Environmental Health

& Toxicology

2 April 2009 EnvHealth&Tox.ppt 1

 Risk
Risk = probability of suffering harm from
hazard.
◦ EVERYTHING we do involves some risk.
 Choices:
 To smoke or not
 To use seat belt or not
 To cross street or not
 That life is risky is not an issue
 Making life choices that manage risk is
personal/family/social issue.

2 April 2009 EnvHealth&Tox.ppt 2

 Risk
Measuring risk.
◦ Probability:
 0 < P < 1.0
◦ Example:
 Lifetime Pcancer from exposure to [chemical] =
0.000001
 = 1/ 1,000,000 (small risk)
 Then, in population of USA, about 300 cases/75 years due to
this cause

2 April 2009 EnvHealth&Tox.ppt 3

Risk
Risk assessment Please list in order of
◦ Using data, models to risk severity:
quantify risk. ◦ homicide
◦ Identifying real or ◦ automobile accident
potential hazard ◦ obesity
◦ Determining ◦ cancer
probabilities of harm,
◦ heart disease
severity of risk
◦ smoking (pack/day)
◦ airplane crash
◦ fire
◦ accident at home

2 April 2009 EnvHealth&Tox.ppt 4

 Risk
Risk assessment
Determining
probabilities of
harm; severity
Nature of risk
◦ Health risk
◦ Environmental risk
◦ Economic risk
◦ Social impact

2 April 2009 EnvHealth&Tox.ppt 5

 Hazards
Physical
◦ Ionizing radiation,
◦ fire,
◦ weather,
 wind, tornado
 lightning
◦ noise,
◦ etc.

2 April 2009 EnvHealth&Tox.ppt 6

 Hazards
Chemical
◦ Natural vs. synthetic
 Water is dangerous in
large quantities
◦ Organic, inorganic
◦ Pollution
 air,
 water,
 land

2 April 2009 EnvHealth&Tox.ppt 7

 Hazards
Biological
◦ Pathogens, parasites &
vectors,
◦ Allergens
 pollen, mold spores, poison
ivy
◦ Dangerous animals
 dogs, cattle, horses,
 snakes
 wasps, bees
 jellyfish, Portuguese man-
of-war

2 April 2009 EnvHealth&Tox.ppt 8

 Hazards
• Cultural hazards
– Working conditions,
– diet,
– drinking,
– driving,
– STDs,
– poverty,
– age (?)
– Exposure to physical,
chemical, & biological
hazards!

2 April 2009 EnvHealth&Tox.ppt 9

 Chemical Hazards
Toxicology: Science that
studies effects of poisonous
substances on humans and
other organisms
◦ Any chemical can be harmful
◦ “The dose makes the poison.”
Toxicity:measure of how
harmful [chemical, toxin]
is.

2 April 2009 EnvHealth&Tox.ppt 10

Toxicology
Whether [chemical] is harmful depends
on
◦ Quantity ingested, absorbed (dose)
◦ Frequency of exposure
◦ Who is exposed?
 gender, age, personal sensitivity, etc.
◦ Body’s detoxification systems & health
Example: Alcohol

2 April 2009 EnvHealth&Tox.ppt 11

Toxicology
Effect = response
◦ How much damage done, to what organs?
◦ Time frame:
 Acute effect: immediate, short term
 Chronic effect: permanent or long-lasting
 Symptoms may begin immediately, or delayed onset
 Single toxin may have acute & chronic effects

2 April 2009 EnvHealth&Tox.ppt 12

 Toxicology
Other factors:
◦ Solubility
 Water soluble
 Fat soluble
◦ Persistence: How long it lasts in body or
environment.
 Excretion = elimination in urine
 Natural degradability

2 April 2009 EnvHealth&Tox.ppt 13

 Toxicology
Other factors:
◦ Bioaccumulation:
increased concentration in
specific tissues over time.
◦ Biomagnification:
increased concentration
up a food web.

