Appendix A: Summary of Health Effects Information for PFOA

Acute toxicity:

oral

Lowest oral LD₅₀ (female rat) = 430 mg/kg-bw [APFO] (IRDC 1978)

[Additional studies: Biosearch Inc. 1976 [PFOA]; Griffith and Long 1980 [APFO]; Haskell Laboratory 1981b [APFO]; Glaza 1990 [not specified], 1997 [APFO]]

Acute toxicity:

dermal

Lowest dermal LD₅₀ (rabbit) = >100 and <1000 mg/kg-bw [APFO, 24 h, covered] (Riker Laboratories Inc. 1979)

[Additional studies: Haskell Laboratory 1979b [APFO]; Kennedy 1985 [APFO]; Glaza 1995 [PFOA-Na]]

Lowest inhalation LC₅₀ (male rat) = 980 mg/m³ [APFO, 4 h] (Kennedy et al. 1986)

[Additional studies: Haskell Laboratory 1969 [APFO]; Griffith and Long 1980 [APFO]]

Lowest oral LOAEL = 0.3 mg/kg-bw per day based on a marked dose-related increase in relative liver weight in mice (serum PFOA concentration 13 µg/mL) and altered lipid parameters in rats (serum PFOA concentration 20 µg/mL) (no NOAEL). Groups of 10 male mice and rats were dosed by gavage with APFO at 0, 0.3, 1, 3, 10 or 30 mg/kg-bw per day for 14 days (Loveless et al. 2006).

[Additional studies: Christopher and Marias 1977 [APFO]; Metrick and Marias 1977 [APFO]; Griffith and Long 1980 [APFO]; Kojo et al. 1986 [PFO or PFOA, unclear]; Kennedy 1987 [APFO]; Kawashima et al. 1989 [PFOA]; Cook et al. 1992 [APFO]; Sohlenius et al. 1992 [PFO, unspecified salt]; Permadi et al. 1993 [PFOA]; Biegel et al. 1995 [APFO]; Henwood 1997 [APFO]; Kudo et al. 1999 [PFO or PFOA, unclear]; Q. Yang et al. 2000 [PFOA], 2001 [PFOA]; Thomford 2001a [APFO]; Loveless et al. 2006 [APFO]; C. Yang et al. 2008 [PFOA]]

Lowest inhalation LOAEC = 8 mg/m³ (2.48 mg/kg-bw per day, mean serum PFOA concentration 47 µg/mL), based on liver cytoplasmic hypertrophy, degeneration and/or necrosis, increased liver weight, and elevated AP in rats (NOAEC = 1 mg/m³, equating to 0.31 mg/kg-bw per day, serum PFOA concentration 13 µg/mL). Male rats were exposed to APFO at 0, 1, 8 or 84 mg/m³for 6 h/day, 5 days/week, for 2 weeks (Haskell Laboratory 1981a; Kennedy et al. 1986).

[Additional studies: Haskell Laboratory 1979a [APFO]]

Lowest dermal LOAEL = 20 mg/kg-bw per day based on increases in liver weight and aspartate aminotransferase (AST)/ALT in rats (no NOAEL). Rats were exposed to APFO at 0, 20, 200 or 2000 mg/kg-bw per day for 6 h/day (covered), 5 days/week, for 2 weeks (Haskell Laboratory 1980; Kennedy 1985).

[Additional studies: Riker Laboratories Inc. 1979 [APFO]; McDonald 1997 [APFO]]

Lowest oral LOAEL = 0.64 mg/kg-bw per day (mean serum PFOA concentration 41.2 µg/mL) based on transiently increased liver weight, hypertrophy and raised palmitoyl coenzyme A oxidase in rats (NOAEL = 0.06 mg/kg-bw per day, serum PFOA concentration 7.1 µg/mL). Male rats were dosed with APFO at 0, 1, 10, 30 or 100 ppm in the diet for 13 weeks (0, 0.06, 0.64, 1.94 or 6.5 mg/kg-bw per day) (Palazzolo 1993; Perkins et al. 2004).

[Additional studies: Goldenthal 1978a [APFO]; Griffith and Long 1980 [APFO]]

Lowest oral LOAEL = 3 mg/kg-bw per day based on increased liver weight in male cynomolgus monkeys dosed with APFO by gavage (capsule) 7 days/week for 26 weeks (serum PFOA concentration 77 µg/mL) (no NOAEL). Groups of six male cynomolgus monkeys were initially dosed at 0, 3, 10 or 30 mg/kg-bw per day. The high-dose animals received no APFO on days 12–21 and resumed dosing on day 22 at 20 mg/kg-bw per day (Thomford 2001b; Butenhoff et al. 2002).

