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Biomonitoring Summary

Perfluorochemicals


General Information

The perfluorochemicals (PFCs) are molecules in which all bonds of the alkyl chain are carbon-fluorine bonds excepting the terminal functional group. Those discussed here include perfluoroalkyl acids, amides, and alcohols which are by-products, end products, or processing aids used in the synthesis of fluoropolymers. Fluoropolymers have applications in waterproofing and protective coatings of clothes, furniture, and other products; and also as constituents of floor polish, adhesives, fire retardant foam, and insulation of electrical wire. A major application of one important fluoropolymer, polytetrafluoroethylene, has been the heat-resistant non-stick coatings used on cooking ware and other protected surfaces. Because of their properties, fluoropolymer products are used in a wide range of industries including aerospace, automotive, building/construction, chemical processing, electrical and electronics, semiconductor, and textiles. There are many other fluorocarbon type chemicals which are not addressed here, such as perfluorochemical telomers, finalized perfluorochemical polymer products, chlorofluorocarbons and investigational blood substitutes.

Perfluorooctanoic acid (PFOA) has been manufactured since the 1950s, primarily as its ammonium salt, as a solubilization aid in the synthesis of polytetrafluoroethylene. PFOA is usually not a residual contaminant in non-stick surfaces made of polytetrafluoroethylene. Worldwide annual production of PFOA was estimated to be 260 metric tons in 1999 (Prevedouros et al., 2006). Production rates and emission rates have fallen since 2002 after conversion to a new synthesis process. Other perfluoroalkyl carboxylates of various chain lengths were also formed in the process used prior to 2002. However, current manufacturing practices reduce the formation of these by exclusively using fluorotelomers (Prevedouros et al., 2006).

Perfluorooctanesulfonyl fluoride (POSF) was synthesized as a polymerization starting material. POSF-based polymers have been used in a wide variety of products such as waterproofing, textiles, and fire protection. Other PFCs (including small amounts of PFOA) can also form as side-reaction by-products in the synthesis of POSF (e.g., perfluorooctane sulfonamide, PFOSA), or form as degradation products during its reaction to create the intermediate reacting monomers, n-methylperfluorooctanesulfonamidoethanol (MeFOSE) and n-ethylperfluorooctanesulfonamidoethanol (EtFOSE), or form in the final product (e.g., perfluorooctane sulfonate, PFOS) (Hekster et al., 2003; Olsen et al., 2005; U.S. EPA, 2003). MeFOSE and EtFOSE have been used in food packaging and textile treatments, and their oxidation products, n-methylperfluorooctane-sulfonamidoacetic acid (Me-PFOSA-AcOH) and n-ethylperfluorooctanesulfonamidoacetic acid (Et-PFOSA-AcOH), respectively, may be markers of food or consumer exposures. In addition, several pathways (during manufacturing) can lead to formation of PFOS or other sulfonyl-containing PFCs as residual contaminants in the final polymer products. Perfluorohexane sulfonate (PFHxS) has also been used to synthesize the fluoropolymers used in firefighting foams and some carpet treatments. U.S. manufacture of POSF-based products began ending in about 2000. Global production that year for POSF materials was 3700 metric tons (Prevedouros et al., 2006). Perfluorononanoic acid (PFNA) was an impurity in the process that produces PFOS.

The PFCs have limited water solubility, low volatility (as salts or ionized) and can remain in the environment and bioconcentrate in animals (e.g., some fish bioconcentrate PFOS greater than 2000-fold over aquatic levels). PFOS and PFOA levels in archived bird eggs from Sweden have increased thirtyfold from 1968 to 2003 (Holmstrom et al., 2005). PFCs have been identified in surface coastal and ocean waters (Yamashita et al., 2005), in a wide variety of marine and land animals (Kannan et al., 2005; Keller et al., 2005; Taniyasu et al., 2003), and in human blood and semen (Calafat et al., 2006a; Guruge et al., 2005; Kannan et al., 2004; Olsen et al., 2003a and 2004a). In some cases, environmental breakdown products of the telomers used to make fluoropolymers or the metabolic products of fluorochemicals in the body can produce PFCs that are measured human blood. For instance, the 8-2 telomer, heptadecafluoro-1-decanol, may metabolize or degrade to PFOA (Dinglasan et al., 2004). It is unclear if environmentally degraded telomer products are a major source of other PFCs.

