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Abstract

Per- and polyfluoroalkyl substances (PFAS) are a class of toxic, ubiquitous, anthropogenic chemicals known to bioaccumulate in humans. Substantial concern exists regarding the human health effects of PFAS, particularly metabolic syndrome (MetS), a precursor to cardiovascular disease, the leading cause of mortality worldwide. This narrative review provides an overview of the PFAS literature on 4 specific components of MetS: insulin resistance/glucose dysregulation, central adiposity, dyslipidemia, and blood pressure. We focus on prospective cohort studies as these provide the best body of evidence compared to other study designs. Available evidence suggests potential associations between some PFAS and type-2 diabetes in adults, dyslipidemia in children and adults, and blood pressure in adults. Additionally, some studies found that sex and physical activity may modify these relationships. Future studies should consider modification by sex and lifestyle factors (e.g., diet and physical activity), as well quantifying the impact of PFAS mixtures on MetS features and related clinical disease. Finally, clinicians can follow recently developed clinical guidance to screen for PFAS exposure in patients, measure PFAS levels, conduct additional clinical care based on PFAS levels, and advise on PFAS exposure reduction.

Keywords

per- and polyfluoroalkyl substances review metabolic syndrome lipid diabetes

“In reviewing studies examining PFAS and MetS features, we observed evidence for an association between perfluorooctanoic acid (PFOA) and T2D in adults.”

Introduction

Per- and polyfluoroalkyl substances (PFAS) are a large class of anthropogenic fluorinated chemicals, where some or all hydrogen atoms on an alkane backbone have been replaced by fluorine atoms (except those associated with functional groups).^1,2 Because the carbon-fluorine bond is the strongest single bond in organic chemistry, these compounds are environmentally persistent and have been dubbed “forever chemicals.”^2,3 PFAS are environmentally ubiquitous and can recirculate in water and the atmosphere.⁴ This has resulted in PFAS having been found on all 7 continents, including Antarctica.^4,5

PFAS have been detected in drinking water, food, household dust, and numerous consumer products and industrial applications where they are then capable of entering the human body, primarily through ingestion (Figure 1).^4,6-11 As a result, PFAS have been found in the blood serum of nearly every human tested on earth in addition to a multitude of other matrices including breastmilk, urine, hair, placental cord blood (serum, whole, and plasma), and amniotic fluid.^12-18 To date, only a handful of PFAS have been studied in humans. However, of those that have been studied, most have been found to be both toxic and bioaccumulative, with half-lives ranging from a few months to a few years.^19-22 Due to their ubiquitous nature, environmental persistence, toxicity, and bioaccumulative properties, substantial concern exists regarding the human health effects of these compounds.

Figure 1.

A summary of primary per- and polyfluoroalkyl substances exposure pathways.

PFAS have been consistently used since the 1950s for a variety of consumer and industrial applications due to their oil-, water-, and heat-resistant properties.^2,11 At the end of the 20^th century, longer-chain PFAS (i.e., PFAS with a longer carbon backbone), such as perfluorooctane sulfonic acid (PFOS) or perfluorooctanoic acid (PFOA) began to be identified as potentially deleterious to human health.² In response, new regulations and voluntary measures began to phase out longer-chain PFAS in nations such as the United States (US), Canada, and the European Union (EU) in the early 21^st century.^2,23-27 Following this, the usage of several shorter-chain PFAS, such as perfluorohexanoic acid (PFHxA), perfluorobutanoic acid (PFBA), and perfluorobutane sulfonate (PFBS) substantially increased as a replacement for longer-chain PFAS (examples of shorter- and longer-chain PFAS can be seen in Table 1). Shorter-chain PFAS have been suggested to be a safer alternative compared to longer-chain PFAS as they generally have shorter biological half-lives of a few months rather than a few years.^19,20 However, a recent study comparing the relative potency factors of 9 PFAS (including 4 short-chain PFAS) to PFOA found that 3 of the 4 short-chain PFAS evaluated (PFBA, PFHxA, and GenX) were more potent than PFOA in relation to relative liver weight increase (PFBS was less potent).²⁸ Additionally, several short-chain PFAS have been associated with multiple adverse health effects.^19,29-34 Thus, questions regarding their safety have arisen in the last several years.^19,29-34 As such, more research is needed evaluating associations between shorter-chain PFAS and human health to determine if these compounds are regrettable substitutions.

Table 1.

Examples of short and long chain per- and polyfluoroalkyl substances.

	PFAS	Acronym
Short chain PFAS	Perfluoroalkyl carboxylic acids (PFCA)
	Perfluorobutanoic acid	PFBA
	Perfluoropentanoic acid	PFPeA
	Perfluorohexanoic acid	PFHxA
	Perfluoroheptanoic acid	PFHpA
Long chain PFAS	Perfluorooctanoic acid	PFOA
	Perfluorononanoic acid	PFNA
	Perfluorodecanoic acid	PFDA
	Perfluorodecanoic acid	PFUnDA
	Perfluorododecanoic acid	PFDoDa
	Perfluorotridecanoic acid	PFTrDa
	Perfluorotetradecanoic acid	PFTeDa
Short chain PFAS	Perfluoroalkane sulfonic acids (PFSA)
	Perfluorobutane sulfonic acid	PFBS
	Perfluoropentane sulfonic acid	PFPeS
Long chain PFAS	Perfluorohexane sulfonic acid	PFHxS
	Perfluoroheptane sulfonic acid	PFHpS
	Perfluorooctane sulfonic acid	PFOS
	Perfluorononane sulfonic acid	PFNS
	Perfluorodecane sulfonic acid	PFDS
	Perfluoroundecane sulfonic acid	PFUnDS
	Perfluorododecane sulfonic acid	PFDoDS
	Perfluorotridecane sulfonic acid	PFTrDS
	Perfluorotetradecane sulfonic acid	PFTeDS
	Perfluoroalkane sulfonamides (PFASA)
	Perfluorooctane sulfonamide	PFOSA
	N-methyl perfluorooctane sulfonamide	Me-PFOSA-AcOH
	N-ethyl perfluorooctane sulfonamide	Et-PFOSA-AcOH