2 April 2009 EnvHealth&Tox.ppt 14

 Toxicology
Three methods, used together, to assess
health threat:
1. Case histories
2. Epidemiology
3. Animal testing

2 April 2009 EnvHealth&Tox.ppt 15

 Toxicology
1. Case histories
◦ Physicians send information of unusual
patient complaints/conditions to [agency]

2 April 2009 EnvHealth&Tox.ppt 16

Toxicology
2. Epidemiology
◦ Human population studies attempt to correlate
exposure (who, state of health, dose &
frequency) to occurrence of effects.
◦ Limited by low numbers of individuals
exposed, genetic & experience variability,
other exposures, population movements.

2 April 2009 EnvHealth&Tox.ppt 17

 Toxicology
2. Epidemiology
◦ Framingham (Mass.) heart study.
◦ Severe Acute Respiratory Syndrome (SARS),
Fall 2003.
◦ Bird flu (avian influenza virus H5N1)
– direct contact with infected poultry
– eye infections (conjunctivitis) to severe respiratory
disease (pneumonia) to death
– spread from person to person rare

2 April 2009 EnvHealth&Tox.ppt 18

 Toxicology
3. Animal testing
◦ Experiments on lab animals determine
 Toxicity & dose-response curve,
 Acute or chronic effects,
 Residence time in body
 Excretion rate,
 What tissues & organs affected,
 How harm occurs.

2 April 2009 EnvHealth&Tox.ppt 19

 Toxicology
Expense of laboratory studies
◦ Drug approval by Food & Drug Administration
(FDA) takes years, $$.
 Safety of medicines
 Effectiveness of medicines
◦ Studies of environmental chemicals, biological
agents also takes time & money.

2 April 2009 EnvHealth&Tox.ppt 20

Toxicology

2 April 2009 EnvHealth&Tox.ppt 21

Principles of Toxicology:
The Study of Poisons
The study of the adverse effects of a
toxicant on living organisms
Adverse effects
◦ any change from an organism’s normal state
◦ dependent upon the concentration of active
compound at the target site for a sufficient time.
Toxicant (Poison)
◦ any agent capable of producing a deleterious
response in a biological system
What is a Poison?
All substances are poisons;
there is none that is not a poison.
The right dose
differentiates a poison and a remedy.

Paracelsus (1493-1541)
Dose
The amount of chemical entering the body
dependent upon
* environmental concentration
* properties of the toxicant
* frequency of exposure
* length of exposure
* exposure pathway
 What is a Response?
Change from normal state
◦ could be on the molecular, cellular, organ, or
organism level--the symptoms
Localvs. Systemic
Reversible vs. Irreversible
Immediate vs. Delayed
Graded vs. Quantal
◦ degrees of the same damage vs. all or none
 Dose-Response Relationship:
As the dose of a toxicant increases,
so does the response.
4

RESPONSE

0-1 NOAEL
2-3 Linear Range 3
4 Maximum Response

0 1 DOSE
DOSE DETERMINES THE BIOLOGICAL RESPONSE
LD50
If Mortality is the response, the dose that is
lethal to 50% of the population LD50 can be
generated from the curve
Different toxicants can be compared--
lowest dose is most potent
LD50 Comparison
Chemical LD50 (mg/kg)
Ethyl Alcohol 10,000
Sodium Chloride 4,000
Ferrous Sulfate 1,500
Morphine Sulfate 900
Strychnine Sulfate 150
Nicotine 1
Black Widow 0.55
Curare 0.50
Rattle Snake 0.24
Dioxin (TCDD) 0.001
Botulinum toxin 0.0001
Exposure: Pathways
Routes and Sites of Exposure
◦ Ingestion (Gastrointestinal Tract)
◦ Inhalation (Lungs)
◦ Dermal/Topical (Skin)
◦ Injection
 intravenous, intramuscular, intraperitoneal

Typical Effectiveness of Route of Exposure

iv > inhale > ip > im > ingest > topical
Exposure: Duration
Acute < 24hr usually 1 exposure
Subacute 1 month repeated doses
Subchronic1-3mo repeated doses
Chronic > 3mo repeated doses

