3 dose-response relationship

Question 1

what are dose-response relationships?

Answer 1

-the most fundamental concept in toxicology and pharmacology is that of the dose-response relationship
-dose-response relationships are used in two main ways:
1. to compare drug potencies and effacies, and to determine drug safety
2. to determine toxicity thresholds of xenobiotics for use in human and ecological risk assessment (e.g. pesticides, food additives, and other environmental contaminants in water, food, air, soil)

Question 2

what are the types of dose-response relationships?

Answer 2

-there are two main types of dose-response relationships: graded and quantal
-all dose-response relationships are plots of dose on the independent (x) axis response on the dependent (y) axis

Question 3

what are graded dose-response relationships?

Answer 3

-show response of individuals and are continuous responses
-Y axis is usually “percent response” from 0 to 100%
-provides information about the intensity of response over a dose range

Question 4

what are quantal dose-response relationships?

Answer 4

-show population responses and are “all-or-none” responses
-y axis is usually “percent of individuals responding” from 0 to 100%
-provides information about the number of individuals exhibiting a specified effect over a dose range

Question 5

what is the quantal dose-response curve example?

Answer 5

mortality

Question 6

what are some LD50 examples?

Answer 6

Question 7

what is the difference between potency and efficacy?

Answer 7

-EC50 or ED50 (concentration or dose causing a 50% maximal response) is used to characterize drugs and compare potencies
-dose-response curves can also be used to determine any effective dose (ED), such as ED1, ED10, ED20, ED99, etc
-dose-response curves can also be used to determine toxic doses (TD) or lethal dose (LD)

-more efficacy is up, more potent is to the left

Question 8

what is therapeutic index vs margin of safety (measures of drug safety)?

Answer 8

-therapeutic index (TI): TI=TD50/ED50 (or LD50/ED50)
-margin of safety: TD1/ED99 (or LD1/ED99)

-margin of safety is a more conservative measure of drug safety; essentially the ratio of drug dose that causes toxicity/death in 1% of the population to drug dose that causes desired therapeutic effect in 99% of the population

Question 9

what is hormesis?

Answer 9

U-shaped dose-response curves
-commonly vitamins
-at very low doses, there is a deficiency (vitamin deficiency)
-at high doses can get into toxicities

Question 10

what is descriptive animal toxicity tests?

Answer 10

-also known as animal bioassays
-not just animals; tests also developed for determining toxicity to microbes and plants
-main goal: determine xenobiotics that have toxic effects on organisms at low (environmentally realistic) exposures
-certain toxicity tests have been standardized and are used in labs throughout the world for human and ecological risk assessment

Question 11

animal toxicity tests are based on two main principles:

Answer 11

-effects produced in lab animals are applicable to humans, or effects produced in non-human animals are applicable to populations and communities of wildlife
-exposure of experimental animals to high doses of a xeno is necessary to identify hazards to human health

Question 12

why do we need to use high doses in laboratory animal toxicity tests?

Answer 12

-the number of animals that can be used in tests is small relative to the size of human population
-need to use higher doses to ensure that the response will occur frequently enough to be detected
-e.g. detecting a cancer incidence of 0.01% (1 in 10,000 humans) would require using 30,000 lab animals
-human cancer risk assessment is based on incidence of 1 cancer in a million people

Question 13

what are the categories of toxicity tests?

Answer 13

-acute lethality
-skin and eye irritations; skin sensitization (delayed hypersensitivity) tests
-subacute toxicity tests
-subchronic toxicity tests
-chronic toxicity tests
-developmental and reproductive toxicity tests
-mutagenicity tests

Question 14

what is acute lethality tests?

Answer 14

-96 hour LD50 is most common
-first animal test for virtually all new chemicals; used to compare toxicity among different xenobiotics

Question 15

what is skin sensitization (delayed hypersensitivity) tests?

Answer 15

-rarely used today due to ethical concerns
-in vitro alternatives are used instead

Question 16

what are subacute toxicity tests?

Answer 16

-14-day, repeated dose is most common design (continuous exposure)

Question 17

what are subchronic toxicity tests?

