Dioxins vs. PFAS: Science and Policy Challenges

Abstract

Background: Dioxin-like chemicals are a group of ubiquitous environmental toxicants that received intense attention in the last two decades of the 20th century. Through extensive mechanistic research and validation, the global community has agreed upon a regulatory strategy for these chemicals that centers on their common additive activation of a single receptor. Applying these regulations has led to decreased exposure in most populations studied. As dioxin-like chemicals moved out of the limelight, research and media attention has turned to other concerning contaminants, including per- and polyfluoroalkyl substances (PFAS). During the 20th century, PFAS were also being quietly emitted into the environment, but only in the last 20 years have we realized the serious threat they pose to health. There is active debate about how to appropriately classify and regulate the thousands of known PFAS and finding a solution for these "forever chemicals" is of the utmost urgency. Objectives: Here, we compare important features of dioxin-like chemicals and PFAS, including the history, mechanism of action, and effective upstream regulatory strategies, with the objective of gleaning insight from the past to improve strategies for addressing PFAS. Discussion: The differences between these two chemical classes means that regulatory strategies for dioxin-like chemicals will not be appropriate for PFAS. PFAS exert toxicity by both receptor-based and nonreceptor-based mechanisms, which complicates mixtures evaluation and stymies efforts to develop inexpensive assays that accurately capture toxicity. Furthermore, dioxin-like chemicals were unwanted byproducts, but PFAS are useful and valuable, which has led to intense resistance against efforts to restrict their production. Nonetheless, useful lessons can be drawn from dioxin-like chemicals and applied to PFAS, including eliminating nonessential production of new PFAS and proactive investment in environmental remediation to address their extraordinarily long environmental persistence.

Headnote

Background: Dioxin-like chemicals are a group of ubiquitous environmental toxicants that received intense attention in the last two decades of the 20th century. Through extensive mechanistic research and validation, the global community has agreed upon a regulatory strategy for these chemicals that centers on their common additive activation of a single receptor. Applying these regulations has led to decreased exposure in most populations studied. As dioxin-like chemicals moved out of the limelight, research and media attention has turned to other concerning contaminants, including per- and polyfluoroalkyl substances (PFAS). During the 20th century, PFAS were also being quietly emitted into the environment, but only in the last 20 years have we realized the serious threat they pose to health. There is active debate about how to appropriately classify and regulate the thousands of known PFAS and finding a solution for these "forever chemicals" is of the utmost urgency.

Objectives: Here, we compare important features of dioxin-like chemicals and PFAS, including the history, mechanism of action, and effective upstream regulatory strategies, with the objective of gleaning insight from the past to improve strategies for addressing PFAS.

Discussion: The differences between these two chemical classes means that regulatory strategies for dioxin-like chemicals will not be appropriate for PFAS. PFAS exert toxicity by both receptor-based and nonreceptor-based mechanisms, which complicates mixtures evaluation and stymies efforts to develop inexpensive assays that accurately capture toxicity. Furthermore, dioxin-like chemicals were unwanted byproducts, but PFAS are useful and valuable, which has led to intense resistance against efforts to restrict their production. Nonetheless, useful lessons can be drawn from dioxin-like chemicals and applied to PFAS, including eliminating nonessential production of new PFAS and proactive investment in environmental remediation to address their extraordinarily long environmental persistence. https://doi.org/10.1289/EHP14449

Introduction

The Stockholm Convention on Persistent Organic Pollutants (POPs) was enacted in 2004 as an international response to concern over some of the world's most harmful chemicals.1 This frame-work targets compounds that are not only toxic but are persistent in the environment and bioaccumulate through trophic levels and serves as the basis for the argument that these chemicals are espe-cially deserving of reduction or elimination. At its inception, 12 chemicals, commonly known as the "dirty dozen," were chosen to be the focus of the Convention. Periodically, new POPs have been added, reflecting both a growing understanding of our exposures and a growing number of industrial chemicals being added to the market.

