Search

Abstract: In some US potable water supplies, 1,2,3-trichloropropane (TCP) has been present at ranges of non-detect to less than 100ppb, resulting from past uses. In subchronic oral studies, TCP produced toxicity in kidneys, liver, and other tissues. TCP administered by corn oil gavage in chronic studies produced tumors at multiple sites in rats and mice; however, interpretation of these studies was impeded by substantial premature mortality. Drinking water equivalent levels (DWELs) were estimated for a lifetime of consumption by applying biologically-based safety/risk assessment approaches, including Monte Carlo techniques, and with consideration of kinetics and modes of action, to possibly replace default assumptions. Internationally recognized Frameworks for human relevance of animal data were employed to interpret the findings. Calculated were a reference dose (=39μg/kgd) for non-cancer and Cancer Values (CV) (=10–14μg/kgd) based on non-linear dose–response relationships for mutagenicity as a precursor of cancer. Lifetime Average Daily Intakes (LADI) are 3130 and 790–1120μg/person-d for non-cancer and cancer, respectively. DWELs, estimated by applying a relative source contribution (RSC) of 50% to the LADIs, are 780 and 200–280μg/L for non-cancer and cancer, respectively. These DWELs may inform establishment of formal/informal guidelines and standards to protect public health. [Copyright &y& Elsevier]

Abstract: Water soluble compounds persistent in humans and the environment pose a challenge for estimating safe levels in tap water. A viable approach to estimate a drinking water equivalent level (DWEL) for perfluorooctanoic acid (PFOA) was applied to its extensive relevant information from human and laboratory animal studies. PFOA has been identified at 3.5μg/L (mean) in tap water in proximity to a manufacturing facility; however, in most supplies, the levels were below 7.5ng/L (usual limit of detection). PFOA has an average half-life in humans of 3.5years. From animal studies, PFOA is considered a possible hepatotoxicant and developmental toxicant for humans. Based on two chronic studies, PFOA was judged to be a possible human carcinogen, whose mode-of-action was likely to be related to receptor activation but not genotoxicity. The Benchmark Dose-Uncertainty Factor approach was selected for dose–response for noncancer and cancer. Based on internal dose of PFOA, the DWEL protective against cancer is 7.7μgPFOA/L tap water, and the noncancer DWELs range from 0.88 to 2.4μg/L. These DWELs can be considered a reliable, albeit conservative, basis to set a Maximum Concentration Level Goal under the US Safe Drinking Water Act. [Copyright &y& Elsevier]

Abstract: Physiologically-based toxicokinetic (“pharmacokinetic”) (PBPK or PBTK) modeling can be used as a tool to compare internal doses of acrylamide (AA) and its metabolite glycidamide (GA) in humans and rats. An earlier PBTK model for AA and GA in rats was refined and extended to humans based on new data. With adjustments to the previous parameters, excellent fits to a majority of the data for male Fisher 344 rats were obtained. Kinetic parameters for the human model were estimated based on fit to available human data for urinary metabolites of AA, and levels of hemoglobin adducts of AA and GA measured in studies in which human volunteers ingested known doses of AA. The simulations conducted with the rat and human models predicted that rats and humans ingesting comparable levels of AA (in mg/kgday) would have similar levels of GA in blood and tissues. This finding stands in contrast to the default approach that assumes a 3.2-fold increase in human risk due to pharmacokinetic differences between rats and humans. This model was used in a companion paper to estimate safe levels of ingested AA. [Copyright &y& Elsevier]