than when the association is nonspecific to the exposure or the health outcome. The committee recognized, however, that perfect specificity could not be expected, given the multifactorial etiology of many of the diseases under examination. The committee also recognized the possibility that many of the agents under study were associated with a broad array of diseases.

The committee members did, however, require that specific outcomes be identified. Studies that provided general outcomes (for example, diseases of the nervous system) or outcomes identified by broad ranges of ICD codes (for example, codes referring to all diseases of the respiratory system) were considered, at best, supportive of an outcome.

Biologic Plausibility

Biologic plausibility reflects knowledge of the biologic mechanism by which an agent can lead to a health outcome. That knowledge comes through mechanism-of-action or other studies in pharmacology, toxicology, microbiology, physiology, and other fields—typically in studies of animals. Biologic plausibility is often difficult to establish or may not be known when an association is first documented. The committee considered such factors as evidence from animal and human studies that exposure to an agent is associated with diseases known to have biologic mechanisms similar to that of the disease in question, evidence that some outcomes are commonly associated with occupational or environmental exposures, and knowledge of routes of exposure, storage in the body, and excretion that suggest that a disease is more likely to occur in some organs than in others. Biologic plausibility was required by the committee only in drawing a conclusion of “sufficient evidence of a causal association” (see below); for the other categories of association, it is not necessary to demonstrate a biologically plausible mechanism. The extent to which all the data are consistent and subject to a biologically plausible mechanism influences the weight attached to the results of a study, as does an indication that the mechanism is similar in the animal(s) under study and humans.

Additional Considerations

The committee carefully considered whether alternative explanations or errors—such as bias and chance—might account for the finding of an association.


Bias refers to systematic or nonrandom error. Bias causes an observed value to deviate from the true value. It can weaken an association or generate a spurious association. Because all studies are susceptible to bias, a goal is to minimize bias or to adjust the observed value of an association by using special methods to correct for bias. Three kinds of bias may compromise the results of an investigation: selection bias, information bias, and confounding.

  • Selection bias occurs when the participants in a study are not representative of the general population. The study participants differ from nonparticipants in characteristics that cannot be observed, that is, the groups differ in measured or unmeasured baseline characteristics because of how participants were selected or assigned.

  • Information bias results from the manner in which data are collected and can result in measurement errors, imprecise measurement, and misdiagnosis. Those types of errors may be uniform in an entire study population or may affect some parts of the population more than others. Bias may result from misclassification of study subjects with respect to the outcome

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