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Reverse dosimetry: interpreting trihalomethanes biomonitoring data using physiologically based pharmacokinetic modeling

Journal of Exposure Science & Environmental Epidemiology volume 17, pages 591–603 (2007)Cite this article

Abstract

Biomonitoring data provide evidence of exposure of environmental chemicals but are not, by themselves, direct measures of exposure. To use biomonitoring data in understanding exposure, physiologically based pharmacokinetic (PBPK) modeling can be used in a reverse dosimetry approach to assess a distribution of exposures possibly associated with specific blood or urine levels of compounds. Reverse dosimetry integrates PBPK modeling with exposure pattern characterization, Monte Carlo analysis, and statistical tools to estimate a distribution of exposures that are consistent with biomonitoring data in a population. The present study used an existing PBPK model for chloroform as a generic framework to develop PBPK models for other trihalomethanes (THMs). Using Monte Carlo sampling techniques, probabilistic information about pharmacokinetics and exposure patterns was included to estimate distributions of THMs concentrations in blood in relation to various exposure patterns in a diverse population. In addition, the possibility of inhibition of hepatic metabolism among THMs was evaluated under the scenarios of household exposure. These studies demonstrated how PBPK modeling can be used as a tool to estimate a population distribution of exposures that could have resulted in particular biomonitoring results. When toxicity level is known, this tool can also be used to estimate proportion of population above levels associated with health risk.

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References

  • Allis J.W., and Zhao G. Quantitative evaluation of bromodichloromethane metabolism by recombinant rat and human cytochrome P450s. Chem Biol Interact 2002: 140: 137–153.

    Article  CAS  PubMed  Google Scholar 

  • Aylward L.L., Brunet R.C., Starr T.B., Carrier G., Delzell E., Cheng H., and Beall C. Exposure reconstruction for the TCDD-exposed NIOSH cohort using a concentration- and age-dependent model of elimination. Risk Anal 2005: 25: 945–956.

    Article  PubMed  Google Scholar 

  • Backer L.C., Ashley D.L., Bonin M.A., Cardinali F.L., Kieszak S.M., and Wooten J.V. Household exposures to drinking water disinfection by-products: whole blood trihalomethane levels. J Expo Anal Environ Epidemiol 2000: 10: 321–326.

    Article  CAS  PubMed  Google Scholar 

  • Batterman S., Zhang L., Wang S., and Franzblau A. Partition coefficients for the trihalomethanes among blood, urine, water, milk and air. Sci Total Environ 2002: 284: 237–247.

    Article  CAS  PubMed  Google Scholar 

  • Brown R.P., Delp M.D., Lindstedt S.L., Rhomberg L.R., and Beliles R.P. Physiological parameter values for physiologically based pharmacokinetic models. Toxicol Ind Health 1997: 13: 407–484.

    Article  CAS  PubMed  Google Scholar 

  • CDC, National Center for Health. Statistics (Ed.) The Third National Health and Nutrition Examination Survey (NHANES III, 1988–94), CDC, Atlanta, GA, 1996.

  • CDC, Department of Health and Human Services (Ed.) Third National Report on Human Exposure to Environmental Chemicals, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, 2005.

  • Clewell III H.J., Gentry P.R., Covington T.R., and Gearhart J.M. Development of a physiologically based pharmacokinetic model of trichloroethylene and its metabolites for use in risk assessment. Environ Health Perspect 2000: 108 (Suppl 2): 283–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Clewell III H.J., Gentry P.R., Covington T.R., Sarangapani R., and Teeguarden J.G. Evaluation of the potential impact of age- and gender-specific pharmacokinetic differences on tissue dosimetry. Tox Sci 2004: 79: 381–393.

    Article  CAS  Google Scholar 

  • Clewell H.J., Gearhart J.M., Gentry P.R., Covington T.R., VanLandingham C.B., Crump K.S., and Shipp A.M. Evaluation of the uncertainty in an oral reference dose for methylmercury due to interindividual variability in pharmacokinetics. Risk Anal 1999: 19: 547–558.

    CAS  PubMed  Google Scholar 

  • Clewell H.J., Lee T.S., and Carpenter R.L. Sensitivity of physiologically based pharmacokinetic models to variation in model parameters: methylene chloride. Risk Anal 1994: 14: 521–553.

    Article  PubMed  Google Scholar 

  • Constan A.A., Sprankle C.S., Peters J.M., Kedderis G.L., Everitt J.I., Wong B.A., Gonzalez F.L., and Butterworth B.E. Metabolism of chloroform by cytochrome P450 2E1 is required for induction of toxicity in the liver, kidney, and nose of male mice. Toxicol Appl Pharmacol 1999: 160: 120–126.

    Article  CAS  PubMed  Google Scholar 

  • Corley R.A., Gordon S.M., and Wallace L.A. Physiologically based pharmacokinetic modeling of the temperature-dependent dermal absorption of chloroform by humans following bath water exposures. Toxicol Sci 2000: 53: 13–23.

