Longitudinal assessment of lipid and hepatic clinical parameters in workers involved with the demolition of perfluoroalkyl manufacturing facilities.

OBJECTIVE: To examine in a longitudinal occupational assessment whether changes in serum concentrations of perfluorooctanoic acid (PFOA) and perfluorooctanesulfonate (PFOS) are associated with changes in non-high-density lipoprotein (HDL) cholesterol. METHODS: Baseline and end-of-project PFOA, PFOS, lipid, and hepatic clinical chemistries were measured in 204 workers involved with the demolition of former perfluoroalkyl manufacturing facilities. Analyses were restricted to the 179 workers who did not take lipid-lowering medications. Two thirds had baseline PFOA and PFOS levels similar to the general population. RESULTS: The change in non-HDL cholesterol was not associated with the changes in PFOA or PFOS. An increase in HDL was associated with an increase in PFOA, although the magnitude was small. This increase in HDL resulted in a decrease in the total cholesterol/HDL ratio. CONCLUSION: Adverse associations were not observed between changes in PFOA, PFOS, non-HDL cholesterol, HDL, and hepatic clinical chemistries.

Temporal trends of perfluoroalkyl concentrations in American Red Cross adult blood donors, 2000-2010.

Eleven perfluorinated alkyl acids (PFAAs) were analyzed in plasma from a total of 600 American Red Cross adult blood donors from six locations in 2010. The samples were extracted by protein precipitation and quantified by using liquid chromatography tandem mass spectrometry (HPLC/MS/MS). The anions of the three perfluorosulfonic acids measured were perfluorobutane sulfonate (PFBS), perfluorohexane sulfonate (PFHxS), and perfluorooctane sulfonate (PFOS). The anions of the eight perfluorocarboxylic acids were perfluoropentanoate (PFPeA), perfluorohexanoate (PFHxA), perfluoroheptanoate (PFHpA), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnA), and perfluorododecanoate (PFDoA). Findings were compared to results from different donor samples analyzed at the same locations collected in 2000-2001 (N = 645 serum samples) and 2006 (N = 600 plasma samples). Most measurements in 2010 were less than the lower limit of quantitation for PFBS, PFPeA, PFHxA, and PFDoA. For the remaining analytes, the geometric mean concentrations (ng/mL) in 2000-2001, 2006, and 2010 were, respectively, PFHxS: (2.25, 1.52, 1.34); PFOS (34.9, 14.5, 8.3); PFHpA (0.13, 0.09, 0.05); PFOA (4.70, 3.44, 2.44); PFNA (0.57, 0.97, 0.83); PFDA (0.16, 0.34, 0.27), and PFUnA (0.10, 0.18, 0.14). The percentage decline (parentheses) in geometric mean concentrations from 2000-2001 to 2010 were PFHxS (40%), PFOS (76%), and PFOA (48%). The decline in PFOS suggested a population halving time of 4.3 years. This estimate is comparable to the geometric mean serum elimination half-life of 4.8 years reported in individuals. This similarity supports the conclusion that the dominant PFOS-related exposures to humans in the United States were greatly mitigated during the phase-out period.

Analysis of a homologous series of perfluorocarboxylates from American Red Cross adult blood donors, 2000-2001 and 2006.

