Public reporting burden for this collection of information is estimated to average I hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302, Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE (DD-MM-YYYY)2 Approved for public release; distribution unlimited. SUPPLEMENTARY NOTESCleared by AFRL/PA on 11 July 2006, case number is AFRLNVS-06-1724.14. ABSTRACT 'A physiologically based pharmacokinetic (PBPK) model was developed which provides a comprehensive description of the kinetics of trichloroethylene (TCE) and its metabolites, trichloroethanol (TCOH), and trichloroacetic acid (TCA), in the mouse, rat, and human, for both oral and inhalation exposure. The model includes descriptions of the three principal target tissues for cancer identified in animal bioassays: liver, lung, and kidney. Dose metrics that can be calculated with the model for cancer risk assessment include the area under the concentration curve (AUC) for TCA in the plasma or liver, the peak concentration and AUC for chloral (CHL) in the tracheo-bronchial region of the lung, and the production of a thioacetylating intermediate from dichlorovinylcysteine (DCVC) in the kidney. Additional dose metrics that can be calculated for noncancer risk assessment include the peak concentrations and AUCs for TCE and TCOH in the blood, as well as the total metabolism of TICE divided by the body weight. There is currently no adequate data available with which to confidently parameterize a description for another metabolite of interest, dichloroacetic acid (DCA). Model predictions of TCE, TCA, and TCOH concentrations in rodents and humans are consistent with a variety of experimental data, suggesting that the model should provide a useful basis for evaluating cross-species differences in pharmacokinetics for these chemicals. In the case of the lung and kidney target tissues, however, only limited data are available for establishing cross-species pharmacokinetics. As a result, PBPK model calculations for these dose metncs are highly uncertain.

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Applying a hockey stick parametric dose-response model to data on late or retarded development in Iraqi children exposed in utero to methylmercury, with mercury (Hg) exposure characterized by the peak Hg concentration in mothers' hair during pregnancy, Cox et al. calculated the "best statistical estimate" of the threshold for health effects as 10 ppm Hg in hair with a 95% range of uncertainty of between 0 and 13.6 ppm. A new application of the hockey stick model to the Iraqi data shows, however, that the statistical upper limit of the threshold based on the hockey stick model could be as high as 255 ppm. Furthermore, the maximum likelihood estimate of the threshold using a different parametric model is virtually zero. These and other analyses demonstrate that threshold estimates based on parametric models exhibit high statistical variability and model dependency, and are highly sensitive to the precise definition of an abnormal response. Consequently, they are not a reliable basis for setting a reference dose (RfD) for methylmercury. Benchmark analyses and statistical analyses useful for deriving NOAELs are also presented. We believe these latter analyses--particularly the benchmark analyses--generally form a sounder basis for determining RfDs than the type of hockey stick analysis presented by Cox et al. However, the acute nature of the exposures, as well as other limitations in the Iraqi data suggest that other data may be more appropriate for determining acceptable human exposures to methylmercury.