Biological Factors

Biological toxicity or poisonous substances produced by birds, animals and micro-

organisms are

Diphthera

Tetradotoxin

Botulinium

Snake Venom

Conotoxin

Ricin.
Species and stain of animal
Species and Strains of animals show differences in metabolism and deposition of the
compound. Deposition of the compound and absorption through the skin show
considerable species variation. Oral absorption depends upon pH of digestive tract
herbivorous carnivorous and omnivorous.

Absorption also depends on quality of food in the gastrointestinal tract. Food decrease
drug absorption because of binding to toxic compound to food

Proteins causes higher production of ketones which induce CYPZE which increases
metabolism of low molecular weight xenobiotics. Strain differences; plasma protein
concentration is a species dependent variable also type of proteins vary between species
•Absorption by inhalation depends upon breathing rate, smaller animals have much
higher ventilation rate than larger animals.

•Excretion rate of urine varies considerably between species (rates in rats is 10

times more than in human).

•Biliary excretion depends on pH of digestive tract segment and composition of

micro-organisms in segment
A Sex- related variabilities

• Barbiturates induce longer sleep in females than in males that have higher activity of liver microsomal enzymes
for hydroxylation of hexobarbital.

• Chloroform is one of the first anesthetic which is abandoned because it may cause lethal arrhytmias or
respiratory arrest.

• It is also hepatotoxic with more severe liver damage in male than in female mice. In males rats testosterone
induces liver microsomal enzymes thus causing higher metabolism of chloroform and production of phosgen
which is hepatotoxic.

• Sex-related variabilities Usually male and female animals have similar toxic response to the same compound.
When differences exist they are mostly quantitative and not qualitative. Male rats metabolize xenobiotics more
rapidly than females. Humans are similar in that aspect to rat because men metabolize xenobiotics faster than
woman. Female mice metabolize compounds more rapidly than male mice. When toxicity is sex-related, toxic
response of males becomes similar to toxicity in females after castration. This can be reversed if testosterone
• Sex-related variabilities Usually male and female animals have similar toxic
response to the same compound. When differences exist they are mostly quantitative
and not qualitative.

• Male rats metabolize xenobiotics more rapidly than females. Humans are similar in
that aspect to rat because men metabolize xenobiotics faster than woman. Female
mice metabolize compounds more rapidly than male mice.

• When toxicity is sex-related, toxic response of males becomes similar to toxicity in

females after castration. This can be reversed if testosterone therapy is applied in
Age-related
•Various toxicants are more toxic in young animals than in adults because of: • undeveloped
mechanisms of detoxication - Aflatoxin B1 is 7 times more toxic in 1 day old rat than in adults

•undeveloped blood-brain barrier • higher absorption of certain compounds - lead is absorbed 4-5
times more by the young than by adults Exception: Young animals and children have fewer
symptoms and recover completely from OPIDP after severe intoxication with some
organophosphates. This is due to the very quick de novo synthesis of the target enzyme in peripheral
nerve

•Various toxicants are also more toxic in old animals and humans because of: • reduced detoxication
• impaired renal excretion • decreased blood flow • lower level of total plasma proteins

•Distribution of toxicants and drugs may be altered because of increased body fat and decreased
Human variability

• Toxic response in humans may be very different because of genetic variability of

humans. Glucose-6-phosphate dehydrogenase deficiency (G6PD) is X-linked
genetic condition that predispose to hemolytic anemia. G6PD-affected males are
immune to malaria. Manifestations of G6PD are:
Route of exposure

•Intravenous and intraperitoneal applications result in higher toxicity because the

toxin enters the circulation avoiding the liver which is the most important organ for
detoxication of xenobiotics the exposure route impact the absorption and
distribution within the body so chemicals that are highly toxic through one route
may be harmless through another.
•The toxin’s ability to be absorbed by the organism – toxicity is higher in organisms that absorb the
toxic chemical more easily

•Gender – physiological differences between men and women can impact toxicity levels of some
chemicals

•Toxic effects of chemicals are in relation with • Biavailability which depends on absorption,
distribution, and excretion of toxic chemicals • Metabolism • Sensitivity of receptors on target organs

•Toxic effects of chemicals can be modified by Environmental factors; Chemical factors •

Lipophilicity • Structure • Ionization • Chilarity -Chilarity is property of molecules with one central
atom (usually carbon) with four different atoms or groups attached on it
Target organs

•Central Nerveous- Lead

•Immune System- Isocyanates

•Liver

•Eye- UV

•Kidney – Heavy Metals

•Skin =-Uv

•Reproduction-
•Form -gas, liquid or solid

•Inherent-soluble Form and intrinsic chemical activity of the toxin – the toxicity level of some substances is

largely influenced by the form of the substance at the time of exposure, -character of the molecule, ability to be

absorbed, metabolism-broken down distribution in the body excretion role respiratory -tobacco, smoke,

asbestos-ozone

•dosage-time exposure route-swallowed, inhaled skin

•Type of exposure-acute result from high concentration at the target site which may cause acute or delayed effect

•Factors associated with treatment animal husbandry and social factors can modify toxicity of chemicals

•Handling of animals housing (single or in groups) type of cage and bed dry is important animals require a

friendly environment,
•Distribution within the body – lipid-soluble toxicants that can penetrate cell
membranes more readily have a higher toxicity level

•Latency of toxic response- how quickly or slowly the toxicity appears after
exposure to a chemical

•Volume of solvent
Factors associated with treatment

 Dose magnituse of exposure-high or lowduration and frequency of exposure.