Among the original "dirty dozen" were 2,3,7,8-tetrachlorodi-benzo-p-dioxin (TCDD) and its structurally related cousins, the polychlorinated dibenzo-p-dioxins (PCDDs) and the polychlori-nated dibenzofurans (PCDFs). TCDD is often cited as the most toxic anthropogenic chemical ever created.2^4 This toxicity, in combination with its extraordinary environmental persistence, secured its position as a top priority for the Stockholm Convention from its inception.2 The PCDDs and PCDFs were unintentionally generated in large quantities beginning in the 1940s and peaking in the 1960s through the early 1980s and are notoriously persistent in the environment.5 The bulk of these chemicals were produced as unwanted byproducts from waste incineration, metal smelting and refining, and the manufacturing of certain useful chlorinated chemicals. In humans and wildlife, these chemicals exert a range of toxic effects, including effects on the immune, endocrine, cardiovascu-lar, neural, and reproductive systems; developmental processes; and cancer.3 TCDD can exert acute toxicity and has been involved in several high-profile poisonings, both accidental, as in the 1976 disaster at Seveso, Italy,6 and intentional, as in the 2004 assassina-tion attempt on former Ukrainian president Viktor Yushchenko.7 From an environmental health perspective, the concern over these chemicals has been lower-level, chronic exposures for the general population8 as well as exposures for some highly contaminated communities.9-11

Regulation of the dioxin-like chemicals has been a resounding success in terms of reducing emissions; today, emissions of PCDDs and PCDFs are a mere fraction of what they were at their peak,12 and concentration of dioxin-like compounds in human serum has also decreased.8,13 Unfortunately, dioxins are slow to de-grade in the environment, and because of their high toxicity, we believe even low levels in serum represent concerning levels of exposure for populations worldwide.13,14

Even though dioxins are no longer in the spotlight, we argue lessons learned from this group of chemicals can help us tackle more contemporary challenges. The toxic effects of per- and poly-fluorinated alkyl substances (PFAS), often referred to as the "forever chemicals," are one of today's most difficult environmental health problems. PFAS are an enormous class of fluorinated organic chemicals that are highly persistent in the environment15 and within humans,16 and several have been added as additional POPs to the Stockholm Convention.17-19 First synthesized in the 1930s20 and initially lauded as an innovative breakthrough in a wide range of industries, PFAS are raising alarms for human health globally because they are ubiquitous in the environment21 and strongly linked in laboratory and epidemiological studies to toxic effects.22-24 Like dioxins, PFAS were produced and emitted exten-sively before any hint of health problems was widely publicized.25 However, unlike dioxins, which were merely unwanted contaminants from uncontrolled combustion and certain industrial processes, PFAS are intentionally produced, highly useful, and valuable.26,27 They have applications ranging from surfactants and chemical engineering processes to consumer products like non-stick items.26 Their physiochemical properties that make them so useful, such as their stability and simultaneous hydrophobicity and

lipophobicity,26 also produce complex interactions in biota28-30 and cause them to defy regulatory strategies.31 Recently, final health advisories from US EPA for two PFAS (PFOA and PFOS) were set at values below current analytical limits of detection and quantitation for routine water monitoring, which has brought addi-tional public attention to this class of compounds.32 Indeed, new information on PFAS and decisions regarding their control and use are currently arising rapidly.

Though there are obvious differences between dioxins and PFAS, including their chemical structure and toxic mechanisms of action, we argue there are striking similarities that warrant a thoughtful comparison between these two groups. Both are extremely persistent in the environment, and both were emitted at high levels decades before the public and the environmental health research community became aware of their negative health effects. These similar characteristics suggest that we can learn from the dioxin-like chemicals to help us tackle the unprecedented chal-lengeof PFAS.

Discussion

Definitions of the Chemical Classes

The boundaries of the category "dioxin-like compounds" have been cleanly defined since the 1990s.33,34 Aninternationally harmonized regulatory approach from the World Health Organization set key criteria for inclusion.34 One criterion is structural similarity - all these chemicals are structurally related to 2,3,7,8-tetrachlorodi-benzo-p-dioxin (TCDD, or simply "dioxin") in that they all have a dibenzo-p-dioxin, dibenzofuran, or a biphenyl core surrounded by a varying number and position of halogen atoms. The term "dioxin-like" chemicals also has a mechanistic component-to be included, these chemicals must bind to and activate the aryl hydrocarbon receptor (AhR).34,35 The group includes 7 PCDDs, 10 PCDFs, and 12 polychlorinated biphenyls (PCBs), as well as the brominated conge-ners. Here, we focus on the unintentionally created PCDDs and PCDFs rather than the mostly synthetic PCBs, which were banned in the United States in 1976 with the passage of the Toxic Substances Control Act.36,37

