Document 5DDgKKqJ1G1XoZY5Kypvzk3K8

"McCrea, Deborah" <mccrea@taftlaw.com> 12/14/2009 03 :38 PM To NCIC OPPT@EPA cc "Bilott, Robert A." <bilott@taftlaw.com> bcc Subject 12/14/2009 Letter To EPA Docket Center Ad2a 6- 3 Q~ / Taft I Deborah McCrea / Legal Assistant Taft Stettinius & Hollister LLP 425 Walnut Street, Suite 1800 Cincinnati, Ohio 45202-3957 Tel : 513.381 .2838 " Fax: 513.381 .0205 www.taftlaw.com / mccrea@taftlaw .com Internal Revenue Service Circular 230 Disclosure: As provided for in Treasury regulations, advice (if any) relating to federal taxes that is contained in this communication (including attachments) is not intended or written to be used, and cannot be used, for the purpose of (1) avoiding penalties under the Internal Revenue Code or (2) promoting, marketing or recommending to another party any transaction or matter addressed herein. This message may contain information that is attorney-client privileged, attorney work product or otherwise confidential . If you are not an intended recipient, use and disclosure of this message are prohibited . If you received this transmission in error, please notify the sender by reply e-mail and delete the message and any attachments . 2348_001 .pdf December 14, 2009 Page 2 5 . 10130109 Letter from Perry Cohn, Ph.D., MPH, to ATSDR with New Jersey Department of Health and Senior Services' "Comments on Draft Perfluoroalkyls Toxicological Profile"; 6. 10127109 Letter from David G. Gray, Ph.D., Tetra Tech Inc., to ATSDR with "Comments on Draft Toxicological Profile for Perfluoroalkyls" ; 7 . 10130109 Comments of Olga V. Naidenko, Ph .D ., Environmental Working Group, on ATSDR draft Toxicological Profile for Perfluoroalkyls; and 8 . 10130109 and 1113109 Letters from Robert A. Biiott to ATSDR with Comments on Draft Toxicological Profile for Perfluoroalkyls. RAB :mdm Enclosures cc: Gloria Post (NJDEP)(w/ encl.) (via U .S. Mail) Helen Goeden (MDHxwI encl.) (via U.S. Mail) Lora Wemer (ATSDR)(wl enc1.) (via U .S . Mail) (W1405808.1) p. 3 Taft/ 425 Walnut Street, Suite 1800 / Cincinnati, OH 45202-3957 / Tel : 513 .381 .2838 / Fax : Taft Stettinius & Hollister LLP 513.381 .0205 / www .taftlaw.com Cincinnati / Cleveland / Columbus / Dayton / Indianapolis / Northern Kentucky / Phoenix / Beijing RoeERT A. eic.on 513-357-9638 bilott@taftlaw.com ,J,) c`~ - December 14, 2009 C7 FEDERAL EXPRESS EPA Docket Center, MC 2822T U .S. Environmental Protection Agency EPA West, Room 3334 1301 Constitution Avenue, NW Washington, D.C. 20004 Re: Submission to IRIS and AR-226 Database For PFOAIPFOS : EPA-HQORD-2003-0016 To IRIS Database for PFOAIPFOS : In response to the Notice issued by USEPA on February 23, 2006, regarding USEPA's efforts to consider perfluorooctanoic acid ("PFOA") and perfluorooctane sulfonate ("PFOS") within the Integrated Risk Information System ("IRIS"), 71 Fed. Reg. 9333-9336 (Feb. 23, 2006), we are submitting the following additional information to USEPA for inclusion in that review, and for inclusion in the AR-226 database : 1 . 10130109 Letter from James Kelly, M .S., to ATSDR with Minnesota Department of Health's "Comments on Draft Toxicological Profile for PerPluoroalkyls" ; 2. 8131109 Letter from Henry A. Spiller, MS, D.ABAT, to ATSDR with Kentucky Regional Poison Center's "Comments on Toxicological Profile for Perfluoroalkyls" ; 3. 10129109 Letter from Suzanne E. Fenton, Ph.D ., of U.S . Department of Health & Human Services, Public Health Service, National Institutes of Health, National Institute of Environmental Health Sciences, to ATSDR Re: "Comments on ATSDR Draft Toxicological Profile on Perfluoroalkyls" ; 4. 10130/09 and 11/2109 Letters from Gloria B. Post, Ph.D ., DABT, to ATSDR with New Jersey Department of Environmental Protection's "Comments on Draft Toxicological Profile for Perfluoroalkyls" ; 115'0219_' CONTAINS NO CF' INI1NNESOTb MDH Protecting, maintaining and intprorring the health ofallMinnesotans October 30, 2009 Agency for Toxic Substances and Disease Registry Division of Toxicology and Environmental Medicine 1600 Clifton Road NE Mail Stop F-62 Atlanta, Georgia 30333 RE: Comments on Draft Toxicological Profile for Perfluoroaikyls Dear Sir/Madam: The Minnesota Department of Health (MDH) is pleased to provide the attached comments on the Agency for Toxic Substances and Disease Registry's (AT"SDR) Draft Toxicological Profile for Periluoroalkyls, dated May 2009. MDH has had extensive experience with perfluoroalkyls (a.lc.a. perfluorochemicals, or PFCs) due to 3M's long history of PFC manufacture and waste disposal in Minnesota. These activities have resulted in contamination of groundwater, drinking water, biota, and other environmental media. In response, MDH has developed health-based exposure limits, conducted health assessments documented in ATSDR-approved Health Consultations and Public Health Assessments, and conducted other relevant studies. Ifyou have any questions regarding these comments, please contact Helen Goeden (651-201-4904; helen. oedena state.mn.us) or myself at 651-201-4910 or 'ames.kellv(@state.mn.us. Ski7erely, r, mes Kelly, M.S . esearch Scientist Site Assessment and Consultation Unit Environmental Health Division Encl . General Information :651-201-5000 " Toll-free: 888-345-0823 " TTY-.651-201-5797 " ww.v.healdi.state .mn.us An equal opportnnity employer General Comments: 1) The draft document represents a good attempt at compiling a large amount ofinformation. However, interpretation ofthe data (i.e., what does this potentially mean for human health) is limited and needs to be expanded . 2) Since multiple chemicals are contained within this review it can be rather confusing. Authors should consider including a subheading for each PFC, as appropriate, under each health effect section . 3) The draft document needs to be updated to include numerous papers that have been published since the literature review for this draft was conducted. In particular, the recently published results from the human C8 Study regarding cholesterol, uric acid and immunological effects need to be included. In addition, an updated study of mortality in PFC workers was recently published (Lundin et al 2009). It is also not clear why some papers, while contained within the reference list, were not cited within the document. For example, in the Mechanism of Toxicity section reviews from 1998 2003 are cited as the major source of information but the more recent review by Lau et a12007 is not. Studies examining humanized PPARa receptors in vitro and in vivo should be included (e.g., Wolfet a12008 and Foreman et a12009). More recently publications regarding mechanism(s) ofaction and other sensitive health effects (e.g., alterations in serum thyroid hormone levels, immunotoxicity) have expanded the discussion well beyond liver and PPARa. 4) There is a general consensus that serum levels are a better dose metric for dose-response and for comparison across species than administered dose. Wherever possible serum levels should be provided, including tables and figures 3-1 through 3-5. In addition, a discussion of human equivalent doses should be presented to allow a more accurate comparison of effect levels. 5) The draft document includes statements that the lack of reported significant exposure-related adverse effects in humans precludes the derivation of MRLs. We are not aware of another chemical in which the absence of clear exposure-related adverse effects in humans was utilized as the major rationale for not deriving guidance. Guidance values, such as MRLs, are rarely based on human evidence but on evidence gathered in laboratory animals. Evidence of adverse effects has been clearly demonstrated in a wide range of laboratory species, including nonhuman primates. While there is limited evidence that some of the endpoints observed in rodents (enlarged livers) may not directly relevant to humans there currently is no evidence that the other health effects in rodents or the health effects in nonhuman primates are not relevant to humans. A secondary rationale, the uncertainty regarding animal-to-human extrapolation, is also given. Typically across species toxicokinetic information for chemicals is not available and therefore the differences are unknown. For several of the PFCs we have this information - it is not an unknown but a known quantitative difference. These differences can be addressed by utilizing serum levels as the dose metric or by adjusting the administered dose to account for differences in elimination half-life. 6) The summary of Regulations, Advisories and Guidelines is incomplete . Several other countries (e.g., Germany, Canada) as well as states have derived health-based guidance. Some of these values are listed below: . a. North Carolina's Public Health Goal for PFOA (June 2007) is 0.63 ug/L; b. German Ministry ofHealth, Drinking Water Commission (July 2006) has several values . The Precautionary Action Values for composite PFOA and PFOS are: 5.0 ug/L immediate action to reduce adult intake ; > 1 .5 - 5.0 ug/L (1 yr tolerable max.); > 0.6 1 .5 ug/L (3 yr tolerable max.); and > 0.1-- 0.6 ug/L (10 yr tolerable max.). The Provisional toxicological assessment lifelong health based guide value is 0.3 ug/L (applies to composite of PFOA & PFOS). c. Health Canada has developed a draft Drinking Water Guidance Value of 0.7 ug/L for PFOA and 0.3 ug/L for PFOS. d. United Kingdom, Drinking Water Inspectorate 2007 has a Tier 2 value of 10 ug/1 for PFOA and of 1 ug/L for PFOS. e. In addition to the values for PFOA and PFOS the Minnesota Department of Health has health-based guidance for PFBA (see http:/lwww.health.state.mn.us/divs/eh/risk/guidance/gw/pfba .pdf ) and PFBS (see http;//www.health.state.mn .us/divs/eh/risk/guidance/gw/nfbs.pdf ). Specific Comments : 1) Comparisons of administered dose and dose duration do not provide an accurate picture of species sensitivity. On page 119 the comparison of monkeys, rats and mice regarding sensitivity to the hepatic effects of PFOA would appear quite different if BMDL serum levels for hepatic effects are compared. The BMDL in Cynomolgus monkeys in the 26 week study (Butenhoff et al 2002) was -23 ug/mT., in rats exposed for 70 - 90 days (Butenlioffet a12004) it was - 25 ug/mL, in mice exposed throughout gestation it was - 29 ug/mL. 2) Half-life of PFBA in humans. The correct units (hours) is listed in Table 3-8, however, throughout the text the units are reported as days . 3) Maternal-infant transfer. It is incorrectly stated that no data regarding concentrations of PFCs in human milk in the US population are available. At least two studies have been conducted: Perfluorinated compounds in human milk from Massachusetts, U.S.A. Tao L et al. Environ Sci Technol. 2008, Apr 15; 42(8):3096-101 and Polyfluoroalkyl chemicals in the serum and milk of breastfeeding women. von Ehrenstein OS et al. Reprod Toxicol. 2009, Jun; 27(3-4):239-45. In fact, Tao et al 2008 is cited in Section 6 of the draft document . 4) Discussion contained in Section 3.10 Populations that are unusually susceptible and Section 6.7 Populations with potentially high exposures should also include issues such as conditions that could impact the ability to eliminate PFCs and health effects beyond liver effects (immunological and thyroid hormone effects) . 5) 3M has reported that information on the import and export of PFCs from the United States is available fiom the U.S. Customs Service databases. 6) Section 6.2 - PFOS is still in use in specific applications exempted by EPA. For example, some chrome platers use surfactants containing PFOS to limit hexavalent chromium emissions. MDH summarized Minnesota's experience with this use in a Health Consultation (http://www .health.state.mn.us/divs/eh/hazardous/topics/pfcs/t)fosdetectbrainerd.pdf). The U.S. EPA also recently completed a study of PFOS levels in wastewater from chrome platers in Region 5 (see h~t .n //www.epa.govlregion5/water/npdestek/notices .htm)7) Section 6.4.2 - The statement attributed to Chang et al (2008) regarding PFBA levels is misleading and inappropriate. PFBA has been detected at a levels as high as 21 micrograms per liter (uglL) in a single private well, and at levels of 1-3 ug/L in literally hundreds of other private wells in Washington County, Minnesota as documented in a Health Consultation (h :t~//www.health.state .mn.us/divs/ehlhazardous/topics/pfcslprwelldata .pdf) and Public Health Assessment (http ://www.health .state.mn.us/divs/eh/hazardous/topics/pfcs/pha/lakeelmooakdalerndex .himl) reviewed and approved by ATSDR. 8) Section 6.4.4 - a recent study published by Guo et al (2009) describes PFC levels in articles of commerce, and should be included here. 9) Section 6.5. MDH recently published the results of a pilot biomonitoring study of Washington County residents exposed to PFOA and PFOS in drinking water (http://www .health.state .mn.us/divs/eh/trackinglbiomonitoringpilot .htm). The results ofthis study should be included in this section. 10)A discussion of drinking water treatment may also be relevant. MDH has conducted a study of water treatment devices for removing PFCs from drinking water. The study can be found at htty :l/www.health .state.mn.usldivs/eh/hazai4ous/topicslpfos/water.html . KENTUCKY REGIONAL POISON CENTER of Kosair Children's Hospital P.O. Box 35070 Louisville, KY 40232-5070 PF,As Co~~,mf~+-t Louisville (5d2) 589-8222 " Kentucky 1-80U-222-1222 " Secretary 502-629-7264 " Administration 502-629-5326 FAX 502-629-7277 August 31, 2009 Agency for Toxic Substances and Disease Registry Division of Toxicology and environmental Medicine 1600 Clifton Rd, NE Mail Stop F-62 Atlanta GA 30333 Re: Comments on Toxicological Profile for pertluoroallcyls Dear Dr Frampkin: I recently received a copy of the ATSDR Toxicological Profile for PerfluoroAllryls (Draft for Public Comment) and am concerned with what appears to be a very significant omission . These chemicals are used (as noted in this document) extensively in surface coating and protectant formulations . There have been numerous reports of human injury over the years (references atzached) but there is no mention of this potential pulnmonary injury in the "Profile". Additionally there have been a number of animal studies and these are also not mentioned or reviewed in the ATSDR "Profile". Several statements bring about my concern. For example on page 15, "regardless of the route of exposure, the liver is the main target for perfluoroalkyl compounds". Our experience with these chemicals shows that significant injury to the lungs occurs when these chemicals are aerosolized iri Spray Sealants (leather protectors grout sealers, etc). In ail the references attached the primary target is the lungs, not the liver. Additionally on page 39 (Health Effect, Inhalation, Respiratory Effects, section 3 .2.1 .2) there is no mention of the potential pulmonary injury these chemical have caused or the potential for human exposure, while thousands of human cases have been reported over the years. The exposure and injury continues to be reported with published reports as recent as this year (2009, see reference 5) I would ask that the authors for this profile consider the attached references when evaluating the potential for human effect after inhalation exposure to perfiuoroalkyls and include this evidence in the profile . Desipna6ed as a Flegional Poison Control Center by the American Association of Poison Control Centers ~~ NORTON HEALTHCARiE TheKer" Regional Polson Center is supported with Stae Cianend Funds provkfed u~der contract txvuph the Kentucky Deparbnent for Public Health and IundB from Federal Hae16 Services ResotnoesAdministration. I believe the authors focus far too heavily on oral exposure, while the evidence for human injury after inhalation is nearly completely ignored. Sincerely Henry A.` Spiller, MS, D.ABAT Director Kentucky Regional Poison Center PO Box 35070 Louisville, KY 40232-5070 Office - 502-629-5326 Einail henrX.spiller(&.nortonhealthcare .org Waterproofing/sealant References 1 . Ebbecke M Schaper A, Kotseronis N, Desel H. Toxicovigillance ofGerman Poisons Centers. An epidemic of serious intoxication caused by new sealing sprays based on nanotechnology. Clin Toxico12007;45; 2. Smolinske S, White S, Daubert GP, Didrichsons R, Eisenga B, Mowry J, Mrvos R, Krcenzelok EP, Casavant M, Baker DA, Spiller HA. Respiratory illness associated with boot sealant products - five states, 2005-2006. MMVdR 2006;55:488-490 3 . Smolinske S, White S, Daubert GP, Eisenga B Didrichsons R, , Mowry J, Mrvos R, Krenzelok EP, , Baker DA, Spiller HA Respiratory illness associated with boot sealant products. Clin Toxicol 2006 ;44:752-753 4. Smolinske S, White S, Daubert GP, Eisenga B, Didrichsons R, , Mowry J, Mrvos R, Krenzelok EP, Casavant M, Baker DA, Spiller HA. National toxicity trends associated with waterproofing agents . Clin Toxico12006;44:704-705 5. Daubert GP, Spiller HA, Crouch BI, Seifert S, Simone K, Smolinske SC . Pulmonary toxicity following exposure to waterproofing grout sealer. J Med Toxico12009;5 :125-129 6. Vernez D, Bruzzi R, Kupferschmidt H, De-Batz A, Droz P, Lazor R. Acute respiratory syndrome after irilialation of waterproofing sprays: a posteriori exposure-response assessment in 102 cases. J Occup Environ Hygiene 2006;3 :250-261 7. Heinzer R, Fitting JW, Ribordy V, Kuzoe B, Lozor R. Recua~ence of acute respiratory failure following use of waterproofing sprays . Tborax 2004;59:541542 8. Lazor-Blanchet C, Rusca S, Vernez D, Berry R, Albrecht E, Droz PO, Boillat MA. Acute pulmonary toxicity following occupational exposure to a floor stain protector in the building industry in Switzerland. Int Arch Occup Environ Health 2004 ;77 :244-248 9. Vernez DS, Droz PO, Lazor-Blanchet C, Jaques S. Characterizing emission and breathing-zone concentrations following exposure cases to fluororesin-based waterproofing spray mists. J Occup Environ Hygeine 2004;1 :582-592 10. Jinn Y, Akizuki N, Ohkouchi M, Inase N, Ichioka M, Marumo F. Acute lung injury after inhalation of waterproofing spray while smoking a cigarette. Respiration 1998 ;65:486-488 11 . Hubbs AF, Castranova V, Ma JYC, Frazer DG, Siegel PD, Ducatman BS, Grote A, Schwegler-Berry D, Robinson VA, Van Dyke C, Barger M Xiang J, Parker J. Acute lung injury induced by a commercial leather conditioner. Toxicl App Pharmacol 1997 ;143 :37-46 12. Burkhart KK, Britt A, Petrini G, O'Donnell S, Donovan JW. Pulmonary toxicity following exposure to an aerosolized leather protector. J Toxicol Clin Toxicol 1996 ;34:21-24 13 . Shintani S, Yshizawa J, Endo Y, Ohashi N. A progress report on toxicovigilance activity for acute inhalation poisonings by waterproofing spray in Japan Clin Toxicol 1996 ;34:589 14. Yamashita M Tanaka J. Pulmonary collapse and pneumonia due to inhalation of a waterproofing aerosol in female CD-1 mice. J Toxicol Clin Toxicol 1995 ;33:631-637 15. Laliberte M Sanfacan G, Blais R. Acute pulmonary toxicity linked to use of a leather protector. Ann Emerg Med 1995 ;25 :841-844 16. Kulig K, Brent J, Phillips S, Messenger T, Hoffrnan RE, Burkhart K,Travis DR, Miller GB, Severe acute respiratory illness linked to use of shoe sprays Colorado, November 1993 . MMWR 1993 ;43 :885-887 17. Smilkstein MJ, Burton BT, Keen W, Barnett M, Hedberg K, Fleming D, Jaconson CM. Acute Respiratory illness linked to use of aerosol leather conditionerOregon, December 1992 MMWR1993 ;41 :965-967 18. Kelly KJ, Ruffing R. Acute eosinophillic pneumonia following intentional inhalation of Scotchguard. Ann Allergy 1993 ;71 :358-361 19. Woo O, Healy K, Sheppard D, Tong TG. Chest pain and hypoxemia from inhalation of a trichloroethane aerosol product. J Toxicol Clin Toxicol 1983 ;20:333-341 20. Perrone H H, Passero M, Hydrocarbon aerosol pneumonitis in an adult. Arch Intern med 1983 ;143 :1607-1608 21 . Testud F, Gabrielle L, Paquin ML, Descotes J. Acute alveolitis after using a waterproofing aerosol: apropos of2 cases. Revue Med Tnterne 1998;19:262-264 (French) 22 . Okonek S, Reinecke HJ, Fabricius W, Preussner K. Poisoning with leatherimpregnation sprays . Aretrospective analysis of224 cases of poisoning. Deutsche Medizinische Wochenschrift 1983;108:1863-1867 (German) 23 . Thibaut G, Wylomanski JL, Laroche D. Pulmonary intoxication by accidental inhalation ofhousehold aerosol water repellent. Toxicol Europ Res 1983 ;5:81-84 p. 13 DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Date : October 29, 2009 National Institutes of Health National Institute of Environmental Health Sciences P,O. Box 12233 Research Triangle Park, N.C . 27709 From : Subject : To: Suzanne E. Fenton, PhD Laboratory Head, Reproductive Endocrinology Cellular and Molecular Pathology Branch National Toxicology Program, MD E1-08 919-541-4141 fentonseaniehs.nih .gav Comments on ATSDR Draft Toxicological Profile on Perfluoroalkyls ATSDR Division of Toxicology and Environmental Medicine Applied Toxicology Branch 1600 Clifton Rd NE Mailstop F-62 Atlanta, GA 30333 Draft Writers and Reviewers: I have read your draft on the perllouroalkyls and wanted to take this opportunity to make some constructive comments on both the content and the interpretation ofwhat is presented. Since my expertise in the general area of health effects, that is where I will focus my comments. I was actually quite impressed with your peer review panel and believe that they were able to give you some good guidance, and will continue to do the same following the next round of edits to the document. In general, this document is outdated . That is no fault ofyours, but the science on this family of chemicals has moved forward so quickly this calendar year that this document is no longer current and many statements are incorrect . A review and inclusion ofthe many documents in the May 2009 Reproductive Toxicology issue 27(3-4) is needed . This is needed to update the toxicokinetic and health effects information available on compounds other than PFOA and PFOS, to provide important information on the disposition of PFOA in the pregnant and lactating mouse and her offspring over the nursing period, compare and contrast PFOS and PFOA in their ability to induce PPAR-a and the requirement for this signaling pathway for more than liver effects, and update some of the information on human exposure and early life end points in humans. Other epidemiological studies should also be added (these are just some examples) Hamm et al., JESEE advance online publication, 28 October 2009, doi :l0.1038/jes .2009.57 ; Lundin et al., Epidemiologv . 2009 Nov ;20(6) :921-8 ; MacNeil et al., Environ Res . 2009 Nov, 109(8) :997-1003 ; Stein et al., Am J EpidemioL 2009 Oct 1 ;170(7) :837-46 ; Joensen et al ., Environ Health Perspect. 2009 Jun; 117(6) :923-7; an update of exposure levels in the USA by Steenland et al., Environ Health Perspect. 2009 Jul ; 117(7) :1083-8 ; and comparisons ofthese data with 2009 data that is accumulating from other areas of the globe, such as Japan, China, Australia, and Denmark should be made. Many of the interpretations of the data presented in the Public Health Statements are too basic - the large majority of the human data to date had not considered early life exposure to this family ofcompounds and that should be stated . Just because these epidemiological studies had no significant associations of current serum levels or even those 10 yr ago (in an adult) does not mean that if early life exposure accumulation was taken into consideration, that the results would be the same. The current animal studies agree that developmental exposure to these compounds is important in manifestation of effects . An example ofthis is the paper by Hines et al, Mol Cell Endocrinol. 2009 May 25 ;304(1-2) :97-105 . In this paper, the investigators demonstrate that the increased weight gain effects in adult mice exposed prenatally to PFOA do not occur when adult mice are exposed to the compound for similar lengths of time and dose. This paper specifically shows a low dose effect of PFOA on end points that are of importance to human health and are not likely related to PPAR-a signaling . There are also discussions in Tardiff et al ., Food Chem Toxicol. 2009 Oct;47(10) :255789; Post et al., Environ Sci Technol . 2009 Jun 15;43(12) :4547-54 ; and the Repro Toxicol issue mentioned above that need to be included in this document for your discussion of IVIRLs . Furthermore, there is now more information on human milk as a source of exposure to PFAAs, not that it would change your presentation of the data much. This area should be updated, however . I also think it is important to point out that the human data that you refer to for comparison of PFAA in serum :milk is from very limited information (I study) with no comparison over time or parity and based on our work in mice (Fenton et al., 2009 Reprod Toxicol) the time of lactation that the sample is collected can have a fair influence on the ratio of PFOA in serum and milk. Although there are many updates needed in the document, there are also a few places where care must be taken to present the actual state ofthe science . Most ofthe epidemiological studies that have been published to date have been careful to state that they found associations of PFAA levels with a certain health outcome, but in your document in several places phrases like "..perflouroalkyl compounds produce cancer . ." and "causality" discussions should be carefully considered and possibly rewritten to reflect the interpretations of the authors of that work. Causality is hard to prove, but significant associations are easy to cite. Finally, I would like to add that the mammary gland tumors that were found in female rats in the 2 yr study (work by Beigel et al., and cited in the PFOA SAB report) should not be brushed under the rug . Because female rats do excrete PFOA nearly as fast as they take it in, the very low circulating levels that may have been in those rats did cause an increased incidence of mammary tumors. Work by my lab, in addition to independent work by Sandra Haslam (in 2009 Reprod Toxicol) has indicated altered mammary gland development in at least two mouse strains and our current work will determine the NOAEL and LOAEL for those end points. The effects of this perturbation of early life development is not fully understood, but other endocrine disrupting compounds demonstrating similar shifts in timing of mammary gland maturity have demonstrated increased risk for mammary hyperplasia, spontaneous adenocarcinoma, and carcinogen-induced tumor development (i.e, dioxin and bisphenol A). With this in mind, expansion of the primary health discussion on liver effects is recommended. Diabetes (and altered growth patterns, leptin, insulin in animal models) is another area to consider when defining the health effects of interest for PFOA and/or a mixture of exposures in this family of compounds. I hope you find these comments helpful and if I can clarify any of my statements or provide further assistance, please feel free to contact me at the address given. p. 17 .ion S. Corzine Governor State of New Jersey Department of Environmental Protection Office of Science PO Box 409 Trenton, NJ 08625 Mark w. nnaurieuo Acting Commissioner October 30, 2009 (Corrected 11/2/09) Ms. Nickolette Roney Division of Toxicology and Environmental Medicine, ATSDR Mailstop F-62,1600 Clifton Road, NE Atlanta, Georgia 30333 RE : Comments on Draft Toxicological Profile for Perfluoroalkyls, Docket Control Number ATSDR-253 Dear Ms. Roney, As requested in the Federal Register notice of July 23, 2009,1 am submitting comments on the ATSDR Draft Toxicological Profile for Perfluoroalkyls . I am the toxicologist with the New Jersey Department of Environmental Protection (NJDEP) with responsibility for developing the human health basis for New Jersey drinking water standards and guidance. I was responsible for the development of the current NJ health-based drinking water guidance for PFOA (NJDEP, 2007); the basis for this guidance has recently been published in a peer-reviewed journal (Post et al., 2009, as referenced in the attached comments) . Currently, the New Jersey Drinking Water Quality Institute (DWQI), an advisory body to the Commissioner of NJDEP, is developing a recommendation for a New Jersey drinking water standard (MCL) for PFOA. I am one ofthe scientists involved with updating the 2007 guidance based on review of recent studies in order to develop a recommended human health basis for this MCL . My comments focus on PFOA since I am most familiar with the literature on that compound. Additional detailed comments focusing on the epidemiological studies of PFOA are being submitted by Dr. Perry Cohn of the New Jersey Department ofHealth and Senior Services . Like me, Dr. Cohn is part of the effort to develop a recommendation for the health basis for the New Jersey drinking water standard for PFOA. Additionally, I am aware of an important new PFOA study which will be published next week . I will submit an addendum to my comments discussing this study after it becomes available. Thank you for the opportunity to comment on the Draft Toxicological Profile for Perfluoroalkyis . Please feel free to contact me at gloria .post(a)dep.state .nj .us if you have any questions or need further information. Sincerely, cc : Judy Louis, NJDEP Perry Cohn, NJ DHSS Gloria B. Post, Ph.D., DABT Research Scientist Gloria B. Post, NJDEP Comments on Draft Toxicological ProfileforPerf1'uoroalkyls General Comments I have several overall comments about the material presented in the document . First, there is often a lack of synthesis and critical analysis of the conclusions made by the authors of the studies described in the document. Instead, the conclusions are given as stated by the authors of the studies, even if they contradict the conclusions of other studies presented in the same section or in other sections, without an attempt to synthesize and draw conclusions from the whole body of information. Some specific examples of where this problem occurs are discussed below. Second, some important literature, both recent and older, is not included in the document . In other cases, key studies that are listed in the Reference section, but are not discussed in the text, should be discussed in the text. Below, I discuss the studies which I consider most important and which I recommend including in the document, and I provide the citations for those studies which are not already cited. It should be noted that there are many additional recent studies on health effects in humans and animals, environmental occurrence, human exposure, and fate and transport of PFOA that I am not including in these comments . Finally, and most importantly, I strongly disagree both with the conclusion that there is insufficient information and too much uncertainty to develop a chronic oral MRL for PFOA and with the reasons given in the draft document to support this conclusion. I believe that there is currently enough information to develop a chronic oral MRL for PFOA and that there is less uncertainty for the chronic risk assessment of PFOA than many of the other contaminants for which chronic MRLs have been developed by ATSDR . This is discussed in detail below. My specific comments follow . The citations for all studies mentioned in the comments which are not already cited in the draft document are provided at the end of the comments . Section 1 -- Public Health Statement Please note : Some ofthe information suggested for inclusion in the comments below may be too detailed for the Public Health Statement. This information could be summarized in this section and then discussed in more detail in the relevant sections later in the document. p. 3 Section 1 .3 Water and Soil PFOA and PFOS have been detected in drinking water not impacted by known sources such as fluorochemical facilities (Post et al ., 2009a, Ericson et al ., 2009, Jin et al, 2009, Rumsby et al ., 2009, Mak et al., 2009, Takagi et al., 2009). The contribution of exposure to the relatively low concentrations commonly detected in drinking water is substantial compared to the total exposure in the general population (Post et al., 2009). Gloria B. Post, NJDEP Comments on Draft Toxicological Profile for Pertluoroalkyls An important source of perfluoroallcyls in surface water and drinking water is discharge from wastewater treatment plants (Kelly and Solem, 2008, Yu et al, 2009, Clara et al, 2008). Precursor compounds (fluorotelomer alcohols) found in wastewater are transformed to PFOA and other perfluoroalkyls through biodegradation which occur during wastewater treatment (Sinclair et al, 2006, Loganathan et al, 2007). The sludge from wastewater treatment plants has been applied to agricultural land . Perfluoroalkyls from the land-applied sludge can contaminate groundwater and soil. These chemicals may then potentially enter the food chain (milk, meat) through grazing of cattle or other animals (Renner, 2009, USEPA Region 4, 2009). Perfluoralkyls have recently been shown to be taken up into crops from soil (Stahl et al., 2009). Recent research (Washington et al., 2009) suggests that an acrylate-linked fluorotelomer polymer can degrade to PFOA in soil. Consumer Products Fluorotelomer alcohols and larger molecules containing fluorotelomer alcohols (e.g. mono- and diphosphates) are widely used in consumer products such as greaseprooffood packaging. These have been shown to break down to PFOA and related compounds both through metabolic transformation in the body and through biodegradation and atmospheric reactions in the environment (D'eon et al., 2009, Martin et al., 2005, Sinclair et al ., 2007, Ellis et al., 2004, Henderson and Smith, 2007, Kudo et al., 2005, D' eon and Mabury, 2007, Mahmoud et al., 2008). Exposure to these precursors in consumer products may be a major source of human exposure to PFCs, and should be mentioned here. p. 4 Section 1 .5 Workers "Inhalation/dermal-Long-term exposure to perfluoroalkyls at work has not been associated with significant adverse health effects, but two studies in workers found changes in sex hormones and cholesterol associated with the levels of PFOA in blood." Comment: I agree with the comment submitted by Dr. Perry Cohn : "This statement falls short of describing the published observations and those from the docket. There is reasonable evidence (see above and below), given that most of the investigations are based on death certificates, that exposed workers are indeed affected ." General Population The C8 Health Study is an ongoing study of almost 70,000 people in Ohio and West Virginia who were exposed for one year or longer to PFOA in drinking water at concentrations ranging from approximately 0.05 ug/L to approximately 3 ug/L or higher . Data collected for each subject in this very large study includes serum PFOA levels, drinking water exposure history (e.g. PFOA concentration, current vs. former residence), levels of many parameters which can be measured in blood, and the subjects' medical histories . Additionally, there are other planned segments ofthis study which are described under Ongoing Studies on p. 224 of the document. It includes the community Gloria B. Post, NJDEP Comments on Draft Toxicological Profle for Perfluoroalkyls studied by Emmett et al . (2006a, 2006b), referred to here, but includes many more people and many more parameters than did Emmett et al . (2006a, 2006b). The currently available data and the data which will later become available from this major study provide crucial information on the relationship in humans between external dose (exposure through drinking water), internal dose (serum level), and biological endpoints and adverse health effects. The median serum levels in the first and second deciles, 6 and 9.8 pg/L are within the range prevalent in the U.S. general population, where, for the 2003-2004 National Health and Nutrition Evaluation Survey (NHANES), the 75th and 95th percentile levels were 5.8 and 9.8 pg/L (Calafat et al., 2007) while the highest serum levels in the C8 Health Study are in the IOOs to 1000s of ug/L range. The median serum level in the study is about 28 ug/L. Such extensive data on the relationship between environmentally relevant exposures and effects in humans is rarely if ever available for environmental contaminants of concern. In the draft document, the only mention of this study is on page 224 under Ongoing Studies, and even here, no background information on the design ofthe study is provided . Perhaps this is because the reports and publications which are now available were not available at the time when the draft document and peer review comments were written . There are currently several sources of information on this study which are essential for inclusion in the ATSDR Toxicological Profile . These include published papers on design and results of the study (Bartell et al., 2009, Frisbee et al., 2009, MacNeil et al., 2009, Steenland et al., 2009a, Steenland et al., 2009b, Steenland et al., 2009c, Stein et al., 2009), reports from the C8 Science Panel, including Fletcher et al. (2009) which reports associations with immune endpoints not yet published in a peer reviewed journal, and extensive data from the C8 Health Project which have not yet been adjusted for confounding factors (West Virginia School ofMedicine, 2009) . Association of PFOA serum levels with biological endpoints, including some which may be considered to be adverse, have been observed down to the lowest exposure groups . Although causality has not been established, as is the case for most epidemiological studies for environmental contaminants, it is notable that elevated cholesterol and other lipids (Steenland et al., 2009a) and elevated uric acid (Steenland et al., 2009b), as well as changes in several indicators of inflammatory and immune response (Fletcher et al ., 2009), were significantly associated with serum PFOA levels, after adjustment for age, gender, body mass index, and other factors . These associations are especially important, because the serum levels in the lower deciles in which the dose-response is seen for these endpoints coincide with the serum levels found in the general US population, as discussed by Steenland et al. (2009b) . In the cholesterol study (Steenland et al., 2009a), the median PFOA serum level was 27 pg/L, and the risk of high cholesterol increased in each quartile of exposure with a 4050% increase in the top quartile compared to the lowest quartile. In the uric acid study (Steenland et al., 2009b), the risk ofhyperuricemia (greater than 6 .0 mg/dl in women and 6 .8 mg/dl in men) increased in a dose-related fashion with serum Gloria B. Post, NJDEP Comments on Draft Toxicological Profilefor Perfluoroalkyls PFOA . The increased risk plateaued in the higher exposure groups, with an odds ratio of 1 .47 and 95% confidence interval of 1 .37-1 .58 in the two highest quintiles . A separate analysis of uric acid within the lower exposure group, with serum PFOA of less than or equal to 20 ug/L, revealed a dose-response by quartile within this group. . The highest quartile with serum levels of 15-20 ug/L serum PFOA had an increase in uric acid of 0.24 mg/dl above the lowest quartile with serum PFOA of less than 5 ug/L . Additionally, data from this study which have not yet been adjusted for confounding factors (West Virginia School of Medicine, 2009) suggest associations between PFOA serum levels and multiple other clinical parameters measured in blood, including liver enzymes, hormones, and electrolytes . As for the other endpoints discussed above, the apparent exposure-response curve for many of these endpoints is steepest in the lowest deciles of exposure, and no threshold is apparent in the dose-response curves . p.5 Laboratory Animals Other effects besides liver should be mentioned here . At a minimum, immune system effects should be mentioned. p. 6 Section 1.6 Effects in Children RE: First paragraph . The C8 Health Study includes 4915 subjects under 10 years old and 7561 subjects from 10 to 18 years old . The serum PFOA levels in these subjects spans a wide range and includes many subjects with serum levels in the range of the US general population. Preliminary data suggest associations of several parameters measured in blood with serum PFOA levels in children (West Virginia University School ofMedicine, 2009). RE: Second paragraph . The studies referred to found associations with PFOA and/or PFOS and birth weight in the general population, notjust with PFOA as stated . Apelberg et al. (2007) found associations with both PFOS and PFOA for birth weight and size, Fei et al. (2007, 2008a,b) found associations with PFOA but not PFOS for several measures of fetal growth, and Washino et al .(2009) found associations with PFOS but not PFOA for birth weight . Also, Stein et al . (2009) identified modest associations of PFOA with preeclampsia and birth defects and of PFOS with preeclampsia, preterm births, and low birth weight in the C8 Health Study population . Laboratory Animals Exposure to low levels of PFOA during gestation in mice has been shown to cause metabolic effects which become apparent in adulthood, including increased weight and changes in insulin and leptin (Hines et al., 2009a). Such exposures have also been shown to cause a unique anatomical change at the junction between the cervix and the uterus in the female offspring (Hines et al, 2009b) . Gloria B. Post, NJDEP Comments on Draft Toxicological Profilefor Perfluoroalkyls p. 7 Section 1 .8 Detecting Exposure RE: Third paragraph. In addition to Little Hocking, elevated PFOA serum levels have been found in the other five communities which are part of the C8 Health Study. These other communities had drinking water concentrations and serum levels lower than those in Little Hocking (Anderson-Mahoney, et al., 2008). Also, elevated serum levels have been found in other communities with contaminated drinking water including in Germany (Holzer et al ., 2008) and Minnesota (MDH, 2009). RE: Last paragraph. The sentence should be revised to say, "For example, mean serum PFOA levels . . .in Decatur, Alabama, were . . ." Elevated serum levels have been found in workers at sites other than Decatur, Alabama, and, as written, it implies that this was the only site where this has been found. p. 8 First full paragraph. It is important to mention that the USEPA Provisional Health Advisories for PFOA and PFOS are intended to protect for short term exposure, not chronic exposure . Relevance to Public Health p. 9, second paragraph, last sentence. Perfluoroalkyls can be formed through degradation of precursor compounds found in consumer products (D'eon and Mabury, 2007, D'eon et al., 2009, Martin et al., 2008, Washington et al., 2009) p. 9, third paragraph . It is very important to discuss the fact that contamination of groundwater with PFOA has been found to occur via release to air from an industrial facility followed by deposition from air onto the soil and migration through the soil to the groundwater (Paustenbach et al., 2007). Unlike other groundwater contaminants, significant groundwater contamination by PFOA does not occur solely through migration ofthe groundwater plume. Thus, significant contamination can occur at some distance from the industrial source, beyond the groundwater plume . Also, fluorotelomer alchols are much more volatile than perfluoroalkyl acids, and are converted to the acids in the atmosphere by chemical reactions . Long range transport of these precursors is thought to be a major contributor to the occurrence of PFOA and related compounds in remote regions (Ellis et al., 2004) p. 10, last paragraph. As noted above, a major source of PFOA exposure may be exposure to the telomer alcohols and the molecules into which they are incorporated (e.g mono- and diphosphates) followed by metabolic conversion to PFOA in the body. These chemicals are present at much higher concentrations in some consumer products than PFOA itself. Gloria B. Post, NJDEP Comments on Draft Toxicological Profile for Perfluoroalkyls p. 11 . Summary of Health Effects Last sentence ofparagraph. Studies of reproductive and developmental effects should also be mentioned here . p. 12. Partial paragraph beginning at top of page. Available results of the C8 Health Study and discussion of additional results that will be available from it should be included here. This information is discussed in detail above. This is a much larger study in the same community where the study of 371 subjects discussed here was done . p. 13 . Partial paragraph beginning at top of page . Several epidemiology studies show an increase in diabetes mellitus associated with PFOA exposure (Leonard et al., 2008; Lin et al., 2009). See comments ofP. Cohn for more detail. Also, regarding animal models, Hines et al. (2009a) found that exposure of mice to low levels of PFOA during gestation significantly increased body weight, and serum insulin and leptin (0.01-0.1mg/kg) in mid-life, while exposure during young adulthood did not have these effects . p. 14 . Partial paragraph beginning at top of page. In the study described here, serum PFOA levels were not available, complicating evaluation of the results. Also, Stein et al. (2009), discussed above, should be mentioned here . Last sentence of the paragraph : The authors ofthe studies themselves never concluded that the associations were causal . Why is it necessary to make the statement in the last sentence? If a statement is included, it should say that it is not known if the associations seen are causal or non-causal . p. 15 First paragraph. I have major concerns with the statements made in this paragraph about the implications of the toxicokinetic differences between humans and animals and of issues related to the mode of action on the relevance ofanimal studies to human health. This paragraph represents a summary of the discussion of these topics in the MRL section starting on p. 21 . My comments on these issues are given in the MRL section, below, but also apply to the shorter discussion in this paragraph . Second paragraph. The discussions of the effects of PFOA that occur through activation of PPAR alpha presented here and in many other places in this document are overly simplistic, do not consider all relevant information, and may convey to the reader the unwarranted implication that all effects of PFOA that occur through PPAR alpha are not relevant to humans . Specific to the writeup on this page, the following sentence should be revised to add the words "IN PART" as follows, as it is incorrect and contradicted by the writeup on the next page (page 16) : Liver toxicity in rodents results IN PART from the ability of these Gloria B. Post, NJDEP Comments on Draft Toxicological Profilefor Per,Jluoroalkyls compounds (with some structural restrictions) to activate the peroxisome proliferatoractivated receptor-a (PPARa), a member of the nuclear receptor superfamily. Additionally, the information on page 20 about the EPA Science Advisory Board's reservations about attributing the hepatocarcinogenicity of PFOA totally to PPAR alpha agonism should be synthesized with the discussions on p. 15 and 16 . In the current draft, the issues related to PPAR alpha and liver effects are presented separately on pages 15, 16, and 20, and the discussions on these three pages are contradictory and confusing to the reader . It has been concluded that humans are refractory to the PPAR alpha mediated peroxisome proliferating effects in liver which are thought to lead to liver cancer in rodents (Klaunig et al., 2003). However, PPAR alpha is known to mediate many effects other than peroxisome proliferation and carcinogenesis in humans, both in liver and in other organs . Thus, the conclusions about liver cancer should not necessarily be extended to other PPAR alpha-mediated effects. It should be noted that Klaunig et al (2003) also concluded that the data are insufficient to characterize the MOA for the Leydig cell tumors and the PACT tumors of PFOA. Effects mediated by PPAR alpha in humans include stimulation of fatty acid metabolism and suppression of inflammation (Fruchart and Duriez, 2004, Lefebvre et al. 2006), and, in fact, this is the basis for the use of PPAR alpha activators such as fbrates as hypolipidemic drugs in humans. Also, the role of PPAR alpha in human and animal development is not well characterized, but, based on their physiological roles, PPARs are expected to have important roles in reproduction and development (Abbott et al . 