Jeffrey H. Mandel

Historical comparison of perfluorooctanesulfonate, perfluorooctanoate, and other fluorochemicals in human blood.

The purpose of this investigation was to determine whether there has been a change in the human blood concentration of perfluorooctanesulfonate (PFOS), perfluorooctanoate (PFOA), and five other fluorochemicals since 1974. Blood samples were collected in 1974 (serum) and 1989 (plasma) from volunteer participants of a large community health study. The study included a total of 356 samples (178 from each time period). These samples were analyzed by high-pressure liquid chromatography/tandem mass spectrometry methods. The median 1974 and 1989 fluorochemical concentrations, respectively, were as follows: PFOS, 29.5 ng/mL vs. 34.7 ng/mL; PFOA, 2.3 ng/mL vs. 5.6 ng/mL; perfluorohexanesulfonate (PFHS), 1.6 ng/mL vs. 2.4 ng/mL; and N-ethyl perfluorooctanesulfonamidoacetate (PFOSAA), less than the lower limit of quantitation (LLOQ; 1.6 ng/mL, vs. 3.4 ng/mL). For N-methyl perfluorooctanesulfonamidoacetate (M570), perfluorooctanesulfonamide, and perfluorooctanesulfonamidoacetate, median serum concentrations in both years were less than the LLOQ values (1.0, 1.0, and 2.5 ng/mL, respectively). Statistical analysis of 58 paired samples indicated that serum concentrations of PFOS, PFOSAA, PFOA, PFHS, and M570 were significantly (p < 0.001) higher in 1989 than in 1974. The data from 1989 were then compared with geometric mean fluorochemical concentrations of serum samples collected in 2001 from 108 American Red Cross adult blood donors from the same region. Except for M570, there were no statistically significant (p < 0.05) geometric mean fluorochemical concentration differences between the 1989 and 2001 samples. In conclusion, based on this study population, PFOS and other serum fluorochemical concentrations have increased between 1974 and 1989. Comparison with other regional data collected in 2001 did not suggest a continued increase in concentrations since 1989.

Serum perfluorooctane sulfonate and hepatic and lipid clinical chemistry tests in fluorochemical production employees

The 3M Company manufactures fluorochemicals, which have as a precursor perfluorooctane sulfonyl fluoride (C8F17SO2F). These compounds may be expected to transform metabolically, to an undetermined degree, to perfluorooctane sulfonate (PFOS, C8F17SO3-) as an end-stage metabolite. Subchronic studies in rats and primates indicate a potential for cumulative toxicity with PFOS with the primary effect related to metabolic wasting with hypolipidemia as a consistent finding. Biennial medical surveillance has been offered to the companys fluorochemical production workers located in Decatur, Alabama, and Antwerp, Belgium. In 1995, the mean serum PFOS level, as measured by high-performance liquid chromatography mass spectrometry, for 178 male employees was 2.19 parts per million (ppm; range, 0.00 to 12.83 ppm), and in 1997, for 149 male employees, it was 1.75 ppm (0.10 to 9.93 ppm). Our analyses suggest that among these production employees, there were no substantial changes in serum hepatic enzymes, cholesterol, or lipoproteins associated with PFOS levels less than 6 ppm. It was not possible to derive inferences from the few employees who had serum PFOS levels > or = 6 ppm. These results may be due to the lower levels of serum PFOS measured among these production employees, compared to those suspected to cause effects in laboratory animals.

Mortality of employees of a perfluorooctanesulphonyl fluoride manufacturing facility.

Aim: To evaluate the mortality experience of a cohort of employees of a perfluorooctanesulphonyl fluoride (POSF) based fluorochemical production facility. Methods: A retrospective cohort mortality study followed all workers with at least one year of cumulative employment at the facility. The jobs held by cohort members were assigned to one of three exposure subgroups; high exposed, low exposed, and non-exposed, based on biological monitoring data for perfluorooctane sulphonate (PFOS). Results: A total of 145 deaths were identified in the 2083 cohort members. Sixty five deaths occurred among workers ever employed in high exposed jobs. The overall mortality rates for the cohort and the exposure subcohorts were lower than expected in the general population. Two deaths from liver cancer were observed in the workers with at least one year of high or low exposure (standardised mortality ratio (SMR) 3.08, 95% CI 0.37 to 11.10). The risk of death from bladder cancer was increased for the entire cohort (three observed, SMR 4.81, 95% CI 0.99 to 14.06). All three bladder cancers occurred among workers who held a high exposure job (SMR 12.77, 95% CI 2.63 to 37.35). The bladder cancer cases primarily worked in non-production jobs, including maintenance and incinerator and wastewater treatment plant operations. Conclusion: Workers employed in high exposure jobs had an increased number of deaths from bladder cancer; however it is not clear whether these three cases can be attributed to fluorochemical exposure, an unknown bladder carcinogen encountered during the course of maintenance work, and/or non-occupational exposures. With only three observed cases the possibility of a chance finding cannot be ruled out.