    Article  CAS  PubMed  Google Scholar 

  • Corley R.A., Mendrala A.L., Smith F.A., Staats D.A., Gargas M.L., Conolly R.B., Andersen M.E., and Reitz R.H. Development of a physiologically based pharmacokinetic model for chloroform. Toxicol Appl Pharmacol 1990: 103: 512–527.

    Article  CAS  PubMed  Google Scholar 

  • Delic J.I., Lilly P.D., MacDonald A.J., and Loizou G.D. The utility of PBPK in the safety assessment of chloroform and carbon tetrachloride. Regul Toxicol Pharmacol 2000: 32: 144–155.

    Article  CAS  PubMed  Google Scholar 

  • Egorov A.I., Tereschenko A.A., Altshul L.M., Vartiainen T., Samsonov D., LaBrecque B., Maki-Paakkanen J., Drizhd N.L., and Ford T.E. Exposures to drinking water chlorination by-products in a Russian city. Int J Hyg Environ Health 2003: 206: 539–551.

    Article  CAS  PubMed  Google Scholar 

  • Evans M.V., Crank W.D., Yang H.M., and Simmons J.E. Applications of sensitivity analysis to a physiologically based pharmacokinetic model for carbon tetrachloride in rats. Toxicol Appl Pharmacol 1994: 128: 36–44.

    Article  CAS  PubMed  Google Scholar 

  • Gargas M.L., Burgess R.J., Voisard D.E., Cason G.H., and Andersen M.E. Partition coefficients of low-molecular-weight volatile chemicals in various liquids and tissues. Toxicol Appl Pharmacol 1989: 98: 87–99.

    Article  CAS  PubMed  Google Scholar 

  • Georgopoulos P.G., Roy A., and Gallo M.A. Reconstruction of short-term multi-route exposure to volatile organic compounds using physiologically based pharmacokinetic models. J Expo Anal Environ Epidemiol 1994: 4: 309–328.

    CAS  Google Scholar 

  • Gordon S.M., Brinkman M.C., Ashley D.L., Blount B.C., Lyu C., Masters J., and Singer P. Changes in breath trihalomethane levels resulting from household water-use activities. Environ Health Perspect 2006: 114: 514–521.

    Article  CAS  PubMed  Google Scholar 

  • Gosselin N.H., Brunet R.C., Carrier G., Bouchard M., and Feeley M. Reconstruction of methylmercury intakes in indigenous populations from biomarker data. J Expo Sci Environ Epidemiol 2006: 16: 19–29.

    Article  CAS  PubMed  Google Scholar 

  • Jo W.K., Weisel C.P., and Lioy P.J. Routes of chloroform exposure and body burden from showering with chlorinated tap water. Risk Anal 1990: 10: 575–580.

    Article  CAS  PubMed  Google Scholar 

  • Kerger B.D., Schmidt C.E., and Paustenbach D.J. Assessment of airborne exposure to trihalomethanes from tap water in residential showers and baths. Risk Anal 2000: 20: 637–651.

    Article  CAS  PubMed  Google Scholar 

  • Krasner S.W., McGuire M.J., Jacangelo J.G., Patania N.L., Reagan K.M., and Aieta E.M. The occurrence of disinfection by-products in US drinking water. J Am Water Works Assoc 1989: 81: 41–53.

    Article  CAS  Google Scholar 

  • Levesque B., Ayotte P., LeBlanc A., Dewailly E., Prud'Homme D., Lavoie R., Allaire S., and Levallois P. Evaluation of dermal and respiratory chloroform exposure in humans. Environ Health Perspect 1994: 102: 1082–1087.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Levesque B., Ayotte P., Tardif R., Charest-Tardif G., Dewailly E., Prud'Homme D., Gingras G., Allaire S., and Lavoie R. Evaluation of the health risk associated with exposure to chloroform in indoor swimming pools. J Toxicol Environ Health A 2000: 61: 225–243.

    Article  CAS  PubMed  Google Scholar 

  • Levesque B., Ayotte P., Tardif R., Ferron L., Gingras S., Schlouch E., Gingras G., Levallois P., and Dewailly E. Cancer risk associated with household exposure to chloroform. J Toxicol Environ Health A 2002: 65: 489–502.

    Article  CAS  PubMed  Google Scholar 

  • Little J.C. Applying the two-resistance theory to contaminant volatilization in showers. Environ Sci Technol 1992: 26: 1341–1349.

    Article  CAS  Google Scholar 

  • Luciene da Silva M., Charest-Tardif G., Krishnan K., and Tardif R. Influence of oral administration of a quaternary mixture of trihalomethanes on their blood kinetics in the rat. Toxicol Lett 1999: 106: 49–57.

    Article  CAS  PubMed  Google Scholar 

  • Mayer P.W., DeOreo W.B., Optiz E.M., Kiefer J.C., Davis W.Y., Dziegielewski B., and Nelson J.O. Residential End Uses of Water. AWWA Research Foundation, Denver, 1999.

