Document O1kD9EZBekONEpxMB91d5pqRe

Hollyhouse Inc. PO Box 474 1771 Sandy Point Rd. `Wicomico Church VA 22579 February 10,2005 U.S. Environmental Protection Agency Science Advisory Board (1400F) Attention: Dr. Sue Shallal, Designated Federal Officer 1200 Pennsylvania Avenue, N.W. Washington, D.C. 20460 Re: OPPT Docket 2002-0001 Re: PointsofDeparturefor PFOARiskAssessment Dear Dr. Shallal: `The EPA SAB PFOA Review Panel has been charged to comment on the scientific soundnessof OPPT's "Draft Risk Assessmentofthe Potential Human Health Effects Associated with Exposure to Perluorooctanoic Acid (PFOA) and Its Salts" (January 4, 2005). These comments willfocuson one issue theReviewPanel is to address: Issue 3: SelectionofEndpoints. Ihave reviewed the PFOAdata in the course of my workasanindependentadviser to 3M and as co-author ofa published risk assessment, Butenhoff, ef a., "Characterization ofRisk for General Population Exposure to Perfluorooctanoate," Regulatory Toxicology aadnddrPeshsaerdmaincothleogtoyx3i9c:ol3o6g3y-d3a8t0ab(a20s0e4aan).d"prTohviidsepsubbleinccahtimoanrkredvoiseewscaplecrutlianteinotnesnfdpooirants. `numberofendpoints. A copy is enclosed for the Panel's reference. ! My career has been as a toxicologist with experience and expertise in developmental and reproductive toxicology and in risk assessment. I previously served as Assistant ADdempiuntiystDriarteocrtoorfoEfPtAhefNoartTiooxnailcsToaxnidPceosltoigcyidPersog(r19a8m3-a1n9d8D9i)r,eactnodproriforTtoxoitchoaltowgays Research & Testing, NIEHS, NIH. `Telephone 804.580.8629 Hollyhouse@ att.net Fax 604.580.2286 1 TashseesEsPmAendtrapfrtesaesnstessmsamrengtineovaflueaxtpeossbuortehcaplrceunlaattailonasndfoardaulntulmifbeesrtoagfeesn.dpTohientdsr,afutsing primate studies, adult rat studies, and developmental studies. My comments are limited to three particular endpoints. 1 urge reconsiderationofthe proposed endpoint selected to rdierpercetsednotsipnregnraattahleerftfheacntsabdeecvaeulsoeptmheenetnadlpeofifnetcts.elSeecctoendda,ppIseuarbsmittotrheaftlectthetovxailcuietysfelreocmted for the assessmentofadult female body weight is inappropriate. Finally, adult male body weight and other endpoints would bebetteraddressed usinag benchmark dose approach rather than no-effect levels. In my view, the reduced body-weight gain seen in male pups dosed from `weaningtosexual maturation is most plausibly due to a direct effectof the PFOA rather than resulting from gestational exposure. Data from several sub-chronic studies in male rats at approximately the samedose support this interpretation, as effects on body weight and weight gain were observed within the first several weeksofdosing. `The two-generation rat reproduction and developmental study on PFOA (York 2002; Butenhofeft al. 2004b) provides a numberof endpoints suitable for use in risk a`gsasiensmsemaesntu.reFdoarftperrensaetvaelraelxpwoeseukrseo,fEdPiArecretldieossionngtchhaatnogcecsuirnreFd mbaeltewereatnbwoedayniwnegigahntdsexual maturity. In the two-generation study, the Fi generation pups received PFOA exposureviathe dwaermesgdiuvreinngdagielsytaotriaolndaonsdeslaocftaPtFioOn;Athhoawtecovnetrian,tuewdeantihnrgo,ugthhemaFtyingge.nerAalttihoonumgahlEePrAa'tss assessment (p. 10) acknowledges that it is not known whether post-weaning effects are due to prenatal, lactational, and/or post-weaning exposures, for the prenatal life-stage marginofexposure, EPA hasuseddecreased body-weight gain in Fy male rats that was first observedduringthe second weekofdirect dosing at the 10mg/kg/day dose. This effect occurred prior to sexual maturation and was considered to represent a developmental effect by EPA definition. `The NOAEL for reduced body-weight and body-weight changepriorto sexual maturation was 3 mg/kg/day for male pups. EPA's assessment presumes that this effect `on male pup body-weight gain could have been the result ofprenatal exposure. `Therefore, EPA calculates the prenatal life-stage marginofexposure using estimated 24hour AUC values for pregnant rat dams receiving 3 mg/kg/day. `The assumption that decreased body-weight gain prior to sexual maturation in the postweaning males being directly dosed with ammonium PFOA is adevelopmental effect runs counter to evidence from several subchronic studies demonstrating that adult males show body weight effects within the first few weeks ofdosing at approximately the same mg/kg/day dose as that given to the post-weaning pups in the two-generation study (Metrick et al. 1977; Goldenthal et al. 1978; Palazzolo 1993). 