The Application of Internal Dose Measures, Biokinetics, and Biomonitoring Data in the Risk Assessment of Dioxin-Like Compounds

This thesis presents a series of investigations into the biokinetic behavior of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds and the application of biokinetic modeling and biomonitoring data in quantitative risk assessment for these compounds. The biokinetic properties of TCDD and related compounds affect nearly every facet of the typical risk assessment procedure as applied to these compounds. Qualitative and quantitative differences in the distribution and elimination of TCDD exist between high and low doses, between species, and even between bolus vs. subchronic dosing administration regimens; similarly, differences exist between TCDD and other dioxin, furan, and PCB compounds of interest. These factors should be considered in risk assessments for dioxins. Because of these complexities, preference should be given to studies most easily interpretable in the context of current human exposure tracking and assessment, which is dominated by the use of biomonitoring efforts. Where possible, use of human studies that rely upon biomonitoring data for exposure quantification concurrent with the measurement of outcome of interest may provide the most reliable basis for risk assessment. Where such data are judged to be unavailable or insufficient, animal studies conducted under chronic or subchronic dosing regimens with measured tissue concentrations may provide the most relevant dose-response data. The substantial uncertainties and interindividual variability in human biokinetics suggests that exposure-response assessments relying on extensive back-calculation of serum TCDD levels should be used only with a great deal of caution, perhaps as supportive analyses rather than the main basis for quantitative risk assessment. Research presented here uses newly-available data sets on elimination of TCDD in highly-exposed human populations to modify and implement a previously-developed model of distribution and elimination for TCDD and to examine the sources of variability and uncertainty involved in the application of such modeling to human occupational cohorts. This research demonstrates that the resulting uncertainty and variations in estimated cumulative exposures may substantially impact a quantitative risk assessment derived based on such estimated exposures. Other research presented in this dissertation demonstrates a variety of approaches for using human biomonitoring and response data in risk assessment for cancer and non-cancer endpoints. Finally, remaining issues related to the role of biokinetics in interspecies extrapolation and risk assessment for dioxins and related compounds are identified. These include the need for assessment of relative potencies on a tissue concentration (rather than intake) basis and the need for further understanding of the role of lactational transfer and interspecies correspondence in critical developmental windows in the occurrence of developmental effects of dioxin-like compounds