Skip Navigation

This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (16)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Haddad, S.
Right arrow Articles by Krishnan, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Haddad, S.
Right arrow Articles by Krishnan, K.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Toxicological Sciences 63, 125-131 (2001)
Copyright © 2001 by the Society of Toxicology

RISK ASSESSMENT

A PBPK Modeling-Based Approach to Account for Interactions in the Health Risk Assessment of Chemical Mixtures

Sami Haddad, Martin Béliveau, Robert Tardif and Kannan Krishnan1,

Groupe de recherche en toxicologie humaine (TOXHUM), Faculté de médecine, Université de Montréal, Case Postale 6128, Succursale centre-ville, Montréal, Québec H3C 3J7, Canada

ABSTRACT

The objectives of the present study were: (1) to develop a risk assessment methodology for chemical mixtures that accounts for pharmacokinetic interactions among components, and (2) to apply this methodology to assess the health risk associated with occupational inhalation exposure to airborne mixtures of dichloromethane, benzene, toluene, ethylbenzene, and m-xylene. The basis of the proposed risk assessment methodology relates to the characterization of the change in tissue dose metrics (e.g., area under the concentration-time curve for parent chemical in tissues [AUCtissue], maximal concentration of parent chemical or metabolite [Cmax], quantity metabolized over a period of time) in humans, during mixed exposures using PBPK models. For systemic toxicants, an interaction-based hazard index was calculated using data on tissue dose of mixture constituents. Initially, the AUCtarget tissue (AUCtt) corresponding to guideline values (e.g., threshold limit value [TLV]) of individual chemicals were obtained. Then, the AUCtt for each chemical during mixed exposure was obtained using a mixture PBPK model that accounted for the binary and higher order interactions occurring within the mixture. An interaction-based hazard index was then calculated for each toxic effect by summing the ratio of AUCtt obtained during mixed exposure (predefined mixture) and single exposure (TLV). For the carcinogenic constituents of the mixture, an interaction-based response additivity approach was applied. This method consisted of adding the cancer risk for each constituent, calculated as the product of q*tissue dose and AUCtt. The AUCtt during mixture exposures was obtained using an interaction-based PBPK model. The approaches developed in the present study permit, for the first time, the consideration of the impact of multichemical pharmacokinetic interactions at a quantitative level in mixture risk assessments.

Key Words: mixtures; PBPK modeling; risk assessment; VOCs; pharmacokinetic interactions; hazard index.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.