All sources of human exposure are uncertain, but probably include dietary sources (Kannan et al., 2004; Prevedouros et al., 2006; Tittlemier et al., 2007). PFOA (and probably other perfluoroalkyl acids) exist in the anionic state at physiologic and environmental pHs and their distribution in the body is determined, in part, by high protein binding in plasma and other proteins. Unlike many organohalogen contaminant chemicals, the perfluoroalkyl acids (PFOA and PFOS) do not tend to accumulate in fat tissue, but still can have long residence times in the body. PFOA is mostly excreted in the urine in animal studies, but limited observations in humans suggest that only one-fifth of the total body clearance is renal (Harada et al., 2005). The elimination half-life of PFOA in humans is roughly estimated to be 3.5 years and for PFOS, approximately 4.8 years (Olsen et al., 2007a). Excepting PFOS and PFOA, there is limited information on the sources, environmental fate, human toxicokinetics, or effects of other PFCs. The PFCs often measured in human serum are listed in the table.

Perfluorinated Chemicals
Perfluorinated Compounds CAS number Abbreviation
Serum Perfluorobutane Sulfonic Acid   PFBuS
Serum Perfluorodecanoic Acid 335-76-2 PFDeA
Serum Perfluorododecanoic Acid 307-55-1 PFDoA
Serum Perfluoroheptanoic Acid 375-85-9 PFHpA
Serum Perfluorohexane Sulfonic Acid 355-46-4 PFHxS
Serum Perfluorononanoic Acid 375-95-1 PFNA
Serum Perfluorooctanoic Acid 335-67-1 PFOA
Serum Perfluorooctane Sulfonic Acid 1763-23-1 PFOS
Serum Perfluorooctane Sulfonamide 754-91-6 PFOSA
Serum 2-(N-Ethyl-Perfluorooctane sulfonamido) Acetic Acid   Et-PFOSA-AcOH
Serum 2-(N-Methyl-perfluorooctane sulfonamido) Acetic Acid   Me-PFOSA-AcOH
Serum Perfluoroundecanoic Acid 2058-94-8 PFUA

Human health effects from PFCs at low environmental doses or at biomonitored levels from low environmental exposures are unknown. The ammonium salt of PFOA has been tested at high doses in mammalian animal studies and produced altered weights of the liver, kidney, thymus and spleen; hepatotoxicity; endocrine and immune effects; and in offspring, growth retardation and delayed sexual maturation (Kennedy et al., 2004; Lau et al., 2004; U.S. EPA, 2003). Both PFOA and perfluorodecanoic acid have been shown to reduce androgen levels in laboratory animal studies (Biegel et al., 1995; Bookstaff et al., 1990). PFOA preparations used in many studies may also contain a small percentage of other chain length perfluoroalkyl acids (i.e., C5, C6, C7). The liver toxicity of several PFCs is evident by vacuolization and lipid accumulation in both rodent and monkey livers (Seacat et al., 2002; Lau et al., 2004) and may be attributable to the ability of PFCs to affect intracellular lipid binding proteins, peroxisomal proliferation, and β-oxidation of lipids (Kudo et al., 2000, 2003; Vanden Heuvel et al., 1993). Some of the effects in animals may be mediated through peroxisomal proliferation, including immunologic effects and tumor induction, but the relevance of peroxisomal pathways in humans is unclear (Kennedy et al., 2004). PFOA has been reported to cause liver, pancreas, and testicular tumors in high dose animal testing (Biegel et al., 2001; Cook et al., 1992; Kennedy et al., 2004). Effects on serum liver enzymes in limited observational studies of human occupational exposures are unclear. Two recent cross-sectional human studies observed a negative correlation of birth weight with serum levels of PFOA (Apelberg et al., 2007; Fei et al., 2007).

