and ALP along with bilirubin in exposed workers; in the most recent and extensive analysis, Olsen and Zobel (2007) reported data from 552 volunteers from three plants (mean serum level = 2,210 ng/mL). For the three plants together, there was a modest pos- itive association for log GGT (coefficient = 0.0326, p = 0.05) and log ALT (coefficient = 0.0249, p = 0.06), in a model with BMI but not in a model with triglycerides, but no evidence of an effect for ALP or AST in either model. However, results were inconsistent across plants, with these overall positive results derived from just of one of the four plants included. For bilirubin, the relationship was consistently negative and significantly nega- tive overall (exposure–response coefficient: in model with BMI, –0.0325, p = 0.001; in model with triglycerides, –0.0267, p = 0.01). These positive findings contrast with earlier cross-sectional analyses of these plants that were essentially negative (e.g., Gilliland and Mandel 1996; Olsen et al. 1999). Lin et al. (2010) assessed the relationships between ALT, GGT, and bilirubin and four PFCs, including PFOS and PFOA, meas- ured in serum in the NHANES surveys of 1999–2000 and 2003–2004 (n = 2,216). They found significant trends for liver enzymes across quartiles of PFOA and in regressions of log-transformed enzyme levels against log- transformed PFOA. However exposure con- trasts were low, with the lowest quartile < 2.9 and the top quartile > 5.95 ng/mL PFOA. Given these small exposure contrasts, the models suggested a much larger effect per unit exposure than did other studies. In summary, studies of liver enzymes have reported some associations with PFOA. Four independent studies (two longitudinal and two cross-sectional studies) reported reduced bilirubin associated with increasing PFOA, and at least two studies showed results sug- gesting increasing AST or GGT in relation to PFOA. However, the changes in liver enzymes are quite small, and the magnitude of effect is quite inconsistent, with results from the NHANES study showing an effect of expo- sure going from 1 to 3 ng/mL, whereas other studies looked at contrasts of thousands of nanograms per milliliter of PFOA, in some cases with no apparent association. These results provide limited evidence of some bio- logical activity of PFOA in human liver, the clinical significance of which is uncertain. Kidney function. PFOA concentrates in the kidney in animals and therefore is of interest as a potential target organ. However, no animal data document kidney toxicity, and human data are also quite limited. In an occupational study, Costa et al. (2009) reported no significant associa- tion between PFOA and either urea nitro- gen or creatinine. These negative results were consistent with those of Emmett et al. (2006b), who found no significant association between either blood urea nitrogen or creati- nine with the serum level of PFOA. Reproductive and Developmental Outcomes Toxicology studies indicate the potential for PFOA and PFOS to affect fetal growth and development. In utero exposure to PFCs is associated with a range of nonspecific adverse developmental outcomes in mouse, rat, and rabbit models (Lau et al. 2007; Olsen et al. 2009), including reduced fetal weight and increased neonatal mortality. Extrapolation across species and end points is particularly problematic in reproductive toxicology. Epidemiologic research on PFOA and reproductive end points was initiated quite recently, with most studies published in 2007 or later (Olsen et al. 2009). With few excep- tions, the studies examine serum PFOA in relation to the risks of a range of different adverse outcomes. Except for fetal growth, most of the end points have been examined in only one or two studies. Starting with fertility, one study of semen quality and reproductive hormones in men (Joensen et al. 2009) reported decrements in sperm count and number of morphologi- cally normal sperm with higher exposure to the combined level of PFOA and PFOS, but weaker associations with PFOA alone. An integrated measure of couple fecundity, time to pregnancy, was examined by Fei et al. (2009). This same population was examined for several other reproductive end points and thus warrants a more extensive description. Starting with > 100,000 participants in the Danish National Birth Cohort, which recruited women from 1996 to 2002 and followed women through the course of pregnancy and continued with childhood assessment, Fei et al. (2009) randomly selected 1,400 women with singleton live births for measurement of PFOA and PFOS in blood collected during the first trimester of pregnancy (mean PFOA = 5.6 ng/mL). The evaluation of time to pregnancy showed increased risk of irregular menstrual cycles in the upper three quartiles of PFOA rela- tive to the lowest quartile (15.0% vs. 9.0%) and an increase in mean PFOA with increas- ing time required to conceive (5.4 ng/mL for < 6 months to conception, 6.0 ng/mL for 6–12 months to conception, and 6.3 ng/mL for > 12 months to conception). The odds of infertility (≥ 12 months without conception) were elevated in the upper three quartiles of PFOA exposure (ORs ranging from 1.6 to 2.5) relative to the lowest quartile. Very sim- ilar patterns were reported for PFOS. The absence of dose–response gradients for fertility across levels suggests the possibility of some Environmental Health Perspectives • volume 118 | number 8 | August 2010 Epidemiology of PFOA peculiarity in the lowest exposure group but does not preclude a causal relationship with a maximum effect at a very low exposure level. The course of pregnancy, including risk of miscarriage and preeclampsia, has been addressed in a study of a subset of women exposed to markedly elevated levels of PFOA in the Mid-Ohio Valley (Stein et al. 2009). No association was found between PFOA and miscarriage, whereas a weak association was found for preeclampsia (for above-me- dian exposure to PFOA: OR = 1.3; 95% CI, 0.9–1.9). Nolan et al. (2009a) used birth cer- tificate information to address pregnancy com- plications in women residing in a high-PFOA area of the Mid-Ohio Valley and reported extremely imprecise associations with anemia and dysfunctional labor and lower overall risk of labor and delivery complications. The most extensive set of studies has exam- ined fetal growth, birth weight, duration of gestation, and related indices of in utero devel- opment. Seven studies reported continuous measures of birth weight in relation to contin- uous measures of PFOA exposure (Apelberg et al. 2007; Fei et al. 2007; Hamm et al. 2009; Inoue et al. 2004; Monroy et al. 2008; So et al. 2006; Washino et al. 2009). Two studies of background exposure to PFOA reported clear evidence of decreased birth weight in relation to increased PFOA (Apelberg et al. 2007; Fei et al. 2007), with smaller decre- ments reported in two other studies of back- ground exposure levels (Hamm et al. 2009; Washino et al. 2009). Magnitude of associa- tion ranged from a decrement of 37 to 104 g per log unit increase in PFOA exposure, with varying degrees of statistical precision, with one study (Fei et al. 2007) reporting a smaller reduction of 10.6 g per ng/mL PFOA. Three smaller studies reported no association between PFOA and birth weight (Inoue et al. 2004; Monroy et al. 2008; So et al. 2006). Risk of low birth weight (< 2,500 g) was ele- vated in the upper three quartiles relative to the first quartile in the analysis of the Danish National Birth Cohort (Fei et al. 2007), but a measure of small-for-gestational-age (which accounts for duration of gestation) was not related to PFOA in the Danish National Birth Cohort (Fei et al. 2007) nor in a study from Alberta, Canada (Hamm et al. 2009). An eco- logic study of residence and birth weight in the Mid-Ohio Valley found no association between PFOA exposure and birth weight (Nolan et al. 2009b). Stein et al. (2009) did not find an association between PFOA and self-reported low birth weight. Cumulatively, the studies provide incon- sistent suggestions of a possible decrement in birth weight associated with PFOA exposure, with studies varying in whether the association with PFOS is similar (Apelberg et al. 2007), stronger (Stein et al. 2009; Washino et al. 1105