2008). Thus, the potential for PPAR alpha mediated effects on human development cannot be dismissed. Most PPAR alpha activators lower cholesterol and lipids in both rodents and humans . Similarly, PFOA lowers lipid levels in experimental animals (e.g. Loveless et al. 2006). However, statistically significant elevations of cholesterol, as well as of the risk of hypercholesterolemia defined as greater than or equal to 240 mg/dl, are associated with serum PFOA and PFOS in a dose-related fashion in humans exposed through drinking water (Steenland et al., 2009a) and are also seen in occupationally exposed individuals, as summarized in Steenland et al. 2009a, 2009b.. As discussed by Steenland et al. (2009a), the findings on human serum cholesterol indicate that PFOA does not have the same effects as other PPAR alpha activators on lipid metabolism in humans . As noted on the following page of the document (page 16), some effects of PFOA on the liver are not mediated by PPAR alpha. Effects ofPFOA seen in PPAR alpha null mice include increased liver weight (Yang et a1 .2002, Wolf et al., 2008) and histological changes and increased cell proliferation (Wolf et al., 2008), while the prototype PPAR alpha agonist Wyeth 14, 643 did not increase liver weight in PPAR alpha null mice in these studies . PFOA also activated genes not associated with PPAR alpha, including genes associated with other nuclear receptors such as CAR in livers of adult mice (Rosen Gloria B. Post, N1DEP Comments on Draft Toxicological Profile for PerJluoroalkyls et al., 2008a, 2008b) and newborn mice (Rosen et al., 2007). Additionally, PFOA caused fatty liver in mice, an effect not associated with PPAR alpha (Kudo and Kawashima, 1997) . As discussed on page 20, the USEPA SAB (2006) review of the USEPA (2005) draft PFOA risk assessment states that available data do not warrant the conclusion PPAR alpha is the sole MOA for liver tumors or that the PPAR alpha MOA for liver carcinogenesis does not occur in children . Finally, a recent paper by Guyton et al. (2009) raises issues about the role of PPAR alpha activation in the liver carcinogenesis even in compounds which are well characterized as rodent peroxisome proliferators and the conclusion that hepatic tumors in rodents caused by PPAR alpha activators are not relevant to human risk. Guyton et al. (2009) discusses the findings of Ito et al. (2007) and David et al. (1999) on the liver carcinogenicity of di(2-ethylhexyl)phthalate (DEHP). DEHP caused liver tumors in wild type B6C3F1 mice which have PPAR alpha (David et al., 1999). However, in another strain of inbred mice, Ito et al (2007) found increased liver tumors from DEHP in PPAR alpha null mice, but not in the analogous wild type mouse strain. They also discuss the potential interindividual variability in human response to liver effects related to PPAR alpha activation due to differences in amount, structure, and function of PPAR alpha among people and the limitations of epidemiological studies on people taking PPAR alpha drugs p. 16, first full paragraph. Reductions in serum cholesterol and triacylglycerols are commonly seen in animals, but, as discussed above, the opposite is seen in humans . This should be mentioned. p. 17 Second paragraph The study of Hines et al . (2009a) showing metabolic effects in adult mice after prenatal, but not adult, exposure should be mentioned. White et al . (2009) conducted crossfostering studies which showed that mammary gland development in mice is affected by exposure to PFOA only in utero or only during lactation. Changes in mammary gland development compared to control mice are still evident at 18 months of age. Also, anatomical changes in the uterus of mice exposed prenatally to very low doses has been reported in an abstract by Hines (2009b). p. 18. First paragraph. The discussion of whether developmental effects are mediated by PPAR alpha needs to be put into context by saying that the role of PPAR alpha in human development is currently unknown (Abbott et al., 2008) . The discussion presented here, in the context of the PPAR alpha discussion on page 15, suggests to the reader that effects mediated through PPAR alpha are by definition not relevant to humans, which is not the case. White et al. (2007) discusses the fact that "PPAR alpha is not a critical element of mammary gland differentiation in the neonate," so that "effects of gestational PFOA exposure on neonatal mammary tissue must not be mediated through this pathway ." Gloria B. Post, NJDEP Comntents on Draft Toxicological Profile for Perjluoroalkyls The cross-fostering studies of Wolf et al (2007), as well as the more recent study of White et al. (2009) which is not cited in the document, showed that decreased body weight, increased liver to body weight ratios, and delayed mammary gland developmental changes occur in mice exposed in utero to PFOA who are nursed by unexposed animals. This finding contradicts the earlier suggestion that these effects are due to poor nutrition resulting from changes in the quantity or quality of milk produced by PFOA exposed mice . p. 19 First full paragraph . Again, the significance of the discussions of whether or not the effects on the immune system are due to activation of PPAR alpha is not clear, particularly in this introductory section intended more for the non-scientist . As above, it has not been established that PPAR alpha mediated effects on the immune system are not relevant to humans . p. 20 As mentioned above, this discussion of the role of PPAR alpha and the SAB's conclusion needs to be synthesized with the earlier discussions on pages 15 and 16. It is important that the fact that about three-quarters of the SAB concluded that "PFOA cancer data are consistent with the EPA guidelines descriptor `likely to be carcinogenic to humans' " be added to this discussion . Minimum Risk Levels I strongly disagree that there is not enough information and too much uncertainty to develop a chronic MRL for PFOA. In general, the issues and uncertainties discussed in this section can be addressed by using 1) available information on the relationship between external dose (intake) and internal dose (serum levels) in humans, and 2) by using serum levels from animal studies, rather than administered dose, as the Point of Departure for the risk assessment. It is important to realize that this approach actually has less uncertainty than the standard approach for extrapolating from humans to animals Detailed comments are provided below: Human Data A general comment is that, as is the case for the vast majority of risk assessments for environmental contaminants, the available human data are not appropriate to serve as the quantitative basis for an MRL . However, the human data do provide important information which can support a risk assessment based on animal data. Bottom of p. 21 . As discussed, a median ratio of approximately 100 :1 between serum level and drinking water concentration was found in Little Hocking, Ohio, which had a high level ofPFOA, about 3.5 ug/L (Emmett et al., 2006a). This approximate 100 :1 ratio has been confirmed in communities with lower PFOA concentrations in their water supplies (about 0.05 ug/L or greater) by Post et al. (2009a) and is supported by the models ofHarada et al. (2005) . Tardiff et al. (2009) predicts similar, but slightly higher, ratios, as discussed by Post et al. (2009a, 2009b). It is also supported by the unpublished work of Hinderliter and Jepson (2001) and Gray (2005) . Gloria B. Post, NJDEP Comments on Draft Toxicological Profilefor PerJluoroalkyls Top of p. 22 . Increased risk of levels of serum cholesterol (Steenland, 2009a) and uric acid (Steenland, 2009b) considered clinically elevated have been associated in a doserelated fashion with specific serum levels of PFOA. As discussed above, these findings are especially notable because dose-related increases are seen in the lower exposure groups which coincide with the exposures of the general United States population . p. 22 Main paragraph. As discussed above, the population study of Emmett et al. (2006b) is greatly expanded upon by the C8 Health Study. Some results ofthis study are available and other portions of this study are ongoing. "Furthermore, even if a wide range of end points had been examined in the studies available and points of departure could have been defined, there is currently not enough information regarding the pharmacokinetics of this group of compounds in humans to facilitate estimations of exposure levels resulting in measurable body burdens of perfluoroalkyls ." Comment: Clewell (2006) predicts the relationship between exposure and serum level in humans, as discussed in Tardiffet al. (2009) . Clewell's model predicts factors of 0.1 and 0.127 relating intake (~Lg/kg/day) to serum concentration (pg/mL). Based on mean water ingestion of 17 mL/kg/day (USEPA, 2004), the 100:1 ratio between serum and drinking water levels (Post et al., 2009a) gives a factor of0.167 ug/kg/day intake per ug/ml in serum (Post et al., 2009b) . Animal Data The issues discussed here relating to differences in serum concentrations resulting from the same administered dose in humans and animals, as a result of differences in elimination rates, can be addressed by using serum levels instead of administered doses as the starting point for the risk assessment. This approach also addresses differences in elimination rates between male and female animals ofthe same species (e.g. rats). Measured or modeled serum levels are available for many of the key studies of PFOA in animals . This approach was used by USEPA (2005) in its draft risk assessment, as well as by Post et al. (2009a) and Tardiff et al. (2009) in their drinking water risk assessments . The serum level at the NOAEL, LOAEL, or Benchmark Dose in animal data can be identified or predicted by modeling and used as the Point ofDeparture. Uncertainty factors are applied to the serum level at the Point of Departure in the same way that uncertainty factors are applied to administered doses in other risk assessments in order to develop target human serum levels . It is important to realize that there are differences in body burden resulting from a given administered dose between species and sexes for all or most chemicals for which MRLs are developed. In most cases, this is addressed through the application of a default uncertainty factor . The approach suggested here for PFOA, which is based on internal dose and uses data specific to this chemical thus actually has less uncertainty in this regard than the approach used for most other chemicals. Gloria B. Post, NJDEP Comments on Draft Toxicological Profilefor Perfluoroalkyls The fact that humans take longer to achieve steady state than animals should not preclude the use of animal studies as the basis for a chronic MRL, if the serum levels in animals are used as the basis for the risk assessment. Even though chronic MRLs are defined as applying to exposures of one year are longer, in practice, they are used to address chronic exposures, such as residential exposure to contaminated soil or drinking water. Humans who are exposed through environmental media (e.g. water, soil) at the level of the chronic MRL for a duration somewhat shorter than the duration required to reach steady state will have somewhat lower serum levels than they will have at steady state. Thus, application of a chronic MRL for exposures through environmental media (e .g. water, soil) for durations longer than those considered to be "Intermediate" but which are not long enough for steady state to be reached will be protective for potential health effects Additionally, the half life of PFOA may be shorter than 1000 days, and/or four half-lives may not be required for PFOA to reach steady state in humans. Emmett et al. (2006a) found that duration of exposure to PFOA in drinking water did not impact serum levels in a group of individuals exposed for two years or longer, suggesting that the time needed to achieve steady state is much shorter than 12 years. Monkeys reached steady state in about two weeks (Butenhoff et al., 2002), much shorter than the predicted 90 days . Recent studies relevant to human half life are Holzer et al. (2009) and Bartell et al. (2009). In summary, based on the above considerations, kinetic extrapolations from animals to humans are likely to be less uncertain than for risk assessments of most chemicals, for which these issues are not considered quantitatively. Maternal-fetal transfer Information on maternal-fetal transfer and levels of the chemical under study in the fetuses of animals and humans is not available for most chemicals for which MRLs are developed . The default approach is to use the maternal dose in the animal study as the starting point and to assume that maternal-fetal transfer occurs similarly in humans and animals. For PFOA, uncertainty factors can be applied to the animal maternal serum level at the Point of Departure (NOAEL, LOAEL, or Benchmark Dose) to develop the target human maternal serum level which is the basis for the MRL . Fenton et al. (2009) showed that mouse pups exposed to a single dose of PFOA on gestation day 17 have significantly higher PFOA concentrations than their dams, and that their body burden increases after birth until at least day S. Monroy et al . (2008) provides data on the concentrations of PFOA, PFOS, and other perfluorinated chemicals in maternal serum and umbilical cord serum in humans at delivery. PBPK Models A human PBPK model developed by Clewell (2006) is discussed by Tardiff et al. (2009) . Harada et al. (2005) also developed a kinetic model for PFOA in humans. Gloria B. Post, NJDEP Comments on Draft Toxicological ProfileforPerjluoroalkyls p. 28 PFOA - Oral Exnosure Throughout this section, there are discussions of whether or not the effects being mentioned have been found to occur through PPAR alpha. The significance of this information as presented in the draft document is likely to be unclear to the reader. If this information is included, it should also be stated that PPAR alpha mediated effects may also occur in humans, with the possible exception of peroxisome proliferation and tumors resulting from peroxisome proliferation in the liver. Several additional studies which provide NOAELs or LOAELs more sensitive than the studies mentioned in the draft document should be included . PFOA serum levels are available or could be modeled for these studies: Significantly increased body weight, leptin, and insulin in mid-life were found in mice exposed to doses of PFOA as low as 0.01 mg/kg/day for 17 days ofgestation, but not in mice exposed as young adults (Hines et al ., 2009a) . In an abstract, Hines et al . (2009b) also reported that mouse pups exposed to doses as low as 0.01 mg/kg/day during gestation had increased uterine weight and a unique anatomical change at the utero-cervical junction. White et al. (2009) reported changes in mammary gland development and differentiation in cross-fostering studies in which mouse pups were exposed during gestation, lactation, or both. Delayed development was seen for exposure periods as short as one day or less in mice exposed only through lactation. Effects were seen at serum levels as low as about 2000 ug/L . The NOAEL for reduced mouse pup survival of 0.3 mg/kg/day for 17 days of gestation (Abbott et al., 2007) is mentioned in the draft document . However, a LOAEL of 0.1 mg/kg/day (the lowest dose tested) for increased pup liver/body weight ratio was also seen in this study, and data on serum levels are presented . Loveless et al. (2006) reported a LOAEL of 0.3 mg/kg/day (the lowest dose tested) for increased liver to body weight ratio in mice given PFOA for 14 days. Serum levels are reported . It should be noted that mortality occurred in 1 of 4 monkeys (25%) in the lowest dose group (3 mg/kg/day) in the study of Butenhoff et al. (2002) . Health Effects Inhalation Exposures Detailed comments on occupational epidemiology studies are being submitted by Dr. Periy Cohn ofNew Jersey Dept. ofHealth and Senior Services . Concise and relevant summaries of some of the findings of the occupational studies are provided in Steenland et al. (2009a, 2009b) . They discuss associations of elevated uric acid in two occupational studies, increased cholesterol in six occupational studies, increased liver enzymes in three occupational studies, and diabetes mortality in one occupational study. 12 Gloria B. Post, NJ'DEP Comments on Draft Toxicological Profilefor Per, fluoroalkyls Oral Exposures p. 56 . In the cynomolgus monkey study of Butenhoff (2002), 1 of 4 monkeys in the 3 mg/kg/day group and 1 of 6 monkeys in the high dose group (30 mg/kg/day lowered to 20 mg/kg/day) were sacrificed in extremis during the study. Thus, mortality should be considered an effect in this study. p. 116 Hepatic Effects The C8 Health Study will provide additional data on liver effects in humans exposed to PFOA through drinking water. Preliminary data associations of increased serum liver enzymes with serum PFOA levels (West Virginia School of Medicine, 2009). No threshold for increase in some liver enzymes is apparent in these preliminary data. These associations have also been observed in occupational studies, as discussed by Steenland et al . (2009a). Second paragraph . The hepatic response of rodents to PFOA is partially independent of PPAR alpha, as shown by studies in PPAR alpha null mice by Yang et al. (2001), which is cited in the document, and Wolf et al . (2008) which is not cited in the document . Wolf et al. (2008) showed increased liver weight and increased labeling index caused by PFOA in PPAR alpha null mice. Additionally, Kudo and Kawashima (1997) showed that PFOA caused fatty liver in mice, an effect not seen with typical PPAR alpha activators such as fibrates . p. 117 As mentioned above, Loveless et al. (2006) reported a LOAEL of 0.3 mg/kg/day (the lowest dose tested) for increased liver to body weight ratio in mice given PFOA for 14 days. As above, the studies in PPAR alpha null mice of Wolfet al. (2008) should be cited along with Yang et al. (2001) . p. 118. Full paragraph beginning with "Treatment. . ." Abbott et al. (2007) is a mouse study, not a rat study as stated here . Also, in this study, liver weight was increased in wild type pups at 0.1 mg/kg/day and higher . p. 119 First paragraph . Regarding the Butenhoff et al. (2002) study, it should be mentioned in this section or elsewhere than 1 of 4 monkeys in the 3 mg/kg/day group and I of 6 monkeys in the high dose (30/20 mg/kg/day) group were sacrificed in moribund condition during the study . Three additional monkeys in the high dose group were removed from the study because they could not tolerate the dosing. p. 124 and 125. Renal Effects, Endocrine Effects Steenland et al. (2009b) reported no interactions between PFOA and creatinine, an indicator of kidney disease in -55,000 adults who were part of the C8 Health Study. The 13 Gloria B. Post, N.IDEP Comments on Draft Toxicological Profilefor Perjluoroalkyls C8 Health Study will provide additional data on whether there is an association between serum PFOA and these effects. Immune Fletcher et al. (2009) reported that changes in several indicators of inflammatory and immune response were significantly associated with serum PFOA levels, after adjustment for age, gender, body mass index, and other factors . These include IgA, IgE, antinuclear antibodies, and C-reactive protein . p. 132 DeWitt et al . (2009) showed that the suppression of humoral immunity by PFOA in mice is independent of increased corticosterone levels and thus is not secondary to liver toxicity or stress . Son et al . (2008) showed effects of PFOA on T lymphocyte phenotypes and cytokine expression in mice . Loveless et al. (2008) studied immune effects of PFOA in rats and mice. p. 133 Neurobehavioral Effects Johansson et al. (2008) which showed permanent behavioral changes in mice after a single dose of PFOA or PFOS at age 10 days should be mentioned here . Also, Johansson et al. (2009) showed that a single dose of PFOA or PFOS given to neonatal mice altered the levels of proteins important for brain development. p. 135 Reproductive Effects Two recent studies in the general population should be mentioned in this section. Joensen et al. (2009) studied associations between semen quality and reproductive hormone levels with serum levels ofperfluoroalkyl acids in young Danish men. They reported a significant association of high levels of PFOS and PFOA with fewer normal sperm, and non-significant associations with other related parameters . Fei et al. (2009) found that increased time to pregnancy, which is considered to be a measure of infertility, was significantly associated with maternal serum PFOA and PFOS in the Danish general population . p. 136 Butenhoffet al . (2002) reported that estradiol levels in the high dose monkeys appeared to be decreased. p. 136 Last paragraph. White et al. (2009) is not mentioned in the document . It is a followup study to White et al. (2007) . This study had a cross-fostering design, so that pups were exposed in utero, through lactation, or both. Exposure only in utero only during the final days of pregnancy or only through lactation caused adverse mammary development as early as post-natal day 1 that persisted beyond post-natal day 63. The findings that these effects occurred in pups exposed only late in gestation, with no exposure through lactation because they were nursed by unexposed mice, contradicts the 14 Gloria B. Post, NJDEP Comments on Draft Toxicological Proftle for Perjluoroalkyls earlier suggestion that the effects on mammary gland development are due to alterations in the quality of the milk which the pups consumed. p. 141 The studies of developmental endpoints in human populations of Monroy (2008) and Stein et al. (2009) should be discussed. p . 142 The rat multigeneration study of Butenhoff et al. (2004) which is mentioned on page 136 should be discussed here . The fact that female rats excrete PFOA very quickly so that exposure to pups is lower than in other species given the same dose should be mentioned. Effects seen included reduced body weight during lactation in the Fl generation given 30 mg/kg/day, increased deaths of F1 males given 30 mg/kg/day at 2-4 days post-weaning, delays in sexual maturation in F1 males and females, p. 143 It should be mentioned that lactational exposure alone caused decreased body weight and increased relative liver weight in the cross fostering studies of Wolf et al. (2007) . p. 144 The findings of the following recent mouse developmental studies should be added : White et al. (2009), Yang et al. (2009), Hines et al. (2009a), Hines et al. (2009b). These studies show developmental effects at lower doses and/or shorter exposures than previous studies. Furthermore, White et al . (2009) showed that mammary gland changes caused by short exposures during development persist into adulthood, Hines et al. (2009a) showed metabolic changes not evident in adulthood as a result of developmental exposures, and Hines et al. (2009b) showed a unique anatomical change in the uterus after exposure to a very low dose for only 3 days of gestation. These effects may be more significant than the developmental delays reported in earlier studies. p. 148 Cancer I suggest removing the following sentence regarding 3M (1983) : "The investigators did not consider PFOA carcinogenic in the rat under the conditions ofthe study." If it is not removed, it should also be stated that the USEPA SAB (2006) judged PFOA to be a "likely carcinogen" based on data from this study and the study of Beigel et al. (2001) . Toxicokinetics p. 162 Oral Exposure Post et al. (2009a) discussed exposures through drinking water with PFOA at lower concentrations than those in Little Hocking studied by Emmett et al. (2006a) . The recent Minnesota Dept of Health Biomonitoring Project (2009, http://www.health .state .mn .us/divs/eh/tracking/finalpfcrpt .pdf) studied exposure to 7 PFCs from drinking water. Data currently being analyzed from this study will provide further information on the relationship between drinking water concentrations and serum levels in residents with contaminated private wells. p. 172 Metabolism It should be stated that PFOA is a stable compound that does not undergo chemical reactions in the body (or in the environment, under normal circumstances) . This is one of 15 Gloria B. Post, NJDEP Comments on Draft Toxfcological Profilefor PerJIuoroalkyls the most notable features of PFOA as compared to most other organic chemicals which are found in the environment (Lau et al ., 2007). p. 190 Risk Assessment As discussed above, I do not agree that the pharmacokinetic differences between humans and animal species preclude development of 1vIRLs, since extrapolations can be done on the basis ofserum levels . A pharmacokinetic model developed for monkeys has been adapted to humans and used in risk assessment, as discussed in Tardiff et al. (2009) . p. 195. 3 .5.2 Mechanisms of Toxicitv The same general comments provided on page 6 above about discussions of PPAR alpha mediated effects apply to this section. This sentence should be changed as follows : Liver toxicity in rodents results IN PART from the ability of these compounds (with some structural restrictions) to activate the peroxisome proliferator activated receptor-a (PPARa), . . . ." As discussed above, PFOA caused increased liver weight, fatty liver, and histological changes in PPAR alpha null mice, and has been shown to activate genes associated with pathways other than PPAR alpha in liver. "Although humans are refractory to the many effects induced by peroxisome proliferators in rodents, humans have a functional PPARa as suggested by the pharmacological reductions in serum triglycerides and cholesterol in patients treated with the peroxisome proliferator clofibrate, a response known to be mediated by the PPARa in mice." As discussed above, PPAR alpha is known to mediate many effects in humans in liver and in other organs, and its role in human development and in young children has not been characterized. Furthermore, PFOA has been shown to be associated with increased cholesterol in humans both in occupational studies and in a very large population exposed through drinking water with much lower serum PFOA levels (Steenland et al., 2009a). In this way, it differs from the fibrate drugs which lower cholesterol in humans. p. 197 In discussing Tilton et al. (2008), it should be mentioned that PFOA acted as a promoter for liver tumors in rainbow trout exposed to an initiator. Rainbow trout have been used for many years as a model for human liver cancer, since they are also insensitive to peroxisome proliferation in the liver. The authors concluded that the liver tumors in trout occurred through an estrogenic mechanism that may be relevant to humans. p. 197, Second paragraph Discussion of non-PPAR alpha mechanisms needs to be mentioned at the beginning of this section on page 195, not just at the end where it is not connected with the earlier discussion. Gloria B. Post, NJDEP Comments on Draft Toxicological Profile for PerJl'uoroalkyls Section 3 .5.3 Animal-to-Human Extrapolations I strongly disagree with the statements made in the first paragraph of this section. Details are given below. Toxicokinetic Differences This issue is also discussed in detail under Animal Studies in the 1VIRL Development section above. As stated above, the issues discussed here relating to differences in serum concentrations resulting from the same administered dose in humans and animals, as a result in differences in elimination rates, can be addressed by using serum levels instead ofadministered doses as the starting point for the risk assessment . This approach also addresses differences in elimination rates between male and female animals of the same species (e.g. rats). Measured or modeled serum levels are available for many of the key studies of PFOA in animals. This approach was used by USEPA (2005) in its draft risk assessment, as well as by Post et al. (2009a) and Tardiffet al. (2009) in their drinking water risk assessments. As discussed above. The serum level at the NOAEL, LOAEL, or Benchmark Dose can be identified and used as the Point of Departure/ Uncertainty factors are applied, in the same way that uncertainty factors are applied to administered dose in other risk assessments, to develop target human serum levels . It is important to realize that there are differences in body burden resulting from a given administered dose between species and sexes for all or most chemicals for which MRLs are developed. In most cases, this is addressed through the application of a default uncertainty factor . The approach suggested here for PFOA, which uses data specific to this chemical thus actually has less uncertainty in this regard than the approach used for most other chemicals. The fact that humans take longer to achieve steady state than animals does not preclude the use of animal studies ifserum levels are used as the basis for the risk assessment . The half-life of PFOA in humans exposed through drinking water has recently been estimated to be 2.3 years (Bartell et al, 2009). Additionally, PFOA may not take four half lives to reach steady state in humans . Emmett et al. (2006a) found that duration of exposure to PFOA in drinking water did not impact serum levels in a group of individuals exposed for two years or longer, suggesting that the time needed to achieve steady state is much shorter than 12 years . Monkeys reached steady state in about two weeks (Butenhoff et al ., 2002), much shorter than the predicted 90 days. p. 198 "As a result of these large differences in kinetics, internal doses (i .e ., serum concentrations of PFOA) achieved during intermediate-duration exposures in rats or monkeys would not represent steady-state internal doses that might be achieved in humans over longer exposure durations." The logic and intent of this sentence is unclear. Animals reach steady-state more quickly than humans, so any comparison based on serum levels in which humans have not yet reached steady state might be slightly overprotective, rather than underprotective, and thus the use of animal serum levels as the basis for human risk assessment should not be precluded . Also, as discussed above, humans may reach steady state more quickly than the 12 years mentioned in the draft document. As above, because of the availability of date on the relationship between 17 Gloria B. Post, NJDEP Comments on Draft Toxicological Profile for PerfYuoroalkyls administered dose and serum levels in both humans and animals, the uncertainties in this area are less than for the risk assessments for most other chemicals for which a default uncertainty factor is used for interspecies extrapolation . Lack of Reported Effects in Humans This paragraph should be rewritten to better convey a balanced summary of the data on associations seen in occupational and general population studies. Concise summaries of some of these data are provided in the introductory sections of Steenland et al . (2009a) and Steenland et al. (2009b), As mentioned above, Steenland et al . (2009a) report a dose-related increased risk of hypercholesteremia in a large population exposed through drinking water, with an odds ratio of 1 .51 in the highest quartile compared to the lowest quartile. The data of Steenland et al. (2009a) are especially significant because the associations exhibited no threshold down to the lowest deciles of exposure, and the serum levels in the lower deciles in the C8 study population are within the range of exposures of the general US population (Calafat et al., 2007). In the uric acid study (Steenland et al ., 2009b), the risk of hyperuricemia (greater than 6.0 mg/dl in women and 6.8 mg/d1 in men) increased in a dose-related fashion with serum PFOA . The increased risk plateaued in the higher exposure groups, with an odds ratio of 1 .47 and 95% confidence interval of 1 .37-1 .58 in the two highest quintiles. A separate analysis of uric acid within the lower exposure group (within the range of the US general population), with serum PFOA of less than or equal to 20 ug/L, revealed a dose-response by quartile within this group. . The highest quartile with serum levels of 15-20 ug/L serum PFOA had an increase in uric acid of 0.24 mg/dl above the lowest quartile with serum PFOA of less than 5 ug/L. Steenland et al . (2009a) summarize some of the literature on associations in humans as follows: "It (PFOA) . . . . has been shown to be weakly associated with lower birth weight in humans (5, 6). It has been shown to be associated with increased liver enzymes in 3 occupational studies of workers (7-9) but not in 1 study of community residents exposed via contaminated drinking water (10) . It has also been found to be positively correlated with cholesterol in 5 occupational studies (7-9, 11, 12) and 1 community study (10), although in several of these the relation was not statistically significant at the 0.05 level." Steenland et al . (2009b) summarizes as follows : "PFOA has been found to be significantly associated with elevated uric acid in two cross-sectional studies of workers (n=160 and n=1024) (Sakr et al. 2007a ; Costa et al. 2009) . There is also evidence in the literature for an association of PFOA with cholesterol and diabetes in humans . A positive correlation ofPFOA with cholesterol was observed in six occupational studies (Sakr et al. 2007a; Costa et al. 2009; Sakr et al. 2007b ; Olsen et al . 2000; Olsen and Zobe12007b; Olsen et al. 2003), and two community studies (Emmett et al. 2006; Steenland et al. 2009), although in one community study and two occupational studies, the relationship was not statistically significant. PFOA exposure was observed to be associated with a 18 Gloria B. Post, NJDEP Comments on Draft Toxicological Profilefor Perjluoroalkyls two-fold increase in diabetes mortality in one cohort study of highly-exposed workers when the exposed workers were compared to non-exposed workers, although no association was seen in another cross-sectional study of diabetes prevalence (Leonard et al. 2008; McNeil et al. 2009)." Additionally, among other studies showing associations of PFOA exposure with health endpoints, Lundin et al . (2009) recently reported associations of occupational exposure with prostate cancer, cerebrovascular disease, and diabetes. Costa et al. (2009) reported associations with increased uric acid, as well as cholesterol. As mentioned above, Dr. P. Cohn ofthe NJ Dept. ofHealth and Senior Services will provide extensive comments .on human studies. Mode(s) of Action As discussed in detail above, the following sentence is an oversimplification and should be modified to add the words in capitals as follows: "As previously mentioned, many PFOA-or PFOS-induced effects in rats and mice are mediated through the PPARa and it is generally agreed that humans and nonhuman primates are refractory, or at least less responsive than rodents, to PPARa-mediated effects IN THE LIVER THAT LEAD TO TUMOR FORMATION." "Therefore, further studies in PPARa-null mice are needed to expand the knowledge regarding PPARa-dependent and independent effects that would allow selection of an appropriate animal model for perfluoroalkyls toxicity ." Comment : This sentence should be rewritten to emphasize that PPAR alpha does mediate effects in humans other than liver cancer. As written, it implies that only effects seen in PPAR alpha null animals are relevant to humans, which is not the case. p. 198 Section 3 .6 Toxicities Mediated Through the Neuroendocrine Axis The following studies which have been discussed above relate to endocrine effects and should be considered for inclusion in this section: Joensen et al . (2009) studied associations between semen quality and reproductive hormone levels with serum levels of perfluoroalkyl acids in young Danish men. They reported a significant association of high levels of PFOS and PFOA with fewer normal sperm, and non-significant associations with other related parameters . Fei et al. (2009) found that increased time to pregnancy, which is considered to be a measure of infertility, was significantly associated with maternal serum PFOA and PFOS in the Danish general population . White et al. (2009) conducted cross-fostering studies which showed that mammary gland development in mice is affected by exposure to PFOA only in utero or only during lactation . Changes in mammary gland development compared to control mice are still evident at 18 months of age. 19 Gloria B. Post, NJDEP Comments on Draft Toxicological ProJilejorPerJluoroalkyls Exposure to low levels of PFOA during gestation in mice has been shown to cause metabolic effects which become apparent in adulthood, including increased weight and changes in insulin and leptin (Hines et al., 2009a) . Such exposures have also been shown to cause a unique anatomical change at the junction between the cervix and the uterus in the female offspring (Hines et al, 2009b) . p. 203 Children's Susceptibility The ongoing C8 Health Project will provide information on associations of many endpoints with PFOA exposure in children as well as in adults. Hoffinan et al. (2009) recently reported an association with serum levels of PFOA and several other perfluorinated chemicals and attention deficit hyperactivity disorder in U.S . children age 12-15 . It should be mentioned that children exposed to PFOA in drinking water have higher serum PFOA levels than adults (Emmett et al., 2006a, Steenland et al., 2009c) . This could be due to a greater volume of water consumed per kilogram body and/or differences in the toxicokinetics ofPFOA in children and adults . p. 204 Last paragraph Hines et al. (2009a, 2009b) which showed metabolic effects in adulthood and anatomical changes in the uterus after fetal exposure should be mentioned here. p. 205 Partial paragraph at top of page In discussing the developmental effects of PFOA in wild type and PPAR alpha null mice (Abbott et al., 2007), it should be mentioned that full litter resorptions were independent of PPAR alpha. Also, if this topic is discussed, it should be mentioned that the role of PPAR alpha in human development is uncharacterized, and that it cannot be concluded that developmental effects mediated through PPAR alpha are not relevant to humans . p. 207 Biomarkers used to characterize effects by perfluoroallcyls It is agreed that there are no biomarkers of effects specific to perfluoralkyls. However, the following sentence is misleading and is also contradicted by the recent publications of Steenland et al. (2009a, 2009b) mentioned above. It is not necessary to include this statement in order to make the point that there are no biomarkers SPECIFIC to perfluoralkyls, and I suggest that it be deleted. "Health evaluations of workers exposed to perfluoroalkyl compounds or of subjects environmentally exposed via their drinking water have not provided evidence of adverse health effects in the groups studied (Emmett et al . 2006a; Mundt et al . 2007 ; Olsen and Zobel 2007 ; Olsen et al. 1999, 2003a; Sakr et al . 2007a, 2007b) ." p. 207 3 10 Populations that are unusually susceptible Steenland et al. (2009a) as well as the occupational studies cited by Steenland et al. (2009a, 2009b) show that PFOA has effects opposite to the hypolipidemic drugs on serum lipid levels . As mentioned in Steenland et al . (2009a), several studies have shown associations with increased liver enzymes, so it is agreed that people with compromised 20 Gloria B. Post, NJDEP Comments on Draft Toxicological Profilefor Perfluoroalkyls liver function may be particularly susceptible. Similarly, Steenland et al. (2009b) has found associations ofPFOA exposure with clinically elevated uric acid and Fletcher et al. (2009) has reported changes in immune function, so that people who already have elevated uric acid or immune system abnormalities may be particularly susceptible. There are also two occupational studies showing increased uric acid, as discussed in Steenland et al. (2009b) p. 208 3 .11 .12 Reducing Body Burden Bartell et al. (2009) recently reported on the rate of decline in serum PFOA concentrations after granular activated carbon filtration in the C8 Health Study population in Ohio and West Virginia. p. 209 3 .11 .3 Interfering with the Mechanism ofAction for Toxic Effects It is agreed that there is no known method for interfering with the mechanism of toxicity of PFOA . However, the statements about no associations being found with adverse health effects should be removed, as they are not needed to make this point. If the statements are not removed, they should be modified as discussed under Section 3 .10 above. p. 212 First full paragraph The data from the C8 Health Study on general population exposure, should be mentioned here. These include published papers on design and results of the study (Bartell et al., 2009, Frisbee et al., 2009, MacNeil et al., 2009, Steenland et al., 2009a, Steenland et al., 2009b, Steenland et al., 2009c, Stein et al., 2009), reports from the C8 Science Panel, including Fletcher et al . (2009) which reports associations with immune endpoints not yet published in a peer reviewed journal, and extensive data from the C8 Health Project which have not yet been adjusted for confounding factors (West Virginia School of Medicine, 2009). These data are quite extensive, so it should be stated that data from both occupational and general population (environmental) exposures are available, without saying that the environmental data is limited . p. 213 3 .12 .2 Identification ofData Needs As discussed in detail above, I do not agree that there is insufficient information or too much uncertainty to develop a chronic oral MRL for PFOA . p. 214. Chronic Duration and Cancer I disagree with the statement that "for the most part, no significant adverse effects have been identified", The DuPont incidence study (Leonard, 2003) and the more recent occupational studies of Lundin et al., (2009), Costa et al. (2009), and others should be discussed. p. 215-216 . "In a 2-year bioassay, PFOA induced a "tumor triad" in rats, that is, liver tumors, Leydig cell tumors, and tumors in pancreatic acinar cells, characteristic of PPARa-agonist activation in rats (3M 1983 ; Biegel et al. 2001). The relevance ofthese findings to 21 Gloria 8. Post, NJDEP Comments on Draft Toxicological Proftlefor Perfluoroalkyls humans has been questioned by some since humans are considered refractory to most, but not all PPARa-activation effects (Klaunig et al. 2003)." Comment: The focus of Klaunig et al . (2003) was on rodent tumors, not "all PPAR alpha activation effects", which include effects on lipid metabolism and many other biological endpoints in the liver and other organs, as well as on development. The statement as written is misleading . "PFOA also increased the incidence of mammary gland fibroadenomas (3M 1983) and of mammary gland adenocarcinomas (mid-dose only)." Since PPAR alpha is discussed so extensively in this draft document, it should be mentioned that PPAR alpha is not known to be involved with mammary gland tumor formation. p. 216. Reproductive Toxicity As above, it should be mentioned that Joensen et al . (2009) found a significant association of high levels of serum PFOS and PFOA with fewer normal sperm, and nonsignificant associations with other related parameters, in young Danish men. Also, it should be mentioned that Fei et al. (2009) found that increased time to pregnancy, which is considered to be a measure of infertility, was significantly associated with maternal serum PFOA and PFOS in the Danish general population . p. 218 Developmental Toxicity As above, the study of Hines et al . (2009a) showing metabolic effects in adult mice after prenatal, but not adult, exposure should be mentioned. White et al . (2009) conducted cross-fostering studies which showed that mammary gland development in mice is affected by exposure to PFOA only in utero or only during lactation. Changes in mammary gland development compared to control mice are still evident at 18 months of age. Also, anatomical changes in the uterus of mice exposed prenatally to very low doses has been reported in an abstract by Hines (2009b). p. 219 . Immunotoxicity The findings of associations with changes in immune parameters in the C8 Health Study population (Fletcher et al., 2009) should be mentioned here, p. 220 Epidemiological and Human Dosimetry Studies The findings of the C8 Health Study should be mentioned here, including the publications of the C8 Science Panel (Bartell et al., 2009, Frisbee et al., 2009, MacNeil et al., 2009, Steenland et al., 2009a, Steenland et al., 2009b, Steenland et al ., 2009c, Stein et al., 2009) as well as the data of Fletcher et al., 2009 and the West Virginia University School of Medicine (2009) . Since the focus of this document is health effects from environmental exposures, these data are even more relevant than the occupational studies . p. 222 Second full paragraph It should be mentioned that mice do not show the marked sex difference in elimination rate seen in rats . It is important to mention this because of the many studies showing developmental effects in mice which were not seen in rat developmental studies. 