at the time of death but not necessarily the one that caused the death).
Birth Certificates.
These can be used in conjunction with data on congenital malformations and pregnancy complications to study the effect of parents' occupations on these conditions.
Morbidity.
The Reporting of Injuries, Diseases and Dangerous Occurrences Regulations 1995 (RIDDOR)
requires the reporting and central recording of industrial accidents and diseases, whilst industrial
injury benefit claims and prescribed diseases are reported to the Department of Social Security.
However, problems with these sources of data include:
- failure to report accidents and injury despite the legal requirement;
- errors in diagnosis or identification of occupational disease.
Local Records.
Depending on the study in question, hospital records, data from family doctors, information collected by professional associations (e.g. the Royal Society of Chemists' morbidity and mortality
study) or trade union records may provide useful data for epidemiological studies.
In addition, some large employers maintain continued surveillance on high-risk workers as they
move within the company, and also when they leave or retire.
If a specific study is being undertaken, this type of local data may provide valuable information to
enable a fuller picture to be built up of particular employees' health and employment history.

5.7 Criteria for Cause and Effect.

A number of important criteria must be satisfied in order to establish a definite relationship between a disease's cause and effect:

Strength: the relative incidence of the disease in exposed and unexposed groups.
Consistency: observing the disease in different places and at different times by different
observers.

Specificity: where the association (between cause and effect) is limited to specific workers
and to a particular type of disease, there is a strong argument in favour of causation.
Biological gradient: if an increase in dose or exposure brings about an increase in incidence, then there is strong evidence of causation.
Biologically plausible: the relationship should not conflict with known facts of the natural
history and aetiology of the disease.
Analogy: similar chemicals, biological agents and physical inputs being likely to have similar effects.
Preventive action: if the preventive action works, i.e. there is a reduction in the effect, then
it is likely the cause was correctly identified, e.g. a reduction in an atmospheric contaminant affecting the frequency or severity of the disease or other associated event. It is perhaps this final criterion which may be said to be the proof of the pudding.

In the case of the original 1976 American Legionella outbreak, health investigators identified the
following causal factors:

Strength: early on, it had been established that the victims were mainly convention delegates.
Consistency: Similar outbreaks had occurred in Pontiac in 1968 and shortly after, other
outbreaks were identified in Vermont (1977), Indiana (1978) and Oxford, England (1979).
Specificity: air conditioning plant was soon implicated as an indirect cause.
Biological gradient: eventually, it was established that potential victims had to inhale an
aerosol containing a high concentration of Legionella pneumophilia.
Biological plausibility: A suggestion that an anti-military madman had murdered the legionnaires smacked of hysteria rather than accounting for the known biological facts.
Analogy: all the evidence pointed to a biological cause (bacterium, virus, etc.)
Preventive action: cleaning and sterilising possible water sources eliminated the bacterium from water tanks and other water supplies.

The success of preventative action is proof that the epidemiologists had correctly identified the
cause of the disease, together with the events and circumstances necessary to link cause with
effect.
PROBLEMS IN ACHIEVING CONTROL.
It is fortunate that the measures implemented for the control of Legionnaire's Disease and elimination of the bacterium from water systems proved simple and effective.
This is not always the case, and sometimes the interval between implementation of control
measures and an observed decline in the incidence of a disease may cover many years.
In these circumstances, it is inevitable that doubts will arise as to the effectiveness of the control
measures and, consequently, as to the actual cause. Some examples will serve to illustrate the
point.
Example 1: Lead Poisoning.
Lead poisoning became notifiable in the potteries in 1896, when there were 351 cases out of
some 5,000 at risk. Although the overall rate began to fall almost immediately, the number of
deaths remained fairly constant for a number of years afterwards.
Lead poisoning became notifiable in all factories in 1899 and the cases of poisoning fell from
more than a thousand in 1900 to 55 in 1960; but again the death rate did not follow a similar pattern. Indeed, it increased in some years (see Figures 4.3 and 4.4).
In the electric accumulator industry, the incidence of lead poisoning rose from 1900 until the
passing of the Lead Accumulator Regulations in 1924, after which there was a decline in the incidence of poisonings (see Figure 4.5). Once again, the death rate remained relatively constant.
It would have been comparatively easy in this period to suggest that it was not lead which was

responsible for the disease; but we now know that the time lag is largely due to the long-term effects of lead poisoning, and because the bones store large amounts of lead, releasing it slowly
over a number of years.
Figure 4.3: Lead Poisoning in the Potteries

Figure 19.4: Notified Cases of Lead Poisoning

Figure 4.5: Notified Cases of Lead Poisoning in the Electric Accumulator Industry

Example 2: Mesothelioma.
Diseases such as mesothelioma may have a latency period of as much as 40 years between exposure and manifestation, so we must expect to diagnose causes of the disease well into this
century, even though asbestos has been subject to tight controls since the 1970s.
Example 3: Dermatitis.
With diseases such as dermatitis, where the victim may become sensitised, the disease may
"flare up" again following only very small exposure to the harmful agent, or to another agent
which is chemically analogous.

5.8 An Early Example of Epidemiology.

An essential feature of epidemiological investigation is a count of the incidence of the disease
and a comparison of affected and unaffected populations. Nowadays it is more usual to resort to
more advanced statistical techniques rather than simple counting.
In 1664 King Charles II ordered that 'Bills of Mortality' be kept for each parish of London, so the
extent of the Great Plague could be established accurately.
The first victim was in November 1664 and each week, the number of victims gradually increased
such that by April 1665 twenty-five died in one week.
By late summer, the parishes of Clerkenwell, Shoreditch, Bishopsgate, Moorgate, Whitechapel
and Stepney had all been affected.
A page from the Bills of Mortality makes interesting reading (Figure 4.6).

Figure 4.6: Page Copied From the Bills of Mortality

From the data contained in these weekly reports, we can calculate the relative incidence of each
cause of death and, from successive weeks, it was possible to tell whether the plague was increasing or decreasing.
We also have a record in this instance of two industrial accidents - a drowning and a fall!
You may be surprised by some of the data; for example, the number who died from 'teeth'. In fact,
this was a combination of blood poisoning and infection as a consequence of poor dental care.
A number died from food poisoning or other digestive disorders (colic, griping in the guts, rising of
the lights, surfeit and wind) as a result of poor hygiene.

One died 'suddenly'!

Modern epidemiological investigations are far more sophisticated than this, as you will see below.

5.9 Types of Epidemiological Study.

We have already acknowledged that epidemiology is concerned with the distribution of a particular occupational disease, and the search to identify the occupational factors that may be involved.
We can therefore see that a representation of the workplace situation involves individuals of different age, sex, occupation, race and duration of employment experiencing continually varying
exposures to workplace agents.
Within this changing workplace population, occupational ill-health may occur either during employment, during future employment or after retirement. From this complicated picture, which is
changing with time, the epidemiologist must try and design studies which will establish a cause
and effect relationship between workplace agents and occupational disease.
If we wish to investigate this process and/or the population, there are two basic studies that we
can make.
Cross-sectional Studies
The cross-sectional study involves a 'snapshot in time' of the relevant workforce. A section of
workforce is examined over a short period of time. The advantage of this type of study is that it is
a quick and cheap opportunity to study the problem in hand, but the disadvantage is that the
population at risk is assessed over a narrow time frame. This means that the investigators cannot
look at exposure and the resulting outcome over a period of time. The cross-sectional study
therefore tends to be:
outcome-selective: the study examines the prevalence of a particular occupational condition
within the population;
exposure-selective: the study examines a particular population that has been exposed to a specified occupational condition.
For this reason, cross-sectional studies are also known as prevalence studies. The design of a
cross-sectional study involves the following main stages:
(a) Establishing precise aims.
(b) Defining the study population.
(c) Determining the sample size - important for statistical purposes.
(d) Recruitment of all relevant cases in the sample.
(e) Analysis - prevalence rates in relation to sample groups.
Longitudinal Studies.
The longitudinal study involves investigation of the workforce over a significant period of time.
This type of investigation takes longer to carry out and is more expensive but, because it takes
place over a period of time rather than at a specific point in time, it provides the opportunity to
study exposure and its outcome as a time-related chain of events. Two types of longitudinal studies are commonly employed:
The Case-control Study.
This type of study is retrospective, beginning with a definition of a group of cases and relating
these (along with non-cases or controls) to the past exposure history. The main drawback of this
type of study is obtaining accurate exposure history, which may need to go back as far as 40
years.
With the case-control study, the investigation compares a group of individuals who have the disease or condition with another group who do not. The comparison is made with respect to past

characteristics of both groups and, unlike the follow-up study (see below), the outcome is known.
The case-control method may be used, for example, to investigate the frequency of asbestos
workers who have respiratory problems or lung disease against a control group drawn from the
general population. It is quicker and less expensive than a cohort study (see below), and is often
used as the first step to see if there may be an association between a suspected cause and a
known effect. It is also useful in investigating a disease of low prevalence. Unfortunately, however, case-controlled studies are generally less informative than cohort studies and spurious associations are likely to occur.
The Follow-up Study.
This study takes a group of exposed (and possibly non-exposed control) persons where the exposure is defined and accurately known. The group is then followed up over an appropriate period of time to assess the eventual outcome of the exposure. This method is prospective (following the group forward in time) and avoids the problem of tracing exposure history retrospectively,
as with the case-control study.
Follow-up studies are useful for:

Special exposure (e.g. Japanese atomic bomb survivors).

Ease of follow-up (e.g. hospital patients, professional groups).
Geographical groupings (e.g. migrant studies).

