Interspecies Dose Extrapolation for Inhaled Dimethyl Sulfate: A PBPK Model-Based Analysis using Nasal Cavity N⁷-Methylguanine Adducts

Abstract

Dimethyl sulfate (DMS) is a volatile sulfuric acid ester used principally as a methylating agent in a wide variety of industrial applications. DMS reacts with organic macromolecules by a S_N2 mechanism. The weight of experimental evidence suggests that DMS possesses genotoxic and carcinogenic potential. Inhalation studies have shown that repeated exposure to DMS leads to tumors in the nasal cavity and lower respiratory tract in both rats and mice. Here we present a quantitative assessment for cross-species dose extrapolation for inhaled DMS using a physiologically based pharmacokinetic (PBPK) model. The model is designed to simulate N⁷-methylguanine (N⁷mG) DNA adduct levels in the nasal mucosa following DMS exposure in rats and humans. This model was parameterized and predictions were tested by comparison against experimentally measured N⁷mG DNA adduct levels in rat nasal mucosa following inhalation exposure to DMS. The model-based interspecies dose comparison, using N⁷mG adduct levels in the nasal respiratory tissue as the appropriate dose metrics, predicts a dose rate seven times higher in rats compared to humans.

Current address for Ramesh Sarangapani is Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936, USA.