22 Gloria B. Post, NJDEP Comrnents on Draft Toxicological Profile for Perfluoroalkyls Bartell et al. (2009) recently reported that there is not a gender difference in elimination ofPFOA in humans exposed through drinking water. The relevance of the discussion of possible gender differences in humans with dose or plasma concentration is not clear, as the data from humans involve serum levels relevant to human exposure . p. 223 Children's Susceptibility As discussed above, the ongoing C8 Health Project will provide information on associations of many endpoints with PFOA exposure in children as well as in adults . It should be mentioned that children exposed to PFOA in drinking water have higher serum PFOA levels than adults (Emmett et al., 2006a, Steenland et al., 2009c) . This could be due to a greater volume of water consumer per kilogram body and/or differences in the toxicokinetics of PFOA in children and adults . p. 224 3.12.3 Ongoing Studies As mentioned above, the C8 Health Study should be discussed in much more detail than in the draft document. In the draft document, the ongoing studies by the C8 Science Panel are simply mentioned with no context provided. This ongoing study is unprecedented in size and scope among studies of exposure and effects of humans exposed to an environmental contaminant. It will provide extensive data on the relationships between human exposure, internal dose, and health effects . The design, scope, and currently available data from this study should be discussed. The design of the study is discussed in Frisbee et al. (2009) . Information on predictors of serum levels is discussed in Steenland et al . (2009b) and on half-life in Bartell et al. (2009) . Data on associations with health endpoints are found at (WVU School of Medicine C8 Health Project website and C8 Science Panel website), as well as in the following peer-reviewed publications : Stein et al . (2009), . MacNeil et al . (2009), and Steenland et al. (2009a, 2009b) . Potential for Human Exposure The following studies should be discussed under this section: Fromme et al. (2009) summarizes perfluorinated chemical concentrations in indoor and ambient air, house dust, drinking water and food, as well as biomonitoring data in blood, breast milk, and human tissues. These data are used to estimate overall human exposures . Vestergren and Cousins (2009) conclude that dietary exposure is a major pathway of PFOA exposure in the general population . Post et al. (2009a) show the exposure contribution of low concentrations of PFOA in drinking water (e.g. 0.01 ug/L) can be substantial relative to the total exposure of the general population . 23 Gloria B. Post, NJDEP Comments on Draft Toxicological Profrle for Perfluoroalkyls Washburn et al . (2005) evaluate exposure from trace levels of PFOA in consumer products . Tittlemier et al. (2007) report on dietary exposure of Canadians to perfluorocarboxylates and PFOS. Tao et al. (2008) report on perfluorinated compounds in human breast milk in Asia, and in infant formula and dairy milk in the U.S . Jogsten et al. (2009) report on dietary exposures to perfluorinated compounds in Spain. Fromme et al. (2007) report on dietary exposures in Germany. Guo et al . (2009) report perfluorocarboxylic acid content in 116 articles of commerce . p. 249 Second full paragraph beginning with "Mean PFOA, PFOS, . . ." It should be mentioned that telomer alcohols from food packaging can be metabolized in the body to PFOA and that this is may to be a greater source of expsosure to PFOA from food packaging than residual PFOA in these products (D'eon and Mabury, 2007, D'eon et al., 2009) . Vestergren et al. (2008) evaluated the contribution ofprecursor compounds in consumer exposure to PFOS and PFOA. 6.2 Releases to the Environment 6.21 _Air Gewurtz et al . (2009) recently reported on studies of pefluoralkyl compounds on indoor and outdoor window films. These data were used to evaluate potential sources by sampling window films before and after new carpet installation and floor wax application, as well as in carpet stores . The results suggested that carpets may be a source of exposure indoors. 6 .22 Water The following studies are relevant to wastewater discharges of perfluorinated chemicals: Kelly and Solem (2008) identified discharge from a chrome plating operation as the major source ofPFOA at a wastewater treatment tlant in Brainerd, Minnesota. In Alabama, perfluoroalkyls from the land-applied sludge from a wastewater treatment plant were found to contaminate groundwater and soil. These chemicals may potentially enter the food chain (milk, meat) through grazing of cattle or other animals (Renner, 2009, USEPA Region 4, 2009). Sinclair and Kannan (2006) studied perfluorinated chemicals in sewage treatment plant influent and effluent. Increased concentrations of some chemicals in effluent was attributed to biodegradation ofprecursors present in the inflent. 24 Gloria B. Post, NJDEP Comments on Draft Toxicological Profilefor Perfluoroalkyls A similar study was reported by Loganathan et al. (2007) . Clara et al . (2008) studied perfluorianted chemicals in industrial wastewaters and wastewater treatment plant effluents. Yu et al . (2009) reported on perfluorinated chemicals in sewage treatment plants. D'eon et al. (2009) Reported on the occurrence ofdi-PAPS, the compound containing fluorotelomer alcohols in paper products, in wastewater and sludge. This compound can biodegrade to fluorotelomer alochol which can further biogegrade to PFOA. 6.3 Environmental Fate 6.3 .1 Transport and Partitioning In addition to long range atmospheric transport, it is very important to discuss that contamination of groundwater near industrial facilities occurs through air emissions followed by deposition on the soil and migration to groundwater, as well as through migration in a groundwater plum from the facility (Paustenbach et al., 2007) . Issues related to environmental fate and transport and pathways of human exposure to PFOA released from an industrial facility are evaluated in Small et al. (2009) . 6.4.2 Water The following studies are relevant to occurrence of perfluorinated chemicals in surface water and ground water: Murakami et al. (2009) reports on groundwater pollution by perfluorinated chemicals in Tokyo. Loos et al. (2008) reports on PFOS and PFOA in European river waters . Konwick et al . (2008) reports on concentrations and patterns of perfluoroalkyl acids in surface waters in Georgia near and distant to a major use source . Orata et al. (2008) reported on PFOA and PFOS in Lake Victoria Gulf in East Africa . Murakami et al. (2008a) reported on perfluorinated chemicals in rivers in Japan. Murakami et al. (2008b) reported on wastewater and street runoff as sources of perfluorinated chemicals in water. p. 281 . Several studies have reported on occurrence of PFOA and other perfluorinated chemicals in drinking water supplies not located near an industrial facility known to discharge these chemicals . Post et al. (2009a) reported on occurrence of PFOA in New Jersey public drinking water supplies. Data on PFOS from this study is found in NJDEP (200?). NJDEP is currently conducting an occurrence study of 30 additional public water supplies for 10 25 Gloria B. Post, NJDEP Comments on Draft Toxicological Profilefor PerJluoroalkyls perfluorinated chemicals, and we will submit these data when available (anticipated to be within the next few months). Ericson et al. (2009) reported on levels ofperfluorinated chemicals in municipal drinking water from Catalonia, Spain. Jin et al . (2009) reported on drinking water levels of PFOA and PFOS in China. Loos et al. (2007) reported on PFOA and PFOS in surface and tap waters around Lake Maggiore in Northern Italy. Rumsby et al. (2009) reviews PFOA and PFOS in drinking and environmental waters worldwide . Mak et al. (2009) presents data on perfluorinated compounds in tap water in China, Japan, India, the U.S ., and Canada. Takagi et al. (2008) reported on PFOA and PFOS in raw and treated tap water in Osaka, Japan . 6.4.3 Sediment and Soils As mentioned above, perfluorinated chemicals in land applied sludge from a local wastewater treatment plant has contaminated grazing land in Alabama. This could potentially be a route of contamination of the food supply . Currently, tissue levels of perfluorinated chemicals in cattle that grazed on this land are being studied. p. 284 Paragraph beginning with "Limited monitoring data . . ." As mentioned above, Paustenbach (2007) discussed soil deposition of PFOA emitted into the air from the Washington Works facility . This is a pathway for groundwater contamination in this vicinity . House Dust Kato et al. (2009) measured perfluoroalkyl chemicals in house dust . Bjorklund et al . (2009) measured PFOA and PFOS in indoor dust in houses, apartments, day care centers, offices, and cars. Section 6.5 General Population and Occupational Exposure The studies listed under Potential for Human Exposure above are relevant to this section (e.g the discussions on p. 291-292). p. 295 . Emmett et al. (2006a) and Steenland et al. (2009c) reported higher serum levels for children than for young adults in a population exposed to PFOA in drinking water. Gloria B. Post, NJDEP Comments on Draft Toxicological Proftle for Perfluoroalkyls Section 6 .7 Populations with Potentially High Exposure Minnesota Department of Health (2009) reported on biomonitoring of populations exposed to perfluorinated chemicals through private wells or public water supplies . Data from the C8 Science Panel about exposure in their study area should be discussed here: Steenland et al. (2009c), Bartell et al. (2009), West Virginia University School of Medicine (2009) . Section 6.8.1 Small et al. (2009) discusses data needs related to environmental fate and transport. p. 315 . 8 . Regulations, Guidelines, and Advisories PFOA and PFOS are included in USEPA's Contaminant Candidate List 3 for consideration for MCL development (USEPA, 2009. http://www.epa.gov/ogwdw000/ccUccl3 .html) and USEPA is currently developing Lifetime Health Advisories for drinking water for PFOA and PFOS. p. 316. Table 8.1 . It is important to note that the provisional USEPA Health Advisories for PFOA and PFOS in drinking water are intended to protect for short term exposure and are not intended to protect for chronic exposure. Citations The citations listed below are not included in the draft document. Additionally, some citations mentioned in the comments above are listed in the citation list of the draft document, but are not currently cited in the text. It is recommended that those citations should be discussed in the text. Abbott BD. Review of the expression of peroxisome proliferator-activated receptors alpha (PPAR alpha), beta (PPAR beta), and gamma (PPAR gamma) in rodent and human development. Reprod Toxicol. 2009 Jun;27(3-4) :246-57. Anderson-Mahoney, P. ; Kotlerman, J.; Takhar, H.; Gray, D.; Dahlgren, J. Self-reported health effects among community residents exposed to perfluorooctanoate. New Solutions 2008,18,129-143. Bartell SM, Calafat AM, Lyu C, Kato K, Ryan PB, Steenland K, 2009. Rate of Decline In Serum PFOA Concentrations After Granular Activated Carbon Filtration at Two Public Water Systems in Ohio and West Virginia. Environ Health Perspect: doi :10.1289/ehp.0901252. Bjtirklund JA, Thuresson K, De Wit CA. Perfluoroalkyl compounds (PFCs) in indoor dust: concentrations, human exposure estimates, and sources . Environ Sci Technol . 2009 Apr 1 ;43(7):2276-81 . Gloria 8. Post, NJDEP Comments on Draft Toxicological Profilefor Perfluoroalkyls Clara M, Schefflarnecht C, Scharf S, Weiss S, Gans O.Emissions of perfluorinated alkylated substances (PFAS) from point sources--identification of relevant branches. Water Sci Technol. 2008;58(1) :59-66 . Clara M, Scharf S, Schefflcnecht C, Gans O. Occurrence ofselected surfactants in untreated and treated sewage . Water Res. 2007 Nov;41(19):4339-48 . Clewell, H. J. Application of pharmacokinetic modeling to estimate PFOA exposure associated with measured blood concentrations in human populations. Powerpoint presentation at Society for Risk Analysis Annual Meeting; 2006. Costa G, Sartori S, Consonni D. 2009 Thirty years ofmedical surveillance in perfluooctanoic acid production workers. J Occup Environ Med . 51(3):364-72 . David RM, Moore MR, Cifone MA, Finney DC, Guest D. 1999. Chronic peroxisome proliferation and hepatomegaly associated with the hepatocellular tumorigenesis of di(2ethylhexyl)phthalate and the effects of recovery . Toxicol Sci 50(2):195-205 . D'eon JC, Mabury SA. Production of perfluorinated carboxylic acids (PFCAs) from the biotransformation ofpolyfluoroalkyl phosphate surfactants (PAPS): exploring routes of human contamination. Environ Sci Technol. 2007 Jul 1 ;41(13):4799-805 . D'eon JC, Crozier PW, Furdui VI, Reiner EJ, Libelo EL, Mabury SA. Observation of a commercial fluorinated material, the polyfluoroalkyl phosphoric acid diesters, in human sera, wastewater treatment plant sludge, and paper fibers . Environ Sci Technol. 2009 Jun 15 ;43(12):4589-94 . DeWitt JC, Copeland CB, Luebke RW. Suppression of humoral immunity by perfluorooctanoic acid is independent of elevated serum corticosterone concentration in mice . Toxicol Sci . 2009 May; 109(l) :106-12. Ericson 1, Domingo JL, Nadal M, Bigas E, Llebaria X, van Bavel B, Lindstrom G. Levels ofperfluorinated chemicals in municipal drinking water from catalonia, Spain: public health implications . Arch Environ Contam Toxicol. 2009 Nov;57(4) :631-8 . Fei C, McLaughlin JK, Lipworth L, Olsen J. 2009 Maternal levels ofperfluorinated chemicals and subfecundity. Hum Reprod ., 24(5):1200-5 . Fenton SE, Reiner JL, Nakayama SF, Delinsky AD, Stanko JP, Hines EP, White SS, Lindstrom AB, Strynar MJ, Petropoulou SS . Analysis of PFOA in dosed CD-1 mice. Part 2. Disposition of PFOA in tissues and fluids from pregnant and lactating mice and their pups. Reprod Toxicol. 2009 Jun;27(3-4) :365-72 . Fletcher, T. ; Steenland, K.; Savitz, D. C8 Science Panel. Status Report: PFOA and Immune Biomarkers in Adults Exposed to PFOA in Drinking Water in the Mid Ohio Valley, March 2009 . http ://www .c8sciencepanel .orp-/ . 28 Gloria B. Post, NJDEP Comments on Draft Toxicological Profilefor Per,Jluoroalkyls Frisbee, S.J. and A. Paul Brooks, Jr., Arthur Maher, Patsy Flensborg, Susan Arnold, Tony Fletcher, Kyle Steenland, Anoop Shankar, Sarah S. Knox, Cecil Pollard, Joel A. Halverson, Ver6nica M. Vieira, Chuanfang Jin, Kevin M. Leyden, Alan M. Ducatman. The C8 Health Project: Design, Methods, and Participants . Environmental Health Perspectives Online . Full text available at: http://dx.doi .orgL.1289/ehp.0800379 Fromme H, Schlummer M, Mliller A, Gruber L, Wolz G, Ungewiss J, Behmer S, Dekant W, Mayer R, Liebl B, Twardella D. Exposure ofan adult population to perfluorinated substances using duplicate diet portions and biomonitoring data. Environ Sci Technol . 2007 Nov 15;41(22) :7928-33. Fromme H, Tittlemier SA, Volkel W, Wilhelm M, Twardella D. Perfluorinated compounds--exposure assessment for the general population in Western countries . Int J Hyg Environ Health . 2009 May ;212(3) :239-70 . Fruchart, J-C and Duriez, P. PPAR-alpha and atherosclerosis from basis creaserch to clinical applications . International Congress Series 1262 (2004) : 25-29. Gewurtz SB, Bhavsar SP, Crozier PW, Diamond ML, Helm PA, Marvin CH, Reiner EJ. Perfluoroalkyl contaminants in window film: indoor/outdoor, uran/rural, and winter/summer contamination and assessment of carpet as a possible source . Environ Sci Technol . 2009 Oct 1 ;43(19):7317-23 . Gray, D. (2005) . Comments on the draft revision of Minnesota's Health Risk Limits (HRLs) for groundwater. Letter from Tetra Tech Inc. to Minnesota Department of Health. November 3, 2005. Guo, Z. and Xiaoyu Liu, Kenneth A. Krebs, Nancy F. Roache. 2009. erfluorocarboxylic Acid Content in 116 Articles of Commerce . EPA/600/R-09/033 March 2009. http://www.epa.gov/nrmrl/pubs/600r09033/600r09033 .pdf Guyton, K.Z. and, Weihsueh A. Chiu, Thomas F. Bateson, Jennifer Jinot, Cheryl Siegel Scott, Rebecca C. Brown, and Jane C. Caldwell . A Reexamination of the PPAR-a Activation Mode of Action as a Basis for Assessing Human Cancer Risks of Environmental Contaminants. Environ Health Perspect 117:1664-1672 (2009) . Hinderliter, P.M. and Jepson, G. W. (2001) . A simple conservative compartmental model to relate ammonium perfluorooctanoate (APFO) exposure to estimate of perfluorooctanote (PFO) blood levels in humans (draft). DuPont Haskell Laboratory for Health and Environmental Sciences . October 10, 2001 . Hines, E. P.; White, S. S. ; Stanko, J. P.; Gibbs-Flournoy, E. A., Lau, C., Fenton, S. E. Phenotypic dichotomy following developmental exposure to perfluorooctanoic acid (PFOA) in female CD-1 mice; Low doses induce elevated serum leptin and insulin, and overweight in mid-life. Mol Cell Endocrinol . 2009a. May 25;304(1-2) :97-105 . 29 Gloria B. Post, NJDEP Comments on Draft Toxicological Profile for PerJluoroalkyls Hines, E. P.; Gibbs-Flournoy, E. A.; Stanko, J. P.; Newbold, R.; Jefferson, W. ; Fenton, S. E. Testing the uterotrophic activity of perfluorooctanoic acid (PFOA) in the immature CD-1 mouse. The Toxicologist 2009b, 108, 297. Hoffman, Kate ; Vieira, Veronica ; Webster, Thomas; White, Roberta. Exposure to Polyfluoroalkyl Chemicals and Attention Deficit Hyperactivity Disorder in U.S. Children Aged 12-15 Years. Epidemiology . 20(6):S70, November 2009. doi : 10.1097/01 .ede.0000362918.40325 .e9 HtSlzer J, Gben T, Rauchfuss K, Kraft M, Angerer J, Kleeschulte P, Wilhelm M. Oneyear follow-up of perfluorinated compounds in plasma of German residents from Arnsberg formerly exposed to PFOA-contaminated drinking water. Int J Hyg Environ Health. 2009 Sep;212(5) :499-504. Ito Y, Yamanoshita 0, Asaeda N, Tagawa Y, Lee CH, Aoyama T, et al . 2007a. Di(2ethylhexyl)phthalate induces hepatic tumorigenesis through a peroxisome proliferatoractivated receptor alpha-independent pathway. J Occup Health 49(3):172--182. Jin YH, Liu W, Sato 1, Nakayama SF, Sasaki K, Saito N, Tsuda S. PFOS and PFOA in environmental and tap water in China. Chemosphere. 2009 Oct;77(5) :605-11 . Joensen UN, Bossi R, Leffers H, Jensen AA, Skakkebaek NE, Jafrgensen N. Do perfluoroalkyl compounds impair human semen quality? Environ Health Perspect. 2009 Jun; 117(6) :923-7 . Jogsten IE, Pere116 G, Llebaria X, Bigas E, Marti-Cid R, Kamnan A, Domingo JL. Exposure to perfluorinated compounds in Catalonia, Spain, through consumption of various raw and cooked foodstuffs, including packaged food. Food Chem Toxicol . 2009 Ju1 ;47(7) :1577-83. Johansson N, Eriksson P, Viberg H. Toxicol Sci. 2009 Apr;108(2):412-8 . Epub 2009 Feb 11 . Neonatal exposure to PFOS and PFOA in mice results in changes in proteins which are important for neuronal growth and synaptogenesis in the developing brain. Kato K, Calafat AM, Needham LL. Polyfluoroalkyl chemicals in house dust . Environ Res. 2009 Jul; 109(5) :518-23. Kelly, J. and Solern, L. Identification of a major source ofperfluorooctane sulfonate (PFOS) at a wastewater treatment plant in Brainerd, Minnesota . Reproductive Toxicology . Volume 27, Issues 3-4, June 2009, Page 420. Konwick BJ, Tomy GT, Ismail N, Peterson JT, Fauver RJ, Higginbotham D, Fisk AT. Concentrations and patterns of perfluoroalkyl acids in Georgia, USA surface waters near and distant to a major use source . Environ Toxicol Chem. 2008 Oct ;27(10):2011-8 . 30 Gloria B. Post, NJDEP Comments on Draft Toxicological Profilefor Perfluoroalkyls Lau C, Anitole K, Hodes C, Lai D, Pfahles-Hutchens A, Seed J. Perfluoroalkyl acids : a review ofmonitoring and toxicological findings. Toxicol Sci . 2007 Oct;99(2) :366-94. Lefebvre P, Chinetti G, Fruchart JC, Staels B. Sorting out the roles ofPPAR alpha in energy metabolism and vascular homeostasis. J Clin Invest . 2006 Mar; 116(3) :571-80. Leonard RC, Kreckmann KH, Sakr CJ, Symons JM. 2008 Retrospective cohort moofrrteagliionalstwuodrkoefrwso. ArknenrsEpiindaemiool lm.,e1r8(pIr)o:d1u5c-t2i2o.n plant including a reference population Lin C-Y, Chen P-C, Lin YC, Lin L-Y 2009 Association Among Serum Perfluoroalkyl Chemicals, Glucose Homeostasis, and Metabolic Syndrome in Adolescents and Adults . Diabetes Care, 32 (4): 702-707.1 Loos R, Gawlik BM, Locoro G, Rimaviciute E, Contini S, Bidoglio G. EU-wide survey of polar organic persistent pollutants in European river waters. Environ Pollut . 2009 Feb ;157(2) :561-8. Lundin JI, Alexander BH, Olsen GW, Church TR. 2009 Ammonium Perfluorooctanoate Production and Occupational Mortality . Epidemiology . On-line September 29 . MacNeil J, Steenland NK, Shankar A, Ducatman A. A cross-sectional analysis oftype II diabetes in a community with exposure to perfluorooctanoic acid (PFOA) . Environ Res . 2009 Nov ; 109(8) :997-1003 . Mahmoud MA, Karrman A, Oono S, Harada KH, Koizumi A. Polyfluorinated telomers in precipitation and surface water in an urban area of Japan. Chemosphere . 2009 Jan;74(3) :467-72 . Mak YL, Taniyasu S, Yeung LW, Lu G, Jin L, Yang Y, Lam PK, Kannan K, Yamashita N. Perfluorinated compounds in tap water from China and several other countries. Environ Sci Technol. 2009 Jul 1 ;43(13):4824-9. MDH. Minnesota Department of Health . East Metro Perfluorochemical Biomonitoring Pilot Project. July 21, 2009 . http ://www.health state mn us/divs/eh/trackin finalpfcrpt pdf Monroy R, Morrison K, Teo K, Atkinson S, Kubwabo C, Stewart B, Foster WG. Serum levels of perfluoroalkyl compounds in human maternal and umbilical cord blood samples. EnvironRes. 2008 Sep;108(1):56-62 . Murakami M, Kuroda K, Sato N, Fukushi T, Takizawa S, Takada H. Groundwater pollution by perfluorinated surfactants in Tokyo. Environ Sci Technol. 2009 May 15;43(10) :3480-6 . Murakami M, Shinohara H, Takada H. Evaluation of wastewater and street runoff as sources ofperfluorinated surfactants (PFSs). Chemosphere . 2009 Jan;74(4) :487-93 . Gloria B. Post, NJDEP Comments on Draft Toxicological Profilefor PerJluoroalkyls Murakami M, Imamura E, Shinohara H, Kiri K, Muramatsu Y, Harada A, Takada H. Occurrence and sources of perfluorinated surfactants in rivers in Japan. Environ Sci Technol . 2008 Sep 1 ;42(17) :6566-72. Murakami M, Takada H. Perfluorinated surfactants (PFSs) in size-fractionated street dust in Tokyo. Chemosphere. 2008 Nov;73(8) :1172-7 . Orata F, Quinete N, Werres F, Wilken RD. Determination ofperfluorooctanoic acid and perfluorooctane sulfonate in Lake Victoria Gulfwater. Bull Environ Contam Toxicol . 2009 Feb ;82(2) :218-22 . Post, G.B., Louis, J.B., Cooper, K.R., Boros-Russo, B.J., Lippincott, R.L., 2009a. Occurrence and potential significance of perfluorooctanoic acid (PFOA) detected in New Jersey public drinking water systems. Environ. Sci. Technol. 43,4547-4554 . Post, G.B., Louis, J.B., Cooper, K.R., and Lippincott, R.L (2009b). Response to Comment on "Occurrence and Potential Significance of Perfluorooctanoic Acid (PFOA) Detected in New Jersey Public Drinking Water Systems" Environ. Sci. Technol., Articles ASAP (As Soon As Publishable) Publication Date (Web): October 5, 2009. DOI: 10 .1021/es9027524 Renner, R, EPA finds record PFOS, PFOA levels in Alabama grazing fields. Environ . Sci . Technol ., 2009, 43 (5), pp 1245-1246 . Rosen MB, Abbott BD, Wolf DC, Corton JC, Wood CR, Schmid JE, Das KP, Zehr RD, Blair ET, Lau C. Gene profiling in the livers ofwild-type and PPARalpha-null mice exposed to perfluorooctanoic acid. Toxicol Pathol . 2008a;36(4) :592-607 . Rosen MB, Lee JS, Ren H, Vallanat B, Liu J, Waalkes MP, Abbott BD, Lau C, Corton JC. Toxicogenomic dissection ofthe perfluorooctanoic acid transcript profile in mouse liver: evidence for the involvement of nuclear receptors PPAR alpha and CAR . Toxicol Sci. 2008b. May 2008;103(1):46-56 Rumsby PC, McLaughlin CL, Hall T. Perfluorooctane sulphonate and perfluorooctanoic acid in drinking and environmental waters . Philos Transact A Math Phys Eng Sci . 2009 Oct 13;367(1904):4119-36 . Sinclair E, Kannan K. Mass loading and fate of perfluoroalkyl surfactants in wastewater treatment plants . Environ Sci Technol. 2006 Mar 1;40(5) :1408-14 . Small, M.J., Editor . 2009. Final Report ofthe Peer Consultation Panel conducting the review for the Scientific Peer Consultation Process for a Site Environmental Assessment Program as part of the DuPont - EPA Memorandum of Understanding and Phase lI Workplan. July 15, 2009. http://itppfoa.ce.cmu.edu/docs/meeting/Final-Report-PCP July-15 .pdf 32 Gloria B. Post, NJDEP Comments on Draft Toxicological ProfileforPerfluoroalkyls Son HY, Lee S, Tak EN, Cho HS, Shin Hl, Kim SH, Yang JH. Perfluorooctanoic acid alters T lymphocyte phenotypes and cytokine expression in mice. Environ Toxicol. 2008 Dec 2. Stahl T, Heyn J, Thiele H, Hiither J, Failing K, Georgii S, Brunn H. Carryover of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) from soil to plants. Arch Environ Contam Toxicol . 2009 Aug; 57(2):289-98 . Steenland K, Tinker S, Frisbee S, Ducatman A, Vaccarino V. Association of Perfluorooctanoic Acid and Perfluorooctane Sulfonate With Serum Lipids Among Adults Living Near a Chemical Plant. Am J Epidemiol. 2009a Oct 21 . Steenland, K., Tinker, S., Shankar, A. and Ducatman, A. Association of Perfluorooctanoic Acid (PFOA) and Perfluorooctanesulfonate (PFOS) with Uric Acid Among Adults with Elevated Community Exposure to PFOA. Environmental Health Perspectives Online . 2009b Full text available at: http://www.ehponline .org/docs/2009/0900940/abstract .html Steenland K, Jin C, MacNeil J, Lally C, Ducatman A, Vieira V, Fletcher T. Predictors of PFOA levels in a community surrounding a chemical plant. Environ Health Perspect. 2009c Jul; 117(7) :1083-8 . Stein CR, Savitz DA, Dougan M. Serum levels of perfluorooctanoic acid and perfluorooctane sulfonate and pregnancy outcome. Am J Epidemiol. 2009 Oct 1 ;170(7):837-46. Epub 2009 Aug 19. Tao L, Ma J, Kunisue T, Libelo EL, Tanabe S, Kannan K. Perfluorinated compounds in human breast milk from several Asian countries, and in infant formula and dairy milk from the United States. Environ Sci Technol . 2008 Nov 15;42(22):8597-602. Tardiff, R. G.; Carson, M. L.; Sweeney, L. M.; Kirman, C. R.; Tan, Y.-M.; Andersen, M. ; Bevan, C .; Gargas, M. L. Derivation of a Drinking Water Equivalent Level (DWEL) related to the Maximum Contaminant Level Goal for PFOA, a persistent water soluble compound. Food Chem. Toxicol . 2009; D01 :10.1016/j .fct.2009.07 .016 . Tittlemier SA, Pepper K, Seymour C, Moisey J, Bronson R, Cao XL, Dabeka RW . Dietary exposure of Canadians to perfluorinated carboxylates and perfluorooctane sulfonate via consumption of meat, fish, fast foods, and food items prepared in their packaging. J Agric Food Chem. 2007 Apr 18;55(8) :3203-10 . USEPA. Estimated Per Capita Water Ingestion and Body Weight in the United States . EPA-822-R-00-001, October 2004. http://www.epa.gov/waterscience%riteria/drinking/percapita/2004 .pdf. Gloria B. Post, NJDEP Comments on Draft Toxicological Profile for Perjluoroalkyls USEPA Region 4. 2009. Perflourochemical Contamination ofBiosolids Near Decatur, Alabama. http://www .epa.gov/region4/water/PFCindex .html Vestergren R, Cousins IT, Trudel D, Wormuth M, Scheringer M. Estimating the contribution of precursor compounds in consumer exposure to PFOS and PFOA . Chemosphere. 2008 Nov;73(10):1617-24 . Vestergren R, Cousins IT . Tracking the pathways of human exposure to perfluorocarboxylates. Environ Sci Technol . 2009 Aug 1 ;43(15):5565-75 . Review. Washington JW, Ellington J, Jenkins TM, Evans JJ, Yoo H, Hafner SC . Degradability of an acrylate-linked, fluorotelomer polymer in soil . Environ Sci Technol. 2009 Sep 1 ;43(17) :6617-23 . Washino N, Saijo Y, Sasaki S, Kato S, Ban S, Konishi K, Ito R, Nakata A, Iwasaki Y, Saito K, Nakazawa H, Kishi R. Correlations between prenatal exposure to perfluorinated chemicals and reduced fetal growth . Environ Health Perspect . 2009 Apr ;117(4) :660-7. West Virginia University School of Medicine. Department of Community Medicine. The C8 Health Project . 2009. http://www.hsc.wvu.edu/som/cmed/c8/ White SS, Kato K, Jia LT, Basden BJ, Calafat AM, Hines EP, Stanko JP, Wolf CJ, Abbott BD, Fenton SE. Effects of perfluorooctanoic acid on mouse mammary gland development and differentiation resulting from cross-foster and restricted gestational exposures. Reprod Toxicol. 2009 Jun;27(3-4):289-98. Wolf DC, Moore T, Abbott BD, Rosen MB, Das KP, Zehr RD, Lindstrom AB, Strynar MJ, Lau C. Comparative hepatic effects of perfluorooctanoic acid and WY 14,643 in PPAR-alpha knockout and wild-type mice. Toxicol Pathol . 2008 ;36(4) :632-9 . Yang C, Tan YS, Harkema JR, Haslam SZ. Differential effects ofperipubertal exposure to perfluorooctanoic acid on mammary gland development in C57B1/6 and Balb/c mouse strains . Reprod Toxicol. 2009 Jun ;27(3-4) :299-306. Yu J, Hu J, Tanaka S, Fujii S. Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) in sewage treatment plants . Water Res. 2009 May;43(9) :2399-408. Jon S. Corzine Governor State of New Jersey Department of Environmental Protection Office of Science PO Box 409 Trenton, NJ 08625 Mark N. Mauriello Acting Commissioner November 2, 2009 Ms. Nickolette Roney Division of Toxicology and Environmental Medicine, ATSDR Mailstop F-62,1600 Clifton Road, NE Atlanta, Georgia 30333 RE: Addendum to Comments on Draft Toxicological Profile for Perfluoroalkyls, Docket Control Number ATSDR-253 Dear Ms. Roney, I would like to bring to your attention two additional studies that have just become available which are relevant to evaluation of effects of perfluorinated chemicals in the general population . Steenland et al. (2009) found a statistically significant increased risk of high cholesterol in children associated with increasing PFOA and PFOS in the C8 Health Study population in Ohio and West Virginia. Nelson et al. (2009) report positive associations between PFOA, PFOS, and PFNA and total and non-HDL-cholesterol in participants of the 2003-2004 NHANES study, representative of the general U .S population . Thank you for the opportunity to comment on the draft Toxicological Profile, and please feel free to contact me at lg oria .postadep.state .nj .us if you need further information. Citations : Nelson, J.W., Hatch, E.E., and Webster, T.F.. Exposure to Polyfluoroalkyl Chemicals and Cholesterol, Body Weight, and Insulin Resistance in the General U .S . Population . Env . Health Perspect . doi : 10 .1289/ehp.0901165 . Online 2 November 2009. Steenland, K., Fletcher, T., and Savitz, D. (The C8 Science Panel) . Status report: Association of perfluorooctanic acid (C8/PFOA) and perfluoroctanesulfonate (PFOS) with lipids among children in the Mid-Ohio Valley . Oct 28, 2009. http://www.c8sciencepanel .org/pdfs/Status Report C8 and lipids_in children_280ct20 09.pdf Sincerely, cc : Judy Louis, NJDEP Perry Cohn, NJ DHSS Gloria B. Post, Ph.D., DABT Research Scientist .ION S. CORZINE Govemor October 30, 2009 Atate of ~~r.~ Jerseg DEPARTMENT OF HEALTH AND SENIOR SERVICES CONSUMER AND ENVIRONMENTAL HEALTH SERVICES PO BOX 369 TRENTON, N.J . 08625-0369 www.nj.gov/health HEATHER HOWARD Commissioner Ms . Nickolette Roney Division of Toxicology and Environmental Medicine Agency for Toxic Substances and Disease Registry Mailstop F-62 1600 Clifton Road, NE Atlanta, Georgia 30333 Subject : Comments on draft Perfluoroalkyls Toxicological Profile, docket control number ATSDR-253 Dear Ms Roney: As requested in the Federal Register notice of July 23, 2009, I would like to submit comments on the ATSDR Draft Toxicological Profile for Perfluoroalkyls . The attached comments on the epidemiological studies reviewed in the draft Toxicological Profile for Perfluoroalkyls represent my analysis of human health effects, primarily focused on perfluorooctanoic acid (PFOA) . They accompany comments focused primarily on laboratory animal studies, submitted separately by Dr. Gloria Post ofthe New Jersey Department ofEnvironmental Protection Dr . Post and I serve on the New Jersey Drinking Water Quality Institute and its Health Effects Committee and develop risk assessments on drinking water contaminants . (The Institute is a legislatively mandated advisory body that recommends drinking water standards to the New Jersey Department of Environmental Protection .) Currently, we are updating our current drinking water guidance on PFOA and developing a New Jersey Health-based Maximum Contaminant Level for New Jersey . We have recently been informed about the imminent publication of another epidemiological study shortly after the due date for these comments and we plan to send a separate letter briefly discussing this study after its release. If there is any question on the material discussed here, I can be reached by email at Perry.cohn(a)doh .state.nj .us or by phone at 609-588-3128 . However, the phone number will be changing shortly because the office is being moved to another location . Sincerely, Pen-y Cohn, PhD MPH Research Scientist New Jersey Department of Health and Senior Services Consumer Environmental and Occupational Health Services P.O. Box 369 Trenton, NJ 08625-0369 C: Jerald Fagliano, NJDHSS Gloria Post, NJDEP Comments on the Draft ATSDR Toxicologic Profile on Perfluoroakyls : Assessment of Epidemiological Studies Perry Cohn, PhD MPH New Jersey Department of Health and Senior Services Consumer Environmental and Occupational Health Service October 30, 2009 Introductory Comments These comments on the draft Toxicological Profile on Perfluoroalkyls are directed at the descriptions and conclusions about the epidemiological studies involving exposures to perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), as requested in the Federal Register notice of July 23, 2009. These include separate sections on occupational and population-based studies. General comments in each section include relevant studies available by August, 2009. Specific comments on studies that were included in the draft ATSDR Toxicological Profile are noted in the page-by-page analysis following the general comments. Citation of new studies, including a synopsis and critique, are listed at the end in each section. An important concern is that the epidemiological studies reviewed in this Toxicological Profile do not seem to have been critically analyzed beyond what each of the cited authors noted in their text . In addition, there was a general absence of reporting on marginally statistically significant findings and trends that tended to show concordance among the studies. Subdividing categories of mortality or morbidity often results in too few cases to achieve statistical significance and can obscure more generalized effects, such as the combination of metabolic disease, hypertension and atherosclerosis that can affect the overall system . I also think that it important that the final draft include findings from both the C8 Health Project and the C8 Science Panel on the populations served by the perfluoroalkyl (largely PFOA) contaminated water systems around DuPont Washington Works in Parkersburg, West Virginia, even though it is a cross-sectional study. Since the focus of this document is health effects from environmental exposures, these data are even more relevant than the occupational studies . The available epidemiological studies have numerous limitations, as discussed in this document, but the health effects reported in the epidemiological literature are more concordant, given those limitations, than reflected in the summary opinions expressed in the Toxicological Profile. In particular, there is insufficient rationale to the statement, "Thus, the lack of reported health effects at the reported body burdens precludes identifying the animal model that would be most appropriate for human risk assessment based on similar toxic effects ." (Animal-to-Human Extrapolation . Lack ofReported Effects in Humans, p. 198). ATSDR should not use that rationale to avoid development of Maximum Risk Levels (MRLs) . Especially for PFOA there is more than adequate data from experiments with laboratory animals to develop a quantitative risk assessment that can be used to develop a chronic oral MRL (further addressed in the comments on the Minimal Risk Levels portion of the Relevance to Public Health section), and there is sufficient evidence from the epidemiological literature, even with the limitations discussed in the draft document and below, to support the development of health-based guidelines and standards for the perfluoroalkyls . General Comments Inhalational Exposure : Occupational Studies Occupational exposures included primarily inhalation, but probably also dermal and oral routes . Occupational studies were conducted at the 3M Cottage Grove, MN, Decatur, AL, and Antwerp, Belgium facilities, the DuPont Washington Works plant in Parkersburg, WV, and the Miteni plant in Italy. These facilities included buildings where PFOA and/or PFOS were manufactured, as well as buildings using these chemicals in the manufacture of other chemicals and films . Workers at the 3M Decatur plant, which manufactured POSF, had elevated serum PFOA and PFOS (Olsen et al., 2003b) . Chronic Diseases Several mortality studies, one incidence study and one health claims study of workers at the two companies, 3M and DuPont, with facilities in the U.S . constitute the literature on health effects from occupational exposures. (The incidence study and the health claims study were not included in the draft Toxicological Profile, but are highly relevant .) Unfortunately, in the DuPont studies did not include any analysis by exposure, except for ischemic heart disease. Some commonalities have been observed among the results of those studies, in contrast to the statements made in the Draft Toxicological Profile. Bladder cancer incidence appeared to be elevated among the entire workforce (no exposure assessment) (Leonard, 2003), but not with mortality data at the DuPont Washington Works. It was also found to be elevated by job exposure assessment using mortality and health claims data at the 3M Decatur plant (Alexander et al., 2003 ; Alexander and Olsen, 2007). Kidney cancer mortality was elevated among the exposed workforce at the 3M Decatur plant (Alexander et al., 2003), and kidney cancer incidence among the entire workforce (no exposure assessment) using incidence (Leonard, 2003). Prostate cancer mortality was increased with exposure at the 3M Cottage Grove plant (Lundin and Alexander, 2007) and prostate cancer health claims were marginally elevated at the 3M Decatur plant (Olsen et al., 2004). (Prostate cancer incidence was elevated with marginal significance versus serum PFOS level in the Danish populationbased study (Eriksen et al ., 2009) .) DuPont did not find an increase in prostate cancer mortality or incidence, but the DuPont studies were not based on exposure (Leonard, 2003; Leonard et al., 2008) . Multiple myeloma incidence and mortality were elevated with marginal statistical significance at the DuPont Washington Works (Leonard, 2003; Leonard et al., 2008), though at the 3M Cottage Grove plant there were fewer deaths. There was no analysis of leukemia and lymphoma health claims at the 3M Decatur plant. Deaths from diabetes, ischemic heart disease (IHD), acute myocardial infarction, and the category, atherosclerosis and aneurysm, were elevated among workers at the Washington Works plant (Leonard et al., 2008) . Death attributed to IHD was elevated among exposed workers in the top two quartiles of serum PFOA (Sakr et al., 2009). These findings are consistent with elevated total cholesterol and LDL (Sakr et al., 2007a,b) . Diabetes and cerebrovascular disease (CVD) mortality was elevated among exposed workers at the 3M Cottage Grove plant (Lundin and Alexander, 2009), which parallels the association (though not in all analyses) of PFOA levels with elevated total cholesterol and TG and decreased HDL (Olsen et al., 2000; Olsen et al., 2007). Death from hypertension with and without heart disease was marginally elevated among those with known or probable exposures (Lundin and Alexander, 2007). In addition, there were increased health claims at the 3M Decatur plant for diabetes, as well as biliary tract disorders and combined acute and chronic cholecystitis (Olsen et al., 2004). It appears that the combination of all heart disease with the related category, cerebrovascular disease, suggests an overall connection between PFOA exposure and atherosclerosis across the various studies, which is also consistent with effects on serum lipid chemistry. There were also notable increases of white cell neoplasms (Leonard, 2003 ; Leonard et al ., 2008) and carcinoid (Morel-Symons et al ., 2007) at the Washington Works. There are general limitations among the available studies assessed in the draft Toxicologic Profile. These were only partially acknowledged for some studies. In addition, some associations that were reported in the literature were not acknowledged. Many of the studies reported on mortality rates. Death certificates provide information that is frequently inaccurate because there can be multiple contributing causes . For example, prostate cancer is usually not the primary of death in men with prostate cancer . Another example is diabetes. In a study of known diabetic patients (N = 2766), only 10% had diabetes listed as the cause ofdeath (Bild and Stevenson, 1992). In addition, incorrect diagnoses increase with age of the patient (Bain et al ., 1998). The issue of the "healthy worker effect" is partly addressed by internal workplace rate comparisons, but the general failure of available studies to include short-term workers who may have had very high exposures (e.g., those cleaning batch-processing equipment) could have missed important associations . There is a history of many chemical companies using short-term workers to clean the most contaminated equipment . The rationale is that the longer the duration of exposure, the better the chances of detecting an effect if it is true, but that is not necessarily the reality. One interesting observation (Olsen et al., 2003b) is that the highest serum PFOA levels among 3M Cottage Grove plant employees who worked 5 years or less. Of the I I male employees with serum PFOA above 10 ppm, 5 worked 5 years or less, and, likewise, above 20 ppm 4 of the 7 worked 5 years or less. It appears that longer-term employees (up to 40 years) had job duties with much less exposure . Therefore, exclusion of short-term workers with < 1 yr employment, as done in the 3M studies reported above, may undercount exposed cases . Another issue is that the small proportion of female employees limits the ability of the occupational epidemiology to adequately address specific effects among women. A final issue is that differences in the exposure to other chemicals between the different manufacturing facilities may also influence outcomes by effect modification . Blood ChemistrS (Hepatic Effects and Endocrine Effects) Regarding serum liver chemistry observations, both the studies at 3M (Olsen and Zobel, 2007), at DuPont (Sakr et al ., 2007a,b) and at Miteni (Costa et al ., 2009) showed elevated levels of either aspartate aminotransferase (AST), alanine aminotransferase (ALT) or gamma glutarnyl transpeptidase (GGT). One of the potential problems with the blood chemistry studies is the failure to account for sample times relative to biorhythms, i.e., shift, time within shift, and time relative to meals, which can affect the parameters studied Not mentioned in the Toxicological Profile is the finding by Sakr et al. (2007a) that serum calcium, iron, potassium, and the enzyme lactate dehydrogenase were significantly associated with serum PFOA, though the direction of those associations was not given. No mention was made of those parameters in any other occupational study, but the C8 Health Project descriptive statistics revealed similar phenomena with calcium iron, magnesium, and, among women, potassium. The point is that there are data in the literature that were not addressed, and that there may be a significant number of parameters that had also been measured to which study author paid inadequate attention. A more subtle issue is that dose-response may be stronger at lower, environmentally relevant, levels (see Oral Exposure section, below) . Therefore, a comparison of blood chemistry results in the occupational setting, where even the least exposed had levels that were high compared to the highest levels seen in environmental studies, might not always show associations with exposures that are observed within the lower range of exposures in the general population . Oral Exposure : Community and Population-Based Health Studies Community health studies include those conducted and in progress in the area around the DuPont Washington Works facility located in Parkersburg, WV (C8 Health Project and C8 Science Panel). These were largely due to a court settlement. In particular, the Little Hocking, OH, water system had the highest water contamination (?3 ug/L) and its residents had the highest serum PFOA level . Five other communities around Little Hocking had lower levels (?0.05 ug/L) of PFOA in the drinking water. People with at least one year of residence, work or school in one of those communities were eligible for inclusion in the studies . There are various studies in progress and completed. Serum PFC and clinical data were collected for most of the 67,000 subjects. Participation was estimated to be approximately 80% (MacNeil et al ., 2009) . The richness and size of the collected data is unusual for situations of environmental contamination, but was relegated to brief mention in the Ongoing Studies section in the draft Toxicological Profile. The median serum levels in the first and second deciles, 6 and 9.8 p.g/L are within the range prevalent in the U.S. general population, as shown in the 2003-2004 National Health and Nutrition Evaluation Survey (NHANES), where the 75th and 95'h percentile levels were 5 .8 and 9.8 pg/L (Calafat et al., 2007). The highest serum levels in the Little Hocking area were in the 100s to 1000s of ug/L range. The median serum level was approximately 29 ug/L . Serum levels of total cholesterol, LDL cholesterol and uric were significantly elevated with increased PFOA among adults and appeared to plateau at higher levels (Steenland et al., 2009a; Steenland et al ., 2009b) . Similar results were seen for the relationships between PFOA and lipids (C8 Science Panel, 2009b) . The liver enzymes, ALT and AST, also showed