A cohort study is a specific type of follow-up study where a population is defined in advance for
exposure characteristics, followed for a period of time and then the outcome measured. Follow-up
studies are designed to observe incidence of occupational ill-health and should, naturally, extend
over a period of time longer than that required for the outcome to develop.
Such retrospective studies are used to determine whether there is an association, for example,
between exposure to asbestos (the cause) and the incidence of lung cancer (the effect), and
uses two groups (cohorts) of subjects:

Exposed.
Unexposed (the control group).

The incidence of lung cancer is then calculated for each group, and if significantly more people
suffer in the exposed group then there is strong evidence for cause and effect.
In cases where there is insufficient past data on which to work, it will be necessary to set up a
prospective study.
Cohort studies are concerned with the relationship between the cause, as evidenced by the history and nature of the exposure, and the effect, i.e. the presence of the disease.
The advantages of cohort studies are that they provide:

a more accurate account of exposure related to deaths or disease and a direct estimate of
the risk associated with the causal factors;
information on secular trends which reveal changes in the degree of risk.

Against this must be set the following disadvantages:

It may be necessary to wait many years for the development of the disease (mesothelioma might take as long as 40 years to manifest itself).
Some of the cohort may be lost over the period of study.

5.10 Uses and Limitations of Epidemiological Studies.

There are five main uses of epidemiology in occupational health and hygiene:

Primary monitoring to identify hazards. Population studies are frequently the only way of
identifying an occupational risk of disease such as lung cancer, coronary heart disease,
varicose veins, or rheumatic disorders, because they are common in the general population.
Secondary monitoring to keep known hazards under control. Surveillance of a group of
workers exposed to recognised hazards identifies any susceptible individuals and assesses the value of preventive measures and the effectiveness of control measures.
Determining causes helps to establish health standards. Studying groups of workers may
lead to a determination of the association with the exposure to a contaminant such as a
dust or vapour; leading to the establishment of the cause and occupational hygiene standards such as workplace exposure limits (WELs).
Community studies reveal how many people are affected and how seriously. Priorities can
then be established, enabling preventive action to be taken when and where it is needed.
Evaluating health services to find out how they are used, their success in reaching certain
standards and the value attached to them by the population they serve.

In terms of the practical application of epidemiological methods to occupational health and hygiene, secondary monitoring is particularly important and is now implemented through the Control
of Substances Hazardous to Health (COSHH) Regulations.
Primary monitoring - the recognition of hazards - may be said to be a consequence of good primary procedures. Thus, if some workers begin to exhibit symptoms of dermatitis where no previous incidence has been recognised, there is a strong possibility that it has been caused by a
change either in the process or in work patterns, or by the introduction of a new or replacement
raw material. Having observed the effect, it should be possible to determine the cause by studying work patterns and raw materials.
As we have seen, the purpose of the epidemiological study is to establish the distribution of
health-related events or states in a specified population, and also the factors responsible. This
information can then be applied in the control of the particular health problem.
Practical Application of Epidemiological Methods.
In order to plan and implement an epidemiological study, the following broad steps need to be
followed:

Establish the objectives of the study and what hypotheses need to be tested. (Is disease A
caused by agent B?)
Define the study population, bearing in mind statistical limitations of study and control
group size.
Prepare a protocol and also any questionnaires needed.
Undertake a pilot study to test methodology.
Collect and analyse data.
Test hypotheses and record and report conclusions.

The exact detail of the study will depend on the type of epidemiological investigation that is being
performed.
Limitations of Epidemiology.
The main problems of epidemiological studies, which have been touched on in the previous sections, include:

The 'healthy worker' effect, whereby the control group has a different health status compared with the cases (pre-employment health screening has the effect of excluding less

healthy individuals, and consequently raising the general health of employed persons in
comparison to those not in work).
A poor response rate which reduces the sample size and its statistical significance.
A high turnover of study populations.
The latency period between exposure and effect is longer than the study period.
Poor quality of health affects data and/or exposure data.
No effect of exposure noted, which may be a consequence of a poor or small study population.

For an epidemiological study to be effective the following factors should be addressed:

Clearly formulated hypothesis and study objective.

Appropriate study design.
Collection of good quality health effects and exposure data.
Valid population choice for case study and control.
High response rate and good sampling strategy.
Population size large enough and correct statistical techniques used.
No effect study result investigated for validity and/or statistical significance.

In this way, the cause-association hypothesis that aims to relate occupational exposure to incidences of ill-health should be able to be validated, either positively or negatively.

5.11 Vertebrate Animal Testing - its Value and Limitations

Toxicology testing, also known as safety testing, is conducted by pharmaceutical companies testing drugs, or by contract animal testing facilities, on behalf of a wide variety of customers. According to 2005 EU figures, around one million animals are used every year in Europe in toxicology
tests; which are about 10% of all procedures. According to Nature, 5,000 animals are used for
each chemical being tested, with 12,000 needed to test pesticides. The tests are conducted without anesthesia, because interactions between drugs can affect how animals detoxify chemicals,
and may interfere with the results.
Toxicology tests are used to examine finished products such as pesticides, medications, food additives, packing materials, and air freshener, or their chemical ingredients. Most tests involve testing ingredients rather than finished products.
The substances are applied to the skin or dripped into the eyes; injected intravenously, intramuscularly, or subcutaneously; inhaled either by placing a mask over the animals and restraining
them, or by placing them in an inhalation chamber; or administered orally, through a tube into the
stomach, or simply in the animal's food. Doses may be given once, repeated regularly for many
months, or for the lifespan of the animal.
There are several different types of acute toxicity tests. The LD50 ("Lethal Dose 50%") test is
used to evaluate the toxicity of a substance by determining the dose required to kill 50% of the
test animal population. This test was removed from OECD international guidelines in 2002, replaced by methods such as the fixed dose procedure, which use fewer animals and cause less
suffering. Nature writes that, as of 2005, "the LD50 acute toxicity test ... still accounts for one-third
of all animal [toxicity] tests worldwide." Irritancy can be measured using the Draize test, where a
test substance is applied to an animal's eyes or skin, usually an albino rabbit. For Draize eye testing, the test involves observing the effects of the substance at intervals and grading any damage
or irritation, but the test should be halted and the animal killed if it shows "continuing signs of severe pain or distress". The Humane Society of the United States writes that the procedure can
cause redness, ulceration, hemorrhaging, cloudiness, or even blindness. This test has also been
criticized by scientists for being cruel and inaccurate, subjective, over-sensitive, and failing to reflect human exposures in the real world. Although no accepted in vitro alternatives exist, a modi-

fied form of the Draize test called the low volume eye test may reduce suffering and provide more
realistic results and this was adopted as the new standard in September 2009. However, the Draize test will still be used for substances that are not severe irritants.
The most stringent tests are reserved for drugs and foodstuffs. For these, a number of tests are
performed, lasting less than a month (acute), one to three months (subchronic), and more than
three months (chronic) to test general toxicity (damage to organs), eye and skin irritancy,
mutagenicity, carcinogenicity, teratogenicity, and reproductive problems. The cost of the full complement of tests is several million dollars per substance and it may take three or four years to
complete.
These toxicity tests provide, in the words of a 2006 United States National Academy of Sciences
report, "critical information for assessing hazard and risk potential". Nature reported that most
animal tests either over- or underestimate risk, or do not reflect toxicity in humans particularly
well, with false positive results being a particular problem. This variability stems from using the
effects of high doses of chemicals in small numbers of laboratory animals to try to predict the effects of low doses in large numbers of humans. Although relationships do exist, opinion is divided
on how to use data on one species to predict the exact level of risk in another.
Acute and Chronic Toxicity
Acute toxicity describes the adverse effects of a substance which result either from a single exposure or from multiple exposures in a short space of time (usually less than 24 hours). To be
described as acute toxicity, the adverse effects should occur within 14 days of the administration
of the substance.
Acute toxicity is distinguished from chronic toxicity, which describes the adverse health effects
from repeated exposures, often at lower levels, to a substance over a longer time period (months
or years).
It is widely considered unethical to use humans as test subjects for acute (or chronic) toxicity research. However, some information can be gained from investigating accidental human exposures (e.g. factory accidents). Otherwise, most acute toxicity data comes from animal testing or,
more recently, in vitro testing methods and inference from data on similar substances.
Limits for short-term exposure, such as STELs or CVs, are only defined if there a particular acute
toxicity associated with a substance.
Short-Term Exposure Limit, STEL;
Threshold limit value-short-term exposure limit, TLV-STEL
Ceiling value, CV;
Threshold limit value-ceiling, TLV-C
Experimental values
No observed adverse effect level, NOAEL
Lowest observed adverse effect level, LOAEL
Maximum tolerable concentration, MTC, LC0;
Maximum tolerable dose, MTD, LD0
Minimum lethal concentration, LCmin;
Mimimum lethal dose, LDmin
Median lethal concentration, LC50; Median lethal dose, LD50;
Median lethal time, LT50
Absolute lethal concentration, LC100; Absolute lethal dose, LD100

5.12 Types of Toxicity Tests

Toxicity tests tend to share certain basic principles. They usually involve exposing experimental
animals to the test substance under controlled conditions.

