Clinical Implications of New Drinking Water Regulation for "Forever Chemicals".

This Viewpoint describes new maximum contaminant levels set by the Environmental Protection Agency for specific perfluoroalkyl and polyfluoroalkyl substances (PFASs) and discusses the role clinicians can play in addressing their patients' PFAS health concerns.

Perfluorocarbons cause thrombocytopenia, changes in RBC morphology and death in a baboon model of systemic inflammation.

A perfluorocarbon (PFC) investigated for treatment of traumatic brain injury (TBI) delivers oxygen to support brain function, but causes transient thrombocytopenia. TBI can cause acute inflammation with resulting thrombocytopenia; an interaction between the PFC effects and TBI inflammation might exacerbate thrombocytopenia. Therefore, PFC effects on platelet (PLT) function and hemostasis in a lipopolysaccharide (LPS) model of inflammation in the baboon were studied. Animals were randomized to receive saline ±LPS, and ± one of two doses of PFC. PLT count, transmission electron microscopy, and microparticle populations were quantified at baseline (BL) and at 2, 24, 48, 72, and 96 hours; hemostatic parameters for aggregometry and for blood clotting were measured at baseline (BL) and days 3 and 4. Injection of vehicle and LPS caused thrombocytopenia within hours; PFCs caused delayed thrombocytopenia beginning 48 hours post-infusion. LPS+PFC produced a more prolonged PLT decline and decreased clot strength. LPS+PFC increased ADP-stimulated aggregation, but PFC alone did not. Microparticle abundance was greatest in the LPS+PFC groups. LPS+PFC caused diffuse microvascular hemorrhage and death in 2 of 5 baboons in the low dose LPS-PFC group and 2 of 2 in the high dose LPS-PFC group. Necropsy and histology suggested death was caused by shock associated with hemorrhage in multiple organs. Abnormal morphology of platelets and red blood cells were notable for PFC inclusions. In summary, PFC infusion caused clinically significant thrombocytopenia and exacerbated LPS-induced platelet activation. The interaction between these effects resulted in decreased hemostatic capacity, diffuse bleeding, shock and death.

Perfluoroalkyl substance mixtures and cardio-metabolic outcomes in highly exposed male workers in the Veneto Region: A mixture-based approach.

BACKGROUND: Perfluoroalkyl substances (PFAS) have been consistently associated with cardio-metabolic traits. Occupational exposures to multiple PFAS with health outcomes have been poorly investigated. The aim of the present study was to examine these associations among former workers involved in PFAS production. METHODS: We considered 232 male ex-employees who had worked in a factory (Trissino, Veneto Region, Italy), which produced PFAS and other chemicals during 1968-2018. Out of twelve serum PFAS, only four (PFOA, PFOS, PFHxS, and PFNA) were quantifiable in at least 50% of samples. Non-fasting serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured. The associations between serum PFAS mixture and considered outcomes were assessed through linear regression mixed models and Weighted Quantile Sum (WQS) regression, adjusting for potential confounders. RESULTS: PFOA was detected at the highest level, with a median concentration (in ng/mL) of 80.8 (min-max: 0.35-13,033), followed by PFOS (median: 8.55, min-max: 0.35-343), PFHxS (median: 6.8, min-max: 0.35-597) and PFNA (median: 0.8, min-max: 0.35-5). We observed that each A quartile increase in the WQS index was positively associated with the levels of TC (ß: 8.41, 95% IC: 0.78-16.0), LDL-C (ß: 8.02, 95% IC: 1-15.0) and SBP (ß: 3.21, 95% IC: 0.82-5.60). No association of serum PFAS concentration on HDL cholesterol and DBP emerged. WQS analyses revealed a major contribution of PFNA and PFHxS for the cholesterol levels, although PFOA reported the highest concentration. PFOA and PFOS emerged as chemicals of concern regarding the association with SBP. CONCLUSIONS: The results showed a clear association between serum PFAS levels and markers of cardiovascular risk and support the importance of clinical surveillance of cardiovascular risk factors in population with a high exposure to PFAS, especially in the occupational setting.

Perfluoroalkyl substance pollutants activate the innate immune system through the AIM2 inflammasome.