The purpose of this study was to determine the concentration trends of a nine-target-analyte homologous series of perfluorocarboxylates from six American Red Cross adult blood donor centers. A total of 645 serum and 600 plasma samples were obtained in 2000-2001 and 2006, respectively, with samples stratified for each 10-year (20-69) age- and sex-group per each location. Samples were extracted by protein precipitation and quantified by using tandem mass spectrometry. The nine perfluorocarboxylates were perfluorobutanoate (PFBA, C(3)F(7)CO(2)(-)), perfluoropentanoate (PFPeA, C(4)F(9)CO(2)(-)), perfluorohexanoate (PFHxA, C(5)F(11)CO(2)(-)), perfluoroheptanoate (PFHpA, C(6)F(13)CO(2)(-)), perfluorooctanoate (PFOA, C(7)F(15)CO(2)(-)), perfluorononanoate (PFNA, C(8)F(17)CO(2)(-)), perfluorodecanoate (PFDA, C(9)F(19)CO(2)(-)), perfluoroundecanoate (PFUnA,C(10)F(21)CO(2)(-)), and perfluorododecanoate (PFDoA, C(11)F(23)CO(2)(-)). The majority of measurements were less than the lower limit of quantitation for PFPeA, PFHxA, and PFDoA. For the remaining targeted analytes, the geometric mean serum and plasma concentrations (ng/mL) for 2000-2001 and 2006 were, respectively, as follows: PFBA 2.61 vs 0.33, PFHpA 0.13 vs 0.09, PFOA 4.70 vs 3.44, PFNA 0.57 vs 0.97, PFDA 0.16 vs 0.34, and PFUnA 0.10 vs 0.18. Estimates of the 95th percent tolerance limits (ng/mL) were as follows: PFBA 5.3 vs 1.4, PFHpA 0.4 vs 0.4, PFOA 12.3 vs 7.7, PFNA 1.4 vs 2.2, PFDA 0.4 vs 0.8, and PFUnA 0.3 vs 0.5. Important observations were the decline in PFBA and increase in PFNA, PFDA, and PFUnA concentrations between 2000-2001 and 2006. The longer chain length perfluorocarboxylates were also highly correlated with each other.

Perfluoroalkyl chemicals and human fetal development: an epidemiologic review with clinical and toxicological perspectives.

Epidemiologists began to focus on human developmental outcomes with perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA) as a consequence of dose-dependent developmental toxicological studies that reported effects of lowered birth weight, increased postnatal mortality, and decreased postnatal growth in surviving rats and mice. Contributing to the epidemiologic interest was the widespread presence of PFOS and PFOA in the general population, lengthy serum elimination half-lives in humans, and the placental transfer of PFOS and PFOA in humans that was established via measurement of paired maternal and umbilical cord blood samples. The purpose of this paper is to qualitatively review the published epidemiologic literature as it pertains to the potential association of exposure to PFOS and PFOA with human fetal development. The published research has focused on birth weight and other measurements that reflect human fetal development. A total of eight epidemiologic studies were reviewed that focused on six general (non-occupational) and two occupational populations. Of the six general population studies, five examined associations between birth weight and other anthropometric measurements in relation to maternal blood and/or umbilical cord concentrations of PFOS and PFOA. In the sixth study, three geographical areas in Washington County, Ohio, were categorized by their public drinking water sources that contained PFOA that had resulted in higher serum concentrations than observed in other general population studies. The occupational studies focused on a perfluorochemical manufacturing site (Decatur, AL) with exposure categorized from work history and biomonitoring data. There were inconsistent associations reported for several different birth outcomes, including birth weight, birth length, head circumference, and ponderal index, among the five general population studies that measured PFOS and PFOA in the study subjects. No association with birth weight or gestational age was reported in the community drinking water study. Only one general population study examined infant Apgar scores and developmental milestones at 6 and 18 months of age with no associations reported. No association with self-reported birth weight and occupational exposure to PFOS materials was observed among female perfluorochemical production workers. These epidemiologic data are discussed in relation to their methodological strengths and weaknesses, coherence with toxicological results, consistency of associations between studies, and plausible alternative explanations. Epidemiological, clinical, and toxicological insights are offered that may be useful for human health risk characterization. Studies scheduled for completion in the next few years are also cited. An appendix to this review describes the results of the only investigation that attempted to determine whether a causal association existed between maternal (4-14 weeks gestation) PFOS and PFOA concentrations in a general population and fecundity, as measured by time to pregnancy (TTP). Important issues are addressed regarding the methods and data analysis that may limit inferences from this particular study.

Decline in perfluorooctanesulfonate and other polyfluoroalkyl chemicals in American Red Cross adult blood donors, 2000-2006.