a strong dose-response with serum levels of PFOA using with univariate analysis (C8 Health Project, 2009), but the dose-response curve appears to plateau within the concentration bounds ofthe study. Anti-nuclear antibody and the self-reported incidence of Sj6gren's disease and scleroderma, which both primarily affect women, were associated with serum PFOA levels in 30-50 year old females (C8 Health Project, 2009a) . (The Emmett et al. (2006) study ofthe C8 exposed population, which was the first analysis of health effects in these communities to be published, was small and suffered from low participation .) In addition, there have been a series of population-based reproductive outcome studies in a variety of locations around the world. A general comment about those studies is that analysis with more data on potential confounders, such as the Apelberg et al . (2007) study in Baltimore, the Danish (Fei et al. (2007, 2008a,b) study, and a Japanese (Washino et al., 2009) study found associations between reproductive effects and perfluoroalkyls, while those with the less data on confounders (Grice et al., 2007 ; Monroy et al., 2007) did not find associations . This trend of being able to detect associations when there is better adjustment for confounding was also noted by Olsen et al . (2009) . Stein et al. (2009) did not find associations between low birth weight or preterm birth with PFOA in the Little Hocking area, but the incidence of preeclampsia was moderately associated. They di d find that PFOS was associated with preterm births and low birth weight, as well as preeclampsia. However, 60% of the women included in the PFOS analysis were excluded from the PFOA analysis due to missing data on residency in a water system of interest, even though the analysis method used only serum PFOA or PFOS levels . Two population-based studies on adult-onset diabetes (i.e., Type 2) are also available, including one by the C8 Science Panel (MacNeil et al., 2009), which was negative. In that study >20 years of residence in the contaminated water systems was required for eligibility, which excluded many cases . Furthermore, ascertainment depended initially on self-reporting, which probably excluded a large number of adults who were unaware that they were insulin-resistant . However, the Lin et al. (2009) study of2003-2004 data from the CDC National Health and Nutrition Evaluation Survey (NHANES) found an association with PFOA and PFOS and was analyzed with much more biochemical detail relevant to the insulin-resistant form of adult onset diabetes . A matter is that is not addressed by any study at this point is whether there are effects in adulthood resulting from exposures during development (prenatal or infancy), such as the effects seen in the study by Hines et al. (2009) on metabolic endpoints and White et al. (2008) on mammary gland development in mice. Specific Comments Page 4. Public Health Statement, HOW CAN PERFLUOROALKYLS AFFECT MY HEALTH? i Workers i i Inhalation/dermal-Long-term exposure to perfluoroalkyls at work has not been associated with significant adverse health effects, but two studies in workers found changes in sex hormones and cholesterol associated with the levels of PFOA in blood. This statement falls short of describing the published observations and those from the unpublished reports available through the USEPA docket AR-226 which contains a tremendous amount ofpublished and unpublished information on these chemicals. There is reasonable evidence (see above and below), given that most of the investigations are based on death certificates, that exposed workers are indeed affected . ; General ! population ILittle research has been done on the general population to answer the question of ' I whether perfluoroalkyls may be associated with adverse health effects. ~ Ingestion-A single study of people whose drinking water contained ; perfluoroalkyls did not find problems in a number of clinical measures tested . The : ; study did not, however, examine developmental risks for children or cancer . The : 326-person, study was too small to address these issues. ' At this time there are unpublished data as well as peer-reviewed studies stemming from the C8 Health Study of 67,000 subject in Ohio and West Virginia exposed to drinking water contaminated with >_0 .05 ug/L to over 3 ug/L ofPFOA. These studies are using data collected on serum perfluoroalkyls, liver enzymes, lipoproteins, hormones, and other blood constituents, as well as self-reported diseases. The lowest decile of serum PFOA, which has a median of6 ug/L of serum, approximates the 75th percentile level, 5.8 pg/L, found in the 2003-2004 National Health and Nutrition Evaluation Survey (Calafat et al., 2007). The highest levels are in the 100s -1000s ug/L range. More studies are underway. The size of this effort dwarfs the small studies by Emmett et al. (2006a,b) that were cited in the draft Toxicological Profile . Two ofthese studies (Steenland et al ., 2009a,b) show an increased percentage of subjects with clinically elevated cholesterol and uric acid, starting with PFOA concentrations just above the lowest category . Preliminary descriptive statistics from the C8 Health Project suggest that there are other clinical parameters, including serum levels of liver enzymes, hormones and electrolytes that are associated with serum PFOA. The slope of some ofthese appears to be steepest at the lowest deciles of exposure . Page b. Public Health Statement, HOW CAN PERFLUOROALKYLS AFFECT CHILDREN? The C8 Health Study includes almost 5000 children under 10 years old and approximately 7500 children from 10- 18 years old. Preliminary evidence suggests associations of several parameters and serum PFOA levels . The developmental studies noted in the Statement also found associations with PFOS. For example, Apelberg et al . (2007) found associations with both PFOS and PFOA for birth weight and size, Fei et al. (2007, 2008a,b) found associations with PFOA but not PFOS for several measures of fetal growth, and Washino et al . (2009) found associations with PFOS but not PFOA for birth weight. Stein et al. (2009) identified modest associations of PFOA with preeclampsia and birth defects and of PFOS with preeclampsia, preterm births and low birth weight in the C8 Health Study population. Page 7 Public Health Statement . IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO PERFLUOROALKYLS? In the Detecting Exposure section, elevated perfluoroalkyl serum levels in residents exposed to contaminated drinking water have also been found in Germany (Holzer et al., 2009) and in Minnesota (Minnesota Department of Health, 2009). Also, elevated serum PFOA among workers has also been found at other facilities, so the last sentence in this section should start with, "For example," . Pages 7-8 Public Health Statement. WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTH? It should be noted that the USEPA Provisional Health Advisories for PFOA and PFOS are intended to protect for short-term exposure, not chronic exposure . Pages 11-14 Relevance to Public Health . Summary of Health Effects This section is densely packed with summary statements . The General Comments (above) and the Specific Comments (below) show some disagreements with those statements . Certainly, the occupational studies, which are the primary source of the statements, have numerous limitations, e .g., use of death certificates, inclusion of few females, and insufficient person-years for less frequent diseases . The DuPont study that was summarized on Page 14 was based on the whole plant and did not include an analysis by exposure, with the exception of one disease category. Nevertheless, there are concordant findings across a larger body of studies, including new studies and older studies not included in the draft document. The concordant morbidity and/or mortality findings, as noted in General Comments, include diabetes, a combination of cardio- and cerebrovascular end points, bladder cancer and prostate cancer. Blood chemistry results from cross-sectional studies indicate that liver enzymes and lipid chemistry results can be seen as concordant across studies at 3M, DuPont, and Miteni (Italy). The developmental studies are not concordant, but the ones that had better adjustment for confounding found significant outcome associations with serum PFOA levels . Pages 21-22 Relevance to Public Health . Minimal Risk Levels . Human Data. As noted in my General Comments, the draft Toxicological Profile does not present sufficient justification for the decision not to develop a chronic oral MRL based on the animal studies supported by the results of the epidemiology . This was more or less acknowledged in the statement, summarized on Page 25 of the draft, "Although MRL derivation is not recommended for perfluoroalkyls at this time based on the information [on humans] summarized above, relevant information from animal studies that could have been considered for IVIRL derivation (i .e ., studies with the LOAELs) for perfluoroalkyls with at least a minimal size database is summarized below." There are similar epidemiological issues for most chemicals for which MRLs have been developed . By comparing across species by using internal dose and using the relationship between external dose in ug/kg.lday and serum concentration (ug/L) discussed by Post et al . (2009a,b) and Tardiff et al . (2009), one can develop a chronic MRI, in mg/kg/day from the extensive scientific literature on health effects of PFOA in laboratory animals. Clewell (2006) predicts the relationship between exposure and serum level in humans, as discussed in Tardiffet al. (2009) . Cleweli's model predicts factors of 0.1 and 0.127 relating intake (p.glkg/day) to serum concentration (p.g/mL) . Based on mean water ingestion of 17 mL/kg/day (USEPA, 2004), the 100 :1 ratio between serum and drinking water levels (Post et al., 2009a) gives a factor of0.167 ug/kg/day intake per ug/ml in serum (Post et al., 2009b).The USEPA (2005) draft risk assessment also made comparisons between species (e .g. experimental animals and humans) by serum PFOA level. Through the use of uncertainty factors established by ATSDR, USEPA, and other regulatory agencies, one can address the interests of public health before fully resolving the issues in the epidemiology . However, as noted in these comments, there is sufficient support from the results of epidemiological studies, as discussed in these comments to warrant moving ahead with an MRL. The comments provided by Dr. Gloria Post elaborate further on this subject. "The fact that humans take longer to achieve steady state than animals should not preclude the use of animal studies as the basis for a chronic MRL, if the serum levels in animals are used as the basis for the risk assessment. Even though chronic MRLs are defined as applying to exposures of one year are longer, in practice, they are used to address chronic exposures, such as residential exposure to contaminated soil or drinking water. Humans who are exposed through environmental media (e.g. water, soil) at the level ofthe chronic MRL for a duration somewhat shorter than the duration required to reach steady state will have somewhat lower serum levels than they will have at steady state . Thus, application of a chronic MRL for exposures through environmental media (e.g. water, soil) for durations longer than those considered to be "Intermediate" but which are not long enough for steady state to be reached will be protective for potential health effects ." Page 35. Inhalation: Death. Subjects in the Gilliland and Mandel (1993) at the 3-M Cottage Grove APFO plant were assembled from workers with >6 months of employment, which may have excluded short-term highly exposed workers. 3M also conducted a major mortality study of workers at the Cottage Grove plant (Lundin and Alexander, 2007; now published as Lundin et al., 2009). This was in the USEPA docket but was missed . The cohort was assembled from workers who spent one year or more employed between January, 1943 and December, 1997. Follow-up continued until December, 2002. Jobs were categorized by a panel of "veteran" workers and industrial hygienists (Alexander, 2001) as having had jobs with definite exposure, probable exposure and no exposure to PFOA (in the absence of air data or serum levels). There were 68, 368 and 371 death certificates available for workers with definite exposure, probable exposure and no exposure to PFOA. Only 25 deaths were ascertained for those with > 1 year of working in ajob with definite exposure . Exposure-stratified SMRs were calculated by life table analysis using data for Minnesota, and internally compared hazard ratios (HR) were calculated using Cox time-dependent modeling. HRs were adjusted for gender, age at entry to the study, birth year, and wage type (hourly versus salary) . In addition, HRs were generated using actual and imputed smoking data, though there was a problem with the degree of missing data. The SMR for diabetes mortality (N = 18) was elevated among workers with probable (2.0, 95% CI 1 .2, 3 .2) PFOA exposure . In contrast, those never exposed had an SMR of 0.5 . The known exposed group had zero deaths from diabetes, but that group was too small and had too little follow-up time to have meaningful numbers . The adjusted HR comparing those with probable exposure to those with no exposure was 3.7 (95% CI 1 .4, 10). Death from hypertension with and without heart disease was somewhat elevated among those with known or probable exposures, SMR = 1 .7 (95% CI 0.3, 5) and 1 .8 (95% CI 0.4, 5), respectively, stemming from 3 cases in each disease category . The weighted SMR for death from hypertension overall would be 1 .75 with an approximate 95% CI of 0.6 to 4 (using tabulated 95% CI factors for estimating a Poisson-distributed variable; Breslow and Day, 1987). Data on all hourly workers includes 5 deaths from heart disease with hypertension and 4 from hypertension only. The respective SMRs are 2.1 and 1 .8 and the combined weighted SMR would be 1 .95 with an estimated 95% CI of 0 .9 - 3 .7. This is marginally significant and is consistent with elevated deaths from diabetes and an increase in total cholesterol in most occupational- and community-based studies of PFOA. No internal HR comparisons were reported for these categories . Cerebrovascular disease (CVD) exhibited statistically significant adjusted HRs in the range of 5 to 7, based on 3 deaths among those definitely exposed for >6 months, and HRs of approximately 2 among those moderately exposed, based on 19 deaths, depending on whether and which smoking data was included (Lundin and Alexander, 2007). (Adjustment included gender, age at study eligibility, birth year and wage type.) In Lundin and Alexander (2009) the HRs for CVD among workers with high or moderate exposure jobs were 4.6 (95% CI 1.3, 17) adjusted for gender and birth year . The HR of workers with >_5 years of cumulative time in a job with definite exposure was 2.1 (95% CI 1 .0, 4.6) compared with those with <1 year. Stratifying on latency period reduced the HR to 4.4 in the analysis with a 10-year exposure lag. (It is notable that the risk dropped with extended follow-up: the SMR was 1 .6 (95% CI 0 .5, 3.7) based on 5 deaths among workers with definite exposures, but in an earlier analysis (Alexander, 2001) the SMR was notably higher, 2.6 (95% C10.84, 6.0), based on the same 5 deaths, and 3 .1 (95% CI 0.89, 8.5) when analyzed by cumulative exposure . In that study workers with >_5 years of exposure to PFOA had 3 observed deaths from CVD while 0.42 deaths were expected, yielding an SMR of7.1 with an estimated 95% CI of 1 .5 to 21 .) This observation would be consistent with decreasing risk after exposure was diminished, e.g., by changingjobs or retirement, but that analysis was not presented. The SMR for death from prostate cancer among workers with known exposure for any amount oftime was 2.1 (95% CI 0.4, 6.1), based on 3 cases, while workers with probable exposure had an SMR of 0.9 and office-based employees had an SMR of 0.5 . Workers with at least one year of known exposure had an SMR of 2.7 (95% CI 0.3 - 10), based on 2 cases . The HR for the high exposure group was statistically significant 6.6 (95% CI 1 .1, 38), based on 2 deaths, while those in the moderately exposed group exhibited an HR of 3.0 (95% CI 0.9, 9.7), based on 10 deaths . The HR in the combined moderate and high exposure category was 3 .2 (95% CI 1 .0, 10) . The HR of workers with >5 years of cumulative time in a job with definite exposure was 3 .7 compared withthose with <1 year . Adding a 10-year latency period (Lundin and Alexander, 2007)) increased the respective adjusted HRs to 8 (95% CI 1 .5, 45) and 3.4 (95% CI 1 .1, 11), based on 2 and 8 deaths, respectively . Inclusion of data on smoking had only a small effect on the observed HRs. Since most prostate cancer is a disease from which men usually die of other causes before it becomes fatal, these numbers may represent death from more aggressive forms of the cancer. Limitations of this study included the reliance on mortality data, the relatively small number of definitely exposed workers and their ascertained deaths, and the exclusion of workers with less than one year of employment. This latter approach may miss very high exposures among short-term workers who have been found in other occupational studies to be used to conduct cleanings of highly contaminated equipment, such as batch reactors . In addition, for the HR analysis those employed for less than 6 months in high exposure job were added to the probable exposure group, which may have removed some employees who should have remained a purely high exposure group analysis. Another limitation was that smoking data, an important risk factor for bladder cancer, was available for only 36% of the cohort, though there was a much greater percentage (65%) from those with definite exposures compared with the unexposed (20%) . Among those with data, workers definitely exposed to PFOA had a higher prevalence of those who ever smoked, 65%, compared to unexposed workers, 47%, but there may be substantial bias due to the minimal data available. Lung cancer was not increased among any exposure group. Page 36. Inhalation: Death. The Alexander et al. (2003) study at the 3-M Decatur plant required at least one year of employment to be included in this analysis, which similarly may have excluded shortterm highly exposed workers. Notably, the 1998 bionaonitoring at the Decatur POSF plant conducted by Olsen et al . (2003b) showed serum PFOA levels as high as PFOS levels, which indicates that PFOA levels were elevated even before initiation of PFOA manufacture in 1999, and that the epidemioiogy conducted at that plant is relevant to the discussion . There was little relationship between individual PFOS and PFOA levels . Deaths from cerebrovascular disease and heart disease were not elevated, but there were too few cases ofthe former to support any conclusion . Diabetes mortality was not reported. Page 36 Inhalation : 'Death . As noted in the Toxicological Profile, follow-up of bladder cancer occurrence (incidence and mortality) among the 2083 3-M Decatur workers through 2002 was more thorough, using a series of outreach efforts with questionnaires to obtain information (Alexander and Olsen, 2007). A total of 11 bladder cancer cases were ascertained, compared with 3 cases in the earlier effort (see above), though 4 more self-reported cases were not included since they did not consent to validation . Thus, the exposures of those 4 cases were not characterized and the effect of their exclusion was not tested in a sensitivity analysis. Bladder cancer was elevated for the whole group of participants, 11 observed versus 8 .6 expected, SIR = 1 .3 (95% C10 .64, 2.3), though ifthe 4 excluded cases were also counted, the SIR would be 1 .7 (0.98, 2.9 ; using tabulated 95% Cl factors for estimating a Poissondistributed variable ; Breslow and Day, 1987). Although there are various study limitations, these findings are consistent with the observation ofelevated bladder cancer incidence among DuPont workers (Leonard, 2003 ; see below). A minor note is that the text in the Toxicological Profile states that this follow-up of bladder cancer at the Decatur plant included "all current, retired, and former employees", as well as information about 188 deceased workers. The writers probably did not intend to confuse the reader by implying that even short-term employees were included in this analysis . In fact, this is exactly the same cohort as in Alexander et al. (2003), but with more through follow-up that also added 5 additional years. Epidemiological investigations at the Decatur plant also included a health claims study (Olsen et al., 2004), which is discussed in more detail below (Inhalation: Cancer and Inhalation : Endocrine Effects) . Pages 37-38 Inhalation : Death. The Leonard (2006) study of mortality at the DuPont Washington Works from 1948 through 2002 has been published (Leonard et al., 2008 and Sakr et al., 2009). The text in the Toxicological Profile should make clear that all SMRs were based on the entire plant, without additional analyses by exposure orjob category. Only the Cox proportional hazards modeling of IHD (Sakr et al., 2009) employed exposure categories and cumulative exposure. Regarding diabetes, the Toxicological Profile states that the "investigator noted that the lack of agreement with other studies ofPFOA workers" . This is in sharp contrast to results at the 3-M Cottage Grove plant (Lundin and Alexander, 2007) where the SMR for diabetes mortality (N = 18) was elevated among workers with probable (2 .0, 95% CI 1 .2, 3.2) PFOA exposure . In contrast, those never exposed had an SMR of 0.5 . At the 3-M Decatur plant health claims for diabetes among those with 10+ years of employment in the chemical plant was 30% elevated above expected with marginal significance . Of course, as note above, death certificate ascertainment of and treatment for adult-onset diabetes are likely incomplete. In addition to the elevated internal SMRs for kidney cancer and diabetes mentioned in the Toxicological Profile, death from hypertension without heart disease was elevated compared to other DuPont workers in the region, though not to statistical significance (SMR = 2 .0 ; 95% CI 0.7, 4 .8 ; based on 5 deaths) . The impact on deaths attributed to hypertension and diabetes is consistent with observations at 3-M plants. Page 46 Inhalation: Cardiovascular Effects. : DuPont Washington Works In contrast to the statement made in the Toxicological Profile that there is "no convincing evidence of increased mortality due to heart disease in general or IHD specifically" in Leonard et al. (2006, now published as Leonard et al . (2008) and Sakr et al. (2009)), death from all heart disease (N = 314) was elevated with marginal statistical significance : the internally-based SMR for all heart disease was 1 .10 (95% CI 0.98, 1 .23) and the internally-based SMR for IHD (N = 239) was (1.09,95% CI 0.96, 1 .24). In heart disease studies even small elevations are regarded as important because of the frequency of occurrence. The SMRs for females were higher, but based only upon a handful of deaths . In addition, death from hypertension without heart disease was elevated compared to other DuPont workers in the region, though not to statistical significance (SMR = 2.0; 95% CI 0.7, 4.8; based on 5 deaths) . Only IHD was examined by exposure category and was found to be 40-60% elevated with marginal statistical significance among those in the third and fourth quartiles of serum PFOA . Sakr et al . (2009) concluded that there was "no convincing evidence" to link PFOA exposure to IHD mortality, but there was a general trend and the inability to adjust for known confounders could easily obscure an actual association. The Toxicological Profile did not include Lundin and Alexander (2007, published in 2009), which is described below. Discussion ofthis study should be added. It provided strong evidence of an association between job exposure to PFOA and cerebrovascular disease as well as the suggestion that deaths attributable to hypertension were also associated with job exposure. In addition, in Leonard (2003, see "new" studies, below) the SMR for acute myocardial infarction was 1 .4 (95% CI 1 .2, 1 .6), based on 126 cases and the SMR for atherosclerosis and aneurysm was 2.0 (95% CI 1 .2, 3.1), based on 18 cases, respectively from the 19572000 period . There was no analysis by exposure measures (job, serum PFOA, or duration) or personal lifestyle, BMI or SES . Page 47 Inhalation : Hepatic Effects . The study at the 3M Cottage Grove conducted by Gilliland and Mandel (1996) was small, as noted, composed of all directly exposed workers employed between 1985 and 1989 (N=50) and 65 randomly picked "low" exposure workers (without direct exposure for at least 5 years) workers. Total serum organic fluorine, representing all polyfluorinated chemicals, was used as a surrogate for PFOA exposure . Having "low" exposure workers was meant to provide a range of exposures, but this group had high total serum fluorine levels as well. Page 48 Inhalation: Hepatic Effects . This longitudinal study (Olsen et al., 1999) of blood sampling at the 3-M plants in Decatur and Antwerp in 1995 and 1997 was small and depended on volunteers. Missing from the description of the study in the draft Toxicological Profile are observations that are consistent with those in other studies . Total cholesterol exhibited a marginal statistically significant increase with serum PFOS in the 1997 sampling at each locations. Alkaline phosphatase displayed a non-significant trend of increase with serum PFOS in both 1995 and 1997 with combined data from both plants, while GGT showed a similar trend of increase in the 1997 data. Those with the highest serum PFOS exhibited a notably higher mean and median AST (33 IU/L) than the lowest category (25 IU/L) in the 1995 testing, while median ALT was notably elevated in the highest serum PFOS category (49 and 45 fU/L) versus the lowest PFOS category (43 and 301U/L) during both years. Unfortunately, there were no statistical tests to compare PFOS categories with the lowest category . As noted in the draft, there were only a handful ofvolunteers in the highest category . Page 48 Inhalation: Hepatic Effects . In addition to what is noted in the draft Toxicological Profile, multivariate analysis of combined data from all 3M plants showed statistically significant associations between PFOA and increased ALT and GGT (Olsen and Zobel, 2007). Analysis of the separate plants found a significant association of PFOA with increased AP, ALT, GGT, and marginally significantly increased cholesterol and TG among the workers at the Decatur plant. Serum AST was associated with PFOA among workers at the Cottage Grove plant. Exceedances of clinical reference range at the combined group of workers were greater in the 7th, 8th and 9th PFOA deciles for ALT and TG and the 9th and l Oth PFOA deciles for GGT. Page 49 Inhalation: Hepatic Effects. In addition to what is noted in the draft Toxicological Profile about the Sakr et al. (2007a) study at the DuPont Washington Works, slopes for TG, LDL and ALT were positive . Statistical significance may have been difficult to achieve for ALT and GGT since there were only 233 tests available for analysis . Because of differences in longitudinal participation and because there were more than one test per individual, some individuals carried greater weight in the analyses . Page 49 Inhalation : Hepatic Effects . In the subset of the Sakr et al . (2007b) study in which persons using lipid/cholesterol control agents were excluded, serum PFOA was statistically significantly associated with elevated serum AST and ALT, in addition to elevated GGT noted by the draft Toxicological Profile . Age and family history were not statistically significant covariates for any measured serum liver enzyme or bilirubin and alcohol use was not significant for bilirubin . The models where PFOA was statistically significant explained 14 - 29% of the variance . This is important because it demonstrates that there was a greater association of liver chemistry endpoints with PFOA after obvious confounding was removed without over-adjusting . Page 49 Inhalation: Hepatic Effects . The Costa et al. (2004) study ofthe Miteni plant (Italy) has been published with updates (Costa et al., 2009). Testing in the 2000-2007 timeframe showed an association between PFOA and AST, ALT and GGT. Pages 51 and 54 Inhalation : Endocrine Effects and Reproductive Effects . The Toxicological Profile correctly notes that among male workers, estradiol and testosterone were elevated with higher serum PFOA in both the 3M (Olsen et al., 1998) and the DuPont (Sakr et al., 2007b) cross-sectional studies . (Unfortunately, the DuPont study did not give the units or further elaborate, so it is difficult to further interpret those findings .) However, the statement, "Taken together, the results showed no significant hormonal changes at the levels of PFOA measured [in the 3M study].", does not fit with the acknowledgement of similar findings at DuPont. The statement refers to the small number of workers in the high exposure groups and confounding by BMI, but the commonality of findings should be the focus ofattention . Unfortunately, hourly changes in the release of many hormones and the pulsatile nature of that release means that multiple samples should be taken and that time of day and, for occupational studies, shift, should be included in the analyses . In these studies there was only one sample. Page 51 Inhalation: Renal Effects. While it is not clear whether renal function was affected, certain serum metals, calcium, iron, magnesium, potassium, and sodium had higher serum levels with increasing serum PFOA among workers at the DuPont Washington Works (Sakr et al., 2007a) . This is consistent with univariate results from the C8 Health Project. Page 52 Inhalation : Endocrine Effects. It should be noted that there is only one occupational study ofthyroid hormones . In addition, iodine sufficiency (urinary iodide) should also be measured in any study of potential thyroidal impact. The health claims study at the 3M Decatur plant (Olsen et al., 2004) found that claims for diabetes was marginally elevated (RR = 1 .3, 95% CI 0.9, 2.0), based on 42 cases among those who worked >10 years in the chemical plant . Page 54 Inhalation : Developmental Effects. The Grice et al. (2007) study of the 3M Decatur plant should be dropped from consideration for developmental effects because gestational age, the single most important determinant of birth weight, was not available for inclusion in the analysis . Page 55 Inhalation: Cancer. Again, the study at the DuPont Washington Works (Leonard, 2006, Leonard et al ., 2008) had no analyses based on exposure, except for the analysis of IHD (Sakr et al., 2009). The DuPont Cancer Registry surveillance report from Leonard (2003) indicated that bladder and kidney cancer incidence among male employees was elevated during the 1959-2001 period . The Registry relies on data from active employees and STRs were calculated based on internal comparison (5-year time and age categories) with companywide incidence rates. The respective SIRs for bladder and kidney cancer were 1 .9 (95% CI 1 .2, 3.1) and 2.3 (95% CI 1 .4, 3.6), based on 18 cases each. They point out that the incidence of both types of cancer was higher in West Virginia than in the U.S . or in neighboring Ohio. However, elevated bladder cancer is consistent with the analysis of mortality among workers at the 3M Decatur facility (Alexander et al., 2003 ; see above). In addition, myeloid leukemia incidence was marginally significantly elevated, SIR = 2.0 (95% CI 0.86, 4.0), based on 6 cases, and multiple rnyeloma incidence had an SIR of 1 .7 (95% CI 0.69, 3 .6), based on 7 cases. Including 2 cases (0 .14 expected) among females attributed to combined multiple myeloma and immunoproliferative neoplasms, resulted in an SIR of 2.1 for the entire group with an estimated 95% CI of 1 .0 - 4.1 (using tabulated 95% CI factors for estimating a Poisson-distributed variable ; Breslow and Day, 1987). There was no analysis by exposure, duration or personal lifestyle (e.g., tobacco and alcohol use), BMI or SES. Leonard (2003) also reported on internally-based SMRs among males from the DuPont Mortality Registry from 1959 through 2000. In general there were too few female employees and too few deaths, with one exception, noted below. Death from bladder (N = 7) and kidney (N = 8) cancer had SMRs of 1 .6 (95% CI 0.64, 3 .3) and 1 .5 (95% CI 0.68, 3 .0), respectively, which is consistent with the incidence results. Similarly, death from myeloid leukemia (N = 6) and combined multiple myeloma and immunoproliferative neoplasms (N = 5) had SMRs of 1 .7 (95% CI 0.62, 3 .7) and 1 .4 (95% CI 0.46, 3 .4), respectively . Including 2 deaths (0.11 expected) among females attributed to combined multiple rnyeloma and immunoproliferative neoplasms, resulted in an SMR of2.0. Death from non-cancer blood and blood-forming diseases had an SMR of 3 .0 (95% CI 0.95, 6.9). The SMR for diabetes deaths (N = 12) was 1.6 (95% CI 0.81, 2.75) . The SMR for acute myocardial infarction was 1 .4 (95% CI 1 .2, 1 .6), based on 126 cases and the SMR for atherosclerosis and aneurysm was 2.0 (95% CI 1 .2, 3.1), based on 18 cases, respectively . There was no analysis by exposure measures (job, serum PFOA, or duration) or personal lifestyle, BMI or SES . In addition, there was an elevated incidence of carcinoid tumor at the Washington Works (Morel-Symons et al., 2007). Epidemiological investigations at the 3M Decatur plant also included a health claims study . Analysis of 1993-1998 health claims compared workers at the POSF ("chemical") plant with workers at the film plant (Olsen et al ., 20l)4) . (This time frame is prior to the start of PFOA production, but biomonitoring in 1998 (Olsen et al., 2003b) showed serum PFOA levels as high as PFOS levels .) There were 652 and 659 workers, respectively, included in the analysis, including 211 and 345 workers employed for >_10 years before 1993. Some workers had worked in both plants, but were not analyzed separately, which might mask associations . The expected number was based on "a normative database, which consisted of the remainder of the 3M manufacturing population" in the U.S. (approximately 20,000 workers) and calculated with an "employee health claim grouper (EHCG) software used by the Ingenix Employer Group. It found that among male workers (N = 530) there were 5 prostate cancer "episodes of care" (involving 5 unique individuals) versus an age-adjusted expected number of 3 .1, an RR = 1 .6. (In this instance that means 5 unique cases.) A relative comparison with male workers at the neighboring "film" facility, which did not have direct exposure to POSF, yielded an RR of 7 .7 (95% CI 0.9, >100). Among long-term workers, the RRs were increased: RR = 2.7 (based on 4 unique cases) and employment in the chemical versus the film plant, RR = 8.2 (95% CI 0.8, >100). In addition, there were 59 episodes ofcare for enlarged prostate (involving 53 unique individuals) versus an expected 40.6, an RR = 1 .5 . Likewise, the number ofacute prostatitis episodes was increased, 73 versus 39 .2 expected based on 55 unique individuals. However, these latter two conditions were also elevated among male workers at the neighboring "film" facility . Therefore, it is possible that the workplace population in that location was more prone to prostate ailments. An important limitation is that the analysis was not adjusted for possible confounders, including smoking. Gastrointestinal tract problems that were increased among long-term chemical plant versus film plant workers included malignant and benign colon cancer. There were 3 unique malignant cases (versus an expected 0.8) in the chemical plant compared to zero cases (versus an expected 1 .6) in the film plant. Among long-term workers, the RR for benign colon cancer in the chemical plant was 2 .4, based on 20 unique individuals, while it was approximately 1 .0 in the film plant, based on 18 unique individuals. The internal comparison RR was 2.4 (95% CI 1 .3, 4.5) . Page 116 Oral: Hepatic Effects. The low participation, 30-50% in the randomly selected portion of the Emmett et al . (2006) study subjects (N = 343 in 161 households) and the additional group of subjects (N = 54 in 35 households) who were volunteers selected by lottery potentially allows for significant selection bias . The median serum PFOA concentration, 354 ng/mL, was much higher in this study than in the C8 Health Project (28 ng/mL, see below). (Eighteen subjects were occupationally exposed and probably accounted for the top 5% ofthe serum PFOA levels.) Despite those negative findings of the small Emmett study, descriptive statistics from the large, high participation C8 Health Project (2009) showed that serum levels of the liver enzymes, AST and ALT, are elevated with increasing serum PFOA levels in the C8 Health Project, while in the Emmett et al. study the slope estimates are negative . However, in the Emmett study the AST and ALT levels over the serum PFOA interquartile range (25%-ile - 75%-ile, 184 - 571 ng/mL) are 18 and 27 IU/L and 15 and 27 IU/L, respectively . In addition, serum levels of the liver enzyme, GGT, over the interquardle range ofserum PFOA were 14 and 27 IU/L . Similarly, the interquartile range for total cholesterol was 172 and 220 mg/dL. These results were univariate (i.e., not adjusted by age, gender or medications) . Recently, analysis oftotal cholesterol by the C8 Science Panel (Steenland et al., 2009a) showed that the OR for cholesterol levels being above the clinical reference range (>240 mg1dL) in adults in the C8 Health Project were 1 .2, 1 .3 and 1 .4 for the second, third and fourth quartiles, respectively, of serum PFOA versus the first quartile . All ORs were statistically significant . Similar results were seen for PFOS . In addition, extensive regression analyses showed statistically significant associations of both PFOA and PFOS with total cholesterol, LchDolLesctheorloelstreartoilo,. toAtnaallnyosins-oHnDlLy cohfolseusbtjeercotls,ttarkiignigycleirpiiddescoanntrdotlhe total cholesteroUHDL medications results in similar, though muted, associations with PFOA, but there was "no consistent trend" for PFOS. All analyses were adjusted for age, gender, BMT, education, exercise level and current alcohol consumption. Also recently, Steenland et al. (2009b) found that uric acid was associated in a doseresponse manner with increasing deciles of both PFOA and PFOS . Elevated uric acid has been linked to hypertension, and with less evidence to stroke, diabetes and metabolic disease. They also showed a dose response by quartile categories set up within the <20 ug/L subgroup, i.e ., the response is present within the range of general population exposure . These results have also been found in children (C8 Science Panel, 2009b) . One question that arises is whether the relationships that seem obvious in the much larger C8 Health Project, a clear dose-response, are not observed in the Emmett et al. study because the effects (e.g., total serum cholesterol) occurred within the lower exposure ranges and plateaued at higher serum PFOA concentrations. This is especially significant because the associations exhibited no threshold down to the lowest deciles of exposure (see figure in Steenland paper), and the serum levels in the lower deciles in the C8 study population are within the range of exposures of the general US population (Calafat et al., 2007). Page 124 Oral : Renal Effects While it is not clear whether renal function was affected even though creatinine levels were not changed (Steenland et al., 2009b), certain serum electrolytes, calcium, iron, magnesium, sodium among adults, and potassium among women, had higher serum levels with increasing serum PFOA in the preliminary descriptive statistics (C8 Health Project, 2009). This finding is consistent with that observed by SalQ et al. (2007a) at the DuPont Washington Works. No other study reported on that, though the data was probably collected . Page 125 Oral : Endocrine Effects. Regarding the overall negative findings in the Emmett et al. (2006) study, the low participation, 30-50% in the randomly selected portion of the study subjects (N = 343 in 161 households) and the additional group of subjects (N = 54 in 35 households) who were volunteers selected by lottery potentially allows for significant selection bias . Regarding the lack of effect on thyroid hormones, iodine sufficiency (urinary iodide) should also be measured in any study of potential thyroidal impact. In addition, the pulsatile nature of protein or peptide hormone release means that multiple blood sample should be taken for greater accuracy . Recently, Lin et al. (2009) examined a subpopulation ofNHANES participants at least 12 years old (N = 3,685) tested for perfluoroalkyl chemicals. This study had a great amount of biochemical, health behavior and body measurement data available for inclusion in the analysis, as well as diabetes diagnostic methods. However, NHANES is a cross-sectional study and it cannot be easily determined whether the diabetes symptoms preceded the exposure or the reverse. Serum PFOA was significantly associated with pancreatic beta-cell function (all three step-wise statistical models), and with blood insulin measurement (in the fully saturated model) . Covariates included age, gender, BMI, family history of diabetes, and use of relevant medicines. PFOS was associated with both measures and with the calculated measure, homeostasis model assessment - insulin resistance (HOMA-IR). Since the authors chose to show probabilities only for statistically significant associations, there may be more diabetes diagnostic indicators that have marginal statistical significance . Also recently, MacNeil et al . (2009) reported on the incidence of self-reported adult-onset diabetes (diabetes 2) that had been validated by medical record check and its relationship to serum PFOA in the C8 Study population. The data was analyzed as a case-control study, and controls were non-cases among the eligible population . The study population was restricted to a subset with at least a 20-year residency in the area prior to diagnosis, though the entire group (without restrictions) was also examined . No association was found in any decile of serum PFOA . Fasting blood glucose levels were also not associated with serum PFOA, though properly treated individuals would be less likely to show elevated glucose levels . There are several limitations . Cases were lost because of missing residency data even though the serum PFOA and PFOS were used in the analysis . This could have introduced an ascertainment bias. In addition, since the study group is based on self-reporting before medical record validation, that may exclude many who are unaware of their adult-onset diabetes, since there is evidence that insulin-resistance is significantly under-diagnosed in the general population, depending on access to health care (U.S. Preventive Services Task Force, 2008). The proportion of unidentified cases was estimated to be 30-50% of the total number of cases. Another concern, which the authors also noted, is that the covariates they used in their analysis "may be intermediates on the pathway from exposure to disease, and therefore arguably should not be controlled in the analysis" . Lastly, the authors also noted that since the study was cross-sectional in nature (even though they used a case-control type ofanalysis), it cannot be used for causality, i.e., one can't determine whether "exposure preceded disease". In the crude descriptive data for estradiol, testosterone and prolactin (C8 Health Project, 2009), there appear to be notable changes with serum PFOA, especially in the tables and figures divided by age and gender. Page 131 Oral : Immunological and Lymphoreticular Effects . The C8 Health Project (2009a) descriptive statistics and the C8 Science Panel (2009) Status Report on immunological effects showed increased levels of anti-nuclear antibodies (suggestive of autoimmune disease) as well as occurrence of self-reported scleroderma and Sj6gren's syndrome (autoimmune diseases) in women with higher serum PFOA. In addition, it is interesting that C-reactive protein levels are notably decreased with increasing PFOA . The change in CRP is of large magnitude and indicates that PFOA at these levels is having a biological effect consistent with known effects of PPAR alpha activators, such as the fibrates, in humans. Serum levels of immunoglobulins A and E also showed a steady, though small, decrease with increasing serum PFOA. Page 135 Oral: Reproductive Effects. The C8 Health Project (2009) descriptive statistics showed notable effects on estradiol and prolactin levels in females with higher serum PFOA. In both girls and women estradiol was lower with higher PFOA, while lower prolactin was associated with higher serum PFOA in females over the 16 years old. The new study by Fei et al., (2009) showed a longer time to conception with increasing maternal serum PFOA and PFOS in the general population . Women in each ofthe three highest quartiles of each chemical exhibited approximately one-third greater risk of having a time-to-pregnancy >12 months than those in the respective lowest quartile. The new study by Joensen et al. (2009) showed an association between serum PFOA and spermatozoa quality and number in young Danish men. Page 141 Oral : Developmental Effects . In the Washino et al. (2009) study maternal serum PFOS was statistically significantly associated with birth weight of females, but not males. Maternal PFOA was not associated with birth weight. However, adjustment only for gestational age, the most significant confounder, resulted in a statistically significant slope coefficient for PFOA versus birth weight of all infants and of female infants and a marginally significant slope coefficient for PFOA versus head circumference among males . One potential major limitation of this study was the low participation rate, 29%, which could have resulted in selection bias. In addition, maternal age, parity and BMI, included as covariates in the fully adjusted models, were also related to serum PFOA level (i.e., they are probably intermediate variables) . This could have reduced the regression coefficients in the fully adjusted models . Lastly, the relatively low levels of PFOA in serum in this study may have limited the accuracy ofthe exposure