Determinants of per- and polyfluoroalkyl substances (PFAS) exposure among Wisconsin residents.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) include thousands of manufactured compounds with growing public health concerns due to their potential for widespread human exposure and adverse health outcomes. While PFAS contamination remains a significant concern, especially from ingestion of contaminated food and water, determinants of the variability in PFAS exposure among regional and statewide populations in the United States remains unclear. OBJECTIVES: The objective of this study was to leverage The Survey of the Health of Wisconsin (SHOW), the only statewide representative cohort in the US, to assess and characterize the variability of PFAS exposure in a general population. METHODS: This study sample included a sub-sample of 605 adult participants from the 2014-2016 tri-annual statewide representative sample. Geometric means for PFOS, PFOA, PFNA, PFHxS, PFPeS, PFHpA, and a summed measure of 38 analyzed serum PFAS were presented by demographic, diet, behavioral, and residential characteristics. Multivariate linear regression was used to determine significant predictors of serum PFAS after adjustment. RESULTS: Overall, higher serum concentrations of long-chain PFAS were observed compared with short-chain PFAS. Older adults, males, and non-Hispanic White individuals had higher serum PFAS compared to younger adults, females, and non-White individuals. Eating caught fish in the past year was associated with elevated levels of several PFAS. DISCUSSION: This is among the first studies to characterize serum PFAS among a representative statewide sample in Wisconsin. Both short- and long-chain serum PFAS were detectable for six prominent PFAS. Age and consumption of great lakes fish were the most significant predictors of serum PFAS. State-level PFAS biomonitoring is important for identifying high risk populations and informing state public health standards and interventions, especially among those not living near known contamination sites.

Characterization of the chemical reactivity and nephrotoxicity of N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine sulfoxide, a potential reactive metabolite of trichloroethylene.

N-Acetyl-S-(1,2-dichlorovinyl)-L-cysteine (NA-DCVC) has been detected in the urine of humans exposed to trichloroethylene and its related sulfoxide, N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine sulfoxide (NA-DCVCS), has been detected as hemoglobin adducts in blood of rats dosed with S-(1,2-dichlorovinyl)-L-cysteine (DCVC) or S-(1,2-dichlorovinyl)-L-cysteine sulfoxide (DCVCS). Because the in vivo nephrotoxicity of NA-DCVCS was unknown, in this study, male Sprague-Dawley rats were dosed (i.p.) with 230 µmol/kg b.w. NA-DCVCS or its potential precursors, DCVCS or NA-DCVC. At 24 h post treatment, rats given NA-DCVC or NA-DCVCS exhibited kidney lesions and effects on renal function distinct from those caused by DCVCS. NA-DCVC and NA-DCVCS primarily affected the cortico-medullary proximal tubules (S(2)-S(3) segments) while DCVCS primarily affected the outer cortical proximal tubules (S(1)-S(2) segments). When NA-DCVCS or DCVCS was incubated with GSH in phosphate buffer pH 7.4 at 37°C, the corresponding glutathione conjugates were detected, but NA-DCVC was not reactive with GSH. Because NA-DCVCS exhibited a longer half-life than DCVCS and addition of rat liver cytosol enhanced GSH conjugate formation, catalysis of GSH conjugate formation by the liver could explain the lower toxicity of NA-DCVCS in comparison with DCVCS. Collectively, these results provide clear evidence that NA-DCVCS formation could play a significant role in DCVC, NA-DCVC, and trichloroethylene nephrotoxicity. They also suggest a role for hepatic metabolism in the mechanism of NA-DCVC nephrotoxicity.

Biomonitoring of perfluoroalkyl and polyfluoroalkyl substances (PFAS) from the Survey of the Health of Wisconsin (SHOW) 2014-2016 and comparison with the National Health and Nutrition Examination Survey (NHANES).

