Skip to main content
NCBI home page
Environmental Health Perspectives logoLink to Environmental Health Perspectives
. 2002 Dec;110(Suppl 6):989–994. doi: 10.1289/ehp.02110s6989

Physiological modeling and extrapolation of pharmacokinetic interactions from binary to more complex chemical mixtures.

Kannan Krishnan 1, Sami Haddad 1, Martin Béliveau 1, Robert Tardif 1
PMCID: PMC1241283  PMID: 12634130

Abstract

The available data on binary interactions are yet to be considered within the context of mixture risk assessment because of our inability to predict the effect of a third or a fourth chemical in the mixture on the interacting binary pairs. Physiologically based pharmacokinetic (PBPK) models represent a potentially useful framework for predicting the consequences of interactions in mixtures of increasing complexity. This article highlights the conceptual basis and validity of PBPK models for extrapolating the occurrence and magnitude of interactions from binary to more complex chemical mixtures. The methodology involves the development of PBPK models for all mixture components and interconnecting them at the level of the tissue where the interaction is occurring. Once all component models are interconnected at the binary level, the PBPK framework simulates the kinetics of all mixture components, accounting for the interactions occurring at various levels in more complex mixtures. This aspect was validated by comparing the simulations of a binary interaction-based PBPK model with experimental data on the inhalation kinetics of m-xylene, toluene, ethyl benzene, dichloromethane, and benzene in mixtures of varying composition and complexity. The ability to predict the kinetics of chemicals in complex mixtures by accounting for binary interactions alone within a PBPK model is a significant step toward the development of interaction-based risk assessment for chemical mixtures.

Full Text

The Full Text of this article is available as a PDF (273.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Andersen M. E., Gargas M. L., Clewell H. J., 3rd, Severyn K. M. Quantitative evaluation of the metabolic interactions between trichloroethylene and 1,1-dichloroethylene in vivo using gas uptake methods. Toxicol Appl Pharmacol. 1987 Jun 30;89(2):149–157. doi: 10.1016/0041-008x(87)90035-4. [DOI] [PubMed] [Google Scholar]
  2. Haddad S., Béliveau M., Tardif R., Krishnan K. A PBPK modeling-based approach to account for interactions in the health risk assessment of chemical mixtures. Toxicol Sci. 2001 Sep;63(1):125–131. doi: 10.1093/toxsci/63.1.125. [DOI] [PubMed] [Google Scholar]
  3. Haddad S., Charest-Tardif G., Tardif R., Krishnan K. Validation of a physiological modeling framework for simulating the toxicokinetics of chemicals in mixtures. Toxicol Appl Pharmacol. 2000 Sep 15;167(3):199–209. doi: 10.1006/taap.2000.8991. [DOI] [PubMed] [Google Scholar]
  4. Haddad S., Tardif R., Charest-Tardif G., Krishnan K. Physiological modeling of the toxicokinetic interactions in a quaternary mixture of aromatic hydrocarbons. Toxicol Appl Pharmacol. 1999 Dec 15;161(3):249–257. doi: 10.1006/taap.1999.8803. [DOI] [PubMed] [Google Scholar]
  5. Haddad S., Tardif R., Viau C., Krishnan K. A modeling approach to account for toxicokinetic interactions in the calculation of biological hazard index for chemical mixtures. Toxicol Lett. 1999 Sep 5;108(2-3):303–308. doi: 10.1016/s0378-4274(99)00102-2. [DOI] [PubMed] [Google Scholar]
  6. Krishnan K., Brodeur J. Toxic interactions among environmental pollutants: corroborating laboratory observations with human experience. Environ Health Perspect. 1994 Nov;102 (Suppl 9):11–17. doi: 10.1289/ehp.94102s911. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Pelekis M., Krishnan K. Assessing the relevance of rodent data on chemical interactions for health risk assessment purposes: a case study with dichloromethane-toluene mixture. Regul Toxicol Pharmacol. 1997 Feb;25(1):79–86. doi: 10.1006/rtph.1996.1075. [DOI] [PubMed] [Google Scholar]
  8. Purcell K. J., Cason G. H., Gargas M. L., Andersen M. E., Travis C. C. In vivo metabolic interactions of benzene and toluene. Toxicol Lett. 1990 Jul;52(2):141–152. doi: 10.1016/0378-4274(90)90148-f. [DOI] [PubMed] [Google Scholar]
  9. Tardif R., Charest-Tardif G., Brodeur J., Krishnan K. Physiologically based pharmacokinetic modeling of a ternary mixture of alkyl benzenes in rats and humans. Toxicol Appl Pharmacol. 1997 May;144(1):120–134. doi: 10.1006/taap.1996.8096. [DOI] [PubMed] [Google Scholar]
  10. Tardif R., Laparé S., Charest-Tardif G., Brodeur J., Krishnan K. Physiologically-based pharmacokinetic modeling of a mixture of toluene and xylene in humans. Risk Anal. 1995 Jun;15(3):335–342. doi: 10.1111/j.1539-6924.1995.tb00326.x. [DOI] [PubMed] [Google Scholar]
  11. Tardif R., Laparé S., Krishnan K., Brodeur J. Physiologically based modeling of the toxicokinetic interaction between toluene and m-xylene in the rat. Toxicol Appl Pharmacol. 1993 Jun;120(2):266–273. doi: 10.1006/taap.1993.1111. [DOI] [PubMed] [Google Scholar]
  12. Thakore K. N., Gargas M. L., Andersen M. E., Mehendale H. M. PB-PK derived metabolic constants, hepatotoxicity, and lethality of BrCCl3 in rats pretreated with chlordecone, phenobarbital, or mirex. Toxicol Appl Pharmacol. 1991 Jul;109(3):514–528. doi: 10.1016/0041-008x(91)90014-6. [DOI] [PubMed] [Google Scholar]
  13. el-Masri H. A., Constan A. A., Ramsdell H. S., Yang R. S. Physiologically based pharmacodynamic modeling of an interaction threshold between trichloroethylene and 1,1-dichloroethylene in Fischer 344 rats. Toxicol Appl Pharmacol. 1996 Nov;141(1):124–132. doi: 10.1006/taap.1996.0268. [DOI] [PubMed] [Google Scholar]

Articles from Environmental Health Perspectives are provided here courtesy of National Institute of Environmental Health Sciences

RESOURCES