Due to marked intergender differences in the elimination of PFOA in rats and substantial differences in the half-life of PFOA in rats, monkeys, and humans, the potential to estimate risks to humans from animal doses is uncertain. However, animal and human serum PFOA levels have been compared: serum levels associated with toxic effects in animals were 66-11,108 times higher than background serum levels in humans (Butenoff et al., 2004; U.S. EPA, 2003). A study of workers chronically exposed to primarily PFOA showed no biochemical evidence of hepatotoxicity or hormonal changes (adrenal, reproductive, thyroidal), and there was no clear evidence of excess all-cause or disease-specific mortality, or increased cancer rates (Alexander et al., 2003; Olsen et al., 1999; U.S. EPA, 2003).

Serum PFOS levels associated with toxicity in test animals were 310-1550 times higher than 95 percent of the levels found in a study of adults (Olsen et al., 2003a, 2005). Animal studies of PFOS have demonstrated weight loss, hepatotoxicity, and changes in thyroid hormone concentrations (Grasty et al., 2003; Thibodeaux et al., 2003; Lau et al., 2004). At doses causing maternal toxicity, developmental and teratogenic effects were demonstrated in offspring. At high but non-toxic maternal doses of PFOS, development in offspring was stunted and hypothyroxinemia was observed. Late gestational exposure to PFOS in animal studies has also demonstrated early neonatal lethality, possibly related to lung immaturity (Lau et al., 2003). PFOA, PFOS, and other PFCs have not been classified as to human carcinogenicity by IARC or NTP.

Biomonitoring Information

Serum levels of PFCs (particularly PFOA and PFOS) tend to reflect cumulative exposure over several years. Twelve different PFCs were measured in the sera of NHANES 2003–2004 participants. Roughly similar levels of PFCs in serum have also been measured previously in other samples of the U.S. population. In such studies, PFOS, PFOA, perfluorohexanesulfonate (PFHxS), and perfluorononanoic acid (PFNA) are detectable in a high percentage of the participants and PFOS levels are generally 3-10 times higher than PFOA levels (Calafat et al., 2007a, 2007b; Olsen et al., 2003a, 2005). Analysis of the NHANES 2003–2004 subsample demonstrated higher levels of PFOA and PFOS in males and a slight increase in levels of PFOS with age (Calafat et al., 2007b). Slightly higher levels of PFOS and PFOA in males than females have been noted in several other studies (Calafat et al., 2007a; Harada et al., 2004; Olsen et al., 2003a). In comparing three separate reports on adults, elderly and children, the median PFCs values tend to be roughly similar in these age categories (Olsen et al., 2003a, 2004a, 2004b), and no substantial age trends were seen within adults ages 20-69 (Olsen et al., 2003a). In a study of 598 blood donors aged 20-69 (Olsen et al., 2003a), surprisingly little variance in across five widely-dispersed U.S. cities was seen in median PFC levels. PFOS and PFOA were shown to be highly correlated in that study and also in NHANES 2003–2004 (Calafat et al., 2007b), possibly due to PFOA being a by-product in POSF-related production. The median levels of various PFCs in Olsen et al. (2003a) were similar to those of pooled samples (1990 through 2002) of the U.S. population (Calafat et al., 2006a). Olsen et al. (2005) also showed that PFCs serum concentrations increased from 1974 to 1989 in 58 paired samples: 25% for PFOS, 162% for PFOA, and 204% for Et-PFOSA-AcOH. Recently, Olsen et al. (2007b) reported reductions in PFOS and PFOA concentrations for a group of Red Cross blood donors in the United States from 2000 to 2005.