The liver weight data were subsequently modelled (Butenhoff et al. 2004c) to estimate the lower 95% confidence limit of a benchmark dose associated with a 10% increase in liver weight (LBMD₁₀) and the associated serum concentration (LBMIC₁₀):

LBMD₁₀ = 3.9 mg/kg-bw per day [APFO] (LBMIC₁₀ was 23 µg/mL)

[Additional studies: Goldenthal 1978b [APFO]; Griffith and Long 1980 [APFO]]

Non-neoplastic effects:

Lowest oral LOAEL = 1.3 mg/kg-bw per day in male rats and 1.6 mg/kg-bw per day in female rats, based on dose-related increases in serum ALT, AP and albumin in males and females; and ataxia and a slight increase in ovarian tubular hyperplasia in females (no NOAEL). CD rats (five per dose per sex) were given APFO at 0, 30 or 300 ppm in the diet for 2 years (0, 1.3 or 14.2 mg/kg-bw per day for males; 0, 1.6 or 16.1 mg/kg-bw/day for females).

Carcinogenicity:

No evidence of carcinogenic activity was seen in the females. In males, there was an increased incidence of testicular Leydig cell adenomas (0/49, 2/50 and 7/50 in control, low-dose and high-dose groups, respectively), significant (p = 0.05) at the high dose (Sibinski 1987).

Additional studies:

Oral LOAEL = 13.6 mg/kg-bw per day based on increased incidences of Leydig cell hyperplasia and adenomas, liver adenomas, and pancreatic acinar cell hyperplasia and adenoma in male rats (no NOAEL). Male CD rats were given APFO at 0 or 300 ppm in the diet (0 or 13.6 mg/kg-bw per day) for 2 years (Biegel et al. 2001). (See Table. Additional Studies)

Negative:

Bacteria, mutation, with and without S9 [PFOA-Na] (Lawlor 1995)

[Additional studies: Kennedy 1976 [not specified]; Litton Bionetics Inc. 1978 [APFO]; Lawlor 1996 [APFO]]

Mammalian cells, chromosomal aberration, with and without S9 [APFO] (Murli 1996a)

[Additional studies: Murli 1996c [APFO], 1996f [PFOA-Na]]

Positive:

Mammalian (CHO) cells, chromosomal aberration [PFOA-Na] (Murli 1996d)

Mammalian (human hepatoma) cells, micronuclei and oxidative DNA damage [PFOA] (Yao and Zhong 2005)

Negative:

Mouse (male/female) bone marrow micronucleus [PFOA-Na], up to 5 g/kg-bw; acute oral gavage (Murli 1995)

[Additional studies: Murli 1996b [APFO], 1996e [APFO]]

Positive:

Rat (male), oxidative DNA damage, increase in 8-hydroxy-deoxyguanosine in liver DNA but not kidney DNA [PFOA]; 0.02% in diet for 2 weeks or 100 mg/kg-bw by a single intraperitoneal injection (Takagi et al. 1991)

Developmental toxicity:

oral

Oral LOAEL = 1 mg/kg-bw per day (mean serum PFOA level 21.9 µg/mL in dams) based on maternal toxicity (increased liver weight) and fetal toxicity (reduced ossification, early puberty in males) in mice (no NOAEL). Pregnant CD-1 mice were given APFO by gavage at 0, 1, 3, 5, 10, 20 or 40 mg/kg-bw on days 1–17 of gestation (Lau et al. 2006).

[Additional studies: Gortner 1981 [APFO], 1982 [APFO]; Staples et al. 1984 [APFO]; Mylchreest 2003 [APFO]; Abbott et al. 2007 [APFO]; White et al. 2007 [APFO]; Wolf et al. 2007 [APFO]]

Developmental toxicity:

inhalation

Random selection of 1400 women and their infants from the Danish National Birth Cohort. Maternal PFOA serum levels were inversely associated with birth weight and length. There were no associations between maternal PFOA and early childhood developmental milestones at 6 and 18 months. In 1240 women with planned pregnancies, increased maternal serum PFOA early in gestation was associated with increased time to pregnancy (mean maternal serum PFOA = 0.0056 µg/mL; lowest [reference] quartile: maternal PFOA = 0.003 91 µg/mL) (Fei et al. 2007, 2008a, b, 2009)

In a cross-sectional study of 293 newborn cord blood samples in Baltimore, Maryland, there was a small negative association of cord blood PFOA level with birth weight (mean cord serum PFOA = 0.0016 µg/mL) (Apelberg et al. 2007b).

