general population), the cross-sectional nature of the data, and the lack of validation of self- reported data. Cerebrovascular disease. Cerebrovascular disease is of interest given the findings for uric acid, which is related to blood pressure, a major determinant of cerebrovascular disease. (No studies directly address PFOA and blood pressure.) Again, however, the epidemiology is limited to the two principal occupational studies described above. Leonard et al. (2008) found a deficit of cerebrovascular mortality in comparing exposed DuPont workers with nonexposed DuPont workers (SMR = 0.86; 95% CI, 0.60–1.20). Lundin et al. (2009) found a suggestion of a positive trend of stroke mortality across nonexposed, probably exposed, and definitely exposed job categories using SMRs [SMRs of 0.5 (95% CI, 0.3– 0.8), 0.7 (0.4–1.1), and 1.6 (0.5–3.7), respectively; no test for trend presented]. Using a cumula- tive measure of weighted years of exposure, the rate ratios were 1.0 (23 deaths), 0.6 (95% CI, 0.2–2.2; 3 deaths), and 2.1 (95% CI, 1.0–4.6; 9 deaths), for < 1 year, 1–5 years, and > 5 years, respectively. Like the data for heart dis- ease, these data are too sparse to draw any conclusions. Diabetes. Diabetes is not a disease of par- ticular interest based on animal data, but some epidemiologic studies have addressed this end point nonetheless. Leonard et al. (2008) found a deficit of diabetes mortality in comparing exposed DuPont workers with the U.S. popu- lation but a 2-fold increase in diabetes mortal- ity compared with other, nonexposed DuPont workers (SMR = 1.97; 95% CI, 1.23–2.98; 22 deaths), arguably a more suitable compari- son group because of the healthy worker effect. Similarly, in internal comparisons among 3M workers, Lundin et al. (2009) found an excess of diabetes mortality in comparing a combined category of probably and definitely exposed workers and nonexposed workers (RR = 3.7; 95% CI, 1.4–10.1; 18 vs. 5 deaths). This find- ing was much less pronounced using years of exposure weighted by a qualitative judgment of intensity. Diabetes mortality is not the optimal meas- ure for a largely nonfatal disease. MacNeil et al. (2009) studied diabetes prevalence in a com- munity exposed to high levels of PFOA via contaminated drinking water near a DuPont plant. Self-reported diabetes prevalence (7.8%) and date of onset were collected from 54,468 adults, who had a median serum PFOA level of 28 ng/mL (mean = 87 ng/mL) in 2005–2006 at the time of the survey. Overall, there was no relation between diabetes prevalence, either self-reported or validated by medical records, and serum PFOA as measured at the time of the survey. A nested case–control analy- sis was conducted in which the population was restricted to participants who had at least 20 years of continuous residence in a specific water district (n = 13,922), to maximize the likelihood that serum levels in 2005–2006 would reflect the relative exposure of subjects in the past. Cases were restricted to those val- idated by medical records and occurring in the 10 years before 2005 (n = 1,055). There was a negative trend in diabetes occurrence by increasing serum PFOA decile (ORs = 1.00, 0.71, 0.60, 0.72, 0.65, 0.65, 0.87, 0.58, 0.62, 0.72). In additional analyses, fasting serum glu- cose showed no consistent trend by increasing decile of serum PFOA. Cancer. Animal data suggest that pancrea- tic, testicular, liver, and perhaps breast cancer may be related to PFOA exposure (Lau et al. 2007). Human studies are again restricted to the two U.S. occupational cohorts, as well as one follow-up study of the general population in Denmark. Leonard et al. (2008) found no excesses for liver, pancreas, testicular, or breast cancer based on small numbers of deaths (8, 11, 1, and 2 respectively). A 2-fold excess of kidney cancer was observed (SMR = 1.81; 95% CI, 0.94–3.16; 12 deaths). Lundin et al. (2009) similarly found no excesses of liver and pancreatic cancers based on small numbers (3 and 13 deaths, respectively) and did not report on testicular or kidney can- cer. Internal analyses by job category were reported for three cancers (prostate, pancreas, bladder). Some positive trend for