assessment, given the detection limit of 0.5 ug/L (7% ofwomen had no detectable PFOA) . The new study by Monroy et al. (2008) was a small hospital-based prospective study (N = 101) that was part of a larger Family Study cohort recruited during 2004-2005 in Hamilton, Ontario. A significant limitation of this study was the very low (10%) recruitment rate, which could allow substantial selection bias. No association was found between PFOA or PFOS and birth weight, but no detail was reported on the regression analysis to find out whether there was a trend that would have been statistically significant in a larger study. Page 142 Oral: Developmental Effects. In addition to the extensive limitations ofthe Nolan et al. (2009) study discussed in the Toxicological Profile, including the lack of any individual-based data on exposure or key confounders known to influence birth weight and gestational age (e.g., parity, smoking status, nutrition, and socioeconomic status), one should also include potential misclassification of residential history related to moving to a residence more appropriate to a larger family prior to the birth, but with a different PFOA exposure level) . This is more important for this study since serum PFOA data was not available for incorporation into the analysis . The C8 Science Panel (Stein et al., 2009) reported results of a case-control study on the outcome of pregnancies during the 5 years before enrollment (August, 2005 through July, 2006) among women whose residence during their live or stillborn singleton pregnancy was completely in one of the water districts targeted by the C8 Health Project or whose residence during the 90 days before their miscarriage was in one of the targeted water districts. In addition, there was a separate analysis of serum PFOS that was not focused on water districts, which looked at all pregnancies regardless of drinking water source . There were 5262 singleton pregnancies in women whose serum was analyzed for PFCs among 3996 unique women. The water system-based PFOA study excluded 3290 pregnancies mostly due to missing data on water district, for a total of 1972. That analysis centered on white women with no history of pre-pregnancy diabetes for whom there was a complete set of data, 1845 pregnancies . The PFOS analysis included all 5262 pregnancies . Preeclampsia, a potentially dangerous syndrome that can occur late in pregnancy, was marginally associated with serum PFOA above the median (adjusted OR = 1 .3, 95% CI 0.9, 1 .9), compared to those below the median, but the risk was lower above the 75th percentile. Miscarriage, low birth weight (LBW, < 5.5 pounds) and preterm birth (?3 weeks early) were not associated. Neither birth weight nor gestational age at birth was analyzed as a continuous variable . Serum PFOS level above the 90th percentile was associated with preterm birth. The 75th - 90th and the 90th percentile of PFOS were associated with a higher risk of LBW in comparison to PFOS less than the median. Preeclampsia was also associated with PFOS, both above versus below the median and above the 90th percentile versus below the median . Birth defects were not associated with PFOS . Important limitations are 1) the quality of the self-reported information, especially since birth records had not been accessed for this study, 2) the PFOA study design that excluded approximately 60% of pregnancies mostly because of incomplete data on residency in water system of concern during pregnancy even though the analysis was based on the serum PFOA level, and 3) lack of data on maternal BMI and infant gender . The study did not conduct a sensitivity analysis by examining the full group, i.e, the same set of subjects analyzed for PFOS. The investigators are developing exposure reconstruction models, which will allow inclusion of greater numbers of pregnancies Page 148 Oral: Cancer. As noted above, the occupational exposures were thought to be primarily from inhalation. However, this has not been studied and at least one author has suggested that oral exposure may have accounted for a significant amount of the absorbed perfluoroalkyl chemicals . Cancer incidence was prospectively studied in a subset of a cohort (N = 57,000) assembled from 50-65 year olds in the Danish general population during December, 1993, through May, 1997 (Eriksen et al., 2009). Cancer cases (713 prostate, 332 bladder, 128 pancreas and 67 liver) that occurred in this cohort were ascertained from the Danish Cancer Registry and the Danish Pathology Data Bank after a median 7 years of follow-up ending at the start of July, 2006. Those cases (N = i 111 males and 129 females) and a random sample (N = 680 males and 92 females) of those not diagnosed with cancer were tested for serum PFOA and PFOS. PFOA and PFOS were high correlated (R = 0.70), and median levels were 6.9 and 35 ug/L, respectively, among control males, and 5.4 and 29 ug/L, respectively, among control females. Females with cancer had slightly higher PFOA, 6.0 ug/L. Only pancreatic cancer exhibited a notably increased, but not statistically significant, RR = 1 .6 among those in the fourth quartile of PFOA. Bladder and liver cancer cases had a reduced incidence with higher PFOA, while prostate cancer incidence was slightly elevated. However, PFOS was marginally associated with increased prostate cancer in the 2nd, 3rd and 4th quartiles. The RR for the 4th quartile was 1 .4 (95% CI 0.99, 1 .9). Page 190 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models. Risk Assessment. Extrapolations based on serum levels, as discussed by Post et al. (2009) and Tardiffet al . (2009) avoids the limitations of extrapolating between pharmacokinetic models for different species. Page 198 Animal-to-Human Extrapolations. The text states that "No significant health conditions have been associated with the serum levels of perfluoroalkyls . . ." and "Health evaluations ofperfluoroallcyl workers . . . or ofpeople undergoing high environmental exposure . . . have not provided evidence of adverse effects" . The summary of human health and serum chemistry results should reflect the concordances noted in these Comments . The weight of evidence is not that clear cut. In addition, there is little rationale for the statement, "Thus, the lack of reported health effects at the reported body burdens precludes identifying the animal model that would be most appropriate for human risk assessment based on similar toxic effects .". The epidemiology has numerous limitations, as discussed in this document ; however, as also noted here, the health effects reported in the epidemiological literature are more concordant, given those limitations, than the opinion expressed in the Toxicologic Profile. ATSDR should not use that rationale to avoid development of Maximum Risk Levels (MRLs). In addition, as noted in the comments by Dr. Post, the public health logic of this sentence is unclear : "As a result ofthese large differences in kinetics, internal doses (i.e., serum concentrations of PFOA) achieved during intermediate-duration exposures in rats or monkeys would not represent steady-state internal doses that might be achieved in humans over longer exposure durations." Page 198-200 Toxicities Mediated through the Neuroendocrine Axis. The Toxicological Profile correctly notes that among male workers, estradiol and testosterone were elevated with higher serum PFOA in both the 3M and the DuPont cross-sectional studies. (iJnfortunately, the DuPont study (Sakr et al., 2007a) did not give the units or further elaborate, so it is difficult to further interpret those findings .) It is interesting that the C8 Health Project findings suggest that estradiol decreased among females with increasing serum PFOA. Page 203 Children's Susceptibility. The ongoing C8 Health Study will also provide information on associations of many endpoints with PFOA exposure in children . Notably, children exposed to PFOA in drinking water had higher serum PFOA levels than adults (Emmett et al., 2006, Steenland et al., 2009c). This could be due to greater water consumption per kilogram body and/or differences in the toxicokinetics . Page 207 Biomarkers Used to Characterize Effects Caused by Perfluoroalkyls . The following sentence should be deleted, based on the comments provided here : "Health evaluations of workers exposed to perfluoroalkyl compounds or of subjects environmentally exposed via their drinking water have not provided evidence of adverse health effects in the groups studied (Emmett et al. 200ba; Mundt et al. 2007; Olsen and Zobel 2007; Olsen et al. 1999, 2003a; Sakr et al. 2007a, 2007b) ." Page 207 Populations that are Unusually Susceptible. As mentioned in Steenland et al . (2009a), several studies have shown associations with increased liver enzymes, so it is agreed that people with compromised liver function may be particularly susceptible. Page 212 Existing Information of Health Effects of Perfluoroalkyls. A variety of C8 Science Panel studies have recently been published in peer-reviewed publications and more are expected. As well, studies based on the NHANES are being published. It can no longer be said that there are "limited" data on environmental exposures . Page 213 Identification of Data Needs. There is currently sufficient information with a "sufficient degree of certainty" to develop a chronic oral MRL for PFOA. This is also addressed in the comments on the Minimal Risk Levels portion of the Relevance to Public Health section. Page 214 Chronic-Duration Exposure and Cancer . I disagree with the statement that "for the most part, no significant adverse effects have been identified", as outlined in the General Comments here and in the Specific Comments . This section should also discuss the DuPont incidence study (Leonard, 2003) the recent occupational 3M mortality study of Lundin et al. (2009), the blood chemistry study of Miteni workers in Italy, as well studies of chronic exposure in the community (Lin et al., 2009; MacNeil et al., 2009; Steenland et al., 2009a,b) . There is more concordance among the studies than discordance . Page 216 Reproductive Toxicity. Both the study on spermatozoa quality and number (Joensen et al., 2009) and the study by Fei et al. (2009) on increased time to pregnancy found associations with PFOA and PFOS . Page 218 Developmental Toxicity. In addition to the extensive limitations of the Nolan et al. (2009) study discussed in the Toxicological Profile, including the lack of any individual-based data on exposure or key confounders known to influence birth weight and gestational age (e.g., parity, smoking status, nutrition, and socioeconomic status), one should also include potential misclassification of residential history related to moving to a residence more appropriate to a larger family prior to the birth, but with a different PFOA exposure level) . This is more important for this study since serum PFOA data was not available for incorporation into the analysis . In the Washino et al. (2009) study adjustment only for gestational age, the most significant confounder, resulted in a statistically significant slope coefficient for PFOA versus birth weight and a marginally significant slope coefficient versus head circumference among males. A major limitation of this study was the low participation rate, 29%, which could have resulted in selection bias. In addition, maternal age, parity and BMI, included as covariates in the fully adjusted models, were also related to serum PFOA level (i.e., they are intermediate variables). This could have reduced the regression coefficients in the fully adjusted models . The C8 Science Panel study of low birth weight, preterm birth, birth defects, miscarriage and preeclampsia of pregnancy by Stein et al. (2009) observed associations between PFOS and low birth weight, preterm birth and preeclampsia and marginally between PFOA and preeclampsia. However, neither birth weight nor gestational age at birth was analyzed as a continuous variable . Important limitations are 1) the quality of the selfreported information, especially since birth records had not been accessed for this study, 2) the PFOA study design that excluded approximately 60% of pregnancies mostly because of incomplete data on residency in water system of concern during pregnancy even though the analysis was based on the serum PFOA level, and 3) lack of data on maternal BMI and infant gender . The study did not conduct a sensitivity analysis by examining the full group, i .e, the same set of subjects analyzed for PFOS. The investigators are developing exposure reconstruction models, which will allow inclusion of greater numbers of pregnancies Page 219 Imrnunotoxicity. The C8 Health Project (2009) descriptive statistics and the C8 Science Panel (2009) Status Report on immunological effects showed increased levels of anti-nuclear antibodies (suggestive of autoimmune disease) as well as occurrence of self-reported scleroderma and Sjligren's syndrome (autoimmune diseases) in women with higher serum PFOA. Page 220 Epidemiological and Human Dosimetry Studies. I disagree with the statement that "No significant health conditions have been associated with the serum levels ofperfluoroalkyls measured in these studies, ..", as outlined in the General Comments here and in the Specific Comments . My disagreement stems from a critical review ofold and new studies . References Apelberg BJ, Witter FR, Herbstman JB, Calafat AM, Halden RU, Needham LL, Goldman LR. 2007 Cord serum concentrations of erfluorooctane sulfonate PFOS and uerfluorooctanoate (PFOA) in relation to weight and size at birth Environ Health Perspect ., 115(11):1670-6 . Axelson O 2004 Negative and non-positive epidemiological studies. International Journal ofOccupational Medicine and Environmental Health, 17(1): 115-121 . Bain MRS, Harvey JC, Muir MS 1998 Epidemiology Research in Ageing : Perspectives and Limitiations . Chapter 5. In: Comprehensive Geriatric Oncology. Balducci L, Lyman GH and Ershler WB. Harwood Academic Publishers, Bild DE, Stevenson JM. 1992 Frequency of recording of diabetes on U.S. death certificates : analysis of the 1986 National Mortality Followback Survey. J Clin Epidemiol . 45(3):275-81 . Bossert PJ, Jr, Rickard RW, Sax SE 2005 Results to Date from the PFOA Worker Health Study. January 11, 2005 . Questions and Answers. DuPont. EPA Docket AR 226. Breslow NE, Day NE 1987 Statistical Methods in Cancer Research . Vol. 2. The Design and Analysis of Cohort Studies. International Agency for Cancer Research, Lyons, France . C8 Science Panel 2009a Status Report : PFOA and immune biomarkers in adults exposed to PFOA in drinking water in the mid Ohio valley . March, 2009. httn://www.c8sciencepanel.org_/pdfs/Status Report C8 and Immune markers March20 09.pdf C8 Science Panel 2009b Status Report: Association of perfluorooctanoic acid (C8/PFOA) and perfluorooctanesulfonate (PFOS) with lipids among children in the MidOhio Valley . October, 2009. Calafat AM, Wong L-Y, Kuklenyik Z, Reidy JA, Needham LL 2007 Polyfluoroalkyl Chemicals in the U.S. Population : Data from the National Health and Nutrition Examination Survey (NHANES) 2003-2004 and Comparisons with NHANES 19992000. Environ Health Perspect. 2007 November; 115(11) : 1596-1602. Clewell Hi Application of phannacokinetic modeling to estimate PFOA exposure associated with measured blood concentrations in human populations . Powerpoint presentation at Society for Risk Analysis Annual Meeting ; 2006. Costa G, Sartori S, Consonni D. 2009 Thirtv years ofmedical surveillance in perfluooctanoic acid production workers J Occup Environ Med . 51(3):364-72 . Emmett EA, Zhang H, Shofer FS, Freeman D, Rodway NV, Desai C, Shaw LM. 2006 Community exposure to perfluorooctanoate : relationships between serum levels and certain health parameters. J Occup Environ Med . 48(8):771-9 . Eriksen KT, Srerensen M, McLaughlin JK, Lipworth L, Tjsnneland A, Overvad K, Raaschou-Nielsen O. 2009 Perfluorooctanoate and perfluorooctanesulfonate plasma levels and risk of cancer in the general Danish population. J Natl Cancer Inst. 101(8) :605-9 . Fei C, McLaughlin JK, Lipworth L, Olsen J. 2008a Prenatal exposure to perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS) and maternally reported developmental milestones in infancy. Environ Health Perspect ., 2008 Oct;116(10) :1391-5 . Fei C, McLaughlin JK, Lipworth L, Olsen J. 2009 Maternal levels of yerfluorinated chemicals and subfecundity . Hum Reprod., 24(5):1200-5 . Fei C, McLaughlin JK, Tarone RE, Olsen J 2007 Perfluorinated chemicals and fetal growth : a study within the Danish National Birth Cohort . Environ Health Perspect, 115(11) :1677-82 . Fei C, McLaughlin JK, Tarone RE, Olsen J. 2008b Fetal growth indicators and perfluorinated chemicals : a study in the Danish National Birth Cohort. Am J Epidemiol, 168(1) :66-72 . ?Frisbee SJ, Brooks AP, Maher A, Flensborg P, Arnold S, Fletcher T, Steenland K, Shankar A, Knox SS, Pollard C, Halverson JA, Vieira VM, Tin C, Leyden KM, Ducatman A. 2009. The C8 Health Project: Design, Methods, and Participants Environ Health Perspect, doi :10 .1289/ehp .0800379. [Online 13 July 2009] Gilliland FD, Mandel JS . 1993 Mortality among employees of a perfluorooctanoic acid production plant. J Occup Med., 35(9):950-4 . Gilliland FD, Mandel JS. 1996. Serum perfluorooctanoic acid and hepatic enzymes, lipoproteins, and cholesterol: A study of occupationally exposed men . Am J Ind Med 29(5) :560-568 . Grice MM, Alexander BH, Hoffbeck R, Kampa DM 2007 Self-reported medical conditions in perfluorooctanesulfonyl fluoride manufacturing workers. J Occup Environ Med. 49(7) :722-9 . Hines EP, White SS, Stanko JP, Gibbs-Flournoy EA, Lau C, Fenton SE. 2009 Phenotypic dichotomy following developmental exposure to perfluorooctanoic acid (PFOA) in female CD-1 mice: Low doses induce elevated serum leptin and insulin, and overweight in mid-life . Mol Cell Endocrinol. 2009 May 25;304(1-2) :97-105 . Holzer J, GtSen T, Rauchfuss K, Kraft M, Angerer J, Kleeschulte P, Wilhelm M. 2009 One-year follow-up of perfluorinated compounds in plasma of German residents from Arnsberg formerly exposed to PFOA-contaminated drinking water. Tnt J Hyg Environ Health. 212(5) :499-504 . Leonard RC 2003 Epidemiology Surveillance Pgm. Cancer Incidence Report 1959-2001 and All-Case Mortality Report 1957-2000 at the Washington Works, Parkersburg, WV. DuPont. USEPA AR226-1307-6 . Leonard RC, Kreckmann KH, Sakr CJ, Symons JM. 2008 Retrospective cohort mortality study of workers in a polymer production plant including a reference population ofregional workers. Ann Epidemiol., 18(1):15-22 . Lin C-Y, Chen P-C, Lin YC, Lin L-Y 2009 Association Among Serum Perfluoroalkyl Chemicals, Glucose Homeostasis, and Metabolic Syndrome in Adolescents and Adults . Diabetes Care, 32 (4): 702-707. Lundin JI, Alexander BH 2007 Mortality of Employees of an Ammonium Perfluorooctanoate Production Facility . Final Report. 3M Chemical Company . EPA Docket AR 226 . Lundin JI, Alexander BH, Olsen GW, Church TR . 2009 Ammonium Perfluorooctanoate Production and Occupational Mortality. Epidemiology . On-line September 29. Maggard MA, O'Connell JB, Ko CY. 2004 Updated population-based review of carcinoid tumors. Ann Surg. 240(1) :117-22 . MacNeil J, Steenland NK, Shankar A, Ducatman A. 2009 A cross-sectional analysis of type lI diabetes in a community with exposure to perfluorooctanoic acid (PFOA) . Environ Res, 109(8) :997-1003 . Minnesota Department of Health 2009 East Metro Perfluorochemical Biomonitoring Pilot Project. Report to the Community. Minnesota Public Health Tracking . July, 2009. Modlin IM, Kidd M, Latich 1, Zikusoka MN, Shapiro MD 2005 Current Status of Gastrointestinal Carcinoids . Gastroenterology 128:1717-1751 . Morel Symons J, Sakr CJ, Kreckmann KH, Leonard RC 2007 Addendum Report on Confirmed and Potential Carcinoid Tumor Cases in the DuPont Cancer Registry . DuPont Epidemiology Program, Newark, DE. DuPont-24117-Addendum. EPA Docket AR 226 Monroy R, Morrison K, Teo K, Atkinson S, Kubwabo C, Stewart B, Foster WG. 2008 Serum levels of perfluoroalkyl compounds in human maternal and umbilical cord blood samples. Environ Res ., 108(1) :56-62. Nolan LA, Nolan JM, Shofer FS, Rodway NV, Emmett EA. 2009 The relationship between birth weight, izestational a e and perfluorooctanoic acid (PFOA)-contaminated public drinking water. Reprod Toxicol., 27(3-4):231-8 . Olsen GW, Burlew MM, Marshall JC, Burris JM, Mandel JH. 2004 Analysis of episodes of care in a Derfluorooctanesulfonyl fluoride production facili1y J Occup Environ Med. 46(8):837-46. Olsen GW, Burris JM, Burlew MM, Mandel JH. 2000 Plasma cholecystokinin and hepatic enzvmes, cholesterol and lipoproteins in ammonium perfluorooctanoate production workers . Drug Chem Toxicol. 23(4):603-20. Olsen GW, Burris JM, Burlew MM, Mandel JH. 2003a Epidemiologic assessment of worker serum perfluorooctanesulfonate (PFOS) and aerfluorooctanoatelPFOA) concentrations and medical surveillance examinations J Occup Environ Med. 45(3):26070 . Olsen GW, Burris JM, Mandel JH, Zobel LR 1999 Serum perfluorooctane sulfonate and hepatic and lipid clinical chemistry tests in fluorochemical production employees J Occup Environ Med., 41(9) :799-806 . Olsen GW, Butenhoff JL, Zobel LR. 2009 Perfluoroal 1 chemicals and human fetal development : an epidemioiogic review with clinical and toxicological perspectives Reprod Toxicol . 27(3-4) :212-30 . Olsen GW, Logan PW, Hansen KJ, Simpson CA, Burris JM, Burlew MM, Vorarath PP, Venkateswarlu P, Schumpert JC, Mandel JH. 2003b An occupational exposure assessment of a perfluorooctanesulfonyl fluoride production site: biomonitoring . AIHA J (Fairfax, Va) . 64(5) :651-9 Olsen GW, Zobel LR 2007 Assessment of lipid, hepatic, and thyroid parameters with serum perfluorooctanoate (PFOA) concentrations in fluorochemical production workers . Int Arch Occup Environ Health ., 81(2):231-46. Post GB, Louis JB, Cooper KR, Boros-Russo BJ, Lippincott RL. 2009a Occurrence and potential significance of perfluorooctanoic acid (PFOA) detected in New Jersey public drinking water systems . Environ Sci Technol . 2009 Jun 15;43(12) :4547-54 . Post, G.B., Louis, J.B ., Cooper, K.R., and Lippincott, R.L (2009b) . Response to Comment on "Occurrence and Potential Significance of Perfluorooctanoic Acid (PFOA) Detected in New Jersey Public Drinking Water Systems" Environ . Sci . Technol ., Articles ASAP (As Soon As Publishable) Publication Date (Web) : October 5, 2009. DOI : 10.1021/es9027524 . Sakr CJ, Kreckmann KH,anGdrelievnerJeWn,zGyimlelisersePlJa,teRdetyonoalsdesrJuLm,bLieoomnaarrkderRCof e2x0p0o7saureCross- sectional study of lipids (ammonium perfluorooctanoate or APFO) as part of a general health survey in a cohort of occupationally exposed workers. J Occup Environ Med., 49:1086-96 . Sakr CJ, Leonard RC, Kreckmann KH, Slade MD, Cullen MR 2007b Longitudinal study of serum lipids and liver enzymes in workers with occupational exposure to ammonium perfluorooctanoate . J Occup Environ Med., 49:872-9 . Sakr CJ, Morel Symons J, Kreckmann KH, Leonard RC 2009 Ischemic Heart Disease Mortality Study among Workers with Occupational Exposure to Ammonium Perfluorooctanoate . Occup. Environ. Med. published online June 23, 2009. Steenland K, Tinker S, Frisbee S, Ducatman A, Vaccarino V 2009a Association of Perfluorooctanoic Acid and Perfluorooctane Sulfonate With Serum Lipids Among Adults Living Near a Chemical Plant. Am J Epidem, published online October 21, 2009. Steenland K, Tinker S, Shankar A, and Ducatman A 2009b Association of Perfluorooctanoic Acid (PFOA) and Perfluorooctanesulfonate (PFOS) with Uric Acid Among Adults with Elevated Community Exposure to PFOA. Environ Health Persp, published online October 22, 2009. Steenland K, Jin C, MacNeil J, Lally C, Ducatman A, Vieira V, Fletcher T. 2009c Predictors of PFOA levels in a community surrounding a chemical plant. Environ Health Perspect . 117(7) :1083-8. Stein CR, Savitz DA, Dougan M. 2009 Serum levels of perfluorooctanoic acid and perfluorooctane sulfonate and pregnancy outcome. Am J Epidemiol . 170(7) :837-46. Tardiff RG, Carson ML, Sweeney LM, Kirman CR, Tan YM, Andersen M, Bevan C, Gargas ML 2009 Derivation of a drinking water equivalent level (DWEL) related to the maximum contaminant level goal for perfluorooctanoic acid (PFOA), a persistent water soluble compound. Food Chem Toxicol, 47(10) :2557-89 . The C8 Health Project . 2009 C8 Health Project Results . WVU Data Hosting Website htW ://www hsc wvu edu/som/cmed/c8/results/otherConditionsAndDiap-noses/index.asa (last accessed July, 2009). USEPA 2005 Draft Risk Assessment of the Potential Human Health Effects Associated with Exposure to Perfluorooctanoic Acid and Its Salts . Office of Pollution Prevention and Toxics, January 4, 2005 . http ://www epa gov/onpt/pfoa/pubs/pfoarisk .pdf. U.S . Preventive Services Task Force (USPSTF) 2008 Screening for Type 2 Diabetes Mellitus in Adults . Recommendation Statement. June 2008. Agency for Healthcare Research and Quality. Rockville, MD, htto://www .ahra.gov/Clinic/us sp ttb8/tvne2/tybe2rs htm Washino N, Saijo Y, Sasaki S, Kato S, Ban S, Konishi K, Ito R, Nakata A, Iwasaki Y, Saito K, Nakazawa H, Kishi R. 2009 Correlations between prenatal exposure to perfluorinated chemicals and reduced fetal growth. Environ Health Perspect, 117(4) :6607. Page 1 October 27, 2009 Agency for Toxic Substances and Disease Registry Division of Toxicology and Environmental Medicine 1600 Clifton Road NE Mail Stop F-62 Atlanta, Georgia 30333 RE : Comments on Draft Toxicological Profile for Perfluoroalkyls Docket Control Number ATSDR-253 To Whom It May Concern: I appreciate the opportunity to comment on the Draft Toxicological Profile for Perfluoroalkyls (Profile) dated May 20fl9. I have served and am currently serving as a toxicology consultant to plaintiffs in litigation involving perfluoroalkyl chemical issues . I have the following comments on the profile. On page 21 the Profile states the following . In the cohort studied by Emmett et al . (2006b), the average concentration of PFOA in water that the subjects may have consumed over a period of 3 years before the health assessment was conducted was 3 .5 ug/L . Median serum PFOA levels in residents were 105 times the level in their residential drinking water. Blood levels of perfluoroalkyl compounds have been measured both in workers and in members of the general population . As indicated in the preceding section, no significant health effects have been associated with specific serum levels of perfluoroalkyl compounds, although minor alterations in serum lipids and in serum estradiol levels in male workers have been reported (Costa 2004 ; Olsen et al . 1998; Sakr et al . 2007b) . There are a number of problems with these statements . First, the elevations in liver enzymes associated with PFOA serum concentration in studies of worker populations are not included (Olsen et al . 2003 ; Sakr et al . 2007). Second, the elevations of serum iipids and serum estradiol (and presumably liver enzymes had they been included) are described as "minor alterations ." These alterations are likely not minor for the subset of individuals experiencing them . While the mean, median, or geometric mean serum levels are not pushed into a clinically unacceptable range by the association with PFOA in these studies, the alterations in central tendencies for these parameters are very likely the result of a larger impact on a small subset of susceptible individuals whose elevations may well be clinically adverse . While the characterization of these elevations as "minor alterations" may be somewhat consistent with those of the industry authors of these studies, the Profile description should represent an independent critique of study data . Accepting the assessment of the industry study authors without an independent assessment of study data is a criticism voiced by Dr. Lynn Goldman who peer reviewed an earlier draft of the Profile. The problem remains. An illustration of the subset effect is the association of PFOA or PFOS with liver enzyme elevations for the Olsen et al . (2003) study of workers in two facilities producing PFOA and PFOS containing products. Tetra Tech Inc . Page 2 The liver enzyme alanine aminotransferase (ALT) is significantly elevated in the fourth serum PFOS/PFOA quartile versus the first quartile. The magnitude of the elevation is 7 IU/L (33 versus 26, respectively) . The upper bound of the reference range for ALT is 40 IU/L so the elevated value of 33 IU/L for the fourth quartile is within the reference range and an individual with such a level would not be considered to be exhibiting signs of liver toxicity . If, however, one considers the small portion of workers that were actually pushed into the clinically excessive ALT range by the association of ALT with PFOS/PFOA, it is apparent that adverse effects likely occurred . The number of individuals exceeding the reference range for the fourth quartile was 13 of 105 while the number for the first quartile was 4 of 105. The difference between first and fourth quartiles is an indicator of the impact of PFOA on ALT. Nine workers (8 .6 percent) may have experience elevated liver enzyme levels beyond the reference range as a result of their exposure to PFOA . ALT values for quartile three are also elevated (7 IU/L) but less so than for the fourth quartile . The analysis shown above for liver enzymes cannot be done for lipids or estradiol because the individual serum data for workers were not included in the reported studies. It is likely that the modestly elevated mean values for these parameters would also be the result of more extreme alterations in a subset of workers . The other problem with the Profile statement shown above is that declares the Emmett et al . (2006b) study to have resulted in "no significant health effects" and then goes on to suggest that a no-observedadverse-effect-level (NOAEL) could possibly be established based on the PFOA human body burden observed in this study. This statement is troubling as the Emmett 2006b study has a serious weakness that would limit its ability to detect a positive association between serum PFOA and any outcome assessed . The major limitation of the Emmett et al . (2006b) study is the participation rate which is only 37 percent. This very low participation rate results in likely self-selection bias . The process normally used to address a low participation rate is a follow up on a sample of nonparticipants to determine if their outcome response would be different from that of participants . No such follow up was done by Emmett (2006b). There is a large literature on self-selection bias, sometimes referred to as volunteer bias, that indicates that individuals with conditions that make them more susceptible to adverse effects tend to participate in health surveillance studies to a lesser extent than do healthy individuals and that the absence of these less healthy study subjects will bias the study results toward the null . Such a bias in the relationship between exposure and health outcomes may underestimate or fail to detect an adverse effect when one exists . Cross sectional volunteer studies have been reported to average 74 percent participation (Morton et al . 2005. Amer J Epidem 163:197-203). Self-selection bias has been detected with participation rates as high as 93 percent (Lyngbye et al . 1988. Scand J Soc Med 16 :209215) . The 37 percent participation rate of the Emmett et al . (2006b) study is very low and likely biased the results of that study toward the null . Emmett et al . (2006b) should not be considered for use as a NOAEL and should not be considered convincing evidence of the absence of an association between PFOA body burden and adverse effects in the general population . The participation rate limitation of the Emmett et al . (2006b) study is also present in most of the occupational studies although to a lesser extent . Many of the occupational studies have participation rates of 55 percent or less . Tetra Tech Inc. p. 90 Page 3 Finally, the Profile does not include a number of important recent reports relating to PFCs and human health . Studies by Lundin et al . (2009)1 and Steenland et al . (2009)z need to be included . Steenland et al . (2009) was conducted in 46, 294 members of the general population with an estimated 81 percent participation rate . The Steenland et al . (2009) findings conflict with those of the much smaller Emmett et al . (2006b) study. Steenland et al . (2009) state the following. A cross-sectional study of lipids and PFOA and PFOS was conducted among 46,294 community residents aged 18 years or above, who drank water contaminated with PFOA from a chemical plant in West Virginia . The mean levels of serum PFOA and PFOS in 2005-2006 were 80 ng/mL (median, 27 ng/mL) and 22 ng/rnL (median, 20 ng/mL), respectively . All lipid outcomes except high density lipoprotein cholesterol showed significant increasing trends by increasing decile of either compound ; high density lipoprotein cholesterol showed no association . The predicted increase in cholesterol from lowest to highest decile for either compound was 11-12 mg/dL. The odds ratios for high cholesterol (>240 mg/dL), by increasing quartile of PFOA were 1.00, 1.21 (95% confidence interval (CI) : 1.21, 1.31), 1.33 (95% CI : 1.23, 1.43), and 1.40 (95% CI : 1.29, 1.51) and were similar for PFOS quartiles. Because these data are cross-sectional, causal inference is limited. Nonetheless, the associations between these compounds and lipids raise concerns, given their common presence in the general population . The negative findings of the Emmett et al . (2006b) study are cited in many locations in the Profile. The Profile concludes that there is an absence of observed health effects in PFOA community studies. This conclusion should be modified given the more recent human studies. Sincerely, David G. Gray, Ph .D . Director, Toxicology Program Tetra Tech Inc. 10306 Eaton PI ., Suite 340 Fairfax, VA 22030 703 385 6000 703 385 6007 FAX ' Lundin J .I . et al . 2009 . Ammonium perfluorooctanoate production and occupational mortality . Epidemiol . 20 :92128. Z Steenland K . et al . 2009 . Association of perfluorooctanoic acid and perfluorooctane sulfonate with serum lipids among adults living near a chemical plant . Am J Edpidemiol . DO : 10 .3093/aje/kwp279 . Tetra Tech Inc . p. 91 . [EE:ENVIRONMENTAL WORKING GROUP www.ewo .org Agency for Toxic Substances and Disease Registry (ATSDR) Toxicological Profile for Perfluoroalkyls Draft for Public Comment Comments of Olga V. Naidenko, Ph.D . Senior Scientist Environmental Working Group "ATSDR needs to protect people and the environment from contamination with perfluoroalkyls" October 30, 2009 Environmental Working Group (EWG) is a non-profit public health and environmental research and advocacy organization based in Washington, DC. We focus much of our research on potential health risks from chemical contamination of food, water, consumer products, and the environment. EWG appreciates this opportunity to comment on the Agency for Toxic Substances and Disease Registry (ATSDR) draft toxicological profile for perfluoroalkyl compounds. We are very concerned, however, with several significant shortcomings of the proposal, most notably that the Agency has decided not to develop minimum risk levels (MRLs) for this entire class of extraordinarily problematic chemicals . For several critical perfluoroalkyl compounds, including perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS), there is a rich scientific literature that both supports the need and provides the basis for establishing an MRL. Several states, including New Jersey, North Carolina and Minnesota, have developed risk-based levels for PFOA in drinking water (MDH 2007; NCDENP 2008; NCSAB 2009; NJDEP 2007). The Agency's decision not to publish an MRL forces state agencies and public health officials across the country to employ their limited resources on developing their own guidance levels for PFOA and PFOS. Perfluoroalkyls contaminate food, water, wildlife, consumer products, and have been detected in every corner of the globe. They have been found in the blood of virtually all Americans tested over the last decade (Calafat 2007). In the human body, these chemicals are persistent, bioaccumulative and toxic to numerous organs . PFOA and PFOS are associated with a broad range of developmental effects, including developmental delays, and organ abnormalities (Lau 2007); liver toxicity (Guruge 2006); suppression of the immune system and predisposition to allergies (DeWitt 2008; Fairiey 2007; Peden-Adams 2008; Yang 2002; Yang 2000) ; behavioral effects (Johansson 2008) ; altered hormonal function (Biegel 1992; Bookstaff 1990; Cook 1992; Liu 2007) as well as liver, pancreatic, testicular, and mammary cancers (Sibinski 1987) . HEADQUARTERS 1436 U St . NW, Suite 100 Washington, DC 20009, P : 202 .667 .6982 F : 202 .232 .2592 CALIFORNIA OFFICE 2201 Broadway, Suite 308 Oaktand, CA 94612 1 P : 510 .444.0973 F: 510 .444 .0982 MIDWEST OFFICE 103 E . 6th Street, Suite 201 Ames, IA 50010 1 P : 515 .598 .2221 EPA researchers have recently developed provisional drinking water guideline levels for PFOA and PFOS (U.S . EPA 2009c), and the agency is currently engaged in developing drinking water standards for both chemicals (Hegstad 2009). EPA Administrator Lisa Jackson recently announced that perfluorinated chemicals are one of the six chemicals or chemical classes of concern that EPA is considering for "action plan development" for targeted risk management (U.S . EPA 2009b) . It makes no sense for ATSDR to claim that it is currently impossible to estimate minimal risk levels for people while the EPA is engaged in that very task - and both agencies are looking at the same basic set of data. Perfluoroalkyl chemicals present a significant, well-characterized risk to human health . There is no reason to delay setting MRLs for both PFOS and PFOA . With this letter, we make three key points regarding the Agency's proposal : The latest science points to the health risks associated with the PFOA and PFOS levels found in the general population ; Determining minimal risk levels for two perfluoroalkyls, perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS), is scientifically feasible; The Agency must develop minimal risk levels in order to protect human health from multiple sources ofPFOA and PFOS exposure . Details and rationale for these recommendations are provided below . 1. Latest science points to the health risks associated with the PFOA and PFOS levels found in the general population . In its draft, ATSDR states (p. 22): " It could be proposed that measured serum levels ofperfluoroalkyls in the populations for whom health data are available be considered body burdens corresponding to noobserved-adverse-effect levels (NOAELs) or perhaps lowest-observed-adverse-effect levels (LOAELs) if the alterations reported in workers are considered adverse ." EWG strongly disagrees with this statement . Instead, the Agency should determine NOAELs and LOAELs using standard scientific practice that incorporates safety margins to account for uncertainties and variable susceptibility in the population and that are based on the most recent scientific findings, which, in this case, have found evidence of adverse health effects at the levels of PFOA and PFOS that are found in the general population. Key studies are listed below: 0 A recent study found an association between PFOA and PFOS levels in the blood and delayed time to pregnancy, a well-established indicator of fertility problems . Analyzing data from a cohort of 1,240 women enrolled in a Danish longitudinal study, a team of scientists based at the University of California-Los Angeles found that women with elevated blood levels of PFOA experienced more difficulties in conceiving and were twice as likely to be diagnosed with infertility as women with lower PFOA body burdens. For women with more than 3 .9 parts per billion (ppb) of PFOA in their bodies, the risk ofinfertility increased by 60 to 150 % (Fei 2009). lEWC : TiiE POWER OF INFORMATION 0 Study by Danish scientists associated PFOA and PFOS with lower sperm quality in otherwise healthy young men (Joensen 2009). This study included 105 Danish men (median age 19 years) from the general population; the median levels of PFOA in this population were 4.9 ppb; the median levels of PFOS were at 24.5 ppb. Researchers observed that men with high combined levels of PFOS and PFOA had a median of 6.2 million normal spermatozoa in their ejaculate compared to 15.5 million normal spermatozoa counts among men with low PFOS-PFOA. The authors of the study hypothesized that "high levels of PFAAs may contribute to the otherwise unexplained low semen quality seen in many young men" (Joensen 2009). 0 An association of the PFOA and PFOS with serum lipids was reported in a multi-year study of 69,000 West Virginians and Ohioans whose drinking water was contaminated by a fluorochemical manufacturing plant in Washington, W.Va ., along the Ohio River (Steenland, Tinker, Frisbee 2009; West Virginia University School of Medicine 2008). These findings of elevated cholesterol and other lipids in people exposed to PFOA in drinking water are in agreement with the increased lipid levels in PFOA-exposed workers in fluorochemical plants (Costa 2009; Sakr, Kreckmann 2007; Sakr, Leonard 2007). The authors of the study concluded : "If a causal relation between perfluorinated compound levels and cholesterol exists, there could be potentially serious consequences in the form of increased risk of cardiovascular disease" (Steenland, Tinker, Frisbee 2009). 0 In the same study, known as the C8 Health Project, greatly decreased concentrations of estradiol were observed in women and in girls with higher serum levels of PFOA (West Virginia University School of Medicine 2008). Adverse effects on the immune system have also been noted (Frisbee 2008). The immune system changes included a significant decrease in serum levels of two immune defense proteins, immunoglobulins IgA and IgE, that correlated with increasing PFOA serum levels (C8 Science Panel 2009). 0 The latest publication from the C8 Health Project found that both PFOA and PFOS were significantly associated with elevated levels of uric acid in serum (Steenland, Tinker, Shankar 2009); similar results have been reported in cross-sectional studies of PFOA-exposed workers (Costa 2009; Sakr, Kreckmann 2007). Increased uric acid is a risk factor for hypertension ; it may also be associated with stroke and diabetes (Heinig 2006; Steenland, Tinker, Shankar 2009). These studies are only the latest addition to the rapidly growing body of data indicating that the levels of PFOA and PFOS in the general population cannot be considered LOAELs or NOAELs. On the contrary, present levels of contamination are associated with a range of adverse health effects. To declare current body burden of perfluoroalkyls as either LOAEL or NOAEL would be irresponsible and indefensible from the scientific perspective . We strongly urge the Agency to re-consider this important point and make the final decision that will protect the health of the American public and help in setting standards for these contaminants rather than condone the persistent perfluoroalkyl pollution in people and the environment . 3 1:W r : 7`1.1EPOWER Oh INFO R N1A'$' l O i\T 2. Determination of the minimal risk levels for two perfluoroalkyls, pertluorooctanoic acid (PFOA) and perfluorooctane snlfonic acid (PFOS), is scientifically feasible. In its draft, the Agency decided not to derive the minimal risk levels (MRLs) for perfluoroalkyls (p . 21), citing insufficient human data and large differences in the metabolism of perfluoroalkyls in humans and various laboratory species as the reasons for not developing the 1VIRLs . This decision seems to be in contradiction with another, very clear, statement in the ATSDR draft that "inspection of the animal database would suggest that there are studies, particularly by the oral route, of PFOS and PFOA in animals that established dose-response relationships that could be usedfor MRL derivation." (p. 23) Currently, EPA is engaged in developing drinking water standards for PFOA and PFOS; both chemicals have been listed in the final Contaminant Candidate List 3 (CCL3) of water contaminants that may require regulation under the Safe Drinking Water Act (U.S. EPA 2009a). Furthermore, EPA Administrator Lisa Jackson recently announced that perfluorinated chemicals are one of the six chemicals or chemical classes of concern that EPA is considering for "action plan development" for targeted risk management (U.S. EPA 2009b) . In light of these simultaneous developments at EPA, EWG finds it incomprehensible that ATSDR refuses to acknowledge that robust and sufficient data are available to develop IVIRLs for PFOA and PFOS . The recommendation to develop NOAELs and LOAELs was also given to ATSDR by one of the four peer reviewers of the initial draft, Dr. Edward Emmett, a recognized expert in this field and the author of several studies of perfluoroalkyls in people (Emmett 2006). EWG is very concerned that ATSDR's decision leaves public health at risk and would slow down rather than facilitate human and environmental health protection. Below we highlight several studies that jointly provide sufficient toxicological data for determining minimal risk exposure levels for people . The list below primarily addresses the case of PFOA; however, a similar dataset is available for PFOS (see item 6) and we urge the Agency to take a focused look at both of these highly toxic chemicals . 1 . Research by EPA scientists demonstrating developmental toxicity at low doses of PFOA exposure in mouse developmental studies (Lau 2007; Lau, Butenhoff 2004) . These developmental effects include full litter resorptions, postnatal mortality, decreased birth weight, delayed growth and development, effects on mammary gland development; increased pup liver weight, structural changes in the uterus and metabolic effects in adulthood after prenatal exposures (reviewed in (Post 2009)) . Some of these developmental changes are observed at doses as low as 0. i mg PFOA/kg body weight/day (LOAEL) (Abbott 2007). 2. In follow up studies, EPA scientists observed that in mice, developmental exposure to even lower doses of PFOA, 0.01 mg/kg/day, lead to significant increases in body weight and levels of serum insulin and leptin hormones in mid-life (Hines 2009). These results indicate that fetal exposure to PFOA, similar to fetal exposure to other toxic chemicals, may predispose towards obesity in adulthood (Hines 2009). 