Toxicology Lec 1-7

Lee. - 5.
Toxicity testing - Chronocity factor, Untowar d effects
Toxicity
• They are potent carcinogens, mutagens and teratogens and liver damaging
agents.
• Liver tumor is a common toxic etlect.
• Acute toxicity is not very common.
• Most sensitive animals include rabbits, ducklings, minks, trout, dogs, turkeys
and small pigs.
• Other animals affected are horse, cattle, sheep, goat and guinea pigs.
• Most resistant animals are monkeys, RIR chicks 16 week old, WLH chicks,
rats, mice and hamsters.
• Chronic toxicity is common.
• Apart from age, sex, breed and strain of animal, other factors of importance
include riboflavin, exposure to light diet low in protein, cholin and vitamin
812.
• Animals on protein, vitamin E and selenium deficient diet are more
susceptible.
• Toxicity varies with the specific compound and route of administration
involved.
• ln general, introduction of an alpha - cyano moiety (type II pyrethroids) results
in an increase in toxicity.
• Drugs, chemicals, nutritional changes that alter the effectiveness of the mixed
function oxidase system can change the toxicity of the pyrethroids .
• Small animal poisoning occurs principally in cats.
• Rodents are also susceptible. Fish are often extremely sensitive.
Toxicity Testing
• Different types of testing methods are undertaken to test the toxicity of drugs
and chemicals.
• This includes acute toxicity, sub-chronic toxicity, chronic toxicity,
developmental toxicity, reproductive toxicity, phototoxicity, behavioural toxicity,
hypersensitivity, ocular and skin irritation tests, mutagenicity , teratogenicity and
carcinogenicity. In addition, toxicokinetic studies are conducted to estimate
the toxicity. In many of these studies rodents are used as experimental animals.
Toxic Variety
2. Acute:
a. Acute poisoning is associated with exposure to a relatively
large, often single, dose of a toxic agent, this being fo llowed by
rapid manifestatio n of more severe clinical signs of intoxication.
b. It is also defined as sudden violent syndrome caused by a single
large dose of poison.
3. Sub-acut e:
n. In sub-ncute poisoning the exposure ~eve~ is lower and ~h:
survivnl time longer, thnn in acute po1son111g. _but_ the_ peno
between exposure and manifestntion of signs of po1so111ng and
possible denth is ngain relatively sho11.
b. Symptoms of toxicity develop gradually.
c. In sub-acute toxicity studies, low doses of poisons are
administered for a period of 90 days. These tests are perfonned
to study, the No Observed Effect Level or No Observed
Adverse Effect Level and to identify the specific organ(s)
affected by the test compound after repeated administration.
4. Chronic:
a. Chronic poisoning is usually caused by multiple exposures to
the poison, while individual quantities are not sufficiently large
to produce clinical intoxication.
b. It is also defined as persistent lingering condition brought about
by small repeated doses. .
c. A relatively long delay is observed between the first exposure
to the toxic agent and the eventual development of signs of
po1somng.
d. Agents that cause chronic poisoning exhibit a cumulative
effect. They either accumulate within the liody or produce
additive tissue damage. Once this level becomes critical,
symptoms of poisoning develop. _
e. In some cases, the development of symptoms of poisoning may
be noticed many months after the exposure, even if there is no
contact with the poison during the intervening period.
f. In the chronic toxicity studies, the exposure time is six months
to two years for rodents and one year for non-rodents.
Chronicity Factor
• The ratio of acute to chronic LD 50 doses is known as chronicity factor.