For existing chemicals, toxicological information may also be obtained from epidemiological data
such as human exposure in the workplace, or humans and animals exposed in the general environment. So, for example, workplace exposure may be determined from the measurement of potentially toxic substances or their metabolites in human body fluids.
Similarly environmental exposure to pesticides may be determined in the field by measurement of
pesticide levels in wild birds.
The main types of toxicity tests are described below.
Acute Toxicity Tests.
These are designed to determine the effects which occur within a short period after dosing.
These tests can determine a dose-response relationship and the LD50 value.
The initial tests will involve increasing the dose to a sample of animals by successive orders of
magnitude (factors of 10) in order to establish the range of toxic effects.
Once this has been established, a study similar to that outlined in Table 3.2 can be carried out in
order to classify the substance. Note that the criterion used is 90% survival.
TABLE HERE
Table 3.2: Investigation of Acute Oral Toxicity
If a large enough sample of animals is used at each dosage level, the LD50 value can be determined from analysis of the data.
Subacute Toxicity Tests.
These involve exposing animals to a substance for a prolonged period of one or three months,
which enables toxic effects which have a slow onset to be detected.
This type of exposure provides information on the target organs affected by the substance, and
the major toxic effects. Such tests also allow measurement of the substance in blood and tissues
to be made.
The information gained can be used in the design of the next type of test, the chronic toxicity test.
Chronic Toxicity Tests.
These tests involve lifetime exposure of animals to the substance under study.
Similar measurements to those described for subacute toxicity tests can be made throughout the
study to identify the development of pathological changes, which can then be detected in a postmortem.
Other long-term changes in measurements such as food and water intake, body weight, and behavioural changes can serve to indicate harmful effects.
These types of study are important in determining possible effects of long-term occupational exposure, or environmental exposure to low levels of chemicals.
For all three types of toxicity test, the following parameters should also be considered:
Type of chemical under study (novel compound or in use for some time)
Selection of doses (quantity; single dose or repeated doses)
Species and strain of animal (extrapolation to human exposure)
Exposure route (comparable with likely occupational exposure route)
Method of exposure (physical and/or chemical properties of substance)
Experimental observations and measurements to be made (similarities with other compounds of
known toxicity)

5.13 Dose-Response Relationship, NOAEL

Introduction
The science of toxicology is based on the principle that there is a relationship between a toxic reaction (the response) and the amount of poison received (the dose). An important assumption in
this relationship is that there is almost always a dose below which no response occurs or can be
measured. A second assumption is that once a maximum response is reached any further increases in the dose will not result in any increased effect.
One particular instance in which this dose-response relationship does not hold true, is in regard to
true allergic reactions. Allergic reactions are special kinds of changes in the immune system; they
are not really toxic responses. The difference between allergies and toxic reactions is that a toxic
effect is directly the result of the toxic chemical acting on cells. Allergic responses are the result of
a chemical stimulating the body to release natural chemicals which are in turn directly responsible
for the effects seen. Thus, in an allergic reaction, the chemical acts merely as a trigger, not as the
bullet.
For all other types of toxicity, knowing the dose-response relationship is a necessary part of understanding the cause and effect relationship between chemical exposure and illness. As
Paracelsus once wrote, "The right dose differentiates a poison from a remedy." Keep in mind that
the toxicity of a chemical is an inherent quality of the chemical and cannot be changed without
changing the chemical to another form. The toxic effects on an organism are related to the
amount of exposure.
Measures of exposure
Exposure to poisons can be intentional or unintentional. The effects of exposure to poisons vary
with the amount of exposure, which is another way of saying "the dose." Usually when we think of
dose, we think in terms of taking one vitamin capsule a day or two aspirin every four hours, or
something like that. Contamination of food or water with chemicals can also provide doses of
chemicals each time we eat or drink. Some commonly used measures for expressing levels of
contaminants are listed in table 1. These measures tell us how much of the chemical is in food,
water or air. The amount we eat, drink, or breathe determines the actual dose we receive.
Concentrations of chemicals in the environment are most commonly expressed as ppm and ppb.
Government tolerance limits for various poisons usually use these abbreviations. Remember that
these are extremely small quantities. For example, if you put one teaspoon of salt in two gallons
of water the resulting salt concentration would be approximately 1,000 ppm and it would not even
taste salty!
Dose-effect relationships
The dose of a poison is going to determine the degree of effect it produces. The following example illustrates this principle. Suppose ten goldfish are in a ten-gallon tank and we add one ounce
of 100-proof whiskey to the water every five minutes until all the fish get drunk and swim upside
down. Probably none would swim upside down after the first two or three shots. After four or five,
a very sensitive fish might. After six or eight shots another one or two might. With a dose of ten
shots, five of the ten fish might be swimming upside down. After fifteen shots, there might be only
one fish swimming properly and it too would turn over after seventeen or eighteen shots.
The effect measured in this example is swimming upside down. Individual sensitivity to alcohol
varies, as does individual sensitivity to other poisons. There is a dose level at which none of the
fish swim upside down (no observed effect). There is also a dose level at which all of the fish
swim upside down. The dose level at which 50 percent of the fish have turned over is known as
the ED50, which means effective dose for 50 percent of the fish tested. The ED50 of any poison
varies depending on the effect measured. In general, the less severe the effect measured, the
lower the ED50 for that particular effect. Obviously poisons are not tested in humans in such a

fashion. Instead, animals are used to predict the toxicity that may occur in humans.
The potency of a poison is a measure of its strength compared to other poisons. The more potent
the poison, the less it takes to kill; the less potent the poison, the more it takes to kill. The potencies of poisons are often compared using signal words or categories as shown in the example in
table 2.
The designation toxic dose (TD) is used to indicate the dose (exposure) that will produce signs of
toxicity in a certain percentage of animals. The TD50 is the toxic dose for 50 percent of the animals tested. The larger the TD the more poison it takes to produce signs of toxicity. The toxic
dose does not give any information about the lethal dose because toxic effects (for example,
nausea and vomiting) may not be directly related to the way that the chemical causes death. The
toxicity of a chemical is an inherent property of the chemical itself. It is also true that chemicals
can cause different types of toxic effects, at different dose levels, depending on the animal species tested. For this reason, when using the toxic dose designation it is useful to precisely define
the type of toxicity measured, the animal species tested, and the dose and route of administration.
Toxicity assessment is quite complex, many factors can affect the results of toxicity tests. Some
of these factors include variables like temperature, food, light, and stressful environmental conditions. Other factors related to the animal itself include age, sex, health, and hormonal status.
The NOEL (no observable effect level) is the highest dose or exposure level of a poison that produces no noticeable toxic effect on animals. From our previous fish example, we know that there
is a dose below which no effect is seen. In toxicology, residue tolerance levels of poisons that are
permitted in food or in drinking water, for instance, are usually set from 100 to 1,000 times less
than the NOEL to provide a wide margin of safety for humans.
The TLV (threshold limit value) for a chemical is the airborne concentration of the chemical (expressed in ppm) that produces no adverse effects in workers exposed for eight hours per day five
days per week. The TLV is usually set to prevent minor toxic effects like skin or eye irritation.
Very often people compare poisons based on their LD50's and base decisions about the safety of
a chemical based on this number. This is an over-simplified approach to comparing chemicals
because the LD50 is simply one point on the dose-response curve that reflects the potential of
the compound to cause death. What is more important in assessing chemical safety is the
threshold dose, and the slope of the dose-response curve, which shows how fast the response
increases as the dose increases. While the LD50 can provide some useful information, it is of limited value in risk assessment because the LD50 only reflects information about the lethal effects
of the chemical. It is quite possible that a chemical will produce a very undesirable toxic effect
(such as reproductive toxicity or birth defects) at doses which cause no deaths at all.
A true assessment of chemical toxicity involves comparisons of numerous dose-response curves
covering many different types of toxic effects. The determination of which pesticides will be Restricted Use Pesticides involves this approach. Some Restricted Use Pesticides have very large
LD50s (low acute oral toxicity), however, they may be very strong skin or eye irritants and thus
require special handling.
The knowledge gained from dose-response studies in animals is used to set standards for human
exposure and the amount of chemical residue that is allowed in the environment. As mentioned
previously, numerous dose-response relationships must be determined, in many different species. Without this information, it is impossible to accurately predict the health risks associated with
chemical exposure. With adequate information, we can make informed decisions about chemical
exposure and work to minimize the risk to human health and the environment.

5.14 LD50 and LC50

What does LD50 mean?

LD stands for "Lethal Dose". LD50 is the amount of a material, given all at once, which causes
the death of 50% (one half) of a group of test animals. The LD50 is one way to measure the
short-term poisoning potential (acute toxicity) of a material.
Toxicologists can use many kinds of animals but most often testing is done with rats and mice. It
is usually expressed as the amount of chemical administered (e.g., milligrams) per 100 grams (for
smaller animals) or per kilogram (for bigger test subjects) of the body weight of the test animal.
The LD50 can be found for any route of entry or administration but dermal (applied to the skin)
and oral (given by mouth) administration methods are the most common.
What does LC50 mean?
LC stands for "Lethal Concentration". LC values usually refer to the concentration of a chemical in
air but in environmental studies it can also mean the concentration of a chemical in water.
For inhalation experiments, the concentration of the chemical in air that kills 50% of the test animals in a given time (usually four hours) is the LC50 value.
Why study LD50s?
Chemicals can have a wide range of effects on our health. Depending on how the chemical will
be used, many kinds of toxicity tests may be required.
Since different chemicals cause different toxic effects, comparing the toxicity of one with another
is hard. We could measure the amount of a chemical that causes kidney damage, for example,
but not all chemicals will damage the kidney. We could say that nerve damage is observed when
10 grams of chemical A is administered, and kidney damage is observed when 10 grams of
chemical B is administered. However, this information does not tell us if A or B is more toxic because we do not know which damage is more critical or harmful.
Therefore, to compare the toxic potency or intensity of different chemicals, researchers must
measure the same effect. One way is to carry out lethality testing (the LD50 tests) by measuring
how much of a chemical is required to cause death. This type of test is also referred to as a
"quantal" test because it is measures an effect that "occurs" or "does not occur".
Who invented the idea of an LD50?
In 1927, J.W. Trevan attempted to find a way to estimate the relative poisoning potency of drugs
and medicines used at that time. He developed the LD50 test because the use of death as a "target" allows for comparisons between chemicals that poison the body in very different ways. Since
Trevan's early work, other scientists have developed different approaches for more direct, faster
methods of obtaining the LD50.
What are some other toxicity dose terms in common usage?
LD01 Lethal dose for 1% of the animal test population
LD100 Lethal dose for 100% of the animal test population
LDLO The lowest dose causing lethality
TDLO The lowest dose causing a toxic effect
Why are LD50 and LC50 values a measure of acute toxicity?
Acute toxicity is the ability of a chemical to cause ill effects relatively soon after one oral administration or a 4-hour exposure to a chemical in air. "Relatively soon" is usually defined as a period
of minutes, hours (up to 24) or days (up to about 2 weeks) but rarely longer.
How are LD/LC50 tests done?

