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TABLE 5-1 Guidelines for Relative Seriousness for Examples of Adverse Effects Obtained from Animal Studies

Category A (most serious)

  • Neoplasia (including genotoxic and nongenotoxic carcinogens), teratogenesis, mortality

  • Severe target organ toxicity

  • Necrosis, dysplasia

  • Reproductive failure, fetotoxicity, severe developmental effects

  • Severe neurobehavioral changes

Category B (moderately serious)

  • Moderate target organ toxicity

  • Atrophy, hyperplasia

  • Reduced reproductive capacity, moderate developmental effects

  • Moderate neurobehavioral changes

  • Clinical chemistry changes associated with histological lesions outside reference value ranges

Category C (less serious)

  • Reduced body weight gain

  • Body weight/organ weight ratios

  • Reduced food consumption

  • Enzyme changes, other biochemical and toxicity biomarker alterations unaccompanied by histological changes

  • Reversible degenerative changes

regardless of the presence of high-quality human data suggesting no acute toxicity. This is because human exposure may need to be prolonged before such toxicities would be detected. Table 5-1 contains classifications of toxicity outcomes, ranked according to the nature of the effect, and provides a perspective on which effects are of greater concern. Three broad categories of effects are described. Those in Category A represent the clearest and most serious manifestations of toxicity, and if such effects are observed in well-conducted animal studies, there is a compelling basis for significant concern about comparable human toxicity (ignoring differences that may occur in dose and metabolism). Effects in Category B, while considered adverse, are of lesser concern, and those in Category C are of concern, but the concern is less than the other categories. Depending upon the ingested dosage at which the effect has been observed in animal studies relative to the level of human intake of the substance, and assuming there is no evidence that raises significant doubts about differences in toxic effects between animals and humans, effects in Category A should raise significant concerns about human toxicity even without data from other categories of evidence (e.g., human data). Effects in Category B may need to be but-tressed by other data, and effects in Category C are considered less useful in



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