Multiple PFAS have been associated with a multitude of adverse health effects including increased preeclampsia risk,^30,31 increased risk of miscarriage,³⁰ preterm birth,^29,30 and lower birth weight,²⁹ decreased vaccine response in children,³² increased incidence of liver disease,³³ increased risk of kidney-,³⁴ testicular-,³⁴ and prostate-cancer,³⁴ as well as multiple adverse cardiometabolic^35-38 and cardiovascular³⁹ outcomes. Of the adverse health effects associated with PFAS, those associated with metabolic syndrome (MetS) are of particular concern. MetS is an umbrella term referring to a constellation of cardiovascular-related metabolic outcomes.^40,41 Examples include insulin resistance, glucose dysregulation, increased central adiposity, dyslipidemia, and increased blood pressure (BP). MetS are of particular concern as these abnormalities are often precursors to cardiovascular disease (CVD), the leading cause of mortality responsible for an estimated 32% of deaths globally.⁴² As such, identification and intervention on a modifiable risk factor for MetS could assist in decreasing the incidence of CVDs, thus having a substantial impact on the overall disease burden.⁴³ Furthermore, gestational and early life exposure is of particular interest as infants or children are potentially more vulnerable to PFAS given that they may have higher PFAS exposure and be more susceptible to environmental exposures than adults due to their rapid development.⁴⁴

The aim of this narrative review is to summarize the current evidence on PFAS and MetS. As the purpose of this review is to provide a general overview of PFAS and MetS rather than explore a single specific component of MetS in depth, a narrative review, rather than a systematic review, was conducted. To accomplish this aim, we will first discuss the biological mechanisms of PFAS action and specific populations that may be affected by PFAS differently or exposed to differing PFAS dosages. We will then discuss the reviews to date on PFAS and MetS. Next, we will provide an overview of the literature on PFAS and 4 specific components of MetS: (1) insulin resistance or glucose dysregulation, (2) central adiposity, (3) dyslipidemia, and (4) BP. We will focus this review on prospective cohort studies as these provide the best body of evidence compared to other study designs such as cross-sectional studies.⁴⁵ Finally, we will summarize recent recommendations set forth by the National Academies of Science Engineering and Medicine for assessing, reducing, and following up on PFAS exposure in clinical settings.

Biological Mechanisms of PFAS Action and Exposure in Specific Populations

The biological mechanisms of action of the PFAS-MetS association are likely multifaceted and only beginning to be understood, with most mechanistic studies focused on PFOA or PFOS specifically. Preliminary animal and human studies have demonstrated that PFAS may have the capacity to target peroxisome proliferator-activated receptor-α (PPAR-α) and, to a lesser extent, peroxisome proliferator-activated receptor-γ (PPAR-γ).^46-51 Through this mechanism, PFAS could adversely affect lipid and glucose metabolism or promote adipogenesis.^46-51 However, studies have found that PPAR-α may respond less to PFOA exposure in humans than in rodents; as such, interpretation of animal studies should be made with care.^51-53 To address this, Schlezinger et al. has conducted research on PFOA in humanized PPAR-α mice that were fed an American diet.^54,55 This research found increased PFOA may induce liver triacylglycerides, skew serum triacylglycerides toward more saturated fatty acids, and activate humanized PPARα and CAR in the liver at human relevant exposure levels.^54,55 However, these effects of PFOA were both independent and dependent on PPARα, suggesting that PFOA may act via multiple biological pathways.⁵⁴ Other studies on other nuclear receptors such as constitutive androstane receptor (CAR) and pregnane X receptor (PXR) have also been conducted, but results from these studies have been inconsistent.^46,54,56-59

PFAS body burden, measured by serum or plasma concentrations, has been found to vary by sex, with studies finding higher concentrations of PFAS such as PFOS, PFOA, perfluorononanoic acid (PFNA), and perfluorooctane sulfonic acid (PFHxS) in males compared to females.^60,61 Potential reasons for this include female reproductive-related characteristics such as menstruation, maternal-fetal transfer during pregnancy, and lactation, as these can be a source of PFAS-elimination.^60,62-64 This is further re-enforced by greater disparities in many of these PFAS concentrations in males and females among those of pre-menopausal age compared to those of a post-menopausal age, suggesting characteristics before menopause, such as lactation or menstruation, may contribute to the disparity between males and females.⁶⁰

In addition to sex-specific differences, differences in several PFAS concentrations by race and/or ethnicity have also been observed.^23,65,66 For example, in the 2017–2018 National Health and Nutrition Examination Survey (NHANES), participants who identified as Hispanic had lower concentrations of PFHxS, PFNA, 2- (N-methylperfluoroctanesulfonamido) acetic acid (Me-PFOSA-AcOH), and PFOS compared to those who identified as non-Hispanic (there were no difference by Hispanic vs non-Hispanic for perfluorodecanoic acid (PFDA) or perfluoroundecanoic acid (PFUA)). Additionally, those who identified as Asian and/or those who identified as non-Hispanic white generally had higher concentrations for PFHxS, PFNA, PFOA, and PFOS compared to those who did not identify as Asian or non-Hispanic white.²³ A study by Nguyen (2020) et al. using 1999-2014 NHANES and another study by Nelson (2012) et al. using 2003-2006 NHANES data evaluated demographic patterns for PFOA, PFOS, PFNA, and PFHxS, with Nelson et al. also looking at Me-PFOSA-AcOH and PFDEA.^65,67 These studies found similar patterns for these PFAS, observing that racial disparities are persistent even when controlling for socioeconomic status (SES).^65,67 Furthermore, Nguyen et al. also found those who identified as non-Hispanic white had the highest PFOA concentrations, with those identifying as non-Hispanic Black or other/multi-racial having the highest PFDA concentrations even after controlling for SES, suggesting these trends may be PFAS specific.⁶⁷ More so, Nelson et al. observed participants from higher income communities had higher PFAS levels for all measured PFAS compared to participants from lower income communities.⁶⁵ Although the reason for these disparities are not fully known, they may be the result of cultural differences, dietary differences, and/or behavioral differences such as usage (or degree of usage) of PFAS-containing products.⁶⁵