An epidemiologic investigation of reproductive hormones in men with occupational exposure to perfluorooctanoic acid

Perfluorooctanoic acid (PFOA), a potent synthetic surfactant used in industrial applications, is a peroxisome proliferator that has resulted in dose-related increases in hepatic, pancreatic acinar, and Leydig cell adenomas in laboratory animals. In addition, PFOA increased serum estradiol levels through the induction of hepatic aromatase activity. In 1993 and 1995, we conducted two cross-sectional studies of 111 and 80 production workers, respectively, and specifically measured their serum PFOA in relation to several reproductive hormones to determine whether such an effect occurs in humans. PFOA was not significantly associated with estradiol or testosterone in either years study. A 10% increase in mean estradiol levels was observed among employees who had the highest levels of serum PFOA, although this association was confounded by body mass index. Neither was PFOA consistently associated with the other measured hormones. Our results provide reasonable assurance that, in this production setting, there were no significant hormonal changes associated with PFOA at the serum levels measured. Limitations of this investigation include its cross-sectional design, the few subjects exposed at the highest levels, and the lower levels of serum PFOA measured, compared with those levels reported to cause effects in laboratory animal studies.

Quantitative Evaluation of Perfluorooctanesulfonate (PFOS) and Other Fluorochemicals in the Serum of Children

ABSTRACTPerfluorooctanesulfonyl fluoride (POSF)–based materials include surfactants, paper and packaging treatments, and surface (e.g., carpet, upholstery, textile) protectants. A metabolite, perfluorooctanesulfonate (PFOS, C8F17SO3−), has been identified in the serum and liver tissue of nonoccupationally exposed adults and wildlife. Results from several repeat-dose toxicological studies consistently demonstrate that the liver is the primary target organ with an apparent threshold for the toxic effects of PFOS that can be expressed in terms of cumulative dose or body burden. The purpose of this study was to characterize the distribution of PFOS and six other fluorochemicals in 598 serum samples obtained from a multi-center study of children (ages 2–12) diagnosed with group A streptococcal infections. Using high-pressure liquid chromatography tandem mass spectrometry methods, serum PFOS concentrations ranged from 6.7 ppb (ng/mL) to 515 ppb (geometric mean 37.5 ppb, 95% CI 36.0–39.1) with an estimate of the...

Data on prior pesticide use collected from self- and proxy respondents

Proxy respondents have often been used in case-control studies of cancer and pesticides. To evaluate the effect of exposure misclassification, we compared data collected during 1981–1983 from participants interviewed for a case- control study of leukemia and non-Hodgkins lymphoma with data collected during 1990–1991 from proxy respondents for participants who died or became incompetent since the initial interview (328 self-proxy pairs). As questions increased in detail, agreement percentages decreased. Agreement percentages were highest for demographic and general farming information (averages = 88–90%) and lowest for specific pesticide use (averages = 68–74%). Generally, odds ratios calculated from proxy respondent data were less than those from self-respondent data; however, several exceptions occurred. The findings indicate that pesticide data provided by proxy respondents will not necessarily result in the same estimate of risk and/or lead to the same conclusions as data provided by self-respondents.

Occupational trichloroethylene exposure and kidney cancer: a meta-analysis.

Background: We conducted a meta-analysis of occupational studies of trichloroethylene-exposed workers to evaluate patterns of associations by study design, exposure assessment methods, and occupational groups. Methods: Estimates of summary relative risk (RR) were calculated using inverse-variance weighting methods. Cohort studies were classified as group I or group II, depending on quality of the study design and exposure assessment procedures. We conducted sensitivity analyses to examine sources of heterogeneity. Results: Across all studies meeting our inclusion criteria (n = 23), the summary RR was 1.42 (95% confidence interval = 1.17–1.77), with heterogeneity present (test for heterogeneity: P = 0.001). After removal of 3 outlier studies, the summary RR for the remaining studies was 1.24 (1.06–1.45 (test for heterogeneity: P = 0.616)). The summary RR for studies of workers who were identified as more likely exposed to trichloroethylene (group I studies) was 1.34 (1.06–1.68). With outlier studies removed, the group II summary RR estimates for the cohort studies was 0.88 (0.58–1.33) and for the case-control studies was 1.33 (1.02–1.73). The summary RR for studies that used biomarkers to classify exposure (n = 3) was 1.02 (0.59–1.77) and for studies of aerospace/aircraft workers (n = 7) was 1.14 (0.84–1.57). Conclusions: Positive associations were observed across various study groups. However, considerations of unmeasured potential confounding, lack of quantitative exposure assessment and lack of exposure-response patterns limit epidemiologic insight into the role of trichloroethylene exposure and its potential causal association with kidney cancer.

