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Taft Stettjriius & Hollister LLP 425 Walnut Street, Suite 1 8 0 0 /Cincinnati, OH 45202-3957/Tel: 513.381 . $ $ 4 ^ ^ 3 8 1 . 0 2 0 5 7www.taftlaw.com Cincinnati / Cleveland / Columbus / Dayton / India napdfa'/ Northkiji Kentucky / Phoenix / Beijing 09JU H I6 M IO :36 Robert A. B ilott 513.357.9638 bilott@taftlaw.com June 5, 2009 '3 > ? 3 TSCA Confidential Business Information Center (7407M) EPA East - Room 6428, Attn: Section 8(e) & FYI U.S. Environmental Protection Agency 1200 Pennsylvania Avenue, NW Washington, DC 20460-0001 Re: Submission To TSCA 8(e)/FYI Database Re: PFOA/PFOS To TSCA 8(e)/FYI Database: W e are hereby providing the following information for inclusion in the TSCA 8(e)/ FYI databases with respect to PFOA/PFOS: 1. Post, G.B., et al., "Occurrence and Potential Significance of Perfluorooctanoic Acid (PFOA) Detected in New Jersey Public Drinking Water Systems." Environ. Sci. Technol., Article ASAP (May 8, 2009). RAB:mdm Enclosure 11423033.1 89090000299 89090000299 Contains W c '> CONTAINS NO CM \ \ 0 \qf5 7 P-2 Environ. Sei. Techno/. XXXX, xxx, 000-000 Occurrence and Potential Significance of Perfluorooctanoic Acid (PF0A) Detected in New Jersey Public Drinking Water Systems GLORIA B. P O S T . *-' JU D IT H B. LOUISA K E I T H R. C O O P E R , B E T T Y JANE B O R O S - R U S S O ,* AND R. L EE L I P P I N C O T T D ivision o f Science, R esearch a n d Technology, N ew Jersey D epartm ent o f E nvironm ental P rotection , P.O. Box 409, Trenton, N ew Jersey 08625, D epartm ent o f B iochem istry an d M icrobiology, Rutgers U niversity, 76 L ipm an D rive, R oom 218, N ew Brunsw ick, N ew Jersey 08901, a n d Bureau o f S afe D rinking W ater, N ew Jersey D epartm ent o f E nvironm ental P rotection, P.O. Box 426, Trenton, N ew Jersey 08625 R eceiv ed Jan u ary 28, 2009. R evised m an u script received A pril 16, 2009. A ccepted A p ril 28, 2009. A fter detection of perfluorooctanoic acid (PFOA) in tw o N ew Jersey (N J ) public w a te r system s (P W S ) a t concentrations up to 0.19 pg/L, a study of PFOA in 23 other N J PW S w as conducted m 2008. PFOA w a s d etected in 15 (65% ) o f th e system s a t concentrations ranging from 0.005 to 00 39 pgIL To assess th e significance o f th ese d ata, the contribution of drinking w ater to human exposure to PFOA w as evaluated, and a health-based drinking w a te r concentration protective fo r lifetim e exposure of 0.04 /g/L w a s developed through a risk assessm ent approach. Both th e exposure assessm ent and the health-based drinking w a te r concentrations are based on th e previously reported 100:1 ratio betw een th e concentration of PFOA in serum and drinking w a te r in a com m unity w ith highly contam inated drinking w a te r. The appR cabiity o f th is ratio to lo w er drinking w a te r concentrations w as confirm ed using data on serum levels and w a te r concentrations from other com m unities. The health-based concentration is based on toxicological end points id entified by U.S. Environm ental Protection Agency (USEPA) in its 2005 d raft risk assessm ent R ecent inform ation on PFOA's toxicity not considered in th e USEPA risk assessm entfurther supports th e health-based concentration of 0.04 pg/L In additional sam pling of 18 PW S in 2007-2008, PFOA in m ost systems w as b e lo w th e health-based concentration. H ow ever, PFOA w as detected above th e health-based concentration in five system s, including one not previously sam pled. Introduction Perfluorooctanoic acid (PFOA) is found in blood of people worldwide (i), including 99.7% of a representative sample of * Corresponding author phone: (609) 292-8497; gloria.post@dep.state.nj.us. ' Division of Science, Research and Technology. * Rutgers University. * Bureau of Safe Drinking Water. e-mail: 10.1021/O S900301S CCC: 4 0 .7 5 X X X X American Chemical Society the U.S. population (2). In studies of U.S. populations, the geom etric m ean serum levels were 3.9 p g /L in 2003--2004 and 3.4p g /L in 2006 [2 ,3 ). This widespread human exposure is o f concern due to PFOA's persistence and toxicity. PFOA has a half-life o f several years in humans (4), and caused adverse effects on development, lipid metabolism, liver, and the immune system, and tumors in several organs in animals (5). In some studies, maternal exposures in the general population were associated with decreased birth