Disparities regarding some PFAS concentrations by age have also been observed.^23,68 In the US, older adults have been found to have higher concentrations of several PFAS compared to those who are younger; however, this age-related difference appears to be PFAS specific.^23,68 For example, participants 60 years and older from the 2017-2018 NHANES had higher PFNA, PFUA, n-PFOA (a linear isomer of PFOA), and PFOS concentrations compared to participants under 60 years; however, no differences were present for perfluorodecanoic acid (PFDeA), PFHxS, or Me-PFOSA-AcOH by age.²³ Reasons for these specific PFAS concentrations being higher in older individuals compared to those who are younger could be due to multiple reasons. These reasons include bioaccumulative properties of legacy PFAS like PFOA and PFOS who had higher use historically,^23,69,70 as well as age-related differences in diet and/or behavior. Conversely, children have been observed to have higher PFAS concentrations compared to adults for PFAS such as PFOA, PFOS, PFNA, and PFHxS.^71,72 This difference in these PFAS concentrations between children and adults is thought to be primarily the result of higher body size to surface area ratios, breastfeeding, proximity to the floor which could increase dust inhalation and/or ingestion, increased hand-to-mouth behavior, and/or dietary differences.^71,72 Furthermore, some occupations can lead to higher exposure to certain PFAS, with firefighters and those who work in making, processing, or using PFAS or a PFAS precursor having higher serum/plasma levels than the general population.^73,74

Reviews on PFAS and Cardiometabolic Outcomes

To our knowledge, only three other review articles have synthesized the literature on PFAS and MetS to date.^75,76 The first article was written by Jeddi (2021) et al. and focused on MetS as an overall diagnosis; as such, this review did not incorporate literature that focused on a specific components of MetS.⁷⁵ This systematic review found 12 cross-sectional studies (10 in the general population and 2 in an occupational setting), with half of these studies conducted in North America (5 in the US and 1 in Canada).⁷⁵ Jeddi et al. did not find any studies investigating the PFAS-MetS relationship in children and only one study,⁷⁷ evaluating this relationship in adolescents.⁷⁵ The most common PFAS assessed in these 12 cross-sectional studies were PFOA (N = 7), PFOS (N = 7), PFHxS (N = 5), and PFNA (N = 5).⁷⁵ As such, this review was not able to draw conclusions on other PFAS or effects in children or adolescence due to the limited number of studies. In their review, the authors conclude there is no evidence of an association between PFAS and MetS, but caution is warranted given that the reviewed studies were cross-sectional and did not include studies of children and adolescents who might be more vulnerable to the effects of PFAS.⁷⁵

The second review on PFAS and MetS in adults was conducted by Gaston (2020) et al.⁷⁶ This review was restricted to studies published between January 2018 and April 2019 and focused on synthetic chemicals (including PFAS) and cardiometabolic health across the life course, specifically in vulnerable populations.⁷⁶ Gaston et al. found 9 studies on PFAS and cardiometabolic health in vulnerable populations (8 studies with children [5 prospective and 3 cross-sectional] and one prospective study with pregnant people).⁷⁶ Among these studies, only 1 study investigated sex as a potential effect measure modifier (EMM), finding stronger PFAS-dyslipidemia associations among girls compared to boys.^76,78 Additionally, one study investigated EMM by maternal race (White, Black, Hispanic, Asian) and found no consistent patterns for race/ethnicity after a false discovery rate (FDR) correction (q < .05).^76,79 Gaston et al. concluded the overall evidence between PFAS and cardiometabolic outcomes in their review was inconclusive, but felt the association between PFAS and cardiometabolic outcomes merited continued investigation.⁷⁶

Another review by Rappazzo (2017) et al. focused on PFAS and general health outcomes in children and adolescents.⁸⁰ This systematic review found 16 studies specific to cardiometabolic outcomes (9 cohort studies and 7 cross-sectional), with studies conducted in Europe (N = 7; mainly Denmark N = 4), the United States (US; N = 5), and Taiwan (N = 4).⁸⁰ Rappazzo et al. observed inconclusive evidence across studies regarding markers of insulin resistance such as glucose^77,81 and insulin.^77,80-82 Additionally, this review also found limited and inconsistent evidence on measures of central adiposity,^82-85 and only a single study on PFAS and BP,⁸⁶ which observed no association.⁸⁰ Rappazzo et al. reports the strongest evidence between PFAS and a cardiometabolic outcome in children and adolescents was for the PFAS-dyslipidemia association, citing five cross-sectional studies.^77,80,87-90 Specifically, Rappazzo et al. details that the majority of included studies found an association between low-density lipoprotein cholesterol (LDL-C)^87-90 and total cholesterol^87-90 but inconsistent evidence for high-density lipoprotein cholesterol (HDL-C)^81,87,88 and triglycerides.^80,87-89 This review urges investigators to focus future studies on longitudinal assessments to establish temporality and mixture-based approaches as well as emphasizes the need for more cohesive outcome definitions.⁸⁰

Cohort Studies on PFAS and Cardiometabolic Outcomes

In our narrative review, we found 52 cohort studies on PFAS and our 4 cardiometabolic outcomes of interest (19 on insulin resistance/glucose dysregulation,^17,91-108 19 on central adiposity,^{82-85,92,95,106,108-119} 12 on dyslipidemia,^{92,95,108,116,118,131-136} and 17 on BP^{95,106,111,116,118,122,137-146}; numbers do not add to 52 due to overlapping studies). Additionally, 3 well-conducted prospective case-control studies were noted as well.^120-122 Details on included studies by MetS subcomponent are available in Supplemental File 1. Most of our studies were identified from previous reviews.^{38,39,51,75,76,80,123-126} However, some were located from a PubMed search on PFAS and each outcome, by reviewing the reference section of identified articles, and through peer recommendation. As no review articles on central adiposity were found, the following PubMed search strategy was employed: PFAS and (“BMI” OR “weight” OR “obese” OR “overweight” OR “length” OR “waist” OR “fat” OR “height” OR “adiposity” OR “anthropometric”). This search returned 280 studies, of which 15 (79% of included studies) were included in the review. Data was extracted by a data single extractor and all studies extracted were in English. We performed the last search on October 7, 2022.

