The committee’s process of reaching conclusions about the various agents and their potential for adverse health outcomes was collective and interactive. As the committee reviewed the literature on the agents under study, it took into consideration a variety of criteria (discussed below) to help evaluate the strength of the evidence for or against an association between exposure to the agent under study and adverse health outcomes. The committee assessed the evidence by considering the six general criteria (strength of association, dose–response relationship, consistency of association, temporal relationship, specificity of association, and biological plausibility) patterned after those introduced by Hill (1971). The committee also assessed the extent for potential errors in the study due to a number of factors including chance and bias (discussed later in the chapter).

Strength of Association

The strength of association is usually expressed as the magnitude of the measure of effect, for example, relative risk or odds ratio. Generally, the higher the relative risk, the stronger the association between the agent and the health effect. Moreover, the greater is the likelihood that the agent–health effect association is causal (i.e., the less likely it is to be due to undetected error, bias, or confounding). Small increases in relative risk that are consistent across a number of studies may provide evidence of an association (IOM, 1994b).

Dose–Response Relationship

A dose–response relationship refers to the finding of a greater health effect (response) with higher doses of an agent. A steep dose–response relationship strengthens the inference that an association is real. Generally, in a strong dose– response relationship, cohorts exposed to presumably low doses show only mild elevations in risk, whereas cohorts with exposure to presumably high doses show more extreme elevations in risk. However, the absence of such a relationship does not discount the possibility of an association. For example, a dose–response relationship would go undetected if the doses were all below a threshold level of exposure, beyond which the relative risk of disease increased steeply.

Many physiologic and pharmacologic actions have thresholds that result in a dose–response curve that is curvilinear rather than linear in shape. Furthermore, a particular agent may produce an effect after a brief latency or after decades (e.g., asbestos-induced mesothelioma). Other mechanisms that may alter the strictly linear dose–response curve are chemical interactions involving synergism and antagonism (e.g., a worker with significant asbestos exposure has a risk about five times greater for developing lung cancer than a person without asbestos exposure); reversibility (e.g., some toxic events are reversible as the

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