Modifying Factors in Toxicity

Question 1

influences of biotransformation

Answer 1

1. Dose
2. Duration and frequency of exposure
3. Species, genetic strain, individual
4. Sex, pregnancy
5. Age
6. Nutritional Status
7. Disease
8. Physical (environmental) factors
9. Social Factors

Question 2

Reminder Dose defines…

Answer 2

the poison; dose, duration of exposure, and frequency of exposure are obvious factors that influence toxicity

Question 3

What causes intraspecific differences among individuals?

Answer 3

Genetics and environment
toxicokinetics (ADME) and toxicodynamics
genetics

Question 4

What are interspecific differences?

Answer 4

Differences among species are also due to differences intoxicokintetics and toxicodynamics, but are commonly much greater than those within a species

e.g. acute toxicity (LD50) of dioxin (TCDD) varies from 2 ug TCDD/kg body weight in guinea pigs to 2000ug/kg in hamsters

Question 5

significant strain differences among laboratory animals (rats and mice)
Consider importance for human health risk assessment, where…

Answer 5

where toxic responses in rats and mice are extrapolated to humans to assess toxicological risk
difference in toxicokinetics and toxicodynamics difference between rats & humans or even older and younger humans

Question 6

Sex, hormonal status, pregnancy (Differences)

Answer 6

-Differences in toxicity between males and females: usually related to differences in biotransformation enzyme activities
- Similarly, differences in certain hormone levels can also influence toxicity, e.g, hormones involved in growth, stress response, energy homeostasis and reproduction

Question 7

Age (interspecific differences)

Answer 7

• in general, young animals are 2-10 times more sensitive than adults; often related to toxicokinetics factors
• older animals may also be more sensitive; usually due to diminished clearance or repair mechanisms

Question 8

Nutritional status - Diets deficient in protein and fatty acids…

Answer 8

• reduce biotransformation enzyme activity

Question 9

Caloric restriction reduces…

Answer 9

Caloric restriction reduces cancerous tumor growth (tumorigenicity)

Question 10

High fat diets cause what?

Answer 10

Greater exposure to lipophilic “legacy” contaminants (POPs), e.g inuit diets from arctic marine animals

Question 11

Dietary antioxidants protect against…

Answer 11

reactive oxygen species and oxidative stress

Question 12

How does grapefruit juice affect enzymes

Answer 12

certain chemicals present in diet can induce or inhibit CYP enzyme activity and modify toxicity (e.g., grapefruit juice inhibits CYP3A4)

Question 13

Diseases (interspecific differences)

Answer 13

• underlying pathology
• impaired liver or kidney function due to disease can greatly influence the rate of xenobiotic clearance
• interactions between certain diseases and cancer e.g hepatitis exacerbates liver cancer (primary hepatocellular carcinoma)
• impaired lung function (e.g asthma) causes greater sensitivity to air pollutants

Question 14

physical environmental factors (interspecific differences)

Answer 14

• temperature
• barometric pressure
• photoperiod (light exposure? UV?)
• electromagnetic radiation
• cell phones?

Question 15

Social factors (interspecific differences)

Answer 15

• stress
• crowded conditions generally exacerbate toxic responses
• alternatively, isolation can also exacerbate toxic responses

Question 16

Thinking Question 1:
Two groups of an identical genetic strain of mice are exposed to the same concentration of a xenobiotic in their daily diet. After one week all the mice in one group are dead, and all the mice in the other group are alive. Provide five reasons for this difference in toxicity between the two groups of mice.

Answer 16

Genetics is not a factor
- Environment
- Food/water etc.
-gender?
-
-

Question 17

Thinking Question 2
Male rats and mice are exposed to the same concentration of a xenobiotic (10mg/kg wt) in their daily diet. Each species is fed the same food ration, are the same age, are healthy, were acclimated to laboratory conditions identically, and are housed under identical conditions (number of animals per cage, access to water, temperature, photoperiod). After one week all the rats are dead and all the mice are alive. Provide 5 reasons for this difference in toxicity between rats and mice.

Answer 17

the answer lies in species differences related to toxicokinetics (ADME) and toxicodynamics
- Due to genetics
-