In nearly all cases, LD50 tests are performed using a pure form of the chemical. Mixtures are
rarely studied.
The chemical may be given to the animals by mouth (oral); by applying on the skin (dermal); by
injection at sites such as the blood veins (i.v.- intravenous), muscles (i.m. - intramuscular) or into
the abdominal cavity (i.p. - intraperitoneal).
The LD50 value obtained at the end of the experiment is identified as the LD50 (oral), LD50
(skin), LD50 (i.v.), etc., as appropriate. Researchers can do the test with any animal species but
they use rats or mice most often. Other species include dogs, hamsters, cats, guinea-pigs, rabbits, and monkeys. In each case, the LD50 value is expressed as the weight of chemical administered per kilogram body weight of the animal and it states the test animal used and route of exposure or administration; e.g., LD50 (oral, rat) - 5 mg/kg, LD50 (skin, rabbit) - 5 g/kg. So, the example "LD50 (oral, rat) 5 mg/kg" means that 5 milligrams of that chemical for every 1 kilogram body
weight of the rat, when administered in one dose by mouth, causes the death of 50% of the test
group.
If the lethal effects from breathing a compound are to be tested, the chemical (usually a gas or
vapour) is first mixed in a known concentration in a special air chamber where the test animals
will be placed. This concentration is usually quoted as parts per million (ppm) or milligrams per
cubic metre (mg/m3). In these experiments, the concentration that kills 50% of the animals is
called an LC50 (Lethal Concentration 50) rather than an LD50. When an LC50 value is reported,
it should also state the kind of test animal studied and the duration of the exposure, e.g., LC50
(rat) - 1000 ppm/ 4 hr or LC50 (mouse) - 5mg/m3/ 2hr.
Which LD50 information is the most important for occupational health and safety purposes?
Inhalation and skin absorption are the most common routes by which workplace chemicals enter
the body. Thus, the most relevant from the occupational exposure viewpoint are the inhalation
and skin application tests. Despite this fact, the most frequently performed lethality study is the
oral LD50. This difference occurs because giving chemicals to animals by mouth is much easier
and less expensive than other techniques. However, the results of oral studies are important for
drugs, food poisonings, and accidental domestic poisonings. Oral occupational poisonings might
occur by contamination of food or cigarettes from unwashed hands, and by accidental swallowing.
How do I compare one LD50 value to another and what does it mean to humans?
In general, the smaller the LD50 value, the more toxic the chemical is. The opposite is also true:
the larger the LD50 value, the lower the toxicity.
The LD50 gives a measure of the immediate or acute toxicity of a chemical in the strain, sex, and
age group of a particular animal species being tested. Changing any of these variables (e.g., type
animal or age) could result in finding a different LD50 value. The LD50 test was neither designed
nor intended to give information on long-term exposure effects of a chemical.
Once you have an LD50 value, it can be compared to other values by using a toxicity scale. Confusion sometimes occurs because several different toxicity scales are in use. The two most common scales used are the "Hodge and Sterner Scale" and the "Gosselin, Smith and Hodge Scale".
These tables differ in both the numerical rating given to each class and the terms used to describe each class. For example, a chemical with an oral LD50 value of 2 mg/kg, would be rated
as "1" and "highly toxic" according to the Hodge and Sterner Scale (see Table 1) but rated as "6"
and "super toxic" according to the Gosselin, Smith and Hodge Scale (see Table 2). It is important
to reference the scale you used when classifying a compound.
It is also important to know that the actual LD50 value may be different for a given chemical depending on the route of exposure (e.g., oral, dermal, inhalation). For example, some LD50s for
dichlorvos, an insecticide commonly used in household pesticide strips, are listed below:

Oral LD50 (rat): 56 mg/kg

Dermal LD50 (rat): 75 mg/kg
Intraperitoneal LD50: (rat) 15 mg/kg
Inhalation LC50 (rat): 1.7 ppm (15 mg/m3); 4-hour exposure
Oral LD50 (rabbit) 10 mg/kg
Oral LD50 (pigeon:): 23.7 mg/kg
Oral LD50 (rat): 56 mg/kg
Oral (mouse): 61 mg/kg
Oral (dog): 100 mg/kg
Oral (pig): 157 mg/kg
Differences in the LD50 toxicity ratings reflect the different routes of exposure. The toxicity rating
can be different for different animals. The data above show that dichlorvos is much less toxic by
ingestion in pigs or dogs than in rats. Using Table 1, dichlorvos is moderately toxic when swallowed (oral LD50) and extremely toxic when breathed (inhalation LC50) in the rat. Using Table 2,
dichlorvos is considered very toxic when swallowed (oral LD50) by a rat.
Table 1: Toxicity Classes: Hodge and Sterner Scale
Routes of Administration
TABLE HERE
Table 2: Toxicity Classes: Gosselin, Smith and Hodge
Probable Oral Lethal Dose (Human)
Can animal LD50 data be applied to man?
In general, if the immediate toxicity is similar in all of the different animals tested, the degree of
immediate toxicity will probably be similar for humans. When the LD50 values are different for
various animal species, one has to make approximations and assumptions when estimating the
probable lethal dose for man. Tables 1 and 2 have a column for estimated lethal doses in man.
Special calculations are used when translating animal LD50 values to possible lethal dose values
for humans. Safety factors of 10,000 or 1000 are usually included in such calculations to allow for
the variability between individuals and how they react to a chemical, and for the uncertainties of
experiment test results.
How should an LD50 value be used?
The LD50 can be used:
As an aid in developing emergency procedures in case of a major spill or accident.
To help develop guidelines for the use of appropriate safety clothing and equipment. For example, if the dermal LD50 value for a chemical is rated as extremely toxic, it is important to protect
the skin with clothing, gloves (etc.) made of the right chemical-resistant material before handling.
Alternatively, if a chemical has an inhalation LC50 value which indicates that it is relatively harmless, respiratory protective equipment may not be necessary (as long as the oxygen concentration in the air is in the normal range - around 18%).
For the development of transportation regulations.
As an aid in establishing occupational exposure limits.
As a part of the information in Material Safety Data Sheets. Remember, the LD50 is only a ball
park figure so that lethal toxicity can be compared. It says nothing about levels at which other
acute toxic, but non-lethal, effects might occur.
The LD50 is only one source of toxicity information. For a more thorough picture of the immediate or acute toxicity of a chemical, additional information should be considered such as the lowest
dose that causes a toxic effect (TDLO), the rate of recovery from a toxic effect, and the possibility
that exposure to some mixtures may result in increasing the toxic effect of an individual chemical.

5.15 Alternatives to Vertebrate Testing - REACH and the EU

The European Union response to the public demand for 'cleaner' products is the 2007 REACH
regulation. REACH deals with Registration, Evaluation, Authorisation and Restriction of Chemical
substances.
REACH requires industry to provide information to users on the risks of every chemical which
they manufacture and market, so that better decisions can be made about their use. For substances on the market in volumes of at least one tonne per year, data about the toxicity must be
registered with the European Chemicals Agency (ECHA).
REACH has therefore created an urgent demand for the testing of large numbers of chemicals for
toxicity. Around 100,000 chemicals may be registered under REACH from 2010 to 2018 for which
toxicity test data will be required.
Legislators, scientists and industry have agreed that chemical testing must respect the "3R's"
the commitment to reduce, refine and replace animal testing wherever possible. REACH has
made the major step of requiring manufacturers and importers of chemicals to share their existing
and new test data, so that tests are not repeated unnecessarily. Plus, when tests on vertebrate
animals are proposed, ECHA publishes a request for existing data that could be used instead of new tests being carried out.
REACH: the challenge
The European Commission have nevertheless estimated that to complete registration in the coming decade could involve the use of up to 9 million laboratory animals, and cost around 1.3 billion.
REACH therefore provides possibilities to use alternative assessment methods as well as existing
data.2 In silico methods are one important way forward.
Traditional toxicology testing is carried out in laboratories using live animals (in vivo testing).
Around a million animals are used every year in Europe in such tests (2005 data4). Alternative
methods include in vitro testing, where small quantities of chemicals are mixed with living cell cultures in test tubes.
In silico methods are a new development in chemical testing that relies on computer simulation or
modelling. Results from existing tests are used to model the ways in which a chemical may be
hazardous in the body and/or in the environment. In this way the toxicity of a particular chemical
used in a particular setting can be predicted and assessed without further tests on animals or living cells.
In silico methods are widely used (including by regulators in the US) to screen and identify
chemicals for priority testing in the laboratory. They are also used in addition to laboratory data to
add another line of evidence or argument. For many scientists, the goal is also to replace and improve on animal tests.
What are in silico methods?
In silico methods use computer simulation or modelling to predict and assess the toxicological
properties of chemicals in the body and the environment.
Examples
The EU-funded CAESAR project has developed in silico predictive models (QSAR) for five types
of endpoints (adverse effects). The software for the models is freely available online through the
www.caesar-project.eu website.
The EU-funded CHEMOMENTUM project has developed a platform to build QSAR models in an
automated way using workflows based on grid technologies.
The EPI (Estimation Programs Interface) Suite is a suite of physical/chemical property and environmental fate estimation programs developed by the US Environment Protection Agency (EPA)
Office of Pollution Prevention Toxics and the Syracuse Research Corporation (SRC). EPI Suite
uses a single input to run 17 estimation programs. It is used by the EPA as a screening level tool.
The EU has funded research into the development of in silico methods because the advantages

are potentially immense.

