Physiologically based pharmacokinetic modeling of persistent organic pollutants for lifetime exposure assessment: a new tool in breast cancer epidemiologic studies.
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.


OBJECTIVE
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.
Verner
Marc-André
MA
Département des sciences biologiques, Université du Québec à Montréal, Montréal, Québec, Canada.
Charbonneau
Michel
M
López-Carrillo
Lizbeth
L
Haddad
Sami
S
D001827:Body Height; D001835:Body Weight; D001942:Breast Feeding; D001943:Breast Neoplasms / Q000139:chemically induced / Q000453:epidemiology*; D003198:Computer Simulation; D004781:Environmental Exposure; D004785:Environmental Pollutants / Q000493:pharmacokinetics* / Q000633:toxicity; D005260:Female; D006801:Humans; D018811:Maternal Exposure; D008954:Models, Biological; D009930:Organic Chemicals / Q000493:pharmacokinetics* / Q000633:toxicity; D018570:Risk Assessment; D013997:Time Factors
D004785:Environmental Pollutants; D009930:Organic Chemicals