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concluding that no hazard exists for humans is the availability of sufficient experimental data that reveal no adverse effects in animal studies. Some experimental data might demonstrate toxicity of limited relevance to humans because of species differences in metabolism or sensitivity, lack of probable human exposure, or human evidence of no effect. Animal data in which no adverse effects are observed do not always preclude human effects, nor do adverse effects in animals inevitably predict human toxicity.

The evaluative process requires an integrated consideration of a variety of data. Integration involves combining the summary statements formulated during the review of animal and human reproductive and developmental toxicity data and considering them in the context of systemic toxicity parameters and pharmacokinetic data. A weight-of-evidence approach is then used to formulate judgments about the potential for human hazard. In this process, the evaluators develop separate statements to address developmental toxicity, female reproductive toxicity, and male reproductive toxicity. In each case, the basis for the judgment is articulated and makes particular note of such critical factors as replication of effect across species, exposure routes, dose-response parameters, relationship of effective dose to doses that cause other forms of toxicity, and comparative metabolic data.

To achieve a degree of consistency in the interpretation of experimental animal data, this report uses “relevance” terms:

  • Irrelevant means that pharmacokinetic or mechanistic features of the experimental animal model are known in detail and are demonstrably inconsistent with human exposure or response.

  • Relevant identifies a data set in an experimental animal species for which pharmacokinetic and mechanism information is adequate to demonstrate a particular similarity to humans.

  • Assumed relevant indicates there is no modifying supplemental information.

For many agents, there is no detailed understanding of absorption, distribution, biotransformation, or excretion in experimental animals or humans. In these cases, studies of the most sensitive experimental animal species are assumed to be relevant, and would thus drive the judgment of potential risk to humans.



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