Perfluorooctanoate (PFOA, CF3, (CF2)6 C00−, CAS No 3825-26-1) is a persistent pollutant in the environment, and found at low concentrations in many diverse human populations globally. PFOA has defined toxicity to experimental species, but the toxicity to humans remains unclear. In this paper we report the first published study of possible health effects of PFOA in a non-occupational group.
PFOA has commercial use primarily as ammonium perfluorooctanoate, an essential surface-active agent in the production of various fluoropolymers, including tetrafluoroethylene. Fluoropolymers are used in a wide variety of industrial and consumer products, including protective coatings for carpets and apparel, consumer house wares, paper coatings, electronics, insecticide formulations, surfactants, aerospace and other applications. PFOA also occurs as a contaminant in other fluorochemicals and telomer products (1
). PFOA is not detectable in fluoropolymer cookware samples studied under simulated cooking conditions (2
). Ammonium perfluorooctanoate is fully dissociated into the anion form, perfluorooctanoate, in environmental media and biological fluids.
PFOA is a man-made chemical with no known natural source (3
) that is persistent in the environment and is resistant to biological, environmental or photochemical degradation. PFOA, along with a related compound perfluorooctane sulphonate (PFOS), is now found both in marine animals inhabiting widely spread geographical biospheres (4
) and in human serum from widely disparate groups. The median serum PFOA concentration ([PFOA]) in the US population is around 4 to 5 µg/L, with occasional values above 20 µg/L (5
The toxicology of PFOA has recently been reviewed (1
). In rats, PFOA is well absorbed following both oral and inhalation exposure (9
) distributing primarily to the liver, plasma, and kidneys (11
). PFOA binds covalently to proteins in the rat liver, plasma, and testes (11
). The serum half-life in rodents is a few days with slower elimination in male rats than female (12
). Urine and feces are the principal routes of excretion in male rats, urine only in females (14
) and castrated male rats (14
). In male rats fecal excretion of PFOA is increased by cholestyramine resin intake, suggesting enterohepatic circulation (16
PFOA is not metabolized in mammals (9
). A number of toxic effects have been observed in experimental species. PFOA is one of a group of compounds that activates the peroxisome proliferator activated receptor (PPAR) alpha in rats leading to a response characterized broadly as peroxisomal proliferation (1
). In rats PFOA is strongly hepatotoxic (10
), male rats are more susceptible (19
). Aged rats are also more susceptible to the liver damage and oxidative stress caused by PFOA (20
). PFOA is immunotoxic to rats, resulting in decrease in spleen and thymus weights (21
) as a result of both PPAR alpha dependent processes (22
) and actions mediated through the brain (23
). PFOA has been associated with increased serum estradiol and reduced testosterone in rats, possibly due to induction of hepatic aromatase activity (24
Monkeys fed PFOA show decreased thyroid hormone levels, increases in liver weight and toxic hepatic changes (25
), slight to moderate hypocellularity of the bone marrow, moderate atrophy of lymphoid follicles, and marked diffuse lipid depletion in the adrenals (19
Carcinogenesis studies in rats fed PFOA show statistically significant increases in liver tumors, pancreatic acinar cell tumors, testicular Leydig cell adenomas (males) and mammary hyperplasia (females) compared with controls (26
). In rodents, PFOA promotes liver carcinogenesis (28
). While the significance of these tumors to humans is unclear, the International Agency for Research on Cancer (IARC) (31
) has concluded that liver tumors induced in rodents by PPAR agents are unlikely to be operative in humans based on the current understanding of the mode of action in animals. Although tumor formation by PFOA was thought to occur only through non-genotoxic mechanisms (32
), Yao and Zhou (33
) have recently reported that PFOA exerts genotoxic effects on human hepatoma HepG2 cells mediated through intracellular reactive oxygen species and oxidative DNA damage.
Because of profound differences in PFOA half-lives between species, toxicokinetics of PFOA in humans cannot be predicted based on animal data (8
). The half-life in the blood of PFOA in rats, following a single oral dose, was 4 hours in females, and 9 days in males (12
). In rabbits, the serum half-life is in the order of 4 hours for both males and females (34
). The serum half-life in cyanomolgus monkeys is approximately 20 days, with urine as the primary source of excretion (35
). The mean half-life in the serum of human retirees from the 3M Company who had previous heavy occupational exposure was 4.37 years (range 1.5 to 13.49 years SD=3.53) without substantial gender differences. Neither age, body mass index (BMI), nor number of years since retirement were significant predictors of the human serum half-lives in multivariate regression analysis (37
). In humans the renal clearance of PFOA is 10−5
fold less than the glomerular filtration rate suggesting the absence of excretion by human kidneys (38
). Thus the published half-life in human females is ~35,000 times longer than that for the female rat.
Human studies addressing potential PFOA toxicity are limited. Cross-sectional analysis of routine medical surveillance results from facilities producing both PFOA and PFOS have found significant positive association between serum PFOA and increased cholesterol, triglycerides and thyroid hormone (T3) levels (39
). Cross-sectional studies of hormonal levels in workers at a PFOA production facility have found significant associations between serum hormones and PFOA in some years (40
) but not other years (41
). Elevated serum liver enzymes were associated with occupational exposure to PFOA but only in obese men (BMI> 35kg/m2) (42
), and not in subsequent years (43
). Preliminary results from two recent unpublished studies of workers occupationally exposed to PFOA, have also observed a positive association between serum [PFOA] and serum cholesterol (Dupont Company, personal communication).
A retrospective cohort mortality study at a plant producing PFOA found an elevated SMR for prostate cancer in chemical production workers, which was significantly associated with length of employment in chemical production. The relative risk of prostate cancer was 3.3 (95% CI 1.02–10.6) for workers employed in chemical manufacturing for 10 years or more (44
). A follow-up study where workers were classified into multiple exposure groups did not confirm the association (45
), but may have been limited by low statistical power to detect elevation in cancer rates in the smaller, reclassified groups. No epidemiologic studies of potential health effects in non-occupational groups have been reported.
We have performed an epidemiologic study of residents in the Little Hocking water district in Southeastern Ohio where there is significant environmental exposure to PFOA. Water supplied by the Little Hocking Water Association has been contaminated with PFOA for many years, over the last three years at a mean level of 3.5 ug/L. PFOA in the environment in the vicinity of Little Hocking is generally believed to be coming from a neighboring industrial facility where it is used as a solvent and dispersant for fluoropolymer production. We have shown that the residents of this water district have a median serum [PFOA] that is approximately 70 times that of the general US population, and that the major source of PFOA is water from either the public water supply or contaminated residential well-water (Emmett EA, Shofer FS, Zhang H, et al, submitted for publication). Serum [PFOA] was also influenced by age (higher in those ≤ 5 or ≥ 60), number of tap water drinks per day, number of weekly servings of home-grown fruits and vegetables and use of a carbon-based residential water filter. Residents of the area who also worked in the production area of the plant had the highest PFOA levels, with residential and occupational exposures appearing to be additive.
In this paper we explore whether certain biomarkers of toxicity and adverse health effects, potentially attributable to PFOA based on animal toxicologic studies, are associated with serum [PFOA] in Little Hocking water district residents. Specifically we examine serum liver function tests, cholesterol, renal function tests, Thyroid Stimulating Hormone (TSH) and various hematologic parameters. We also examine whether studied individuals reporting a previous clinical diagnosis of either liver or thyroid disease have elevated [PFOA] compared with study participants without such diagnoses.