studies often focus on one agent at a time, they more easily enable the study of chemical mixtures and their potential interactions.

Research on health effects of toxic substance includes animal studies that characterize absorption, distribution, metabolism, elimination, and excretion. Animal studies may examine acute (short-term) exposures or chronic (long-term) exposures. Animal research may focus on the mechanism of action (i.e., how the toxin exerts its deleterious effects at the cellular and molecular levels). Mechanism-of-action (or mechanistic) studies encompass a range of laboratory approaches with whole animals and in vitro systems using tissues or cells from humans or animals. Also, structure–activity relationships, in which comparisons are made between the molecular structure and chemical and physical properties of a potential toxin versus a known toxin, are an important source of hypotheses about mechanism of action.

In carrying out its charge, the committee used animal and other nonhuman studies in several ways, particularly as a marker for health effects that might be important for humans. If an agent, for example, was absorbed and deposited in specific tissues or organs (e.g., uranium deposition in bone and kidney), the committee looked especially closely for possible abnormalities at these sites in human studies.

One of the problems with animal studies, however, is the difficulty of finding animal models to study symptoms that relate to uniquely human attributes, such as cognition, purposive behavior, and the perception of pain. With the exception of fatigue, many symptoms reported by veterans (e.g., headache, muscle or joint pain) are difficult to study in standard neurotoxicological tests in animals (OTA, 1990).

For its evaluation and categorization of the degree of association between each exposure and a human health effect, however, the committee only used evidence from human studies. Nevertheless, the committee did use nonhuman studies as the basis for judgments about biologic plausibility, which is one of the criteria for establishing causation (see below).

Human Studies

Epidemiologic Studies

Epidemiology concerns itself with the relationship of various factors and conditions that determine the frequency and distribution of an infectious process, a disease, or a physiological state in human populations (Lilienfeld, 1978). Its focus on populations distinguishes it from other medical disciplines. Epidemiologic studies characterize the relationship between the agent, the environment, and the host and are useful for generating and testing hypotheses with respect to the association between exposure to an agent and health or disease. The following section describes the major types of epidemiologic studies considered by the committee.

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