Insulin Resistance and Glucose Dysregulation

Outcomes related to insulin resistance or glucose dysregulation include hyperinsulinemia, impaired fasting glucose, impaired glucose tolerance, and type 2 diabetes (T2D). Nineteen cohort studies examined the relationship between PFAS and insulin resistance or glucose dysregulation.^17,91-108 Of these, 8 were in non-pregnant adults,^17,91-97 8 were in pregnant adults,^17,98-104 and 7 were in children or adolescents.^{17,93,105-108} Additionally, 2 well conducted prospective case-control studies in non-pregnant adults were also noted.^120,121

In non-pregnant adults, 2 studies observed that higher PFOS and PFOA concentrations were associated with higher serum insulin levels,⁹⁵ higher insulin area under the curve (AUC),¹⁷ and/or higher Homeostatic Model Assessment of Insulin Resistance (HOMA-IR).⁹⁵ In 621 overweight and obese participants in Boston, MA and Baton Rouge, LA (POUNDS Lost Study), higher PFNA was associated with higher cross-sectional blood plasma insulin levels; this study also found higher PFNA and PFDA were associated with a greater increase in blood plasma insulin over the course of 6 to 24 months.⁹⁵ However, a prospective nested case-control study by Donat-Vargas (2019a) reported that ΣPFAS, PFDA, and perfluoroundecanoic acid (PFUnDA) were inversely associated with HOMA-IR in 124 case-control pairs in a Northern Sweden.¹²⁰ Two other studies observed no association between PFAS and insulin, both evaluating PFOS and PFOA and one also evaluating PFHxS, PFNA, and PFDA.^17,92 Similarly, the POUNDS Lost Study also observed higher PFNA was associated with higher glucose blood plasma levels⁹⁵; however, 3 other studies did not find a PFAS-glucose association with regards to fasting blood glucose levels, glucose AUC, or the Oral Glucose Tolerance Test (OGTT).^17,92,93

Also in adults, the majority of studies assessing PFAS and T2D (4 of 6) observed that higher PFAS exposure was associated with greater T2D risk, with half of the studies observing an association with PFOA or n-PFOA specifically.^{91,94,96,97,120,121} For example, a 2022 study by Park et al. using data from the Study of Women’s Health Across the Nation (SWAN) found higher n-PFOA, PFHxS, Me-PFOA-AcOH, and ΣPFAS exposure were associated with higher incidence of T2D in US women who were followed for ∼17 years.⁹⁷ However, no associations were observed for PFNA, PFOS, or 2-(N-ethyl-perfluorooctane sulfonamido) acetic acid (Et-PFOSA-AcOH).⁹⁷ Additionally, Cardenas et al. explored the association of PFOS, PFOA, PFHxS, Et-PFOSA-AcOH, Me-PFOSA-AcOH, PFNA, and ΣPFAS with T2D incidence in the Diabetes Prevention Program Trial.⁹¹ This RCT was designed to evaluate the risk of T2D in participants randomly assigned to a lifestyle intervention aimed at increasing physical activity and dietary modification or a placebo arm receiving only information on diet and exercise.⁹¹ Cardenas et al. found that sb-PFOA was significantly associated with increased T2D incidence for participants in the placebo group but not the lifestyle group, suggesting diet and exercise as potential modifiers of the PFOA-diabetes relationship.⁹¹ In pregnant adults, evidence was inconsistent for a relationship between PFAS and gestational diabetes, with almost half (N = 3/7) not observing any associations.^98,99,101 However, of those where a relationship was observed, all studies found that higher PFOA, specifically, was associated with greater risk of gestational diabetes.^100,102-104

In children and adolescents, 7 studies on PFAS and insulin resistance or glucose dysregulation were found, with 4 observing an association^{17,105,106,108} and 3 not observing an association.^92,93,107 Of those finding a relationship, associations were observed for the same 2 PFAS: PFOA (N = 3)^105,106,108 or PFOS (N = 2).^17,108 For example, a 2021 study by Li et al. found higher prenatal PFOA concentrations were related to higher insulin resistance as measured using HOMA-IR at age 12 years.¹⁰⁸ Furthermore, a 2022 study by Braun et al. explored modification of this association by physical activity (determined from a physical activity questionnaire) and found that prenatal PFOA was associated with worse HOMA-IR scores for those with low but not high physical activity scores.¹⁰⁶

Overall, the studies identified in this review provided inconsistent evidence for an association of PFAS with insulin resistance, and glucose dysregulation in children, adolescents, and adults.^{17,92,93,95,105-108,120} Furthermore, studies assessing gestational diabetes in pregnant people were also inconsistent.^98-104 The strongest evidence for a PFAS-glucose/insulin association in adults was found was for some PFAS and T2D diabetes, with 4 of 6 studies observing an association.^96,97 Still, the number of identified studies in non-pregnant adults looking at T2D is low and these studies were heterogenous with regards to population- and analysis-related factors. Additionally, 30% (3 of 10) of the studies assessing insulin resistance, glucose regulation, or T2D in adults were conducted in female-only populations, further contributing to the heterogeneity of these studies.^{17,92-97,120,121} Of the 7 adult studies in both men and women, 4 evaluated modification by sex, with 2 finding no association and 2 studies finding modification with PFAS-insulin/glucose associations among females but not males.^17,92,93,120 This was consistent with studies in pregnant adults but inconsistent with studies in children and adolescents that generally observed no associations.^{17,93,100,105,107,108} However, these null results could be reflective of a small sample size to assess statistical interaction. More so, the 2 studies evaluating modification by physical activity and diet (1 in adults and 1 in children)^91,106 found that both physical activity and/or diet may help to mitigate these associations. As such, future studies should consider evaluating physical activity and diet as a potential modifier.