Although the dioxin-like chemical class is neatly defined, there is no universal agreement on which chemicals are included within the boundaries of the term PFAS. The first proposal for a standard definition of PFAS was made in 2011 by Buck et al.38 They defined PFAS as aliphatic substances containing the CnF2n+1 moiety- molecules containing at least one carbon atom whose hydrogens have all been replaced by fluorine that terminate in a -CF3 group, and that also have a variable functional group. This classic definition is still widely referenced, though subsequent influential publications have offered alternative definitions.16,26,39 In 2018, the Organisation for Economic Co-operation and Development (OECD) reported PFAS lacking the terminal -CF3 group,39 and in 2021 the OECD published a definition that included chemicals containing either a perfluorinated methyl group or a perfluorinated methylene group.40 There is also debate about whether the definition should be expanded to include additional fluorinated compounds, such as those with an aromatic component or compounds which are polyfluorinated and contain one or more other halogens (I, Br, or Cl).16 In 2021, the OECD tallied more than 4,700 PFAS with an assigned CAS number that may be on the global market,40 but the number grows when we expand the scope to include degra-dants and impurities that are themselves PFAS. For instance, a recent tally by the US EPA's CompTox Chemistry Dashboard reports more than 14,000 PFAS.41 And as analytical chemistry techniques continue to innovate, new PFAS are discovered all the time.42 In this article, when we refer to all PFAS as a class, we will reference the 2021 OECD definition; however, we recognize that stakeholders are having active conversations about which definition of PFAS is best. Nevertheless, for any of these definitions, the number of PFAS dwarfs the dioxin-like chemicals, which is one reason PFAS pose such aproblem.

In addition to the sheer number of chemicals in the group, PFAS are subcategorized along many axes, with each grouping strategy lending itself to different applications.31 We can, for example, consider short-chain vs. long-chain PFAS, which differ in the length of their carbon chain. Long-chain PFAS (generally containing 8 for the carboxylic acids and 6 for the sulfonic acids), are the earlier, "legacy" PFAS and have longer biological halflives, whereas short-chain PFAS are a more recent innovation and have shorter biological half-lives.38 There are also the ultrashort chain PFAS43 such as trifluoroacetic acid and pentafluoropropionic acid. We can also categorize PFAS based on how they were made: Mixtures made with electrochemical fluorination (ECF) tend to contain isomers with branched carbon chains, whereas products of telomerization have linear carbon chains.38 These structural characteristics may enable identification of the manufacturer of PFAS samples from the environment.44 Researchers and risk assessors also group PFAS based on whether they are perfluorinated (fully fluorinated) or poly fluorinated (incompletely fluorinated); by their functional group (with the carboxylic and sulfonic acids getting the most attention); whether they are the original products, degradation byproducts, or production byproducts; what they degrade into (with some terminal degradation products being of greater concern); polymers or nonpolymers; by their volatility; by their pKa; and so on.16 An excellent summary of these categories can be found in the Interstate Technology and Regulatory Council's tech-nical resources on PFAS.16 Although each method of subcategori-zation has uses, most are limited when it comes to regulating PFAS for their toxicity because each subgroup contains significant toxi-cological heterogeneity.15

We argue the class definitions of both dioxin-like chemicals and PFAS inform and are informed by the toxic mechanisms of action and the regulatory approaches used. For dioxin-like chemicals, a neat definition is firmly cemented in the World Health Organization's toxic equivalencies (TEQ) approach from the 1990s.34 However, the story is still unfolding for PFAS, because a consensus definition has not yet been reached. The unclear boundaries of the term PFAS pose serious communication road-blocks for groups working on regulatory strategies. To gain fur-ther insight, we will next examine the timelines, mechanisms, and regulatory strategies of these two groups.

Timeline of Dioxins and PFAS

Many anthropogenic toxicants found in the environment have timelines that fit a general pattern described by the Interstate Technology and Regulatory Council.16 In this paradigm, the chemical of interest is first produced in enormous quantities with low concern for potential toxicity, either intentionally (as for PFAS) or unintentionally as a contaminant of some large-scale industrial processes (as for PCDDs and PCDFs). Then, awareness of potential health effects by researchers and society develops in subsequent decades as concerning evidence emerges. Around this time, we also see efforts from governments, industry, and others to reduce or eliminate the chemical. The sequence of events for PFAS, from initial production to the extensive health concerns and regulatory efforts unfolding today, has parallels to the story of the dioxin-like chemicals.

