Potential pitfall in using cumulative exposure in exposure-response relationships: demonstration and discussion.

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.