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North Bethesda, MD, United States

Tardiff R.G.,The Sapphire Group Inc. | Carson M.L.,The Sapphire Group Inc.
Food and Chemical Toxicology | Year: 2010

In some US potable water supplies, 1,2,3-trichloropropane (TCP) has been present at ranges of non-detect to less than 100. ppb, 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/kg. d) for non-cancer and Cancer Values (CV) (=10-14μg/kg. d) 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. © 2010 Elsevier Ltd. Source


Kimbrough R.D.,Center for Health Risk Evaluation | Krouskas C.A.,Center for Health Risk Evaluation | Leigh Carson M.,The Sapphire Group Inc. | Long T.F.,The Sapphire Group Inc. | And 2 more authors.
Regulatory Toxicology and Pharmacology | Year: 2010

Trace amounts of polychlorinated dibenzo-p-dioxins/furans (PCDD/Fs) and polychlorinated biphenyls (PCBs) are ubiquitous in the environment. Because of industrial activity, other human activities, and accidents, higher concentrations of these chemicals may be present in soil, in residential and recreational areas. Human uptake of these chemicals from such soils has been assumed by regulators, and people contacting such soils may be concerned about potential adverse health effects. Accordingly, clean up levels have been set by state and federal agencies. Whether and to what extent humans actually take up these chemicals from soil is the focus of this review. Since humans are also exposed to PCDD/Fs and PCBs in food and air, their concentrations in these media are presented. We find that their presence in soils is unlikely to increase human body burdens. © 2009 Elsevier Inc. Source


Tardiff R.G.,The Sapphire Group Inc. | Gargas M.L.,The Sapphire Group Inc. | Kirman C.R.,The Sapphire Group Inc. | Leigh Carson M.,The Sapphire Group Inc. | Sweeney L.M.,The Sapphire Group Inc.
Food and Chemical Toxicology | Year: 2010

Acrylamide (AA), a human neurotoxicant and rat tumorigen, is produced in starchy foods when cooked. AA is also an industrial chemical used in polyacrylamide production. A safety evaluation of ingested AA by humans was conducted using a newly developed, state-of-the-art physiologically-based toxicokinetic (PBPK or PBTK) model to compare internal doses of AA and its metabolite glycidamide (GA) in humans and rats. Based on modes of action (MoA), a nonlinear dose-response approach was applied for neurotoxicity (non-genotoxicity) and carcinogenicity (mixed: genotoxicity and epigenetic MoA). Tolerable daily intake (TDI) for neurotoxicity from AA was estimated to be 40 μg/kg-day; TDIs for cancer were estimated to be 2.6 and 16 μg/kg-day based on AA or GA, respectively. Margins of exposure (MoE) were calculated for average AA consumers to be 300 and 500 based on AA and GA, respectively; for cancer, the MoE for average AA consumers was estimated to be 200 and 1200 based on AA and GA, respectively. For high consumers of AA, MoEs were somewhat less. © 2009 Elsevier Ltd. All rights reserved. Source


Sweeney L.M.,The Sapphire Group Inc. | Kirman C.R.,The Sapphire Group Inc. | Gargas M.L.,The Sapphire Group Inc. | Carson M.L.,The Sapphire Group Inc. | Tardiff R.G.,The Sapphire Group Inc.
Food and Chemical Toxicology | Year: 2010

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/kg day) 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. © 2009 Elsevier Ltd. All rights reserved. Source

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