Steenland et al. 2009), or weaker (Fei et al. 2009; Hamm et al. 2009) than that reported for PFOA. Different measures of fetal growth across stud- ies make it difficult to assess whether the stud- ies of background PFOA and those addressing more elevated PFOA levels are consistent with one another, but thus far the positive evidence for an effect on birth weight comes from stud- ies of background exposure levels. Although an adverse impact of PFOA on birth weight would be of some concern in suggesting sensi- tivity of the fetus, shifts of the reported mag- nitudes within the normal birth weight range are of little or no clinical significance. Other indices of fetal growth have been examined in isolated studies with sugges- tions of adverse effects of PFOA on head cir- cumference and ponderal index (Apelberg et al. 2007) and on abdominal circumference and birth length (Fei et al. 2008b). Studies addressing preterm birth reported elevated risks for intermediate exposure categories only (Fei et al. 2007) or no association (Hamm et al. 2009; Stein et al. 2009). Child health and development have been examined to a very limited extent. Stein et al. (2009) reported an association between PFOA levels exceeding the 90th percentile and birth defects in aggregate (OR = 1.7; 95% CI, = 0.8–3.6). Birth defects in aggregate were not associated with residence in a high-PFOA area of the Mid-Ohio Valley in a study based on birth certificates (Nolan et al. 2009a). Fei et al. (2008a) examined parent-reported developmental milestones in infants 6 and 18 months of age and found no indication of delays associated with higher PFOA exposure. Discussion Although the epidemiologic literature on the health effects of PFOA is growing rapidly, overall it remains limited in volume and qual- ity. Many studies are cross-sectional in nature, making causal inference difficult. Other stud- ies are small and have too few outcome events to draw firm conclusions. The range of PFOA varies greatly in different populations studied, with some studies of biomarkers identifying effects at low general population levels and others with a much higher and large range of exposures finding smaller or no effects. The most consistent findings have been for modest increases in cholesterol, and to a lesser degree for a modest increase in uric acid, among those with higher PFOA levels. However, these findings have been largely based on cross-sectional data (exposure and outcome measured simultaneously), calling into question whether the relationship is causal. Three longitudinal studies show that PFOA changes over time correlate with changes in cholesterol levels (Costa et al. 2009; Olsen et al. 2003; Sakr et al. 2007b), and one longi- tudinal study shows a similar effect on uric acid 1106 (Costa et al. 2009). These longitudinal studies strengthen the case for a causal relationship, although they do not necessarily preclude that PFOA and cholesterol, or PFOA and uric acid, are both associated with some other biologi- cal process that is changing over time. Other cross-sectional findings show some evidence of an increase in liver enzymes with higher serum PFOA, but these findings have not been consistent across studies, and observed enzyme increases have been modest. Cohorts followed for mortality have the potential to shed more light on the occurrence of chronic disease. There have been only two of these, both occupational (Leonard et al. 2008; Lundin et al. 2009). Findings in these two cohorts have not been consistent, with the exception of diabetes mortality, which was significantly elevated in both studies when worker comparison groups were used. However, a large study of diabetes prevalence, a more sensitive outcome, using retrospective exposure estimates, showed no relation with PFOA (MacNeil et al. 2009). Other findings from the occupational cohort mortality stud- ies have been inconsistent, with excesses in one but not the other. There is some evidence of increased kidney cancer and heart disease in one cohort (Leonard et al. 2008; Sakr et al. 2009), whereas stroke and prostate cancer showed a positive exposure–response trend in the other (Lundin et al. 2009). All these find- ings (except for the heart disease finding) were based on small numbers of deaths. Another nonoccupational cohort, with much lower exposure levels, has been followed for can- cer in Denmark, with no significant excesses observed (Eriksen et al. 2009). In summary then, for chronic disease, sparse and inconsis- tent evidence prohibits any conclusions. The research on reproductive and develop- mental health end points is expanding rapidly and offers sporadic evidence that is difficult to interpret. A range of indicators of fetal devel- opment, including birth weight, may be sub- tly affected by relatively low levels of PFOA, but the potential for an artifactual relationship with PFOA metabolism cannot be discounted (Savitz 2007). Furthermore, the associations, although often statistically significant, are quite small in absolute terms and of limited direct clinical significance. Other studies that address more clinically consequential out- comes report or marginal adverse effects, with none replicated in independent studies at this time. In summary, the epidemiologic evi- dence accumulated thus far on health effects of PFOA comes principally from two occu- pational cohorts and several occupational cross-sectional studies, as well as community populations with background exposure levels, and one community with elevated exposure in the Mid-Ohio Valley. Although the occupational studies have the advantage of substantially elevated expo- sure ranges, they suffer from several limita- tions. They are primarily limited to males. The cohort mortality data are limited for rare diseases and those that are typically not fatal. The prevalence studies measure subclinical end points, typically blood chemistry, and are limited for causal inference and are of variable clinical significance. The community studies of populations with background exposures are more broadly repre- sentative of the general population, but it is difficult to discern clear associations within the limited exposure range available to study. In contrast to these important but inherently lim- ited sources of epidemiologic information, we are pursuing an unusual opportunity to extend our knowledge regarding the health effects of PFOA considerably by conducting a series of studies of an exposed community popu- lation in the Mid-Ohio Valley (Frisbee et al. 2009) (see http://www.c8sciencepanel.org for a description of the studies currently under way). Levels of PFOA exposure in this population are markedly above background (median values were 5 times background but included a wide range; mean levels were 15 times background), although still below occupational levels (which often have mean levels 200 times background). The population is large (> 60,000 individu- als) and comprises a wide age range (including children). In addition, we are also studying disease incidence in a cohort of approximately 6,000 workers with much higher levels (e.g., levels of 1,000 ng/mL, 200 times background). [Leonard et al. (2008) studied this same cohort for mortality.] Although there are method- ologic challenges in this setting as well, par- ticularly in reconstructing historical exposure levels and in ascertaining health end points accurately, these studies should provide new evidence complementary to that which has been generated to this point. To the extent that there are other such communities around the world that are exposed to elevated levels of PFOA due to a point source, epidemiologic research in those settings would be of clear value and help to evaluate the consistency of future findings in the Mid-Ohio Valley. Ref Rencs Andersen ME, Butenhoff JL, Chang SC, Farrar DG, Kennedy GL Jr, Lau C, et al. 2008. Perfluoroalkyl acids and related chemistries—toxicokinetics and modes of action. Toxicol Sci 102:3–14. Apelberg BJ, Witter FR, Herbstman JB, Calafat AM, Halden RU, Needham LL, et al. 2007. Cord serum concentrations of perfluorooctane sulfonate (PFOS) and perfluorooctano- ate (PFOA) in relation to weight and size at birth. Environ Health Perspect 115:1670–1676. Bartell S, Calafat A, Lyu C, Kato K, Ryan B, Steenland K. 2010. Rate of decline in serum PFOA concentrations after gran- ular activated carbon filtration at two public water sys- tems in Ohio and West Virginia. Environ Health Perspect 118:222–228. Becker AM, Gerstmann S, Frank H. 2008. Perfluorooctane ovlume 118 | number 8 | August 2010 • Environmental Health Perspectives