Dosage – larger doses will almost always have a higher toxicity level.

 Dose-time relationship – exposure to large doses of a chemical does much more

damage than exposure to a small dose just once or fewer times over a shorter
window of time.

 Route of exposure – the exposure route impact the absorption and distribution
within the body so chemicals that are highly toxic through one route of exposure
may be harmless through another.
Factors associated with treatment

 Absorption levels – toxins that are more readily absorbed by the system will
do more damage than toxins that are poorly absorbed.

 Presence of other chemicals – presence of some chemicals may increase the

toxicity level of a substance while others may reduce its toxicity level.

 Metabolism of the organism – some organisms may detoxify toxic chemicals

through their metabolic activity, while others may convert it to a more toxic
or reactive form.

 Health of the organism – chemicals typically display higher toxicity levels in

Other conditions

•Diet and Nutritional status

•Diseases- the absorption and excretion of drugs are frequently reduced by diseases. Excretion is
reduced by impaired renal function often found in elderly and this increase the toxic response (rate
of removal)
•Distribution of toxicities and drugs may be altered because of increased body fat and increased
body weight
•Distribution within the body – lipid-soluble toxicants that can penetrate cell membranes more readily
have a higher toxicity level

•Latency of toxic response- how quickly or slowly the toxicity appears after exposure to a chemical

•Volume of solvent

•Type of exposure-acute result from high concentration at the target site which may cause acute or delayed
Presences of other chemicals /Interactions
• Presences of other chemicals may increase (additive) the toxicity levels of a
substance while others may reduce its toxicity- (antagonistic)

• Additive effect in pharmacology describes the situation when the combining

effects of two drugs equal the sum of the effects of the two drugs acting
independently.

• The concept of additive effect is derived from the concept of synergy. Wikipedia,
synergistic and antagonistic effects. Interactions are additive when their combined
effect is the sum of each independently,,
Synergistic effects

Synergistic effects are the effects which occur when chemical substances or
biological structures interact resulting in an overall effect that is greater than the
sum of individual effects of any of them. synergistic when the combined effect is
greater than the sum of each independently

Synergistic effects are the combined effects of at least two substances making an
impact that is more significant than both of them could have shown by themselves.
Synergistic effects examples cont,----
• Skin harm caused by both tobacco smoke and UV radiation is more prominent than
by tobacco smoke alone or by UV radiation alone.
 Both carbon tetrachloride and ethanol (ethyl liquor) are harmful to the liver. When
administered together, they produce more considerable liver injury than the entirety
of their individual impacts on the liver.

 The toxicity of some insecticides pyrethrin (from chrysanthemums) and synthetic

pyrethrins (pyrethroids) can be increased many times by the addition of compounds
that themselves are not insecticides such as (sesamin, sesamolin, and sesame.

 Piperonyl butoxide is perhaps the most widely used synthetic pyrethroid synergist.
Synergistic effects
 When physicians treat bacterial heart infections with ampicillin and gentamicin.
This is done on the grounds that the two antimicrobials target various pieces of
the microorganisms, and taking them together kills the microscopic organisms
faster, thus speeding up recovery.,

 Cancer treatment presents yet another example of synergism. Patients with

cancers are quite frequently put on both chemotherapy and radiation therapy.
They work to stop the growth of cancer cells by targeting different parts of the
replication process.
Antagonistic effect

• The effect produced by the contrasting actions of two (or more) chemical groups.
Or antagonistic is when the combined effect is less than the sum of each
independently.
 An example of antagonistic effect is the effect between the opposing actions of
insulin and glucagon to blood sugar level. While insulin lowers blood sugar
glucagon raises it. Thus, regulating the major physiological function of these two
chemicals is crucial in order to keep up a healthy level of glucose in blood
• Antagonistic effects are the basis of many antidotes for poisonings or for medical
treatments. For example, ethyl alcohol (ethanol) can antagonize the toxic effects
of methyl alcohol (methanol) by displacing it from the enzyme that oxidizes the
methanol.
•Metabolism small animals metabolize compounds at faster rate than larger animals per
unit of body weight. Male rate metabolizes xenobiotics more rapidly than females

•Age related -young animals’ metabolism is compounded by underdeveloped systems.

•Diseases- the absorption and excretion of drugs are frequently reduced by diseases.
Excretion is reduced by impaired renal function often found in elderly and this increase
the toxic response (rate of removal)

•Distribution of toxicities and drugs may be altered because of increased body fat and
increased body weight
 Chemicals in the diet, air or water
Chemicals in diet, air or water affect Humans under medication with several drugs
while exposed to an industrial chemical. The toxicity of a chemical in an organism
may be increased or decreased by a simultaneous or consecutive exposure to another
chemical in food. –
) grapefruit juice increases the bioavailability of immunosuppressive drug
Cyclosporin A by inactivating the CYP 3A4 in liver and small bowel enterocytes.
Cyclosporin A is used for immunosuppression in renal allograft recipients. –
i) polyphenol epiggalocatechin gallate from green tea prevent tumor death induced
by antitumor drug Bortezomib (proteosome inhibitor) used in treatment of multiple
myeloma and mantle cell lymphoma). Green tea decreases the effect of
Bortezomib.
ii)Cigarette smoking and alcohol intake are also known to affect drug metabolism
and pharmacological responses