Assessing the Human Health Risks of Trichloroethylene Key Scientific Issues (2006) / Chapter Skim
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11 Pharmacokinetic Modeling
11 Pharmacokinetic Modeling
Pages 297-314
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the evaluation of model uncertainties. Discussion of the uses of pharmacokinetic modeling results for risk assessment of trichloroethylene focuses on (1)
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In a basic PBPK model, the tissue compartments are linked by blood flow and have associated physical volumes and partition coefficients that describe the relative degree to which a given chemical (e.g., trichloroethylene) is soluble in each of those tissues versus blood.
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The richly perfused tissue group typically includes organs and tissues such as the brain, kidney, and alveolar region of the lungs, and the poorly perfused group includes tissues such as muscle and skin. Advantages and Limitations PBPK models hold particular promise in assessing human health risks from multiple routes of exposure to the same chemical or from exposures to related chemical mixtures, because of their ability to predict doses at the tissues where relevant toxic effects occur.
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However, oversimplification may lead to a biased prediction. Because health risk assessment is concerned with prediction rather than hypothesis testing or other forms of inference, loss of precision in parameter estimates is acceptable to avoid bias in the prediction.
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Ideally, partition coefficients are determined experimentally for each test article and in tissues from each species to be modeled. Partition coefficients for a "typical" tissue may be used as the partition coefficient in a lumped tissue compartment (e.g., liver tissue partition coefficient may be used for the liver and the lumped "richly perfused" tissue compartment)
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302 ASSESSING THE HUMAN HEALTH RISKS OF TRICHLOROETHYLENE Uncertainty Typical PBPK models include many unknown parameters and often highly multimodal likelihood surfaces, leading to challenging inference problems. In particular, parameter uncertainty can complicate inference.
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For example, dichloroacetic acid and trichloroacetic acid are by-products of water chlorination and are often present in drinking water at very low concentrations, some individuals are directly exposed to chloral via medicinal use, and other parent compounds produce some of the same metabolites as trichloroethylene.
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reviewed selected pharmacokinetic models for trichloroethylene in mice and humans, focusing on liver cancer as the outcome of interest for risk assessment. As noted in Chapter 4, trichloroethylene causes liver cancer in mice but not in rats, and trichloroacetic acid is considered the principal metabolite responsible for trichloroethylene-induced liver cancer in mice.
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(2000) pharmacokinetic model structure for trichloroethylene in mice, rats, and humans is much more complex than the Fisher models and includes submodels for metabolites in the three principal target tissues for cancer identified in animal bioassays: lung for chloral, kidney for dichlorovinylcysteine, and liver for chloral, trichloroacetic acid, dichloroacetic acid, trichloroethanol, and trichloroethanol glucuronide.
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, which is very similar in structure to the Clewell model, and a number of submodels for specific tissues (e.g., trancheobronchial and liver compartments) and specific metabolites (trichloroethanol, trichloroethanol glucuronide, trichloroacetic acid, dichloroacetic acid, and 1,2-dichlorovinylcysteine)
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, concentrations and AUC for trichloroacetic acid in plasma and liver (dose metric for liver cancer) , concentration and AUC for trichloroethanol in blood (dose metric for noncancer end points in liver)
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This five-compartment pharmacokinetic model included brain, fat, slowly perfused tissue, rapidly perfused tissue, and liver. Partition coefficients for trichloroethylene in blood, fat, muscle, brain, and liver were determined for the Long-Evans rats.
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. Studies were done in animals exposed to dichloroacetic acid as a parent compound rather than as a metabolite of trichloroethylene, which bypasses questions related to ex vivo production of dichloroacetic acid from trichloroacetic acid.
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310 ASSESSING THE HUMAN HEALTH RISKS OF TRICHLOROETHYLENE experiments designed to compare the predictive ability of different metrics or without understanding the mechanisms of toxicity in detail. Similarly, for toxicants such as trichloroethylene that have several potentially toxic metabolites, it is difficult to determine which metabolite(s)
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PHARMACOKINETIC MODELING 311 by the large number of parameters and small amounts of data. The use of least-squares estimation is reported after imposing constraints for several parameters (Hack et al.
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(2000) PBPK models for trichloroethylene in its 2001 draft risk assessment was reasonable given the available data for liver and kidney cancer.
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The model could be used to investigate alternative study designs. For ex ample, one could simulate liver concentrations of trichloroacetic acid in several different groups of laboratory animals that receive the same lifetime average daily dose by different dosing regimens to compare the lifetime average daily dose with an internal dose metric (that is, trichloroacetic acid concentration or AUC in liver)
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2000) ; this approach could be applied to trichloroethylene to investigate dose metrics rel evant to developmental effects of trichloroethylene exposure.
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