In 2000, 3M Company, the primary global manufacturer, announced a phase-out of perfluorooctanesulfonyl fluoride (POSF, C8F17SO2F)-based materials after perfluorooctanesulfonate (PFOS, C8F17SO3-) was reported in human populations and wildlife. The purpose of this study was to determine whether PFOS and other polyfluoroalkyl concentrations in plasma samples, collected in 2006 from six American Red Cross adult blood donor centers, have declined compared to nonpaired serum samples from the same locations in 2000-2001. For each location, 100 samples were obtained evenly distributed by age (20-69 years) and sex. Analytes measured, using tandem mass spectrometry, were PFOS, perfluorooctanoate (PFOA), perfluorohexanesulfonate (PFHxS), perfluorobutanesulfonate (PFBS), N-methyl perfluorooctanesulfonamidoacetate (Me-PFOSA-AcOH), and N-ethyl perfluorooctanesulfonamidoacetate (Et-PFOSA-AcOH). The geometric mean plasma concentrations were for PFOS 14.5 ng/mL (95% CI 13.9-15.2), PFOA 3.4 ng/ mL (95% CI 3.3-3.6), and PFHxS 1.5 ng/mL (95% CI 1.4-1.6). The majority of PFBS, Me-PFOSA-AcOH, and Et-PFOSA-AcOH concentrations were less than the lower limit of quantitation. Age- and sex-adjusted geometric means were lower in 2006 (approximately 60% for PFOS, 25% for PFOA, and 30% for PFHxS) than those in 2000-2001. The declines for PFOS and PFHxS are consistent with their serum elimination half-lives and the time since the phase-out of POSF-based materials. The shorter serum elimination half-life for PFOA and its smaller percentage decline than PFOS suggests PFOA concentrations measured in the general population are unlikely to be solely attributed to POSF-based materials. Direct and indirect exposure sources of PFOA could include historic and ongoing electrochemical cell fluorination (ECF) of PFOA, telomer production of PFOA, fluorotelomer-based precursors, and other fluoropoly-mer production.

Half-life of serum elimination of perfluorooctanesulfonate,perfluorohexanesulfonate, and perfluorooctanoate in retired fluorochemical production workers.

BACKGROUND: The presence of perfluorooctanesulfonate (PFOS), perfluorohexanesulfonate (PFHS), and perfluorooctanoate (PFOA) has been reported in humans and wildlife. Pharmacokinetic differences have been observed in laboratory animals. OBJECTIVE: The purpose of this observational study was to estimate the elimination half-life of PFOS, PFHS, and PFOA from human serum. METHODS: Twenty-six (24 male, 2 female) retired fluorochemical production workers, with no additional occupational exposure, had periodic blood samples collected over 5 years, with serum stored in plastic vials at -80 degrees C. At the end of the study, we used HPLC-mass spectrometry to analyze the samples, with quantification based on the ion ratios for PFOS and PFHS and the internal standard (18)O(2)-PFOS. For PFOA, quantitation was based on the internal standard (13)C(2)-PFOA. RESULTS: THE ARITHMETIC MEAN INITIAL SERUM CONCENTRATIONS WERE AS FOLLOWS: PFOS, 799 ng/mL (range, 145-3,490); PFHS, 290 ng/mL (range, 16-1,295); and PFOA, 691 ng/mL (range, 72-5,100). For each of the 26 subjects, the elimination appeared linear on a semi-log plot of concentration versus time; therefore, we used a first-order model for estimation. The arithmetic and geometric mean half-lives of serum elimination, respectively, were 5.4 years [95% confidence interval (CI), 3.9-6.9] and 4.8 years (95% CI, 4.0-5.8) for PFOS; 8.5 years (95% CI, 6.4-10.6) and 7.3 years (95% CI, 5.8-9.2) for PFHS; and 3.8 years (95% CI, 3.1-4.4) and 3.5 years (95% CI, 3.0-4.1) for PFOA. CONCLUSIONS: Based on these data, humans appear to have a long half-life of serum elimination of PFOS, PFHS, and PFOA. Differences in species-specific pharmacokinetics may be due, in part, to a saturable renal resorption process.

Assessment of lipid, hepatic, and thyroid parameters with serum perfluorooctanoate (PFOA) concentrations in fluorochemical production workers.