Reducing the testing on animals
In silico methods use the findings from in vivo and in vitro laboratory tests. But they allow scientists to reduce the repetition of animal testing, by replacing further tests with computer modelling.
This reduces both animal suffering and the chemical waste from further laboratory tests.
Reducing costs and delays
For industrial manufacturers, importers and users of chemicals, in silico testing can help to avoid
the costs and delays associated with animal experiments. Some in silico tools are freely available
online.
Enabling the testing of large numbers of chemicals
For regulators and citizens, in silico methods can reduce the costs and increase the feasibility of
testing, and so make it more possible to evaluate the safety of the wide range of chemical substances in use. In silico methods therefore become important, as now under REACH, when the
requirement is to assess whole inventories of chemicals, rather than just a few priority substances.
Advantages of in silico methods
Increasing the quality of information
Computer models can potentially integrate findings from both in vivo and in vitro research, and
from a number of laboratory studies, to generate a more sophisticated and more reliable understanding in the future of how a chemical may affect humans and the environment. This may increase the scientific intelligence in chemical planning and reduce the number of unforeseen toxic
effects.
In silico methods assess probability in a way that is useful to regulators when they are assessing
risk and uncertainty. In silico methods can address particular hazards or adverse effects (endpoints) for which animal testing methods are not fully accepted.
The models available
In silico models are developed from existing data from laboratory tests, so a model can only be as
reliable as the data it is based on. In some key areas, such as long term toxicity to mammals, the
available laboratory data is limited, so the range of in silico models is also currently limited.
While laboratory tests exist for both acute and chronic toxicity, tests for chronic toxicity take
longer and are more expensive. In silico methods have correspondingly been developed and become effective in modelling, predicting and assessing acute toxicity, while remaining less developed for the more pervasive problem of chronic toxicity.
Current in silico methods cannot evaluate the toxicity of mixtures of chemicals, or of impure substances.
Progress and uptake
In silico methods are an inter-disciplinary area of work, in which models are developed by experts
in chemo-informatics for use by toxicologists. The strength and use of a model depends on
whether it clearly provides what industry toxicologists and regulators need in their decisionmaking.
Current limitations in the use of in silico methods
The level of use of in silico methods primarily depends on industry. Under REACH, it is the responsibility of the registrant of a chemical to select the assessment methods and to show that
their application to a particular case is scientifically valid.
Regulatory acceptance
The scientific validity of in silico methods depends on an in silico model being rigorously developed, and then used solely for what it was intended. It also depends on the model being documented well enough by the developers, and by the industry users, for ECHA to carry out an inde-

pendent and transparent review.

While REACH welcomes alternative methods, ECHA inevitably has to be cautious in accepting
their use. If a chemical is wrongly assessed, there may be serious consequences for human
health or the environment. That same caution is also important for the future of in silico methods;
if particular models are applied incorrectly or overused, then in silico methods may wrongly lose
credibility.

5.16 Alternatives to Vertebrate Testing - ECVAM

Reason for ECVAM
ECVAM was created by a Communication from the Commission to the Council and the Parliament in October 1991*, pointing to a requirement in Directive 86/609/EEC** on the protection of
animals used for experimental and other scientific purposes, which requires that the Commission
and the Member States should actively support the development, validation and acceptance of
methods which could reduce, refine or replace the use of laboratory animals. The Directive
86/609/EEC was subsequently revised and is being replaced by the Directive 2010/63/EU*** that
requires:
Article 4:
Member States shall ensure that, wherever possible, a scientifically satisfactory method or testing
strategy, not entailing the use of live animals, shall be used instead of a procedure.
Article 47:
The Commission and the Member States shall contribute to the development and validation of
alternative approaches which could provide the same or higher levels of information as those obtained in procedures using animals, but which do not involve the use of animals or use fewer
animals or which entail less painful procedures, and they shall take such other steps as they consider appropriate to encourage research in this field.
ECVAM was established at the Joint Research Centre in 1992, and is now part of the In Vitro
Methods Unit (IVMU) of the Institute for Health and Consumer Protection (IHCP) located in Ispra,
Italy.
You can get to know more about ECVAM's activities by watching the video "Finding alternatives
to animal testing" or dowloading the leaflet "Alternatives to animal testing" produced by the IHCP.
Duties of ECVAM
The new Directive 2010/63/EU*** has further enforced the role of ECVAM (referred to it the Union
Reference Laboratory) and its duties and tasks are defined as follows (see also Article 48/Annex
VII):
a. Coordinating and promoting the development and use of alternatives to procedures including in
the areas of basic and applied research and regulatory testing;
b. Coordinating the validation of alternative approaches at Union level;
c. Acting as a focal point for the exchange of information on the development of alternative approaches;
d. Setting up, maintaining and managing public databases and information systems on alternative
approaches and their state of development;
e. Promoting dialogue between legislators, regulators, and all relevant stakeholders, in particular,
industry, biomedical scientists, consumer organisations and animal-welfare groups, with a view to

the development, validation, regulatory acceptance, international recognition, and application of

alternative approaches.
The Union Reference Laboratory shall also participate in the validation of alternative approaches.
Moreover, ECVAM should help to expand the JRC's role in prenormative research. ECVAM thus
seeks to promote the scientific and regulatory acceptance of alternative methods which are of
importance to the biosciences, through research, new test development and validation, and the
establishment of specialised databases, with the aim of contributing to the replacement, reduction
and refinement of laboratory animal precedures (in accordance with the 3Rs concept of Russell &
Burch****)
ECVAM has its own Scientific Advisory Committee (ESAC), at present composed of 15 external
scientists working in academia, industry and industry organisations, public institutions or as independent consultants expressing opinions on the scientific validity of alternative methods. Currently, ECVAM si setting up the ECVAM Stakeholder Forum (ESTAF) which will bring together
ECVAM's non-governmental stakeholders (e.g. industry associations, civil society / nongovernmental organisations and research foundations & organisations).
The Validation Process
Validation is the process by which the reliability and relevance of a procedure are established for
a specific purpose.
In 1995, based upon experience gained during several recent large-scale validation studies, and
in consultation with various international experts (including members of ERGATT), ECVAM published recommendations concerning the practical and logistical aspects of validating alternative
test methods (ECVAM workshop report 5). Five main stages in the evolution of new test methods
were identified: test development; prevalidation; validation (involving a formal interlaboratory
study with the testing of coded chemicals); independent assessment; and progression toward
regulatory acceptance. ECVAM has implemented a prevalidation scheme, which includes three
main phases: protocol refinement, protocol transfer, and protocol performance. The objective of
the prevalidation process is to ensure that any method included in a formal validation study adequately fulfills the criteria defined for inclusion in such a study, so that financial and human resources are used more efficiently, and so that there is a greater likelihood that the expectations of
those in the scientific, regulatory and animal welfare communities, who seek the replacement of
current animal tests by relevant and reliable alternative methods, will be met. In 2004, ECVAM
has published the "Modular Approach to the ECVAM Principles on Test Validity" (select from the
top-menu bar the sector "Publications" followed by "ECVAM Selected Articles") that makes the
validation process more flexible, by breaking down the various steps in validation into indipendent
modules, and defining for each module the information needed for assessing test validity.
More recently, ECVAM has established a formal procedure for the evaluation of the readiness of
a Test Method to enter the ECVAM (pre)validation process which follows now 2 mandatory steps:
Pre-submission and Complete Submission.
Access: on the ECVAM website select the 'Submission of new Test Methods to ECVAM' section
from the top bar menu.
Collaborations
ECVAM's activities are undertaken in collaboration with numerous laboratories and organisations
in the EU Member States, and all over the world. ECVAM also works in close collaboration with
other Commission services, such as DG Environment, DG Enterprise, DG Research and DG
Health and Consumer Protection and International Organisations and is a member of the European Partnership for Alternative Approaches to Animal Testing (EPAA).
On April 27, 2009, representatives from international agencies of validation organizations from
the United States, Japan, the European Union and Canada signed a Memorandum of Cooperation establishing the International Cooperation on Alternative Test Methods (ICATM). The agree-

ment promotes enhanced international cooperation and coordination on the scientific validation of
non- and reduced-animal toxicity testing methods.

