Potential Pitfall in Using Cumulative Exposure in Exposure‐Response Relationships: Demonstration and Discussion

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Abstract
Cumulative exposure is frequently used as a measure of exposure in the quantitative analysis of epidemiologic studies. It is recognized that the imposed symmetry between duration and intensity of exposure is a potential problem with this measure, but it is less widely recognized that the finding of an exposure‐response relationship, using cumulative exposure as the exposure metric, does not necessarily imply that exposures were accurately or even consistently estimated. This report describes a simulation study drawn from a nested case‐control analysis of mesothelioma in a cohort of asbestos cement workers. Intensity of exposure in the range of 0.1‐40 fibers/ml was randomly assigned to subjects. Logistic regression analysis demonstrated that there was no association between mesothelioma risk and the randomly assigned intensity of exposure. However, in 171 (86%) of 200 trials, mesothelioma risk was significantly associated with cumulative exposure, even though intensity of exposure remained randomly assigned. A strong exposure‐response relationship might thus be misleading. One would be more confident about quantitative risk assessment when there are a large number of independent studies available for analysis.