Attenuation of exposure-response curves in occupational cohort studies at high exposure levels.

Numerous occupational cohort mortality studies have observed exposure-response curves to have an increasing slope at low exposure levels that attenuates or even turns negative at high exposure levels. Examples discussed in this paper include dioxin, silica, 1,3-butadiene, cadmium, beryllium, radon daughters, diesel fumes, nickel, arsenic, and hexavalent chromium. Possible explanations for this phenomenon include (i) bias introduced by the healthy worker survivor effect, (ii) a depletion of the number of susceptible people in the population at high exposure levels, (iii) a natural limit on the relative risk for diseases with a high background rate, (iv) mismeasurement or misclassification of exposures, (v) the influence of other risk factors that vary by the level of the main exposure, and (vi) the saturation of key enzyme systems or other processes involved in the development of disease.