Q 3: comparative toxicology Flashcards
what factors influence chemicals exposure
dose, size (weight, fat, developmental stage gender, age
what influences the effect of chemical exposure
age at exposure, route of exposure, duration of exposure, species
Why is it important to know species differences
in response to toxicants?
metabolism, extrapolate results from toxicity studies
choosing appropriate test species
understanding evolution of detoxfication/ resistance mechanism
“designing” drugs/chemicals
aflatoxin
mold, corn- peanuts (liver cancer in humans but not in mice)
phenylthiourea
can cause pulmonary edema in rats but not monkeys
norbormide
causes respiratory failure in rats but not cat, dogs, mouse
ddt
carcinogen in mouse and rats but not monkeys
thalidomide
teratogen (birth defects in rabbits and man but not in hansters, rate or mice)
Species differences in toxicity are usually
attributable to differences in:
adme
Absorption
Deistribution
Metabolism
Elimination
absorption
plays an important role in affecting toxicity
- DDT is more readily absorbed across the skeletal chitin
of insects than the skin of humans
Metzbolism
- rate of metabolism often biggest influence on toxicity
- primarily in the liver
- products of metabolism -> metabolites
- two types of metabolism:
two types of metabolism
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
metabolism example in mammals vs insects
EXAMPLE:
• metabolism of malathion in mammals > insects
• mammals = fast metabolism à excreted
• insects metabolize slower à malaoxon
Distribution
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
Elimination
- kidney is the primary excretory organ
- gastrointestinal tract, and the lungs (for gases).
- other ways that toxicants can be excreted???
Toxicity Testing
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)
case study: thalidomide
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
Why did the drug only show birth defects and
sedative characteristics when given to humans and
not in the animals originally used in testing?
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
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
take home message
