based on knowledge of a specific industry; if specific exposures were associated with an occupational title or industry, such as when a JEM was used to categorize exposure; or if an assessment was made by an industrial hygienist. Studies that had self-reported exposures were considered, at best, support studies.

Dose-Response Relationship

The existence of a dose-response relationship—that is, an increased strength of association with increasing intensity or duration of exposure or other appropriate relation—strengthens an inference that an association is real. However, the lack of an apparent dose-response relationship does not rule out an association, as in the case of a threshold exposure beyond which the relative risk of disease remains constant and high. If the relative degree of exposure among several studies can be determined, indirect evidence of a dose-response relationship may exist. For example, if studies of presumably low-exposure cohorts show only mild increases in risk whereas studies of presumably high-exposure cohorts show larger increases in risk, the pattern would be consistent with a dose-response relationship.

Temporal Relationship

If an observed association is real, exposure must precede the onset of disease by at least the duration of disease induction. The committee considered whether a disease occurred within a period after exposure to the putative agent that was consistent with current understanding of the natural history of the disease. The committee interpreted the lack of an appropriate time sequence as evidence against association but recognized that insufficient knowledge about the natural history and pathogenesis of many of the diseases under review limited the utility of this consideration.

Consistency of Association

A consistent association requires that the association be found regularly in a variety of studies, for example, in more than one study population and with different study methods. However, consistency alone is not sufficient evidence of an association. The committee considered findings that were consistent in direction among different categories of studies to be supportive of an association. It did not require exactly the same magnitude of association in different populations to conclude that there was a consistent association. A consistent 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 differences in dose.

Thus, for a health outcome to be considered associated with an agent there had to be corroboration, that is, replication of findings among studies and populations and under relevant conditions. The degree to which an effect could be consistently reproduced gave the committee confidence that they were observing a true effect.

Specificity of Association

Specificity of association is the degree to which exposure to a given agent predicts the frequency or magnitude of a particular outcome. A positive finding seems more strongly supported when the association between the exposure and the health outcome is specific to both



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