weight and other measures o f fetal growth ( 6 - , while other studies did not find these effects (9,101. Som e studies o f exposed workers found associations with adverse outcomes including diabetes mellitus and increased cholesterol, whereas other studies were negative (5). Preliminary results of a study o f almost 70 000 people exposed through drinking water suggest an association with several clinical parameters measured in blood, including increased cholesterol (1 1 ,1 2 ). Sources o f exposure to PFOA include consum er products (13), house dust (14), diet (15), and drinking water (16). Exposure also occurs through metabolism and environmental transformation of the related chemical, 8:2 fluorotelomer alcohol which is widely used in food packaging and other products (17). PFOA and other perfluorinated chemicals were detected in surface waters ( 1 8 -2 3 ) and drinking water (2 0 ,2 4 ,2 5 ) in several countries, and in groundwater contaminated by fire fighting foams (26). Drinking water has been contaminated by sources such as industrial facilities and landfills (J 6 , 27), and by use o f a contam inated soil conditioner on agricultural land (20). Blood levels o f PFOA are elevated in communities with contaminated drinking water (1 6 ,2 0 ), with the median serum concentration approximately 100-fold higher than in drinking water in those exposed for at least two years (16). The first goal of this study was to evaluate the occurrence o f PFOA in NJ public water systems (PWS), following its detection in groundwater of two PWS at concentrations from 0.007 to 0.19 ftg /L (28). An occurrence study was conducted by NJDEP in 2006, and additional sampling was performed by NJ PWS in 2007--2008. The additional goals were to evaluate the significance o fPFOA in drinkingwater for human exposure and potential hum an health risk. The contribution o f drinking water concentrations such as those found in NJ to total exposure to PFOA was evaluated. A health-based drinkingwater concentration was developed using end points for toxicity identified by U.S. Environmental Protection Agency (USEPA) (29). Both the exposure assessm ent and health-based water concentration were based on the ob served relationship between the concentration o f PFOA in drinking water and serum in humans (16). Experimental Section Sam ple Site Selection. For the 2006 occurrence study, 36 samples collected by the New Jersey Department of Envi ronm ental Protection (NJDEP), including 29 from 23 PWS, one duplicate sample, six field blanks, and one trip blank, were analyzed for PFOA. The study included systems supplied by groundwater and surface water. The systems chosen included seven with surface water intakes within 10 miles, or with public wells within 1 mile, of five facilities where PFOA or related chemi.cals may have been present. Four additional systems with a history of organic contamination were included, since these systems are thought to be impacted by releases from industrial and com mercial activities, increasing the likelihood o f PFOA detection (30). One groundwater and one surface water system with no history of organic contamination were VOL. xxx, NO. XX. XXXX / ENVIRONMENTAL SCIENCE 1 TECHNOLOGY A P-3 TABLE t. PFOA NJ PWS Sampled by HJDEP, 2016* public water system site no. ID number source water raw/ finished PFOA frrg/L) 1 NJ2119001 GW, unconfined Raw ND" 2-W1 NJ0217001, GW, unconfined raw Well 1 0.026 2-W2 NJ0217001, GW, unconfined raw 0.033 Well 2 3 NJ0221001 GW, unconfmed raw 0.033 4 NJ1604001 GW, unconfined raw 0.029 5 NJ1107002 GW, unconfined raw 0.007 6 NJ0424001 GW, unconfined raw NO 7 NJ0119002 GW, unconfmed raw NQC 8 NJ0717001 GW, unconfmed raw 0.021 9 NJ1434001 GW, unconfined raw 0.008 10 NJ0614003 GW, unconfined raw ND 11R NJ1435002 GW, unconfined raw 0.006 11F NJ1435002 GW, unconfined finished 0.006 12 NJ1007002 GW, unconfined finished 0.005 13GW* NJ1712001 GW, semiconfined raw 0.027/0.025' 14 NJ13160Q1 GW, confined raw ND 15 NJ0514001 GW, confined finished ND 16 NJ1613001 SW raw 0.008 13SW* NJ1712001 SW raw 0.010 17 NJ1219001 SW raw 0.014 18 NJ1915001 SW finished NQ 19R NJ0327001 SW raw NQ 19F NJ0327001 SW finished NQ 20R NJ1605002 SW raw 0.026 20F NJ1605002 SW finished 0.027 21R NJ2013001 SW raw 0.035 21F NJ2013001 SW finished 0.039 22 NJ1352005 SW, reservoir raw 0.011 23 NJ0238001 SW, reservoir raw 0.021 * GW, ground water; SW, surface water. ND, not detected. NQ, detected below RL. dThere is no history of organic contamination at these PWS. 