Document omj8kx5opbqEdddVgKyqK249D

M z i G - I D S 0! Benchmark Doses for Tumors in Sprague Dawley Rats fed N-Ethyl Perfluorooctanesulfonamido Ethanol (N-EtFOSE) David W. Gaylor, Ph.D. Sciences International, Inc. January 31, 2002 Introduction PTrhoeteccatricoinnoAggeennrciysk(1a9s9se9s)smreecnomt gmueidnedlitnheesupsreopoofsaedbebnychthmeaUrk.Sd.oEsnev(iBroMnmD)enatpaplroach for low dose cancer risk assessment. Unless stipulated otherwise, which the excess lifetime tumor incidence is 10%, denoted by BthMe DBiMo.DAisvtahleuedoosfe1a0t% was selected as this is precision from typical about the lowest incidence that can be chronic bioassays in rodents. Further, eastliomwaetred95w%ithcoandfeiqduenatcee limit is calculated for the variation of the bioassay. bTenhcehBmMarDkLdioosise (BMDLio) to account for the experimental then used as a point-of-departure for low dose cancer risk assessment. When a nonlinear dose response curve is expected in the low dose range, a margin levels is considered. low dose cancer risk eoOsfttihemxearpwtoiosisuner.,elIibnneeteawirtheeeexrntrctaahpseeoB,latMhtieoDnBLMfirooDamnLdtihoaesneBtriMcviepDsaLatesidoththoeumzpeoarinontei-sxopuf-osesdurfeor departure. Bioassay Data The data used for calculation o f the BMDLio were collected in the 104-Week Dietary Carcinogenicity Ethanol in Rats. STtuhdeyBwMitDhLNiasrrcoawlcuRlaatnegdef(o9r8t.h1y%ro)iNd -fEoltlhicyalrPceerlflluaodreonoocmtaanseasunldfonamido carcinomas combined in males and for hepatocellular adenomas and carcinomas combined for females. All tumors were adenomas except for one carcinoma in the 30 mg/kg group in males and one carcinoma in the 100 mg/kg females. In order to calculate lifetime incidence rates for each dose group, it is necessary to calculate the number o f animals at risk. Clearly, animals that were removed from the study for interim sacrifices or that died before the terminal sacrifice were not at risk for a lifetime. The Poly-3 approach developed by the National Toxicology Program (Bailer and Portier, 1988) is used here to calculate the effective number o f animals at risk. Obviously, an animal that survives for the lifetime o f the study until the terminal sacrifice counts as a whole lifetime exposure. Also, any animal that is removed from the study with a tumor o f interest (thyroid follicular cell in males or hepatocellular in females) prior to the terminal sacrifice lived long enough to develop the tumor is counted as a lifetime exposure. All other animals are given a weight of (t/T)3, where t is the week that an animal was removed from the study without the tumor of interest and terminal sacrifices began at 000317 i week T=105. 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 at 53 weeks receive a weight o f (53/105)3 = 0.13 o f a lifetime, whereas an animal that died on week 96 receives a weight o f (963/105) = 0.76 o f a lifetime. The weights are summed for each dose group to obtain the effective number o f animals at risk for each group. The number o f male rats with thyroid follicular cell adenomas or carcinomas combined, effective number o f animals at risk, and average serum levels o f PFOS at 14 weeks for each dose group are displayed in Table 1. Table 1. Results from the 104-week carcinogenicity study in male SD rats fedN-EtFOSE. Group Dose (ppm) Serum PFOS at 14 weeks (ug/ml) Number of rats with thyroid tumors8 Effective number of rats at risk 1 0 0.078 2 3 6.14 3 30 59.1 4 100 192 8 0 0.039 9 1 2.19 0 3 2 6 1 2 34 35 36 37 34 37 *Thyroid follicular cell adenomas except one carcinoma in Group 3. 000318 2 The number o f female rats with hepatocellular adenomas or carcinomas combined, effective number of animals at risk, and the average serum levels o f PFOS at 14 weeks are shown in Table 2. Table 2. Results from the 104-week carcinogenicity study in female SD rats fed N-EtFOSE. Group Dose (ppm) Serum PFOS at 14 weeks (ug/ml) Number of rats with liver tumorsa Effective number of rats at risk 1 0 0.196 2 3 12.2 3 30 104 4 100 268 8 0 0.126 9 1 3.26 0 1 3 7 2 1 32 32 33 38 33 36 *Hepatocellular adenomas except one carcinoma in Group 4. Benchmark Dose Calculations The numbers o f animals with hepatocellular adenoma/carcinoma and the effective number o f animals at risk were entered into the U.S. Environmental Protection Agency benchmark dose software program (BMDS). Estimates ofthe benchmark dose were obtained using the multistage model P = 1 - exp[-( qo+qid + q2d2+ q3d3 +q4d4)] where P represents the proportion o f animals with tumors, d is the dietary dose or serum level, and the q's are estimated from the experimental dose response data. Goodness-of-fit p-values for the multistage model are above 0.1 indicating an adequate fit of the model. Small p-values would indicate a statistically significant deviance from the multistage model. The goodness-of-fit p-values, BMDio, and BMDLio in terms o f dietary concentration o f N-EtFOSE and 14-week serum levels o f PFOS for males and females are displayed in Table 3. ,,^ 000319 3 Table 3. Goodness-of-fit p-values for the multistage model, BMDio, and BMDLio values obtained using the US EPA benchmark dose software program (BMDS). Sex p-value BMDio BMDLio Male Female Male Female Dietarv Concentration 0.23 89 ppm 0.99 58 ppm 14-Week Serum Level 0.23 171 ug/ml 0.98 166 ug/ml 40 ppm 32 ppm 77 ug/ml 91 ug/ml References Bailer, A. mortality Jo.natnedstPsofrotriecra,rCci.Jn.oEgeffneicctistyoifntrsemaatmll esnatm-ipnldeusc. eBd imomorettarliictys and tumor-induced 44:417-431 (1988). U.S. Environmental Protection Agency. Guidelinesfo r Carcinogen Risk Assessment NCEA-F-0644, Risk Assessment Forum, U.S. Environmental Protection Agency, Washington, DC. July, 1999. 000320 4