Lecture 6 - In Vivo Toxicity

Question 1

Organizations involved in tox testing

Answer 1

-government agencies: envronemtn Canada, health Canada, FDA
Industry
Contact laboratories
Academic institutions

Question 2

Descriptive Toxicity

Answer 2

Drugs go through stages of development and then the ICH brings tgoether international regulatory agencies and pharma; they come up with guidelines for regulatory agencies and industries to follow
However, most everyday chemicals are not properly tested - there is no basic toxicity testing for all products, and in facts, of the 3000 chemicals produced/imported by the uS at amounts of over 1 million lbs per year, most have not been properly tested
We also dp not have data on these chemicals
Most of these chemicals have never been teste for their toxicity, therefore there is an organziation that fills in. The gap: the Organization for economic cooperation and development came up with guidelines for the testing of chemicals

Question 3

Organization for Economic Cooperation and Development (OECD)

Answer 3

Using input from industry and labs, they came up with collection of ~100 most relevant internationally agreed upon testing methods
Allow us to characterize the potential hazards of new and existing chemcial substances, substances, preparations –> allow us to rank candidate chemicals, ex: when choosing bw prodicyts
====CHEMICAL REGISTRATION

Question 4

Which 6 basic tests are considered necesary for a minimal understanding of a chemical’s toxicity?

Answer 4

THESE 6 BASIC TESTS = SCREENING INFORMATION DATA SET (SIDS)

• acute tox
• chronic tox
• developmental and reproductive tox
• mutagenicity
• ecotoxicity
• environmental fate
• ——> trigger further questions

Question 5

Important points on DR curve

Answer 5

NOAEL
LOAEL
POD - marks the point of extrapolation back to zero; usually it is the NOAEL or right below; it is where the curve kicks off, below it we dont know anything
Reference dose=NOAEL/UF X MF=ADI

Question 6

Acute Toxicity Tests

Answer 6

• often uses LD10, which is done by looking at efefcts ofingestings a subatcne one or more times within 24 hours and then looking at the consequence, then observing conseuences over the next 14 days
• LD50 classic study invovled administering diff doses of the substance to 6-7 diff cohorts to determine the average amount that killed half the cohort –> thsi required 140 animals

Question 7

Human to Rat

Human to Mouse

Answer 7

HR - 7

HM - 4

Question 8

Length of chronic tox experiemnts

Answer 8

Subacute: 8 months
Subcrhonic: 12 months
Chronic: 54 months

For cancer: study animal for 2 years=10-12 yrs in humans (rare bc expensive) –> use higher dose, thats why

Question 9

Developmental and Reproductive Toxicology

Answer 9

• can be done with a single generation of animals who can reproduce
• expose M &. F to toxin and then let me reproduce; look at the effects of thsi toxin on theri offspring
• *MALES ARE TREATED W/ THE TOXIN EARLIER, BC THEY NEED TO BE TREATED FOR THE ENTIRE DYRATUON OF SPERMATOGENEISA

Question 10

Teratology

Answer 10

• looks specifically at organogenesis
• THE PREGANNT ANIMAL WILL ONLY BE DONE UDRING PERIOD OF ORGANOGENESIS (WHICH IS WHAT WE WANT TO STUDY) BC EMBRYO WOULD POSISBLY DIE IF GIVEN BEFORE

Question 11

Multigenerational and Reproductive Toxicology Studies

Answer 11

Take much longer but give information about longterm efefcts of exposure

Question 12

How are biologicals tested?

Answer 12

Biological measure the quality of biological origin chemicals such as vaccines; a vaccine/drug is administered o grouof animals and the target disease will be introduced into this group and unprotected group. Resuslnt illness is compared.
How is illness co,pared? –> [pyrogens]

Question 13

Model Organisms for Tox Testing

Answer 13

Bacteria: can be engineered via ames test