2  I10n0a, 1330-0,weacnkdd1ie0t0a0ryusgtaudmymoinnmiaulme PanFdOAf/emgalfeeerdat(sNw=i5t/hgrdoiuctpa)ry(dGoosldeesnotfhal10e,f3a0l,. 1978), weight-gain effects were seenwithinthree weeks at the 100 ppm dietary dose thatwasequivaletnto 7 mg/kg/day. Idnoases13o-fw1e,e1k0,di3e0t,arayndstu1d0y0 buyg HaamzmloetnoinuWmisPcFoOnsAi/ng, fIenec.dc(oNnd=u5c5t/egdraotudpi)etary (rPoaulgahzlzyol8o;mgP/ekrgk/indsayefparlo.,du2c0e0d4a)a,stadtiiesttaircyaldlyosseiognfif1i0c0antugd/egcrfeeaesdeeiqnuimveaalennbtotdoy weight and body-weight gain compared to controls beginning in the second weekofdosing. Aovefroutrh-ewfeoeukr-diweeteakrypesrtiuoddya(tMaetdriiectkareyfdaol.se19l7e7ve)lnofo10a0tdiegceraemadsmeoniin uwemigPhFtOAg/agi,n feed approximating 10 mg/kg/day. Btweon-cghemnearraktidoonsestcuadlycualnadtfioonrsmfaolrebsodiynt-hweeiGgohltdegnatihnfaolerbtoalt.h(F1o97a8n)daFnydmPaalleaszzforloom(t1h9e93) studies fallin arange between 1.5 and 5.2 mg/kg/dayatthe lower 95% confidence limit based on a 10% change in the distribution (see Table 2 below). Considering the data pbroodvyidweedigbhyt-tghaeisne etfhfreecetsstiunditehse,FtIhegweeneirgahttioofnmtaheleervaitdsenicsemsousptpolritkeslay caornecsluultsiooftnhtehdaitrtehcet dosing and not an effect resulting from gestational exposure. EPA'sdraftcorrectlynotesthereare a numberofendpoints from the two generation study that dobear directly on development which should beusedto represenat d`meovretalloiptmy,eanntadldetloxaiycsitiynesnedxpuoailntm.atTuhraetsieoni.nclBuednebcihrmtahrwkeidgohste,s wfoerigvhatrigoauisndienvelalcotpamtieonnt,al endpoints are calculated in the published risk assessment (ButenhofeTf al. 2004a). A ``occocmupraartisaolnoowfebrednocshemtahrakn vdaolaudevsefrrsoemdreavtesltoupdmieenstianldiecfafteectsst.hat adult body weight effects In sum, the available data provide a sound basis for selecting a developmental toxicity endpoint, separate from body weight-gain effects that are best interpreatsead consequenceofdirect dosing. The two endpoints should not be confused. In addition, I note that gestational and lactational data submitted to EPA after thecut-offdate for the risk assessment will allow further refinementofthe risk assessment, as will developmentaldata on mice we understand to be forthcoming from EPA's laboratory. Use of female rat body-weight and body-weight gain reduction in the second yearofdietary dosing with ammonium PFOA in a cancer bioassay does not provide as compelling data for this endpoint as does female body-weight gain `and body-weight reduction data from the two-generation study. EPA's risk assessment appropriately notes (on p. 96)thatthesignificanceofbody weight for human health is not clear, but that this endpoint is conservative. As discussed above, 3 e`xmpaelreireatnscecbleoadrlyyweexipgehriteenffceecbtso,dbyutwtehieghsteeeffffeeccttss.ocFceumraalte rhatisgheexrpdoosseedst.o PFOA also oFforretdhueceaddublotdfye-mwaelieglhitfeg-satiangaenmdabrogidnyofweexipgohstuirnea,tEwoP-Ayecahrodsieettaoruysceanacnearpbpiaoraenstsaeyftfhecatt in1c01l.u6daenddon1l6ymtgw/okgd/odsaeygr(oSiubpisn,s3ki0a1n98d7)3.00TuhgedaecmrmeoanseiduwmePiFghOtA/inffeeemda,lewsihincthheetquwaot-ed y`emaarrgciannocfeerxsptousduyraet.thAelttohpoduogshetihesraenisunacterretnadinivnadleucereoansewdhibcohdtyowbeaisgehtanaemsotnigmafteemoafles i`nwatshere1d6umcge/dkagt/adsatyadtiosstiecaglrloyuspigbneigfiicnannitnlgeavfetle(0a.b05o)uotnwleyeakt w8e0oekfsth9e2satnuddy9,4boofdtyhweei1g04ht rweepeorkt)s.tuIdnya(dsdeietifoenm,aolbeesbiotdyy-isweaicghhatradcatetraifstoiucnodfaognipnaggeisn8t4h7eaSnprdag8u4e8o-fDtawhleeystsutdryain of rEaPt Aanadsoaftbeansicslfoourdstheeffaedcutlstofnembaoldeylwfeei-gshtta.geTmhaerrgefionoref,etxhpeobsoudrye-wareeignhott cdaotmapeulsleidnbgyor relevant for risk assessment. Two studies with sub-chronic dosing periods (Goldenthal et al, 1978; ButenhoeffT al. 2004b) provide