experimental research in humans is not ethically or practically possible (NRC 1991). Such studies permit a stressor to be introduced under conditions controlled by the researcher—such as its intensity and duration—to probe health effects on many body systems. Nonhuman studies are also a valuable complement to human studies of genetic susceptibility.

Animal studies may determine the degree of response to acute (short-term) or chronic (long-term) exposures to stressors. Animal research may focus on the mechanism of action (that is, how a stressor 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.

In carrying out its charge, the committee used animal studies to provide a basis for a mechanism of action for the impact of stress on biological functions, including changes in brain structure, hormone concentrations, and neurological activity (see Chapter 4), to help establish biologic plausibility. 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. Many symptoms reported by veterans (for example, 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).

Epidemiologic Studies

Epidemiologic studies examine the relationship between exposures to agents of interest in a human population and the health effects seen in that population. The challenge of epidemiologic studies is to isolate the risk factors that contribute to health effects in populations that are inherently uncontrollable in the experimental sense; therefore, statistical techniques are used to take into account factors such as bias and confounding. Such studies can be used to generate hypotheses for future study or to test hypotheses posed in advance by investigators.

A principal objective of epidemiology is to understand whether exposures to specific agents are associated with disease or other health effects and, with additional available information, to decide whether such associations are causal. Although they are frequently used synonymously by the general public, the terms “association” and “causation” have distinct meanings (Alpert and Goldberg 2007).

Epidemiologic studies can establish statistical associations between exposures and health effects; associations are generally estimated by using relative risks or odds ratios. To conclude that an association exists, it is necessary for the exposure to be followed by the health effect more frequently than it would be expected to by chance alone. Furthermore, it is almost always necessary to find that the effect occurs consistently in several studies. Epidemiologists seldom consider a single study sufficient to establish an association; rather, it is desirable to replicate the findings in other studies to draw conclusions about the association. Results of separate studies are sometimes conflicting. It is sometimes possible to attribute discordant study results to differences in such characteristics as soundness of study design, quality of execution, and the influence of different forms of bias. Studies that result in a tight confidence interval around a statistically significant relative risk of association suggest that the observed result was unlikely to be due to chance. When the measure of association does not show a statistically significant

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