Answer 17

-usually 90 days, two species (general rule: test duration is 10% of lab animal’s lifespan)
-main use: determine toxicity threshold (no observed adverse effect level: NOAEL) for use in risk assessment

Question 18

what are chronic toxicity tests?

Answer 18

-6 months to 2 years duration (major portion of a lab animal’s lifespan)
-mainly used for carcinogenicity testing; follow strict protocols (good laboratory practice; GLP)
-very expensive tests
-problem: high incidence of many cancers in lab rodents (highly inbred)

Question 19

what is developmental and reproductive toxicity tests?

Answer 19

-developmental toxicity is defined as adverse effects that occur any time between conception to puberty (teratology is between conception and birth)
-reproductive toxicity is defined as adverse effects on female and male reproductive systems
-developmental toxicity testing using alternative models (e.g. zebrafish, xenopus) can potentially be used due to similarity in embryo development and organogenesis (most sensitive time point) among vertebrates

Question 20

what is mutagenicity tests?

Answer 20

-mutagenicity is defined as the ability of chemicals to cause alterations in DNA or chromosomes (genotoxicity) 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
-best known is the Ames test in salmonella typhimurium:
-CYP enzymes from liver can bioactivate xenos and create electrophiles which can create DNA damage

Question 21

what are the toxicity tests required for a new pesticide?

Answer 21

Question 22

what are biomarkers?

Answer 22

-“ a xenobiotically-induced alteration of cellular or biochemical components, or processes, structure or functions, that is measurable in a biological system or sample”
-“measurable molecular, cellular, histological, physiological or behavioral responses that provide evidence of either exposure to, or effects of, toxicants”
-usually molecular, biochemical, physiological or morphological indicators or exposure to, and/or effects of, toxicants
-used as sensitive early markers of potential toxicity

Question 23

what are examples of biomarkers?

Answer 23

-many examples in human diagnostic medicine
-e.g. biomarkers of cancer risk (prostate-specific antigen (PSA), breast cancer susceptibility protein (BRCA))
-e.g. biomarkers of organ damage (ALT, AST, GGT, etc)

-also examples in ecological toxicology
-e.g. serum cholinesterase activity, CYP enzyme induction, vitellogenin in male oviparous (yolk-bearing) vertebrates

Question 24

what makes a good biomarker?

Answer 24

PANSI TERMS
-sensitive (occurs at earlier time points or lower exposures than “traditional” responses such as growth, reproduction, lethality)
-specific: to a specific class of toxicants
-easy to measure (doesn’t require advanced equipment or technical training)
-reproducible and reliable (good accuracy and precision)
-inexpensive
-non-invasive (samples collected without harming animal)
-mechanistically-based (linked to negative effects at higher levels of biological organization)
-time for response to occur (following exposure)
-permanence of response (reversibility; too transient a response is difficult to choose an appropriate time point; e.g. mRNA)
-applicable to field studies; ideally validated in field

Question 25

what are bioindicator species?

Answer 25

-also known as “sentinel species”
-used mainly in ecotoxicology, but origins are in human risk assessment: canaries in coal mines (methane toxicity in miners and leave canary in mine to see if dead or not)
-can be any living organism: animals, plants, bacteria, fungi
-bioindicator species are also “early warning systems” for human health risk

-usually mussels and clams

Question 26

what makes a good bioindicator species?

Answer 26

-size: sufficiently large to allow adequate tissue/blood samples
-longevity: sufficiently long-lived to provide data over prolonged period and be able to accumulate toxicants
-availability: the organism should be abundant (sampling should not impact the population)
-indigenous species are preferred since they are natural habitants of the area of concern
-sensitivity: the organism should be sensitive enough to exhibit effects at environmentally relevant toxicant levels; however not so sensitive that a slight increase in toxicant levels causes local extinction
-distribution: a broad geographical and ecological distribution is ideal so that comparisons can be made amongst regions
-type of contamination: aquatic vs terrestrial vs atmospheric (higher trophic level animals are useful for persistent xenobiotics that bio magnify in food webs e.g. fish-eating birds)