Long-RangeResearchInitiative(LRI)ProjectAbstractProjectID:MTH1201-01
ReverseCausality ofPolybrominatedDiphenylEthersandPolychlorinatedBiphenyls
HarveyJ.Clewell,III and MiyoungYoon, TheHamnerInstitutesforHealth Sciences.
Published epidemiologicalstudieshaveidentified associationsbetweenblood concentrationsof perflourinatedcompounds(PFCs),polybrominateddiphenylethers (PBDEs),andpolychlorinated biphenyls(PCBs)andavariety ofhumanhealtheffects. Thehealtheffectsinclude increasedtime-to- pregnancy,decreasedbirthweight,increasedageatmenarche,anddecreased ageatmenopause. The effectshavebeenobservedatbloodconcentrations farbelowwhichany effectswereobservedin experimentalanimalmodels.The observed associations between human health outcomes and chemical concentrations can be explained by pharmacokinetic variability in humans as physiological or biochemical factors related to the health outcome also affect the disposition or clearance of the chemical. In the past two years, TheHamner Institutes for Health Sciences (Hamner) has established a reverse causality modeling program in collaboration with Dr. Matthew Longnecker at the National Institutes of Environmental Health Sciences (NIEHS) to use physiologically-basedpharmacokinetic (PBPK)models to assesswhetherassociationsreportedin epidemiologicstudiesofexposures to chemicalsmay bedueto normalchangesinphysiology andtheir impact onchemicaldisposition rather than thechemical. This research program combines the Hamner’sexpertise in life-stage PBPK modeling and reverse dosimetry derived from previous ACCLRI-funded research projects as well as the experience with reverse causality modeling of perfluorinated chemicals in other programs at the Hamner.
The initial focus has been on persistent chemicals. The case study on evaluating the association between blood PCBs and reduced birthweightsuccessfully demonstrated theimportanceofconsidering pharmacokineticsinevaluating epidemiological associationsbetween healtheffectsand chemicalexposurein potentially vulnerable lifestagessuch as pregnancy (Verner et al., 2013). In the second case study with PBDE and altered timing of menarche, the life-stage modeling platform has been refined to simulate an individual’s age-dependent kinetics longitudinally including the pubertal period, which is key to interpreting the biomarker levels of a persistent chemical such as PDBE across ages in a population. Incorporation of correlations between physiological changes and major pubertal events such as onset of menarche, growth spurts, and body weight gain, which are often used as a marker for an adverse health effect, was also critical. Estimation of individual exposure was identified as a major source of uncertainties in the current approach requiring further investigation. The case studies can serve as a basis for future research linking exposure and dosimetry modeling together to further strengthen our approach for linking exposure and health effects through PBPK modeling, of which the reverse causality modeling is one of the important parts.
Implications:A Monte Carlo PBPK modeling approach can provide a tool to critically assess whether findings in epidemiology studies can be attributed to extant correlations between individual pharmacokinetics and health outcomes. Other health endpoints such as diabetes, obesity and cardiovascular disease for other persistent chemicals as well as concerns for reverse causality for short half-life chemicals such as the phthalates can be addressed in a similar manner. Based upon the experience built with a few case studies, ageneral modeling platform can be built to support evaluation and prediction of potential (spurious) associations for chemicals.
Keywords:PBPKmodels,pharmacokinetics, MonteCarlo,epidemiology, PBDEs, PCBs
Projectstartandend dates:January2012 – December2014
Peer-reviewed publication(s):
Verner, M.A., McDougall, R., Glynn, A., Andersen, M.E., Clewell, H.J. 3rd, Korrick, S.A., and Longnecker, M.P. (2013). Is the relationship between prenatal exposure to PCB-153 and decreased birth weight attributable to pharmacokinetics? Environmental Health Perspective 121(10):1219-1224.
Peeples, C.R., Yoon, M., Wu, H., Verner, M.A., Luo, M., Andersen, M. E., Longnecker, M. P. and Clewell, H.J. Are epidemiological associations between health effects and chemical concentrations in blood always meaningful?(In preparation).
Otherpublication(s):None to date
Abstractcreation date:July 2014
Thisabstractwaspreparedbytheprincipalinvestigatorfortheproject.Pleasesee