4 I--'WtT : T; I-IF POWER OF INFORMATION 3. Chronic dietary exposure to PFOA has been associated with liver, pancreatic, testicular, and mammary cancers in laboratory animals (Sibinski 1987). These results prompted the U.S. EPA's Science Advisory Board to classify PFOA as a "likely human carcinogen" (SAB 2006). 4. Chronic dietary exposure to PFOA in adult female rats was associated with decreased body weight and blood changes; this study reported NOAEL at 1 .6 mgVday dose of PFOA (U.S. EPA 2005). 5. A study in Cynomolgus monkeys linked oral PFOA exposure with sudden mortality ; this study reported a LOAEL of 3 mg/kg/day ofPFOA (U.S. EPA 2005). 6. For PFOS, U.S. EPA scientists recently identified the subchronic toxicity study in Cynomolgus monkeys (Seacat 2003) as acceptable and "critical" for the derivation of the Provisional Health Advisory value for PFOS contamination of drinking water (U.S. EPA 2009c). In this study, effects of PFOS on liver, thyroid hormones and serum lipids have been observed, with a NOAEL of 0 .03 mg/kg/day (U.S. EPA 2009c). Overall, the existing data provide a strong foundation for deriving MRLs for PFOA and PFOS. EWG urges the ATSDR to recognize that this important next step is scientifically feasible and should be done to provide the necessary guidance to state agencies and public health officials across the country . 3. The Agency should develop minimal risk levels in order to protect human health from multiple sources of PFOA and PFOS exposure. Perfluoroalkyl chemicals are found in a wide range of consumer products, including water, stain and grease repellants, cookware, food wrap, carpeting, furniture and clothing. Perfluoroalkyls contaminate food because of bioaccumulation in the food supply (Martin 2004; Tittlemier 2007) and due to leaching from food packaging materials (Begley 2008; Begley 2005; Deon 2007). Furthermore, according to recently published EPA research, degradation of perfluorochemical-based polymers, like those used in grease-proof food packaging or waterproofing clothing, releases stable short-chain perfluoroalkyl compounds that are exceptionally persistent in the environment (Renner 2009; Washington 2009). Children and infants are at particular risk from widespread presence of perfluoroalkyl pollutants . Scientists have found that children tend to have elevated exposure to PFOA, PFOS, perfluorohexansulfonate (PFHxS) and related perfluoroalkyls (Emmett 2006; Olsen 2004) . Moreover, PFOA and PFOS have been found in maternal and umbilical cord blood, so there is transplacental exposure whereby these pollutants cross the placenta and transfer from mother's body to the fetus (Apelberg, Goldman 2007; Fei 2007; Inoue 2004; Midasch 2007). Perfluoroalkyls have been also found in breast milk, so infants are exposed to these chemicals via lactational transfer (Karrman 2007 ; Kuklenyik 2004; Tao 2008 ; Volkel 2008). Two large cohort studies have found an association between PFOA levels in umbilical cord or maternal blood and smaller weight and size in newborn infants, indicating the human health risks of gestational 5 li; ih' (T : THE POWER ..)F 1 NFf ) R M AT ION exposure to perfluoroalkyls (Apelberg, Witter 2007; Fei 2007). Low birth weight is a well-known indicator of potentially serious medical problems later in life (Lau and Rogers 2004). In addition to other sources of exposure, perfluoroalkyl contamination of drinking water is a problem that needs urgent attention from the federal agencies . EWG's review of water quality data from both scientific literature and government dockets found that PFOA and PFOS pollute drinking water sources in at least 11 states and the District of Columbia (EWG 2009). The true number of states with PFOAand PFOS-contaminated water is probably higher, since no nation-wide surveillance has been conducted as of now. Meanwhile, research by scientists in the New Jersey Department of Environmental Protection demonstrates both the feasibility and the great need for developing the MRLs for PFOA in drinking water (Post 2009). It is a standard ATSDR practice to develop MRLs as an integral part of toxicological profiles for hazardous substances. EWG analyzed the existing ATSDR toxicological profiles and the list of MRLs that the Agency has developed in the past (ATSDR 2009a, b). Specifically, the latest update of ATSDR's Toxicological Profile Information Sheet, published on October 19, 2009, includes 190 entries for Finalized Toxicological Profiles (ATSDR 2009b) . For comparison, the last list of MRLs, last updated on January 14, 2009, included 173 entries (ATSDR 2009a) . Based on this review, EWG confirmed that for the majority of cases, ATSDR has developed an MRL, making the present decision not to develop MRLs for perfluoroalkyls very unusual. We agree that for some perfluoroalkyls, such as six- and four- carbon fluorinated chemicals, the data are currently limited. This is, indeed, a problem that should be resolved by the manufactures who should be responsible for generating and publishing data for these chemicals as soon as possible. However, we already know enough about PFOA and PFOS to carry out comprehensive risk assessments for these chemicals on the basis of extensive toxicological data from animal studies and the growing number of human epidemiological studies. In conclusion, EWG urges ATSDR to strengthen and improve its draft toxicological profile for perfluoroalkyls by developing the minimal risk levels for PFOA and PFOS. The development of the MRLs will address a severe gap in our current public health policy and protect the health of millions of Americans who may be exposed to perfluoroalkyls from a variety of sources . References Abbott BD, Wolf CJ, Schmid JE, Das KP, Zehr RD, Helfant L, et al. 2007. Perfluorooctanoic acid induced developmental toxicity in the mouse is dependent on expression of peroxisome proliferator activated receptor-alpha. Toxicol Sci 98(2): 571-81 . Apelberg BJ, Goldman LR, Calafat AM, Herbstman JB, Kuklenyik Z, Heidler J, et al. 2007. Determinants of fetal exposure to polyfluoroalkyl compounds in Baltimore, Maryland. Environ Sci Technol 41(11) : 3891-7 . Apelberg BJ, Witter FR, Herbstman JB, Calafat AM, Halden RU, Needham L, et al. 2007. Cord Serum Concentrations of Perfluorooctane Sulfonate (PFOS) and Perfluorooctanoate (PFOA) in Relation to Weight and Size at Birth . Environ Health Perspect 115(11): 1670-6 . 6 EVi'C : THE POWER OF INFORNSA'TdE?N ATSDR. 2009a. Minimal Risk Levels (MRLs) for Hazardous Substances. Available: htta ://www.atsdr.cdc.g,ov/mrls/ [accessed October 30, 2009]. ATSDR. 2009b . Toxicological Profile Information Sheet. Available: http ://www atsdr cdc. ov/toxpro2 .htm1 [accessed October 30, 2009]. Begley TH, Hsu W, Noonan G, Diachenko G. 2008 . Migration of fluorochernical paper additives from food-contact paper into foods and food simulants. Food Addit Contain Part A Chem Anal Control Expo Risk Assess 25(3): 384-90 . Begley TH, White K, Honigfort P, Twaroski ML, Neches R, Walker RA. 2005. Perfluorochemicals : potential sources of and migration from food packaging. Food Addit Contain 22(10): 1023-31 . Biegel LB, Hurtt ME, Frame SR, Applegate M, O'Connor JC, Cook JC. 1992. Comparison of the effects of Wyeth-14,643 in Crl:CD BR and Fisher-344 rats. Fundarn App] Toxicol 19(4): 590-7. Bookstaff RC, Moore RW, Ingall GB, Peterson RE . 1990 . Androgenic deficiency in male rats treated with perfluorodecanoic acid. Toxicol Appl Pharmacol 104(2) : 322-33 . C8 Science Panel. 2009. Status Report: PFOA and immune biomarkers in adults exposed to PFOA in drinking water in the mid Ohio valley . March 16. CS Science Panel (Tony Fletcher, Kyle Steenland, David Savitz) Available : httn://www c8sciencepanel orgJstudv results .html [accessed April 28 2009]. Calafat AM, Kuklenyik Z, Reidy JA, Caudill SP, Tully JS, Needham LL . 2007 . Serum concentrations of I 1 polyfluoroalkyl compounds in the U.S. population: data from the national health and nutrition examination survey (NHANES). 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Available: http //www hsc wvu edu/som/cmed/ophp/grandRoundsWebcast .asp [accessed May 12 2008] . 7 ENN`~'; : T HE POWER ()F 1N1F ii R :1%1 A T n ij N Guruge KS, Yeung LW, Yamanaka N, Miyazaki S, Lam PK, Giesy JP, et al. 2006. Gene expression profiles in rat liver treated with perfluorooctanoic acid (PFOA). Toxicol Sci 89(1): 93-107 . Hegstad M. 2009. EPA Begins PFOA Risk Study Anew, Leaving Interim Measure In Place. Inside EPA -Wednesday July 29, 2009. Heinig M, Johnson RJ. 2006. Role of uric acid in hypertension, renal disease, and metabolic syndrome . Cleve Clin J Med 73(12) : 1059-64. Hines EP, White SS, Stanko JP, Gibbs-Flournoy EA, Lau C, Fenton SE. 2009. Phenotypic dichotomy following developmental exposure to perfluorooctanoic acid (PFOA) in female CD-1 mice: Low doses induce elevated serum leptin and insulin, and overweight in mid-life. Mol Cell Endocrinol 304(1-2): 97- 105. Inoue K, Okada F, Ito R, Kawaguchi M, Okanouchi N, Nakazawa H. 2004. Determination of perfluorooctane sulfonate, perfluorooctanoate and perfluorooctane sulfonylamide in human plasma by column-switching liquid chromatography-electrospray mass spectrometry coupled with solid-phase extraction. J Chromatogr B Analyt Technol Biomed Life Sci 810(1) : 49-56. Joensen UN, Bossi R, Leffers H, Jensen AA, Skakkebaek NE, Jcrrgensen N. 2009 . Do Perfluoroalkyl Compounds Impair Human Semen Quality? Environ Health Perspec 117(6) : 923-27 . Johansson N, Fredriksson A, Eriksson P. 2008. Neonatal exposure to perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) causes neurobehavioural defects in adult mice. Neurotoxicology 29(1) : 160-9. Karrman A, Ericson I, van Bavel B, Darnerud PO, Aune M, Glynn A, et al . 2007 . Exposure of perfluorinated chemicals through lactation: levels of matched human milk and serum and a temporal trend, 1996-2004, in Sweden. Environ Health Perspect 115(2) : 226-30 . Kuklenyik Z, Reich JA, Tully JS, Needham LL, Calafat AM. 2004. Automated solid-phase extraction and measurement of perfluorinated organic acids and amides in human serum and milk . Environ Sci Technol 38(13) : 3698-704. Lau C, Anitole K, Hodes C, Lai D, Pfahles-Hutchens A, Seed J. 2007 . Perfluoroalkyl acids : a review of monitoring and toxicological findings . Toxicol Sci 99(2) : 366-94. Lau C, ButenhoffJL, Rogers JM. 2004. The developmental toxicity of perfluoroalkyl acids and their derivatives. Toxicol Appl Pharmacol 198(2) : 231-41 . Lau C, Rogers JM. 2004. Embryonic and fetal programming of physiological disorders in adulthood. Birth Defects Res C Embryo Today 72(4): 300-12 . Liu C, Du Y, Zhou B. 2007. Evaluation ofestrogenic activities and mechanism of action of perfluorinated chemicals determined by vitellogenin induction in primary cultured tilapia hepatocytes . Aquat Toxicol 85(4) : 267-77 . Martin JW, Whittle DM, Muir DC, Mabury SA. 2004. Perfluoroalkyl contaminants in a food web from Lake Ontario. Environ Sci Technol 38(20) : 5379-85 . MDH. 2007. Minnesota Department ofHealth : Groundwater Health Risk Levels . Available: httn ://www.health .state .mn .us/divs/eh/goundwater/hritable html, [accessed May 20 2008]. Midasch 0, Drexier H, Hart N, Beckmann MW, Angerer J. 2007. Transplacental exposure of neonates to perfluorooctanesulfonate and perfluorooctanoate : a pilot study. Int Arch Occup Environ Health 80(7) : 643-8. NCDENP . 2008. North Carolina Department of Environment and Natural Resources: Recommended Interim Maximum Allowable Concentration for Perfluorooctanoic Acid (PFOA or C8). Available : h2.oenr.state .nc .us/csu/documents/IMACBasisC8 ndf [accessed May 20 2008] . 8 I?WG : THE POWER OF INFORMATION NCSAB. 2009. North Carolina Division ofEnvironment and Natural Resources Division ofAir Quality . Secretary's Science Advisory Board on Toxic Air Pollutants . One hundred-and-thirty nineth meeting of the science advisory board (NCSAB) on toxic air pollutants . Proceedings of the February 25, 2009 Teleconference . Available : http://dap state nc us/4-bin/sab cgiwear=2009 [accessed October 29, 2009]. NJDEP . 2007. New Jersey Department ofEnvironmental Protection: Guidance for PFOA in Drinking Water at Pennsgrove Water Supply Company Available : http ://www state nj us/dep/watersupply/pfoa.htm [accessed May 20 2008] . Olsen GW, Church TR, Hansen KJ, Burris JM, Butenhoff JL, Mandel JH, et al . 2004 . Quantitative Evaluation of Perfluorooctanesulfonate (PFOS) and Other Fluorochemicals in the Serum of Children . Journal of Children's Health 2(1) : 53-76. Peden-Adams MM, Keller JM, Eudaly JG, Berger J, Gilkeson GS, Keil DE. 2008. Suppression of Humoral Immunity in Mice Following Exposure to Perfluorooctane Sulfonate (PFOS) . Toxicol Sci 104(1): 144-54. Post GB, Louis JB, Cooper KR, Boros-Russo BJ, Lippincott RL. 2009. Occurrence and Potential Significance of Perfluorooctanoic Acid (PFOA) Detected in New Jersey Public Drinking Water Systems . Environ Sci Technol 43(12) : 4547-54 . Renner R. 2009. Perfluoropolymer degrades in decades, study estimates. Environ Sci Technol 43: 17. SAB . 2006. US EPA Science Advisory Board Review of EPA's Draft Risk Assessment of Potential Human Health Effects Associated with PFOA and Its Salts. EPA-SAB-06-006 ; Washington, DC, 2006. Sakr CJ, Kreckmann KH, Green JW, Gillies PJ, Reynolds JL, Leonard RC. 2007. Cross-sectional study of lipids and liver enzymes related to a serum biomarker of exposure (ammonium perfluorooctanoate or APFO) as part of a general health survey in a cohort of occupationally exposed workers. J Occup Environ Med 49(10) :1086-96. Sakr CJ, Leonard RC, Kreckmann KH, Slade MD, Cullen MR. 2007. Longitudinal study of serum lipids and liver enzymes in workers with occupational exposure to ammonium perfluorooctanoate . J Occup Environ Med 49(8): 872-9 . Seacat AM, Thomford PJ, Hansen KJ, Clemen LA, Eldridge SR, Elcombe CR, et al. 2003 . Sub-chronic dietary toxicity of potassium perfluorooctanesulfonate in rats . Toxicology 183(1-3): 117-31 . Sibinski LJ. 1987. Two-Year oral (diet) toxicity/carcinogenicity study of fluorochemical FC-143 (perfluorooctane ammonium carboxylate) in rats. Report prepared for 3M, St Paul, Minnesota by Riker Laboratories Inc Study No 0281CR0012; 8EHQ-1087-0394, October 16, 1987 Reviewed in US EPA "Revised Draft PFOA Hazard Assessment-Robust Study Annex" AR226-1137, (pp . 260-267 ; PDF pp 157-164) . Steenland K, Tinker S, Frisbee S, Ducatman A, Vaccarino V. 2009. Association of Perfluorooctanoic Acid and Perfluorooctane Sulfonate With Serum Lipids Among Adults Living Near a Chemical Plant. American Journal of Epidemiology : in press. Steenland K, Tinker S, Shankar A, Ducatman A. 2009 . Association of Perfluorooctanoic Acid (PFOA) and Perfluorooctanesulfonate (PFOS) with Uric Acid Among Adults with Elevated Community Exposure to PFOA. Environ Health Perspec: in press. Tao L, Kannan K, Wong CM, Arcard KF, Butenhoff JL. 2008. Perfluorinated Compounds in Human Milk from Massachusetts, U.S.A. Environ Sci Technol 42: 3096-101 . Tittlemier SA, Pepper K, Seymour C, Moisey J, Bronson R, Cao XL, et al. 2007. Dietary exposure of Canadians to perfluorinated carboxylates and perfluorooctane sulfonate via consumption of meat, fish, fast foods, and food items prepared in their packaging . J Agric Food Chem 55(8): 3203-10 . 9 fl'.Wf; : T U. E ..&7 OWEld' 01.4 INFORMATION U.S. EPA. 2005. Draft Risk Assessment of Potential Human Health Effects Associated with PFOA and Its Salts . Available: http://epa .gov/oppt/pfoa/pubs/pfoarisk.htm [accessed May 20 2008] . U.S . EPA. 2009a. Drinking Water Contaminant Candidate List and Regulatory Determinations. Contaminant Candidate List 3 (CCL 3). Available: http ://www.e,pa.eov/ogwdw000%cUccl3 .htm1 [accessed October 30 2009] . U.S . EPA. 2009b. Enhancing EPA's Chemical Management Program. Available: http://www.epa.gov/oppt/existingchemicalslpubs/enhanchems.html [accessed October 29, 2009] . U.S. EPA. 2009c. Provisional Health Advisories for Perfluorooctanoic Acid (PFOA) and Perfluorooctane Sulfonate (PFOS). Available: http ://www .epa,gov/waterscience%riteria/drinkins/ [accessed October 25, 2009]. Volkel W, Genzel-Boroviczeny O, Demmelmair H, Gebauer C, Koletzko B, Twardella D, et al . 2008 . Perfluorooctane sulphonate (PFOS) and perfluorooctanoic acid (PFOA) in human breast milk : Results of a pilot study. Int J Hyg Environ Health 211(3-4) : 440-6. Washington JW, Ellington J, Jenkins TM, Evans JJ, Yoo H, Hafner SC. 2009. Degradability of an acrylate-linked, fluorotelomer polymer in soil . Environ Sci Technol 43(17) : 6617-23 . West Virginia University School of Medicine. 2008 . The C8 Health Project: WVU Data Housing Website. Available: http://www .hsc.wvu.edu/som/cmed/c8/ [accessed May 12 2008] . Yang Q, Xie Y, Alexson SE, Nelson BD, DePierre JW. 2002. Involvement of the peroxisome proliferator-activated receptor alpha in the immunomodulation caused by peroxisome proliferators in mice . Biochem Pharmaco163(10): 1893-900. Yang Q, Xie Y, Depierre JW. 2000. Effects of peroxisome proliferators on the thymus and spleen of mice . Clin Exp Immunol 122(2) : 219-26. 10 EVG : TtIE POWER ()F ttiFOR :11ATtON p. 102 Taft/ Taft Stettinius & Notlister LLP 425 Walnut Street, Suite 1800 /Cincinnati, OH 45202-3957 /Tel : 513 .381 .2838 /Fax : 513 .381 .0205 /www.taftlaw.com Cincinnati /Cleveland /Columbus /Dayton /Indianapolis /Northern Kentucky /Phoenix /Beijing ROBERT A. 81LOTT 513.357,9838 bilottQtaftlaw.0om October 30, 2009 VIA ELECTRONIC AND REGULAR U.S . MAIL Ms. Nickolette Roney Division of Toxicology and Environmental Medicine Agency For Toxics Substances and Disease Registry Mailstop : F-62 1600 Clifton Road, NE Atlanta, GA 30333 Re : Docket ATSDR-253: Comment On Draft Toxicological Profile For Perfluoroalkyls Ms. Roney: On behalf of our clients in various States whose residential drinking water is contaminated with one or more perfluoroalkyls, including PFOA and/or PFOS, and in response to ATSDR's July 23, 2009, Federal register notice, we are submitting the following comments on ATSDR's Draft Toxicological Profile for PerFluoroalkyls (the "Profile") . In general, we believe that the current draft Profile inappropriately down-plays the significance of the available data confirming significant risks of adverse health effects among humans exposed to one or more perfluoroalkyls, particularly among perfluoroalkyl workers and those living near industrial sources of perfluoroalkyls that have contaminated nearby drinking water supplies . Although we recognize that research relating to the potential adverse health effects of perfluoroalkyls is on-going and will be continuing for quite some time, we believe that there is a considerable amount of recent data that does not appear to have been considered within the scope of the existing draft Profile that should be before the Profile is finalized. In particular, recently-published studies of perfluoroalkyl workers have strengthened and reaffirmed the consistency of associations previously reported between perfluoroalkyl exposure and adverse health outcomes, and new studies of tens of thousands of community residents exposed to perFluoroalkyis in their drinking water, including new published, peer-reviewed articles, confirm similar and additional associations at even lower internal serum levels . We believe this additional data renders inaccurate and misleading statements in the current draft Profile such as "longterm exposure to perfluoroalkyls at work has not been associated with significant 11527307 .1 Ms . Nickolette Roney October 30, 2009 Page 2 adverse health effects" and that the available data on "people whose drinking water contained perfluoroalkyis did not find problems."2 On behalf of our clients, we request that all portions of the draft Profile be revised to the extent necessary to thoroughly and properly reflect the impact of this more-recent data now available through the following publications, studies, and reports:3 1 . Lundin, J .I ., et al., "Ammonium Perfluorooctanoate Production and Occupational Mortality." 20 Epidem. 921-28 (Nov . 2009); 2. West Virginia University, "C-8 Health Project Results," (available online Oct. 30, 2009 at www.hsc.wvu .edulsomlcmedlc8h-esultsTindex.asp );10/ 3. C-8 Science Panel, "Status Report: Association of Perfluorooctanoic Acid (C8/PFOA) and Perfluorooctane Suffonate (PFOS) With Lipids Among Children in the Mid-Ohio Valley," (available online at www.c8sciencepanel.orq ) (Oct. 28, 2009); 4. Steenland, K., et al., "Association of Perfluorooctanoic Acid (PFOA) and Perfluorooctane Sulfonate (PFOS) with Uric Acid Among Adults with Elevated Community Exposure to PFOA," Environ. Health Persp. (online doi : 10.12891ehp10900940 (Oct. 22, 2009)); 5. Bartelf . S.M., et al., "Rate of Decline in Serum PFOA Concentrations After Granular Activated Carbon Filtration at Two Public Water Systems in Ohio and West Virginia," Environ. Health Persp. (online doi : 10.1289/ehp.0901252 (Oct. 22, 2009)); 6. Steenland, K., et al ., "Association of Perfluorooctanoic Acid and Perfluorooctane Suffonate With Serum Lipids Among Adults Living Near A Chemical Plant," Am. J. Epidem. (online doi:10 .10931ajelkwp279 (Oct. 21, 2009)) ; 7. Dallaire, R., et al., "Thyroid Function And Plasma Concentrations Of Polyhalogenatal Compounds In Inuit Adults," 117(9) Environ. Health Persp. 1380-86 (Sept. 2009); 1 Draft Profile, at 4. 2 Id. 3 Because all of these materials are available either in the published literature, have been submitted into public files (including USEPA public dockets EPA-HQ-OPP"r-2203, AR-226, EPA-HQ-ORD-2003-0016, and/or TSCA 8(e)), or are available through public websites sponsoring the work (such as the DuPont PFOA MOU peer review work), we have not enclosed additional copies of any of these materials. Please let us know, however, if the Agency Is unable to locate any of the documents and would like for us to forward a copy . Ms. Nickolette Roney October 30, 2009 Page 3 8. Stein, C.R., et al., "Serum Levels of Perfluorooctanoic Acid and Perfluorooctane Sulfonate and Pregnancy Outcome ." Am. J. Epidem . (online doi:10.10931aje/kwp212 (Aug . 19, 2009)); 9. MacNeil, J ., et al., "A Cross-Sectional Analysis of Type II Diabetes In A Community With Exposure To Perfluorooctanoic Acid (PFOA)," Environ. Res. (online doi:10.10161j.envres .2009.08 .002 (Aug. 2009)) ; 10. Minnesota Department of Health, "East Metro Perfluorochemcial Biomonitoring Pilot Project" (available online at www.health .state .mn.usldivslehlhazarriousltogicslafcslindex .htmi) (July 21, 2009) ; 11 . "Final Report of the Peer Consultation Panel: Scientific Peer Consultation Process For A Site Environmental Assessment Program as Part of the DuPontEPA Memorandum of Understanding and Phase li Workplan" (available online at http:llitp-Qfoa .ce.cmu .edul) (July 15, 2009); 12. Steeniand, K., et al., "Predictors of PFOA Levels In A Community Surrounding A Chemical Plant." 117 Environ. Health Persp. 1083-88 (July 2009); 13 . Frisbee, S.J., et al., "The C8 Health Project: Design, Methods, and Participants," Environ. Health Persp. (online doi :10.12891ehp.0800379 (July 13, 2009)) ; 14. Sakr, C.J., et al., "Ischemic Heart Disease Mortality Study Among Workers With Occupational Exposure To Ammonium Perfluorooctanoate," Occp. Environ. Med. (online doi:10 .1136/oern .2008.041582 (June 23, 2009); 15. Fenton, S.E ., et al., "Analysis Of PFOA In Dosed CD-1 Mice Part 2: Disposition Of PFOA In Tissues And Fluids From Pregnant And Lactating Mice And Their Pups," Reprod. Toxicol. (online doi:10.10161j.reprotox.2009.02.012 (2009)); 16. von Ehrenstein, O.S ., et al ., "PerHuoroalkyl Chemicals In The Serum And Milk Of Breasifeeding Women," Reprod. Toxicol. (online doi:10 .10161j.reprotox.2009.03.001 (2009)); 17 . Hines, E.P ., et al., "Phenotypic Dichotomy Following Developmental Exposure To Perfluorooctanoic Acid (PFOA) In Female CD-1 Mice: Low Doses Induce Elevated Serum Leptin And Insulin, And Overweight In Mid-Life ." 304 Molecular & Cellular Endocrinology 97-105 (2009) ; 18. Guyton, K.Z ., et al ., "A Reexamination of the PPAR-a Activation Mode of Action as a Basis for Assessing Human Cancer Risks of Environmental Contaminants," Environ. Health Persp . (online doi: 10.12891ehp.0900758 (May 15,2009)); Ms. Nickolette Roney October 30, 2009 Page 4 19. Post, G.B ., et al., "Occurrence And Potential Significance Of PerFluorooctanoic Acid (PFOA) Detected In New Jersey Public Drinking Water Systems." 43(12) Environ. Sci. Technol. 4547-54 (May 8, 2009)); 20. C-8 Science Panel, "Status Report : PFOA And Immune Biomarkers In Adults Exposed To PFQA In Drinking Water In The Mid Ohio Valley" (available online at www.c8scienceoane[ .orq ) (March 16, 2009); 21 . Costa, G., et al., "Thirty Years Of Medical Surveillance In Perfluorooctanoic Acid Production Workers," 51 J.O.EM. 1-9 (March 2009); 22 . Joensen, U.N ., et al., "Do PerFluoroalkyl Compounds Impair Human Serum Quality?" Environ, Health Persp. (online doi:10.12891ehp .0800517 (March 2, 2009)); 23. Kato, K., et al., "Polyfluoroalkyl Compounds In Pooled Sera From Children Participating In The National Health And Nutrition Examination Survey 20012002," Evfron . Sci. Technol. (online doi/abs110 .10211es803156p (Feb. 19, 2009)) ; 24. Fel, C., et al., "Maternal Levels Of Perfluorinated Chemicals And Subfecundity," 1 Hum. Reprod. 1-6 (January 28, 2009); 25 . Minnesota Pollution Control Agency, "PFCs In Minnesota's Ambient Environment: 2008 Progress Report" (available online at vwvw.pca .state .mn.uslcleanuplpfclindex .htrnl ) (Jan. 2009); 26 . Chen-Yu Lin, et al., "Association Among Serum Perfluoroalkyl Chemicals, Glucose Homeostasis and Metabolic Syndrome In Adolescents And Adults," Diabetes Care (online December 29, 2008); 27. Monroy, R., et al., "Serum Levels Of Perfluoroalkyl Compounds In Human Maternal And Umbilical Cord Blood Samples," 108(1) Environ. Res. 56-62 (Sept. 2008); 28. Anderson-Mahoney, P ., et al., "Self-Reported Health Effects Among Community Residents Exposed to Perfluorooctanoate," 18(2) New Solutions 129-43 (2008) ; 29. Vieira, V., et al., "PFOA Community Health Studies: Exposure Via Drinking Water Contaminated By A Teflon Manufacturing Facility" (Abstract 2008); 30 . White, S., et al ., "Effects Of Perfluorooctanoic Acid On Mouse Mammary Gland Development and Differentiation Resulting From Cross-Foster And Restricted Gestational Exposures," Repro. Toxicol. (online doi:10.10161j.reprotox.2008.11 .054 (2008)); and Ms. Nickolette Roney October 30, 2009 Page 5 31 . DeWitt, Jr., et al ., "Immunotoxicity Of Perfluorooctanoic Acid And Perfluorooctane Suifonate And The Role Of Peroxisome Proliferator-Activated Receptor Alpha," Critical Rev. !n Toxicol. (online doi :10.1080110408440802209804 (2008)). In addition to the health and toxicology data referenced above, we recognize that the Agency also has specifically requested "any additional studies, particularly unpublished data" that might be of use to the Agency as it finalizes its Profile. In that regard, we believe the Agency should consider and incorporate all available data reflecting levels of perfluoroalkyls in the serum/blood of residents exposed to the chemicals in their drinking water, even If that data is not formally published or peerreviewed. On that issue, our law firm has submitted voluminous data to USEPA over the last several years confirming the levels of PFOA, PFOS, and other perfluoroalkyils detected in the serum/blood of residents in West Virginia, Ohio, Minnesota, and New Jersey whose residential source of drinking water has been contaminated with one or more perfluoroalkyls. A listing of several of those letters to USEPA (each of which is publicly-available in one or more USEPA public dockets, such as AR-226, EPA-HQOPPT-2003, and/or TSCA 8(e), along with the supporting analytical data sheets (with names redacted for privacy)) follows : 9 . Letter from R. Bilott to C. Auer, et al. Re: PFOA-Exposed Community Blood Sample Results - Lubeck PSD, Washington, County, West Virginia (Sept. 15, 2004); 2. Letter from R. Bilott to C. Auer, et al. Re: Perfluorochemical Residential Exposure Data For Washington County, Minnesota (May 12, 2005); 3. Letter from R. Bilott to C. Auer, et al. Re: Perfluorochemical Residential Exposure Data For Washington County, Minnesota (Oct. 20, 2005); 4. Letter from R. Bilott to C. Auer, et al . Re: Perfluorochemical Residential Exposure Data For Washington County, Minnesota (Jan . 13, 2006); 5. Letter from R. Bilott to C . Auer, et al. Re: Perfluorochemical Residential Exposure Data For Washington County, Minnesota (Feb. 2, 2007); 6. Letter from R. Bilott to C. Auer, et al. Re: Perfluorochemical Blood Exposure Data For New Jersey (April 16, 2007); and To assist in retrieving the letters and supporting data from the public files, we have enclosed additional copies of the text of these fetters . Ms. Nickolette Roney October 30, 2009 Page 6 7. Letter from R. Bilott to C. Auer, et al. Re : PFOAIC-8 Blood Levels From OhioMlest Virginia Drinking Water Contamination (April 9, 2008). We appreciate the opportunity to provide these comments and to submit this additional data for consideration and incorporation into any final Profile released by the Agency for perfluoroalkyls. We hope that such information will assist the Agency in promptly developing and releasing to the public a Minimal Risk Level to help ensure the protection and safety of our clients' drinking water. RAB :mdm Enclosures p. 109 p. 110 NOIiTNERN KENTUCKY OFFICE SSME 3" 1797 ppf$ NONYYAY COYINGTWi, KF,IITtICKY 41011 .iTOf 806-331-2838 515-397-1830 . FAX- 513-M-6613 DAYTON, OHIO OF09CP SUITE 900 110NORT14 MAIN STREET OAYTON. MOO OM-1760 937-7Z6dW! FAX : y37-728.Z816 Rosmv A. 8&Lorr (5'f3) 357-9B98 bitott@tatdalv.tom .AFT, STETTINIUS & HOLLISTER L%-P 425 WALNUT STREET, SUITE '}800 CINCINNATI, OHIO 45202-3957 5'13-3$1-2838 FAX'513481-0205' WViW.tafflallY.CofR September 15, 2004 CLVELAND:OHIOOFHCE 3600 BP TOWER CLEVELAND. 0410 44111-2302 FAX2*192-13e41s-a2t-M3701 COLUY6K OHIO OFFICE Zt ENT STATE STREET cOS.uMu$60190 m1s+a+ au42t-" FAM4121-9907 Dr. Charles M. Auer (7405M) USEPA 12a0 Pennsylvania Avenue, N.W. Washington, DC 20460 Mary Ellen Weber (7406M) USEPA 1,200 Pennsylvania Avenue, N.W. Washington, DC 20460 Mary Dominiak (7405M) USEPA 1200 Pennsylvania Avenue, N.W. Washington, DC 20460 Oscar 1`iemandez (7405M) USEPA 1200 Pennsylvania Avenue, N. W. Washington, DC 20460 Jennifer Seed (7403M) USEPA 1200 Pennsylvania Avenue, N.W. Washington, DC 20460 Re: PFOA-Exposed Community Blood Sample Results (For AR226 And OPPT-2003-0012) Ladies and Gentlemen: In response to- USEPA's previous requests for infonnation_relating to the threat to human health and the environment involving PFOAIC-8, we have enclosed the results of PFOA serum testing performed through DuPont and its contractor, Exygen, for twelve members of the general population living near DuPonYs Washington Works facility in Wood County, WV. All twelve of the individuals tested have been exposed to PFOAIC-8 through drinking water provided by the Lubeck Public Service District where, according to DuPont, the level of PFOAJC-8 in the drinking water has averaged approximately 0.5 ppb over the last several years. These individuals also claim to have stopped using the contaminated public drinking water as their prirnaiy source of drinking water approxinnately three years ago, and switched to alternative sources, such as bottled water. Only one of the individuals (with a PFOA serutn result of 90.4 ppb) ever worked wozz3o75 .1 Dr. Charles M. Ac.ier Oscar Hernandez Jennifer Seed Mary Ellen Weber Mary Dominiak September 15, 2004 Page 2 at the DuPont Washington Works Plant. A chart summarizing the results from the enclosed lab report (EII)871401-10) is presented below. Please include this information in AR226 and OPPT-2003-0012 . APPROX. YEARS SEX AGE PFOA SERUIvIjgPBI ON WATER F 55 128 M 52 103/103 M 70 90_4 F 80 83 .1 M 63 78 .5173 .7 I' 46 65 M 69 61 .3 M 36 56 .4150.8 M 57 ' 51 .2 F 55 42 .6 F 48 40.1 M 57 15 .7 >20 . >20 >20 10-20 10-20 5-10 <5 >20 10-20 10-20 10-20 <5 RAB/mdm Enclosure w=a75.i ,,,acIMw,KOmrcyot~ce MM w 1727 OM HKOMW ep,nc,nq,xanVOcrasml-ao . soc03*aM SLS3tlilOt FA79E13aft4t3 sxtESOo 110 iMmw wa s110wr DAYTON, Ofp 4HOSAtE AA-aspam fA7L MJa3Mt RoaERTA Biw-rr tsM 357-9M txlopetaf0avr.ccm TAFT, STETTINIUS & HOLUSTER LLP 425 WALNUT STREET, SUiTE 9800 CINCINNIA71, OHIO 45202-3957 519-3d1-2Cl8 FAX: 573-3a1-0205 WM1W.tWi11XCOIR q,EyFlJlNpy O1Ep p/i:ICE asM OP rawAL monOucsoume eLVAaAMRaM a1er-aes =1saa .aM FAX: 17Cif417CT o0LURUui.0111CORWC~ 21 E0.9T STRIE b1ftM cowreuaaMaasrae swast4m FAX0tQH.0lff FEDERAL EXPRFSS Dr. Charles 1vL Auer USfiPA 1201 Constitution Avenue, N.W. 'Room 3166A Washington, DC 20004 Jennifer Seed USEPA 1201 Constitution Avenue, N. W. Room 6334A XVaslungton, DC 20004 James Kelly, M.S. Health Assessor Site Assessmeat and Consultation Unit Environmental kiealth Division Minnesota Department of Health 121 E 7th Place, Suite 360 St Paul, MN 55364 Mary Ellen Weber USEPA 1201 Constitution Avenue, N. W. Room 5124A Washington, DC 20004 Mary Domini~ USEPA 1201 Coautittvtion Aveme, N.W . Room 4470S Washington, DC 20004 Re: Perfluorochemicai Residential BxRosiue Data For Washington County. Ladies and Gcattlemen: We serve as counsel forPlaintiffs in a lawsuit that is currentlypending against the 3M Company in State Court in Ivl"uonrsota involving claims arising from exposutcs to perfluorochenzicals released by or otherwise attributable to 311L The lawsuit is styled, Palmer, et al. v 3M Company (M'uui . Dist Ct . Court File No. C2-04-6309). 3M owns and operates a manufacturing facility in Cottage Grove where various perfluoroclxmicals, including PFOS and PFOA, were manufactured, released, and disposed for several decades. In the context of tvoasa331t Dr. Charles M. Auer Mary Ellen Weber Jennifer Seed Mary Dominiak James Kelly May 12, 2005 page 2 . Plaintiffs' investivion oftheir claims, Plaintiffs' counsel arranged for sampling of private water wellsandsoil in the vicinity of 3Ms Cottage Grove operations, along with blood sampling of individuals residing in areas that may have been impacted from pexfluorochemical wastes attributable to 3M's Cottage Grove operations. in recognition of the potential threat to human health-and the environmentrevealed by this data, and in response to USEPA's prior public requests for perIIaornchernical monitoriM data, we are providing copies of Us initial -round of data to you for inclusion in USEPA's Administrative Record 226 and OPPT20d3-OOt 2 The PFOS and PFOA rcstilts for the serum, whole blood, water, and soil samples collected and analyzed to date on behalf of Plaintiffs are summarized below. Pleasc note that a11 results were provided by Axys Analytical Services LTD in Canada and were obtained, arranged for, and paid forwithout any involvement by 3M. 1. PFOAIPPO S SERUM/WHOLE BLOOD DATA Tlhe following charts present summarics of the PFOA and PFOS serumand whole blood data collected from residents of Washington County, Minnesota. Please note that whole blood results were obtained for only 2 of the individuals tested (as indicated in the chart) . We have grouped the available serum and whole blood data by drinking water source. The first chart (Chart A) summarizes the blood data obtained from individuals consuming drinking waterprovided by the City of Oak-date, Ku:aesota, where recent t.,-sting has confu-med PFOS in 2 of the CiVs water supply wells in levels exceeding the State of Minnesota's recommended Health Based Value of I part per billion (1 ppb), and levels of PFOA just below 1 ppb. (See AR-2-7&1929,1933, and 1935) 3M has reported detectingPFOS in tap samples collected from a 3MlDyneon facility in Oakdale as high as 0.9 ppb and PFOA as high as 0-8 ppb. (See AR-226-1934) The second chart (Chart B~ summarizes blood data obtained from individuals whose drinking water is provided by either the City of Lake Elmo, Minnesota, the City ofCottage Grove, Minnesota, or the City of Hastings, Minnesota, where it ltzs been reported that the levels of both PFOS and PFOA in those municipalities' water supplies are either not-derectable or below quantification levels. (See AR-226-1929,1931, and 1932. See also Exhibit A) In regard to Hastings water, 3M has reported having detected PFOA in a municipal water supply, well woGM .i Dr. Charles M. Auer Mary Ellen Weber 3ern;ifer Seed Maty Dominialc Jaincs Kelly May 12, 2005 Page 3 above the dftction lituit of0.025 ppb but belowthe: laboratory quantification limit of0.05 ppb . (See AR-7-26-1929 and 1931) - The third chart(Chart C), sumnmarizes data obtained from individuaLs consuming drinlang water from private wells, the vast majority of which have not yet been analyzed for perfltwrochernicals. To the extent information is availableregarding the level of perflaocochemicals actually detected in diespecific private well providing water to the individuals whose blood was sannpled, that information is provided in Chart C. Maps showing the general residential location of those whose blood was sampled =attached at ExhibitB. Mic lab results for each of the serum and whole blood results are attached at Exhibit C_ For privacy reasons, theijames, addresses, and specific ages of each ofthose sampled are not provided with this subnmdssion. Also enclosed at Exhibit A are copies of materiats, including maturials distributed by theMinnesotaDeparnnent of Health ("1vDH"), discussing the levels of pertluoroclteanicals recently detected by MDR in the City of Oakdale municipal.watersupply and private Lake Efmo area wells, inclodiug debectioos of FFOS in both private and public water supply wells in levels exceeding the States current recommended Health Based Value o 1 ppb for PFOS in water. We understand that MDH already is arranging for users ofsome of the eontaxninated private wells to begin receiving bottled water and water treatment. (See Exhibit A) SEX M F M Ivi F F ww19Z3.i CHART A - OAKDALE CITY WATER CUSTOMERS AGB PFOA (ppb) I!FOS (Bob) MARS ON WATER 41-50 51-60 >70 >70 41-50 51-60 121 .0 117.0 823 78.6 77 .5 74.9 109.0 91 .8 118.0 112.0 78.4 61 .1 N!A >30 NIA >30 N/A 20-30 Dr. Charles lvt. Aucr Mary Ellen Weber I'eEmifex Seed Mary Dorniniak James Kelly May 12, 2005 Page 4 ax- AGE F >70 F 61-70 M 61-70 F 61-70 F 41-50 Iv1 51-60 ]VI 41-50 '.K 61-70 F 18-30 M 51-60 F 51-60 M 41-50 M 51-60 F 18-30 F 51-60 F <18 F 61-70 F 18-30 N,/A=data not available W0438333.1 PFOA lnnbl PFOS (Mb) YEARS ON WATER 69.3 59.9 58.7 58.3 57.8 44.6 44.1 39-8 38.8 37.1 312 32.1 24 .523 .1 22 .2 19 .1 6.96 6.09 102 .0 71.0 61.7 68.1 70.4 60.4 55.2 46_5 47.6 51 .1 59.5 57 .6 37-2 292 46.1 42.9 ' 22.6 17.7 >30 N/A <10 20-30 20-30 10-20 <10 20-30 20-30 >30 10-20 10-20 10-20 20-30 .. 20-30 10-20 >30 - 10-20 Dr. Charles M. Auer Mary Ellen Weber 7ennifer Seed MaryAonoSniak Ian= Kelly MW 12, 2005 Page 5 CHART B - LAKE ELMOICUITAGE, GROVE/ HASTINGS MY WATER CUSTOIVM YEARS ON SEX AGE PROA Wb1 PFOS (ppb2 WATER 51-R NIA M 31-40 31-40 >70 51-60 4 51-60 E NIA 51-60 * = whole blood analysis "*= former 3M employee N/A=data not available 42.3 6.9 6.78 (4 .22*) 6.13 434 4-10 3.89 3 .36 2?1 49.5 19.6 10 .5 (7 .95*) 13 .5 14.0 17.3 21-2 21_4 7.85 <10 NIA 10-20 >30 >30 10-20 10-20 NIA >30 CHART C - WASHINGTON COUNTY PR7VATE WELL USERS 1. Lake Eim0 Area Privaie Wells SEX AGE PFOA fp,gbZ PFOS (pvbl YEARS ON WATER PFOA IN WATER PROS IN WATER ]v1 41-50 45 .7 19 .7 W0439333.1 20-30 NIA NIA Dr. Charles M. Auer Mary Ellen Weber Jennif'er Seed Mary Domiuiak James Kelly May 12, 2005 Page 6 . YEARS PFOA PFOS ON PFOA IN PFOS II1 SEX AGE fpnbl fpPbl WATER WATER WATER F 51-60 24.0 M NIA 16_4 F 41-50 15.7 F >70 14.3 M 61-70 12.1 1vI 18-30 7.56 M 6170 6_95 M 51-60 6.78 M 61-70 6.1 M 51-60 5.35 F 41-50 3.14 F 61-70 2.4 N/A-data not available 17.0 22 .1 9.27 8.90 9.78 173 43.7 21 .0 43 .7 20.4 11 .2 12 .0 >30 VA 10-20 y30 >30 20-30 20-30 20-30 >30 NIA NIA >30 NIA NIA NIA NIA NIA NIA NIA NIA NIA NIA NA N/A NIA N/A NIA NIA NA NIA NIA N/A NIA NIA NfA NIA 2. Cottage Grove/AastinQs Area Private Wells SEX M'"* AQ ,E >70 PFOA (ppb) 14.7 PFOS ft!pbI 108 .0 YEARS ON WATER PFOA IN WATER fnPbl . PFOS IN WATER (ppb) 20-30 NIA MA WQ43Ei33 .1 Dr. C2mrles M Auer Mary Ellen Weber Jennifer Seed Mary Doxuiniak Jan= Kelly May (2, 2005 Page 7 i i F YEARS PFOA IN Ph'US IN PFt?A PFiJS UN WATER WATER fWhl W-b.L WATER Cggb.L...... igj!hL.._ F 31-40 17 .1 16.9 F 61-70 7.38 32.5 F 51-60 9.12 42.8 M >70 6.42 32.5 F 41-50 4.97 16 .3 F 41-50 4.68 12 .0 F <18 3.87 15 .8 F NIA 3.54(2.98') 8.51(8.3-) F 41-50 3 i9 14.9 M <18 2.83 14 .8 M 41-50 2.01 22 .4 *-whole blood analysis **--farnmer 3M employee N/A=data not available AD-not detected <10 >30 20-30 >30 20-30 <10 <10 NIA >30 <10 <10 0.02 NIA N/A N/A 0.003 N/A NIA N/A N/A NlA 0.004 ND N/A NIA NIA ND NIA N/A N1A NIA MA ND II. PlY A_TE WATER WELL DATA Attached at ExNbst D are the private water well water results obtained to date . For privacy reasons, thespecific addresses and names ofthe owners of the wells tested have been redacted . A map showino ggenerally where the wells are located is attached at Exhibit E. W04-3,033.1 Dr_ Charles M Auer Mary Ellen Weber Jennifer Seed Mary I?ominialc James Kelly May 12, Zoos Pa~ s J17. PRIVATE pROPERTY SOJLRFSUJ,TS Attached at Exhibit F am the private property soil results obtained to date. For privacy reasons, the specific addresses and names of the owners of the properties tested have been redacted. A map showing generally where the soil results were obtained is attached at Exhibit 0- Very truly yours, bert A. Bilott RABIrndm Actachruents r.e: Gale D. Peaison, Esq. (WIattachments) Stephen J. Randall, F,sq. (w/ attachments) Rhore E. Jones, Esq. (wl attachments) J. Mark Englehart, Esq. (wl attachments) David B_ Byrnne IIL, Esq. (wd attachments) R. Edison Hill, Esq. (w/ attachment) Larry A. Winter, Fsq. {w/attachments) -MDATBFJIY He"Tuo"OFF" 1qp7E3Yr 17p o14&Nl6fMAY tOVw7W.1tMNICtcY 41 s114TO+ OW0a-21131 stsararem FJl7C i11,70lEi17 DRYTm1, DWp0lf7CE wrf.+m J10 NOR1N YN11,6TRFE7 DxYTVlL OHpaf~ .17-17~ W7.tL!-7A~0 FAY: W7:?~.m76 RowttTA. BicoTr fs1yl m-90s Glbn4aletUu"m TAM STET'1HUS & HOLlJSTER LLP 425 WALNUT STREET, SLUE 980D CINCINNATI, OHIO d5Z02-3857 siaaet-2a3a FAX; S1 U78Y-02C5 vm'1V.lERIYW.Cofn CLflYf7.AA1D.O1qA OF1i6e ,600 BP 10'N91 ' aVvrtkV .orav aw "raoa r64"41M rnu aw,ut.37m COWiI8l4^,OIIOOFRCfi n e4sr srltwmMr oDi.uwaus.DwDaus-4m G14-?21-Mb PA&G tt2H.7Dp1 October 20, 2005 FEDERAL EXPRFUSS Dr . Mattes M. Auer USEPA 1201 ConsEituiitxm Averwz. N-W. Room 3166A Wa4hirgbon, DC 20004 Jennifer Seed C JSET'A 1201 Constiturion Avenue, N.W_ Roortm 6334A 'Washington, DC 2000q David Douglas Rernediation Dbu-isicm Superfund & F.nnergenc} Response Section hfinnesor-a Polluti"on Control Agency 5201afayetre Road North St. Paul. NlAl 55155 Mary Dominiak USEI!'A 1201 Constitution AMritie, N.W. Room 44It',lS Washington, DC 20m lames Kelly, M-S . Health Assesscr Site Assessment and Cottu,vlnison Unit Envirotnttnental Health Division Mutnesota Department of Hesech 121 E. ?th Place, Suite .36Q St . Paul, MN 55164 Donald Kri=s Industrial Division Land & Water Quality Section Minnesota Pollution Control Agency 520 Lafayebto Road North St. Paul, MN 55155 Re : !'erllutx-cx:hem'scal Rr,siS.nti;tl Extsosure Data For Washin!.non !Qountv, Mirtne,saia i,adies and Getulcertea : ' In a iettir dated May 12, 2005, we provided informtion regarding levels ofvarious QcrlluorocEizaaicals, including PFOA and PFOS, detected in blood, soil : and water in the vicinity of 3M'x palluorocticnucal operations in Miratesota. Since [bat suomissiots, we have arranged for additional bloodsamples of individuals tr.siding in cotnmunities that may have been impacced w-osl7662-t Or. Chatles M. Amer Jentifor Seed Mary DOMInLak James Kelly DQvnl Douglas Donald tCt3ens CJc,Kober 20. 2005 paw 2 from pert2uoeacheu,ical wastes atttibuuaWe to Ws 14imtesola opeialiont. In rccogution of the potentiat threat to humanhealth and the cnvironment revealed by this dam and in response to USEPA's prior public requcscs for pertloocac6etnical maritoring data, we are pctrvidiag copies of this additional daca co you for ineiusion in USEPA's Administrative Ramed 225 and OPPT- 2003-ot112 - The perfluorockernical ('raclciding P'FOS and PFY3A) resvtis for seturn samples collected au1 analyzed on behalf of PlaintiSfs am sunutarized below. Please note that all ttsalcs were provided by Axps Analytical Suvices I;fD in Canada and were obtained, arranged for, and paid fur witbout any invroltiemer:l by 3M. In our May 12, 2005, letter, we presented charls sunvnarizing the PFOA and PFOS =um and whoJe blood data collected &om rcs'sdaits of Washington County, Nlinnesoca, with the data organized by ckinidag water sounre. Sinceour May 12,200S. submission, sdditional blood data has teen collocted from individuals consumingwater provided by the Cilty of pakdale, NTiamota, wh= teating of the Citfswater supply wells has, on occasion, conOcrnsd FFOS in Iclels exceeding the Smie of M'mnesota's rtcommectded Health Based Value ("HBV") of 1 put. per billion (1 ppb), and levels of PFOA just below i ppb- (See AR-226-1929,1933, and 1935) 3M also has rePqrted dctecting PFOS in tap samples from Oakdale as high as 0.95 ppb and PFOA as high as 0.71 ppb, irndic:ating lhst duecombined level of PFOS and PFO.4 in Oakdale watcr has cxcooded the States &zacd bid= ("EP) of ( for Making water containing both PFOS ant! PFOA. (See AR-226-2737-39; AR-226-I<345-q6;1aciribit A (3M's ~~11 calculations)) As 3M expfained in its hum 14, 2005, letter W USF.1`A, such cuzrsulaiive amounts of PFCs in rap water exceeding t6e Hl of 1 represent a level of PFCs tlhat also epcecods the States owad, t+ecotnmemkd HB Vs, which [be State uses to assess wliether there is an ucucasortable risk [o hivnart hcaltix (See id) Thcreare now also data sugsesfiM the possibility oCadditional per$uotochernicals, including PF9S (C-4) (a chea,tical3M uses in on-going ma;nufactuainR proaeStses)_ in (he vvatec near the inmpaoced public watersupplies. Thc pricsenx:e oFthcsc other peffluorociternicals in water ahrady contarninsited wiitt both PF06 andPFOA Contributes to the thrcat of even syeater c:unulative coxicity concsrns . (SeE F_<hibit H) Some: of ftme other PFCs, including PFHS (C-4), al<eady have been detected 3n the blood of acm residents, leading to very high cumulative PFC levels in d)eir blood. (See F=tibit D; May 12, 2005, Letter (attachcd lab aheeft)) C3sart A below wn5)7w- r 13r. C'haries M. Auer Jennifer Seed Mary Dominisk janies Kelly David Douglas Donald Krierrs October 20,2005 Page 3 ics;Iudes ait of the origins[ and new blood data for City of oa]tdale water eustorners, including [be cumulative, total amount of various petluorochenicals detected in the blood sat7aples.Y The new data are in bold typc. In our May 12, 2UQ5, subniss'son, we also provided doca rvgavding the level of PerfluorochemicaLs found in the Wood of individuals cottsumiagdriaEcing water from private ;vc)ls in the area of WS Mimnesofia operations. Shim that submission, we have eollected additiona161ood dam ftom private wclt users in the Lake Elmo, Minncsola, area and havc obtained some additional information From 3M and Nmi-L regarding the level of 1'FOS and PFOA in sorne of those weils. (See Exhibit C (Exccrpts from 3M's Sepiember 2, 20f}5, Answers to Plaiatiffs' Interrogacories))'-'. Chari B beiow provides a summary of all of the original Lake >r.ltno am private well blood and %+rater data (now with atrnalativc 6aals for the perfhiorochemical blood data), Plus =he newdata obtained since May 12, 24U5 . The aew dwa is in bold type. [n order lo avoid idealificationof individual idenlitics, we treve pfovk[W available private waIer well PFC data in a geaerai range, as opposed to speaific resviis. The 1ab =suits for the blood results are attached at Exhibit D. For privacy reasons, the names, addrcsscs. and specific ages of each of those sampled arc oinitred from this submission . '-' Al(hough the. individual blood zest result sheets attached co ow May 12, 2005, letter jrtfcrenced ft levels of various oertluorochemricals detected in the individual blood samples, we did not includc the cumulative lolals in the ehads set farth in our original, May l2, 2005, letter. We have now included the cuiuulafi+e total PFC results frottf those Jab sheets in !he curtrqt chaos. " The Minnesota Departrnant ofRea]th is currently using detecticxsfteporting limits of 0.5 ppb and 1.0 ppb for PFOS and PFOA, respeotively- (See fizhibit C ) wosa7ssz.1 Dr. Charles M- Auer Jennifer Seed Mary Dominoialc James Kelly David I3otTlas DonQid Rrieas Ocinbar 20, 2005 Page 4 MET A - QAIRALE MY WAMR CUSTOMERS S~ AGE YEARS ON PFOA WATER fapbVDua PF(?S (ppblMup. TOTAL pFCaluobl+ M M M M F F M M F M F F M F F M M was17s6z_i 41-50 51-60 >70 51-0 61-70 51-60 41-50 51-60 >70 61-70 >70 41-50 51-60 31-40 >70 4150 -1 8 41-50 MA >30 >30 20-30 20-30 20-30 <10 20-311 NIA 20-30 >30 NIA 20-30 10-20 >30 NIA r10 10-20 121 .0 117.0 1050 llW.41103 .0 10000 96.1 95.1l89 .1 86.8 92-3 8" 78.6 77.5 74.9 74 .6 69.3 69.0 683 633 109.0 91.8 113.0 70 -I17Z.7 131.0 67.8 8"J79.8 Me 118.0 163.0 112.0 79A 61 .1 41.0 102.0 77.2 50-1 76.7 267.12 240_06 241_45 197-441195 .54 293A 180.2 200.711186 .15 748_A1 221.79 212.40 210.63 178.S1 152.7Z 18236 191:8d163.79 134.12 158_98 Dr. Charles M. Auer3cwiFer Seed Mary Dominink Jmes Kelly David Douglas Donald Kcitns 4claber 20, 2Q05 page 5 SEX AGE F 41-50 F 61-70 F 61-70 M 61-70 F 61-70 F 41-50 F 31-40 M 51-60 M 41-50 M 78-M r+i <18 hi 61-70 1. 