Document jmepe2RvpZ54YyKQmjZOqKwQO

BACK TO MAIN -. internal Correspondence To: Dr.John Butenhoff, Manager Corporate Toxicology From: Subject: Date: Dr.Robert Roy Corporate Toxicology Draft Drinking Water Health Advisory (DWHA) - PFOS July 7,1999 John - The attached document presents the derivation of a draft Metime OWHA for PFOS. The draft DWHA is based on a reference dose (RfD) which was derived using a conservative,composite uncsrtainty kctor (UF). A very similar process of RfD development (e.g. seledion of appropriateUFs - based on available data) has been used by PA for Arochbr 1016; this is also included for your reference (Appendix). If you have questions or would like to discuss, please let me know. Rob BACK TO MAIN - DRAFT Lifetime Drinking Water Health Advisory (DWHA) for PFOS Background' The DWHA for PFOS was calculated using standard EPA methodology. Briefly, the following three equations were used: R f o = (NO.4EL) or (LOAEL) = rnglkg body weight -day (L'O Lifetime DWH.4 = DWEL x RSC = nag/&or K / L - where: RfD = Chronic Reference Dose [the estimate (with uncertainty spanning an order of magnitude) of a daily exposure to the human population (including sensitive subgroups) that is likely to be without appreciable risk of deleterious effects during a lifetime] NOAEL = No Observed Adverse Effect Level [theexposure level at which there are no statistically or biologicallysignificant increases in the frequency or severity of adverse effects between the exposed population and the appropriate control; some effects may be produced at this level but they are not considered to be adverse, nor to be a precursor to specific adverse effects) LOAEL = Lowest Observed Adverse Effect Level [the exposure level at which there are statisticallyor biologically significant increases inthe frequency or severity of adverse effects between the exposed populationand the appropriate control] UF = Total Uncertainty Factor (chosen using PA guidance). The total UF is composed of five sub-factors that attempt to account for uncertainty with regard to: 1) interhuman variability; 2) extrapolation of resub from I BACK TO MAIN - DRAFT experimental animal to human: 3) extrapolation from subchronic to chronic exposure; 4) extrapolation from LOAEL to NOEL; and 5) incomplete database to complete database. A modifyingfactor (MF)may also be applied to account for areas of scientific uncertainty not accounted for in the five sub-UFs. The standard EPA default factor for each of the five sub-UFs = I O ; that for the MF = I.Sub-UFs 4 0 may also be used when existing data reduce or eliminatethe needto account for a particular area of uncertainty. 7 7 ch~oice of appmpdate sub-UFs and the MF is accompIishedon a cas&by=cme basis using professional judgment by experienced risk assessom. DWEL = Drinking Water EquivalentLevel [theconcentration of a substance in drinking water that is not expected to cause any non-cansinogenic health effects in humans'over a lifetime of exposure] RSC = Relative Source Contributionlis the proportionofexposure to a chmeical from drinking water relative to other sources such as food and airJ(in the absence of any other data the PA default value = 20% is used) Lifetime Drinking Water Health Advisory (OWHA) = The concentrationof a chemical in drinking water that is not expected to cause any adverse noncarcinogenic effects over a lifetime of exposure, with a margin of salbty. 