Document pmm7xzazer21E2J806J6ybr77

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 wlPTorhhwoeitcedchcaottrsihcoeeinnceaoAxnggcceeeensnrsrcriylisiskfk(e1ata9isms9sse9eess)stsmrumemecenoonmtrt.gimnuUceidinndedleelinstnhsceeesstuipispsreu1o0lpoa%otfesa,deddboeebtnnhyocehttrehmwdeaibsUreyk,.SBtd.hMoEesDneBviM(oiBr.DoMnAimDsv)etanhalteupapedlrooosfaec1ha0t%for was selected as this is about the lowest incidence that can be estimated with adequate vlpiamrreiicatitsiiisooncnaolfcrfuotmlhaettebydipofiacosarsltahcyhe. rboTennhiccehBbmiMoaarDsksLadiyoossiseint(hBreoMndeDunsLtesid.o)aFstuoartaphcoecrion,utan-oltoff-wodreeprtha9er5t%euxrpeceofronirmfildeonewntacdleose llcdoeaovwnseceldesrroaissrneigcsckeoa,nanasscisdmeeresarsrremigdsike.nneoOts.fttihemWxearphwtoeiosinsunera.,enlIibonneneetalwiitrnheeeeeaxrnrtrctdaahopseesoBe,latMrtheieoDspnBLoMfinroosDaemnLcdtiuohraevsneeBtriiMcvsiepeDsaxLatpesiedotchthtoeeudmzpeoianrinontthei-sxeopufl-ooseswdurfeor departure. Bioassay Data The data used for calculation o f the BMDLio were collected in the 104-Week Dietary Carcinogenicity Study with Narrow Range (98.1%) N-Ethyl Perfluorooctanesulfonamido Ethanol in Rats. The BMDL is calculated for thyroid follicar cell adenomas and 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 1 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 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 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 fed N-EtFOSE. Group >/ 1 2 3 4 8 9 Dose (ppm) 0 3 30 100 0 1 Serum PFOS at 14 weeks (ug/ml) 0.078 6.14 59.1 192 0.039 2.19 Number of rats with thyroid tumors" 0 3 2 6 1 2 Effective number of rats at risk 34 35 36 37 34 37 a Thyroid follicular cell adenomas except one carcinoma in Group 3. 2 The number o f female rats with hepatocellular adenomas or carcinomas combined, aerffeeschtiovwennuinmTbaerbloef2a.nimals at risk, and the average serum levels of PFOS at 14 weeks 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 tumors* Effective number of rats at risk 10 23 3 30 4 ' 100 80 91 0.196 12.2 104 268 0.126 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 of animals at risk were entered into the U.S. Environmental Protection Agency benchmark dose software program (BMDS). Estimates of the benchmark dose were obtained using the multistage model P = 1 - exp[-( qo+qid + qjd2+ 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 tfhiteomf tuhlteismtaogdeeml. oSdmela. llTph-evaglouoedsnweossu-lodf-ifnidt ipc-avtaeluaesst,aBtiMstiDcaioll,yasnidgnBiMficDanLtiodienvitaenrmcesforofm dietary concentration o f N-EtFOSE and 14-week serum levels o f PFOS for males and females are displayed in Table 3. 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 Dietarv Concentration Male 0.23 89 ppm 40 ppm Female 0.99 58 ppm 32 ppm 14-Week Serum Level Male 0.23 171 ug/ml 77 ug/ml Female 0.98 * 166 ug/ml 91 ug/ml References Bmaoirletarl,itAy.Jo.natnedstPsofrotriecra,rCci.nJ.oEgeffneicctistyoifntrsemaatmll esnatm-inpdleusc. 