5.17 QSAR and Read-Across.

In Silico methods
In silico is an expression that means "performed using a computer simulation" and was coined in
1989 during the workshop "Cellular Automata: Theory and Applications" in Los Alamos, New
Mexico by a mathematician from National Autonomous University of Mexico (UNAM).
In silico models for predicting toxicological, biological and physico-chemical properties are models
able to find relations between particular characteristics of molecules and the property of interest.
Example of in silico methods are: (Q)SAR, Read-Across and Virtual Screening.
Quantitative Structure-Activity Relationship (QSAR) are computer-based models for the prediction
of toxicological, biological and physico-chemical properties. QSAR models aim at establishing, if it
exists, the relationship between structural-derived properties of chemicals and their properties,
such as toxicity. For the relationship between the activity and the chemical information a mathematical function is used. The chemical information can be given by chemical descriptors or fragments. Many thousands of chemical descriptors have been proposed, constitutional, geometrical,
physico-chemical, topological, etc.
In the specific case of the evaluation of a qualitative relationship, for instance between the presence of a certain chemical fragment and the occurrence of a certain toxicity effect, the typical
name is structure-activity relationship (SAR). (Q)SAR is used sometimes to refer to both QSAR
and SAR. Here we will present QSAR and SAR together, using the acronym QSAR.
Read-across is a very simplified version of QSAR model. Basically, the property of one or few
chemicals is predicted on the basis of one or more similar compounds, using or not some chemical descriptors.
Virtual screening are docking simulation based methods used to evaluate the binding between a
chemical compound and a biological macromolecule, such as a protein.
Areas of applicability
QSAR models have been developed for many applications:
Physico-chemical properties, such as boiling point, water solubility, partition coefficients. The
U.S. EPA Estimation Program Interface (EPI) suite comprise models for these endpoints
(http://www.epa.gov/oppt/exposure/pubs/episuite.htm).
Environmental properties, such as bioconcentration factor (included in the CAESAR software),
degradation, soil adsorption, photodegradation.
Ecotoxicological properties, such as fish, daphnia, bird, bee toxicity. Models for these endpoints
have been developed by the DEMETRA project.
Toxicity, such as carcinogenicity, mutagenicity, developmental toxicity, skin sensitisation. All
these endpoints have been modelled by the EC funded project CAESAR and implemented in the
on line freely available CAESAR software.
Typically, the performance of the QSAR models are better for physico-chemical properties, and
decrease with the increase complexity of the studied system. For certain human endpoints, such
as carcinogenicity and developmental toxicity, the general position is that in silico models should
be used as unique tool, but as support for the evaluation based on several methods.
For aquatic toxicity, most of the models address acute toxicity, mainly in fish. Results are good for
chemicals which do not carry residues which increase their toxicity, which applies to about 30% of
the cases. Specific models for more toxic compounds should not be used in these cases.
Models for mutagenicity (mainly Ames test) generally give good results (accuracy about 80%,
which is close to the test reproducibility).
Models for bioconcentration factors (BCF) give good results (R2 about 80%; error about 0.5 log

unit). Care should be taken if the predicted value is close to the threshold, while if the predicted
value is well above or below the BCF threshold, the prediction is much more reliable.
Models for carcinogenicity give a quite large error. About one out three chemicals is wrongly predicted. Better results can be obtained if the applicability domain of the model is evaluated. At
least three models for carcinogenicity should be used, because the results vary. In case of
agreement, the prediction is more reliable.
Relation/Comparison with other methods
Any model, such as animal models (also called in vivo) or cellular models (in vitro models), is a
system which applies to a specific situation, and simplifies a complex system, which cannot be
used experimentally for investigation. For instance, in case of toxicity studies, the target is human
health, and for environmental studies the target may be a certain ecosystem. In practice, all current models simplify the final target. The rabbit model will never replace the human being, and
similarly the trout used in a tank cannot replace the complex environmental system where many
different fishes, and animal, and environmental conditions exist. Methods like in vitro and in silico
models are often called alternative methods, because they can be used as alternative to animal
models. In addition, these methods can be used to provide further information, to better address
the final target: human beings and environment. Thus, it would be reductive to see in silico methods simply as surrogate of animal models.
The comparison and integration of in vivo, in vitro and in silico, have been discussed during the
workshop organized by the EC funded project RAINBOW.
The debate
There is a debate on the use of QSAR in particular, and in silico models in general. The acceptability of these tools depends on the user and the purpose.
Major criticisms are:
In silico models are not reliable
Toxicity is too complex to be modeled
In vivo veritas. This means that only the real experiment on the animal will provide the real result.
Indeed, all in silico models should give a proof of their performance. In the past, the classical
models were developed using all data, which were used to build up a model without any validation of the model. The points were fitted in a linear regression, and no demonstration was given if
this regression was applicable to other chemicals (Kaiser, K. L. E. at all, 1999).
The interest on the use of in silico models for regulatory purposes contributed to the discussion
on the validation of the in silico models. A clear definition of the possible use of the model should
be given, and pitfalls clearly indicated, for all in silico methods, such as QSAR, read-across and
docking studies. Examples in this direction are the tools developed within CAESAR, which guide
the user, indicating results on similar compounds, and errors.
Even if toxicity is complex, some phenomena are simplier and rules have been identified. For instance, in case of aquatic toxicity most of the chemicals can be explained with quite simple relationships (for more info refer to the DEMETRA project). Genotoxicity has been modeled in large
extent on the basis of some toxic fragments or related QSAR models (more info at CAESAR project). Improvement seems possible, on the basis of more data (and there are huge initiatives in
this direction, such as ToxCast), better models, and integration of models.
Even in vivo models cannot provide all answers. A wise integration of models, including in silico
models, can only improve our knowledge. In silico models take advantage of computers to better
examine the data and information available. Disregard this would mean not to use all pieces of
information we have.
Challenges
In silico tools can offer immediate, world-wide, free (in many cases) access to a formidable
amount of tools: databases, libraries of structures and properties, literature studies, models.
Within a few years ToxCast will produce experimental data on 100,000 chemicals, omics will pro-

duce huge amount of data, HTPS will generate unprecedented amount of data. No single human
expert will have the time and the possibility to dig these incredibly large collections of results.
Even today thousands of chemicals are present in libraries with their toxicity properties.
The sooner the correct use of in silico models will be widespread, the better, in order to take advantage and exploit these results.
QSAR and REACH
REACH legislation states that Non-Testing Methods (NTM) can be used within REACH. These
methods include Quantitative Structure-Activity Relationship (QSAR) models and read-across.
Before making an animal experiment the industry should verify if alternative methods exist. However, so far there is a deep gap of knowledge on which methods are available and can be used in
practice. READ MORE
The EU Regulation REACH which entered into force in 2007 in the EU represents today the most
advanced system in the world to register, evaluate and authorize chemical substances. According
to latest estimates some fourty or fifty thousand substances will be processed in three phases,
starting with high production volumes (beyond 1,000 t) and the most concerning substances. The
deadline of the first phase has been on 30 November 2010.
To correctly evaluate the impact on the environment and human health industry will pay a high
cost (billions of euros), and there is the risk that millions of animals will be sacrified to produce the
necessary toxicity data. It is also uncertain if the number of certified laboratories is sufficient to
cope in a reasonable time (years) with the need to produce such data.
To limit these problems, the REACH legislation promotes the use of non-testing methods. These
methods include the read across and quantitative structure-activity relationship (QSAR). Read
across bases the evaluation of the unknown compound on the values of similar chemicals, while
the QSAR (or SAR in case of models non quantitative) uses some chemical descriptors to evaluate the toxicity. Experience on the validity, predictivity and feasibility of these tools is still under
discussion

5.18 The Ames Test

The Ames test, named for its developer, Bruce Ames, is a method to test chemicals for their cancer-causing properties. It is used by cosmetic companies, pharmaceutical manufacturers, and
other industries that must prove that their products will not cause cancer in humans.
Ames, a cancer researcher at the University of California, began development of his method in
the late 1950s. He believed an efficient, less-expensive means could be found to screen substances than the cumbersome methods in use. He hit upon the use of bacteria, which could be
grown (cultured) cheaply, and grew rapidly so that testing could be completed quickly, yet could
indicate the carcinogenic (cancer-causing) potential of many chemicals.
The bacterium used is a strain of Salmonella typhimurium that lacks an enzyme needed to form
colonies. The bacterium is grown on agar culture (agar is a gelatin-like substance with nutrients).
The substance to be tested is blotted on a bit of paper and placed on the agar. If the substance is
a carcinogen it will cause mutations in the bacterium as the cells divide. The mutant cells will
have the enzyme to form colonies. The test can be completed in a day.
Bacterial mutations are the result of DNA damage. Because DNA in bacteria is similar to that in
the higher animals, it is assumed the substance also will damage DNA in those animals and
cause cell mutations and possibly cancer.
The Ames test is a screening test; it is not the final test that any substance must undergo before
being commercially produced. It is designed to detect a cancer-causing agent quickly and inexpensively.
Prior to development of this test the procedure to determine whether a substance was a carcino-

gen required feeding the test substance to or injecting it into laboratory animals such as rats or
mice and then examining them for evidence of tumor formation. Testing took years to complete,
hundreds of animals, and millions of dollars.
Any substance that causes bacterial mutation in the Ames test is not given further consideration
for development. A substance that does not produce bacterial mutation still must undergo animal
testing, but at least the manufacturer has a good idea that it is not a cancer-causing agent.