18-30 M 51-60 F 51-60 F 41-50 M 41-50 F <10 <s o YEARS OW PFOA ti1%AT1:R (ppfijfflLup. PPOS h nn <1 0 N/A >30 <10 20-30 20-30 .10-20 10-24 =10 10-20 10~2e 20-30 20-34 >30 10-20 40 10-20 <10 <10 63,3 73a 59.9 71.0 58.7 73.4 53.7 61.7 58.3 68.1 57.8 704 48.4 77.9 44.6 60.4 44.1 55.2 43.5 ' 54A 42.4 51 .1 3+3.8 46.5 38.9 47.6 37 .1 51 .1 332 59.5 32.7 41.5 32.1 57.6 30.7 56.8 273 60-0 TOTAL PFC Fpb~ 1.51O1 L 145 .61 349.48 134.64 154 .95 146 .46 137,.83 115 .40 114 .29 107.12 107.94 10437 96_33 102.01 10524 89-66 103 .35 49.11 9a63 1?r. Charles Ivi- Aucr Jencufer Seed May Dominiak Jsacncs Kelly David Douglas Donald Krkas Octobcr 2U. 2{l05 Page 6 SE7i AGE YEARS ON PFOA WATER ~, "Os ~pb)(Dna TOTAL Pl~(oob) ~ 1vF 51-60 10-20 24.5 37.2 69-72 F 18-30 20-30 23.1 29.2 59.83 F 51-60 20-30 22.2 46.1 74.88 F 31-40 MA 21.1119r6 1 .62 w1 29.64l36.80 F <19 10-20 19.1 42.9 71.21 F <18 c10 17.1 2:0.1 43.08 A~[ 31-40 <10 15.5 127 29.31 M 47.-50 <10 14.6 30.8 49.49 19-30 <10 13.3 17..3 27_14 F 18-30 <10 10.7 23.1 35.87 3YI >70 24-30 10.2 24 .2 35.31 F 18-30 S10 7.35 10 .5 19.39 1w 51 -60 <10 7.21 38 .9 57.56 F 61-70 >30 6.96 22.6 36 .00 F 18-30 k0 20 6A9 17,7 26.79 NJA=dam not a"railabl e "Total of decactr.d )etiets of PFPeA, PFl~Le.A, PPHpA, PFOA, PFNA, PFDA, PFUnA, P>~boA, Pl~$S, PFiixS, PFOS. and PFOSA in The blood swnple wojja6x .I Dr. Charles M. Auar Jennifer Seed May Domiaialc 38mes KeUy David Douglas Donald Krieas October 20, 2005 Page 7 CIIAR'1' B -i.AKE ELMO_A~P1tI~'ATE WEU, U.S,FR.S SEX AGE YEARS ON WATER PFOA (ppb}l _DM- PFOS (Pgb) MO. PPB PFOA IN WATER Pi'Ii PFGS IN WATER TOTAL PFCSi j"b,I'" F .c1g <lp 11Qa 111-0 lA-IA F 41-50 10--20 72.9 87.6 1.U-IA F <18 10-20 55.4 60.0 1.0-I.4 1~4 41-50 20-30 45-7 19-7 ND F 61-70 20-30 30.9 88.6 9.S-l).9 M 5I-b0 1Q-20 27.0126.7 ZS.Sl32.7 t.0-1.4 At 61-70 2030 24.2 38.0 0.5-0.9 F 51-60 >30 21.d 17.0 ND lvt NIA NIA 16.4 22.f ND F 41-50 10-20 15.7 9.27 NIA F >70 >30 14.3 8.90 ND M 61-70 >30 12.1 9.78 ND M 41-50 10-20 9-" 2G.6 NA F 41-50 <10 9.25 23.4 NIA M 18-30 20-30 7.56 17.3 , NIA M 61-70 20-30 6.95 43.1 NIA M 51-GO 20-30 6.78 21 .0 N/A 0.5-0.9 9.5-0.9 0-5-0.9 ND ND 0.5~fl9 ND ND ND NIA ND ND ND N/A NlA 1JlA WA 247.19 l7$.25 124.35 72.11 12&93 6?.3'Z165.74 69.91 50.96 44.43 27.68 26.27 2.4.89 42.53 41 .58 33.70 55.00 36-91 arfl5s7dsa I Dr. Ctuvlr.s M. Aucr .itmifer Sccd Mmy Dorniniak Javrm Kelly David Douglas i?onaM Krims October 20, 2005 Page 8 SEX A!A Y>EARS ON WATER PFQA (ppb)f DR , PFOS (pQb) 1Dsa. PPB PFOA IN wATER pPB PE~'(?S 1N WATER TOTAL. PFCa jMhA" M 61-70 >30 6.1 43.7 NIA N/A F 51-6v 10-20 5.92 Z9-5 ND ND M 51-60 NIA 5.35 2D.4 NIA NIA F 41-50 NIA 3.14 11 .2 NIA NIA F 18-30 <19 2.63 17 .4 NIA NIA F 6170 >30 2A 12 .0 NIA NIA N/A-data not sYailable ND- not dratcc"cd above reported dct=iOn limits *Total of detected levels of PFPeA, PFN.~cA, PFHpA, PFOA, PFNA, PFDA, PFUnA, C'FVoA . PFBS, FFF{xS, PF4S. and PFOSA in the blood sample 54.19 4l.26 29.02 16.29 26.09 17.91 RABhndro Enc1osurcs erv lY Ya d obert A. Bilott W4537(,d?,1 nannvtm Re+aucnr Of ;,'-CE 3WM >" 17if am 1!(pFMAY !'*WGYOKMFfUQCr ltW1 .4TOl i0i-rit-21J! SfhWf.2aH FA7L 513.71F4ctJ OA1(rC1LOllq OFi1Cf SWIE "a awMTrruw srql:Er pAYl0K0W011O1-f7K 231no-I:i .SI FA)(! *27-Z29-Z914 Roartr a t3suorT (513) 357-963a bilolQlaRlaw .aovn TAFT, STETTINIUS 8 HOLLUSTER LLP 425 WALNUT STREET, SUITE 1800 CINCINNATI, OHIO 45202-3957 M-391.2333 FAX: $13-3814205 1V1YW.tifttiYlt .CoAl REYB[/WD.OO100FFICE 3"Q 1W rowtw xo wlxlc sCRwM CLErEIwwD,Olq U114-t702 ilb1ll-zw FAR: t21-3414M CGOLU1r9VS .QIODOFJiGE ZI E/l51 9rArE STRfE7 ta.uMeVS, Gf4p MtSt]21 f11-Z:1." FJiX.NM?I1,700) January 13,2006 FEDERAL EXPRESS Dr. Charles M_ Auer USEP A 1201 Constitution Avenue, N.W. Room 3166A Washington, DC 20004 Jennifer Seed, Ph-D . USEPA 1201 Constitution Avenue, N_W. Room 6334A Washington, DC 20004 GaY Krueger Remediation Division Superfund & Emergency Response Section Minnesota Pollution Control Agency 520 Lafayene Road North St_ Paul, MN 55155 Mary Dominiak USEPA 1201 CConstitution Avenue, N.W . Room 4410S Washington, DC 20004 lames Kelly, M.S_ Health Assessor Site Assessment and Consultation Unit Environmental Health Division Minnesota Department of Health 121 E. 7th Place, Suite 3b+D St. Paul, MN 55 164 Donald Kriens Industrial Division [,and & Water Quality Section Mittnesota Pollution Control Agency 520 Lafayette Road North St_ Paul, MN 55 155 Re: Perftuorochemica! Residential Exposure Data For Washiagton County Minnesota Ladies and Gentlemen : In letters dated May 12, 2005, October 20, 2005, and November 10, 2005, we provided information regarding levels of various perlluorochemicals (PFCs), -including PFOA and PFOS, detected in blood, soil, and water in the vicinity of 3M's perfauorochemical operations in Minnesota_ In recognition of the potential threat to human health and the envicommenl revealed w061Z>_Ei t Dr. Charles Iw. Auer Jennifer Seed Mary Dominiak James Kelly' Gary Kimeger Donald Kriens January 13, 2006 Page 2 by this data, and in response to USEPA's prior public requests for perfluorochemical monitoring data, we are providing additional data to you for inclusion in USEPA's Administrative Record 226 and EPA-HQ-OPPT-2403-0012 relating to cumulative perBuorochemical levels detected in tap water samples obtained from areas serviced by the City of Oakdale, Minnesota, and the City of Lake Elmo, Minnesota!, along with aMtional data relating to the cumulative level of PFCs detected in the blood of residents consuming drinking water supplied by the City of Oakdale, Minnesota. We are also providing this data to the Minnesota Department of Health, the Minnesota Pollution Control Agency, and to the Cities of Oalcdale, Minnesota, and Lake Elmo, Minnesota, to enhance understanding of the potential impact of cumulative PFC levels in drinking water. The individual tap water results are summarized below in Chart A. Three tap water samples were obtained and analyzed from three different residences served by the City of Oakdate and two tap water samples were obtained from two different residences served by the City of Lake Elmo .' A map showing the general location of the tap water samples in relation to the City of Oakdale's municipal wells is attached at Exhibit A. Copies of the lab sheets (with specific addresses redac(ed) are enclosed at Exhibit B. For privacy reasons, the specific '-` We understand that there is a plan to connect certain properties with PVC-contaminated private water wells in the Cake Elmo area to the City of Lake Eltno public water supply_ We understand that, in the meantime, MDH is arranging for bottled water to be provided to certain users of some of these PFC-contaminated private wells. Based on the recent detection of PFOA in certain bottled water supplied to those using PFOA-contaminated water supplies in Ohio (see Exhibit D), we request clarification from MDH as to whether the bottled water being supplied in the Lake Elmo area has been tested for PFCs, which PFCs were included in any such analysis, and what the detection limits are for any such analysis that has been performed . '-' The tap samples identified in Chart A as "Oakdale City I," "Oakdale City 2," and "Oakdale City 3" correspond to the tap water sample locations identified in approximate terms on the map attached at Exhibit A with diamonds labeled '0 1," "02," and "03" respectively. The tap samples identified in Chart A as "Lake Elmo City l" and "Lake Elmo City 2" correspond to the tap water sample locations identified in approximate terms on the map attached at Exhibit A with diamonds labeled "LEI" and "LE2" respectively. The stars on the map attached at Exhibit A are the approximate locations of certain City of Oakdale municipal %vater supply wells. tv0612285 1 Dr. Charles M. Auer Jennifer Seed Mary Dominiak James Kelly Gary Kn)eger Donald Kriens January 13, 2006 Page 3 addresses where the tap samples were collected have been omitted from this subnmission- please note that all results were provided by Axys Aalyticat Services Ltd . in Canada, and were obtained, arranged for, and paid for without lay involvement by 31V(_ CHART A - CITY TAP WATER RESUGTS {PARTS PER BILLIONI OAKbALE C(TY ! OAImALE CCTV 2 OAKDALE CITY 3 LAKE ELMO CM 1 LAKE ELMO CITY 2 PFgA 0.3800/0.4390 PFPeA 0.0201J0_0188 PFHxA 0.0543/0.0515 PFHpA 0.022610 .0183 PFOA 0-1140/0-1120 PFNA ND/ND PFDA NDIND PFUnA ND/ND PFDoA NDIND PFBS 0.0067610 .00744 PFHxS 0.0133I0 .0l08 PFOS 0.050810_0509 PFOSA ND1ND TOTAL PFCs 0.6619610 .70854 ND-not detected 0_4760 0.0239 0.0588 0.0251 0.1360 ND ND ND ND 0_00915 0.0149 0_0632 ND 0.80705 1 .7200 0.0834 0.1970 0.1020 0.6260 0.00245 0.00309 ND ND 0.0386 0.0663 0.7550 0.00341 3.59725 0.0920 ND ND ND ND ND ND ND ND ND ND ND 0.00126 0.09326 0_0865 ND ND ND ND ND ND ND ND ND NO ND ND 0.0865 %V%122&5 .1 Dr. Charles M. Auer Jennifer Seed Mary Dorniniak James Kelly Gary Krueger Donald Kriens January 13, 2006 Page 4 The updated PFC results for senun samples collected and analyzed from City of Oalcdaie water customers (including total PFCs and individual PFOA and PFOS levels) are summarized below in Chart B. The new data are in bold type. The tab results for the new blood results are attached at Exhibit C. For privacy reasons, the names, addresses, arul specific ages ofeach of those sampled are omitted from this submission. Please note that all results were provided by Axys Analytical Services LTD ire Canada and were obtained, ananged for, and paid for without any involvement by 3M- SEX N( M F F M F M M M F F M w06I2Z85 .1 CHART B - OAKDALE CITY WATER CUSTOMERS AGE YEARS ON WATER PFOA (2pbllDup. PFOS (ob)IDup. TOTAL PFCs(ppb)"l Dup. <18 41-50 51-60 51-60 >70 51-60 51-60 61-70 41-50 51-60 41-50 51-60 <10 NIA >30 10-20 >30 10-20 20-30 20-30 10-20 20-30 <10 10-20 155.0 121 .0 117 .0 113.0 105 .0 104.0 104-01103 .0 100-00 97.9 96.1 95-1I89_1 92.7192-5 180.0 109_0 91 .8 167.0 113.0 108.0 70-3l72 .7 131-0 121-0 67.8 85_9J79 .8 88-01111 .0 371 .35 267-12 240_06 35734 241 .45 252 .23 192.441195 .54 293 .08 244.71 180-2 200 .711186.15 2 1 1.78n4o .23 Dr. cnartes M. Auer Jennifer Seed Mary Dominiak James Kelly Gary Kmeger Donald Kriens J2mUary 13, 2006 Page S SEX M F M F M F F F M F F F M h'1 M F F wo612 za5 . 3 AGE 51-60 6170 >70 61-70 >70 41-50 31-40 51-60 31-40 18-30 >70 41-50 <18 10-30 41-50 41-50 51-60 61-70 YEARS ON PFOA WATER (pjrb}IDnp. PFOS fppbUDup. TOTAL PFCs(ppb)*1 Dup. 20-30 >30 NIA 20-30 >30 NIA 10-20 20-30 10-20 N/A >30 N/A <10 <10 10-20 <10 10-20 NIA 86.8 85.7 82.3 80.5 78.6 77.5 75.9 74 .9 74_6 70.9 69.3 69.0 68.3 67.4 63.3 63-3 60.6 59-9 125 .0 121 .0 118-0 163 .0 112 .0 78.4 103.0 61 .1 91 .0 112 .0 102 .0 77_2 50.1 833 76-7 73 .1 92.5 71 .0 248.01 232.86 221 .79 2 1 2-40 210.63 178.51 196.84 152.72 182 .36 200 .91 191 .84 163 .79 134 .12 167.12 158.88 150.11 184.71 145 .61 Dr. Charles M. Auer Jennifer Seed Mary Dominiak James Kelly Gary Krueger Donald Kriens 3anuraiy 13, 2006 Page 6 SEX F M M F M . M M M M M M F F F M F wos1i2ss 1 AGE 61-70 61-70 61-70 4 1 -50 41-50 31110 <18 51-60 41-50 18-30 <18 61-70 61-70 41-50 41-50 18-30 51-60 41-50 YEARS ON WATER PFOA (ppb)IDup- PFOS (ppb)/Dup. TOTAL PFCs(ppb)*! Dup. ,^ >30 <10 20-30 20-30 10-20 10-20 <10 10-20 <10 ) 0-20 10-20 >30 20-30 10-20 <10 20-30 >30 10-20 58.7 58.7 58.3 57.8 56.2 48.4 45.4146 .4 44_6 44-1 43.5 42.4 40.7 39_8 39_3 39.0 38.8 37.1 33-8 73A 61-7 68.1 70.4 116.0 71 .9 68.2I71 .7 60.4 55_2 54.4 51 .1 80.3 46.5 46.3 57_4 47.6 51 .1 46.4 149.48 134_64 154-95 146 .46 193.95 132_83 130.851132 .92 115 .40 114-29 107 .12 107-84 137 .38 104 .37 94.34 112.63 96.33 102.01 91_07 Dr. Charles M- Auer Jennifer Seed Mary Dominiak James Kelly Gary Krueger Donald Kriens January 13, 2006 Page 7 EX F F M F F F F M F F F F F F F M M F tV0612285 .f AGE 51-60 41-50 41-50 <10 <10 51-60 51-60 51-60 41-50 18-30 51-60 3 i -40 51-60 <18 <18 <18 31-40 31-40 YEARS ON PFOA WATER (Qpb)lDan . PFOS b u 10-20 <10 10-20 <10 <10 10-20 <10 10-20 10-20 20-30 20-30 N/A 10-20 10-20 <10 <10 <10 10-20 33.2 32-7 32.1 30.7 27..5 26.2 25.2 24.5 23.6 23-1 22.2 21 .1 /19.6 19.7 19.1 17.1 16.1 15.5 14.6 59.5 41 .5 57.6 56.8 62.0 104-0 46_2 37 .2 72.9 29.2 46-1 12.8/8.81 52.6 42-9 20.1 24.3 12.7 37.4 TOTAL PFCs(ppb)'I Dup. 105.24 89.66 103.35 99.11 98.63 149.68 77.18 69_72 107.32 59-83 74.88 29.64/36.80 76.87 71.21 43.08 51.95 29.31 59.61 Dr. Charles M. Auer Jennifer Seed Mary Dominiak James Kelly Gary Knxger Donald Kriens January 13, 2006 Page 8 TOTAL YEARS ON PFOA PFOS PFCs(ppb)*! S,,~FX ACE WATER b /Du . b n . Dup. -- M 41-50 <10 14_6 30.8 49.49 M <18 <10 13.4 50.1 83.18 F 18-30 <10 13_3 12.3 27.14 M 41-50 <10 12.8 30.1 47.16 M 18-30 10-20 11.4 50-8 72.75 M <18 <10 11-2 27.7 57.94 P 18-30 <10 10.7 23.1 35.87 M >70 20-30 10.2 24.2 35.31 F 31-40 <10 8.76 30.1 4535 F 18-30 <10 7.35 10.5 1939 M 51-60 <10 7 .21 38.9 57.56 F 61-70 >30 6.96 22.6 36.00 M 3140 <10 6.16 16.1 26.90 F 18-30 10-20 6.09 17.7 26.79 M 41-50 <10 5_52 8.27 15_82 N/A=data not available *Total of detected levels of PFPeA, PFHxA, PFHpA, PFOA, PFNA, PFDA, PFUnA, PFDoA, PF8S, PFHxS, PFOS, and PFOSA in the blood sample wos122g5 . i Dr. Charles M . Aaer Jennifer Seed Mary Dominialc James Kelly Gary Krueger Donald Kriens January 13, 2006 Page 9 RABImdm Enclosures cc_ Fardin Oliaei, Ph.D . (wl encls.)(NIPCA) James Golembeck, Esq. (w/ encls_)(City ofOakdale Special Counsel) Jerome P . Filla, Esq . (w/ e,ncls_xCity of Lake Elrrw Counsel) Crate D. Pearson, Es9. (w/o encls.) J_ Mark Engiehan, Esq. (w/o encls .) R Edison Hill, Esq_ (w/o encls.) Larry A. Winter, Fsq. (w/o encls.) Gerald 1. Rapien, Esq. (wlo encls .) . waizzas .i p. 137 pOR7H8RN KEN7UCKY oFPICE SIRiE 30 17170M fOGNWAY pDYiNGMN, KOITUCKY 4t0t1-47W 666-771-i656 Sl7-i61-2676 FN(: S13i30f~i617 DAY1011, 06pOOFRGE surdr we 970NOBiHMANi SYAEET OAYZOIi.ON10 45pW176i 977.221s-26J6 FAK:237-424-2616 ROBERT A. BILOTT (513) 357-9838 bBott@bMaw-coa+ TAFT, STETTINIUS 8 HOLLISTER LL, 425 WALNUT STREET, SUITE 1800 CINCINNATI, OHIO 45202-3957 513,381-2838 FAX: 513,389-0205 YWWN.ti1t1SYY.CofY1 aEVQ.A11q.ObIQOFRCE 3506 S! TONER 206MOMspqARt: Cl.hYBANp pY0 461U.2762 2f"1-2676 FAX: 216-24t,ilq POUIMBVS. 01UC OFqCE 21 E"7 $TA7E $1REET cocVtOMls.OHlo axtsrW 614-12f-2676 FAXs611-I21-M7 February 2, 2007 FEDERAL EXPRESS AND ELECTRONIC MAIL Dr. Charles M. Auer USEPA 1201 Constitution Avenue, N.W. Room 3166A Washington, DC 20004 Mary Dominiak USEPA 1201 Constitution Avenue, N.W. Room 4410S Washington, DC 20004 Jennifer Seed, Ph.D. USEPA 1201 Constitution Avenue, N.W. Room 6334A Washington, DC 20004 John Stine Site Assessment and Consultation Unit Environmental Health Division Minnesota Department of Health 625 Robert St., ht. 5t. Paul, MN 55164 James Kelly, M.S. Health Assessor Site Assessment and Consultation Unit Environmental Health Division lvlinnesota Department of Health 625 Robert St., N. St. Paul, MN 55164 Helen Goeden Minnesota Health Department 625 Robert St., N. St. Paul, MN 55164 Gary Krueger Remediation Division Superfund & Emergency Response Section Minnesota Pollution Control Agency 520 Lafayette Road North St. Paul, MN 55155 Donald Kriens Industrial Division Land & Water Quality Section Minnesota Pollution Control Agency 520 l.afayette Road North St. Paul, MN 55155 woass592. 1 February 2, 2007 Page 2 Michael Kanner Manager Superfund & Emergency Response Section Minnesota Pollution Control Agency 520 Lafayette Road North St. Paul, MN 55155 Greg Harnmond Environment Canada Policy 351 St. Joseph Blvd . Gatinesu, Quebec K 1 A OH3 Canada Doug Vhetzstein Supervisor Superfund & Emergency Response Section Minnesota Pollution Control Agency 5201.afayette Road North St. Paul, MN 55155 Re: Perfluorochecnical Residential Expasure Data For Washington County Minnesota Ladies and Gentlemen: In letters dated May 32, October 20, November 10, 2005, and January 13, 2006, we provided infornuation regarding levels of various pertluorochenicals (PFCs), including PFOA and PFOS, detected in blood, soil, and water in the vicinity of 3M's perfluorochemical operations in Washington County, Minnesota. 1n recognition of the potential threat to human health and the envirorunent revealed by the data, and in response to i3SEPA's prior public requests for pertluorochenical monitoring data, we are providing additional data to you for inclusion in LISEPA's Administrative Record 226 and EPA-HQ-OPPT-2(103-0012 to supplement the data we provided previously. In particular, we are providing clarification with respect to the extent of our available data regarding detections of PFBA in the blood of residents exposed to PFBA in their drinking water. We thought this information might be of value in connection with the recent disclosure by the Minnesota Department of Health ("MDH") that PFBA has now been found in additional public water supply wells in Washington and Dakota Counties at levels exceeding the State's current guideline of 1 .0 part per billion_ (See Exhibit A) (n our last letter on this topic dated January 13, 2006, we provided our own tap water sampling data confirming that PFBA had been found in tap water supplied by the City ofOakdale, Minnesota, at a level exceeding 1 .0 part per billion, and that the level of PFBA in that water was actually more than double the amount of either PFOA and PFOS in the tap water. MDH's own recent sampling confirms that similar, if not higher, PFBA concentrations are present in additional public water supplies serving tens of thousands of additional residents of Washington and Dakota Counties. (See id) Data independently collected and provided to us recently by art area resident reveal similarly elevated PFBA Wo886542 .r February 2, 2007 Page 3 concentrations in water from three wells identified to us as "Old Cottage Grove wells" (1 .83 ppb, 1 .85 ppb, and 1 .25 ppb) and from tap water identified to us as being supplied by the City of South St. Paul (1 .64 ppb) .-" (See Exhibit B) These levels all also exceed the current 1 .0 ppb well guideline for PFBS in drinking water. Although a substantial number of the area blood samples referenced in our earlier letters were not analyzed for PFBA, some of the later samples included PFBA analysis and reveal detections as high as 2.92 ppb in the blood ofan exposed individual . We have highlighted the available PFBA blood results in the following charts . We thought data confirming detections of PFBA in any exposed individuals would be of use to regulatory agencies evaluating this issue, particularly in light of MDH's current understanding that "PFBA does not appear to accumulate in animals or people." (Exhibit A) Updated PFC results for serum samples collected and analyzed from Washington County, Minnesota, residents (this time, also noting PFBA blood results, if any) are sununarized in the charts below. New serum data not included with our previous letters or included in 3M's August 4, 2006, letter forwarding some of our additional sampling information are highlighted below in bold type. The lab results for the new blood data are attached as Exhibit C_ For privacy reasons, the names, addresses, and specific ages of those sampled are omitted from this submission. Please note that all results were provided by Axys Analytical Services LTD in Canada and were obtained, arranged for, and paid for without any involvement by 3M. CHART A - OAKDALE CITY WATER CUSTOMERS AGE ON WATER PFOA b /Da . PFOS b u. PFBA b IDu . TOTAL PFCs(ppb)*/ Due. M <18 <10 M 41-50 N/A F 51-60 >30 155.0 180_0 1 .16 121 .0 109 .0 N/T 117.0 91 .8 N/r 371 .35 267 .12 240 .06 '-l We understand that the private citizen who reported these data to us arranged and paid for this testing and analysis through Axys Analytical Services, LTD in Canada. W0986592. 1 February 2, 2007 Page 4 SEX F M F M M M F F M M F M F M F F F M F F F ACE YEARS ON WATER PFOA b u. PFOS b u. PFBA (ppb)/Dup. TOTAL PFCs(ppb)*1 Dup. 51-60 >70 51-60 51-60 61-70. 41-50 51-60 41-50 51-60 51-60 61-70 >70 61-70 >70 41-50 31-40 51-60 31-40 18-30 >70 41-50 10-20 >30 10-20 20-30 20-30 10-20 20-30 <10 10-20 20-30 >30 NIA 20-30 >30 N/A 10-20 20-30 10-20 NIA >30 NIA 113.0 167.0 N/D 357.34 105 .0 113.0 N/T 241 .45 104.0 108.0 NID , 252.23 104.01103 .0 70 .3172.7 N/T 192.44/195.54 100.00 131 .0 NlT 293 .08 97 .9 121 .0 NID 244.71 96 .1 67 .8 N/T 180.2 95.1/89 .1 85.9/79 .8 N1T 200.711186 .15 92.7192 .5 88.0/111 .0 2.92 211 .78/240 .23 86.8 125.0 N/'1' 248.01 85.7 121 .0 NlD 232 .86 82.3 118 .0 N/1' 221 .79 80.5 163 .0 Nr1' 212.40 78.6 112.0 NfT 210.63 77.5 ' 78.4 NIT 178.51 75.9 103 .0 NlD 196.84 74.9 61 .1 NIT 152.72 74.6 91 .0 NlT 182 .36 70.9 112 .0 NID 200.91 69.3 102.0 NIT 191 .84 69.0 77.2 Nll' 163 .79 wossss92. I February 2, 2007 Page 5 SEX M M M F F F F F M F F M F M M M M M M M M AGE YEARS ON WATER PFOA (pab)/Dup, PFOS b IDu - PFBA lnnblVDun. TOTAL PFCs(ppb)*/ Due. <18 10-30 41-50 41-50 51-60 61-70 N/A 61-70 61-70 61-70 41-50 41-50 31-40 61-70 <18 51-60 41-50 18-30 <18 61-70 61-70 <10 <10 10-20 <10 10-20 N/A 10-20 >30 <10 20-30 20-30 10-20 10-20 >30 <10 10-20 <10 10-20 10-20 >30 20-30 68.3 50.1 NIT 67.4 83.3 N/D 63.3 76.7 NrT 63.3 73.1 NJT 60.6 92.5 N!D 59.9 71 .0 NIT 59_8 109.0 NID 58.7 73 .4 N(1' 58.7 61-7 NIT 58.3 68.1 NID 57.8 70.4 N(T 56.2 116.0 NID 48.4 71 .9 NIT 46.1 85.3 NID 45.4/46.4 68_2/71.7 N/D 44 .6 60 .4 N!1' 44 .1 55 .2 /T 43 .5 54 .4 N/T 42 .4 51 .1 NtT 40_7 80.3 NID 39 .8 46 .5 NID 134.12 167.12 158 .88 150.11 184 .71 145.61 183 .42 149.48 134 .64 154-95 146.46 193 .95 132 .83 131 .40 130.85/132.92 115.40 114.29 107.12 107.84 137.38 104.37 W0336592. 1 February 2, 2007 Page 6 SEX F F M F F F M F F F F M F F F F F lvl F F F AGE YEARS ON WATER PFOA b /Du . PFOS lr !Da . PFBA b u. TOTAL PFCS(ppb)*/ Dua. 41-50 18-30 51-60 41-50 51-60 41-50 41-50 <10 <10 51-60 51-60 51-60 41-50 41-50 18-30 51-60 31-40 41-50 51-60 <18 41-50 10-20 20-30 >30 10-20 10-20 <10 10-20 <10 <10 10-20 <10 10-20 10-20 10-20 20-30 20-30 <10 10-20 10-20 10-20 <10 39.3 38.8 37.1 33.8 33.2 32.7 32.1 30.7 27.5 26.2 25.2 24.5 23.8 23 .6 23.1 22.2 21-1/19.6 20_3 19.7 19.1 18.6 46.3 47.6 51 .1 46.4 59.5 41 .5 57.6 56.8 62.0 104.0 46.2 37.2 40.3 72.9 29.2 46.1 12.8/8 .81 32 .5 52.6 42.9 21 .0 N/D NIT Nfl` N/D Nrl' NIT NIT NR' NIT 1 .06 N/D NlD NID N/D NIT Nli' Nff N/D N/D NIT NlD 94.34 96.33 102.01 91 .07 105 .24 89_66 103 .35 99.11 98.63 149.68 77.18 69.72 74.18 107.32 59.83 74.88 29 .64/36.80 60 .23 76.87 71 .21 43_83 wosa6s9z. 1 February 2, 2007 Page 7 AGE YEARS ON WATER PFOA fppMur PFOS b a PFBA (pbUDkp-. TOTAL PFCs(ppb)*/ Dup. F <18 <10 17.1 M <18 <10 16.1 M 31-40 <10 15.5 F 41-50 <10 14.9 F 31-40 10-20 14.6 M 41-50 <10 14.6 M <18 <10 13.4 F 18-30 <10 13 .3 M 41-50 <10 12.8 M 41-50 <10 11 .2 F 18-30 <10 10.7 M 41-50 10-20 10.5 M >70 20-30 10.2 F 31-40 <10 8.76 F 18-30 <10 7.35 F 61-70 >30 6.96 M 3 1 -40 <10 6.16 F 18-30 10-20 6.09 20.1 24.3 12_7 23_6 37.4 30.8 50.1 12.3 30.1 27.7 23.1 35.2 24_2 30.1 10.5 22.6 16.1 17.7 NIT N/D N/T N/p N/D N/T NID N/T N/D N1D N/T N/D NIT N/D Nrl' NlT NID N1D 43.08 51 .95 29.31 42.94 59.61 49.49 83 .18 27.14 47_16 57.94 35.87 52.66 35.31 45.35 19.39 36.00 26.90 26.79 February 2, 2007 Page 8 SEX Ag E YEARS ON WATER PFOA b u. PFOS b u, PFBA (n2byDua. TOTAL PFCs(ppb)*I Uup. , M 41-50 <10 5 .52 8.27 N!D 15 .82 NIT=not tested N/A=data not available N/D=not detected above laboratory detection limits *Total of detected levels of PFPeA, PFHxA, PFHpA, PFOA, PFNA, PFDA, PFUnA, PFDoA, PFBS, PFHxS, PFOS, PFBA, and PFOSA in the blood sample SEX F M M M F M M I' M F M CHART B - LAKE ELMOlCOTTAGE GROVE/ HASTINGS CITY WATER CUSTOMERS AGE YEARS ON WATER PFOA (R"b PFOS (p" PFBA {Pnb} TOTAL PFCs(pub)*** 51-60 18-30 <18 51-60 N/A 31-40 31-00 41-50 >70 51-60 51-60 <10 10-20 <10 <10 N/A 10-20 >30 <10 >30 10-20 10-20 42.3 49.5 NIT 11 .4 50.8 NJT 7.89 19.0 NID 7.21 38.9 N/T 6.9 19.6 NIT 6.78 (4.22*) 10.5 (7.95 ") N/D 6.13 13.5 N/D 4_97 12.9 NID 4.34 14.0 NID 4.10 17.3 N/T 3.89 21 .2 N/T 106.04 72.75 29.72 57.56 33.04 24.07 22.77 21 .57 21 .99 26- 1 2 29.84 W98B6592 .1 February 2, 2007 Page 9 MX AGE YEARS ON WATER PFOA (Pgb) PFOS rrb,~ PFBA (DQb? TOTAL P~CSPPb)*** M 31-40 <10 3.79 14 .9 N/D 24.16 F NIA N/A 3 .36 21 .4 N/D 29 .36 F** 51-60 >30 2.21 7_88 NIT 18 .27 F <18 <10 1 .95 N/D N/D 1 .95 * = whole blood analysis *#= fonner 3M employee NIT=not tested N/A=data not available NlD=rnot detected above laboratory detection limits ***Total of detected leveis of PFPeA, PFHxA, PFHpA, PFOA, PFNA, PFDA, PFUnA, PFDoA, PFBS, PFI-1xS, PFOS, PFBA, and PFOSA in the blood sample CHART C - WASHINGTON COUNTY PRIVATE WELL USERS 1 . Lake Elmo Area Private Wells SEX M F F F M F F AGE 41-50 <18 41-50 <18 41-50 41-50 61-70 YEARS ON WATER <10 <10 10-20 10-20 20-30 <10 20-30 PFOA WpI1Z 133.0 110.0 72.9 55.4 45_7 39.0 30.9 PFOS fppbl 155.0 111 .0 87.6 60.0 19.7 57.4 88.6 PFBA Jppbj NID NrT NIT N!I' N/D N/D N/t TOTAL PFCs{aab)* 322.93 247 .19 175.25 124 .35 72.11 112.63 128.93 W0886592 . 1 February 2, 2007 Page !0 SEX M AGE 61-70 YEARS ON WATER 20-30 PFOA (Pub) 24.2 PFOS (nnb) 38.0 PFBA jpabZ N!T TOTAL PFCs(nub)* 69.91 M 51-60 10-20 27.0 28.5 NIT 62.32 F 51-60 >30 24.0 17.1 N/D 50.96 M 51-60 10-20 20.1 53.5 N/D 86.21 M NIA NIA 16.4 22.1 NID 44_43 F 41-50 10--20 15.7 9,27 TUD 27.68 F >70 >30 14.3 8.90 N/D 26.27 M 61-70 >30 12.1 9.78 NlD 2419 M 61-70 10-20 10.4 42.0 NJD 61 .40 M 41-50 10-20 9.66 26.6 NlC 42.51 M 18-30 20-30 7_56 17.3 Nrl' 33.70 M 61-70 20-30 6.95 43.1 NlT 55.00 M 51-60 20-30 6.78 21.0 NIT 36.91 M 61-70 >30 6.10 43.7 NIT 54.19 F 61-70 10-20 6.06 36.9 N/I) 49.09 F 51-60 10-20 5.92 29.5 NIT 41 .26 M 51-60 N/A 5.35 20.4 N(I' 29.02 F 41-50 N/A 3_14 11 .2 NfT 16.29 F 61-70 >30 2.4 12.0 NIT 17.91 N/T=not tested NIA=data not available N/D==not detected above laboratory detection limits *Total of detected levels of PFPeA, PFHxA, PFHpA, PFOA, PFNA, PFDA, PFUnA, PFDoA, PFBS, PFHxS, PFOS, PFBA, and PFOSA in the blood sample wose6M .i Febrnary 2, 2007 Page 11 , 2. Cotta_,ge GrovelHastimgs Area Private Wells SEX M** F F F F M M F M M F F F F M F F F F M AGE >70 31-40 61-70 61-70 51-60 61-70 31-40 61-70 >70 <18 41-50 41-50 41-50 51-60 61-70 <18 NIA 41-50 41-50 <18 YEARS ON WATER 20-30 <10 10-20 <10 20-30 <10 10-20 >30 >30 <10 20-30 <10 <10 10-20 10-20 <10 N/A >30 10-20 <10 PFOA (ob) PFOS ~b~, 19.7 108.0 17-1 16.9 14.2 35.6 10.3 28.7 9.12 42.8 9.40 39.0 8_80 40.6 7.38 32.5 6.42 32.5 5.75 14.9 4.97 16.3 4.68 12.0 4.31 23.5 4.12 12.4 3.88 38.6 3.87 15.8 3.54 (2.98*) 8.51 (8.3*) 3.39 14.9 3.24 24.5 2.83 14.8 PFBA (pPb1 NIT N/D 2.34 NJD NID N/D NIT N/T N!T NID N1D N/D NID N/T N/D N!T NID NIT NlT NIF WOa86592.l TOTAL PFCsSppb)*** 151 .41 45.18 57.93 45.53 57.61 61 .40 61 .82 66.46 45.32 27.01 25.08 20.71 32.92 18.60 49.39 28.51 15.76 21 .83 35 .27 23.53 Febtuary 2, 2007 Page 12 SEX AGE YEARS ON WATER PFOA (nnb) PFOS ipp-b~ PFBA ~ TOTAL PFCs(ppb)*'` * M 41-50 <10 2.01 22.4 N/D 29.52 *-whole blood analysis **=former 3M employee N/A=data not available N/T=not tested N/D=not detected above laboratory detection limits 'Total of detected levels of PFPeA, PFHxA, PFHpA, PFOA, PFNA, PFDA, PFUnA, PFDoA, PFBS, PFHxS, PFOS, PFBA, and PFOSA in the blood sample RA8/mdm Enclosures CC. Alan Williams, Esq. (w/ encls.) Gale D. Pearson, Esq . (w/o encls .) Stephen J. Randail, Esq. (w/o encls_) 7. Mark Englehart, Esq. (w/o encls.) R. Edison Hill, Esq. (w/o encls.) Larry A . Winter, Esq. (w/o encls .) Martha K. Wivell, Esq . (w/o encls.) WO8Y6592 .1 NomNOrwxeNrucicroFrice suffew 1717 OM W"AY cownHCJroKw0lnoltnaw11+toa eosss1 .asse 513-8tf .n76 FAX. 513-7t1407 MIYTON, QM GFIX :E SWTEaos 110 NoonIafaw SrnseT 1b1Y70N, CNIO 4SNt-1Tp f37-Z20-iN0 FAX. aa7,21f-2s1s TAFT, STETTINiUS & HOLLISTER I.LP 425 WALNUT STREET, SUITE 1800 CINCINNATI, OHIO 45202-395T 513-381-2838 FAX: 513-381fi2p5 www.taftlaw.com c1.VVCLruao. ONO oFrxE no av Towet ct,EVevwD.ofro 441"-zaez I16-M"=pi Fa7L tt6dM47Ct COUwwsus. OH10 OPfiOi st 64T SrAM SUM" COLUMUM am "Man olazz+ .wx FOM614-221-zoor iWBERTA . BlLOTI 513-357-9638 bilottotaltlaw.com April 16, 2007 FEDERAL EXPRESS Charles M. Auer USEPA 1201 Constitution Avenue, N. W. Room 3166A Washington, DC 20004 Mary Dominiak USEPA 1201 Constitution Avenue, N .W . Room 4410S Washington, DC 20004 Jennifer Seed, PhD. USEPA 1201 Constitution Avenue, N-W . Room 6634A Washington, DC 20004 Gloria Post New Jersey DEP 401 East State Street, ls` Floor P.0. Box 409 Trenton, NJ 08625 Re: Perfluorochernical Blood Exposure Data For New Jersey Ladies and Gentlemen: We serve as counsel for Plaintiffs in a lawsuit that is currently pending against E .I . duPont de Nemours and Company {"DuPont"} in Federal Court in New Jersey involving claims arising from exposures to perlluorocbemicals released by or otherwise attributable to DuPont_ Tlie lawsuit is styled Rowe, et at v. E.l. duPont de Nemours and Company, Civil Action No. 061810 (RBK), iTSDC, Camden Vicinage, New Jersey . DuPont owns and operates a manufacturing facility in New Jersey known as the Chambers Works Plant where perfluorochemicals, including PFDA, were handled, released, and/or disposed for several decades- In the context of Plaintiffs' investigation of their claims, Plaintiffs' counsel arranged for sampling of private water wells in the vicinity of DuPont's Chambers Works Plant, along with blood sampling of individuals whose private or public source of drinking water is contaminated by perfluorochernicais attributable to the plant. In recognition of the potential threat to human health and the environment revealed by the results, and in response to USEI'A's prior public requests for perfluorochemical monitoring data, we are ;wo9sovas. 11 April 10, 2007 Page 2 providing copies of this initial data to you for inclusion in USEPA's Administrative Record 226 and public docket EPA- NQ-OPPT-2003-00012 . The PFOA, PFOS and total perfluorochemical ("total PFCs") results for the blood and water samples collected and analyzed to date on behalfof Plaintiffs are summarized below. Please note that all results were provided by Axys Analytical Services Ltd . in Canada and were obtained, arranged for, and paid for without any involvement by DuPont.' The PFC blood data is divided into the following categories : (1) customers ofthe Pews Grove Water Supply Company (Chart A)Z; and (2) individuals whose drinking water is obtained from private drinking water wells (Chart B) . The lab results for each of the blood results presented below are attached at Exhibit A. For privacy reasons, the natnes, addresses and specific ages of each of those sampled are not provided with this submission. The lab results for the private water well sampling are attached at Exhibit B. All blood and water results are presented in parts per billion (Ppb)- . CHART A - PENNS GROVE PUBLIC WATER CUSTOMERS SEX AGE PFOA *M 41-50 421 .00 M <18 24.3 *M 41-50 23.5 F 41-50 12.9 F 51-60 12.8 *M 51-60 10.3 M 31-40 9.65 F 61-70 9.58 F 51-60 9.56 >70 9.45 F 61-70 8.04 F 41-50 7.51 M 51-60 7.48 M <18 7.4 M 51-60 6.6 A'1 <18 6.32 M 18-30 6.31 F 51-60 5.61 F <18 4.83 F 18-30 2.72 M 51-60. 2.55 * = DuPont Chambers Works Employee NA = Data not currently available PFOS 16.6 22.8 21 .4 22.4 13.7 14.0 44.5 36.8 14 .8 34.1 26.2 11 .8 24.1 14.6 27.4 9.95 8.45 25.3 10.8 6.61 8.39 TOTAL PFCS 444.86 59.94 58.10 44.84 32.23 30.98 63.08 55.04 30.20 60.65 42.65 20.74 37.64 26.71 46.93 21 .06 19.01 34.77 18.55 10.44 13.10 YEARS ON WATER <10 <10 ld/A 10-20 20-30 NIA 10-20 21-30 NIA NIA <10 10-20 NIA 10-20 NIA <10 10-20 NIA <10 20-30 10-20 ~ Blood results were, however, previously reported to DuPont by Plaintifrs' Counsel ~foPrFPOFAOAhasdebveeelnopdeedtebcytetdheinNtehewPJeerrusnesyGDreopvacrtpmubelnitc owfaEtenrvisruopnpmleynattallePverlosteecxtcieocnd. ing the current 0.04 ppb guideline (Wo950D8B. )J April 10, 2007 Page 3 CHART B - PRIVATE WELL USERS SEX AGE PFOA PFOS TOTAL M 51-60 11.9 16.8 39.25 F 51-60 11.2 66.4 89.54 51-60 11.1 76.2 91 .24 M <18 9.36 24.6 38.32 F 61-70 5.1 12.3 22.07 F 18-30 2.82 11 .1 18 .03 ND = Not detected at laboratory detection limits N/A = Data not currently available PFOA! WATER 0.041 0.041 0.28 0.28 ND ND PFOS/ WATER ND ND 0.02 0.02 ND ND TOTAL PFCs IN VfIATER YEARS 0.041 0.041 0.30 0.30 ND ND 20.30 20_30 10-20 10-20 N/A N/A RAB :itc Attachments (Exhibit A and H) cc_ R Edison Hill, Esq. Larry A. Winter, Esq . Rhon E. Jones, Esq. David B. Byrne, III, Esq . Slaari M. BlecEier, Esq . Taft/ Taft Stettinius & Hoqister LIP 425 Walnut Street, Suite 1800 /Cincinnati, Ohio 4520z-3957 /Tel : 513 .38} .2838 1Fax : 513 .381 .OZ05 /www .taftlaw.com Cincinnati /Columbus /Cleveland /Dayton /Covington /Phoenix ROBERT A. 811.0rT 513-357-9638 bdfott@taftlaw.com April 9, 2008 VIA ELECTRONIC MAIL AND REGULAR U.S . MAIL Charles M. Auer USEPA Headquarters Ariel Rais Building, Mail Code 7409M 1200 Pennsylvania Avenue, NW Washington, DC 20460 M . Cathy Fehrenbacher USEPA Headquarters Ariel Rois Building, Mail Code 7406M 1200 Pennsylvania Avenue, NW Washington, DC 20460 Toni Krasnic USEPA Headquarters Ariel Rios Building, Mail Code 7405M 1200 Pennsylvania Avenue, NW Washington, DC 20460 Lara Werner ATSDR 1650 Arch Street (3HS00) Philadelphia, PA 19103 Jennifer Seed USEPA Headquarters Ariel Rios Building, Mail Code 7403M 1200 Pennsylvania Avenue, NW Washington, DC 20460 Re: PFOAIC-8 Blood Levels From OhioNVest Virginia Drinking Water Contamination: For Ar-226IOPPT-2003-00121TSCA 8(e)/IRIS Ladies and Gentlemen: Enclosed is information relating to the levels of PFOAIC-8 detected in the blood of tens of thousands of people who used for at least one year drinking water from one or more pubiic and/or private drinking water supplies in West Virginia and/or Ohio contaminated with PFOAIC-8 at or above 0.05 parts per billion. This information was collected through the Health Project implemented under a 2005 settlement of a class action lawsuit against E.1. du Pont de Nemours and Company. Additional information relating to this data and health effects reported among those tested (and other information) can be found at the following Web site hosted by West Virginia University : httpllwww.hsc.wvu .edulsomlcmedic8l . We understand that additional data will be posted on this Web site in the future . (W1247252 .1) April g, 2008 Page 2 We request that USEPA include this information in its AR-226, OPPT-2003-0012, TSCA 8(e), and IRIS dockets and databases for PFOAIC-8, except any portion that EPA is prohibited by law from including in its public files. ruly . rsI~ I a ./ Robert A. Bilott RAB:mdm Enclosure cc: Chris Kor(eski, OEPA (wt encf.) Lisa McClung, WVDEP (wi encl .) Gloria Post, NJDEP (wl encl.) John Linc Stine, MDH (wl encl.) Helen Goeden, MDH (w/ encl .) James Kelly, MDH (w! encl .) {Wi247252.1} Taft/ Tall Stettinius & HoPlister LLP 425 Walnut Street, Suite 1800 /Cincinnati, OH 45202-3957 /Tel: 513 .381 .2838 /Fax: 513 .381 .0205 /vwvvvv.taftfaw.corn Cincinnati /Cleveland / Columbus / Dayton /Indianapolis /Northern Kentucky / Phoenix /seijinq ROBERT ABILOTT 513.357 .9638 bitott@taRlaw .cvm November 3, 2009 VIA ELECTRONIC AND REGULAR U.S. MAIL Ms. Nickolette Roney Division of Toxicology and Environmental Medicine Agency For Toxics Substances and Disease Registry Mailstop: F-62 1600 Clifton Road, NE Atlanta, GA 30333 Re: Docket ATSDR-253: Supplemental Comment On Draft Toxicological Profile For Perfluoroalk r Ms. Roney: As a supplement to our October 30, 2009, comments on the referenced draft Toxicological Profile For Perfluoroalkyls, we wish to include references to three additional documents that we believe should be reviewed and considered before finalizing the current draft Profile: 9 . Nelson, J.W ., "Exposure to Polyfluoroalkyl Chemicals and Cholesterol, Body Weight, and Insulin Resistance in the General U .S. Population," Environ. Health Persp. (online doi: 10.12891ehp.0901165 (Nov. 2, 2009)) ; 2. Hoffman, K., et al., "Exposure to Poiyfluoroaikyl Chemicals and Attention Deficit Hyperactivity Disorder in U.S . Children Aged 12-15 Years," 20 (6) Epidem. S70 (Nov . 2009) (ISEE 2009 Conference Abstract/Poster) ; and 3. Pinney, S.M., et al., "Perfluorooctanoic Acid (PFOA) and Pubertal Maturation in Young Girls," 20 (6) Epidem. S80 (Nov . 2009) (ISEE 2009 Conference AbstractlPoster) . Although these materials became available after the October 30, 2009, public comment deadline, we note that ATSDR has committed to consider "comments received after the public comment period" on "the basis of what is deemed to be in the best interest of the general public." As these new materials relate to potential health risks to people exposed to perftuoroaikyls, we believe that consideration of these materials is in the 11532654 .1 Ms. Nictcolette Roney November 3, 2009 Page 2 best interest of the general public and that ATSDR should afford the information due consideration prior to any finalization of the current draft Profile. Thank you. RAB=mdm Enclosures ehponline.arg ENVIRONMENTAL HEALTH PERSPECTIVES Exposure to Polyfluoroalkyl Chemicals and Cholesterol, Body Weight, and Insulin Resistance in the General U.S . Population Jessica W. Nelson, Elizabeth E. Hatch, and Thomas F Webster doi : 10.12891ehp.0901165 (available at http :/ldx.doi.org/) Online 2 November 2009 A% N1ENS ~ Natie~af In9iduEe of r f Emionrunental Neaflft Scienoes National Institutes of Health U.S. Department of Hea1lh and Human Services Page t of 37 Exposure to Polyfluoroaikyl Chemicals and Cholesterol, Body Weight, and Insulin Resistance in the General U.S. Population Jessica W. Nelson,' Elizabeth E. Hatch,' Thomas F. Webster,' ~ Boston University School of Public Health, Department of Environmental Health, 715 Albany Street, T4W, Boston, Massachusetts 02118 ' Boston University School o Public Health, Department of Epidemiology, 715 Albany Street, T3E, Boston, Massachusetts 02118 To whom articles should be addressed and all other information: Jessica W. Nelson BU SPH Department of Environmental Health 715 Albany Street, T4W Boston, MA 02118 "wnelsci @bu.edu Phone : 617-638-4620 Fax : 617-638-4857 Page 2 of 37 Running Title: PFCs and Cholesterol in the General U.S. Population Key words: body mass index (8MI), cholesterol, insulin resistance, National Health and Nutrition Examination Survey MANES), polyfluoroalkyl chemicals (PFCs), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA), pert7uorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), waist circumference (WC) Article Descriptor: Cardiovascular, Obesity Acknowledgements and grant information : We acknowledge the invaluable work of the National Center for Heafth Statistics and the National Center for Environmental Health of the U.S. Centers for Disease Controls and Prevention in conducting the National Health and Nutrition Examination Survey, and the contributions of Lynn L. Moore, Mustafa Qureshi, Martha Singer, and Janice Weinberg. This work was supported in part by grant R21 ES013724 from the National Institute of Environmental Health Sciences (NIEHS) . Jessica Nelson was supported in part by Award Number T32ES014S62 from NIEHS. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIEHS or the National Institutes of Health. The authors declare they have no competing financial interests . Abbreviations and acronyms : BMI CDC CHD Ci HDL HOMA LDL LOD NCEH NHAhfES Non-HDL PFCs PFHxS PFNA PFOA PFOS PPARs SES TC VLDL WC Body mass index Centers for Disease Control and Prevention Coronary heart disease Confidence interval High-density lipoprotein Homeostatic model assessment Low-density lipoprotein Limit of detection National Center for Environmental Health National Health and Nutrition Examination Survey Non-high-density fipoprotein Polyfluoroalkyl chemicals Perfluorohexane sulfonic acid Perfluorononanoic acid Pertluorooctanoic acid Perfluorooctane sulfonic acid Peroxisome proliferator-activated receptors Socioeconomic status Total cholesterol Very low-density lipoprotein Waist circumference Outline ofsection headers : Abstract Introduction Materials and Methods Study Population PFC Concentrations Outcomes Covariates Statistical Analysis Results Cholesterol Body Weight HOMA Discussion Previous Studies in Humans Previous Studies in Animals Possible Modes of Action Implications for the Current Study Limitations and Strengths Conclusion References Tables Figure Legends Page 5 of 37 Figures p. 161 Abstract Background . Polyfiuoroalkyl chemicals (PFCs) are used commonly in commercial applications and are detected in humans and the environment world-wide. Concern has been raised that they may disrupt lipid and weight regulation . Objectives. We investigated the relationship between PFC serum concentrations and lipid and weight outcomes in a large publicly-available dataset . Methods . We analyzed data from the 2003-2004 National Health and Nutrition Examination Survey (NHAIYES) for participants aged 12-80 . Using linear regression to control for covariates, we studied the association between serum concentrations of perfluorooctanoic acid (PFOA), perftuorononanoic acid (PFNA), perfluorooctane sulfonic acid (PFOS), and perfiuorohexane sulfonic acid (PFHxS), and measures of cholesterol, body size, and insulin resistanceResults . We observed a positive association between concentrations o PFOS, PFOA, and PFNA and total and non-HDL-cholesterol . We found the opposite for PFHxS. Those in the highest quartile of PFOS exposure had total cholesterol levels 13.4 mgIdL (95% Cl, 3.8, 23 .0) higher than those in the lowest. For PFOA, PFNA, and PFHxS, this effect estimate was 9.8 (95% Cl, -0.2, 19.7), 13.9 (95% CI, 1 .9, 25.9), and -7.0 (95% Cl, -13 .2, -0.8), respectively. A similar pattern emerged when exposures were modeled continuously . We saw little evidence of a consistent association with body size or insulin resistance. Conclusions. This exploratory cross-sectional study is consistent with other epidemiologic studies in finding a positive association between PFOS and PFOA and cholesterol, despite much lower exposures in NHANES . Results for PFNA and PFHxS are novel, emphasizing the need to study PFCs other than PFOS and PFOA. Page 8 of 37 Introduction Polyfluoroalkyl chemicals (PFCs) are a class of highly stable compounds used widely in commercial and industrial applications as surfactants, paper and textile coatings, and in food packaging (Calafat et al. 2007). Numerous chemicals belong to this class, including the products used industrially, by-products of manufacturing, and degradation products. They are composed of a fluorinated carbon backbone of varying length terminated by a carboxylate or sulfonate functional group. This amphipathic structure provides them the properties of water and oil repellency and stain resistance (Conder et al . 2008). The perfluorinated carboxylates include perfluorooctanoic acid (PFOA) and perfiuorononanoic acid (PFNA), and the perfluorinated sulfonates include perfluorooctane sulfonic acid (PFOS) and perfluorohexane sulfonic acid (PFHxS). Biomonitoring studies have documented human exposure to PFCs, both in occupational ly-expose:d cohorts (Costa et al. 2009; Olsen and Zobel 2007; Sakr et al. 2007a) and in the general population (Apelberg et al . 2007 ; Calafat et al. 2007; Fei et al. 2007). While the major sources of human exposure are poorly known, possibilities include diet (either directly from food or migration from food packaging), drinking water, and house dust (reviewed in Lau et al. 2007). Once taken into the human body, PFCs are slowly eliminated and are not known to undergo biotransformation (C.au et al . 2007). They bioaccumulate, but not in lipid like many other persistent organic pollutants. Instead, they have been shown to bind to proteins in the liver and serum (Conder et al . 2008). Mean serum half lives in humans are estimated as 5.4 years for PFOS and 3 .8 years for PFOA (Olsen et al . 2Q07). Shorterchain compounds are generally assumed to have shorter half lives, though PFHxS is an Page 9 of 37 exception with an estimated mean half life of 8.5 years (Olsen et al . 2007). The half life for PFNA in humans has not been estimated . Various adverse health effects have been observed in animal studies of PFOS and PFOA, including tumors in certain organs and developmental delays (Biegel et al. 2001 ; White et al. 2007). The structural resemblance of PFCs to fatty acids and the discovery that they bind to peroxisome proliferator-activated receptors (PPARs), nuclear receptors that play a key role in lipid metabolism and adipogenesis, have raised the concern that PFCs may disrupt lipid and weight regulation. Indeed, among the early reported health effects in animal studies that administered high PFC doses was hypolipidemia (Seacat et al. 2002). However, several studies in humans suggest that exposure to PhOA, and possibly to FFOS, may be associated with increased cholesterol in people (C8 Science Panel 20(18 ; Costa et al . 