Document oModwx7zExXeqy2aQZK7DdjXR

I @BILIL V,f,P-I)d-l,4A-4-f(A@lLAYA\JI)Q @em InternalCorrespondence To: From: Subject: Date: Dr.John Butenhoff,Manager CorporatI e Toxicology Dr. Robert Roy Corporate Toxicology DraftDrinkingWater HealthAdvisory(DWHA) - PFOS July 7, 1999 John - The attacheddocument presentsthe derivationofa draftlifetimDeWHA for PFOS. The draftDWHA isbased on a referencedose (RfD)which was derived usinga conservative,composite uncertaintfyactor(UF). A very similarprocess of RfD development (e.g.selectionof appropriateUFs based on availabledata)has been used by EPA forArochlor1016; thisisalso includedforyour reference(Appendix). Ifyou have questionsor would liketodiscuss,please letme know. Rob DRAFT - LifetimeDrinking Water Health Advisory (DWHA) forPFOS Background' The DWHA forPFOS was calculatedusingstandardEPA methodology. Briefly, the followingthreeequations were used: RJD (NO,4EL) oi-(LOAEL) mglkg body weight- day (UF) DWEL r (AfD) (70 kg) MGIL or pgll 2 LI@day LifetimeD WI-I.=4D WEL x RSC = mgll or ugIL Where: RfD Chronic Reference Dose [theestimate(withuncertaintyspanning an orderof magnitude) of a dailyexposure tothe human population(including sensitivesubgroups) thatislikeltyo be withoutappreciableriskof deleterious effectsduringa lifetime] NOAEL = No Observed Adverse EffectLevel[theexposure levelatwhich thereare no statisticalolrybiologicallsyignificanitncreasesinthe frequency or severityofadverse effectsbetween the exposed populationand the appropriatecontrols;ome effectsmay be produced at thislevelbut they are not consideredto be adverse,nor to be a precursorto specificadverse effects] LOAEL = Lowest Observed Adverse EffectLevel[theexposure levelatwhich thereare statisticalolrybiologicallsyignificanitncreasesinthe frequency or severityof adverse effectsbetween the exposed populationand the appropriatecontrol] UF = TotalUncertaintyFactor(chosen using EPA guidance). The totalUF is composed offivesub-factorsthatattemptto account foruncertaintywith regardto: 1)interhumarivariabilit2y);extrapolatioonf resultsfrom I DRAFT - experimentalanimal to hui-nan;3) extrapolatiofnrom subchronicto chronic exposure;4) extrapolatiofnrom LOAEL to NOAEL; and 5) incomplete database to complete database. A modifyingfactor(MF) f-nayalsobe appliedto accountforareas of scientific uncert:aintnyot accounted forinthe fivesub-UFs. The standard EPA defaultfactorforeach ofthe fivesub-UFs = 10;thatfor the MF = 1. Sub-UFs <1 0 may also be used when existingdata reduce or eliminatethe need to account fora particulaarrea of uncertainty.TIhe choice of appropriate sub-UFs and the MF is accomplished on a case by-case basis using professionaijudgment by experienced risk assessors. DWEL = DrinkingWater EquivalentLevel [theconcentrationofa substance in drinkingwater thatisnot expected to cause any non-carcinogenichealth effectsinhumans over a lifetimoef exposure] RSC = RelativeSource Contribution[isthe proportionofexposure to a chmeical from drinkingwater relativteo othersources such as food and air](in the absence ofany otherdatathe EPA defaultvalue= 20% isused) LifetimeDrinking Water Health Advisory (DWHA) = The concentrationofa chemical indrinkingwater thatisnot expected tocause any adverse noncarcinogeniceffectsover a lifetimoef exposure,witha margin of safety. 'References Cicmanec, J.L etal.(1996).Noncancer riskassessment: presentand emerging issues.In-Fan, A.M. and Chang, L.W. (editors)Toxicologyand Risk Assessment.-PrinciplesM,ethods, and ApplicationsM.arcel Dekker, Ne*w York,pp.293-310.(copyofpaper attached) Dourson, M.L. etal.