'References Cicmanec, J.L et a/. (1996). Noncancer risk assessmt: present and emerging issues. In: Fan, A.M. and Chang, L.W. (editon) Toxicology end Risk Assessment: Principles, Methods, and Applications. Marcel Dekker, New York, pp. 293-310 (copy ofpaper aftached) Dourson, M.L. et ai. (I995).Evolution of science-based uncertainty factors in noncancer risk assessment. Regulatory Toxicology and Pharmacology 24: 108-120. (copy of paper attached) EnvironmentalProtectionAgency (9I99). Integrated Risk Information System (IRIS). WWW address: http://wvvw.epa.gov/nceaSiris. htm Environmental Protection Agency (1999). Office of Water. Drinking Water Regulations and Health Advisories. WWW address: http://www.epa.gov/OSTlTools/dwstdsO. html 2 DRAFT- I. Liitime Drinking Water Health Advisory (DWHA) far PFOS Step 1. RfD Calculation BACK TO MAIN NOAEL = 0.15 mglkg-day [NOAEL from &month monkey oral capsule study] UF 900 (rounded up = 1000) [total UF = 900 (10~3~10x1~I3n)d.ividual subUFs were as follows [also refer to Appendix]: lnterhuman (pemon-to-personvariability) = 10 [standard EPA defautt] Extrapolation from experimentalanimal-to-human (Inbrspecb variability) = 3 [used non-hurnan primate] Extrapolationto chronic exposure (chronicity) = $0[based on exposun duration longer than subchronic but significantly less than chronic (6 months in a non-human primate): PFOS also appears tb accumulate in the body on repeated exposure due to poor elimination] LOAEL to NOAEL = I [standard default - NOAEL used] Incomplete database = 3 [significantdata accumulated on chemical; resub ofthe 2-year bioassay are still pending] Modifying Factor = 1 [human data available; significant data accumulated on chemical; sensitive endDoint established in studies; uncertaintiesaccounted for in other sub-factors] 3 . - - DRAFT Therefore: BACK TO MAIN RJD = 0.15 mglkg-dlg. =O.O0015 mgjkg-day =(0.2m/kg-dbY) 1000 Note: The precisionassociatedwith the RtD is usually one significantMure, therefore, RfD should be rounded to = 0.2 pgkgday II. Lifetime DrlnkhgWater HealthAdvisory (DWHA) for PFOS Step 2. DWEL Calcula'bn DWEL = (0.2 kg- C/UY}) (70 kg) - 7 & L 2 L duy 111. Lifetime Drinking Wa?mHealth Advisory (MNHA) for PFOS Step 3. Lifetime DWHA Calculation Lifclime DWHA = DR'EL s RSC' = mg)L or %/I. 4 BACK TO MAIN DRAFT- L. APPENDIX Precedent exists (see Arochlor example,below) for a reduction in sub-UFs (h. versus using standard defaults = 10 for each sub-UF) when the experimental data warrant. Based on the significant amount of availabletoxicologicaldata for PFOS (including data from studies on other FCs in which PFOS is hypothesi@ to be the "toxic"metabolite)it is very relevantto use both professional risk assessment and toxicologiwljudgment to "adjust"the sub-UFs based on available data. The EPAderived RfD for Arochlor 1016 is 7 x lod mgkgday. The total uncertaintyfactor used by EPA was 100; an MF of 1 was also used. Reductions in sub-UFs (from a default vplue of I O ) weie made based on the availabledata and professionaljudgment (similarto the dase for RfD derivation far PFOS). The following is excerpted from the IRIS file for Arochlor 1016: Arochlor 1016: UNCERTAINTY AND MODIFYING FACTORS( O W RfD) UF -A 3-fdd factor is applied to account for sensitive individuals. The results of these studies. 65 well as data for humanexposumto PCBs, indicate that infants exposed transplacentally represent a sensitive subpopulation. A factor of 3 is appliedfor Extrapolationfrom hews monkeysto human. A full 1O-fold factor for interspeciesextrapolationis not consideredneosssary because of similarities in toxic responsesand metabolismd PCBsbetwesn monkeys and humans and the general phj;siblagi similarity between thwrs species, In addition, the rhesus monkey data are predictiveof OWr'changeS noted in human studies such as chloracne, hepatic changes,and effect8bn reproductivefunction. A foctor of 3 is applied becauseof IlrniCatiomr in the data base. Despite the extensive amount of animal labowtory data and human epidemiologic information regarding PCBs, the issue of male reproductive effects is not directly addressed and two-gonerationrepradudive studb am not available. As the study durationwas consideredas sotnewhatgreater than subchronic, but less than chronic, a partialfactor of3 is used to occount for extrapolation from a subchronic exposure to B chronic R1D. - MF None