The exposure-response for hexavalent chromium (Cr(VI))-induced lung cancer among workers of the Painesville Ohio chromate production facility has been used internationally for quantitative risk assessment of environmental and occupational exposures to airborne Cr(VI). We updated the mortality of 714 Painesville workers (including 198 short-term workers) through December 2011, reconstructed exposures, and conducted exposure-response modeling using Poisson and Cox regressions to provide quantitative lung cancer risk estimates. The average length of follow-up was 34.4 years with 24,535 person-years at risk. Lung cancer was significantly increased for the cohort (standardized mortality ratio (SMR)=186; 95% confidence interval (CI) 145–228), for those hired before 1959, those with >30-year tenure, and those with cumulative exposure >1.41 mg/m3-years or highest monthly exposures >0.26 mg/m3. Of the models assessed, the linear Cox model with unlagged cumulative exposure provided the best fit and was preferred. Smoking and age at hire were also significant predictors of lung cancer mortality. Adjusting for these variables, the occupational unit risk was 0.00166 (95% CI 0.000713–0.00349), and the environmental unit risk was 0.00832 (95% CI 0.00359–0.0174), which are 20% and 15% lower, respectively, than values developed in a previous study of this cohort.

Current drinking water standards for chromium are for the combined total of both hexavalent and trivalent chromium (Cr(VI) and Cr(III)). However, recent studies have shown that Cr(III) is not carcinogenic to rodents, whereas mice chronically exposed to high levels of Cr(VI) developed duodenal tumors. These findings may suggest the need for environmental standards specific for Cr(VI). Whether the intestinal tumors arose through a mutagenic or non-mutagenic mode of action (MOA) greatly impacts how drinking water standards for Cr(VI) are derived. Herein, X-ray fluorescence (spectro)microscopy (µ-XRF) was used to image the Cr content in the villus and crypt regions of duodena from B6C3F1 mice exposed to 180 mg/l Cr(VI) in drinking water for 13 weeks. DNA damage was also assessed by γ-H2AX immunostaining. Exposure to Cr(VI) induced villus blunting and crypt hyperplasia in the duodenum—the latter evidenced by lengthening of the crypt compartment by ∼2-fold with a concomitant 1.5-fold increase in the number of crypt enterocytes. γ-H2AX immunostaining was elevated in villi, but not in the crypt compartment. µ-XRF maps revealed mean Cr levels >30 times higher in duodenal villi than crypt regions; mean Cr levels in crypt regions were only slightly above background signal. Despite the presence of Cr and elevated γ-H2AX immunoreactivity in villi, no aberrant foci indicative of transformation were evident. These findings do not support a MOA for intestinal carcinogenesis involving direct Cr-DNA interaction in intestinal stem cells, but rather support a non-mutagenic MOA involving chronic wounding of intestinal villi and crypt cell hyperplasia.

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