5.19 Communication of Chemical Hazards to Users

We have already dealt with the requirements for information provided to users of substances under CHIP4. The communication of information is also covered in the CLP and REACH under Articles 14 and 31.
The CLP
Labelling.
In labelling terms, the provisions introduce two 'signal words': Danger designates more serious
hazard categories; Warning is used for less severe hazard categories. The first stage of the labelling matrix is below:
Name, address, and telephone number of supplier;
Any relevant signal words;
Nominal quantity of substance or mixture in package;
Any relevant hazard statements;
Product identifiers (name, CAS number, etc.);
Any relevant precautionary statements;
Any relevant hazard pictograms;
Any supplementary information.
The regulation does not specify a label format, just a set of label elements that must be included.
REACH
ARTICLE 14: Chemical safety report and duty to apply and recommend risk reduction measures
1. Without prejudice to Article 4 of Directive 98/24/EC, a chemical safety assessment shall be
performed and a chemical safety report completed for all substances subject to registration in accordance with this Chapter in quantities of 10 tonnes or more per year per registrant.
The chemical safety report shall document the chemical safety assessment which shall be conducted in accordance with paragraphs 2 to 7 and with Annex I for either each substance on its
own or in a preparation or in an article or a group of substances.
2. A chemical safety assessment in accordance with paragraph 1 need not be performed for a
substance which is present in a preparation if the concentration of the substance in the preparation is less than the lowest of any of the following:
(a) the applicable concentrations defined in the table of Article 3(3) of Directive 1999/45/EC;
(b) the concentration limits given in Annex I to Directive 67/548/EEC;
(c) the concentration limits given in Part B of Annex II to Directive 1999/45/EC;
(d) the concentration limits given in Part B of Annex III to Directive 1999/45/EC;
(e) the concentration limits given in an agreed entry in the classification and labelling inventory
established under Title XI of this Regulation;
(f) 0,1 % weight by weight (w/w), if the substance meets the criteria in Annex XIII of this Regulation.
3. A chemical safety assessment of a substance shall include the following steps:

(a) human health hazard assessment;

(b) physicochemical hazard assessment;
(c) environmental hazard assessment;
(d) persistent, bioaccumulative and toxic (PBT) and very persistent and very bioaccumulative
(vPvB) assessment.
4. If, as a result of carrying out steps (a) to (d) of paragraph 3, the registrant concludes that the
substance meets the criteria for classification as dangerous in accordance with Directive
67/548/EEC or is assessed to be a PBT or vPvB, the chemical safety assessment shall include
the following additional steps:
(a) exposure assessment including the generation of exposure scenario(s) (or the identification of
relevant use and exposure categories if appropriate) and exposure estimation;
(b) risk characterisation.
The exposure scenarios (where appropriate the use and exposure categories), exposure assessment and risk characterisation shall address all identified uses of the registrant.
5. The chemical safety report need not include consideration of the risks to human health from
the following end uses:
(a) in food contact materials within the scope of Regulation (EC) No 1935/2004 of the European
Parliament and of the Council of 27 October 2004 on materials and articles intended to come into
contact with food (39);
(b) in cosmetic products within the scope of Directive 76/768/EEC.
6. Any registrant shall identify and apply the appropriate measures to adequately control the risks
identified in the chemical safety assessment, and where suitable, recommend them in the safety
data sheets which he supplies in accordance with Article 31.
7. Any registrant required to conduct a chemical safety assessment shall keep his chemical
safety report available and up to date.
ARTICLE 31: Requirements for safety data sheets
1. The supplier of a substance or a preparation shall provide the recipient of the substance or
preparation with a safety data sheet compiled in accordance with Annex II:
(a) where a substance or preparation meets the criteria for classification as dangerous in accordance with Directives 67/548/EEC or 1999/45/EC; or
(b) where a substance is persistent, bioaccumulative and toxic or very persistent and very bioaccumulative in accordance with the criteria set out in Annex XIII; or
(c) where a substance is included in the list established in accordance with Article 59(1) for reasons other than those referred to in points (a) and (b).
2. Any actor in the supply chain who is required, under Articles 14 or 37, to carry out a chemical
safety assessment for a substance shall ensure that the information in the safety data sheet is
consistent with the information in this assessment. If the safety data sheet is developed for a
preparation and the actor in the supply chain has prepared a chemical safety assessment for that
preparation, it is sufficient if the information in the safety data sheet is consistent with the chemical safety report for the preparation instead of with the chemical safety report for each substance
in the preparation.
3. The supplier shall provide the recipient at his request with a safety data sheet compiled in accordance with Annex II, where a preparation does not meet the criteria for classification as dangerous in accordance with Articles 5, 6 and 7 of Directive 1999/45/EC, but contains:
(a) in an individual concentration of 1 % by weight for non-gaseous preparations and 0,2 % by

volume for gaseous preparations at least one substance posing human health or environmental
hazards; or
(b) in an individual concentration of 0,1 % by weight for non-gaseous preparations at least one
substance that is persistent, bioaccumulative and toxic or very persistent and very bioaccumulative in accordance with the criteria set out in Annex XIII or has been included for reasons other
than those referred to in point (a) in the list established in accordance with Article 59(1); or
(c) a substance for which there are Community workplace exposure limits.
4. The safety data sheet need not be supplied where dangerous substances or preparations offered or sold to the general public are provided with sufficient information to enable users to take
the necessary measures as regards the protection of human health, safety and the environment,
unless requested by a downstream user or distributor.
5. The safety data sheet shall be supplied in an official language of the Member State(s) where
the substance or preparation is placed on the market, unless the Member State(s) concerned
provide otherwise.
6. The safety data sheet shall be dated and shall contain the following headings:
1. identification of the substance/preparation and of the company/undertaking;
2. hazards identification;
3. composition/information on ingredients;
4. first-aid measures;
5. fire-fighting measures;
6. accidental release measures;
7. handling and storage;
8. exposure controls/personal protection;
9. physical and chemical properties;
10. stability and reactivity;
11. toxicological information;
12. ecological information;
13. disposal considerations;
14. transport information;
15. regulatory information;
16. other information.
7. Any actor in the supply chain who is required to prepare a chemical safety report according to
Articles 14 or 37 shall place the relevant exposure scenarios (including use and exposure categories where appropriate) in an annex to the safety data sheet covering identified uses and including specific conditions resulting from the application of Section 3 of Annex XI.
Any downstream user shall include relevant exposure scenarios, and use other relevant information, from the safety data sheet supplied to him when compiling his own safety data sheet for
identified uses.
Any distributor shall pass on relevant exposure scenarios, and use other relevant information,
from the safety data sheet supplied to him when compiling his own safety data sheet for uses for
which he has passed on information according to Article 37(2).
8. A safety data sheet shall be provided free of charge on paper or electronically.
9. Suppliers shall update the safety data sheet without delay on the following occasions:
(a) as soon as new information which may affect the risk management measures, or new information on hazards becomes available;
(b) once an authorisation has been granted or refused;
(c) once a restriction has been imposed.
The new, dated version of the information, identified as "Revision: (date)", shall be provided free
of charge on paper or electronically to all former recipients to whom they have supplied the sub-

stance or preparation within the preceding 12 months. Any updates following registration shall
include the registration number.
Communication of chemicals hazards to users, in respect of the typical content (format
and types of data) of labels and Safety Data Sheets (Ref GHS Chapters 1.4 and 1.5)

5.20 Notification of New Substances Regulations 1993.

REACH is a new European Union regulation concerning the Registration, Evaluation, Authorisation and restriction of CHemicals. It came into force on 1st June 2007 and replaces a number of
European Directives and Regulations with a single system.
Aims.
REACH has several aims:

To provide a high level of protection of human health and the environment from the use of
chemicals.
To make the people who place chemicals on the market (manufacturers and importers)
responsible for understanding and managing the risks associated with their use.
To allow the free movement of substances on the EU market.
To enhance innovation in and the competitiveness of the EU chemicals industry.
To promote the use of alternative methods for the assessment of the hazardous properties
of substances e.g. quantitative structure-activity relationships (QSAR).

No data, no market.
A major part of REACH is the requirement for manufacturers or importers of substances to register them with a central European Chemicals Agency (ECHA). A registration package will be supported by a standard set of data on that substance. The amount of data required is proportionate
to the amount of substance manufactured or supplied.
If a manufacturer does not register their substances, then the data on them will not be available
and as a result, they will no longer be able to manufacture or supply them legally, i.e. no data, no
market.
Scope and exemptions.
REACH applies to substances manufactured or imported into the EU in quantities of 1 ton per
year or more. Generally, it applies to all individual chemical substances on their own, in preparations or in articles (if the substance is intended to be released during normal and reasonably foreseeable conditions of use from an article).
Some substances are specifically excluded:

Radioactive substances.
Substances under customs supervision.
The transport of substances.
Non-isolated intermediates.
Waste.
Some naturally occurring low-hazard substances.

Some substances, covered by more specific legislation, have tailored provisions, including:

Human and veterinary medicines.

Food and foodstuff additives.
Plant protection products and biocides.