Perfluoroalkyl substances (PFAS) are widely used in various manufacturing processes. Accumulation of these chemicals has adverse effects on human health, including inflammation in multiple organs, yet how PFAS are sensed by host cells, and how tissue inflammation eventually incurs, is still unclear. Here, we show that the double-stranded DNA receptor AIM2 is able to recognize perfluorooctane sulfonate (PFOS), a common form of PFAS, to trigger IL-1ß secretion and pyroptosis. Mechanistically, PFOS activates the AIM2 inflammasome in a process involving mitochondrial DNA release through the Ca2+-PKC-NF-κB/JNK-BAX/BAK axis. Accordingly, Aim2-/- mice have reduced PFOS-induced inflammation, as well as tissue damage in the lungs, livers, and kidneys in both their basic condition and in an asthmatic exacerbation model. Our results thus suggest a function of AIM2 in PFOS-mediated tissue inflammation, and identify AIM2 as a major pattern recognition receptor in response to the environmental organic pollutants.

Drinking water contamination from perfluoroalkyl substances (PFAS): an ecological mortality study in the Veneto Region, Italy.

Background: Perfluoroalkyl substances (PFAS), a heterogeneous group of highly stable man-made chemicals, have been widely used since 1960s and can be detected almost ubiquitously in all environmental matrices. In Italy, on January 2014, drinking water contamination in an area of the Veneto Region was detected mainly due to the drain of fluorinated chemicals by a manufacturing company operating since 1964. Methods: The present ecological mortality study was aimed at comparing mortality for some causes of death selected on the basis of previous reported associations, during the period 1980-2013, in municipalities with PFAS contaminated and uncontaminated drinking water on the basis of the levels indicated by the Italian National Health Institute (ISS). Sex-specific number, standardized mortality rates and rate ratios (RR) for PFAS contaminated and uncontaminated areas were computed for each cause of death through the ENEA epidemiological database. Results: In both sexes, statistically significant RRs were detected for all causes mortality, diabetes, cerebrovascular diseases, myocardial infarction and Alzheimer's disease. In females, RRs significantly higher than 1.0 were also observed for kidney and breast cancer, and Parkinson's disease. Increased risk, although not statistically significant, was observed for bladder cancer in both sexes, and for testicular cancer, pancreatic cancer and leukemia in males only. Conclusions: Higher mortality levels for some causes of death, possibly associated with PFAS exposure, were detected in contaminated municipalities in comparison with uncontaminated ones with similar socioeconomic status and smoking habits. These results warrant further individual level analytic studies to delineate casual associations.

Prenatal Exposure to Perfluoroalkyl Substances and Behavioral Development in Children.

BACKGROUND: In recent years, prevalence rates of behavioral disorders in children have increased. One factor possibly implied in the etiology of behavioral disorders is exposure to perfluoroalkyl substances (PFASs). The use of PFASs is highly integrated into everyday life, and exposure is ubiquitous. Exposure to PFASs during early life may be particularly harmful, as it represents a critical time window for brain development. However, research in the area is limited, especially among preschool children. The objective of the current study was to explore the relationship between prenatal exposure to several PFASs and behavioral development at the age of 18 months. METHODS: Data from the Dutch cohort LINC (Linking Maternal Nutrition to Child Health) were used. Perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) were measured in cord plasma. The total exposure of PFASs was also calculated (ΣPFASs). Behavioral development was assessed with the Child Behavior Checklist 1.5-5 (CBCL 1.5-5). The CBCL scales "Attention Deficit Hyperactivity Disorder" (ADHD) and "Externalizing problems" were used for further analysis. Separate regression models were composed for each combination, in which exposure levels were classified in tertiles. Both whole population and sex-stratified analyses were performed. A family history of ADHD, the educational level, smoking or using alcohol or illicit drugs during pregnancy were considered as confounders. In total, data from 76 mother-child pairs was included. RESULTS: No significant associations were found between prenatal PFAS exposure and ADHD scores in the whole population and in the sex-stratified analyses. With regard to externalizing behavior, a significant negative association was found between the highest levels of ΣPFAS exposure and externalizing problem behavior in the whole population, but only in the crude model. After stratifying for sex, boys in the second and third tertile of exposure to PFOA presented significantly lower scores on the Externalizing Problem Scale than boys with the lowest exposure levels in the adjusted model. Girls exposed to higher levels of ΣPFAS exposure (T2) showed significantly lower scores on the Externalizing Problem Scale, in both crude and adjusted models. No significant associations with PFOS were found. CONCLUSIONS: RESULTS from the current study show that prenatal exposure to PFOA was negatively related to externalizing behavior in boys. RESULTS were different for boys and girls, emphasizing that mechanisms at work might be sex-dependent. However, results should be interpreted with caution as the sample size was small.

