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DEVELOPMENT OF A REFINED DATABASE OF RELATIVE POTENCY ESTIMATES TO FACILITATE BETTER CHARACTERIZATION OF VARIABILITY AND UNCERTAINTY IN THE CURRENT MAMMALIAN TEFS FOR PCDDS, PCDFS, AND DIOXIN-LIKE PCBS
Citation:
Haws, L., M. Harris, S. Su, L S. Birnbaum, M. DeViot, W. H. Farland, N. Walker, K. Connor, A. Santamaria, AND B. Finley. DEVELOPMENT OF A REFINED DATABASE OF RELATIVE POTENCY ESTIMATES TO FACILITATE BETTER CHARACTERIZATION OF VARIABILITY AND UNCERTAINTY IN THE CURRENT MAMMALIAN TEFS FOR PCDDS, PCDFS, AND DIOXIN-LIKE PCBS. Presented at Dioxin 2004, Berlin, Germany, Sept. 3-11, 2004.
Description:
The toxic equivalency factor (TEF) approach has been widely accepted as the most feasible and plausible method presently available for evaluating potential health risks associated with exposure to mixtures of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin-like polychlorinated biphenyls (PCBs)1,2,3,4,5,6. In accordance with this approach, the relative potency of each congener is expressed as some fraction of the potency of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The current TEFs for PCDDs, PCDFs, and dioxin-like PCBs were established by the World Health Organization (WHO) following the meeting of an international expert panel in June of 19972. In the course of their review, the WHO expert panel examined data from an extensive body of in vivo and in vitro studies that had been compiled into a database of relative potency (REP) values by scientists at the Karolinska Institute in Stockholm, Sweden (hereafter referred to as the Karolinska database). As the database was intended to be all-inclusive, data were taken from published manuscripts, manuscripts in press, conference proceedings, theses, dissertations, and unpublished studies. Studies were determined to be suitable for inclusion in the database when the following criteria were met: 1) at least one test congener (PCDD, PCDF, or PCB) and a reference compound (tetrachlorodibenzo-p-dioxin [TCDD] or PCB126) were included in the study or the reference compound (TCDD or PCB126) was from an identical experiment by the same authors; and 2) the relevant endpoint used as the basis for the REP was affected by the test congener, as well as by the reference compound. An effort was also made to include information in the Karolinska database regarding a number of specific study elements. Consensus-based TEF values were established by the WHO expert panel based on scientific judgment, after consideration of the mammalian data in the Karolinska database and previously published TEFs2. Specifically, as mammalian TEFs had been previously established for PCDD/Fs 5,7 and dioxin-like PCBs8, it was decided by the WHO expert panel that the existing TEFs would remain unchanged unless there was sufficient information to warrant modification2. The final TEFs recommended by the WHO expert panel represent order-of-magnitude estimates of potency of each congener relative to the most potent member of this class of compounds, TCDD.
The WHO TEFs are currently used by numerous governmental agencies and others to regulate or otherwise assess health risks associated with exposure to PCDD/Fs and dioxin-like PCBs in foods, consumer products, and environmental media. As has been noted by others, for any given congener, the underlying REP values typically represent a heterogeneous data set, and the range of REPs often spans several orders of magnitude2,9,10,11,12. It would therefore be helpful to better understand the degree to which the TEF values contribute to variability and uncertainty in the risk assessment process. As such, the goal of this project was to develop a database that will better characterize the range of REPs, allow for the development and application of quantitative weighting schemes, and facilitate quantitative analyses. This in turn will allow for better characterization of variability and uncertainty inherent in the mammalian TEFs. The development of this database was necessary since the Karolinska database was not intentionally designed or annotated in such a way as to allow for characterization of the variability and uncertainty associated with the current consensus-based TEFs. The analysis reported herein describes our efforts with regard to the development of a refined REP database. We also provide recommendations regarding possible next steps for developing and interpreting a refined REP database for risk assessment purposes.