ToxSci Advance Access originally published online on February 19, 2004
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Toxicological Sciences 79, 28-37 (2004)
Toxicological Sciences vol. 79 no. 1 © Society of Toxicology; all rights reserved.
Kinetic Modeling of ß-Chloroprene Metabolism: II. The Application of Physiologically Based Modeling for Cancer Dose Response Analysis
* E.I. du Pont de Nemours and Company, Haskell Laboratory for Health and Environmental Sciences, PO Box 50, 1090 Elkton Road,Newark, Delaware 19711, and National Health and Environmental Effects Research Laboratory, Office of Research and Development,U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711
Received October 18, 2003; accepted January 28, 2004
ß-Chloroprene (2-chloro-1,3-butadiene; CD), which is used in the synthesis of polychloroprene, caused significant incidences of several tumor types in B6C3F1 mice and Fischer rats, but not in Wistar rats or Syrian hamsters. This project investigates the relevance of the bioassay lung tumor findings to human health risk by developing a physiologically based toxicokinetic (PBTK) model and exploring a tissue specific exposure-dose-response relationship. Key steps included identification of the plausible genotoxic mode of action, experimental quantification of tissue-to-air partition coefficients, scaling of in vitro parameters of CD metabolism for input into the PBTK model, comparing the model with in vivo experimental gas uptake data, selecting an appropriate tissue dosimetric, and predicting a corresponding human exposure concentration. The total daily milligram amount of CD metabolized per gram of lung was compared with the animal bioassay response data, specifically combined bronchiolar adenoma/carcinoma. The faster rate of metabolism in mouse lung agreed with the markedly greater incidence of lung tumors compared with the other rodent species. A lung tissue dose was predicted for the combined rodent lung tumor bioassay data at a 10% benchmark response. A human version of the PBTK model predicted that the lung tissue dose in humans would be equivalent to continuous lifetime daily exposure of 23 ppm CD. PBTK model sensitivity analysis indicated greater dependence of model predictions of dosimetry on physiological than biochemical parameters. The combined analysis of lung tumor response across species using the PBTK-derived internal dose provides an improved alternative to default pharmacokinetic interspecies adjustments for application to human health risk assessment.
Key Words: 2-chloro-1,3-butadiene; PBTK or PBPK modeling; benchmark dose; liver; lung; mouse; rat; hamster; human.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  H. Barton 4.7 Biological modeling as a method for data evaluation and integration in toxicology Human and Experimental Toxicology, February 1, 2009; 28(2-3): 143 - 145. [PDF]
|
|
|
|
 |
|
 M. W. Himmelstein, S. C. Carpenter, and P. M. Hinderliter Kinetic Modeling of {beta}-Chloroprene Metabolism: I. In vitro Rates in Liver and Lung Tissue Fractions from Mice, Rats, Hamsters, and Humans Toxicol. Sci., May 1, 2004; 79(1): 18 - 27. [Abstract] [Full Text] [PDF]
|
|