In a study of 101 pregnant women and their infants in Hamilton, Ontario, there was no association between maternal or cord serum PFOA and birth weight (mean maternal serum PFOA = 0.002 54 µg/mL at 24–28 weeks’ gestation and 0.002 24 µg/mL at delivery; mean cord serum PFOA = 0.001 94 µg/mL) (Monroy et al. 2008).

In a retrospective cohort study of 428 women in Japan, there was no association between maternal serum PFOA levels and birth weight (mean maternal serum PFOA = 0.0014 µg/mL) (Washino et al. 2009).

In a study of 252 pregnant women and their babies in Alberta, there was no association between maternal serum PFOA and fetal weight (median maternal serum PFOA = 0.0015 µg/mL) (Hamm et al. 2009).

In a cross-sectional study of 1555 singleton births in Ohio, a subset of 380 of the mothers lived in a county where drinking water was known to be contaminated with PFOA (mean drinking water concentration 2002–2005: 6.78 µg/L). There was no difference in mean birth weight or in the incidence of low birth weight in the highly exposed group compared with those in surrounding counties with levels of PFOA in drinking water of approximately 20–1000 times lower (Nolan et al 2009a). In a follow-up study, the investigators reported no association between elevated exposure to PFOA (as determined by living in an area serviced by contaminated drinking water) and congenital anomalies (Nolan et al. 2009b). Serum levels of PFOA were not measured in these studies; however, a previous study of a population in this drinking water area reported a median serum PFOA concentration of 0.354 µg/mL (Emmett et al. 2006b; see above).

In a cross-sectional study of 1845 pregnancies in communities in Ohio and West Virginia served by drinking water contaminated with PFOA, serum PFOA was measured up to 5 years following the birth, and health outcomes were self-reported. There was no association between maternal serum PFOA level and birth weight (mean serum PFOA level: 0.048 µg/mL; median serum PFOA level: 0.0212 µg/mL) (Stein et al. 2009).

In a cross-sectional general population study of 371 subjects in Ohio in a county where the drinking water contained PFOA at a mean level of 3.5 µg/L for the previous 3 years, there were no significant relationships between serum PFOA concentration and liver or renal function tests, cholesterol levels or other hematological papameters (median serum PFOA concentration: 0.354 µg/mL) (Emmett et al. 2006b).

In a cross-sectional study of 54 468 adults living in Ohio and West Virginia served by drinking water contaminated with PFOA (C8 Health Project), the self-reported age-adjusted prevalence of diabetes was similar to state-wide levels for Ohio and West Virginia. Odds ratios for type II diabetes were <1 for all serum PFOA levels above the lowest (reference) decile, including when analysis was restricted to those who had lived in contaminated water districts for at least 20 years and with at least 10 years of exposure before diagnosis (mean serum PFOA level: 0.0868 µg/mL; median serum PFOAlevel: 0.0281 µg/mL; lowest [reference] decile: serum PFOA <0.0079 µg/mL) (MacNeil et al. 2009).

In a cross-sectional study of 46 294 adults living in Ohio and West Virginia served by drinking water contaminated with PFOA (C8 Health Project), there were positive trends between increased serum PFOA and total cholesterol, LDL-cholesterol and triglycerides. The odds ratio for high cholesterol increased for each quartile, up to 1.4. There was no association between serum PFOA levels and HDL-cholesterol (mean serum PFOAlevel: 0.080 µg/mL; median serum PFOA level: 0.027 µg/mL; lowest [reference] quartile: serum PFOA <0.0131 µg/mL; highest quartile: =0.067 µg/mL) (Steenland et al. 2009).

Liver enzymes, hormones, lipids and other serum parameters:

In a cross-sectional and longitudinal (3–6 years) examination of medical records for 263 workers in fluorochemical production, no significant relationships were noted between serum PFOA and hematological, thyroid or liver parameters. There were positive associations between serum PFOA and total cholesterol and triglycerides (mean serum PFOA level: 1.78 µg/mL; range: 0.04–12.7 µg/mL) (Olsen et al. 2003a).

In two small cross-sectional studies (111 and 80 workers in PFOA production), serum PFOA levels were not significantly associated with serum estradiol or testosterone in either study (serum PFOA: up to 115 µg/mL) (Olsen et al. 1998).