Central Adiposity

For our review, 19 cohort studies on central adiposity were identified, with most studies in children and adolescents (14 studies in children/adolescents; 6 studies in adults).^{82-85,92,95,106,108-119} All but one study assessed central adiposity using waist circumference (WC), which has been found to be a good predictor of central adiposity and subsequent T2D diabetes and CVD.^{82-85,92,95,108-119,127} As such, we emphasize this outcome in the discussion below. Additionally, other central adiposity measurements utilized in these studies included waist-to height ratio,^85,116 waist-to-hip ratio,¹¹⁷ hip circumference¹¹⁷ or girth,¹⁰⁹ visceral fat via DXA^106,108 or CT⁹⁵ scan, trunk-, android-, or gynoid-fat percentage,¹¹⁵ and subscapular to triceps skinfold thickness.¹¹⁷

Six studies on PFAS and central adiposity in adults were identified.^{84,92,95,109-111} In 3 studies, higher concentrations of PFOS were associated with increased WC^92,95,110 (the other 3 studies found no association^84,109,111). Ding (2021a) et al. evaluated 10 PFAS in relation to WC in 1381 women (around 50 years old) in SWAN.¹¹⁰ This study observed that women in the highest PFOS, Et-PFOSA-AcOH, and Me-PFOSA-AcOH tertiles had annual increases in WC of 12% (P = .002), 15% (P = .0006), and 10% (P = .02), respectively, compared to women in the lowest tertile.¹¹⁰ Halldorsson (2012) et al. evaluated the association between prenatal PFAS concentrations and WC at 20 years of age using 665 mother–child pairs from the Danish National Birth Cohort.⁸⁴ This study observed that females born to women PFOA concentrations in the 4^th quartile had a greater risk of having an elevated WC (>88 cm in females and >102 cm in males)¹²⁸ compared to those in the first quartile; no associations were observed for males.⁸⁴

Among 8 studies observing PFAS-WC association in children,^{82,92,112-115,117-119} half observed an inverse association.^114,118,119 Bloom (2022) et al. found that higher prenatal blood plasma perfluoroundecanoic acid (PFUnDA) concentrations were associated with increased WC in 803 4- to 8-year-old multiethnic US children in the Fetal Growth Study.¹¹² Additionally, a 2021 study by Papadopoulou et al. observed a positive association between pre- and post-natal PFAS mixture and WC in 1101 mother–child pairs in a study of 6 multinational European studies. This study was inconsistent with the 2 other PFAS mixture studies,^108,119 one finding no association¹⁰⁸ and the other finding an inverse association for boys and a positive association in girls.¹¹⁹ Additionally, modification of the PFAS-central adiposity relationship by child sex was evaluated in 12 of the 14 studies, with 7 not observing modification,^{82,83,92,108,112,115,116} 3 observing stronger effects in boys and no effects in girls,^117-119 and 2 observing stronger effects in girls and no effects in boys.^85,113

Overall, the association between PFAS and WC was inconsistent in adults, children, and adolescents.^{82,84,92,95,109-115,117-119} All 6 studies in adults that evaluated relations of PFOS and PFOA with central adiposity reported similar median concentrations of these compounds.^{84,92,95,109-111} As such, differences between studies on the PFOS- or PFOA-WC relationship in adults are likely not the result of differences in dose. On the other hand, studies in children appeared to differ by dose; however, no clear patterns in relation to median serum concentrations were observed. Furthermore, although the majority of studies in children did not observe modification by child sex, half (N = 6) had samples sizes under 500 total participants, with only 2 studies having sample sizes over 1000 children.^{82,85,92,108,113,115,117-119} As a result, many of these studies may be underpowered to detect subtle sex-specific differences. Therefore, null results in relation to EMM of the PFAS-central adiposity association in children should be interpreted with caution. Furthermore, only two studies from the same cohort evaluated modification by diet, finding no association.^82,108 However, as both of these studies contained less than 225 mother-child pairs, more and larger longitudinal studies are needed to make inferences about whether diet modifies the PFAS-central adiposity relationship.

Dyslipidemia

Dyslipidemia refers to an imbalance in lipids such as triglycerides and lipoproteins.¹²⁹ Our review found 12 PFAS-dyslipidemia cohort studies, with 8 in adults^{92,95,130-135} and 5 in children or adolescents.^{92,108,116,118,136} Additionally, a prospective nested case-control study was noted as well.¹²²

The association of PFAS with dyslipidemia was fairly consistent in the adult literature, with most studies finding an association for triglycerides (N = 5/7),^{92,95,122,130,131,133,134} LDL-C (N = 4/5),^{95,130,131,133,134} HDL-C (N = 3/5),^{95,130,131,133,134} and hypercholesterolemia (N = 2/2),^132,135 but not total cholesterol (N = 2/5)^{95,122,130,131,134} or hypertriglyceridemia (N = 0/1).¹³² However, not all associations in these studies were in the expected directions. For example, a study by Donat-Vargas (2019b) et al. observed PFAS was inversely related to triglycerides in 187 participants in the Vasterbotten Intervention Programme (VIP) Study in Northern Sweden.¹²² Similarly, 2 of 3 studies found a positive relationship between PFOA and HDL-C, with Liu (2018) et al. being the only study to observe an inverse relationship.⁹⁵ Additionally, a study by Dunder (2022) et al. observed associations between a 10-year change in 6 of 8 PFAS evaluated with changes in total cholesterol, triglycerides, LDL-C, and/or HDL-C in 404 70-year old participants from the Prospective Investigation of Vasculature in Uppsala Seniors (PIVUS) study.¹³⁰ For example, this study observed that decreases in perfluoroheptanoic acid (PFHpA), PFHxS, PFOA, and PFNA concentrations were associated with greater decreases in total cholesterol, triglyceride, and HDL-cholesterol levels.¹³⁰ These findings were similar to a study by Fitz-Simmons (2013) et al. that also evaluated within-person change in PFAS.¹³¹ They found that declines in PFOA and PFOS concentrations were associated with decreases in LDL cholesterol over a 4.4 year period in 560 adults in the Ohio Valley using the C8 Short-Term Follow-up Study.¹³¹ The change-in-change approach used by both studies is robust to confounding from fixed within-person factors, thus enhancing the strength of the association between some PFAS and dyslipidemia.

