Linked Life Data

16097137

Source:http://linkedlifedata.com/resource/pubmed/id/16097137

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2005-8-15
pubmed:abstractText
One of the more problematic aspects of the application of physiologically based pharmacokinetic (PBPK) models in risk assessment is the question of whether the model has been adequately validated to provide confidence in the dose metrics calculated with it. A number of PBPK models have been developed for perchloroethylene (PCE), differing primarily in the parameters estimated for metabolism. All of the models provide reasonably accurate simulations of selected kinetic data for PCE in mice and humans and could thus be considered to be "validated" to some extent. However, quantitative estimates of PCE cancer risk are critically dependent on the prediction of the rate of metabolism at low environmental exposures. Recent data on the urinary excretion of trichloroacetic acid (TCA), the major metabolite of PCE, for human subjects exposed to lower concentrations than those used in previous studies, make it possible to compare the high- to low-dose extrapolation capability of the various published human models. The model of Gearhart et al., which is the only model to include a description of TCA kinetics, provided the closest predictions of the urinary excretion observed in these low-concentration exposures. Other models overestimated metabolite excretion in this study by 5- to 15-fold. A systematic discrepancy between model predictions and experimental data for the time course of the urinary excretion of TCA suggested a contribution from TCA formed by metabolism of PCE in the kidney and excreted directly into the urine. A modification of the model of Gearhart et al. to include metabolism of PCE to TCA in the kidney at 10% of the capacity of the liver, with direct excretion of the TCA formed in the kidney into the urine, markedly improved agreement with the experimental time-course data, without altering predictions of liver metabolism. This case study with PCE demonstrates the danger of relying on parent chemical kinetic data to validate a model that will be used for the prediction of metabolism.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
1040-8444
pubmed:author
pubmed:issnType
Print
pubmed:volume
35
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
413-33
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
2005
pubmed:articleTitle
Evaluation of physiologically based pharmacokinetic models in risk assessment: an example with perchloroethylene.
pubmed:affiliation
ENVIRON Health Sciences Institute, Ruston, Louisiana, USA. hclewell@environcorp.com
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Review, Research Support, Non-U.S. Gov't