OBJECTIVES: Perfluorooctanoic acid (PFOA) results in peroxisome proliferator mediated effects in rats and mice resulting in hypolipidemia but not in monkeys. Counterintuitive modestly positive associations between PFOA and cholesterol levels in production workers have been inconsistently reported. The purpose of this assessment was to examine this association in male workers who manufactured or used PFOA at three facilities. METHODS: Subjects were male employee voluntary participants of a fluorochemical medical surveillance program who provided blood samples for serum measurement of PFOA (perfluorooctanoate) and various lipid, hepatic, and thyroid parameters. Statistical analyses included multiple and logistic regression and analysis of covariance. RESULTS: A total of 506 employees, who did not take cholesterol-lowering medications (93% of all male participants), were analyzed. Serum PFOA concentrations ranged from 0.007 to 92.03 microg/ml [arithmetic mean 2.21 microg/ml (95% confidence interval 1.66-2.77), median 1.10 microg/ml]. Adjusted for age, body mass index, and alcohol usage in regression analyses, PFOA was not statistically significantly (P>0.05) associated with total cholesterol or low-density lipoproteins (LDL). High-density lipoproteins (HDL) were significantly negatively (P<0.01) associated with PFOA for the three facilities combined but not by individual sites, indicating the overall result was likely a consequence of residual confounding due to different demographic profiles at these sites. Serum triglycerides were significantly positively associated with PFOA but not consistently by locations. There were no statistically significant associations observed between PFOA and hepatic enzymes for the three facilities combined although some modest positive associations were observed between PFOA and hepatic enzymes at one of the three facilities. Analyses of all locations showed no associations with TSH or T4 and PFOA. A negative association was observed for free T4 and positive association for T3; however, the findings were well within these assays' normal reference ranges. CONCLUSION: There was no evidence that employees' serum PFOA concentrations were associated with total cholesterol or LDL. A negative association with HDL was explained by demographic differences across the three locations. Several explanations are offered for the inconsistent triglyceride associations with PFOA including both methodological as well as biological possibilities.

Preliminary evidence of a decline in perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA) concentrations in American Red Cross blood donors.

The purpose of this pilot study was to determine whether perfluorooctanesulfonate (PFOS,C(8)F(17)SO(3)(-)) and perfluorooctanoate (PFOA,C(7)F(15)CO(2)(-)) concentrations in American Red Cross blood donors from Minneapolis-St. Paul, Minnesota have declined after the 2000-2002 phase-out of perfluorooctanesulfonyl-fluoride (POSF, C(8)F(17)SO(2)F)-based materials by the primary global manufacturer, 3M Company. Forty donor plasma samples, categorized by age and sex, were collected in 2005, and PFOS and PFOA concentrations were compared to 100 (non-paired) donor serum samples collected in 2000 from the same general population that were analyzed at the time using ion-pair extraction methods with tetrahydroperfluorooctanesulfonate as an internal standard. Eleven of the 100 samples originally collected were reanalyzed with present study methods that involved (13)C- labeled PFOA spiked into the donor samples, original samples, control human plasma, and the calibration curve prior to extraction, and was used as a surrogate to monitor extraction efficiency. Quantification was performed by high performance liquid chromatography tandem mass spectrometry methods. Among the 100 serum samples analyzed for PFOS, the geometric mean was 33.1 ng ml(-1) (95% CI 29.8-36.7) in 2000 compared to 15.1 ng ml(-1) (95% CI 13.3-17.1) in 2005 (p<0.0001) for the 40 donor plasma samples. The geometric mean concentration for PFOA was 4.5 ng ml(-1) (95% CI 4.1-5.0) in 2000 compared to 2.2 ng ml(-1) (95% CI 1.9-2.6) in 2005 (p<0.0001). The decrease was consistent across donors' age and sex. To confirm these preliminary findings, additional sub-sets of year 2000 samples will be analyzed, and a much larger biomonitoring study of other locations is planned.

Characterization of risk for general population exposure to perfluorooctanoate.