Other substances have tailored provisions within the REACH legislation, as long they are used in
specified conditions:
Isolated intermediates.
Substances used for research and development.
Pre-registration.
It is estimated that there are around 30,000 substances on the European market in quantities of 1
ton or more per year. Registering all of these at once would be a huge task for both industry and
regulators. To overcome this, the registration of those substances already being manufactured or
supplied is to take place in three phases. These phases are spread over 11 years. To benefit
from these phased-in deadlines, manufacturers or importers needed to pre-register their substances from 1st June to 1st December 2008.
Registration.
Registration is a requirement on industry (manufacturers/importers) to collect and collate specified sets of information on the properties of those substances they manufacture or supply at or
above 1 tonne per year. This information is used to perform an assessment of the hazards and
risks that a substance may pose and how those risks can be controlled. This information and its
assessment is submitted to the European Chemicals Agency in Helsinki. Further information on
registration can be found on the ECHA website.
Joint registration and data sharing.
This is the principle that for any one substance, a single set of information on its intrinsic properties is produced that is shared by all those companies that manufacture or supply that substance.
Business specific (e.g. company name) and business sensitive (e.g. how it is used) information is
submitted separately by each company. The Companies will work together to get an agreement
on information sharing through a Substance Information Exchange Forum (SIEF). It is the responsibility of the businesses involved in the SIEF to work out the details of how the information
is shared. A role for national authorities in this aspect of REACH is not foreseen. Companies who
submit joint registrations via a SIEF benefit from a reduced registration fee.
Evaluation.
Dossiers submitted in support of registration will be subject to evaluation under REACH as follows:
Compliance checking: This is a check of the quality of the information submitted by industry. It will
be undertaken by the European Chemicals Agency (ECHA) in Helsinki and will be on a sample
(at least 5%) of dossiers submitted at each tonnage level.
Dossier Evaluation: For substances registered at the highest tonnage levels (=100 tonnes/annum) a proposal is made by the registrant detailing those animal tests they consider are
required from the list of standard tests in Annexes IX and X of REACH. The ECHA will evaluate
these testing proposals to prevent unnecessary animal testing.
Substance evaluation: This is undertaken by national Competent Authorities on substances that
have been prioritised for potential regulatory action because of concerns about their hazardous
properties. A key regulatory outcome of evaluation could be the imposition of restrictions on the
manufacture, supply or use of a substance. Substance evaluation may also lead to a substance
being added to the priority list for authorisation, or a proposal to change the classification and labelling.
All dossiers will undergo an automated completeness check to ensure that all the relevant pieces
of information are present. This completeness check will not assess the quality or suitability of the
information. Further details on evaluation can also be found on the ECHA website.
Authorisation.
In order to place on the market or use substances with properties that are deemed to be of 'very
high concern', industry must apply for an authorisation. The European Chemicals Agency (ECHA)
in Helsinki will publish an initial list containing substances to be considered for the authorisation
process by 1 June 2009. A company wishing to market or use such a substance must submit an
application to the ECHA for an authorisation. Decisions on authorisation are made by the Euro-

pean Commission, taking advice from the ECHA and member states. Applicants will have to
demonstrate that risks associated with uses of these substances are adequately controlled or that
the benefits of their use outweigh the risks. Applicants must also analyse whether there are safer
suitable alternatives or technologies. If there are, then they must prepare substitution plans and if
not, then they should provide information on research and development activities if appropriate.
Restrictions.
If any substance poses a particular threat and it is deemed to require Community-wide action, it
can be restricted. Restrictions take many forms, from a total ban to not being allowed to supply it
to the general public. Restrictions can be applied to any substance, including those that do not
require registration. This part of REACH takes over the provisions of the Marketing & Use Directive.
Classification and labelling.
An important part of chemical safety is clear information about any hazardous properties of a
substance. The classification of different chemicals according to their characteristics (for example, those that are corrosive, or toxic to fish, etc.) currently follows an established system, which
is reflected in REACH. The CLP regulation deals with this and dovetails with REACH.
Substances of Very High Concern.
Some substances have hazards that have serious consequences, e.g. they cause cancer, or they
have other harmful properties and remain in the environment for a long time and gradually build
up in animals. These are 'substances of very high concern'. This category also includes substances shown to be of equivalent concern, such as "endocrine disruptors". One of the aims of
REACH is to control the use of such substances via authorisation and encourage industry to substitute these substances for safer ones.
Information in the supply chain.
The passage of information along the supply chain is a key feature of REACH. Users should be
able to understand what manufacturers and importers know about the dangers involved in using
chemicals and how to control risks. However, in order for suppliers to be able to assess these
risks, they need information from the users. REACH provides a framework in which information
can be passed both up and down supply chains.
REACH adopts and builds on the previous system for passing information - the Safety Data
Sheet (see section 1.5). This needs to accompany materials down through the supply chain, providing the information users require to ensure chemicals are safely managed. In time, it is intended that these safety data sheets will include information on safe handling and use.

5.21 Summary.
In this study unit, we have seen that there are legal requirements as to the toxicological testing of
new substances - the level of testing depends on the quantity of substance to be produced.
A key concept in toxicology is the dose-response relationship, 'dose' being the amount per unit of
body mass of toxic substance to which the organ is exposed, and 'response' being the resultant
effect.
The mid-point of the S-shaped dose-response curve represents the dose which would cause
death in 50% of the organisms - LD50. LD90 enables estimation of the dose that will kill the majority (i.e. 90% of a sample of animals). Lethal concentration (LC) can be determined for a specified duration of exposure.
There are three types of toxicity test acute (to determine the effects which occur within a short period after dosing);
subacute (to provide information on the target organs affected by the substance and the major
toxic effects); and

 chronic (lifetime exposure of animals to the substance under study).

Mutagenicity occurs as a result of interaction between mutagenic agents and the genetic materials of organisms. The Ames test is the most common test for gene mutation.
Long-term animal toxicity studies, often with rats and dogs, are carried out to assess the effects
of human exposure to chemicals over long periods.
Chemical analogy studies assume that chemically related substances will show similarities in
toxic properties.
A collection of resources can be found here:
http://toxnet.nlm.nih.gov/
http://www.labexplorer.com/toxicology.htm
http://www.rphworld.com/link-421.html
Epidemiology is the determination of the cause, having first observed the effects. Sources of epidemiological data include national records, such as birth and death certificates and morbidity records, and local medical and trade union records and surveillance of high risk workers.
Important criteria that must be satisfied in order to establish a definite relationship between a disease's cause and effect include: strength; consistency; specificity; biological gradient; biologically
plausible; analogy; and preventive action.
There are two main types of epidemiological study.
Cross-sectional studies (prevalence studies) are outcome-selective (examines the prevalence of
a particular occupational condition within the population) or exposure-selective (examines a particular population that has been exposed to a specified occupational condition).
The design of a cross-sectional study involves establishing precise aims; defining the study population; determining the sample size; recruitment of all the relevant cases in the sample; and
analysis.
Longitudinal studies investigate the workforce over a significant period of time. The case-control
study (retrospective) begins with a definition of a group of causes, and relates these (along with
controls) to the past exposure history.
The follow-up study (prospective) takes a group of exposed persons (and possibly non-exposed
controls) and follows them up over an appropriate time period to assess the eventual outcome of
the exposure. Cohort studies are a specific type of follow-up study.
There are, of course, limitations to epidemiology including the healthy worker effect; a poor response rate; a high turnover of the study population; latency period between exposure and effect
longer than the study period; poor quality of data; and no effect of exposure noted, perhaps due
to a poor or small study population.
For an epidemiological study to be effective, there should be: a clear hypothesis and study objective; appropriate study design; collection of good quality data; valid population choice; high response rate and good sampling strategy; large enough population; and a no effect study result
investigated for validity.
Weblink: http://pmep.cce.cornell.edu/profiles/extoxnet/TIB/epidemiology.html discusses the link
between cigarette smoking and lung cancer.
Types of toxic effects caused by industrial chemicals
Toxic property

Part of body
affected

Time scale of
appearence

Effect

Example

Irritant or cor- Any, but usually A few minutes Inflammation, burns and blisters of
Ammonia, sulphuric a
rosive
the eyes, lungs to several days exposed area. Frequently healed af- nitrogen oxides, caust

and skin

ter acute exposure. Chronic exposure may lead to permanent damage.

soda

Fibrogenic

Generally lungs Years

Gradual cumulative loss of lung func- Bauxite dust, asbesto

tion leading to disability and death if gasse
there is chronic exposure.

Allergic

Any, but frequently lungs

and skin

Days to years

In lungs may lead to chronic asthma- Toluene, di-isocyanat

like disease and permanent disabil- (TDI), amine hardene
ity. In skin may produce industrial
epoxy resins.
dermatitis.

Dermatitic

Skin

Days to years

Inflamed, peeling skin rashes. May

result from chronic exposure to irritants, allergenic agents, solvents or
detergents.

Strong acids, alkalis, d

gents, carbon tetrachl
trichloroethylene.

Carcinogenic Any organs, but 10 to 40 years

frequently skin,
lungs, bladder

Cancer in affected organ or tissue.

2-Naphthylamine, cer
Ultimately this may cause premature tars and oils, benzidin
death.
bestos

Poisonous

Any organs but

frequently liver,
brain, kidney

A few minutes
to many years

Death of cells in vital organis with

eventula failure of organ to carry out
important biological functions. Ultimately can cause death.

Carbon tetrachloride,
cury, cadmium, carbo
monoxide, hydrogen c
nide.

Asphyxiants

Lungs

Minutes

Gases replace normal oxygen content of air

Acetylene, carbon dio

Page 5.
Examples of commonly occurring _____ substances include -acids, ammonia, sodium hydroxide
Multiple Choice (HP)
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corrosive

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harmful

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dermatitic

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carcinogenic

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Page 6.
The deposition of aerosols and particles in the respiratory system by the Ciliary escalator mechanism is for particle sizes of
Multiple Choice (HP)
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Above 10m

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7-10m

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0.5-7m

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Page 7.
_____ grow rapidly without restraint, spread into surrounding tissue and have their own cell structure, unlike the cells of origin. The term cancer is used to describe the formation of these tumours.
Multiple Choice (HP)
Answer 1:

Benign tumours

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Malignant tumours

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Page 8.
Irritation symptoms may be caused by
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Eye toxins

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Cutaneous agents

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Hematopoietic agents

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Neurotoxins

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Page 9.
Mercury, Chloroform, ether are likely to damage which Target Organ/System
Multiple Choice (HP)
Answer 1:

Skin

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Reproductive

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Nervous

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Kidney

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