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. ' 4 BenchPmerafrlukoDroooscestafnoer SLuivlfeornTicuAmcoidrsPiontaSspsriuagmueSaDlatw(PleFyORSa)ts fed David W. Gaylor, Ph.D. Sciences International, Inc. January 24, 2002 Introduction wPlTorhhwoeitcedchcaottrsihcoeeinnceaoAxnggcceeeensnrsrcriylisiskfk(e1ata9isms9sse9ees)sstsmrumemecenoontmrt.gimnuUceidinndedleleintsnhsceeesstuipispsreu1o0lpoa%oftesa,deddboeebtnnhyocehttrehmwdeaibsUreyk,.SBtd.hMoEesDenBviM(oiBr.DoMnADmisv)etanhaltepuapedlrooosfaec1ha0t%for was selected as this is about the lowest incidence that can be estimated with adequate vpliarmreiicatitsiiisooncnaoflcrfuotmlhaettebydipofiacosarsltahcyhe.rboTennhiccehbBmiMoaarDsksLadiyoossiseint(hBreoMndeDunsLtesid.o)aFtsuoartaphceocrion,utan-oltoff-wodreerptha9er5t%euxrpeceofronirmfildeonewntacdleose llcdoeaovwnseceldesrroaissrneigcsckeoa,nanasscismdeeresarsrremigdsike.nneoOts.fttihemWxearphwtoeiosinsunear.,enlIibonneneetalwiirtnheeeeeaxrnrtrctdaahopseesoBe,latMrtheieoDspnBLoMfinrosoDaemnLcdtuihoraevsneeBtriiMcvsiepeDsaxLatpesiedotchthtoeeudmzpeoianrinontthei-sxeopufl-ooseswdurfeor departure. Bioassay Data The data used for calculation o f the BMDLio were collected in the 104-Week Dietary Chronic Toxicity and Carcinogenicity Study with Perfluorooctane Sulfonic Acid Potassium Salt (PFOS; T-6295) in Rats. The BMDL is calculated for hepatocellular adenomas and carcinomas combined for males and females. All tumors were adenomas except for one carcinoma in the high dose 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 hepatocellular adenoma/carcinoma 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 o f (t/T)3, where t is the week that an animal was removed from the study without a hepatocellular adenoma/carcinoma and terminal sacrifices began at 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 1 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 of animals with hepatocellular adenoma/carcinoma, effective number of 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 SD rats fed PFOS. Dose 14-wk Serum Number of animals (ppm) (ug/ml) with liver tumors1 Effective number o f animals 0 0.05 0.5 4.04 2.0 17.1 5.0 43.9 20.0 148 0 2.67 0.5 6.96 2.0 27.3 5.0 64.4 20.0 223 Males 0 3 3 1 7 Females 0 1 1 1 6 33 32 37 38 38 39 35 29 37 41 1Hepatocellular adenomas except one hepatocellular carcinoma in the high dose females. As noted before, the effective numbers o f 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 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 of the benchmark dose were obtained using the multistage model P = 1 - exp[-( q0+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 tfhiteomf tuhlteismtaogdeeml. oSdmela. llTph-evaglouoedsnweossu-lodf-ifnidt ipc-avtaeluaesst,aBtiMstiDcaioll,yasnidgnBiMficDanLtiodienvitaenrmcesforofm dietary concentration and 14-week serum levels o f PFOS for males and females are displayed in Table 2. Table 2. obtained uGsionogdntheessU-oSf-EfiPt pA-vbaelnucehsmfoarrkthdeomseuslotifsttwagaerempordogelr,aBmM(BDMio,DaSn)d. BMDLio values Sex p-value BMDio BMDLio Male Female Male Female Dietarv Concentration 0.24 18.2 ppm 0.54 16.7 ppm 14-Week Serum Level 0.23 135 ug/ml 0.54 193 ug/ml 7.9 ppm 8.0 ppm 62 ug/ml 92 ug/ml 3 References mBaoirletarl,itAy.Jo.natnedstPsofrotriecra,rCci.Jn.oEgeffneicctitsyoifntrsemaatmll esnatm-ipnldeus.ceBdimomorettarliictsy and tumor-induced 44:417-431 (1988). U.S. Environmental Protection Agency. Guidelinesfor Carcinogen Risk Assessment. NCEA-F-0644, Risk Assessment Forum, U.S. Environmental Protection Agency, Washington, DC. July, 1999. 4