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A search for thresholds and other nonlinearities in the relationship between hexavalent chromium and lung cancer.
Risk Anal 2006 Feb; 26(1):79-88
The exposure-response relationship for airborne hexavalent chromium exposure and lung cancer mortality is well described by a linear relative rate model. However, categorical analyses have been interpreted to suggest the presence of a threshold. This study investigates nonlinear features of the exposure response in a cohort of 2,357 chemical workers with 122 lung cancer deaths. In Poisson regression, a simple model representing a two-step carcinogenesis process was evaluated. In a one-stage context, fractional polynomials were investigated. Cumulative exposure dose metrics were examined corresponding to cumulative exposure thresholds, exposure intensity (concentration) thresholds, dose-rate effects, and declining burden of accumulated effect on future risk. A simple two-stage model of carcinogenesis provided no improvement in fit. The best-fitting one-stage models used simple cumulative exposure with no threshold for exposure intensity and had sufficient power to rule out thresholds as large as 30 mug/m(3) CrO(3) (16 mug/m(3) as Cr(+6)) (one-sided 95% confidence limit, likelihood ratio test). Slightly better-fitting models were observed with cumulative exposure thresholds of 0.03 and 0.5 mg-yr/m(3) (as CrO(3)) with and without an exposure-race interaction term, respectively. With the best model, cumulative exposure thresholds as large as 0.4 mg-yr/m(3) CrO(3) were excluded (two-sided upper 95% confidence limit, likelihood ratio test). A small departure from dose-rate linearity was observed, corresponding to (intensity)(0.8) but was not statistically significant. Models in which risk-inducing damage burdens declined over time, based on half-lives ranging from 0.1 to 40 years, fit less well than assuming a constant burden. A half-life of 8 years or less was excluded (one-sided 95% confidence limit). Examination of nonlinear features of the hexavalent chromium-lung cancer exposure response in a population used in a recent risk assessment supports using the traditional (lagged) cumulative exposure paradigm: no intensity (concentration) threshold, linearity in intensity, and constant increment in risk following exposure.
Lung-cancer; Cancer; Chromium-compounds; Models; Mortality-data; Mortality-rates; Workers; Worker-health; Occupational-exposure; Exposure-assessment; Pulmonary-system-disorders; Respiratory-system-disorders; Risk-factors; Risk-analysis
Robert M. Park, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Education and Information Division, MS C-15, 4676 Columbia Parkway, Cincinnati, OH 45226
Issue of Publication
Research Tools and Approaches: Risk Assessment Methods