Lecture 5

Question 1

Practical Considerations for Toxicity Tests

Answer 1

• Use most appropriate species and gender.
• Animal husbandry.
• Numbers of animals to be used.
• Dose range.
• Administration of the test agent.
• Endpoints of interest specified before test.

Question 2

What age animal will we used when doing toxicity testing?

Answer 2

Young animals (just weened) because we monitor weight gain and it is easier to track with young animals.

Question 3

Acute Toxicity Tests

Answer 3

• Determine toxic effects which occur within a short time (7–14 days) after
  a single dose.
• Determine potency, LD50.
• Results used for dose selection for longer term studies.
• Useful first approximation of hazards to workers.

Question 4

Acute Tests: Irritation and Sensitization

Answer 4

• Draize eye irritation test:
  – Albino rabbit used; one eye test, other eye control.
  – Graded responses of cornea, iris, conjunctiva, blood vessels.
  – Criticized as inhumane, highly variable results, overly sensitive species.
• Primary skin irritation:
  – Two shaved areas on back (one abraded).
  – Graded on severity of lesions developed.
• Cutaneous sensitization:
  – Test systemic immune response following
  dermal exposure.
• Phototoxicity/photosensitization:
  – Combined chemical and UV exposure

Question 5

Classic Acute Toxicity Tests – Major Criticisms

Answer 5

• Requires large numbers of animals.
• LD50 data are subject to considerable variability.
• LD50 data are of limited value and could be
  approximated with fewer animals.
• Extrapolation to humans can be questionable.
• Tests considered inhumane.

Question 6

Subchronic Testing

Answer 6

• 90-day repeated dosing study.
• Provides information on all types of toxicity.
• Establish doses for chronic studies (MTD).
• Provide information on target organs and potential to
  bioaccumulate.
• Provide data for use in risk assessment.

Question 7

Chronic Testing

Answer 7

Can be 2 to 7 years depending upon species.(2 years rodents, up to 7 for dogs)
* Provides information on:
– Non-cancer toxicity for very prolonged exposure.
– NOAEL for very prolonged exposure.
– Reversibility and recovery.
* Sometimes combined with carcinogenesis study.
* Expensive.

Question 8

Toxicity Testing Challenges

Answer 8

• Issues:
  – The universe of chemicals that require testing for potential adverse health and
  environmental effects is enormous; 100,000+.
  – Current assays take too long, are too costly in terms of dollars and animals.
  – Harmonization is needed.
• Future directions:
  – New animal models (e.g., transgenics, knockouts).
  – More humane endpoints.
  – Use of less sentient species.
  – In vitro systems.
  – Computational (in silico) toxicology.
  – Application of “omics” (genomics, transcriptomics, proteomics, metabolomics).

Question 9

ADME

Answer 9

Absorption, Distribution, Metabolism, Excretion and Pharmacokinetics