Document ba2G3eDEVwmJwjJ25g3xXk0vZ

,, Benchmark Doses for Liver Tumors in Sprague Dawley Rats fed ' Perfluorooctane Sulfonic Acid Potassium Salt (PFOS) Introduction David W. Gaylor, Ph.D. Sciences International,Inc. Sanuary 24, 2002 The carcinogen risk assessment guidelines proposed by the U.S. Environmental Protection Agency (1999) recommend the use of a benchmark dose (BMD) approachfor low dose cancerrisk assessment. Unless stipulated otherwise, the BMD is the dose at which the excess lifetime tumor incidence is 10%, denoted by BMD1o. A value of 10% was selected as this is about the lowest incidence thatcan be estimated with adequate precision from typical chronic bioassays in rodents. Further,a lower 95% confidence limit is calculated for the benchmark dose (BMDLI0) to account forthe experimental variation of the bioassay. The BMDLI0is then used as a point-of-departurefor low dose cancer risk assessment. When a nonlinear dose response curve is expected in the low dose range, a marginof exposure between the BMDLI0and anticipated human exposure levels is considered. Otherwise, linear extrapolation from the BMDLm to zero is used for low dbse cancer risk esti_'mationI.n either case, the BMDLIoserves as the po_,.-ofdeparture. / ' .... Bioassay Data The data used for calculation of the BMDLIo were collected in the 104-Week Dietary Chronic Toxicity and Carcinogenicity Study with PerfluorooctaneSulfonic Acid Potassium Salt (PFOS; T-6295) in Rats. The BMDL is calculated for hepatoceliular adenomas and carcinomas combined for nudes and females. All tumors were adenomas except for one carcinoma in the high dose females. In order to calculate life,me incidence rates for each dose group, it is necessary to calculatethe number of animals at risk. Clearly, animals thatwere removed from the study for interim sacrifices or thatdied before the terminal sacrifice were not at risk for a lifetime. The Poly-3 approachdeveloped by the National Toxicology Program (Bailer and Pottier, 1988) is used here to calculate the effective number of animals at risk. Obviously, an animal thatsurvives for the lifetime of the study until the terminal sacrifice counts as a whole lifetime exposure. Also, any animalthat is removed from the study with a hepatocellular adenomgcarcinoma prior to the terminal sacrifice lived long enough to develop the tumor is counted as a Lifetimeexposure. All other animals are given a weight of (t/T)s, where t is the week that an animal was removed from the study without a hepatoceUular adenoma/carcinoma and terminal sacrifices began at week Tffil05.. Relatively little weight is given to an animal removed early in a study. For example, the animals removed at an interim sacrifice halfway through the study 1 (_ at 53 weeks receive a weight of(53/105) 3 = 0.13 of a Lifetime,whereas an animal that died on week 96 receives a weight of(963/105) = 0.76 of a lifetime. The weights are summed for each dose group to obtainthe effective number ofardmals at risk for each group. The number of animals with hepatocellular adenoma/carcinoma, effective number of animals at risk, and average serumlevels of PFOS at 14weeks for each dose group are displayed in Table 1. Table 1. Resultsfrom the 104-week carcinogenicity study in SD rats fed PFOS. Dose (ppm) 14-wk Serum (ug/ml) Number of animals with liver tumors" Effective number of animals M_les 0 . 0.05 0 33 .t 0.5 4.04 3 32 ( 2.0 17.1 3 37 5.0 43.9 1 38 20.0 148 7 38 Females 0 2.67 0 39 0.5 6.96 1 35 2.0 27.3 1 29 5.0 64.4 1 37 20.0 223 6 41 Hepatocellularadenomas except one hepatocellular carcinoma in the high dose females. /" 2 ( As noted before, the effective numbers of animals at risk reflect the lower survival in the controls and low dose males and the females fed 2 ppm and the higher survival in the high dose females. Benchmark Dose Calculations The numbers of animalswith hepatocellular adenoma/carcinomaand the effective number of _imals at riskwere entered into theU.S. Environmental Prote_.ion Agency benchmarkdose software program(BMDS). Estimates of the benchmark dose were obtained using the multistage model P = 1 - exp[-( qo+qld + q2d2+qsd3 +q4d4)] where P representsthe proportionof animals with tumors, d is the dietary dose or serum level, and the q's are estimatedfrom the experimental dose responsedata. Goodness-of-fit p-values forthe multistage model are above 0.1 indicating an adequate fit of the model. Small p-values would indicate a statistically sisnificant deviance from the multistage model. The goodness-of-fit p-values, BMDm,and BMDLIoin terms of dietaryconcentration and M-week serum levels of PFO$ for males and females are displayed in Table 2. / Table 2. Goodness-of-fit p-values for the multistage model, BMDm, and BMDLI0 values obtained using the US EPA benchmark dose software program (BMDS). Sex p-value BMDI0 BMDLI0 Male Female Male Female DietarCyoncentration 0.24 18.2ppm 0.54 16.7ppm 4-Week SerumLevel 7.9ppm 8.0ppm 0.23 135ug/ml 62ug/ml 0.54 193ug/ml 92ug/nd ( 3 :.... References Bailer, A.J. and Portier, C3. Effects of treatment-induced mortality and tumor-induced mortality on tests for carcinogenicity in small samples. Biometrics 44:417-431 (1988). U.S. Environmental Protection Agency. Guidelines for Carcinogen Risk Assessment. NCEA-F-0644, Risk Assessment Forum, U.S. Environmental Protection Agency, Washington, DC. July, 1999. ( \ 4