Abstract

High concentrations of hexavalent chromium [Cr(VI)] in drinking water induce villous cytotoxicity and compensatory crypt hyperplasia in the small intestines of mice (but not rats). Lifetime exposure to such cytotoxic concentrations increases intestinal neoplasms in mice, suggesting that the mode of action for Cr(VI)-induced intestinal tumors involves chronic wounding and compensatory cell proliferation of the intestine. Therefore, we developed a chronic oral reference dose (RfD) designed to be protective of intestinal damage and thus intestinal cancer. A physiologically based pharmacokinetic model for chromium in mice was used to estimate the amount of Cr(VI) entering each intestinal tissue section (duodenum, jejunum and ileum) from the lumen per day (normalized to intestinal tissue weight). These internal dose metrics, together with corresponding incidences for diffuse hyperplasia, were used to derive points of departure using benchmark dose modeling and constrained nonlinear regression. Both modeling techniques resulted in similar points of departure, which were subsequently converted to human equivalent doses using a human physiologically based pharmacokinetic model. Applying appropriate uncertainty factors, an RfD of 0.006 mg kg–1 day–1 was derived for diffuse hyperplasia—an effect that precedes tumor formation. This RfD is protective of both noncancer and cancer effects in the small intestine and corresponds to a safe drinking water equivalent level of 210 µg l–1. This concentration is higher than the current federal maximum contaminant level for total Cr (100 µg l–1) and well above levels of Cr(VI) in US drinking water supplies (typically ≤ 5 µg l–1). © 2013 The Authors. Journal of Applied Toxicology published by John Wiley & Sons, Ltd.

Highlights

  • Exposure to hexavalent chromium [Cr(VI)] has long been recognized to increase the risk of lung cancer among workers in certain industries (IARC, 1990), as well as in rodents via inhalation or intratracheal instillation (Glaser et al, 1986; Steinhoff et al, 1986)

  • This study focuses on the intestinal toxicity and carcinogenicity of Cr(VI) following ingestion, and does not discuss other effects of Cr(VI) outside the small intestine (SI)

  • The National Toxicology Program (NTP) study authors concluded that the meaning of histiocytic infiltration was uncertain (NTP, 2008b), and our own mode of action (MOA) analysis did not consider this a critical effect (Thompson et al, 2013)

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Summary

Introduction

Exposure to hexavalent chromium [Cr(VI)] has long been recognized to increase the risk of lung cancer among workers in certain industries (IARC, 1990), as well as in rodents via inhalation or intratracheal instillation (Glaser et al, 1986; Steinhoff et al, 1986). Cr(VI) has not been shown to cause a significantly increased cancer risk in the alimentary canal of exposed workers (Gatto et al, 2010). A recent 2-year cancer bioassay indicated that chronic exposure to Cr(VI), administered as sodium dichromate dihydrate, caused a dose-dependent increase in intestinal damage and intestinal tumor formation in B6C3F1 mice, but not F344 rats (NTP, 2008b). Subchronic bioassays indicated increased intestinal damage in mice after 90 days of exposure, but without evidence of preneoplastic lesions (NTP, 2007; Thompson et al, 2011b). The disparate outcomes observed in mice and rats suggested that the intestinal tumors observed in mice aToxStrategies, Inc., Katy, TX 77494, USA bSummit Toxicology, LLP, Orange Village, OH 44022, USA cToxStrategies, Inc., Rancho Santa Margarita, CA 92688, USA dToxStrategies, Inc., Austin, TX 78731, USA eSummit Toxicology, LLP, Allenspark, CO 80510, USA

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