Benchmark Dose Calculations for Noncancer Effects from TCDD Exposure Using Different Dose Metrics. A. H. Kim, UNC-Chapel Hill and NIEHS, P.O. Box 12233, MD D4-01, Research Triangle Park, NC, 27709; and C. J. Portier and N. J. Walker, NIEHS, P.O. Box 12233, MD D4-01, Research Triangle Park, NC 27709
The benchmark dose (BMD) approach is being evaluated as a replacement for the traditional no-observed-adverse-effect-level/lowest-observed-adverse-effect-level methodology currently used by regulatory agencies to assess noncancer risk of toxicants. Using this BMD approach, administered dose or (target) tissue concentration can be used as a dosimeter to estimate a specific effective dose level. In this analysis, the dose-response relationships were evaluated for cytochrome P450 (CYP) gene expression following chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in female Sprague-Dawley rats in a continuous dose-response study and an alternate discontinuous study in which exposure duration rather than administered dose was varied. CYP1 mRNA levels were quantitated using competitive RT-PCR, and the effective dose resulting in a 10% increase (ED10) in TCDD-induced CYP1 levels over controls was determined using U.S. EPA’s Benchmark Dose Software. In a 30-week biweekly gavage continuous study using administered dose as the dosimeter, the EDs10 in CYP1A1, CYP1A2, and CYP1B1 were 5.6, 17, and 14 ng/kg/day, respectively. The lower bounds on each ED10 (LEDs10) in CYP1A1, CYP1A2, and CYP1B1 were 4.5, 14, and 14 ng/kg/day, respectively. In a biweekly gavage discontinuous study, rats were exposed to similar average daily doses of TCDD for different periods/durations. Using this study’s "lifetime" average daily doses as administered doses, the EDs10 in CYP1A1, CYP1A2, and CYP1B1 were 71, 86, and 75 ng/kg/day, respectively, and LEDs10 for CYP1A1, CYP1A2, and CYP1B1 were 70, 72, and 74 ng/kg/day, respectively. Using tissue burden as the dose metric, the EDs10 for CYP1A1, CYP1A2, and CYP1B1 were 1.6, 5.0, and 4.7 parts per billion (ppb) in the continuous study and 13, 12, and 1.0 ppb, respectively, in the discontinuous study. The estimated LED10 in CYP1A1 was comparable between the continuous and discontinuous studies: 1.1 ppb and 1.6 ppb. Comparison of the benchmark doses on an equivalent body burden based on the ED10 and LED10 (BB10 and LBB10) revealed that selecting administered dose versus tissue concentration as the dosimeter results in 2- to 47-fold decreases in BBs10, suggesting a more conservative benchmark dose. In addition, when liver burden was used as the dose metric, the BB10 and LBB10 between the continuous and discontinuous studies were within an order of magnitude. Using the benchmark dose methodology together with tissue concentration as a dose metric, uncertainty from external to internal dose extrapolation is removed, which may improve estimation of the noncancer risks due to chronic TCDD exposure.
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