Occupational trichloroethylene exposure and non-Hodgkin's lymphoma: a meta-analysis and review.

Methods: Meta-analysis and review of 14 occupational cohort and four case-control studies of workers exposed to trichloroethylene (TCE) to investigate the relation between TCE exposure and the risk of non-Hodgkin’s lymphoma (NHL). Studies were selected and categorised based on a priori criteria, and results from random effects meta-analyses are presented. Results: The summary relative risk estimates (SRRE) for the group of cohort studies that had more detailed information on TCE exposure was 1.29 (95% CI 1.00 to 1.66) for the total cohort and 1.59 (95% CI 1.21 to 2.08) for the seven studies that identified a specific TCE exposed sub-cohort. SRREs for three studies with cumulative exposure information were 1.8 (95% CI 0.62 to 5.26) for the lowest exposure category and 1.41 (95% CI 0.61 to 3.23) for the highest category. Comparison of SRREs by levels of TCE exposure did not indicate exposure-response trends. The remaining cohort studies that identified TCE exposure but lacked detailed exposure information had an SRRE of 0.843 (95% CI 0.72 to 0.98). Case-control studies had an SRRE of 1.39 (95% CI 0.62 to 3.10). Statistically significant findings for the Group 1 studies were driven by the results from the subgroup of multiple industry cohort studies (conducted in Europe) (SRRE = 1.86; 95% CI 1.27 to 2.71). The SRRE for single industry cohort studies was not significantly elevated (SRRE = 1.25; 95% CI 0.87 to 1.79). Conclusions: Interpretation of overall findings is hampered by variability in results across the Group 1 studies, limited exposure assessments, lack of evidence of exposure response trends, lack of supportive information from toxicological and mechanistic data, and absence of consistent findings in epidemiologic studies of exposure and NHL. Although a modest positive association was found in the TCE sub-cohort analysis, a finding attributable to studies that included workers from multiple industries, there is insufficient evidence to suggest a causal link between TCE exposure and NHL.

Analysis of episodes of care in a perfluorooctanesulfonyl fluoride production facility.

The observed to expected episodes of care experience of 652 employees at a fluorochemical (perfluorooctanesulfonyl fluoride) production facility was compared with 659 film plant (nonfluorochemical) employees at the same site (Decatur, AL). Episodes of care were defined by a hierarchical analysis of health claims data from 1993 through 1998. The age- and sex-adjusted expected number of episodes of care was calculated from the companys U.S. manufacturing workforce. For a priori interests, the observed to expected episodes of care ratios were comparable for fluorochemical and film plant employees for liver tumors or diseases, bladder cancer, thyroid and lipid metabolism disorders, and reproductive, pregnancy, and perinatal disorders and higher for biliary tract disorders and cystitis recurrence. Non-a priori associations among the fluorochemical plant workers included benign colon polyps, malignant colorectal tumors, and malignant melanoma.

Urinary Nitrate, Thiocyanate, and Perchlorate and Serum Thyroid Endpoints Based on NHANES 2001 to 2002

Objective: To determine, on the basis of iodide uptake inhibition (IUI), whether associations between urinary concentrations of IUI agents (perchlorate, nitrate, and thiocyanate), as total perchlorate equivalent concentration (PEC), and serum thyroid parameters suggest functional thyroid abnormalities. Additional thyroid hormone measures were released to augment the National Health and Examination Survey (NHANES) 2001 to 2002 data set, which we used in this study. Methods: Enhanced thyroid hormone measures released to augment the National Health and Examination Survey (NHANES) 2001–2002 data set were used in this study. Multiple regression was used to assess the relationships among total thyroxine (TT4), free thyroxine, total triiodothyronine (TT3), free triiodothyronine, and thyroid- stimulating hormone (TSH) and PEC. Results: PEC was weakly and negatively associated with TT4, but not with TSH, TT3, or free hormone. This association with TT4 appears to be dominated by nitrate and thiocyanate. Conclusion: No evidence of functional thyroid abnormality (eg., low thyroid hormone coupled with high TSH) was seen with exposure to the combined IUI agents and enhanced estimates of thyroid function.