A critical review of perfluorooctanoate and perfluorooctanesulfonate exposure and immunological health conditions in humans.

Whether perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS), two widely used and biopersistent synthetic chemicals, are immunotoxic in humans is unclear. Accordingly, this article systematically and critically reviews the epidemiologic evidence on the association between exposure to PFOA and PFOS and various immune-related health conditions in humans. Twenty-four epidemiologic studies have reported associations of PFOA and/or PFOS with immune-related health conditions, including ten studies of immune biomarker levels or gene expression patterns, ten studies of atopic or allergic disorders, five studies of infectious diseases, four studies of vaccine responses, and five studies of chronic inflammatory or autoimmune conditions (with several studies evaluating multiple endpoints). Asthma, the most commonly studied condition, was evaluated in seven studies. With few, often methodologically limited studies of any particular health condition, generally inconsistent results, and an inability to exclude confounding, bias, or chance as an explanation for observed associations, the available epidemiologic evidence is insufficient to reach a conclusion about a causal relationship between exposure to PFOA and PFOS and any immune-related health condition in humans. When interpreting such studies, an immunodeficiency should not be presumed to exist when there is no evidence of a clinical abnormality. Large, prospective studies with repeated exposure assessment in independent populations are needed to confirm some suggestive associations with certain endpoints.

Serum levels of perfluorooctanoic acid and perfluorooctane sulfonate and pregnancy outcome.

The authors examined the association of serum perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) with self-reported pregnancy outcome in Mid-Ohio Valley residents (2000-2006) highly exposed to PFOA. Data on 1,845 pregnancies within the 5 years preceding exposure measurement were analyzed for PFOA, and data on 5,262 pregnancies were analyzed for PFOS. Generalized estimating equations were used to calculate adjusted odds ratios and 95% confidence intervals. Neither PFOA nor PFOS showed any association with miscarriage or preterm birth. Preeclampsia was weakly associated with PFOA (adjusted odds ratio = 1.3, 95% confidence interval: 0.9, 1.9) and PFOS (adjusted odds ratio = 1.3, 95% confidence interval: 1.1, 1.7) exposures above the median. PFOA was not associated with an increase in low birth weight, but PFOS showed an increased risk above the median (adjusted odds ratio = 1.5, 95% confidence interval: 1.1, 1.9) and a dose-response gradient. Birth defects were weakly associated with PFOA exposures above the 90th percentile (adjusted odds ratio = 1.7, 95% confidence interval: 0.8, 3.6). This study identified modest associations of PFOA with preeclampsia and birth defects and of PFOS with preeclampsia and low birth weight, but associations were small, limited in precision, and based solely on self-reported health outcomes.

Self-reported health effects among community residents exposed to perfluorooctanoate.

Serious health effects due to perfluorooctanoate (PFOA) exposure are suspected. The aim of this study was to evaluate the health status of nearby residents, with prolonged exposure to PFOA in their drinking water. A population of 566 white residents who were plaintiffs or potential plaintiffs in a lawsuit was evaluated by questionnaire for health history and symptoms. Standardized Prevalence Ratios were estimated using National Health and Examination Survey (NHANES) data files for comparison rates. The exposed subjects reported statistically significant greater prevalence of angina, myocardial infarction, and stroke (SPR=8.07, 95% C.I.=6.54-9.95; SPR=1.91, 95% C.I.=1.40-2.62, and SPR=2.17, 95% C.I.=1.47-3.21, respectively), chronic bronchitis, shortness of breath on stairs, asthma (SPR=3.60, 95% C.I.=2.92-4.44; SPR=2.05, 95% C.I.=1.70-2.46; SPR=1.82, 95% C.I.=1.47-2.25, respectively), and other serious health problems. The increased prevalence of adverse health effects may be due to PFOA. Further study is needed.