'T h is PWS has both a groundwater and a surface water source. 'Laboratory duplicate. selected for comparison (30). Other sites were chosen to expand the geographic extent of the sampling. Both raw and finished water samples were collected at three surface water and one groundwater system. In 2 0 0 7 -2 0 0 8 , additional sampling was conducted by NJ PWS. Samples (201) were collected from points of entry (POEs) into the distribution system, individual wells, and surface water intakes at 18 systems, including 12 with detectable levels o f PFOA in 2006, and sue not sampled in 2006. Sam pling Procedure. Sample collection was performed by NJDEP personnel, following the standard operating procedure for the analytical method (31). A single unfiltered 250 m L grab sample was collected from designated sampling locations used for other monitoring purposes. Six field blanks were prepared by pouring distilled water into collection bottles at sites where the greatest and least possibility of contamination was expected. The trip blank containing distilled water was prepared by the analytical laboratory, shipped to NJDEP personnel, and returned to the laboratory unopened with that day's other samples. A duplicate sample was collected at one site (Table 1). Procedures for sampling conducted by NJ systems in 2007--2008 conformed to relevant NJDEP and USEPA regu lations, with analysis performed by several NJDEP certified laboratories. Analytical Method. The 2006 samples were analyzed for PFOA by Test America, Denver, CO using liquid chrom a tography and tandem mass spectrometry (LC/MS/MS) (Micromass Ultima MS/MS or Waters Micromass Quattro Premier tandem mass spectrometer) (31). An isotope dilution technique using a 13C labeled PFOA analog is used to quantify FIGURE 1 . Lo catio ns o f N J PW S sam pled in 2006 PFOA occurren ce study. PFOA. The PFOA parent ion (m lz = 413 amu) and two daughter ions (m lz = 369 and 219 amu) are used for qualitative identification. This approach provides low detec tion limits and a high level of qualitative certainty. The laboratory's reporting limt (RL) for this study was 0.004 ftg lh . Detections below the RL are reported as not quantifiable (NQ). The 2 0 0 7 -2 0 0 8 samples were analyzed by several labo ratories certified by NJDEP using the LC/MS/MS technique. Samples w ere generally collected and analyzed quarterly. Reporting values differ among laboratories and ranged from 0.01 to 0.015 fig lt . Results and Discussion 2006 Study o f O ccu rrence o f PFOA in NJ PWS. PFOA was detected at or above the RL in 20 (69%) of the 29 samples, and in four additional samples below the RL (Table 1, Figure 1). Of the 23 PWS in this study, 15 (65%) had detections at or above the RL, and three additional systems had detections below the RL. PFOA was detected in 9 o f 12 (75%) raw groundwater samples from unconfined or semiconfined aquifers, but was not detected in the two raw (e.g., untreated) groundwater samples from confined aquifers. All three samples of finished (e.g., treated) groundwater from un confined aquifers had detectable levels of PFOA. Seven of B ENVIRONMENTAL SCIENCE & TECHNOLOGY / V O L xxx. NO. xx, XXXX P-4 TABU 2. NJ W S with PFOA Detections >8.04 ^g/L m Data Submitted ta NJDEP. 2007-2018" site no. PWSID source water 8A NJ0717001 GW, unconfined 8B NJ0717001 GW, unconfined 24 N J 0809002 GW, unconfined 25A NJ1707001 GW,unconfined 25B NJ1707001 GW, unconfined 25C NJ177001 GW, unconfined 21 NJ2013001 SW 3 NJ0221001 GW, unconfined * GW, ground water; SW, surface water. type POE POE POE Well 1 Well 2 POE POE POE number of samples 4 4 3 5 6 6 1 4 average (//g/L) 0.068 0.069 0.050 0.083 0.078 0.079 0.040 0.034 range (/ig/l) 0.058-0.084 0.063-0.072 0.018-0.069 0.062-0.1 0.055-0.14 0.053-0.10 0.040 0.029-0.048 the eight raw surface water samples and two of the four finished surface water sam ples had detectable levels o f PFOA. There was no apparent difference between raw and finished water collected at the sam e system. PFOA was not detected above the health-based concentration (see below) o f 0.04 //g/L in this study. PFOA was not detected in the six field blanks or the one trip blank. Additional details are provided in an NJDEP report (23). Additional PFOA D ata from NJ PWS. In 2006, PFOA data were subm itted to NJDEP from two PWS with wells located near a