Over time, the amount of chemical in the body

can build up, it can redistribute, or it can
overwhelm repair and removal mechanisms
 ADME:
Absorption, Distribution,
Metabolism, and Excretion
Once a living organism has been exposed
to a toxicant, the compound must get into
the body and to its target site in an active
form in order to cause an adverse effect.
Body defenses:
◦ Membrane barriers
◦ Biotransformation enzymes, antioxidants
◦ Elimination mechanisms
Absorption:

abilityof a chemical to enter the blood

(blood is in equilibrium with tissues)
Inhalation
Ingestion
Dermal
 Distribution:
the process in which a chemical agent
translocates throughout the body

Blood carries the agent to and from its site

of action, storage depots, organs of
transformation, and organs of elimination
Rate of distribution (rapid) dependent upon
◦ blood flow
◦ characteristics of toxicant (affinity for the tissue,
and the partition coefficient)
Distribution may change over time
 Distribution:
Storage and Binding
• Storage in Adipose tissue--Very
lipophylic compounds (DDT) will store in
fat. Rapid mobilization of the fat
(starvation) can rapidly increase blood
concentration
• Storage in Bone--Chemicals analogous
to Calcium--Fluoride, Lead, Strontium
• Binding to Plasma proteins--can
displace endogenous compounds.
Target Organs: adverse effect is dependent
upon the concentration of active compound at the
target site for enough time
Not all organs are affected equally
◦ greater susceptibility of the target organ
◦ higher concentration of active compound
Liver--high blood flow, oxidative reactions
Kidney--high blood flow, concentrates chemicals
Lung--high blood flow, site of exposure
Neurons--oxygen dependent, irreversible damage
Myocardium--oxygen dependent
Bone marrow, intestinal mucosa--rapid divide
Target Sites:
Mechanisms of Action

Adverse effects can occur at the level of the

molecule, cell, organ, or organism
Molecularly, chemical can interact with
Proteins Lipids DNA
Cellularly, chemicals can
◦ interfere with receptor-ligand binding
◦ interfere with membrane function
◦ interfere with cellular energy production
◦ bind to biomolecules
◦ perturb homeostasis (Ca)

2 April 2009 38
Excretion:
Toxicants are eliminated from the body by
several routes
Urinary excretion
Exhalation
Biliary Excretion via Fecal Excretion
Milk Sweat Saliva
Metabolism:
 The process by which the administered chemical (parent
compounds) are modified by the organism by enzymatic
reactions.
 1o objective--make chemical agents more water soluble
and easier to excrete
◦ decrease lipid solubility -->
decrease amount at target>increase ionization

◦ -> increase excretion rate --> decrease toxicity

 Bioactivation--Biotransformation can result in the
formation of reactive metabolites
Biotransformation (Metabolism)
Compound Without With
Metabolism Metabolism
Ethanol 4 weeks 10mL/hr

Phenobarbital 5 months 8hrs

DDT infinity Days to weeks

Biotransformation
Key organs in biotransformation
◦ LIVER (high)
◦ Lung, Kidney, Intestine (medium)
◦ Others (low)
Biotransformation Pathways
* Phase I--make the toxicant more water soluble
* Phase II--Links with a soluble endogenous
agent (conjugation)
 Individual Susceptibility
--there can be 10-30 fold difference in response
to a toxicant in a population

Genetics-species, strain variation, interindividual

variations (yet still can extrapolate between
mammals--similar biological mechanisms)
Gender (gasoline nephrotox in male mice only)
Age--young (old too)
◦ underdeveloped excretory mechanisms
◦ underdeveloped biotransformation enzymes
◦ underdeveloped blood-brain barrier
Individual Susceptibility
Age--old
◦ changes in excretion and metabolism rates,
body fat
Nutritionalstatus
Health conditions
Previous or Concurrent Exposures
◦ additive --antagonistic
◦ synergistic
Toxicology
 Exposure + Hazard = Risk
 All substances can be a poison
 Dose determines the response
 Pathway, Duration of Frequency of Exposure and
Chemical determine Dose
 Absorption, Distribution, Metabolism & Excretion
 The extent of the effect is dependent upon the
concentration of the active compound at its site of action
over time
 Bioactivation: compounds to reactive metabolites
 Individual variation of the organism will affect ADME