Establishing a total allowable concentration of o-toluidine in drinking water incorporating early lifestage exposure and susceptibility

Abstract

o-Toluidine is a monocyclic aromatic amine present in the formulation of some materials that contact drinking water. NSF/ANSI 61 Annex A (2011) and US EPA (2005a) risk assessment guidelines were used to determine an acceptable drinking water level. Occupational exposure to o-toluidine is associated with an increased risk of bladder cancer but human disease rates could not be used to establish risk values due to inadequate exposure data and coexposures in the epidemiology cohorts. Chronic dietary exposure to o-toluidine hydrochloride was associated with benign and malignant tumors in both sexes of F344 rats and B6C3F1 mice. o-Toluidine is genotoxic in vitro and in vivo. A 10(-5) cancer risk level was extrapolated from the human equivalent BMDL(10) of 13mg/kg-day for the combined incidence of papillomas and carcinomas of the bladder transitional epithelium in female rats. Considering varying susceptibility to tumor development at different life stages, the unit risk was modified to incorporate potency adjustments for early-life exposures. A framework for lifestage adjustment is presented that makes assumptions evident. For this assessment, the lifetime unit risk derived was ∼2-fold greater than the unadjusted adult lifetime unit risk, and the resulting Total Allowable Concentration in drinking water is 20μg/L.

Evaluation of the Mechanisms Involved in the Development of Bladder Toxicity following Exposure to Occupational Bladder Cancer Causative Chemicals Using DNA Adductome Analysis

“…Furthermore, the mutagenic activity of OTD is controversial. In several studies, including ours, OTD did not exhibit mutagenicity in the Ames salmonella assay with or without metabolic activation systems [3,28,29]. However, Beyerbach et al reported that the 2 ′ -deoxyguanosine-8-yl-OTD (2-methylaniline) adduct could be chemically synthesized [7].…”

“…Thus, the possible mechanisms of OTD genotoxicity are shown in Figure 6. The p-aminophenol metabolites of OTD, N-acethyl-4-amino-m-cresol, are thought to form protein adducts in urinary epithelial cells [29], which might stimulate immune cells and possibly induce inflammation along with ROS production via NADPH oxidase. This hypothesis was tested by conducting an animal experiment, which confirmed the effect of the NADPH oxidase inhibitor, apocynin, on urinary epithelial hyperplasia in rats induced by OTD (Figure 5).…”