Only 5 cohort studies evaluated PFAS and dyslipidemia in children and adolescents.^{92,108,116,118,136} These studies were primarily in Europe (N = 4), with all studies mostly evaluating the same 4 PFAS (PFOS [N = 5], PFOA [N = 5], PFHxS [N = 4], and PFNA [N = 4]), and one study also assessing PFDA.^{92,108,116,118,136} Of these studies, 3 observed an association between PFAS and triglycerides, with 2 studies specifically finding a PFHxS-triglyceride association.^{92,108,116,118,136} The majority of studies assessing HDL-C and LDL-C observed an association (HDL-C: 3 of 4 studies; LDL-C: 2 of 3 studies), but a PFAS-total cholesterol association was only observed in 1 of 2 studies.^{92,108,116,118,136} Bloomberg (2021) et al. found that higher PFNA exposure at 5 years was associated with higher total cholesterol at age 9 in 490 mother–child pairs in the Faroe Islands.¹³⁶ This paper also observed several cross-sectional associations at age 9, including positive associations of several PFAS concentrations with higher total cholesterol, HDL-C, or LDL-C levels.¹³⁶ Additionally, Papadopoulou et al. used the HELIX cohort to assess a combination of pre- and post-natal PFAS mixture concentrations in 1101 mother-child pairs.¹¹⁸ This study found PFAS was positively associated with HDL-C but negatively associated with LDL-C and triglycerides; these negative associations were the only negative associations observed in this literature for PFAS and dyslipidemia (including HDL-C associations).¹¹⁸

The strongest evidence for an association between PFAS and a component of MetS in our review was found for dyslipidemia, specifically in relation to higher PFAS and higher LDL-C. However, all but one observed a positive association for PFAS and HDL-C, which is unexpected as one would hypothesize an inverse association (i.e. higher PFAS would lead to lower HDL-C). Reasons for this unexpected directionality are unclear and could be truly biologic but also may be reflective of confounding by positive behaviors associated with better health outcomes that also lead to increased PFAS exposure (examples could include drinking more water or eating more fish). Additionally, while all of these studies were conducted longitudinally, many of the observed associations were cross-sectional. Therefore, the inability to establish temporality for these cross-sectional associations must also be considered. Furthermore, only one study evaluated PFAS mixture on individual dyslipidemia outcomes, finding that the PFAS mixture was positively associated with HDL-C and negatively associated with LDL-C and triglycerides.¹¹⁸ As such, the potential for joint effects should not be dismissed and future studies should consider mixture analyses in addition to assessing PFAS in single-pollutant models.

Blood Pressure

A total of 17 cohort studies have evaluated PFAS and BP.^{95,106,111,116,118,122,137-146} Of these, the majority (N = 9) were in pregnant people,^138-146 4 were in adults,^{95,111,122,137} and 4 were in children.^{106,108,116,118}

Of the 4 studies in adults, all observed associations between PFAS and BP were positive, with increasing exposure leading to an increasing outcome.^{95,111,122,137} All of these studies also observed some PFAS-BP association, with all studies evaluating systolic blood pressure (SBP; N = 3) and hypertension (N = 2) and most studies evaluating DBP (2 of 3 studies) finding a positive association.^{95,111,122,137} Additionally, all studies observed an association with PFOS specifically.^{95,111,122,137} For example, a 2022 study by Ding et al. found higher sm-PFOS and Et-PFOSA-AcOH were related to hypertension, higher SBP, and higher DBP in 1058 women in the SWAN study.¹³⁷ Furthermore, this study observed higher PFOS was associated with greater hypertension risk and higher SBP, higher n-PFOS was associated with greater hypertension risk, and higher Me-PFOSA-AcOH was associated with higher SBP and DBP.¹³⁷ Liu (2018) et al. was the only other study to observe a PFAS-BP association in a PFAS other than PFOS, finding higher PFNA was associated with higher DBP and SBP, and higher PFOS, PFOA, and PFHxS were associated with higher DBP in 621 participants in the POUNDS Lost study.⁹⁵

In pregnant people, the majority of PFAS-BP studies evaluated preeclampsia (N = 6 of 9 studies) and pregnancy-induced hypertension (N = 6 of 9 studies), finding inconsistent results.^138-146 Regarding BP, PFAS was consistently associated with SBP and DBP, with PFOS-DBP associations and PFHxS-SBP associations observed in 3 of 4 studies.^{138,139,142,146} However, while all observed PFOS-DBP associations were positive, the directionality of the PFHxS-SBP associations were inconsistent, with the majority of studies observing an inverse relationship.^{138,139,142,146} A 2021 study by Birukov observed an inverse PFHxS-SBP association and a positive PFOS-DBP association but no associations for PFOA, PFNA, or PFDA in 1283 pregnant people in Southern Denmark.¹³⁸ Borghese (2021) et al. found higher PFHxS was weakly associated with higher odds of preeclampsia.¹³⁹ Furthermore, this study observed positive PFOA-SBP, PFOA-DBP, PFHxS-SBP, and PFOS-DBP associations.¹³⁹ Preston (2022) et al found positive associations between several PFAS and gestational hypertension, DBP, and SBP in 1558 pregnant people in Boston, MA.¹⁴² Yang (2022) et al. observed positive associations between PFOS, PFDA, PFUnDA, and PFDoDA and risk of gestational hypertension and lower SBP.¹⁴⁶ Additionally, this study observed inverse associations between PFHxS and perfluorotridecanoic acid (PFTrDA) and SBP as well as PFHxS and DBP.¹⁴⁶

