A search for thresholds and other nonlinearities in the relationship between hexavalent chromium and lung cancer.
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 microg/m3 CrO3 (16 microg/m3 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/m3 (as CrO3) with and without an exposure-race interaction term, respectively. With the best model, cumulative exposure thresholds as large as 0.4 mg-yr/m3 CrO3 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.
National Institute for Occupational Safety and Health, Cincinnati, OH 45226, USA. rhp9@cdc.gov
Robert M
RM
Park
Leslie T
LT
Stayner
D000395:Air Pollutants, Occupational / Q000633:toxicity*; D015142:Baltimore / Q000453:epidemiology; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D002857:Chromium / Q000008:administration & dosage / Q000633:toxicity*; D003043:Cocarcinogenesis; D015331:Cohort Studies; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000401:mortality; D008954:Models, Biological; D017711:Nonlinear Dynamics; D009784:Occupational Diseases / Q000139:chemically induced / Q000401:mortality; D016273:Occupational Exposure; D012307:Risk Factors
D000395:Air Pollutants, Occupational; D002273:Carcinogens; D002857:Chromium; C074702:chromium hexavalent ion