Cross-sectional study of lipids and liver enzymes related to a serum biomarker of exposure (ammonium perfluorooctanoate or APFO) as part of a general health survey in a cohort of occupationally exposed workers.

OBJECTIVE: To examine the relationship between serum perfluorooctanoate (PFOA), a biomarker of ammonium perfluorooctanoate (APFO) exposure, and lipids and liver enzymes in a cross-sectional study among workers with potential occupational exposure to APFO. METHODS: We conducted a cross-sectional study of 1,025 active workers with potential exposure to APFO using linear regression to examine the relationship between PFOA and selected outcomes from a standard metabolic health screening survey, emphasizing lipids and liver enzymes. RESULTS: Most outcome parameters were within normal limits. After adjusting for potential confounders, we observed a modest but statistically significant, positive relationship between serum PFOA and total cholesterol, low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), and gamma glutamyl aminotransferase (GGT). No associations were seen for high-density lipoprotein (HDL) or bilirubin; associations with AST (aspartate aminotransferase) and ALT (alanine transpeptidase) did not reach statistical significance. CONCLUSIONS: Our findings indicate a modest positive association of PFOA on some lipid parameters and a need for follow-up studies.

Self-reported medical conditions in perfluorooctanesulfonyl fluoride manufacturing workers.

OBJECTIVE: To evaluate whether some cancers, other conditions, and pregnancy outcomes were related to occupational perfluorooctane sulfonate (PFOS) exposure. METHODS: We surveyed current and former employees of a perfluorooctanesulfonyl fluoride production facility, using a self-administered questionnaire to ascertain several cancers and health conditions. Female cohort members also completed a brief pregnancy history. We requested medical records to validate reported melanoma, breast, prostate, and colon cancers. PFOS exposure was estimated based on a job exposure matrix up to the year of the diagnosis of the condition. RESULTS: Of the 1,895 eligible participants, 1,400 questionnaires were returned. No association was observed between working in a PFOS-exposed job and the risk of any of the surveyed conditions. CONCLUSION: We observed no association between working in a PFOS-exposed job and several cancers, common health conditions, and birth weight.

Community exposure to perfluorooctanoate: relationships between serum concentrations and exposure sources.

OBJECTIVE: The objective of this study was to determine serum (perfluorooctanoate [PFOA]) in residents near a fluoropolymer production facility: the contributions from air, water, and occupational exposures, personal and dietary habits, and relationships to age and gender. METHODS: The authors conducted questionnaire and serum PFOA measurements in a stratified random sample and volunteers residing in locations with the same residential water supply but with higher and lower potential air PFOA exposure. RESULTS: Serum (PFOA) greatly exceeded general population medians. Occupational exposure from production processes using PFOA and residential water had additive effects; no other occupations contributed. Serum (PFOA) depended on the source of residential drinking water, and not potential air exposure. For public water users, the best-fit model included age, tap water drinks per day, servings of home-grown fruit and vegetables, and carbon filter use. CONCLUSIONS: Residential water source was the primary determinant of serum (PFOA).

Community exposure to perfluorooctanoate: relationships between serum levels and certain health parameters.

OBJECTIVE: The objective of this study was to determine whether certain biomarkers of toxicity and/or a past diagnosis of liver or thyroid disease were associated with serum perfluorooctanoate concentrations (PFOA) in a community with longstanding environmental exposure to PFOA. METHODS: Serum (PFOA), hematologic and biochemical biomarkers, and a questionnaire were administered to 371 residents selected by stratified random sampling and a lottery among volunteers. Median PFOA was 354 ng/mL (interquartile range, 181-571 ng/mL). RESULTS: No significant positive relationships between serum (PFOA) and liver or renal function tests, cholesterol, thyroid-stimulating hormone, or with red cell indices, white cell, or platelet counts. Mean serum (PFOA) was not increased in those with a history of liver or thyroid disease. CONCLUSIONS: No toxicity from PFOA was demonstrated using the measured end points; other end points need to be addressed.