facility that used PFOA in manufacturing processes and processed waste containing PFOA. These samples were analyzed by Axys Analytical Services, Sidney, Canada, and Exygen Research, State College, PA. At one o f these systems (NJ1707001, site no. 25), PFOA was detected at up to 0.123 and 0.19 //g/Lin shallow, unconfined wells from two different wellfields, but was not detected in deep unconfined wells from these wellfields. At the other system (NJ1708001, site no. 26), PFOA was detected in one of eight raw groundwater samples at 0.0176 and 0.0179 //g/L, and in finished water up to 0.0081 /tg /L (23). In 2007 -2 0 0 8 ,2 0 1 samples collected by 18 PWS, including 12 sam pled in the 2006 study, were analyzed for PFOA. Samples were collected from one or more POE at each system, with one to six samples for each POE, as well as from individual wells and surface water intakes. PFOA concentra tions ranged from nondetectable (<0.01 //g/L) to 0.14 /tg /L . PFOA w jis detected at or above the health-based concentra tion (see below) o f 0.04 /tg /L in at least one sample from five systems (Table 2), including one not sampled in 2006. Yearly average concentrations (average results from four consecutive quarters) exceeded the health-based concentration for four POE from three different systems. Potential Contribution o f PFOA at Concentrations Found in NJ Drinking W ater to PFOA in Serum . A median ratio o f approximately 1:100 was observed between the concentration o f PFOA in drinking water and serum in Little Hocking, Ohio (16). In this community, drinking water had been contam inated by a nearby industrial facility, with an average concentration of3.55//g/Lin 2002-2005. The median PFOA serum concentration in 282 individuals tested in 2004--2006 was 371 /tg /L , with occupationally exposed individuals excluded. This ratio is based on those six years and older, while a higher ratio was observed for younger children (76). The ratio was based on data from individuals who had resided in Little Hocking for at least two years and was n ot related to years o f residence. If a similar relationship is valid at lower drinking water concentrations, such as those detected in NJ (Tables 1 and 2), then such concentrations may contribute substantially to total exposure to PFOA. Data are available on both the range o f historic drinking water concentrations (32) and the serum levels o f PFOA in sam ples taken in 2 0 0 5 -2 0 0 6 (33) in five Ohio and West Virginia water districts with lower PFOA concentrations them Little Hocking. The median serum level in each of these districts (Table 3) is higher than the U.S. median of 4 /tg /L TABU 3. PFOA Levels ia Driakiag Water and Senna ia Curamunities ia OMe and West Virginia w a te r d istric t PFOA levels m edian serum reported by PFOA level w a te r d istrict (//g /L ) (32) (//g /L ) (33) Little Hocking, OH Lubeck, WV Tuppers Plains, OH City o f Belpre, OH Mason County, WV Village o f Pomeroy, OH 1.7-4.3 0.4--3.9 0.25-0.37 0.08-0.13 0.06-0.1 0.06-0.07 224 70 35 37 12 12 (2). The range of PFOA levels in these districts m ay include results from multiple POEs, and the num ber o fpeople served by each POE, as well as the variation o f concentration over time, are not known. Therefore, the mean or median drinking water concentrations in these districts cannot be accurately estimated from the range of concentrations. For this reason, the median ratio o f drinking water to serum concentrations for these districts cannot be reliably determined, as was done for Little Hocking (16). However, it can be seen that the median PFOA serum concentration increases with increasing PFOA concentration in the drinking water. Village o f Pomeroy had the lowest PFOA concentration (0.06--0.07//g/L), about 50-fold lower than in little Hocking. Since this range is narrow, the average can be reliably estim ated as 0.065 /g/L. Based on this estimate, the average ratio o f PFOA in serum to drinking water in this district is 185:1. For lower drinking water concentrations, nonwater sources are likely to contribute a greater proportion o f the PFOA in the blood than in those using highly contaminated water. To find a lower bound on the ratio o f serum to water PFOA concentrations, it can be assumed that none o f the U.S. background serum concentration of about 4 /tg /L results from drinking water. If this serum concentration o f 4 /tg /L is subtracted from the median