Serum levels of PFCs, particularly PFOS, appear to be higher in the U.S. than in some other countries: about two to threefold higher than in Columbia, Brazil, Poland, Belgium, Malaysia, Korea and Japan; and about eight to sixteenfold higher than in Italy and India (Kannan et al., 2004); and more than thirtyfold higher than in Peru (Calafat et al., 2006b). Notably, the sample sizes were small in these studies. In Japan, PFOS levels tended to vary within regions of the country ranging from U.S. median levels to about fivefold lower levels (Harada et al., 2004). PFC levels for the U.S. population, representing environmental exposures, are much lower than those reported for occupational exposure. In monitored workers employed at a POSF production facility with no biochemical or clinically observable effects, median levels of PFOS and PFOA were over 40 to 300-fold higher, respectively (Olsen et al., 2003b).

Finding a measurable amount of PFCs in serum does not imply that the levels of PFCs cause an adverse health effect. Biomonitoring studies of serum PFCs can provide physicians and public health officials with reference values so that they can determine whether or not people have been exposed to higher levels of PFCs than are found in the general population. Biomonitoring data can also help scientists plan and conduct research on exposure and health effects.

References

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Biegel LB, Hurtt ME, Frame SR, O'Connor JC, Cook JC. Mechanisms of extrahepatic tumor induction by peroxisome proliferators in male CD rats. Toxicol Sci 2001;60(1):44-55.

Biegel LB, Liu RC, Hurtt ME, Cook JC. Effects of ammonium perfluorooctanoate on Leydig cell function: in vitro, in vivo, and ex vivo studies. Toxicol Appl Pharmacol 1995;134(1):18-25.

Bookstaff RC, Moore RW, Ingall GB, Peterson RE. Androgenic deficiency in male rats treated with perfluorodecanoic acid. Toxicol Appl Pharmacol 1990;104(2):322-333.

Butenhoff JL, Gaylor DW, Moore JA, Olsen GW, Rodricks J, Mandel JH, et al. Characterization of risk for general population exposure to perfluorooctanoate. Regul Toxicol Pharmacol 2004;39(3):363-380.

Calafat AM, Kuklenyik Z, Caudill SP, Reidy JA, Needham LL. Perfluorochemicals in pooled serum samples from United States residents in 2001 and 2002. Environ Sci Technol 2006a;40:2128-2134.

Calafat AM, Needham LL, Kuklenyik Z, Reidy JA, Tully JS, Aguilar-Villalobos M, et al. Perfluorinated chemicals in selected residents of the American continent. Chemosphere 2006b;63:490-496.

Calafat AM, Kuklenyik Z, Reidy JA, Caudill SP, Tully JS, Needham LL. Serum concentrations of 11 polyfluoroalkyl compounds in the U.S. population: Data from the National Health and Nutrition Examination Survey (NHANES) 1999–2000. Environ Sci Technol 2007a;41:2237-2242.

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Hekster FM, Laane RW, de Voogt P. Environmental and toxicity effects of perfluoroalkylated substances. Rev Environ Contam Toxicol 2003;179:99-121.

Holmstrom KE, Jarnberg U, Bignert A. Temporal trends of PFOS and PFOA in guillemot eggs from the Baltic Sea,1968--2003. Environ Sci Technol 2005;39(1):80-84.

Kannan K, Corsolini S, Falandysz J, Fillmann G, Kumar KS, Loganathan BG, et al. Perfluorooctanesulfonate and related fluorochemicals in human blood from several countries. Environ Sci Technol 2004;38(17):4489-4495.

Kannan K, Yun SH, Evans TJ. Chlorinated, brominated, and perfluorinated contaminants in livers of polar bears from Alaska. Environ Sci Technol 2005;39(23):9057-9063.

Keller JM, Kannan K, Taniyasu S, Yamashita N, Day RD, Arendt MD, et al. Perfluorinated compounds in the plasma of loggerhead and Kemp's ridley sea turtles from the southeastern coast of the United States. Environ Sci Technol 2005;39(23):9101-9108.

