healthy volunteers (FDA, 2002). Doses of occupationally and environmentally encountered chemicals may also be high enough to elicit reversible biochemical, physiological, or toxicological effects.

The intentional human dosing studies with pesticides reviewed by this committee involved low doses that produce no effects or minimal, reversible changes in sensitive biomarkers, albeit in one study the effect was sufficiently large to warrant termination of the study. Although epidemiological investigations of exposed populations may identify associations of adverse effects and chemical exposures and support inferences of cause and effect, epidemiological data are nonetheless usually limited by inadequate characterization of exposures and by an inability to recognize or control confounding factors (Dourson et al., 2001). Most clinical case reports of toxicant exposures have the same limitations. Such information, however, can alert us to previously unrecognized toxicities and identify critical effects to evaluate in subsequent investigations. Human cells and tissues can be very useful for metabolism and mode of action studies (MacGregor et al., 2001). Good correlation is often found between the metabolism of chemicals in vivo and metabolism by isolated hepatocytes of the same species (Oesch and Diener, 1995). Mechanistic studies with humans and laboratory animals may identify relevant toxicity end points and bioactive moieties and facilitate development of the most pertinent animal models (Jorkasky, 1998; Gregus and Klaassen, 2001).

Toxicological data from human exposure to pesticides and other chemicals are often limited or nonexistent. Obviously, one cannot administer sufficient amounts of a chemical to characterize the dose dependency of major adverse effects that exposed individuals could experience. Long-term exposures cannot be conducted in order to elicit chronic conditions. Parallel laboratory animal-human experiments, however, can be very useful in assessing the relevance of particular animal models to humans. Ideally, toxicologists and risk assessors would like to have dose-response data from experiments in which the same parameters were monitored and in which there was overlap of the range of doses given to each species. The doses administered to humans would be relatively low, but they should produce changes in sensitive adaptive effects, or biomarkers. Pharmacokinetic (PK), metabolic, and mechanistic studies in humans and animals also provide valuable information for scientifically based interspecies extrapolations (Jorkasky, 1998). Nonetheless, comprehensive toxicology investigations in different species of laboratory animals are necessary to fully evaluate the hazard potential of most chemicals.

Evaluation of the toxicity of chemicals in laboratory animals is a cornerstone of human safety evaluation. Experimentation with animals makes it possible to learn a great deal about the toxic potential of drugs and other chemicals. Explicitly defined investigations in laboratory ani-

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