Cumulative exposure (average intensity times duration) is one of the most common summary measures for exposure used in occupational epidemiology. Its utility for describing quantitative exposure-effect relationships is based on several interlocking assumptions about the processes relating exposure to tissue dose, and tissue dose to adverse effects. The pharmacokinetic relationship between cumulative exposure and tissue dose was examined with models for two common exposures: inhalation of insoluble, respirable particles, and toxic metabolites of a nonpolar organic solvent. It was found that the assumption of a linear relationship between cumulative exposure and tissue dose was violated for typical exposure intensity for both substances. This caused strong nonlinear exposure-tissue dose relationships and variability in the relationship. The findings provide a possible explanation for the common observation of a disproportionately high risk of pulmonary effects for workers with relatively short, intense dust exposures, and for the finding that workers exposed to metabolically activated organic agents have a risk that is related to years of exposure but not to intensity.