serum concentration for Village of Pomeroy (12 //g/L), the ratio o f the remaining serum concentration (8 //g/L) to the drinking water concentration (0.065//g/L) is 123:1. Therefore, PFOA appears to concentrate in serum o f people exposed to lower drinking water con centrations in a similar ratio to that reported in a highly exposed com munity (16). It should be noted that serum levels for individuals with occupational exposure (2% current, 3% fomer) (33) were not excluded from the data shown in Table 3. However, since the num ber o f subjects in each district is large, and the serum concentrations are medians, rather than m eans, it is unlikely that the overall trend would change if occupationally exposed individuals were excluded. This observed serum/drinking water ratio o f approxi mately 100:1 is in agreement with a one-com partm ent model (34) which predicts that ingestion o f0.0017 /zg/kg/day would result in serum levels of 13 //g/L in males and 8 //g/L in VOL. xxx. NO. xx, X X X X t ENVIRONMENTAL SCIENCE & TECHNOLOGY C females, or a m ean of 10.5 ftg /L . Assuming a drinking water intake o f 0.017 L/kg/day (35), a dose of 0.0017 /ig/kg/day would result from a water concentration o f 0.1 ftg /L . The ratio between a serum concentration o f 10.5 /<g/L and this water concentration of 0.1 ftg /L is 105:1, identical to the median ratio reported in Little Hocking (16). These results suggest that PFOA in drinking water at concentrations such as those found in NJ PWS can sub stantially contribute to total exposure to PFOA. For example, PFOA was found at >0.01 ftg /L in 13 o f 29 samples in the 2006 study (Table 1). Based on the 100:1 ratio, a drinking water concentration of 0.01 ftg /L is estimated to contribute about 1 ftg /L to PFOA in serum, or about 25% o f the 4 ftg /L median serum level in the general population. Development of a Health-Based Drinking W ater Con c en tra tio n fo r PFOA. The draft risk assessm ent for PFOA developed by USEPA (29), w hich identified toxicological end points in experimental animals, was used as the starting point for development of a health-based drinking water concen tration protective forlifetime exposure. The goal o f the USEPA risk assessm ent (29) was to evaluate the significance of exposure in the general population. Because the half-life of PFOA is much longer in humans (several years) than in the animals studied (2 -4 h to 30 days) ( 5 ,29), a given external dose (e.g., administered dose in units of mg/kg/day) results in a m uch greater internal dose (as indicated by serum level) in hum ans than in animals. Therefore, comparisons between effect levels in animal studies and hum an exposures were made on the basis of serum levels rather than external dose (29). USEPA (29) compared serum levels o f PFOA at the No Observed Adverse Effect Levels (NOAELs) or Lowest Observed Adverse Effect Levels (LOAELs) from animal studies to serum levels o f PFOA in the general hum an population to develop margins o f exposure for noncancer end points. Additionally, USEPA (29) classified PFOA as having "suggestive evidence of carcinogenic potential", whereas the USEPA Science Advisory Board (36) disagreed and recommended a clas sification of "likely to be carcinogenic to hum ans". The blood concentrations at the NOAELs and LOAELs for noncancer end points (29), as well as for the data used for cancer risk assessm ent (37), are shown in Table 4. USEPA (29) did not develop a Reference Dose (RfD) or cancer slope factor for PFOA, nor did they address the relationship between the external dose and the human serum level. Information on this relationship is valuable for development ofa health-based drinkingwater concentration. To develop a health-based drinking water concentration for PFOA, we derived target hum an serum levels by applying standard uncertainty factors (UFs) for RfD development (36) to the measured or modeled serum levels identified (29,39) as NOAELs or LOAELs for noncancer end points (Table 4). The UF o f 10 for interspecies extrapolation typically includes two factors of 3 each for toxicokinetic and toxicodynamic differences between humans and animals (36). Since the health-based drinking water concentrations are based on comparison of serum levels in animals and humans, the question arose as to whether com parison on this basis fully addresses interspecies toxicokinetic differences, and whether an interspecies UF of 