Q 3: comparative toxicology

Question 1

what factors influence chemicals exposure

Answer 1

dose, size (weight, fat, developmental stage gender, age

Question 2

what influences the effect of chemical exposure

Answer 2

age at exposure, route of exposure, duration of exposure, species

Question 3

Why is it important to know species differences

in response to toxicants?

Answer 3

metabolism, extrapolate results from toxicity studies
choosing appropriate test species
understanding evolution of detoxfication/ resistance mechanism
“designing” drugs/chemicals

Question 4

aflatoxin

Answer 4

mold, corn- peanuts (liver cancer in humans but not in mice)

Question 5

phenylthiourea

Answer 5

can cause pulmonary edema in rats but not monkeys

Question 6

norbormide

Answer 6

causes respiratory failure in rats but not cat, dogs, mouse

Question 7

ddt

Answer 7

carcinogen in mouse and rats but not monkeys

Question 8

thalidomide

Answer 8

teratogen (birth defects in rabbits and man but not in hansters, rate or mice)

Question 9

Species differences in toxicity are usually
attributable to differences in:

adme

Answer 9

Absorption
Deistribution
Metabolism
Elimination

Question 10

absorption

Answer 10

plays an important role in affecting toxicity
- DDT is more readily absorbed across the skeletal chitin
of insects than the skin of humans

Question 11

Metzbolism

Answer 11

• rate of metabolism often biggest influence on toxicity
• primarily in the liver
• products of metabolism -> metabolites
• two types of metabolism:

Question 12

two types of metabolism

Answer 12

1: Detoxification: process by which zenobiotic is converted to a less toxic form
2: bioactivation: process by whic a zenobiotic may be converted to a more reactive or toxic form

Question 13

metabolism example in mammals vs insects

Answer 13

EXAMPLE:
• metabolism of malathion in mammals > insects
• mammals = fast metabolism à excreted
• insects metabolize slower à malaoxon

Question 14

Distribution

Answer 14

ultimately determines the sites where toxicity occurs
- blood (and lymph) are main avenues for distribution
- many toxicants are stored in the body
- fat tissue, liver, kidney, and bone are the most common
storage depots

Question 15

Elimination

Answer 15

• kidney is the primary excretory organ
• gastrointestinal tract, and the lungs (for gases).
• other ways that toxicants can be excreted???

Question 16

Toxicity Testing

Answer 16

early 20th century à need for toxicity testing grew

• several animal models were developed
• such testing had obvious advantages + disadvantag: expensive, ethics, variation between each individual (advantages: get to see the whole effect, faster

can be done by in vitro and in vivo (injection- in water)

Question 17

case study: thalidomide

Answer 17

synthesized in Germany in 1940s
• subjected to animal testing in hamsters and species of mice
• results indicated that it appeared relatively safe under the
regulatory approaches used in some countries
• prescribed in Canada, Europe, Australia, and Asia (not US)
a sleep and anti-nausea aid
prescribed to pregnant women
• critical time period of exposure was
around gestation days (GD) 35-50
• common effects include:
o amelia (absence of limbs)
o phocomelia (absence of most of the arm
with hands extending flipper-like from
the shoulders)
o dysmelia (malformation, missing or
extra limbs)
o bone hypoplasticity (incomplete
development of cells)Over 2000 research papers and the proposal of
approx. 15 plausible mechanisms
• Inhibition of angiogenesis is one theory
o Angiogenesis is critical during limb development of the fetus
o Loss of newly formed blood vessels à limb malformation

Question 18

Why did the drug only show birth defects and
sedative characteristics when given to humans and
not in the animals originally used in testing?

Answer 18

related to the altered degree of metabolism
• hydroxylated metabolites are much more soluble than the
parent drug à eliminated from the system FASTER!
• hydroxylation of thalidomide occurs extensively in mice,
moderately in rabbits, and lowest in humans

Question 19

no one species handles all chemicals in the the same
manner as other species
ü there is no single animal model that can be used to
study the toxicity of all chemicals
ü extrapolation of toxicity of chemicals (particularly to
humans) must be done with caution

Answer 19

take home message