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Concentration-dependent TCDD elimination kinetics in humans: toxicokinetic modeling for moderately to highly exposed adults from Seveso, Italy, and Vienna, Austria, and impact on dose estimates for the NIOSH cohort

Journal of Exposure Science & Environmental Epidemiology volume 15, pages 51–65 (2005)Cite this article

Abstract

Serial measurements of serum lipid 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) concentrations in 36 adults from Seveso, Italy, and three patients from Vienna, Austria, with initial serum lipid TCDD concentrations ranging from 130 to 144,000 ppt, were modeled using a modified version of a previously published toxicokinetic model for the distribution and elimination of dioxins. The original model structure accounted for a concentration-dependent increase in overall elimination rate for TCDD due to nonlinear distribution of TCDD to the liver (secondary to induction of the binding protein CYP1A2), from which elimination takes place via a first-order process. The original model structure was modified to include elimination due to lipid partitioning of TCDD from circulation into the large intestine, based on published human data. We optimized the fit of the modified model to the data by varying the hepatic elimination rate parameter for each of the 39 people. The model fits indicate that there is significant interindividual variability of TCDD elimination efficiency in humans and also demonstrate faster elimination in men compared to women, and in younger vs. older persons. The data and model results indicate that, for males, the mean apparent half-life for TCDD (as reflected in changes in predicted serum lipid TCDD level) ranges from less than 3 years at serum lipid levels above 10,000 ppt to over 10 years at serum lipid levels below 50 ppt. Application of the model to serum sampling data from the cohort of US herbicide-manufacturing workers assembled by the National Institute of Occupational Safety and Health (NIOSH) indicates that previous estimates of peak serum lipid TCDD concentrations in dioxin-exposed manufacturing workers, based on first-order back-extrapolations with half-lives of 7–9 years, may have underestimated the maximum concentrations in these workers and other occupational cohorts by several-fold to an order of magnitude or more. Such dose estimates, based on a single sampling point decades after last exposure, are highly variable and dependent on a variety of assumptions and factors that cannot be fully determined, including interindividual variations in elimination efficiency. Dose estimates for these cohorts should be re-evaluated in light of the demonstration of concentration-dependent elimination kinetics for TCDD, and the large degree of uncertainty in back-calculated dose estimates should be explicitly incorporated in quantitative estimates of TCDD's carcinogenic potency based on such data.

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Acknowledgements

We thank Alex Exuzides for assistance with statistical analyses, and Joel Michalek for assistance with data. This research was supported in part by Grant 2896 from Regione Lombardia, Milano, Italy, and by funding from the Chlorine Chemistry Council and Tierra Solutions, Inc. Some serum TCDD analyses for female Seveso residents were funded by grants (P.I. B. Eskenazi) from the National Institutes of Health (R01 ES07171) and the US Environmental Protection Agency (R82471).

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Author notes

  1. Pier Mario Gerthoux, Paolo Brambilla and Paolo Mocarelli: Participation limited to modeling and analysis of Seveso data.

Authors and Affiliations

  1. Exponent, Inc., 1800 Diagonal Road, Suite 355, Alexandria, VA, 22314, USA

    Lesa L Aylward

  2. Département de Mathématiques et de Statistique and Centre de Recherches Mathématiques, Université de Montréal, C.P. 6128, Succ. Centre-ville, Montreal, QC, Canada, H3C 3J7

    Robert C Brunet

  3. Département de Santé Environnementale et Santé au Travail, Faculté de Médecine, Université de Montréal, C.P. 6128, Succ. Centre-ville, Montréal, QC, Canada, H3C 3J7

    Gaétan Carrier

  4. Intertox, 2505 2nd Avenue, Suite 415, Seattle, WA, 98121, USA

    Sean M Hays

  5. Exponent, Inc., 4940 Pearl East Circle, Suite 300, Boulder, CO, 80301, USA

    Colleen A Cushing

  6. Organic Analytical Toxicology Branch, Division of Laboratory Sciences, Centers for Disease Control and Prevention, 4770 Buford Hwy, NE, Atlanta, GA 30341-3724, USA

    Larry L Needham & Donald G Patterson Jr

  7. Department of Laboratory Medicine, School of Medicine, University Milano – Bicocca, Desio Hospital, Desio, Milan, Italy

    Pier Mario Gerthoux & Paolo Mocarelli

  8. Department of Clinical Pathology, San Leopoldo Mandic Hospital, Merate, Lecco, Italy

    Paolo Brambilla

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  1. Lesa L Aylward
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Correspondence to Lesa L Aylward.

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Aylward, L., Brunet, R., Carrier, G. et al. Concentration-dependent TCDD elimination kinetics in humans: toxicokinetic modeling for moderately to highly exposed adults from Seveso, Italy, and Vienna, Austria, and impact on dose estimates for the NIOSH cohort. J Expo Sci Environ Epidemiol 15, 51–65 (2005). https://doi.org/10.1038/sj.jea.7500370

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