Annual medical surveillance of 53 male workers in PFOA production (exposed for 0.5–32.5 years) and 107 unexposed controls was carried out. Over 30 years, there was no clinical evidence of any specific disease in exposed workers, and all biochemical parameters tested were within normal range. In 2007, total cholesterol was significantly greater in 34 exposed workers compared with 34 controls matched by age and other factors. Multivariate analysis on 56 subjects who had serum PFOA assessed concurrently with biochemical parameters over the last 6 years showed that total cholesterol was weakly but significantly correlated with serum PFOA (serum PFOA analyzed 2000–2007; in 2007, median serum PFOA in currently exposed workers: 5.71 µg/mL; median in formerly exposed workers: 4.43 µg/mL) (Costa et al. 2009).

Medical surveillance data on male workers involved in PFOA production in 1993 (n = 111), 1995 (n = 80) and 1997 (n = 74) (only 17 subjects were common for the 3 surveillance years) indicated that serum cholecystokinin levels were negatively associated with serum PFOA levels. There were no associations with serum PFOA and liver enzymes or lipids (serum PFOAlevels: means for each year 5.0–6.8 µg/mL, overall range up to 114.1 µg/mL) (Olsen et al. 2000).

In a cross-sectional study in 1025 workers in fluoropolymer production, using multivariate linear regression, serum PFOA was significantly positively associated with cholesterol, very low density lipoprotein (VLDL), LDL and gamma glutamyl aminotransferase (GGT), and in men, with serum estradiol and testosterone. There was no association of serum PFOA with HDL, triglycerides, AST, ALT or bilirubin (serum PFOA levels ranged from 0.0046 to 9.55 µg/mL; mean 0.428 µg/mL) (Sakr et al. 2007a).

Medical surveillance data and serum PFOA measurements were collected for up to 25 years for 454 workers in fluoropolymer production. A linear mixed effects model was used. Serum PFOA was positively associated with total cholesterol and AST and negatively associated with total bilirubin. There was no association of serum PFOA with triglycerides, LDL, HDL, GGT, ALT or AP (serum PFOA levels ranged from 0 to 22.66 µg/mL; mean 1.13 µg/mL over 23-year study period) (Sakr et al. 2007b).

Mortality and cancer:

A retrospective cohort mortality study of 2083 employees at a fluorochemical production facility was conducted. The exposure of the cohort members to fluorochemicals was grouped as high, low or non-exposed based on biomonitoring for PFOS. The overall mortality rate was less than expected in the general population. There were two deaths due to liver cancer in the high- and low-exposure groups (SMR 3.08) and three deaths due to bladder cancer, all in the high-exposure group (SMR 12.77) (Alexander et al. 2003). PFOA was not manufactured at this site, but workers showed occupational levels of serum PFOAalong with six other perfluorochemicals (serum PFOA: geometric mean 0.899 µg/mL) (Olsen et al. 2003c).

A retrospective cohort mortality analysis of 6027 workers at a West Virginia fluoropolymer manufacturing plant was done. The SMRs were derived based on comparison with the US population, state population and a regional employee population. Most SMRs were less than or equal to 1. The only statistically significant elevation in mortality was for diabetes mortality compared with the regional employee population (SMR = 1.97). There was also a non-significant elevation for ischemic heart disease (IHD) mortality compared with the regional employee population (SMR = 1.09). The numbers of deaths due to liver, pancreatic and testicular cancers (8, 11 and 1, respectively) were less than expected for the US population (Leonard et al. 2008). PFOA in serum of workers had previously been measured at this facility and was found to be detectable regardless of job description. In 1025 workers, serum PFOA levels ranged from 0.0046 to 9.55 µg/mL (mean 0.428 µg/mL) (Sakr et al. 2007a; see above).

A mortality study was conducted on a cohort of 3993 employees in APFO production. Jobs were classified as “definite” or “probable” APFO exposure or non-exposed. Previously collected data on serum PFOA levels for various areas of the plant were used to estimate cumulative exposure. SMRs for the general population of Minnesota were =1 for most causes of death, including liver cancer, liver cirrhosis, pancreatic cancer, IHD and all heart disease. There were no deaths from testicular cancer (no SMR estimated). The SMRs for subjects in jobs with definite exposure were >1 for prostate cancer and cerebrovascular disease (SMRs of 2.1 and 1.6, respectively). Comparing the highest and lowest cumulative exposure categories gave an increased risk for prostate cancer and cerebrovascular disease (hazard ratios [HRs] of 6.6 and 4.6, respectively). The SMR for subjects in jobs with probable exposure was 2.0 for diabetes, and the HR compared with the low-exposure group was 3.7. There were no deaths from diabetes in the definite exposure group (Lundin et al. 2009).