body has the potential for self repair); and susceptibility or resistance to a particular agent (Brooks et al., 1995).

Consistency of Association

A consistent association is similar in magnitude and direction across several studies representing different populations, locales, and times (Hill, 1965). The greater the number of studies with the same results, the more consistent is the association and the greater is the likelihood of a true association. However, consistency alone is not sufficient evidence of an association. The committee considered findings that were consistent in direction across different categories of studies to be supportive of an association. The committee did not require exactly the same magnitude of association in different populations to conclude that there was a consistent association. A consistent positive association could occur when the results of most studies were positive and the differences in measured effects were within the range expected on the basis of sampling error, selection bias, misclassification, confounding, and difference in actual dose levels (IOM, 1994b).

Temporal Relationship

The finding of an agent–disease association begins the process of trying to decide whether the agent is a cause, correlate, or consequence of the disease. Determining causality requires that exposure to the agent precede the onset of the health outcome by at least the duration of disease induction. If, in a cohort study, exposure to the agent occurs after the appearance of the health outcome, the agent could not have caused that outcome. Establishing a temporal relationship is often difficult, especially with health outcomes that have long induction periods, such as cancer. The committee interpreted the lack of an appropriate time sequence as evidence against association, but recognized that insufficient knowledge of the natural history and pathogenesis of many of the health outcomes under review limited the utility of this criterion (IOM, 1994b).

Specificity of Association

Specificity refers to the unique association between exposure to a particular agent and a health outcome (i.e., the health outcome never occurs in the absence of the agent). Two examples of highly specific associations are the pathologically distinctive tumors mesothelioma of the lung and angiosarcoma of the liver in workers exposed to asbestos and vinyl chloride, respectively. The committee recognized, however, that perfect specificity is unlikely given the multifactorial etiology of many of the health outcomes noted in this study. Additionally, the committee recognized that the agents under review might be associated with a broad spectrum of health outcomes.

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