| Physiologically Based Pharmacokinetic Modeling of Persistent Organic Pollutants for Lifetime Exposure Assessment: A New Tool in Breast Cancer Epidemiologic Studies Marc-André Verner,1 Michel Charbonneau,2* Lizbeth López-Carrillo,3 and Sami Haddad1* 1Département des sciences biologiques, Université du Québec à Montréal, Montréal, Québec, Canada; 2INRS-Institut Armand-Frappier, Université du Québec, Laval, Québec, Canada; 3Instituto Nacional de Salud Publica, Cuernavaca, Mexico Abstract
Background: Despite experimental evidence, most epidemiologic studies to date have not supported an association between exposure to persistent organic pollutants (POP) and breast cancer incidence in humans. This may be attributable to difficulties in estimating blood/tissue POP concentration at critical time periods of carcinogenesis. Objectives: In this work we aimed to develop a tool to estimate lifetime POP blood/tissue exposure and levels during any hypothesized time window of susceptibility in breast cancer development. Methods: We developed a physiologically based pharmacokinetic (PBPK) model that can account for any given physiologic lifetime history. Using data on pregnancies, height, weight, and age, the model estimates the values of physiologic parameters (e.g., organ volume, composition, and blood flow) throughout a woman's entire life. We assessed the lifetime toxicokinetic profile (LTP) for various exposure scenarios and physiologic factors (i.e., breast-feeding, growth, pregnancy, lactation, and weight changes) . Results: Simulations for three POPs [hexachlorobenzene, polychlorinated biphenyl (PCB) -153, PCB-180] using different lifetime physiologic profiles showed that the same blood concentration at 55 years of age can be reached despite totally different LTP. Aside from exposure levels, lactation periods and weight profile history were shown to be the factors that had the greatest impact on the LTP. Conclusions: This new lifetime PBPK model, which showed the limitations of using a single sample value obtained around the time of diagnosis for lifetime exposure assessment, will enable researchers conducting environmental epidemiology studies to reduce uncertainty linked to past POP exposure estimation and to consider exposure during time windows that are hypothesized to be mechanistically critical in carcinogenesis. Key words: breast cancer, epidemiology, exposure assessment, persistent organic pollutants, physiologically based pharmacokinetic modeling. Environ Health Perspect 116:886–892 (2008) . doi:10.1289/ehp.10917 available via http://dx.doi.org/ [Online 19 March 2008]
Address correspondence to S. Haddad, Université du Québec à Montréal, C.P.8888 Succ. Centre-ville, Montréal, Québec, Canada H3C 3P8. Telephone: (514) 987-3000. Fax: (514) 987-4647. E-mail: haddad.sami@uqam.ca *Both authors contributed equally to all parts of the work. Supplemental Material is available online at http://www.ehponline.org/members/2008/10917/suppl.pdf We thank R. McDougall from Aegis Technologies for his technical help during this project. This work was performed at Université du Québec à Montréal, C.P. 8888 Succ. Centre-ville, Montréal (Québec) , Canada H3C 3P8. S.H. is recipient of a research scholarship from Fonds de Recherche en Santé du Québec. The authors declare they have no competing financial interests. Received 25 September 2007 ; accepted 19 March 2008.
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