Dose response and toxicity testing lecture:

Question 1

what makes AChE a good biomarker?

Answer 1

can measure this in the blood from humans and wild species. A clear dose-response curve. Once it gets inhibited above 50% that is when it becomes toxic. This is really good because it tells you the exposure and its linked to the effect

Question 2

what are 4 examples of biomarkers?

Answer 2

1. CYP
2. Antioxidant enzymes or factors like GSH
3. AChE
4. Vitellogenin induction

Question 3

describe sub-chronic toxicity tests and the main use

Answer 3

usually 90 days, 2 species (general rule: test duration is 10% of lab animals lifespan)

Main use is to determine toxicity threshold

Question 4

what would make a good bio indicator species?

Answer 4

1. size
2. abundant
3. sensitive
4. native
5. R-selected
6. Lifespan
7. homerage
8. trophic status
9. global distribution

Question 5

under sub-chronic toxicity tests you take the dose that safe for rats and mice and divide that by what?

Answer 5

100

Question 6

Potency vs efficacy, which curve is the most potent and which is the most efficacy?

Answer 6

the curve to the left is the most potent (A), you always thin side to side for this.

The curve to the right (B) has the word efficacy (think up and down)

Question 7

therapeutic index=

Answer 7

LD50/ ED50

Question 8

Why do we need to use high doses in lab animal toxicity tests?

Answer 8

In order to determe the threshold level we need to have data points on the eentire sigmoid curve, we need to chareacrerize the entire dose response curve.

The acceptable human risk is less than 1 cancer out of a million human beings. To determine that we would need 30,000 animals and we cannot do that, so that is why we have to use high doses in lab animals

Question 9

4 examples of quantal?

Answer 9

1. Frequency of response in population 2. Cumulative response in population 3. Probit analysis (a way to lineraize data) 4. LD50 (dose causing lethality in 50% of population)

Question 10

Under acute lethality, what is the most common way in whcih almost all new xenobiotics are firest tested to figure out how acutely toxic they are?

Answer 10

96 hour LD50

Question 11

somatic cell mutation:

Answer 11

major concern is carcinogenesis

Question 12

describe sub-acute toxicity tests?

Answer 12

14-day, repeated dose is most common design

Question 13

define mutagenecity:

Answer 13

the ability of chemicals to cause alterations in DNA or chromosomes of either somatic or germ cells

Question 14

what do you want your therapetic index to be?

Answer 14

you want this to essentially be greater than 1000! you do not want a low number because that means that if you take 1000 tablets you can kill yourself, but 20 is not ok

Question 15

Germincal cell mutations:

Answer 15

major concern is DNA damage in ova/sperm that may be transffered to offspring and cause developmental toxicties.

Question 16

what is the deal with vistellogenin induction?

Answer 16

It is an estrogen dependent gene. Male fish, frogs and birds do not express this protein naturally. But when they are exposed to estrogen disrupting chemicals that actually do produce this gene which can be measurable in their blood streams!

Question 17

what are the two types of dose- response relationships?

Answer 17

1. Quantal (all or none)(yes or no) 2. Graded (continous)

Question 18

what is the main goal of descriptive animal toxicity tests?

Answer 18

determine xenobitoics that have toxic effects on organisms at low (environmetally realistic) exposures.

Question 19

What are the 7 categories of toxicity tests?

Answer 19

1. Acute lethality
2. Skin and eye irritations; skin sensitization test
3. Sub-acute toxicity tests
4. Sub-chronic toxoicity tests
5. Chronic toxicity tests
6. Developmental and reproductive toxicity tests
7. Mutagenicity tests

Question 20

describe chonric toxicity tests, what is it mainly used for?

Answer 20

6 months to 2 years duration (major portion of lab animals lifespan). Mainly used for carcinogeneicity testing.

Question 21

Margin of safety=

Answer 21

LD1/ED99

Question 22

what makes CYP such a good biomarker?

Answer 22

when you are exposed to xenobitoics CYP increases, and they can be speicifc for the xenobitoic. These are more biomarkers of exposure

Question 23

what makes a good biomarker?

Answer 23

1. easy to measure
2. Specific to the xenobitoic that you are assessing
3. cheap
4. non-destructive, or non-invasive
5. sensitive
6. Reproducible
7. applicable to all humans

Question 24

define repropductive toxicity

Answer 24

adverse effects on female and male reproductive systems

Question 25

define developmental toxicity:

Answer 25

adverse effects that occur any time between conception to puberty

Question 26

draw a hormesis: U-shaped dose-response curve

Answer 26

Question 27

what make antioxidant enzymes or factors good biomarkers?

Answer 27

They increase in activity to increase in reactive oxygen species exposure. ex.) glutathione (GSH) a good one is to look at the ratio between reduced to xoidized form of glutathione FSH: GSSG. This also just gives us info about exposure.

Question 28

define biomarkers?

Answer 28

usually molecular, biochemical, physiological or morphological indictors of exposure to and/or effects of toxicants