Alan H Stern1. 1. New Jersey Department of Environmental Protection, Office of Science, 428 E. State St., Trenton, NJ 08625, USA. alan.stern@dep.state.nj.us
Abstract
BACKGROUND: Hexavalent chromium (Cr(6+)) has long been recognized as an inhalation carcinogen. Useful data on its carcinogenicity by ingestion have been slower to develop. The 2008 NTP chronic bioassay of sodium dichromate dihydrate in drinking water found clear evidence of carcinogenicity in rodents and allows a generalizable estimate of the human ingestion cancer potency of Cr(6+). OBJECTIVES: To estimate the human ingestion cancer potency of Cr(6+) and evaluate its relevance for human exposure. METHODS: Tumors of the small intestine in male mice were selected as the critical endpoint, for the derivation of cancer potency. Following the 2005 USEPA Cancer Risk Assessment Guidelines, the point of departure in the dose-response data was defined using benchmark-dose modeling. Linear extrapolation was carried out from the point of departure and interspecies dose conversion was based on allometric scaling of body weight. RESULTS: Small intestine tumor incidence in male mice provided a robust and nearly identical fit with most available dose-response models using benchmark-dose modeling. A human equivalent cancer slope factor of 0.5 (mg/kg/day)(-1) was derived based on linear extrapolation from the point of departure. Statistical and kinetic analysis carried out on the NTP data as well as data reported in other studies support that the carcinogenicity of Cr(6+) did not result from an exceedance of the reduction capacity of the mouse gastrointestinal tract at the doses in the NTP study. CONCLUSIONS: Mouse gastric emptying time and human Cr(6+) dosing studies strongly suggest that even at doses considerably lower than those in the NTP study, Cr(6+) escapes reduction in both the mouse and human stomachs due to kinetic competition from Cr(6+) absorption and gastric emptying. The cancer potency derived from the NTP data is, therefore, deemed to be relevant and applicable to human exposure. Cr(6+) is, therefore, identified as "likely to be carcinogenic to humans" in accordance with the USEPA's cancer characterization rubric.
BACKGROUND: Hexavalent chromium (Cr(6+)) has long been recognized as an inhalation carcinogen. Useful data on its carcinogenicity by ingestion have been slower to develop. The 2008 NTP chronic bioassay of sodium dichromate dihydrate in drinking water found clear evidence of carcinogenicity in rodents and allows a generalizable estimate of the human ingestion cancer potency of Cr(6+). OBJECTIVES: To estimate the human ingestion cancer potency of Cr(6+) and evaluate its relevance for human exposure. METHODS: Tumors of the small intestine in male mice were selected as the critical endpoint, for the derivation of cancer potency. Following the 2005 USEPA Cancer Risk Assessment Guidelines, the point of departure in the dose-response data was defined using benchmark-dose modeling. Linear extrapolation was carried out from the point of departure and interspecies dose conversion was based on allometric scaling of body weight. RESULTS: Small intestine tumor incidence in male mice provided a robust and nearly identical fit with most available dose-response models using benchmark-dose modeling. A human equivalent cancer slope factor of 0.5 (mg/kg/day)(-1) was derived based on linear extrapolation from the point of departure. Statistical and kinetic analysis carried out on the NTP data as well as data reported in other studies support that the carcinogenicity of Cr(6+) did not result from an exceedance of the reduction capacity of the mouse gastrointestinal tract at the doses in the NTP study. CONCLUSIONS:Mouse gastric emptying time and humanCr(6+) dosing studies strongly suggest that even at doses considerably lower than those in the NTP study, Cr(6+) escapes reduction in both the mouse and human stomachs due to kinetic competition from Cr(6+) absorption and gastric emptying. The cancer potency derived from the NTP data is, therefore, deemed to be relevant and applicable to human exposure. Cr(6+) is, therefore, identified as "likely to be carcinogenic to humans" in accordance with the USEPA's cancer characterization rubric.
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