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are a growing class of manufactured chemical compounds found in a variety of consumer products. PFAS are ubiquitous in the environment and were found in many humans sampled in the United States (U.S.). Yet, significant gaps in understanding statewide levels of exposure to PFAS remain. OBJECTIVE: The goals of this study are to establish a baseline of exposure at the state level by measuring PFAS serum levels among a representative sample of Wisconsin residents and compare to United States National Health and Nutrition Examination Survey (NHANES). METHODS: The study sample included 605 adults (18+ years of age) selected from the 2014-2016 sample of the Survey of the Health of Wisconsin (SHOW). Thirty-eight PFAS serum concentrations were measured using high-pressure liquid chromatography coupled with tandem mass spectrometric detection (HPLC-MS/MS) and geometric means were presented. Weighted geometric mean serum values of eight PFAS analytes from SHOW were compared to U.S. national levels from the NHANES 2015-2016 sample (PFOS, PFOA, PFNA, PFHxS, PFHpS, PFDA, PFUnDA), and the 2017-2018 sample for Me-PFOSA, PFHPS using the Wilcoxon rank-sum test. RESULTS: PFOS, PFHxS, PFHpS, PFDA, PFNA, and PFOA were detected in over 96% of SHOW participants. In general, SHOW participants had lower serum levels across all PFAS when compared to NHANES. Serum levels increased with age and were higher among males and whites. Similar trends were seen in NHANES, except non-whites had higher PFAS levels at higher percentiles in NHANES. IMPACT STATEMENT: The present study conducts biomonitoring of 38 PFAS among representative sample of residents in the state of Wisconsin. Results suggest that while the majority of Wisconsin residents tested have detectable levels of PFAS in their blood serum, they may have a lower body burden of some PFAS compared to a nationally representative sample. Older adults, males, and whites may have a higher body burden of PFAS relative to other groups, both in Wisconsin and the wider United States.

Biomonitoring of perfluoroalkyl and polyfluoroalkyl substances (PFAS) from the Survey of the Health of Wisconsin (SHOW) 2014-2016 and comparison with the National Health and Nutrition Examination Survey (NHANES).

Background: Per- and polyfluoroalkyl substances (PFAS) are a growing class of manufactured chemical compounds found in a variety of consumer products. PFAS have become ubiquitous in the environment and were found in many humans sampled in the United States (U.S.). Yet, significant gaps in understanding statewide level exposures to PFAS remain. Objective: The goals of this study are to establish a baseline of exposure at the state level by measuring PFAS serum levels among a representative sample of Wisconsin residents and compare to United States National Health and Nutrition Examination Survey (NHANES). Methods: The study sample included 605 adults (18+ years of age) selected from the 2014-2016 sample of the Survey of the Health of Wisconsin (SHOW). Thirty-eight PFAS serum concentrations were measured using high-pressure liquid chromatography coupled with tandem mass spectrometric detection (HPLC-MS/MS) and geometric means presented. Weighted geometric mean serum values of eight PFAS analytes from SHOW were compared to U.S. national levels from the NHANES 2015-2016 sample (PFOS, PFOA, PFNA, PFHxS, PFHpS, PFDA, PFUnDA), and the 2017-2018 sample for Me-PFOSA, PFHPS using the Wilcoxon rank-sum test. Results: Over 96% of SHOW participants had positive results for PFOS, PFHxS, PFHpS, PFDA, PFNA, and PFOA. In general, SHOW participants had lower serum levels across all PFAS when compared to NHANES. Serum levels increased with age and were higher among males and whites. These trends were seen in NHANES, except non-whites had higher PFAS levels at higher percentiles. Significance: Wisconsin residents may have a lower overall body burden of some PFAS compounds compared to those seen by a nationally representative sample. Additional testing and characterization may be needed in Wisconsin, particularly among non-whites and low socioeconomic status, for which the SHOW sample had less representation compared to NHANES. Impact Statement: The present study conducts biomonitoring of 38 PFAS in the state of Wisconsin and suggests that while most residents of Wisconsin have detectable levels of PFAS in their blood serum, they may have a lower body burden of some PFAS compared to a nationally representative sample. Older adults, males, and whites may have a higher body burden of PFAS relative to other groups both in Wisconsin and the wider United States.

N-biotinyl-S-(1,2-dichlorovinyl)-L-cysteine sulfoxide as a potential model for S-(1,2-dichlorovinyl)-L-cysteine sulfoxide: characterization of stability and reactivity with glutathione and kidney proteins in vitro.