Perfluorooctanoate (PFOA), an environmentally and metabolically stable perfluorinated carboxylic acid, has been detected in the serum of children, adults and the elderly from the United States with the upper bound of the 95th percentile estimate in the range of 0.011-0.014 microg/mL (ppm). In this risk characterization, margins of exposure (MOE), which can provide a realistic perspective on potential for human risk, were determined by comparison of general population serum PFOA concentrations with serum concentrations from toxicological studies that are associated with the lower 95% confidence limit of a modeled 10 percent response or incidence level (LBMIC(10)) using USEPA BMDS software. The LBMIC(10) was estimated using surrogate data from other studies or pharmacokinetic relationships if serum PFOA data were not available. Modeled dose-responses (with resulting LBMIC(10) values) included post-natal effects in rats (29 microg/mL), liver-weight increase (23 microg/mL), and body-weight change (60 microg/mL) in rats and monkeys, and incidence of Leydig cell adenoma (125 microg/mL) in rats. MOE values based on the upper bound 95th percentile population serum PFOA concentration were large, ranging from 1600 (liver-weight increase) to 8900 (Leydig cell adenoma). These MOE values represent substantial protection of children, adults, and the elderly.

Serum concentrations of perfluorooctanesulfonate and other fluorochemicals in an elderly population from Seattle, Washington.

Perfluorooctanesulfonyl fluoride (POSF, C8F17SO2F) related-materials have been used as surfactants, paper and packaging treatments, and surface (e.g., carpet, textile, upholstery) protectants. A metabolite, perfluorooctanesulfonate (PFOS, C8F17SO3-), has been identified in the serum and liver of non-occupationally exposed humans and wildlife. Because of its persistence, an important question was whether elderly humans might have higher PFOS concentrations. From a prospective study designed to examine cognitive function in the Seattle (WA) metropolitan area, blood samples were collected from 238 dementia-free subjects (ages 65-96). High-pressure liquid chromatography-electrospray tandem mass spectrometry determined seven fluorochemicals: PFOS; N-ethyl perfluorooctanesulfonamidoacetate; N-methyl perfluorooctanesulfonamidoacetate; perfluorooctanesulfonamidoacetate; perfluorooctanesulfonamide; perfluorooctanoate; and perfluorohexanesulfonate. Serum PFOS concentrations ranged from less than the lower limit of quantitation (3.4 ppb) to 175.0 ppb (geometric mean 31.0 ppb; 95% CI 28.8-33.4). An estimate of the 95% tolerance limit was 84.1 ppb (upper 95% confidence limit 104.0 ppb). Serum PFOS concentrations were slightly lower among the most elderly. There were no significant differences by sex or years residence in Seattle. The distributions of the other fluorochemicals were approximately an order of magnitude lower. Similar to other reported findings of younger adults, the geometric mean serum PFOS concentration in non-occupational adult populations likely approximates 30-40 ppb with 95% of the population's serum PFOS concentrations below 100 ppb.

Perfluorooctanesulfonate and other fluorochemicals in the serum of American Red Cross adult blood donors.

Perfluorooctanesulfonyl fluoride-based products have included surfactants, paper and packaging treatments, and surface protectants (e.g., for carpet, upholstery, textile). Depending on the specific functional derivatization or degree of polymerization, such products may degrade or metabolize, to an undetermined degree, to perfluorooctanesulfonate (PFOS), a stable and persistent end product that has the potential to bioaccumulate. In this investigation, a total of 645 adult donor serum samples from six American Red Cross blood collection centers were analyzed for PFOS and six other fluorochemicals using HPLC-electrospray tandem mass spectrometry. PFOS concentrations ranged from the lower limit of quantitation of 4.1 ppb to 1656.0 ppb with a geometric mean of 34.9 ppb [95% confidence interval (CI), 33.3-36.5]. The geometric mean was higher among males (37.8 ppb; 95% CI, 35.5-40.3) than among females (31.3 ppb; 95% CI, 30.0-34.3). No substantial difference was observed with age. The estimate of the 95% tolerance limit of PFOS was 88.5 ppb (upper limit of 95% CI, 100.0 ppb). The measures of central tendency for the other fluorochemicals (N-ethyl perfluorooctanesulfonamidoacetate, N-methyl perfluorooctanesulfonamidoacetate, perfluorooctanesulfonamidoacetate, perfluorooctanesulfonamide, perfluorooctanoate, and perfluorohexanesulfonate) were approximately an order of magnitude lower than PFOS. Because serum PFOS concentrations correlate with cumulative human exposure, this information can be useful for risk characterization.