Development of an updated PBPK model for trichloroethylene and metabolites in mice, and its application to discern the role of oxidative metabolism in TCE-induced hepatomegaly.

Trichloroethylene (TCE) is a lipophilic solvent rapidly absorbed and metabolized via oxidation and conjugation to a variety of metabolites that cause toxicity to several internal targets. Increases in liver weight (hepatomegaly) have been reported to occur quickly in rodents after TCE exposure, with liver tumor induction reported in mice after long-term exposure. An integrated dataset for gavage and inhalation TCE exposure and oral data for exposure to two of its oxidative metabolites (TCA and DCA) was used, in combination with an updated and more accurate physiologically-based pharmacokinetic (PBPK) model, to examine the question as to whether the presence of TCA in the liver is responsible for TCE-induced hepatomegaly in mice. The updated PBPK model was used to help discern the quantitative contribution of metabolites to this effect. The update of the model was based on a detailed evaluation of predictions from previously published models and additional preliminary analyses based on gas uptake inhalation data in mice. The parameters of the updated model were calibrated using Bayesian methods with an expanded pharmacokinetic database consisting of oral, inhalation, and iv studies of TCE administration as well as studies of TCE metabolites in mice. The dose-response relationships for hepatomegaly derived from the multi-study database showed that the proportionality of dose to response for TCE- and DCA-induced hepatomegaly is not observed for administered doses of TCA in the studied range. The updated PBPK model was used to make a quantitative comparison of internal dose of metabolized and administered TCA. While the internal dose of TCA predicted by modeling of TCE exposure (i.e., mg TCA/kg-d) showed a linear relationship with hepatomegaly, the slope of the relationship was much greater than that for directly administered TCA. Thus, the degree of hepatomegaly induced per unit of TCA produced through TCE oxidation is greater than that expected per unit of TCA administered directly, which is inconsistent with the hypothesis that TCA alone accounts for TCE-induced hepatomegaly. In addition, TCE-induced hepatomegaly showed a much more consistent relationship with PBPK model predictions of total oxidative metabolism than with predictions of TCE area-under-the-curve in blood, consistent with toxicity being induced by oxidative metabolites rather than the parent compound. Therefore, these results strongly suggest that oxidative metabolites in addition to TCA are necessary contributors to TCE-induced liver weight changes in mice.

Radioactive materials in biosolids: dose modeling.

The Interagency Steering Committee on Radiation Standards (ISCORS) has recently completed a study of the occurrence within the United States of radioactive materials in sewage sludge and sewage incineration ash. One component of that effort was an examination of the possible transport of radioactivity from sludge into the local environment and the subsequent exposure of humans. A stochastic environmental pathway model was applied separately to seven hypothetical, generic sludge-release scenarios, leading to the creation of seven tables of Dose-to-Source Ratios (DSR), which can be used in translating from specific activity in sludge into dose to an individual. These DSR values were then combined with the results of an ISCORS survey of sludge and ash at more than 300 publicly owned treatment works, to explore the potential for radiation exposure of sludge workers and members of the public. This paper provides a brief overview of the pathway modeling methodology employed in the exposure and dose assessments and discusses technical aspects of the results obtained.

Radioactive materials in biosolids: national survey, dose modeling, and publicly owned treatment works (POTW) guidance.

The Nuclear Regulatory Commission (NRC) announced the availability of three new documents concerning radioactive materials in sewage sludge and ash from publicly owned treatment works (POTW). One of the documents is a report presenting the results of a volunteer survey of sewage sludge and ash samples provided by 313 POTWs. The second document is a dose modeling document, using multiple exposure pathway modeling focused on a series of generic scenarios, to track possible exposure of POTW workers and members of the general public to radioactivity from the sewage sludge or ash. The third document is a guidance report providing recommendations on the management of radioactivity in sewage sludge and ash for POTW owners and operators. This paper explains how radioactive materials enter POTWs, provides criteria for evaluating levels of radioactive material in sludge and ash, and gives a summary of the results of the survey and dose modeling efforts.