sufficient evidence of an association (below) and satisfies several of the guidelines used to assess causality: strength of association, dose-response relationship, consistency of association, biologic plausibility, and a temporal relationship.

Sufficient Evidence of an Association

Evidence from available studies is sufficient to conclude that there is a positive association. A consistent positive association has been observed between exposure to a specific agent and a specific health outcome in human studies in which chance1 and bias, including confounding, could be ruled out with reasonable confidence. For example, several high-quality studies report consistent positive associations, and the studies are sufficiently free of bias, including adequate control for confounding.

Limited/Suggestive Evidence of an Association

Evidence from available studies suggests an association between exposure to a specific agent and a specific health outcome in human studies, but the body of evidence is limited by the inability to rule out chance and bias, including confounding, with confidence. For example, at least one high-quality2 study reports a positive association that is sufficiently free of bias, including adequate control for confounding. Other corroborating studies provide support for the association, but they were not sufficiently free of bias, including confounding. Alternatively, several studies of less quality show consistent positive associations, and the results are probably not3 due to bias, including confounding.

Inadequate/Insufficient Evidence to Determine Whether an Association Exists

Evidence from available studies is of insufficient quantity, quality, or consistency to permit a conclusion regarding the existence of an association between exposure to a specific agent and a specific health outcome in humans.

Limited/Suggestive Evidence of No Association

Evidence from well-conducted studies is consistent in not showing a positive association between exposure to a specific agent and a specific health outcome after exposure of any

1  

Chance refers to sampling variability.

2  

Factors used to characterize high quality studies include, the statistical stability of the associations, whether dose-response or other trends were demonstrated, whether the association was among numerous comparisons that were made, and the quality of the assessments of exposure and outcome. Specifically, the quality of exposure assessment refers to specificity and sensitivity in relation to the association of interest. For instance, for insecticides, studies assessing specific insecticides (such as chlorpyrifos) have more specificity than those assessing classes of insecticides (such as organophosphorous), which in turn are more specific than those assessing pesticides more generally. With respect to sensitivity, studies are judged by the instruments used to measure exposure. Biologic monitoring data are theoretically the most preferable but are almost never obtainable in the context of a nonpersistent chemical and a disease with long latency, like cancer. Other kinds of efforts can obtain sensitive measures of exposure, such as use of occupational or environmental monitoring data, use of more extensive industrial hygiene assessments, use of interview techniques that help to minimize recall bias (for example, photos of products, and home and workplace walkthroughs). Similarly, there are questions about quality of outcome assessment-whether an outcome has been verified by a medical diagnosis in a consistent fashion.

3  

Factors used to make this judgment include the data on the relationship between potential confounders and related health end points in a given study, information on subject selection, and classification of exposure.



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