Abstract：
:A physiologically based pharmacokinetic (PBPK) model has been developed for trichloroethylene (1,1,2-trichloroethene, TRI) for rat and humans, based on in vitro metabolic parameters. These were obtained using individual cytochrome P450 and glutathione S-transferase enzymes. The main enzymes involved both for rats and humans are CYP2E1 and the μ- and π-class glutathione S-transferases. Validation experiments were performed in order to test the predictive value of the enzyme kinetic parameters to describe 'whole-body' disposition. Male Wistar rats were dosed orally or intravenously with different doses of trichloroethylene. Obtained exhaled radioactivity, excreted radioactivity in urine, and obtained blood concentration-time curves of trichloroethylene for all dosing groups were compared to predictions from the PBPK model. Subsequently, using the scaling factor derived from the rat experiments predictions were made for the extreme cases to be expected in humans, based on interindividual variations of the key enzymes involved. On comparing these predictions with literature data a very close match was found. This illustrates the potential application of in vitro metabolic parameters in risk assessment, through the use of PBPK modeling as a tool to understand and predict in vivo data. From a hypothetical 8 h exposure scenario to 35 ppm trichloroethylene in rats and humans, and assuming that the glutathione S-transferase pathway is responsible for the toxicity of trichloroethylene, it was concluded that humans are less sensitive for trichloroethylene toxicity than rats.
journal_name
Environ Toxicol Pharmacoljournal_title
Environmental toxicology and pharmacologyauthors
Hissink EM,Bogaards JJ,Freidig AP,Commandeur JN,Vermeulen NP,van Bladeren PJdoi
10.1016/s1382-6689(02)00019-4subject
Has Abstractpub_date
2002-07-01 00:00:00pages
259-71issue
3-4eissn
1382-6689issn
1872-7077pii
S1382-6689(02)00019-4journal_volume
11pub_type
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