3 rather than 10 is thus appropriate. The USEPA Science Advisory Board (36) believed that overall uncertainty about the interspecies differences in PFOA toxicity was not sufficiently reduced by comparison on the basis o f serum levels to justify modifying the default interspecies UF. Therefore, die standard interspecies UF of 10 was used. For the cancer end point, the serum level resulting in a 10~6risk level was estimated by linear extrapolation from the serum level in animals at a dose resulting in an approximate 10% tum or incidence (Table 4 (37)). Linear extrapolation is recommended by USEPA (40) as a default approach when the mode o f action for carcinogenicity is unknown. In developing health-based drinking water values for noncancer end points, a relative source contribution (RSQ is applied to account for nondrinking water exposures to the contam inant [4 1 ,4 2 ). The default value for this factor is 20% (e.g., nondrinking water sources are assumed to provide 80% ofexposure) when the relative contributions o fdrinkingwater versus nondrinking water sources are not fully characterized, as is the case for PFOA. Therefore, an RSC o f20% was applied to the target human serum levels for noncancer end points to derive the serum concentrations that are the target contribution to the human serum levels from drinking water (Table 4). No RSC is used for the cancer end point, as the target human serum concentration is based on the 10-6 risk level from drinking water exposure only. As discussed above, the relationship between external dose and serum level was used for development of a healthbased drinking water concentration for PFOA. The ratio of 100:1 between the concentration o f PFOA in serum and in drinking water which was reported for a high drinking water concentration (76) also appears to be valid at lower con centrations relevant to this analysis (Table 3). The healthbased drinking water concentration for each end point was derived using the 100:1 ratio from the target human serum concentration contributed by drinking water for that end point (Table 4). As this approach is based o n the observed relationship between serum and drinking water concentra tions, assumptions for body weight and volume o f water ingested daily are not required. The range o fhealth-based drinking water concentrations for the seven end points assessed is 0.04-0.26 ftg/L , and several o fthe concentrations are very sim ilar 0.04,0.05,0.06, 0.07, and 0.08 ftg /L (Table 4). The most sensitive end points, resulting in the lowest drinking water concentration of 0.04 ftg/L , were decreased body weight and hematological effects in the adult female rat. Cancer was not the most sensitive end point, as the drinking water concentration based on the 10~ cancer risk level is 0.06 ftg /L . Therefore, the recom mended health-based drinking water concentration for PFOA is 0.04 ftg /L . Both tire USEPA Site Specific Action Level for PFOA in drinking water in West Virginia and Ohio (43), and the M innesota Department o f H ealth's (MNDOH) Health Based Value (44) for PFOA in groundwater are 0.5 ftg /L . These assessments are based on a 6 month (subchronic) study in male cynomolgus monkeys (Table 4), and use the Tatio of half-lives for PFOA to extrapolate between animals and humans, rather than the 100:1 ratio between serum and drinking water used in Table 4. Based on pharmacokinetic principles, both approaches should give the same result if the parameters and assumptions used are correct The drinking water concentration derived in Table 4 for the same study and end point used by USEPA (43) and MNDOH (44) is 0.05 ftg /L . The 10-fold difference arises only because the drinking water concentrations developed in Table 4 include an UF for extrapolation from subchronic to chronic exposure, while the USEPA and MNDOH risk assessments do not. Aside from the 10-fold difference, which is explained by the use of the UF for duration o f exposure, the approach used in Table 4 and the approaches used by USEPA and MNDOH give identical results, providing further strength for the use of the 100:1 ratio in developing a health-based drinking water concentration fo r PFOA. Recent Human and Animal Data Not Considered in Development of a Health-Based Drinking Water Concen tration. The health-based drinking water concentration of 0.04 ftg /L considered only toxicological end points identified O ENVIRONMENTAL SCIENCE & TECHNOLOGY I VOL. xxx, NO. xx. XXXX V O L X X X , NO. X X . X X XX / ENVIRONMENTAL SCIENCE & TECHNOLOGY E TABLE 4. Derivation of Health-Based Drinking W ater Concentrations for PFOA from End Points in Anim al Studies {29) species adult female rat key study {231 chronic diet end point (23) 1body weight, hematology NOAEL or LOAEL (29) NOAEL 1.6 mg/kg/day (30 ppm) animal serum level (/rg/L) at LOAEL or NOAEL (29) 1800 (based on modeled AUC) uncertainty factor 100 (10 Intraspecies, 10 interspecies) target human serum level* (/rg/L) 18 target contribution to human serum from drinking water* (/rg/l) 4 health-based drinking water concentration' WgA.) 0.04 adult male rat two-generation 1body weight, I LOAEL 1 mg/kg/day 42 000 (USEPA 1000(10 42 8 0.08 reproductive, liver and kidney model) intraspecies, 10 gavage weight in FI Interspecies, 10 generation LOAEL to NOAEL) nonhuman primate subchronic male increased liver LOAEL 3 mg/kg/day 77 000 (measured) 3000(10 26 5 0.05 cynomolgus weight and intraspecies, 3 monkey, capsule possible mortality interspecies, 10 subchronic to chronic, 10 LOAEL to NOAEL) pregnant female rat two-generation reproductive, gavage 1body weight in male F1 pups during postweaning NOAEL 3 mg/kg/day 3600 (based on modeled AUC) 100(10 intraspecies, 10 interspecies) 35 7 0.07 male rat pups, postweaning two-generation reproductive, gavage I body weight in male F1 pups during postweaning NOAEL 3 mg/kg/day 8400(based on modeled AUC at week 4) 100(10 intraspecies, 10 interspecies) 84 17 0.17 female rat pups, postweaning two-generation reproductive, gavage 1 body weight in female FI pups during postweaning NOAEL 10 mg/kg/day 13 000 (based on modeled AUC at week 7) 100(10 intraspecies, 10 interspecies) 130 26 0.26 male rats (tumor) (37) chronic diet Leydig cell, pancreatic, and liver tumors 13.6 mg/kg/day (300 ppm) i--10% tumor Incidence) (LOAEL or NOAEL not applicable) 572 000 ug/L (USEPA model) not applicable, target human serum level is based on linear extrapolation from 10_1 tumor incidence to 10"' incidence 5.7 5.7 0.06' 'T a rget human serum level is derived by application of uncertainty factors to animal serum level at NOAEL or LOAEL. '' Target contribution to human serum from drinking water is derived by applying a relative source contribution factor of 20% (to account for nondrinking water sources of exposure) to target human serum level. 'Health-based drinking water concentration assumes a 100:1 ratio between PFOA concentrations In serum and drinking water (76). 'N o te : 20% relative source contribution factor was not used for cancer endpoint. p o> P-7 by USEPA {29). Additional data from human and animal studies not considered by USEPA (29) have since becom e available. The developmental studies considered by USEPA (29) were conducted in rats. The rat is not an appropriate model for evaluating potential hum an developmental effects o f PFOA because its half-life in the fem ale rat is very short ( 2 - 4 h) (5). In the two-generation rat study considered by USEPA (29) in which PFOA was administered as a bolus dose, blood levels did n o t reach steady state and exposure to the developing fetuses was not continuous. The mouse is more appropriate for developmental studies o f PFOA, since the half-life in fem ale m ice is longer (17 days) (5), and PFOA levels reach steady state, with continuous exposure to the fetuses. Recent mouse developmental studies (5, 4 5 -4 8 ) show significant effects not seen in the rat, including 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. USEPA (49) has recently (January 2009) developed a Provisional Short-term H ealth Advisory for PFOA in drinking water of 0.4 /tg/L, based on increased maternal liver weight after administration o f PFOA for 17 days (45). Applying a standard UF of 10 for subchronic to chronic exposure to this value would result in a drinking water concentration o f 0.04 /tg/L, identical to the lifetime health-based guidance devel oped here. However, exposure for 17 days is insufficient to be considered subchronic {50). and therefore may not be appropriate for extrapolation to a chronic risk assessment based on a systemic effect such as increased liver weight. Additionally, other studies o f similar or shorter duration not considered by USEPA (49) show effects in mice at doses below those used in the study selected by USEPA {45). These effects include increased liver weight in dosed adults (57), and increased pup fiver weight (46), m etabolic effects in adulthood (47), and structural changes in the uterus (48) following prenatal exposure. Evaluation of these studies could result in a short-term health-based concentration below 0.4 ftg IL . Preliminary data are available from the C8 Health Study, a study of approximately 70 000 people in Ohio and West Virginia exposed to PFOA in drinking water at 0.05 /(g/L or above {11, 33). This study is unique because serum levels were measured, so that effects may be correlated with internal dose rather than with a surrogate such as drinking water concentration for this very large study group. The median serum levels in the first and second deciles, 6 and 9.8 /(g/L (77) are within the range prevalent in the U.S. general population, where, for 2003--2004, the 75th and 95th percentile levels were 5.8 and 9.8 /(g/L (2). Increased cholesterol and other lipids were associated with serum PFOA levels, after adjustment for age, gender, body mass index, and other factors (72). In the cholesterol study (72), the median PFOA serum level was 27 /(g/L, and the risk o f high cholesterol increased in each quartile of exposure with a 4 0 -5 0 % increase in the top quartile compared to the lowest quartile. Similarly, serum PFOA was significantly associated with increased uric acid levels (52) and changes in several indicators of inflammatory and immune response (53) in this population. Additionally, preliminary data suggest an association between PFOA serum levels and several other clinical parameters measured in blood, including liver enzymes (77). It should be noted that these studies are ongoing and the results are currently undergoing peer review. The health-based drinking water concentrations devel oped in this paper (Table 4) are intended to protect against adverse effects from a lifetime of exposure. They are based on target human serum levels developed from animal data through a conservative approach using standard UFs for RfD development However, recent data suggest that biological effects may occur in humans in the range ofthe target serum levels presented in Table 4. The lowest target serum level derived from anim al studies (18 /g/L) falls within the second quartile o f the C8 Health Study (72), where associations with elevated cholesterol and uric acid, and changes in immune system function, were seen (72, 33, 52, 53). Additionally, associations with effects on growth o f infants {6 -8 ), increased time to pregnancy (54), and decreased normal sperm count (55) were reported in humans at serum levels below the target hum an serum levels in Table 4, although other studies {9 ,1 0 ) did not show effects on infant growth. In conclusion, PFOA was commonly detected in raw and finished water from NJ PWS using both surface and groundwater sources. Based on the relationship between the PFOA concentrations in drinking water and serum in humans, drinking water concentrations such as those detected in NJ (e.g., 0.01 /(g/L) may contribute substantially to total exposure to PFOA. A health-based drinking water concentration o f 0.04/<g/L was developed based on effects in animal studies. Recent anim al and hum an studies provide additional in form ation on exposure to and effects o f PFOA. While PFOA in most NJ PWS was below the health-based concentration, several New Jersey PWS exceeded this concentration. Acknow ledgm ents The occurrence study was conducted through the cooperative efforts o f the staff o f the NJ Department of Environmental Protection Bureau o f Safe Drinking Water, Office o f Quality Assurance, and Division of Science, Research and Technology (DSRT), including Edward Apalinski, John Berchtold, Linda Bonnette, Alan Dillon, M arc Ferko, Karen Fell, Barker Hamill, Dr. Eileen Murphy, M ichele Putnam, and Dr. Bem ie Wilk. We thank Gail Carter o f DSRT for creating the map, Dr. Thomas Atherholt o f DSRT for helpful com ments, and Dr. Alan Stem o fDSRT and Dr. Perry Cohn o fthe NJ Department of H ealth and Senior Services for their earlier review o f the basis for the health-based drinking water concentration. Finally, we especially thank Dr. Eileen Murphy, Director, DSRT, for h er enthusiastic support o f this work! The views expressed are those of the authors and do not necessarily represent those o f the New Jersey Department of Environ mental Protection. 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