• Compounds with cumulative effects have a high chronicity factor.
• A chronicity factor greater than 2.0 indicates a relatively cumulative toxicant.
• Chronicity factpr may be influenced by the tendency to accumulate rs. being
rapidly eliminated or detoxified. '
• It may also be influenced by cumulative and progressive damage that occurs
from repeated toxic insults to a target tissue.
• A compound may have low acute toxicity, but if it has the tendency to
accumulate in body tissues it can cause sub-acute or chronic toxicity. Such
toxicants are termed as cumulative poisons.
• The chronicity factor gives an indication of cumulative effects of poisons.
• However, chronicity factor may be influenced by the tendency to produce
tolerance.
• The biological system may tolerate higher dose after prolonged exposure.
Potassium cyanide is an example. Its acute LDso is 10 mg/kg, but pre-exposed
animals tolerate 250 mg/kg. Therefore the chronicity factor is 0.04 for potassium
cyanide.
Untoward Effects due to Poisonous Substances
There are other untoward effects caused by poisonous substances irrespective of the
poisoning being acute. sub-acute or chronic. These may be produced by certain drugs even at
therapeutic dose levels.
• Allergy -The individual becomes sensitized to a previous dose of the same

material.
• Teratogenic ity (Greek word meaning monster) - The exposure to certain
naturally occurring or man-made agents during certain stages of gestation
results in malfonnations of the offspring. Teratogen is defined as an agent
which, when administered during gestation, produces nonlethal structural or
functional changes in the embryo or fetus. Some plants and drugs .have been
identified to cause teratogenicity. For example: plants
like Veratrum and lupinus and drugs like thalidomide and colchicine.
• Carcinogenicity - The agent after a considerable delay may induce neoplasia .
The compound has the ability to transform normal cell into progressively and
uncontrollably proliferating ones.
• Mutagenicity - The agent induces mutation or changes through a change in
the genotype or genetic material of a cell by covalent modification of bases in
DNA particularly generation of DNA; which passes on when the cell divides.
• Certain common terms used in toxicology studies include
• Parts Per Million (ppm) is the term commonly used to express the quantity
oftoxicant mixed within another substance (e.g., feed) I ppm= 0.0001% = I
mg toxicant/kg feed.
• Lethal concentration (LC) is the lowest concentration of compound in feed
water or even in air that causes death. It is expressed as milligrams of
compound per kilogram of feed (parts per million or billion as ppm or ppb)
• Toxic concentration ITC} relates to the first recognition of toxic effects. The
specific (threshold) toxic effects should be identified when a toxic
concentration is given.
• Highest nontoxic dose (HNTD) is the largest dose that does not result in
clinical or pathologic drug-induced alterations.
• Toxic-dose-low (TDL) is the lowest dose that will produce alterations;
administration of twice this dose is not lethal.
• Toxic-dose-high (TOH) is the dose that will produce drug-induced alterations
and administration of twice this dose is lethal.
• Lethal dose (LD) is the lowest dose that causes death in any animal during the
period of observation. LDso is a commonly used measure of toxicity.
• Median Lethal Dose (LDso) is the dose at which a toxicant causes lethality in
50% of the population or animals exposed to that particular agent/compound.
• No observed adverse effect level (NOEL or NOAEL) is 1the largest dose that
will produce no deleterious effects when administered over a given period of
time. This study is generally conducted in two sp~cies (rats and dogs) at three
doses by the route of choice.
• Reference dose (RID) is the highest dose expected to have no effect on the
species of interest (often human beings) despite a lifetime of exposure. The
. RID may be set at 1/10 of the HNTD or l/10 of the NOAEL.
• Maximum tolerated dose (MTD) is sometimes used to indicate maximum
tolerated dose (highest dose not causing death). Other times it is used to
sing any abnonnalit y). Thu s. it
indi cate minimum toxi c dose (lowest dose cau
is best to ask what is meant by MTD.
• Saf ety factor (SF) reflects the quality
of the toxicological investigat ion and
lts can be extrapo lated to human
the degree of ce11ainty with which the resu
beings.

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Lee. - 5.

Toxicity testing - Chronocity factor, Untowar d effects

• The ratio of acute to chronic LD 50 doses is known as chronicity factor.

• Allergy -The individual becomes sensitized to a previous dose of the same

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