Kennedy GL Jr, Butenhoff JL, Olsen GW, O'Connor JC, Seacat AM, Perkins RG, et al. The toxicology of perfluorooctanoate. Crit Rev Toxicol 2004;34(4):351-384.

Kudo N, Bandai N, Suzuki E, Katakura M, Kawashima Y. Induction by perfluorinated fatty acids with different carbon chain length of peroxisomal beta-oxidation in the liver of rats. Chem Biol Interact 2000;124(2):119-132.

Kudo N, Kawashima Y. Induction of triglyceride accumulation in the liver of rats by perfluorinated fatty acids with different carbon chain lengths: comparison with induction of peroxisomal beta-oxidation. Biol Pharm Bull 2003;26(1):47-51.

Lau C, Butenhoff JL, Rogers JM. The developmental toxicity of perfluoroalkyl acids and their derivatives. Toxicol Appl Pharmacol 2004;198(2):231-241.

Lau C, Thibodeaux JR, Hanson RG, Rogers JM, Grey BE, Stanton ME, et al. Exposure to perfluorooctane sulfonate during pregnancy in rat and mouse. II: postnatal evaluation. Toxicol Sci 2003;74(2):382-392.

Olsen GW, Burris JM, Mandel JH, Zobel LR. Serum perfluorooctane sulfonate and hepatic and lipid clinical chemistry tests in fluorochemical production employees. J Occup Environ Med 1999;41(9):799-806.

Olsen GW, Church TR, Miller JP, Burris JM, Hansen KJ, Lundberg JK, et al. Perfluorooctanesulfonate and other fluorochemicals in the serum of American Red Cross adult blood donors. Environ Health Perspect 2003a;111(16):1892-1901. (Erratum in: Environ Health Perspect. 2003a;111(16):1900)

Olsen GW, Burris JM, Burlew MM, Mandel JH. Epidemiologic assessment of worker serum perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA) concentrations and medical surveillance examinations. J Occup Environ Med 2003b;45(3):260-270.

Olsen GW, Church TR, Larson EB, van Belle G, Lundberg JK, Hansen KJ, et al. Serum concentrations of perfluorooctanesulfonate and other fluorochemicals in an elderly population from Seattle, Washington. Chemosphere 2004a;54(11):1599-1611.

Olsen GW, Church TR, Hansen KJ, Burris JM, Butenhoff JL, Mandel JH. Quantitative evaluation of perfluorooctanesulfonate (PFOS) and other fluorochemicals in the serum of children. J Children's Health 2004b;2(1):53-76.

Olsen GW, Huang HY, Helzlsouer KJ, Hansen KJ, Butenhoff JL, Mandel JH. Historical comparison of perfluorooctanesulfonate, perfluorooctanoate andother fluorochemicals in human blood. Environ Health Perspect 2005;113(5):539-545.

Olsen GW, Burris JM, Ehresman DJ, Froehlich JW, Seacat AM, Butenhoff JL, et al. Half-life of serum elimination of perfluorooctanesulfonate,perfluorohexanesulfonate, and perfluorooctanoate in retired fluorochemical production workers. Environ Health Perspect. 2007a;115(9):1298-1305.

Olsen GW, Mair DC, Reagen WK, Ellefson ME, Ehresman DJ, Butenhoff JL, et al.. Preliminary evidence of a decline in perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA) concentrations in American Red Cross blood donors. Chemosphere 2007b;68:105–111.

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Seacat AM, Thomford PJ, Hansen KJ, Olsen GW, Case MT, Butenhoff JL. Subchronic toxicity studies on perfluorooctanesulfonate potassium salt in cynomolgus monkeys. Toxicol Sci 2002;68(1):249-264.

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Tittlemier SA, Pepper K, Seymour C, Moisey J, Bronson R, Cao XL et al. 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 Ag Food Chem 2007;55:3203-3210.

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