Evaluating noncancer effects of trichloroethylene: Dosimetry, mode of action, and risk assessment

被引:42
作者
Barton, HA
Clewell, HJ
机构
[1] ICF Consulting, KS Crump Grp Inc, Res Triangle Pk, NC USA
[2] ICF Consulting, KS Crump Grp Inc, Ruston, LA USA
关键词
benchmark dose; chloral; developmental toxicity; dose-response assessment; kidney toxicity; liver toxicity; neurotoxicity; PBPK modeling; trichloroacetate; trichloroethylene;
D O I
10.1289/ehp.00108s2323
中图分类号
X [环境科学、安全科学];
学科分类号
08 ; 0830 ;
摘要
Alternatives for developing chronic exposure limits for noncancer effects of trichloroethylene (TCE) were evaluated. These alternatives were organized within a framework for dose-response assessment-exposure:dosimetry (pharmacokinetics):mode of action (pharmacodynamics): response. This framework provides a consistent structure within which to make scientific judgments about available information, its interpretation, and use. These judgments occur in the selection of critical studies, internal dose metrics, pharmacokinetic models, approaches for interspecies extrapolation of pharmacodynamics, and uncertainty factors. Potentially limiting end points included developmental eye malformations, liver effects, immunotoxicity, and kidney toxicity from oral exposure and neurological, liver, and kidney effects by inhalation. Each end point was evaluated quantitatively using several methods. Default analyses used the traditional no-observed adverse effect level divided by uncertainty factors and the benchmark dose divided by uncertainty factors methods. Subsequently, mode-of-action and pharmacokinetic information were incorporated: Internal dose metrics were estimated using a physiologically based pharmacokinetic (PBPK) model for TCE and its major metabolites. This approach was notably useful with neurological and kidney toxicities. The human PBPK model provided estimates of human exposure doses for the internal dose metrics. Pharmacodynamic data or default assumptions were used for interspecies extrapolation. For liver and neurological effects, humans appear no more sensitive than rodents when internal dose metrics were considered. Therefore, the interspecies uncertainty factor was reduced, illustrating that uncertainty factors are a semiquantitative approach fitting into the organizational framework. Incorporation of pharmacokinetics and pharmacodynamics can result in values that differ significantly from those obtained with the default methods.
引用
收藏
页码:323 / 334
页数:12
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