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Section B
Toxicity Assessment
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Dangerous Stuff
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Toxicity Assessment
! Hazard identification
- Do the chemicals/agents present cause or have the
potential to cause adverse health affects?
! How determined?
- Human epidemiology data
- Testing (bioassay) data
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Systems for Toxicity Assessment
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Purpose of Toxicity Testing
! Determine
- Range of doses over which the toxic responses are
produced
- Identify the nature of the toxic responses produced
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Guiding Principle for all In Vivo Toxicity Testing
! 3Rs
- Reduction
- Refinement
- Replacement
! Guides the use of animals in testing and research
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In Vivo Tests
Main Principles or Default Assumptions
1. The effects produced in
properly conducted laboratory
experiments are, under
appropriate qualifications,
applicable to humans
2. High-dose exposure of
experimental laboratory
animals to toxic agents is a
necessary and valid method of
discovering possible hazards
in humans
3. A positive bioassay showing
toxicity (e.g., cancer) is
sufficient proof of a toxicity
hazard in humans
4. Humans are at least as
sensitive as the most sensitive
animal species unless
mechanism of action not
applicable to humans
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Elements of Risk Assessment: Exceptions
! Kidney tumors in male rats
- Caused by chemicals such as:
! ! 1,4-dichlorobenzene
! Tetrachloroethylene
! Unleaded gasoline
Male rats have a serum protein known as α-2µ-globulin,
which binds certain chemicals to form a protein-chemical
complex that is removed from circulation in the kidney
- Humans lack this protein!
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Toxicity Testing
! EPA Science Advisory Board recommendation:
- Data not be used as evidence of potential human
carcinogenicity
! Use mechanistic information to inform bioassay results
- Short-term test data
- Structure/activity data
- Experimental data
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Toxicity Testing: Controversial Issues
! Extrapolation
- Animals to humans
! Extrapolation
- High dose to low dose
! Cost relative to benefits
! Animal use and welfare
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