    Google Scholar 

  • Nieuwenhuijsen M.J., Toledano M.B., Eaton N.E., Fawell J., and Elliott P. Chlorination disinfection byproducts in water and their association with adverse reproductive outcomes: a review. Occup Environ Med 2000: 57: 73–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nuckols J.R., Ashley D.L., Lyu C., Gordon S.M., Hinckley A.F., and Singer P. Influence of tap water quality and household water use activities on indoor air and internal dose levels of trihalomethanes. Environ Health Perspect 2005: 113: 863–870.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Phillips L.J., Fares R.J., and Schweer L.G. Distributions of total skin surface area to body weight ratios for use in dermal exposure assessments. J Expo Anal Environ Epidemiol 1993: 3: 331–338.

    CAS  PubMed  Google Scholar 

  • Poulin P., and Krishnan K. Molecular structure-based prediction of the partition coefficients of organic chemicals for physiological pharmacokinetic models. Toxicol Methods 1996: 6: 117–137.

    Article  CAS  Google Scholar 

  • Poulin P., and Theil F.P. A priori prediction of tissue:plasma partition coefficients of drugs to facilitate the use of physiologically-based pharmacokinetic models in drug discovery. J Pharm Sci 2000: 89: 16–35.

    Article  CAS  PubMed  Google Scholar 

  • Reitz R.H., Mendrala A.L., Corley R.A., Quast J.F., Gargas M.L., Andersen M.E., Staats D.A., and Conolly R.B. Estimating the risk of liver cancer associated with human exposures to chloroform using physiologically based pharmacokinetic modeling. Toxicol Appl Pharmacol 1990: 105: 443–459.

    Article  CAS  PubMed  Google Scholar 

  • Roy A., Weisel C.P., Gallo M.A., and Georgopoulos P.G. Studies of multiroute exposure/dose reconstruction using physiologically based pharmacokinetic models. J Clean Technol Environ Toxicol Occup Med 1996: 5: 285–295.

    CAS  Google Scholar 

  • Sohn M.D., McKone T.E., and Blancato J.N. Reconstructing population exposures from dose biomarkers: inhalation of trichloroethylene (TCE) as a case study. J Expo Anal Environ Epidemiol 2004: 14: 204–213.

    Article  CAS  PubMed  Google Scholar 

  • Stern A.H. A revised probabilistic estimate of the maternal methyl mercury intake dose corresponding to a measured cord blood mercury concentration. Environ Health Perspect 2005: 113: 155–163.

    Article  CAS  PubMed  Google Scholar 

  • Tan Y.M., Liao K.H., Conolly R.B., Blount B.C., Mason A.M., and Clewell H.J. Use of a physiologically based pharmacokinetic model to evaluate biomonitoring data of human chloroform exposure. J Toxicol Environ Health A 2006: 69: 1727–1756.

    Article  CAS  PubMed  Google Scholar 

  • Thomas V. Biological-mathematical modeling of chronic toxicity. Base Research Report. AMRL-TR-75-5. In: Force W.P.A. (Ed.) Wright-Patterson Air Force Base. Aerospace Medical Research Laboratory, OH, 1975.

    Google Scholar 

  • US EPA. In: Office of Research and Development (Ed.) Descriptive Statistics Tables From a Detailed Analysis of the National Human Activity Pattern Survey (NHAPS) Data, Publisher: US EPA, Las Vegas, NV, 1996.

  • USEPA. Estimated per capita water ingestion in the United States: based on data collected by the United States Department of Agriculture's 1994–1996 Continuing Survey of Food Intakes by Individuals. In: Office of Water (Ed.) US EPA, Washington, DC, 2000.

  • USEPA. EPA on-line tools for site assessment calculation. In: http://www.epa.gov/athens/onsite.

  • Wallace L.A. Human exposure and body burden for chloroform and other trihalomethanes. Crit Rev Environ Sci Technol 1997: 27: 113–194.

    Article  CAS  Google Scholar 

  • Weisel C.P., Little J.C., Chiu N., Pandis S.N., Davidson C., and Wilkes C.R. Developing exposure estimates. In: Olin S.S. (Ed.) Exposure to Contaminants in Drinking Water. International Life Sciences Institute, Washington, DC, 1999 pp. 89–101.

    Google Scholar 

  • WHO. Guidelines for Safe Recreational-Water Environments, Volume 2: Swimming Pools, Spas and Similar Recreational-Water Environments, Vol. 2005, World Health Organization, Geneva, 2000.

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Acknowledgements

We thank Bruce Allen for his help on the development of the second (Bayesian) approach for conducting reverse dosimetry. We also thank Drs Melvin Andersen and Andy Nong from CIIT for their valuable reviews and comments. This work was supported by the Chlorine Chemistry Council.

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  1. CIIT Centers for Health Research, Center for Human Health Assessment, 6 Davis Drive, P.O. Box 12137, Research Triangle Park, NC, USA

    Yu-Mei Tan, Kai H Liao & Harvey J Clewell III

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  1. Yu-Mei Tan
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Correspondence to Yu-Mei Tan.

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Tan, YM., Liao, K. & Clewell, H. Reverse dosimetry: interpreting trihalomethanes biomonitoring data using physiologically based pharmacokinetic modeling. J Expo Sci Environ Epidemiol 17, 591–603 (2007). https://doi.org/10.1038/sj.jes.7500540

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