[Identification of the related gene of mouse tolerant to exposure to perfluoroisobutylene by DDRT-PCR].

OBJECTIVE: The mice surviving acute exposure to low dose of perfluoroisobutylene (PFIB) could tolerant to lethal dose of PFIB. Discovering the gene related with the tolerance would be significant to find preventive agents for PFIB. METHODS: By static exposure to PFIB for 3 times, the survival animals could tolerate to lethal dose of PFIB. Three anchoring primers and 4 arbitrary primers were applied in differential display reverse transcription PCR (DDRT-PCR) of lung tissues and the products were analyzed by sequencing PAGE and silver staining. The differential DNA fragments were cloned and sequenced. RESULTS: There were obvious differences of gene expression between control and tolerant animals. Three expressed sequence tags (EST) have been cloned and sequenced,which were homologous to some mouse gene in Genbank. CONCLUSION: Specific gene up-regulation might be the cause of tolerance to PFIB, and they are very important to clarity the tolerant mechanisms to PFIB.

[Five fatalities due to inhalation of "asphyxiant gases": pathophysiological analysis in autopsy cases].

Five autopsy cases were examined to investigate fatal factors involved in inhalation of "asphyxiant gases": carbon monoxide (CO, n=3), fluorocarbons (n=1) and butane (n=1). In all cases, there was severe pulmonary edema and congestion in all viscera, suggesting advanced circulatory failure. The airway was filled with bloody froth in cases of fluorocarbons and butane inhalation. In CO intoxication, a marked increase in serum cardiac troponins suggested severe myocardial damage. There were also biochemical findings of respiratory distress (an evident increase in intra-alveolar pulmonary surfactant protein A), alveolar injury (an increase in serum surfactant protein A and D), rhabdomyolysis (myoglobinuria) and prolonged hypoxia (myogenic hyperuricemia) in cases of inhaling incomplete combustion gases. In a case of fluorocarbons gas inhalation, biochemical findings suggested respiratory distress, myocardial ischemia (an increase in serum CK-MB) and advanced hypoxia. Similar findings were observed in a case of butane inhalation, although cardiac troponin levels were low in the peripheral blood. These observations suggested that myocardial damage was prominent in CO intoxication, accompanied by respiratory distress in cases of inhaling incomplete combustion gases, whereas respiratory distress and hypoxia were major findings in cases of fluorocarbons and butane gas inhalation.

Polymer fume fever-like syndrome due to hairspray inhalation.

Inhalation of fluoropolymer pyrolysis products causes a self-limited illness termed polymer fume fever; symptoms include fever, chills, myalgias and non-productive cough, and are easily mistaken for an acute viral illness. We report a 29-y-old male who developed fever and pneumonitis shortly after the inhalation of pyrolyzed hairspray. Chest x-rays showed pictures consistent with pneumonitis. The patient was treated solely with supplemental oxgen, and his symptoms resolved over 24 h. Inhalation of pyrolyzed hairspray may cause a syndrome resembling polymer fume fever.

Effects of perfluorooctane sulfonate and perfluorooctanoic acid on the zooplanktonic community.

This comparative survey summarizes six individual studies on the ecological effects of two common perfluorinated surfactants, PFOS and PFOA, on zooplankton. We compare the test designs and quantify the relative sensitivity and statistical power (1-beta > or = 0.8). The survey compares 30-L indoor microcosm to 12,000-L outdoor microcosm experiments, with 225-mL single species laboratory tests as reference. By this we elucidate the extrapolation of ecological effects in space and complexity. Generally, zooplankton had lower tolerance toward PFOS than toward PFOA. With increasing concentrations the zooplankton community became simplified toward more robust rotifer species, which, as an indirect effect, increased their abundance due to a shift in competition and predation. The statistical power of the designs exhibits inverse proportionality between complexity and realism, indoor microcosm>outdoor microcosm. Surprisingly, the 30-L study had a lower LOEC value for Daphnia magna than the laboratory chronic test, indicating that D. magna and D. pulicaria were not the most sensitive species and that laboratory tests are not always conservative relative to microcosm experiments. Food scarcity due to phytotoxicity was not the reason for the difference.