(1996).Evolutionofscience-baseduncertaintfyactorsin noncancer riskassessment. RegulatoryToxicologyand Pharmacology 24: 108-120. (copyofpapei-attached) EnvironmentalProtectionAgency (1999).IntegratedRisk Information System (IRIS).WWW address:hftp://www.epa.gov/ncea/iris.htm EnvironmentalProtectioAigiency (1999).Officeof Water. DrinkingWater Regulationsand HealthAdvisories.WWW address: http://www.epa.gov/OSTqools/dwstdsO.htmi 2 DRAFT 1. Lifetime Drinking Water Health Advisory (DWHA) for PFOS Step 1. RfD Calculation R)D (NOAEL) or (LO.-IEL) mglkg body weight -day (UF) NOAEL 0.15 mg/kg-day [NOAEL from 6-month monkey oralcapsule study] UF=900 (rounded up= 1000)[totaUlF= 900 (lOx3xlOxlx3).IndividualsubUFs were as follows[alsorefertoAppendix]: lnterhuman (person-to-person variability=)10 [standardEPA default] Extrapolationfrom experimentalanimal-to-human (interspecies variability) 3 [usednoii-humanprimate] Extrapolationto chron;c exposure (chronicity=) 10 [basedon exposure durationlongerthan slibchronibcut significantlleyssthan chronic(6 months ina non-human primate),P-FOS also appears to accumulate inthe body on repeated exposure due to poor elimination] LOAEL to NOAEL = 1 [standarddefault- NOAEL used] Incomplete database = 3 [significadnatta accumulated on chemical;results ofthe 2-year bioassay are stilplending] Modifying Factor = 1 [i@Limandata availables;ignificandtata accumulated on chemical;sensitiveend;)ol:netstablishedinstudies;uncertaintieasccounted forinothersub-factors] 3 DRAFT Therefore: 0.15mg /k,,(- clcil RfD 0.00015mglkg - day= (0.2pglkg- day) 1000 Note: The precisionassociatedwiththe RfD isusuallyone significafnitgure, thereforeR,fD should be rounded to = 0.2 @tg/kg-day ii. LifetimeDrinkingWaier HealthAdvisory (DWHA) forPFOS Step 2. DWEL Calcula'.ion DWEL (RJD)(70 kg) 1.77,oUrILugIL 2 Llday DWEL (0.2pglk,,-,, 2L (70kg) 7 ugIL Ill. LifetimeDrinkingW@l.'fH.eearlthAdvisory (DWHA) forPFOS Step 3. LifetimeDWHA Calculation Lifc,iiDiWiHiAe = Dg'EL NRSC'= mgll orugIL ILifetimDeWHA = (7 L)(0.2=)1.0,ugIL 4 DRAFT - APPENDIX Precedentexist(sseeAroch*!ecx)armple,below)fora reductioinnsub-UFs(ie. versususingstandardefault=s10foreach sub-UF)when theexperimental datawarrant.Based on thesignificanmtountofavailablteoxicologidcaatlafor PFOS (includidnagtafromstudieosn otherFCs inwhichPFOS ishypothesized to be the "toxicm"etabolite)itisveryreleva!itto use both professionalrisk assessment and toxicologicfjludgment to "adjust"the sub-UFs based on availabledata. The EPA-derived RfD forArochlor1016 is7x 10-'mg/kg-day. The total uncertaintyfactorused by EFA was 100; an MF of 1 was also used. Reductions insub-UFs (froma defaultvplue of 10) were made based on the availabledata and professionajludgment (similatrothe case forRfD derivatiofnorPFOS). The followingisexcerpted from the IRIS fileforArochlor1016: Arochlorl016: UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF --A 3-foldfactorisapp@iedtoaccount forsensitiveindividualsT.he resultsofthese studies,E;swellas data forhuman exposure to PCBS, indicate thatinfantsexposed transI)Iacentalrleypresenta sensitivesubpopulation.A factorof3 isappliedforextrapolatiofnrom rhesus monkeys to human. A full I0-foldfactorforinterspec@esextrapolatioinsnot considered necessary because of similaritiienstoxicresponses and metabolism of PCBs between monkeys and humans anc,thegeneral ph@'siologiscimilaritbyetween these species. Inadditiont,he riiesusmonkey data are predictivoefotherchanges noted inhuman studiessuch as chloracne,hepaticchanges, and effectson reproductivefunction.A fe,,ctoofr3 isappliedbecause of limitationisnthe data base. Despitethe extensiveamount ofanimal laboratorydata and human epidemialogicinformationi-egardinPgCBS, the issueof male reproductive effectsisnot directlaydd@essed and two-generationreproductivestudiesare notavailable.As the stud@,d,u/rationwas considered as somewhat greaterthan subchronic,butlessthan chronic,a partiaflactorof3 isused to account forextrapolatiofnrom a sui)chronicexposure toa chronicRfD. MF - None 5