2009 ; Sakr et al . 2007a). The evidence for an association between PFC exposure and body size and insulin resistance is much weaker (Lin et al. 2009). The rising prevalence of the metabolic syndrome, which includes obesity, dyslipidemia, and insulin resistance, is of increasing public health concern in the U_S . and globally, and is linked closely with coronary heart disease (CHD) and related disorders (Ramos and Olden 2008). While changes in diet and lifestyle are undoubtedly important factors in this trend, there is growing interest in the hypothesis that endocrine disrupting chemicals may be playing a role (Grun and Blumberg 2009). This exploratory, cross-sectional epidemiologic study investigated the relationship between exposure to four PFCs, including two compounds that have been little studied in humans, and cholesterol levels, obesity, and insulin resistance. Materials and Methods Study Population. The National Health and Nutrition Examination Survey (NHANFS) is an ongoing survey of the civilian non-institutionalized U.S. population conducted by the U.S. Centers for Disease Control and Prevention (CDC) that gathers data on dietary and health factors. Participants are selected using a complex multistage probability sampling design, and come to a mobile examination center for a physical examination and to provide blood and urine samples. Various questionnaires are administered by trained interviewers (CDC 2408). The survey also includes biomonitoring for different environmental chemicals, including PFCs, of a random onethird subsample of participants by the National Center for Environmental Health (NCEH) . NHANES obtained informed consent from all participants. PFC Concentrations. PFCs were measured in serum of participants aged 12 and older by the NCEH using automated solid-phase extraction coupled to isotope dilutionhigh-performance liquid chromatography-tandem mass spectrometry ; details of laboratory methods are available elsewhere (Calafat et at. 2t107) . Our study examined the four PFCs detected in greater than 98 percent of people : PFOS, PFOA, PFHxS, and PFNA. The other eight PFCs measured were detected in less than 28 percent of people. Values below the limit of detection (LOD) were reported by NHANES as the LOD divided by the square root of two. Page 11 of 37 Outcomes . Several cholesterol measures are commonly used in clinical and epidemiologic studies . Cholesterol is carried in plasma within different lipoproteins, including low-density lipoproteins (LDL) and very low-density lipoproteins (VLDL) which carry cholesterol to peripheral tissues and are considered "bad" cholesterol, and high-density lipoproteins (HDL) which transport cholesterol back to the liver for excretion and are considered "good" cholesterol . LDL carries around 70 percent of total plasma cholesterol, and HDL 20 to 30 percent (Tietz et al. 20()6) . Total cholesterol (TC) is the sum of the cholesterol content of LDL, HDL, and VLDL. The non-HDL cholesterol fraction, which includes LDL and VLDL cholesterol, has been shown to be a better predictor of CHD risk than LDL alone (Liu et al. 2.006). We studied TC, HDL, non-HDL, and LDL . TC and HDL were measured by NHANF.S directly in serum ofall participants ; TC was measured enzymatically through coupled reactions that hydrolyze cholesteryl esters, and HDL after the precipitation of apolipoprotein B lipoproteins with a blocking agent (CDC 2007b) . We calculated nonHDL by subtracting HDL from TC. LDL was available only for the subsample of fasting participants and was not measured directly in serum, but estimated by IVHANES using the widely-accepted Friedewald formula (CDC 2007c) . Body size outcomes considered include body mass index (BMI, weight (kg) divided by height (m)-squared) and waist circumference (WC, in cm) . Weight, height, and WC were measured during the examination using standard protocols (CDC 2007d) . To assess insulin resistance, we studied homeostatic model assessment (HOMA), used in epidemiologic studies as a simple, inexpensive, and reliable alternative to more complicated methods (Bonora et al. 2000). We calculated HOMA using the method of Page 12 of 37 Matthews et al.: HOMA = [fasting insulin (ftU/mL) x fasting glucose (mmol/L)1/22 .5 (Matthews et al. 1985) . Plasma insulin and glucose were measured enzyrnatically by NHANES in the fasting subsample of participants (CDC 2007a) . Covariates. NHANES collected data on potential confounding variables through questionnaires . As we had a large sample size, our models included a priori a number of eovaciates that are important predictors of cholesterol and body weight: age, gender, race/ethnicity, socioeconomic status (SES, a dichotomous indicator which combined income, education, and food insecurity to minimize missing data), saturated fat intake (tertiles, as percent of total caloric intake), exercise (performed moderate or vigorous physical activity in the past 30 days), and time in front of a TV or computer (categories of hours per day in the past 30 days) . For those aged 20 and older, we also included alcohol consumption (categories of drinks per week), smoking, and, for women, parity. For the cholesterol analyses, we included continuous BMi as a covariate, and tested for confounding by continuous serum albumin . See Supplemental Material, Table t for details on covariates. Statistical Analysis . We performed regression analyses in gender and age (12-19, 20-59, 60-80) subgroups for each PFC separately. When results showed similar trends by age and gender, we combined groups . Cholesterol and weight outcomes were analyzed as continuous variables; HOMA was log-transformed as it was log-normally distributed . For the main analysis, exposure was modeled in quartiles of PFC concentration, with quartiles formed in the population overall and separately for the age/gender group used in 12 Page 43 of 37 the analysis . We present effect estimates for each quartile compared to the reference group (the first quartile) and their corresponding 95% confidence intervals (Cls) . Tests for trend in the quartile analyses were performed by treating PFC category as a linear predictor in the models. In addition, for cholesterol outcomes in adults, we performed a sensitivity analysis that modeled exposure as a continuous predictor. We identified influential points and outliers by examining studentized residuals, predicted values, and scatterplots, and excluded them from the analysis if they changed the effect estimates by 5 percent or more. All analyses excluded those over age 84, pregnant, breastfeeding, on insulin, or undergoing dialysis . Cholesterol analyses also excluded those who reported current use of cholesterol-lowering medications in the blood pressure portion of the questionnaire or who were missing this variable. See Supplemental Material, Figure I for the number of people in each exclusion group. Covariates described above were used in all models for which they were available, depending on age group and gender. To perform analyses, we used the SAS 9.1 Proc SURVEYREG procedure, which takes into account possible correlation between the strata and clusters by which NHANES samples the population. Models were adjusted for relevant covariates instead of using hEHANES sampling weights ; this adjustment is regarded as a good compromise between efficiency and bias (Korn and Graubard 1991) . Results Page 14 of 37 PFC concentrations were available for 2,094 participants of the original subsample of 2,368 people . PFOS levels were an order of magnitude higher than the other PFCs, with a median of 19.91sg1L serum compared to 3.8 for PFOA. Similar to results in the same dataset reported by Calafat et al. (2007), concentrations were higher in males compared to females, non-Hispanic whites compared to Mexican Americans and non-Hispanic blacks, and people of higher SE.S compared to lower SES . There were no striking concentration differences by age. The four PFCs were log-normally distributed, and were moderately correlated with one another. PFOA and PFOS were most strongly correlated, with a Spearman correlation coefficient of 0.65; PFHxS and PFNA were the least correlated at 0.12 . Cholesterol, body weight, and insulin resistance outcomes varied with age, gender, and race/ethnicity, and were correlated with one another in predictable ways . The number of participants in each analysis depended on the outcome and missing data. We present results for the cholesterol analyses among adults (20-80 year-olds) in Tables I and 2 and Figure 1 . Supplemental Material, Figure 1 illustrates how we arrived at our final sample size, which does not include 12-19 year-olds (n=640) . Of adults with PFC and cholesterol measures (n=1310), we excluded the 20% who reported using cholesterol-lowering medications and the 396 who were missing this variable . None of the covariates were missing in more than 9% of people. Table 1 shows the distribution of outcomes and PFC concentrations in this sub-population, including PFC range and number of people in each quartile. In all cases, the PFC range in the fourth quartile is much wider than in the other three quartiles. Supplemental Material, Table 1 provides information on the distribution of covariates . 14 Page 75 of 37 Cholesterol. Figure 1 presents the adjusted associations between the four cholesterol measures and PFC serum concentrations for adults (Supplemental Material, Table 2 presents crude associations). We omitted 12-19 year-olds because no data were available for two important covariates, alcohol and smoking . See Supplemental Material, Table 3 for results stratified by age (including 12-19 year-olds) and gender. We found a positive association between TC and PFOS, PFOA, and PFHA concentrations (Figure IA). Adults in the highest PFOS quartile had TC levels 13.4 mg/dL (95% Cl, 3.8, 23.0) higher than those in the lowest quartile. For PFOA, there was a 9.8 mgldL (959'o Cl, -0.2, 19.7) increase, and for PFNA, 13.9 mg/dl. (9546 Cl, i .925.9) . TC appeared to increase linearly across the quartiles of PFC exposure, particularly for PFNA (p-value for trend = 0.04). When examined in age and gender subgroups, results were similar, with associations of greater magnitude among 60-80 year-olds. Associations were fewer and of smaller magnitude among 12-19 year-olds_ In contrast, results for PFHxS indicated an inverse trend among adults (p-value for trend = 0.07). Those in the top PFHxS quartile had TC levels that were lower than those in the lowest quartile by -7.0 mg1dL (95% Cl, -13 .2, -0.8) . The same pattern held in the female age subgroups in particular. We found fewer consistent trends in the HDL analyses . We observed differences by age and gender; results for all adults (Figure I B) may in some cases mask these findings (see Supplemental Material, Table 3). PFOA and PFOS were associated with higher HDL in adolescent girls (effect estimates for the top quartile compared to lowest of4.3 (959b CI, 0.1, 8.5) and 3.7 (95lo CI, -0 .5, 7 .9), respectively), with some evidence 15 Page 16 of 37 of the opposite in the older age group (in 60-80 year-old males. effect estimate for the top PFOA quartile compared to lowest of -8.7 (45% Cl, -16 .3, -1 .1)). No meaningful associations were observed between PFNA and PFHxS concentration and HDL. Results for non-HDL were similar to those for TC, as would be expected because the non-HDL fraction makes up 70 to 80 percent of TC (Figure IC) . The magnitude of effect increased slightly for PFNA and PFHxS. LDL results (Figure iD) should mirror those for non-HDL ; however, the sample size for LDL analyses was half as large. We found a somewhat similar pattern for PFNA and PFHxS, but no association with PFOA and PFOS concentration . We repeated all cholesterol models adjusting for albumin. Results were substantively the same as those presented above (data not shown). Results were similar as well in models that considered PFC concentration as a continuous predictor (Table 2)_ PFOS, PFOA, and PFNA were ail positively associated with TC and non-HDL (effect estimates were statistically significant for PFOS and PFOA)_ The opposite was seen for PFHxS, which was negatively associated with 'PC, non-HDL, and LDL . In addition, we performed a number of sensitivity analyses that also had no qualitative effect on results from the quartile analysis: the inclusion of adults missing data on use of cholesterol-lowering medication, the inclusion of all adults (even those who reported taking medications), the exclusion of points identified as outliers in the continuous models from Table 2, and use of NHANES sampling weights . Body Weight . We found fewer meaningful associations between body weight and PFC concentrations (see Supplemental Material, Table 3). The strongest effects were 16 Page 17 of 37 seen with PFOS among males. In 12-19 and 20-59 year-olds, BMI decreased with increasing PFOS exposure. Teenage boys in the highest PFOS quartile had BM Is that were 2.8 points (95% CI, -4.1, -1 .4) lower than those in the lowest quartile (p-value for trend = 0.004) . In 60-80 year-old men, on the other hand, increasing PFOS exposure was associated with increased SMI (effect estimate for the top quartile compared to lowest of 1 .6 (95% CI, 0.14, 3 .0)). We did not see evidence of a relationship in the female age groups. Results for the other PFCs were less consistent, and those for WC were similar to BMI . HOMA. On the whole, we found no association between PFC concentrations and HOMA. Although there were isolated suggestive trends, such as a significant positive trend with PFNA in adult females and a negative one with PFHxS in adolescent females, effects were not consistent (see Supplemental Material, Table 3). Discussion This exploratory study examined associations between serum concentrations of four PFCs and cholesterol levels, body size, and insulin resistance in a sample of the general U.S. population. Most striking were the findings for TC and non-HDL. These outcomes were positively associated with PFOS, PFOA, and PFNA and negatively associated with PFHxS after controlling for numerous covariates in categorical and continuous models . The LDL analyses were more limited by study size, but, for PFHxS and PFNA, revealed similar trends, though of less consistency and magnitude- No strong trends emerged in the HDL analyses. These results suggest that exposure to background 17 Page 18 of 37 levels of certain PFCs may exert effects on the non-HDL fraction of cholesterol . We did not find consistent associations between PFCs and BMI, WC, or HOMA . Previous Studies in Humans: Studies of the association between cholesterol levels and PFCs are found primarily in the occupational health literature. While results are not entirely consistent, the general trend is one of positive associations between PFOA concentration and cholesterol levels. Results for PFOS are less clear as it has been lessstudied . Sakr et al. studied a large cohort of DuPont workers (n=454 for a longitudinal study and 1,025 for a cross-sectional study) (Sakr et al. 2007a; Sakr et al. 2fl07b) . In both, PFOA was positively associated with TC, but not with HDL. A positive association was observed with LDL in the cross-sectional study only. When restricted to those not taking cholesterol-lowering medications, the magnitude of effect in the cross-sectional study increased . A study of a smaller group of Italian workers (n=53)* which included a substudy excluding those being treated for hyperlipidemia, found a similar positive association between TC and PFOA (Costa et al. 2009). Findings from studies of workers at different 3M Company locations are more mixed. The most recent study conducted by Olsen et al. did not find evidence of an association between serum PFOA and TC or LDL among 506 employees at three facilities (Olsen and Zobel 2007). An earlier study of the same workers at two of those locations, which did not adjust for use of cholesterollowering medications, found a positive association between serum PFOS and PFOA and TC in a cross-sectional analysis (n=421) and PFOA in a longitudinal analysis (n=174) (Oisen et al. 2003). Page 19 of 37 Exposure levels in these workers are much higher than in NHANES participants. Median serum concentrations in the 3M cohort were 1100 ug/L for PFOA and 720 pglL for PFOS (Olsen and Zobel 2007). The mean PFOA level was 4300 pg/L in the DuPont studies (Sakr et al. 2007a) ; the median was 3890 p.gJL in 2007 measurements from the Italian cohort (Costa et al. 2009). In comparison, median serum concentrations in NHANES were 4 and 20 ftglL for PFOA and PFOS, respectively. Two studies have also been conducted on PFCs and cholesterol outcomes in communities surrounding a DuPont plant who have much higher exposures than the general population. Emmett et al. examined PFOA concentrations among 371 residents of a water district area bordering the plant (Emmett et al. 2006). While the study found no association between PFOA and total cholesterol, the analyses neither controlled for possible confounders nor excluded people on cholesterol-lowering medications_ The C8 Health Project, a much larger study conducted in relation to a legal case, has released preliminary, non-peer reviewed findings from its analysis of 46,294 people living in six water districts near the plant (C8 Science Panel 2008) . The study, which excluded those on cholesterol medications and controlled for confounding, found significant positive associations between PFOA and PFOS concentrations and TC and LDL. A recent study using NHANES data examined the relationship between PFCs and components of the metabolic syndrome in 1999-2000 and 2003-2004 participants (Lin et al. 2009). It is difficult to compare our study to these results, as the authors examined an additional two years of data, did not report results for TC, non-HDL, or LDL, and conducted logistic regression analyses for two of the outcomes . They found a significant positive association between HOMA and PFOS concentrations in adults . similar to the 19 Page 20 of 37 -direction of association we observed (though, in our study, the trend did not come close to statistical significance) . PENA concentrations were found to have a protective effect on the odds of having low HDL in adolescents and adults, with the opposite seen for PFOS in adults. Our study did not observe these relationships with HDL as a continuous outcome . Finally, the authors found that higher PFHxS, PFOA, and PFOS concentrations in adolescents were associated with decreased WC, findings we also observed for PFOS. There have been few studies of non-developmental PFC exposure and body size. A cross-sectional study of 3M workers found BMl to be slightly higher in the highest category of PFOA exposure, although there was no adjustment for confounding (Olsen et al . 1998) . Another study found that mothers who were overweight or obese before pregnancy had higher plasma levels of PFOS and PFOA (Fei et al. 2007), and a third observed higher PFOS and PFOA levels in cord blood of both overweight and underweight women (Apelberg et al. 2007). Previous Studies in Animals : Unlike in humans, studies in rodents found consistent inverse associations between cholesterol levels and exposure to PFOS and PFOA, though doses administered were much higher than typical human exposure levels (Martin et al. 2007; Thibodeaux et al. 20Q3). [n cynomotgus monkeys, decreased total cholesterol was reported as the earliest reliable measure of a clinical response following PFOS exposure (Seacat et al. 2002). This hypolipidemic effect in primates has not been seen with PFOA exposure, however (Butenhoff et al . 2002) . We are not aware of similar animal studies of PFNA or PFHxS exposure . Weight loss has also been a common finding in high dose animal studies of PFOS and PFOA (Seacat et al. 2002; Thibodeaux et al. 2003). A recent study in mice of PFOA exposure and body weight tested a wide range of doses and looked at both adult and developmental exposure (Hines et al. 2009). Exposure during adulthood was not associated with later-life body weight effects, whereas low-dose developmental exposure led to greater weight in adulthood and increased serum leptin and insulin levels. Animals exposed to higher doses of PFOA, on the other hand, had decreased weight. Possible Modes of Action. The hypothesized mode of action for the hypolipidemic effects of PFCs in animals is through activation of PPAR-alpha, the PPAR isoform involved in lipid homeostasis and peroxisome proliferation (Wolf et al. 2008). Multiple in vitro studies have shown PFCs to be PPAR-alpha ligands in rodent and human cells (Vanden Heuvel et al . 2006 ; Wolf et al . 2008). Activation is greater as carbon backbone length increases, and carboxylates (PFOA and PFNA) have higher activation than sulfonates (PFOS and PFHxS) . PFCs may also indirectly activate PPAR-alpha by interacting with fatty acid binding proteins (Luebker et al . 2002). PPAR-alpha ligands, such as the fibrate class of cholesterol-lowering medications, inhibit secretion of cholesterol from the liver, reducing cholesterol in the serum (Kennedy et al . 2004). PPAR-gamma is another PPAR isoform more closely involved in adipogenesis (Grun and Blumberg 2009). Some PFCs weakly activate PPAR-gamma in certain human cell lines (Vanden Heuvei et al . 2006). PPAR-independent mechanisms could be involved as well . PFOS and PFOA have been shown to interact with other nuclear receptors, including the constitutive activated receptor (CAR) and pregnane X receptor (PXR) (Ren et al. 2009). Interspecies differences may partly explain the inconsistent cholesterol findings between animal and human studies. Humans are less sensitive to PPAR-alpha-related effects than rodents, with approximately 10-fold lower expression of PPAR-alpha in liver compared to mice (Tilton et al. 2008). There are also major differences in PFC half-life and metabolism. While the half-life of PFOA in human serum is estimated to be 3.8 years, in mice it is around 18 days (Lau et al. 2007). Finally, rodents and humans have different plasma lipid profiles, with HDL, rather than LDL, predominating in rodents (Lima et al. 1498). Implications for the Current Study. The positive associations we observed between serum concentrations of PFOS, PFOA, and PFNA and TC are consistent with much of the occupational health literature regarding PFOA, even though serum concentrations in studies of workers were at least one order of magnitude higher than in MANES. Our findings for PFOA and PFOS are also consistent with emerging results from the very large C8 Health Study cohort . Although hypeflipidemia is not consistent with the animal literature, this may he explained by differences between species and/or doses studied . The strongest, most consistent cholesterol results were seen for PFNA despite lower serum concentrations in the MANES population . This is biologically plausible given that PFC toxicity seems to increase with carbon chain length . Cotrelation with 22 Page 23 of 37 PFOS and/oar PFOA could also partly explain the results, though PFNA is only moderately correlated with them (r--0.5) . Very few studies have been conducted on the possible health effects of PFNA. Another notable finding was that PFHxS consistently acted in the opposite direction of the other PFCs in the cholesterol analyses. Of the compounds studied, PFHxS has the shortest carbon chain and the longest estimated half life. This differential effect of PFHxS is not found in the literature; more research is needed to assess possible mechanisms of PFHxS action that may differ from longer-chain PFCs. The lack of consistent findings regarding body size is not entirely surprising. While interesting findings have been recently published on developmental exposures in both humans and animals (Fei et al. 2007, Hines et al. 2009), adult exposures appear to be less of a concern . Effects on insulin resistance have been very little studied. Limitations and Strengths. Our study has a number of limitations that make it exploratory in nature. The MANES data are cross-sectional, limiting our ability to rule out reverse causality . It is possible that PFCs behave differently in the bodies of people who have higher cholesterol levels. In addition, the hypothesis has been raised that the positive associations observed here and in occupational health studies between PFCs and TC may be due to the fact that PFCs bind to beta-lipoproteins and albumin in the blood (Olsen and Zobel 2007). Han et al. concluded that, in human and rat serum, more than 90 percent of PFOA would be bound to albumin (Han et al. 2003). The only report regarding PF'C binding to beta-lipoproteins is a short non-peer reviewed document found in a U.S. Environmental Protection Agency docket-that found that PFOS, PFOA, and PFHxS all 23 bind tightly to, albumin, but that differences exist in binding to beta-lipoproteins, with 96 percent of PFOS binding compared to 64 percent of PFHxS and 40 percent of PFOA (Kerstner-Wood 2003). The authors conclude, "The data. . .shows that albumin is by far the largest single protein binder for three of the four compounds tested. . .The fourth compound, PFOS, was found to be highly bound by both albumin and beta-lipoproteins :" To address these concerns, we showed that controlling for serum albumin did not affect associations between serum PFCs and cholesterol . Confounding by PFC binding to beta-lipoproteins is still an issue, though we would expect this to be most striking for PFOS, which binds most highly . The fact that we see similar results for PFOS, PFOA, and PFNA is somewhat reassuring, as is the fact that we see an inverse association with PFHxS . If major confounding by beta-lipoprotein binding were occurring, we would expect to see a stronger positive association between cholesterol and PFHxS than PFOA. Our results for PFOA are also consistent with occupational studies that were able to model longitudinal data. Additional limitations of our study include the fact that we have only one measurement of PFC and cholesterol concentrations . As PFCs have relatively long half lives, we can be fairly confident that blood concentrations reflect longer-term exposure, but cholesterol levels have significant variability and multiple measures are ideal (Tietz et al. 2006). If this measurement error is random and not related to PFC level, which seems likely, it should not bias the estimate, but rather increase the standard deviation . There is also the potential for residual confounding by diet or other factors . Because NHANES measures different classes of environmental chemicals in different subsamples of the Page 25 of 37 population, we were unable to consider co-exposure to other chemicals suspected to disrupt weight and lipid regulation . Despite these limitations, our study has a number of strengths . Ii has a relatively large sample size and the ability to account for key covariates such as alcohol consumption and use of cholesterol-lowering medications . The large population also allows for consideration of modification by age and gender . In addition to PFOA and PFOS, we examined PFNA and PFHxS, compounds that have received less scientific attention but appear important to study further. Conclusion Though these results are based on cross-sectional data and are exploratory, they are consistent with much of the human epidemiologic literature, and indicate that PFCs may be exerting an effect on cholesterol metabolism at environmentally-relevant exposures . Our study affirms the importance of investigating PFCs other than PFOS and PFOA, particularly as industrial uses of PFOS and PFOA decline and other PFCs are substituted . PFNA may be of particular concern, as the chemical was detected in 98 percent of MANES participants and serum concentrations rose between the time periods of 1999-2000 and 2003-2004 (Calafat et al. 2(l07). In some cases, PFNA had a greater magnitude of effect on cholesterol levels than PFOS and PFOA. While this study does not demonstrate a causal association between PFC exposure and serum cholesterol levels, it provides clues about where to focus future epiderniologic and toxicology research. In particular, additional studies are needed to shed light on explanations for the opposite associations with cholesterol observed for PFHxS compared 25 Page 26 of 37 to the other PFCs studied, and on the relationship between PFC binding to proteins in the blood, particularly beta-lipoproteins, and cholesterol levels. Despite its limitations, this study contributes to the literature suggesting that PFC exposure may disrupt cholesterol metabolism or homeostasis in humans . Page 27 of 37 References Apelberg BJ, Goldman LR, Calafat AM, Herbstman JB, Kuklenyik Z, Heidler J, et al. 2007. Determinants of fetal exposure to polyfiuoroalkyl compounds in Baltimore, Maryland. Environ Sci Techno141(l 1):3891-3897 . Biegel LB, Hurtt ME, Frame SR, O'Connor JC, Cook JC. 2001 . Mechanisms of extrahepatic tumor induction by peroxisome proliferators in male CD rats. Toxicol Sci 60(1):44-55 . Bonora E, Targher G, Alberiche M, Bonadonna RC, Saggiani F, Zenere MB, et al. 2000. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity. Diabetes Care 23(1):57-b3 . Butenhoff J, Costa G, Elcombe C, Farrar D, Hansen K, iwai H, et al. 2002. 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Thirty years of medical surveillance in perfluooctanoic acid production workers. J Occup Environ Med 51(3) :364-372 . Emmett EA, Zhang H, Shofer FS, Freeman D, Rodway NV, Desai C. et at. 2006. Community exposure to perfluorooctanoate : relationships between serum levels and certain health parameters. J Occup Environ Med 48(8):771-779 . Fei C, McLaughlin JK, Tarone RE, Olsen J. 2007. Perfluorinated chemicals and fetal growth: a study within the Danish National Birth Cohort . Environ Health Perspect 115(11):1677-i 682 . Grun F, Blumberg B . 2009. Endocrine disrupters as obesogens. Mot Cell Endocrinol 344(1-2):19-29. Han X, Snow TA, Kemper RA, Jepson GW. 2003. Binding of perfluorooctanoic acid to rat and human plasma proteins. Chem Res Toxicol 16(6) :775-781 . Hines EP, White SS, Stanko JP, Gibbs-Flournoy EA, l.au C, Fenton SE. 2009. Phenotypic dichotomy following developmental exposure to perfluorooctanoic acid (PFOA) in female CD- t mice: Low doses induce elevated serum leptin and insulin, and overweight in mid-life. Mot Cell Endocrino1304(1-2) :97-IQ5 . Kennedy GL, Jr., Butenhoff JL, Oisen GW, O'Connor yC, Seacat AM, Perkins RG, et al . 2004. The toxicology of pertiuorooctanoate . Crit Rev Toxicoi 34(4) :351-384. Kerstner-Wood C, Coward, L, Gorman, G. 2003. Protein Binding of Perfluorohexane Sulfonate, Perfluorooctane Sulfonate and Perfiuorooetanoate to Plasma (Human, Rat, and Monkey), and Various Human-Derived Plasma Protein Fractions : Southern Research Institute . US EPA Docket AR-226-1354 . US Environmental Protection Agency, Washington, DC . Korn EL, Graubard Bl. 1991 . Epiderniologic studies utilizing surveys: accounting for the sampling design. Am 1 Public Health 81(9) :1166-1173 . 29 Lau C, Anitole K, Hode,s C, Lai D, Pfahles-Hutchens A, Seed J. 2007. Perfluoroalkyl acids : a review of monitoring and toxicological findings. Toxicol Sci 99(2):366- 394. Lima VL, Sena VL, Stewart B, Owen JS, Dolphin PJ. 1998. An evaluation of the marmoset Cailithrix jacchus (sagui) as an experimental model for the dysiipoproteinemia of human Schistosomiasis mansoni . Biochim Biophys Acta 1393(2-3):235-243 . Lin CY, Chen PC, Lin YC, Lin LY. 2009. Association among serum perlluoroalkyl chemicals, glucose homeostasis, and metabolic syndrome in adolescents and adults . Diabetes Care 32(4) :702-707 . Liu J, Sempos CT, Donahue RP, Dorn J, Trevisan M, Grundy SM. 2006. Non-highdensity lipoprotein and very-low-density lipoprotein cholesterol and their risk predictive values in coronary heart disease . Am J Cardio198(l0) :1363-1368. Luebker DJ, Hansen KJ, Bass NM, Butenhoff JL, Seacat AM. 2002. Interactions of fluorochemicals with rat liver fatty acid-binding protein . Toxicology 176(3) :175- 185 . 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Environ Health Perspect It 5(9):1298-1305 . Olsen GW, Gilliland FD, Burlew MM, Burris JM, Mandel 1S, Mandel JH. 1998. An epidemiologic investigation of reproductive hormones in men with occupational exposure to perfluorooctanoic acid. J Occup Environ Med 40(7) :614-622. Olsen GW, Zobel LR. 2007. Assessment of lipid, hepatic, and thyroid parameters with serum perfluorooctanoate (PFOA) concentrations in fluorochemical production workers . Int Arch Occup Environ Health 81(2):231-246. Ramos RG, Olden K. 2008. The prevalence of metabolic syndrome among US women of childbearing age. Am Y Public Health 98(6) :1122-1127. Ren H, Vallanat B, Nelson DM, Yeung LW, Guruge KS, Lam PK, et al . 2009. Evidence for the involvement of xenobiolic-responsive nuclear receptors in transcriptional effects upon perfluoroalkyl acid exposure in diverse species. Reprod Toxicol 27(3-4):266-277 . Sakr CJ, Kreckmann KH, Green JW, Gillies PJ, Reynolds TL,, Leonard RC. 2007a. Crosssectional study of lipids and liver enzymes related to a serum biomarker of exposure (ammonium perfluorooctanoate or APFO) as part of a general health survey in a cohort of occupationally exposed workers . J Occup Environ Med 49(10) :1086-1096 . Sakr CJ, Leonard RC, Kreckmann KH, Slade MD, Cullen MR. 2007b . Longitudinal study of serum lipids and liver enzymes in workers with occupational exposure to ammonium perfluorooctanoate . ! Occup Environ Med 49(8):872-879. Seacat AM, Thomford PI, Hansen K.I, Olsen GW, Case MT, Butenhoff IL 2002. Subchronic toxicity studies on perfluorooctanesulfonate potassium salt in cynomolgus monkeys . Toxicol Sci 68(t):249-264. Thibodeaux JR, Hanson RG, Rogets JM, Grey BE, Barbee BD, Richards JH, et al. 2003. Exposure to perfluorooctane sulfonate during pregnancy in rat and mouse . I: maternal and prenatal evaluations . Toxicot Sc174(2) :369-38 1 . Tietz NW, Burtis CA, Ashwood ER, Bruns DE. 2006. Tietz textbook of clinical chemistry and molecular diagnostics . St. Louis, Mo. :Elsevier Saunders. Tilton SC, Orner GA, Benninghoff AD, Carpenter HM, Hendricks JD, Pereira CB, et al. 2008 . Genomic profiling reveals an alternate mechanism for hepatic tumor promotion by perfluorooctanoic acid in rainbow trout. Environ Health Perspect 116(8) :1047-1055. Vanden Heuvel JP, Thompson JT, Frame SR, Gillies PJ . 2006 . Differential activation of nuclear receptors by perfluorinated fatty acid analogs and natural fatty acids: a comparison of human, mouse, and rat peroxisome proliferator-activated receptor- 32 Page 33 of 37 alpha, -beta, and -gamma, liver X receptor-beta, and retinoid X receptor-alpha . Toxicol Sci 92(2);476-489. ' White SS, Calafat AM, Kuklenyik Z, Villanueva L, Zehr RD, Helfant L, et al . 2007. Gestational PFOA exposure of mice is associated with altered mammary gland development in dams and female offspring . Toxicol Sci 96(1):133-144 . Wolf C7, Takacs ML, Schrnid JE, Lau C, Abbott BD. 2008. Activation of mouse and human peroxisome proliferator-activated receptor alpha by perfluoroalkyl acids of different functional groups and chain lengths . Toxicol Sci 106(1) :162-17t . Table 1 . Distribution of cholesterol outcomes and PFC concentrations, 20-80 year-old? N TC (mg/dl.) 860 HDL (mgldL) 860 Non-HDL (mg/dL) 860 LDL (mg/dL) 416 PFOA (4g/1.) 860 Quartile 1 223 Quartile 2 211 Quartile 3 186 Quartile 4 240 PFOS (Pg/L) 860 Quartile 1 193 Quartile 2 198 Quartile 3 211 Quartile 4 258 PFNA (p.g11.) 860 Quartile I 170 Quartile 2 183 Quartile 3 246 Quartile 4 261 PFHxS (PgIL) 860 Quartile 1 217 Quartile 2 239 Quartile 3 233 Quartile 4 171 Median 199.0 53 .0 143.0 115.0 3.9 2.1 3.4 4.6 6.9 21 .0 9.9 17.3 23 .5 37 .5 1 .0 0.4 0.7 1 .0 2.0 1 .8 0.8 1 .5 2 .4 5.3 Mean (SD) 202.1 (42.3) 54.6 (15.4) 147.5 (43.4) 117.1 (35.6) 4.6 (3 .0) 1.9 (0.6) 3 .4 (0.4) 4.6 (0.4) 8.0 (3.3) 25.3 (20.6) 9.6(2-9) 17.0 (1 .8) 23 .6 (2.4) 44.8 (28 .0) 1 .3(l.2) 0.4 (0.1) 0.7 (0.1) LIMA) 2.5(l .5) 2.6 (2.7) 0.7 (0.3) 1.5 (0.2) 2.6 (0.5) 6.7 (3.7) Range 86-394 23-122 52-361 21-252 0.1-37.3 0.1-2.7 2.8-3.9 4.0-5.4 5.5-37 .3 1 .4-392 .0 1 .4-13 .6 13.8-19 .7 19.9-28 .1 28 .2-392 .0 0.1-10.3 0.1-0.5 0.6-0.8 0.9-1 .3 1 .4-10 .3 0.2-27 .1 0.2-1.1 1 .2-1 .9 2.0-3.5 3.6-27 .1 'This table presents data for the population analyzed in Figure I and Table 2: 20-80 yearolds with full information on outcomes, exposures, and covariates . Quartiles of PFC exposure were calculated in the overall population (which included 12-19 year-olds and people missing covariate information) . Therefore, the number ofpeople in each PFC quartile is unequal . Page 35 of 37 Table 2. Change in cholesterol measure (mgldL) per pg/L increase in PFC, 20-80 yearolds' PFOS PFOA PFNA PFHxS TC Coefficient (95% Cl) 0.27 (.05-48) 1 .22 (.04, 2.40) 2.01 (-1 .16, 5.18) -0.93 (-1 .80.-0-06) HDL Coefficient (95% CO 0.02 (-0.05,0.09) -0.12 (-0.41,0.16) -0.40 (-0.90,0.09) 0.19 (-0.18,0-55) Non-HDL Coefficient (95% CI) 0.25 (0,0.50) 1 .38 (0.12, 2.65) 2.56 (-1 .19,6.30) -1 .13 (4 .90, -0.35) LDL Coefficient (95% CI) 0.12 (-0.17,0.41) -0.21 (-1 .91, 1.49) 0.50 (-3.94,4.93) -2.06 (-3-54,-0.58) a All models are adjusted for age, gender, racelethnicity, socioeconomic status, saturated fat intake, exercise, time in front of a TV or computer, BMT, alcohol consumption, and smoking . We excluded values identified as influential points and outliers from the population of adults (n=860) in Table l and Figure 1 . Most analyses excluded one or two points except: PFNA and TC (4), PFNA and HDL (6),1'FNA and non-HDL (4), PFHxS and non-HDL (0), and PFHxs and LDL (5)_ See Supplemental Material, Table 4 for a full listing of the number of outliers excluded in each analysis. Figure Legend Figure 1 . Differences in cholesterol levels, 20-80 year-olds, with increasing quartile of PFC exposure. Figure 1A presents change in total cholesterol (n=860), Figure 1 B change in HDE. (n=860), Figure lC change in non-HDL (n=860), and Figure 1 D change in LDL (n=416). All models control for age, gender, racelethnicity, socioeconomic status, saturated fat intake, exercise, time in front of a TV or computer, alcohol consumption, smoking, and BMI . Median PFC levels (lcg/L) for each quartile are shown below/above the bar . Error bars represent standard errors of the effect estimates (i.e. the difference between the quartile and the reference group), and p-values for trend are presented . 95% confidence intervals for each effect estimate are available in Supplemental Material, Table 3. N o') cs v S( o u a 0 0 11 \W 7 00 0 N C1 I 0 lV Q p_ v 0 m O ~ LnL. v~ M -- -, , 7 w N I U s a ' o nCL . a m co M t N I a v ^ (lPlBw) -IOH ut a6ueyC) -- a c "i o Q co =X `t~i fl. ~ a 0 N z n o LL v c m ,Q a O v; a tV m M V N O ~ _ clPlBw) '7a-i ui a6ueyo ~ _ io. m > N N U n. 0 m 3 MEMMI \\\\\\~ EEEN p. 194 Exposure to Polyfluoroalkyl Chemicals and Attention Deficit. .. : Epidemiology Page 1 of 1 Epidemiology: November 2009 - Volume 20 - Issue 6 - p S7o doi: 1o.1o97/oi.ede .oooo362918.4o925~e9 Abstracts: ISEE 21st Annual Conference, Dublin, Ireland, August 25-29, 2009: Poster Presentations Exposure to Polyfluoroalkyl Chemicals and Attention Deficit Hyperactivity Disorder in U.S, Children Aged ia-i5 Years Hoffman, Kate; Vieira, Veronica; Webster, Thomas ; White, Roberta 0 Abstract An abstract is unavailable. This article is available as HTML full text only. 2009 Lippincott Williams & Wilkins, Inc. You currently do not have access to this article . You may need to: . Register an account. " I_.oi.n ifyou are a registered subscriber. " Subscribe to this Journal , or " Purchase access to this article if you are not a current subscriber. " View this article in Ovid ifyour institution subscribes to thisjournal. Note : If your society membership provides for fall-access to this article, you may need to login on your society's web site first. htfn .'//itlnrilalC lWW C.A717IPt111jP.mIC'7tatinri/7I~~qI1 1INj1IFvnneizrP tn Pnivfhinrna11sw1 f`hwmirale anri 17R ao*,.r 1 1 !7/7nf1Q 0579 .htm p. 195 Page 1 of 1 OS2.2.5 Exposure years. to potyfluoroalkyi chemicals and attention deficit hyperactivity disorder In U.S . children aged 12-15 Kate Hofiman , Veronica Vieira, Thomas Webster, Roberta White Department of En vlronmental Health, Boston Unlverslty School of Public Health, United States BinacthkegrUo.uSn.danadndwoOrbljdecptoipvuel:atPioloyntsiuaorreowalikdyeiscphreemaidc.aAlssso(cPiFaCtsi)onhsavbeetbweeeennweixdpeolysuurseesdtoinfcouornscuommemropnroPdFucCtss-anEdxppoarseunrteasl report of diagnosis of Attention Deficit Hyperactivity Disorder (ADHD) were evaluated . Methods: Data were obtained from the National Health and Nutrition Examination Survey (NHANES) 1999-2000 and 2003-2004 for children aged 12-15. Parental report of a previous diagnosis by a doctor or heaithcare professional of ADHD in the child was the outcome measure. PFOA, PFOS, PFNA, and PFHS levels were measured in serum samples from each child. The association between each PFC and ADHD was examined using smoothing, categories, and linear models. All analyses were adjusted for age, sex, race, maternal smoking during pregnancy, and environmental tobacco smoke . Confounding by variables such as lead and socioeconomic status was also assessed but associations were not altered. Results: Of the 586 children aged '! 2 to 15 in the sample, 51 were reported by their parents to have been diagnosed with ADHD. When PFOS was entered into analyses as a continuous predictor, a 1 .22 fold increased odds was observed for each 10 pglL increase (95% Cl 1 .03-1 .45). Similarly, compared to the first quartile of PFOS exposure, individuals in the fourth quartile were 1 .92 times more likely to have ADHD (9596 CI a.82-4.51; p-value for trend=0.039). There were also significant dose response relationships between PFHS and PFOA exposures and ADHD . For each ,uglL increase, the odds of ADHD increased 1 .06 and 1 .09 times respectively (9596 CI 1 .02-1 .11 and 1 .t)0-1 .18). S1i.m9i5l)a.rly, children with higher PFNA levels were more likely to have ADHD (OR=1 .33 for pgIL increase ; 95% Cl 0.91Cwiotnhclcuoshoirotnss:tuTdhieesseis rneesueldtesda.re consistent with an affect of PFCs on ADHD risk. Follow-up of these cross-sectional data httnR'//iQP.P fYlnf-rPnr.r> .ePrvirr~c nPt/rPnn,-tc/tPtnr~~tP/nnPtPVto~cfront vrn17vo1-1nrn .~/neo/n. .nfn,.f~l~~~r. .n~ ,.1 9, .. 1 1 in 1,)nnn p. 196 Perflporooctanoic Acid (PFOA) and Pubertal Maturation in You. .. : Epidemiology Page i of 1 Epi.demiology : November 2009 - Volume 20 - Issue 6 - p S8o doi: xo.xo97/ox .ede.oooo362949.3o847.cb Abstracts : ISEE 2ist Annual Conference, Dublin, Ireland, August 2g-29, 2009 : poster Presentations Perfluorooctanoic Acid (PFOA) and Pubertal Maturation in Young Girls Pinney, Susan M.; Windham, Gayle C. ; Biro, Frank M.; Kushi, Larry H.; Yaghjyan, Lusine ; Calafat, Antonia; Kato, Kayoko; Succop, Paul; Brown, M Kathryn; Hernick, Ann ; Bornschein, Robert ' 0 Abstract An abstract is unavailable . This article is available as I-1TML full text only. 2oog Lippincott Williams & Wilkins, Inc. You currently do not have access to this article. You may need to : " Register an account. " Log.'t,n ifyou are a registered subscriber . " Subscribe to this Journal , or " Pur~hase_, access to this article ifyou are not a current subscriber . . View this article in Ovid ifyour institution subscribes to this journal . Note : If your society membership provides for full-access to this article, you may need to login on your society's web site first. httn :/iiclntnalR.lww .c;nm/Pniclp.m/('.itatinn/~.(1(19/l 1nr11/PPrflnnrnnr.tannir Ar-irl PFYIA sand Pii},wrFol 7(1Oa i ilil7l1l1o a763,htm Page 1 of 1 OS10.5.4 t'erfluorooctanoic acid (PFOA) and Pubertat Maturation in Young Girls Susan M. Pinney 1, Gayle C. WindhamZ, Frank M. Biro3 ~4, Larry H. Kushi$, Lusine Yaghjyan', Antonia Calafat6, Kayoko Kaloe, Paul Succop', M. Kathryn Brownl, Ann Hernick', Robert Bornschein' 'University of Cincinnati College of Medicine, Dept of Environmental Health, United States, 2Environmental Health Investigation Branch, California Department of Public Health, United States, 3University of Cincinnati College of Medicine, Dept. of Pediatrics, United States, 4Cincinnati Children's Hospital Medical Center, United States, 5Division of Research, Kaiser Permanents, United States, 6Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, United States Background : Polyfluoroalkyl compounds (PFCs) and their salts, such as pertiuorooctanoic acid (PFOA), have been reported to change mammary gland structure and function in laboratory animals. : We explored the relationship between serum PFOA concentration and timing of pubertal maturation in young girls. ' Methods: Within the NIH Breast Cancer and the Environment Research Centers (BCERC), we conducted a study of multiple environmental biornarkers, including PFOA and other PFCs in serum of young girls (age 6-7 years at entry) from two sites (N=689 girls) . Puberta! staging (breast (B) and pubic hair (PH)) has been conducted by clinicians or trained research staff, every year or more frequently, for as long as four years . After calculating adjusted geometric means for all PFCs, we examined the relationship between PFOA serum concentration at the beginning of the study with body mass index (BMI) and pubertal Stage 2 at baseline and one year follow-up. Results: Detectable serum levels of five PFCs, including PFOA, were found in >95% of the girls. The PFOA median was 6.4 nglml (range < I-OD 0.'t to 55 .9 nglml), with 24 .9% having values above the 9511' percentile for children 12-19 years (NHANES 2003-2004 population (8.6 nglml)). At the follow-up visit, 28 .3% of girls had reached Tanner stage B2+, 19 .2% were PH2+ and 30 .3% had a BMI percentile for age >85. In analyses where serum PFOA was modeled as a continuous variable, we found a direct relationship with pubertal breast status and an inverse relationship with BMI percentile at the follow-up visit, with adjustment for age, race, site and caregiver education. Conclusions: It appears that PFOA acts as an endocrine disruptor although perhaps not by the usual mechanism. Although the relationship with BMI was inverse, there was a direct relationship with breast maturation . We continue to explore these complex relationships in models including other covariates . 190 ON SNId.iNOO https:l/isee.conference-services .net/renort.s/temnlatelnnetextahctrant xml`htcl=tPrnnlatPJnnptPxtal~etra~f vot Rrr 11 /?i?nno