sential substances. Because well-conducted animal studies can be controlled, establishing a causal relationship is not difficult.

Six key issues that are addressed in the data evaluation of human and animal studies are the following:

  1. Evidence of adverse effects in humans. In the hazard identification step, all human, animal, and in vitro published evidence addressing the likelihood of a nutrient eliciting an adverse effect in humans is examined. Decisions regarding which observed effects are “adverse” are based on scientific judgments. Although toxicologists generally regard any demonstrable structural or functional alteration to represent an adverse effect, some alterations may be considered of little or self-limiting biological importance.

  2. Causality. Is a causal relationship established by the published human data? Criteria for judging the causal significance of an exposure-effect association indicated by epidemiologic studies have been adopted by two reports, Diet, Nutrition, and Cancer (NRC, 1982) and Diet and Health (NRC, 1989b). These criteria include: demonstration of a temporal relationship, consistency, narrow confidence intervals for risk estimates, a biological gradient, specificity, biological plausibility, and coherence.

  3. Relevance of experimental data. Consideration of the following issues can be useful in assessing the relevance of experimental data.

    • Animal data. Animal data may be of limited utility in judging the toxicity of nutrients, because of highly variable interspecies differences in nutrient requirements. Nevertheless, all such data should be considered in the hazard identification step, and explicit reasons should be given whenever such data are judged not relevant to human risk.

    • Route of exposure.1 Data derived from studies involving ingestion exposure (rather than inhalation or dermal exposure) are most useful for the evaluation of nutrients. Data derived from studies involving inhalation or dermal routes of exposure may be considered relevant if the adverse effects are systemic and data are available to permit interroute extrapolation.

    • Duration of exposure. Because the magnitude, duration, and fre-

      1  

      The terms route of exposure and route of intake refer to how a substance enters the body, for example, by ingestion, inhalation, or dermal absorption. These terms should not be confused with form of intake, which refers to the medium or vehicle used—for example, supplements, food, or drinking water.



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