Development of a Tolerable Daily Intake for N-Nitrosodimethylamine Using a Modified Benchmark Dose Methodology

Abstract

N-Nitrosodimethylamine (NDMA) is an environmental contaminant that has recently been detected in Australian drinking-water supplies and that is principally generated in chloramination systems. NDMA is acutely toxic to humans at high doses, is genotoxic after cytochrome P-450 metabolism, and is carcinogenic in several animal species. An extremely large lifetime cancer dose-response study reported by Peto and colleagues (1984, 1991a, 1991b) of NDMA in drinking water given to rats is used in risk assessment by various jurisdictions. We have recently reported on use of an Australian modified benchmark dose (mBMD) methodology for developing tolerable daily intakes (TDIs) and guideline values for environmental carcinogens based on cancer dose response in the low-dose region, and have applied this to the NDMA rat liver tumor data. The application of a suite of mathematical models to the incidence data for hepatocellular carcinomas and hemangiosarcomas, followed by arithmetic and exponential-weight averaging of the 5% extra risk dose (mBMD_0.05) for the various models, produced an mBMD_0.05 range of 0.020–0.028 mg/kg/d. This was then divided by a range of modifying factors to account for seriousness of the carcinogenic endpoint, adequacy of the database, and inter- and intraspecies differences, generating a TDI range of 4.0 to 9.3 ng/kg/d. This may be employed in developing guideline values for NDMA in environmental media.