Dose-Response Relationships

Question 1

What is a biomarker?

Answer 1

“a xeno-induced alteration of cellular or biochemical components, or preocesses, structures or functions, that is measurable in a biological system or sample” or “measurable molecular, cellular, hisological, physiological or behaviourable responses that provide evidence of either exposure to or effects of, toxicants”–> usually something molecular, biochemical, physiological, or morphological, that indicates exposure to and/or effects of toxicants

Question 2

what are adverse outcome pathways (AOPs)?

Answer 2

links molecular effects of xenos (e.g. enzyme inhibition) to the overall health on the organism (or ecosystem?)

Question 3

what is a biomarker of cancer risk?

Answer 3

PSA, prostate specific antigen– found in blood above 5-10 something
BRCA mutation– breast cancer

Question 4

what makes a good biomarker?

Answer 4

• -specific to the disease
• -easy to measure (want most labs to be able to do it)
• -well characterized (know what normal levels should be)–> validated; not always known the valid levels in wildlife animals
• -non-invasive, easy-to-collect samples (collecting urine, exhaling)
• -cheap
• -allows for early detection; sensitive
  
  • -> permanence of response (how long it “lasts”)
• -reversiblity
  
  • -> e.g. mRNA; expression will only be turned on for maybe 30 min; better to measure the protein that comes from the mRNA to have a better idea of the amount
• -patient history
• -robust/reliable
  
  • ->want to avoid false pos or negs
  • ->accurate and precise
• -quick
• -reproducible (in all labs around the world)

Question 5

what are the categories of toxicity tests?

Answer 5

acute lethality; skin and eye irritation (delayed hypersensitivty) tests; subacute tox tests; subchronic tox tests; chronic tox tests; developmental and reproductive tests; mutagenicity tests

Question 6

what is the acute lethality test, and what is the information obtained?

Answer 6

96 hour LD50 most common to test for; first animal test for virtually all new xenos; used to compare toxicity between different xenobiotics;
info obtained: symptoms of toxicity; ID of target organs; mechanism of toxicity; and dosing range for further testing

Question 7

skin and eye irritation (delayed hypersensitivty) tests are rarely used due to ethical concerns; in vitro tests are used instead

Answer 7

ya

Question 8

what is a subacute toxicity test?

Answer 8

14-day, repeated daily dose most common form

Question 9

what are subchronic toxicity tests, and what information does it provide?

Answer 9

usually 90 days; uses two species–>general rule: test duration is 10% of animal’s lifespan;
provides the toxicity threshold (NOAEL) for risk assessment

Question 10

what are chronic toxicity tests?

Answer 10

much longer in duration– 6 months to 2 years (major portion of an animal’s lifespan); mainly used for carcinogenicity testing

Question 11

what are developmental and reproductive tests?

Answer 11

tests that analyze developmental toxicity–adverse effects that occur between conception and puberty (whereas teratogenicity is between conception and birth; and repro tox–>adverse effects on repro systems

Question 12

what are mutagenicity tests?

Answer 12

testing for the ability of a xeno to cause alteration in DNA/chromosomes of either somatic or germ cells–>somatic cell mutation: major concern is carcinogenesis; germinal cell mutation: major concern is DNA damage in ova/sperm that may be transferred to offspring and cause developmental toxicities; Ames test is the best known one

Question 13

what is the ames test?

Answer 13

mutagenicity test performed on salmonella typhimurium; quick test and relatively cheap–>grow S. typhimurium (his dependent in his+ media) –> separate into two samples, give one sample a possible mutagen, plate on his- or minimal his media; if there are lots of colonies growing on the plate with the possible mutagen, then the cells have turned from his dependent to his independent–>mutated

Question 14

what is a bioindicator?

Answer 14

a species of any organism (animals, plants, bacteria, fungi, etc) whereby the levels of toxicants are measured in that species and extrapolated to humans; aka sentinel species

Question 15

what makes a good bioindicator?

Answer 15

What makes a good bioindicator species
• Exposure vs effect
○ Want to use an animal that really accumulates (bioconc) or are you more concerned with how the xenos are affecting the population?
• Sensitive
○ Don’t want it to be “tolerant” or too sensitive–>wiped out too fast
• Animal easy to collect
• Abundant–>want a lot of info, also will be easy to get a permit bc if endangered, they’ll need to be conserved
• Easy to sample (non-invasive); size of animal
○ Larger animal–>easier to collect a sample
• Linked to human health/physiology
○ Pigs have very similar CV system; will undergo the same effects when exposed to a xeno as human would
○ Sheep has similar placenta–good for investigating teratogenicity
• Circumpolar distribution
○ Can compare animal studies in canada to australia
• Some cell lines are used over others
○ E.g. chinese hamster ovary cell line
• Nonmobile/sessile
○ How do you know they didn’t pick of xenos elsewhere?
• Longevity
○ How long a species lives
○ May want a short-lived species if you want to assess transgenerational effects
• Genetic variation
○ A lot of lab animals are inbred, really similar in genetics