2 modifying factors of toxicity

Question 1

what are the modifying factors of toxicity?

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

what is dose?

Answer 2

dose defines the poison
-dose, duration of exposure, and frequency of exposure are obvious factors that influence toxicity
-higher dose=more likely to have toxic effect

Question 3

what are intraspecific differences?

Answer 3

what causes these differences among individuals?
-genetics and environment
-toxicokinetics (ADME) and toxicodynamics

Question 4

what are interspecific differences?

Answer 4

-differences among species are also due to differences in toxicokinetics and toxicodynamics, but are commonly much greater than those within a species
-ex: acute toxicity (LD50) of dioxin (TCDD) varies from 2ug TCDD/kg body weight in guinea pigs to 2000ug/kg in hamsters (ability to bind to receptors)
-also significant strain differences among laboratory animals (rats and mice)
-consider importance for human health risk assessment, where toxic responses in rats and mice are extrapolated to humans to assess toxicological risk

Question 5

what are the modifying traits of sex, hormonal status and pregnancy?

Answer 5

-differences in toxicity between females and males have been observed for certain toxicants; usually related to differences in biotransformation enzyme activities
-similarly, difference in certain hormone levels can also influence toxicity (ex: hormones involved in growth, stress response, energy homeostasis and reproduction)

Question 6

what are the modifying traits of age?

Answer 6

-in general, young animals are 2-10 times more sensitive than adults; often related to toxicokinetic factors (BBB not fully developed)
-older animals may also be more sensitive; usually due t diminished clearance or repair mechanisms

Question 7

what is nutritional status?

Answer 7

-recall: certain chemicals present in diet can induce or inhibit CYP enzyme activity and modify toxicity (ex: grapefruit juice inhibits CYP3A4 which is highly expressed in the liver and can bind to the most substrates)
-caloric restriction reduces cancerous tumor growth (tumorigenicity)
-high fat diet causes greater exposure to lipophilic “legacy” contaminants (POPs) (ex: inuit diets from arctic marine animals; considered toxic waste when die)
-diets deficient in protein and fatty acids reduce biotransformation enzyme activity
-dietary antioxidants (colourful fruits and veggies) protect against reactive oxygen species and oxidative stress (cumulative oxidative stress=aging)

Question 8

what are the modifying factors of diseases?

Answer 8

-called “underlying pathology” in medicine
-discussed earlier in toxicokinetics; impaired liver or kidney function due to disease can greatly influence the rate of xenobiotic clearance
-also interactions between certain diseases and cancer ex: hepatitis exacerbates liver cancer (primary hepatocellular carcinoma)
-impaired lung function (ex: asthma) causes greater sensitivity to air pollutants (PM2.5)

Question 9

what are physical (environmental) factors?

Answer 9

-temperature
-barometric pressure
-photoperiod (amount of light vs dark)
-electromagnetic radiation (people that live close to high power voltage towers have higher rates of diseases like cancer)
-cell phones (EM radiation linked to cause brain tumors)

Question 10

what are social factors?

Answer 10

-“stress”
-crowded conditions generally exacerbate toxic responses
-alternatively, isolation can also exacerbate toxic responses

Question 11

two groups of an identical genetic strain of mice are exposed to the same concentration of a xeno 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 11

cant rely on genetic (all genetically identical) so must rely on environment
-the answer lies in the modifying factors covered previously in this lecture
-dead: looking at phone, high phone use, barometric pressure, temperature, fat diet, all females

Question 12

Male rates and mice are exposed to the same concentration of a xeno 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 (numbers per cage, water, temperature, photoperiod). After one week all the rats are dead and all the mice are alive. Provide five reasons for this difference in toxicity between rats and mice

Answer 12

must rely on genetic differences
-the answer lies in the species differences related to toxicokinetics (ADME) and toxicodynamis (receptors, enzymes)