prostate cancer was found by exposure group based on job category [nonexposed, probably exposed, definitely exposed; RRs of 1.0, 3.0 (95% CI, 0.9–9.7), and 6.6 (95% CI, 1.1–37.7), based on 4, 10, and 2 cases respectively. For pan- creatic cancer, the corresponding RRs were 1.0 and 1.7 (95% CI, 0.5–4.8), respectively, for nonexposed and for combined probable/ definite exposure groups. The data from both occupational cohorts are clearly quite sparse and prohibit any firm conclusions. There is also a study of 55,053 Danish adults 50–65 years of age who were followed from enrollment in 1993–1997 until 2006 through linkage with the Danish cancer reg- istry (Eriksen et al. 2009). There were 713, 332, 128, and 67 incident cases of prostate, bladder, pancreatic, and liver cancers found in this period. A case–cohort approach was used. Dividing the population into quartiles of serum PFOA (based on the cases), no signifi- cant linear trends by quartile were seen for any of the four cancers studied, although modest positive associations with prostate and pan- creas cancers were reported [RR for highest quartile vs. lowest quartile: prostate cancer, 1.18 (95% CI, 0.84–1.65); pancreatic cancer, 1.55 (95% CI, 0.85–2.80)]. Trends were of borderline significance for prostate cancer and pancreatic cancer and were absent or nega- tive for bladder and liver cancer. Findings for PFOS largely paralleled those for PFOA, which Environmental Health Perspectives • volume 118 | number 8 | August 2010 Epidemiology of PFOA is not surprising given that the Spearman cor- relation between the two was 0.80. This study, although much larger than the occupational studies cited above, had much lower ranges of PFOA exposure (mean = 6–7 ng/mL), typical of a general population. Immune, Thyroid, Liver, and Kidney Function and Sex Hormones Immune function. Animal studies have demon- strated that PFOA causes lymphoid organ atro- phy and decreased de novo antibody production in certain strains of mice (DeWitt et al. 2008; Yang et al. 2000). Total doses received in the Dewitt et al. (2008) study appear to have been about an order of magnitude higher than the total lifetime dose received by people drink- ing water contaminated with 1 ng/mL PFOA. There appears to be strain as well as species sen- sitivity to the immunotoxic effects of PFOA, with rats being considerably less sensitive than mice (Loveless et al. 2008), leading some to question the relevance of these data to humans. Immunotoxicity by PFOA in rodents appears to occur both through and independent of peroxisome proliferation (Yang et al. 2000). Immunosuppression, at least in part, occurs in exposed mice lacking the PPARα receptor (DeWitt et al. 2009). There is also evidence from animal studies that PFOA can suppress inflammatory responses (Taylor et al. 2006), which is similar to the effects of other PPAR agonists (DeWitt et al. 2009). Human studies to date are very limited and have included only relatively insensitive test measures, such as white blood cell count or serum immunoglobulin (Ig) levels. Emmett et al. (2006a) examined the effects on PFOA on hematologic parameters in a cross-sectional community study composed of residents who lived in a contaminated water district for at least 2 years and a smaller group of volun- teers who met the same eligibility criteria (Emmett et al. 2006b). They found no associ- ation between serum PFOA and lymphocytes, neutrophils, eosinophils, or basophils. There was one small statistically significant associa- tion between PFOA and absolute monocyte counts; elevated numbers of monocytes are often associated with recent infection, which was not controlled in the analysis. Costa et al. (2009) measured serum levels of IgG, IgM, and IgA in 34 male workers engaged in the production of PFOA. Almost 13% of the workers showed levels of serum IgA outside the laboratory referent values. Because of the small population and lack of controls, it is difficult to draw any conclusions from these data. Furthermore, the levels of serum Igs, which represent circulating anti- bodies, are extremely variable in the popu- lation and relatively insensitive markers for immune system effects. 1103