To date, only 4 cohort studies have evaluated PFAS-BP associations in children, all assessing the same 4 PFAS: PFOS, PFOA, PFNA, and PFHxS.^106,116,118 Li et al. evaluated pre- and post-natal PFAS on the mean of the DBP and SBP z-score in 221 12-year old children in the HOME study finding no association.¹⁰⁸ Also using the HOME study, Braun (2022) et al. assessed the impact of prenatal PFAS on SBP in 166 12-year old children in the HOME study observing no association.¹⁰⁶ Similarly, Manzano-Salgado (2017) et al. evaluated the impact of prenatal PFAS on DBP and SBP in 1083 children at ages 5 and 7 years in Spain, also observing no associations.¹¹⁶ Conversely, Papadopoulou et al. found that prenatal PFAS mixture was associated with children’s SBP but not DBP at ages 7–11 years in 1101 mother-child pairs in a multi-country European.¹¹⁸

PFAS was consistently associated with both DBP and SBP in the only 4 studies assessing BP in non-pregnant adults, emphasizing a potential association between some PFAS and BP.^{138,139,142,146} Therefore, more studies are needed to evaluate this association. Additionally positive associations between PFAS and BP or hypertension risk were mostly consistent across studies, with PFOS-BP associations specifically noted in all studies in non-pregnant adults.^{95,111,122,137} However, inferences are largely limited by the number of studies in non-pregnant adults (with only 4 adult studies having been performed).^95,111,137 As a result, more studies are needed assessing PFAS in adults. Furthermore, 2 of the 4 studies on PFAS and BP in adults were conducted in female-only populations.^111,137 Therefore, future studies would ideally consider evaluating PFAS and BP in populations with both men and women. In pregnant people, most studies assessed preeclampsia and hypertension, finding inconsistent results with regards to an association.^138-146 However, as preeclampsia and hypertension are fairly rare, the number of cases in each study were relatively small, thus, analyses may have been underpowered to detect an association.^138-146 Therefore, larger prospective studies are needed, specifically ensuring large enough sample sizes of preeclampsia or hypertension cases. In children, as only 4 PFAS-BP studies were conducted, inferences should be made with care.^106,116,118 Two of 4 studies did not observe any PFAS-BP associations^106,116; however, all but Li et al. were conducted using only prenatal PFAS measurements.^106,116,118 As such, future studies should additionally consider collecting information on postnatal PFAS concentrations to evaluate how these may related to MetS outcomes during childhood and adolescents.

Clinical Considerations

In response to the ubiquitous human PFAS exposure and concerns over the adverse health effects of PFAS, the National Academies of Science Engineering and Medicine (NESEM) convened a panel to develop clinical guidance for PFAS exposure, testing, and clinical follow-up.¹⁴⁷ There is precedence for this as exposure controls and/or effects of exposure to some environmental agents are managed clinically. For example, the current recommendations for blood lead testing and lead poisoning treatment in pediatric populations are informed by epidemiological research of lead exposure and its health effects in children. Although there is uncertainty about the risks and benefits of integrating these guidelines into clinical practice, they provide a standard of care that could be adopted, particularly in communities where PFAS contamination is present. Below we highlight practices that the panel recommended for integration into clinical care and describe them in depth in Table 2:

1. Determine if patients are exposed to PFAS and what exposures they are interested in reducing (e.g., working with fluorochemicals, drinking water contamination, etc.).

2. Use shared, informed decision making, offer patients serum/plasma PFAS testing if the patient is likely to have a history of elevated exposure.

3. Use serum PFAS concentrations to guide additional clinical screening (Table 3).

4. Advise patients on ways to reduce PFAS exposure (e.g., drinking water filtration).

Table 2.

Recommended clinical practices to identify and care for patients with elevated per- and polyfluoroalkyl substances (PFAS) exposure.

Recommendation	Guidance	Clinical Resources/Actions
Conduct PFAS exposure assessment	• Assess occupational sources of exposure (e.g., fluorochemical manufacture, firefighting)	• Occupational exposure: Consult with occupational health and safety professionals
	• Assess exposure from PFAS-contaminated local drinking water	• Water, fish, and game exposure: Consult with local public health agencies, Pediatric Environmental Health Specialty Units (PEHSUs). Review results from locally conducted research studies
	• Assess exposure from PFAS-contaminated fish and game consumption
Measure serum/plasma PFAS concentrations in patients likely to have history of elevated exposure	• Describe benefits and harms of testing	• Labs can be ordered using Test Code 39 307 Current Procedural Terminology [CPT] code 82 542
	• Calculate additive sum of concentrations of Me-PFOSA-AcOH, PFHxS, PFOA (linear and branched isomers), PFDA, PFUnDA, PFOS (linear and branched isomers), and PFNA in serum or plasma	• Use fasting or non-fasting serum/plasma
		• For PFAS with concentrations below limit of detection, substitute limit of detection divided by √2
Develop care plan based on PFAS concentrations	• Summed concentrations can be interpreted as <2 ng/mL: Adverse health effects are not expected	• Sensitive populations include pregnant people and nursing infants
	• 2 to 20 ng/mL: Potential for adverse health effects, especially in sensitive populations	• Plan care based on guidance in Table 3
	• >20 ng/mL: Increased risk of adverse health effects	• Plan care based on guidance in Table 3
Advise on PFAS exposure reduction	• Advise to use drinking water filter	• Drinking water filters: Consult NSF International database for filters that reduce PFAS
	• Advise that PFAS can be present in local fish, wildlife, meat, and dairy products	• Occupational exposure: Occupational health and safety professionals
	• Direct patients to authoritative sources of information on how to reduce PFAS exposure	• Water, fish, and game exposure: Local public health agencies, Pediatric Environmental Health Specialty Units (PEHSUs), locally conducted research studies
	• For nursing infants, discuss infant feeding and steps that can be taken to reduce PFAS exposure	• Exposure reduction: Agency for Toxic Substances and Disease Registry (ATSDR), and the U.S. Environmental Protection Agency (EPA)
	• For bottle-fed infants, advise to use filtered drinking water to reconstitute formula

Note: Guidance is a summarized version of recommendations based on report for National Academies of Science Engineering and Medicine, Figure S-6.¹³⁸ Me-PFOSA-AcOH, N-methyl perfluorooctane sulfonamide; PFHxS, perfluorohexane sulfonic acid; PFOA, perfluorooctanoic acid; PFDA, perfluorodecanoic acid; PFUnDA, perfluoroundecanoic acid; PFOS, perfluorooctane sulfonic acid; PFNA, perfluorononanoic acid.