S-(1,2-Dichlorovinyl)-L-cysteine sulfoxide (DCVCS) is a reactive and potent nephrotoxic metabolite of the human trichloroethylene metabolite S-(1,2-dichlorovinyl)-L-cysteine (DCVC). Because DCVCS covalent binding to kidney proteins likely plays a role in its nephrotoxicity, in this study biotin-tagged DCVCS, N-biotinyl-DCVCS (NB-DCVCS), was synthesized, and its stability in buffer alone and in the presence of rat blood or plasma was characterized in vitro. In addition, reactivity toward GSH and covalent binding to selected model enzymes and isolated kidney proteins were characterized. The half-lives of NB-DCVCS (39.6 min) and the DCVCS (diastereomer 1, 14.4 min; diastereomer 2, 6 min) in the presence of GSH were comparable. Incubating the model enzymes glutathione reductase and malate dehydrogenase with 10 µM NB-DCVCS for 3 h at 37 °C followed by immunoblotting using antibiotin antibodies demonstrated that glutathione reductase and malate dehydrogenase were extensively modified by NB-DCVCS. When rat kidney cytosol (6 µg/µL) was incubated with NB-DCVCS (312.5 nM to 5 µM) for 3 h at 37 °C followed by immunoblotting, a concentration-dependent increase in signal with multiple proteins with different molecular weights was observed, suggesting that NB-DCVCS binds to multiple kidney proteins with different selectivity. Incubating rat kidney cytosol with DCVCS (10-100 µM) prior to the addition of NB-DCVCS (2.5 µM) reduced the immunoblotting signal, suggesting that NB-DCVCS and DCVCS compete for the same binding sites. A comparison of the stability of NB-DCVCS and DCVCS in rat blood and plasma was determined in vitro, and NB-DCVCS exhibited higher stability than DCVCS in both media. Collectively, these results suggest that NB-DCVCS shows sufficient stability, reactivity, and selectivity to warrant further investigations into its possible use as a tool for future characterization of the role of covalent modification of renal proteins by DCVCS in nephrotoxicity.

Mutagenicity of the cysteine S-conjugate sulfoxides of trichloroethylene and tetrachloroethylene in the Ames test.

The nephrotoxicity and nephrocarcinogenicity of trichloroethylene (TCE) and tetrachloroethylene (PCE) are believed to be mediated primarily through the cysteine S-conjugate ß-lyase-dependent bioactivation of the corresponding cysteine S-conjugate metabolites S-(1,2-dichlorovinyl)-l-cysteine (DCVC) and S-(1,2,2-trichlorovinyl)-l-cysteine (TCVC), respectively. DCVC and TCVC have previously been demonstrated to be mutagenic by the Ames Salmonella mutagenicity assay, and reduction in mutagenicity was observed upon treatment with the ß-lyase inhibitor aminooxyacetic acid (AOAA). Because DCVC and TCVC can also be bioactivated through sulfoxidation to yield the potent nephrotoxicants S-(1,2-dichlorovinyl)-l-cysteine sulfoxide (DCVCS) and S-(1,2,2-trichlorovinyl)-l-cysteine sulfoxide (TCVCS), respectively, the mutagenic potential of these two sulfoxides was investigated using the Ames Salmonella typhimurium TA100 mutagenicity assay. The results show both DCVCS and TCVCS were mutagenic, and TCVCS exhibited 3-fold higher mutagenicity than DCVCS. However, DCVCS and TCVCS mutagenic activity was approximately 700-fold and 30-fold lower than DCVC and TCVC, respectively. DCVC and DCVCS appeared to induce toxicity in TA100, as evidenced by increased microcolony formation and decreased mutant frequency above threshold concentrations. TCVC and TCVCS were not toxic in TA100. The toxic effects of DCVC limited the sensitivity of TA100 to DCVC mutagenic effects and rendered it difficult to investigate the effects of AOAA on DCVC mutagenic activity. Collectively, these results suggest that DCVCS and TCVCS exerted a definite but weak mutagenicity in the TA100 strain. Therefore, despite their potent nephrotoxicity, DCVCS and TCVCS are not likely to play a major role in DCVC or TCVC mutagenicity in this strain.

Role of reactive metabolites in the circulation in extrahepatic toxicity.

INTRODUCTION: Reactive metabolite-mediated toxicity is frequently limited to the organ where the electrophilic metabolites are generated. Some reactive metabolites, however, might have the ability to translocate from their site of formation. This suggests that for these reactive metabolites, investigations into the role of organs other than the one directly affected could be relevant to understanding the mechanism of toxicity. AREAS COVERED: The authors discuss the physiological and biochemical factors that can enable reactive metabolites to cause toxicity in an organ distal from the site of generation. Furthermore, the authors present a case study which describes studies that demonstrate that S-(1,2-dichlorovinyl)-L-cysteine sulfoxide (DCVCS) and N-acetyl-S-(1,2-dichlorovinyl-L-cysteine sulfoxide (N-AcDCVCS), reactive metabolites of the known trichloroethylene metabolites S-(1,2-dichlorovinyl)-L-cysteine (DCVC), and N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine (N-AcDCVC), are generated in the liver and translocate through the circulation to the kidney to cause nephrotoxicity. EXPERT OPINION: The ability of reactive metabolites to translocate could be important to consider when investigating mechanisms of toxicity. A mechanistic approach, similar to the one described for DCVCS and N-AcDCVCS, could be useful in determining the role of circulating reactive metabolites in extrahepatic toxicity of drugs and other chemicals. If this is the case, intervention strategies that would not otherwise be feasible might be effective for reducing extrahepatic toxicity.