better insight into adult female rat weight effects. Indtoshees uGpoltdoen1t0h0a0luegfaal.mm(1o9n7i8u)smtuPdFyO,An/ogefefedf(o8ne0bmcogd/tykg/wdeaiyg)h.t Iwtaiss noobtseedrvtehdatat there were a small number offemale rats (5) per dose group. In the two-generation rat study (ButenhofefT al. 2004b), there was no effect on female body weightinthe Fo generation at thehighestdoseof 30 mg/kg/day. There was a mild but statistically significant effect on body weight or body``wbeoidgyhwtegiagihntienfffeecmtasliens aadtu3lt0 fmegm/aklge/draatys winatshe10F)mgg/eknegr/adtaiyo.n." The NOEL for `Consideritnheg weightofthe evidence,includingthe natureofthe findings in the Sibinski (1987) study and the findings in other studies, useof1.6 mg/kg/day from the >The terminal body weights in adult females (Butenhofeft al. 2004b, Table7)were: Table 1 Terminal Body Weights in Adult Femalesin Two-Generation Stud, mykeg/day [control(m8) [I eo Females Fo Generation (5)|Adult Females Fy Generation (g) [34520 [mez | Tse mead | 4 Sibinski study as the NOEL for body-weight effects in adult female rats does not fairly represent the available database. I recommend the SAB ask EPA to re-evaluate the adult female body weight effect. The NOEL of 10 mg/kg/day from the F, females would provide amore rational basisforthe adult female life-stage marofegxpoisurne. Indeed, iffabenchmarkdoseapproachwereusedinaccordancewith EPAguidance,Iexpectit `would provide an even higher value than the 10 mg/kg/day NOEL from the two`generation study. A benchmarkdose would better represent the data on body weight effects in adult male rats and other endpoints. EPA uses a LOEL of1 mg/kg/day for F1 males from the two-generation study as its point ofdeparture for body weight effects in adult males. This isan appropriate endpoint to review,but abenchmadorske approach wouldbetterreflect the dose-response relationship thandoesthe LOEL. Using the EPA software program, BMDLio values for adult male rat bodyweight are: Table 2. Benchmarkdose estimates faoornestandarddeviationchange (~10%)at the lower 95% confidence limit (BMDL1o) for decreased body-weight gain in male rats. [en Tome Gwin BMlowae [Mod [poe | [Palszzolo |Diewry -- [Towks [30 [Power | 046 | `The SAB may wish to suggest EPA provide a benchmark dose calculation for the adult `male body weight calculation, andfor otherendpoints. Variousbenchmarkdose calculations may be found in Butenhofef al. (2004a). Thank youfortheopportunitoy provide these written comments. I look forwtaoradn `opportunity to respond to any questions the panel members may have. Sincerely yours, ---- Jgf A. Moore, D.V.M., DABT ce: Dr. Seed s References Butenhoff, J, et al., "CharacterizationofRisk for General Population Exposure to Perfluorooctanoate," Reg Tox d Pharm 39: 363-380 (2004a) Butenhoff, J. et al., "The Reproductive Toxicology ofAmmonium Perfluoroocianoate (APFO) in the Rat." Toxicology 196:95-116 (2004b). Goldenthal, E.L. 1978. Final Report, Ninety-Day Subacute Rat Toxicity Study on F1l3u7-o0r8a9d,"3FlMuoRreofcehreemnicceaNloF.CT--134134.1,InNtoervneamtiboenral6R,e1s9e7a8r.chUaSndECPoArpAoRr2at2i6o-n0,4S4t1u.dy No. Metrick, M.,et a. 1977. Final Report, 28-Day Oral Toxicity Study with FC-143 in Albino Rats, Industrial Bio-Test Laboratories, Inc., IBT No. 8532-10654, September 29, 1977. US EPA AR226-0445. Palazzolo, M.J. 1993. Thirteen-Week Dietary Study with T-5180, ammonium periluorooctanoate (CAS No. 3825-26-1)inmale rats. Final Report. Laboratory Project Identification HWI 6329-100. Hazleton Wisconsin, Inc. US EPA AR-226-0449. Perkins, R.J., ct al., "13-Week Dietary Toxicity Study ofAmmonium Perfluorooctanoate (APFO) in Male Rats," Drug Chem Toxicol. 26 (4): 361-78 (2004). Sibinski, LJ. 1987. Final Report. Two-Yearoral (diet) Toxicity and Carcinogenicity Studyof Fluroochmical FC-143 (perfluorooctane ammonium carboxylate) in rats. Vol. 1-4, 3M Company/Riker Experiment No. 0281CR0012; 8EHQ-1087-0394, October 16, 1987. York, R.G. 2002. Oral (gavage) Two-Generation (one litter per generation) Reproduction Study ofAmmonium Perfluorooctancate (APFO) in rats. Argus Research Laboratories, Inc. Protocol No. 418-020, Sponsor Study No. T-6889.6. March 26, 2002. US EPA AR226-1092. 6