Table 3.

Interpretation of serum/plasma per- and polyfluoroalkyl substances (PFAS) concentrations and clinical guidance for follow-up with patients after PFAS testing.^a

Interpretation of Serum/Plasm PFAS Concentrations^b	Recommendation
Adverse health effects not expected: Concentrations < 2 ng/mL	Treat patients with the usual standard of care
Potential for adverse effects, especially in sensitive populations: Concentrations 2 to 20 ng/mL	• Encourage PFAS exposure reduction if an exposure source is identified, especially for pregnant persons
	• Prioritize screening for dyslipidemia with a lipid panel (once between 9 and 11 years of age, and once every 4 to 6 years over age 20) as recommended by the American Academy of Pediatrics (AAP) and the American Heart Association (AHA)
	• Screen for hypertensive disorders of pregnancy at all prenatal visits per the American College of Obstetricians and Gynecologists (ACOG)
	• Calculate additive sum of concentrations of Me-PFOSA-AcOH, PFHxS, PFOA (linear and branched isomers), PFDA, PFUnDA, PFOS (linear and branched isomers), and PFNA in serum or plasma
	• Screen for breast cancer based on clinical practice guidelines based on age and other risk factors such as those recommended by the U.S. Preventive Services Task Force (USPSTF)
Increased risk of adverse effects: Concentrations >20 ng/mL	• Encourage PFAS exposure reduction if an exposure source is identified, especially for pregnant persons
	• Within the usual standard of care, conduct the recommendations for PFAS levels of 2 to 20 ng/mL and at all well visits
	• Conduct thyroid function testing (for patients over age 18) with serum thyroid stimulating hormone (TSH)
	• Assess for signs and symptoms of kidney cancer (for patients over 45), including with urinalysis
	• For patients over 15, assess for signs and symptoms of testicular cancer and ulcerative colitis

^aGuidance is a summarized version of recommendations based on report for National Academies of Science Engineering and Medicine, Figure S-6.¹³⁸

^bAdditive sum of N-methyl perfluorooctane sulfonamide (Me-PFOSA-AcOH), perfluorohexane sulfonic acid (PFHxS), perfluorooctanoic acid (PFOA; linear and branched isomers), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), perfluorooctane sulfonic acid (PFOS; linear and branched isomers), and perfluorononanoic acid (PFNA).

The National Academies panel developed disease screening guidelines based on serum/plasma PFAS concentrations (Table 3).¹⁴⁷ Simple additive sums of Me-PFOSA-AcOH, PFHxS, PFOA (linear and branched isomers), PFDA, PFUnDA, PFOS (linear and branched isomers), and PFNA concentrations can be used to categorize patients into three groups: adverse health effects not expected (<2 ng/mL), potential for adverse effects (especially in sensitive populations; 2–20 ng/mL), and increased risk of adverse effects (>20 ng/mL) for these assessments.

Clinical care and follow-up was developed for health outcomes that the NASEM committee deemed had sufficient, suggestive, or limited evidence of being caused by PFAS exposure.¹⁴⁷ In addition, the panel carefully considered that decisions on PFAS testing and related clinical care are made with uncertainty. As such, the development of these recommendations was made based on the principals of proportionality (risk-benefit assessment), justice, autonomy, feasibility, and adaptability. Ultimately, the panel selected six health outcomes that should be screened for within the standard of care or at all well visits (Table 3).

Clinicians can advise patients on ways to reduce exposure. The primary sources that should be considered include occupational exposures, consumption of PFAS-contaminated drinking water, and consumption of PFAS-contaminated fish, wildlife, meat, or dairy products. Additionally, nursing and bottle-fed infants may be a vulnerable to excess PFAS exposure due to consumption of PFAS-contaminated breastmilk or formula that has been reconstituted with PFAS-contaminated drinking water.¹⁴⁸ While there is still uncertainty about the risks of consuming PFAS-contaminated breastmilk, breastmilk is the optimal source of nutrition for infants with few exceptions. Thus, clinicians will need to engage in informed decision making with nursing mothers to reduce their PFAS exposure and continue breastfeeding. Additional research is needed to understand the routes and contributions of various sources of PFAS, particularly in vulnerable populations like pregnant people and infants.

Conclusions

In reviewing studies examining PFAS and MetS features, we observed evidence for an association between perfluorooctanoic acid (PFOA) and T2D in adults. Additionally, there was also evidence that some PFAS was associated with dyslipidemia in children and adults and possibly blood pressure in adults. While there was emerging evidence suggesting that the relation between PFAS and MetS was modified physical activity and sex, future research should clarify this as it might provide an avenue to prevent exposure-related health effects and identify susceptible subpopulations. Moreover, future studies should incorporate mixture-based analyses in addition to single pollutant assessments to better characterize the effects of aggregate PFAS exposure. Finally, clinicians can integrate PFAS exposure testing and clinical follow-up into their practice to identify patients who might be at increased risk of PFAS exposure-related disease.

Footnotes

Declaration Conflict of Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Braun was compensated for serving as an expert witness on behalf of plaintiffs in litigation related to PFAS-contaminated drinking water.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by NIEHS grants R01 ES032836 and R01 ES033252.

ORCID iDs

Amber M. Hall

Joseph M. Braun

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Per- and Polyfluoroalkyl Substances and Outcomes Related to Metabolic Syndrome: A Review of the Literature and Current Recommendations for Clinicians

Abstract

Keywords

Introduction

Biological Mechanisms of PFAS Action and Exposure in Specific Populations

Reviews on PFAS and Cardiometabolic Outcomes

Cohort Studies on PFAS and Cardiometabolic Outcomes

Insulin Resistance and Glucose Dysregulation

Central Adiposity

Dyslipidemia

Blood Pressure

Clinical Considerations

Conclusions

Footnotes

Declaration Conflict of Interests

Declaration of Conflicting Interests

Funding

ORCID iDs

References