After the beginning of anthropogenic emissions of dioxin-like chemicals in the 1930s and 1940s, uncontrolled municipal waste incineration, as well as emission from industrial processes, contrib-uted to their rapid growth and their peak in the 1960s through 1980s.5,45 In addition to industrial combustion, other important sources were metal smelting and refining, production of chlori-nated biocides, and production of paper and pulp products. Dioxin-like chemicals experienced a boom in attention from the public sphere and research communities in the 1970s and 1980s due to high-profile exposures, including rice oil poisoning events in Japan and Taiwan,46 exposure to Agent Orange during the Vietnam War,47,48 soil contamination in Times Beach, Missouri,49 and an industrial explosion in Seveso, Italy in 1976.50 Focused research efforts rapidly generated toxicological data and culminated in de-velopment of a cohesive, globally standardized approach to defin-ing toxicity of mixtures of dioxin-like chemicals.34 Attention from the public sphere drove efforts to curb emissions of PCDDs and PCDFs, and regulatory actions played a key role in their successful control in the United States.12 Between 1987 and 2000, there was a 90% reduction in emissions of PCDDs/PCDFs to all media in the United States, in large part due to regulation of large-scale combus-tion by the Clean Air Act Amendments of 1990.12 Actions were taken to decrease emissions from other sources as well.12,51 In the 1980s and 1990s, the US EPA canceled registrations of several pesticides that were contaminated by PCDDs and PCDFs by virtue of their production process.12 And in 1998, the US EPA published a final rule limiting toxic chemicals, including dioxins and furans, in effluent from paper and pulp facilities.52

As a direct result of these control measures, new emissions of dioxin-like chemicals from all sources are down in the United States, and a similar trend is found in other developed nations.45,53 Due to this dramatic decline, the historically steady, low levels of nonindustrial combustion, such as backyard burning, are now the major source of dioxin-like chemicals in developed countries.53-55 The trend of declining dioxin emissions in the United States and Europe has translated to a decline in exposure; dioxin concentrations in serum in the United States peaked around 1970,45 and this trend has fortunately continued into the 21st century.8,13

In developing and more-recently developed nations, dioxin emissions are higher and may have different sources. Cao et al. found that countries with lower GDPs tend to have more emissions from geographically dispersed nonindustrial sources, such as burn-ing of residential waste, and that these sources are more difficult to regulate.56 Ssebugere et al. concluded that dioxin emissions in African nations stem from both industrial and nonindustrial anthro-pogenic sources and urged more government intervention to con-trol these emissions.57 Simultaneously, countries with more recent booms in industrial activity are making progress on regulating dioxin pollution, albeit on a delayed timeline.58 Critically, data on dioxin-like chemical emissions are incomplete for many parts of the world,8,13,57 and there is a need to fill these data gaps to inform health-protective policies.

Despite the overall trend toward decreased emissions and increased regulation, even low levels of dioxins in the environment pose a threat to human health.13,14 And even in places where emis-sions have been cut, there is nontrivial exposure from food because of the extraordinary persistence of these chemicals.14 Public atten-tion has moved on, but the extraordinary environmental persist-ence of dioxin-like chemicals ensures we will not soon forget the errors of decades past.

The saga of the dioxin-like compounds was characterized by uncontrolled pollution and widespread exposure before concern from the general public and extensive research efforts drove ini-tiatives to reduce emissions.45,59 These same features are cur-rently playing out with PFAS.

The first synthesis of any PFAS compound occurred in 1938 when a chemist at DuPont was experimenting with fluorinated refrigerants and inadvertently created polytetrafluorethylene (PTFE), which was later marketed as Teflon.20 The new sub-stance had interesting chemical properties, including repelling oil and water and being resistant to heat, and DuPont quickly recog-nized the potential applications of this new substance. Mass production of PFAS started in the 1950s and increased dramatically through the rest of the 20th century,16 resulting in extensive releases into the environment.

Until the late 1990s, nonindustry research communities and the general public were not aware of the general presence of PFAS in people or of the dangers posed by PFAS.60 However, PFAS were recognized as toxic by the companies that made them as early as 1978 as evidenced by corporate documents revealed in lawsuits af-ter the turn of the century.61-63 One famous lawsuit64 in 2005 revealed massive quantities ofdocuments that proved the manufac-turer knew the dangers of PFOA but failed to notify the US EPA as required by the Toxic Substances Control Act. However, all the while, PFAS were being emitted into the environment, and popula-tions worldwide were being exposed-through spills near chemical plants, through routine industrial waste, spraying of firefighting foams, and through use of consumer products.65-69 In 1999, scien-tists working at 3M published investigations of PFAS in human sera,70 spurring a first step toward reduction in PFAS production; between 2000 and 2002, one famous PFAS compound, PFOS, and some of its precursors were voluntarily phased out by3M.70,71

Today, PFAS are copiously emitted into the environment from both point and nonpoint sources. Emissions into both air and water come from industrial production of a variety of PFAS, and in some cases the contamination of drinking water can be traced to nearby PFAS production and use facilities.72,73 Firefighting foams, or aqueous film-forming foams, used at military installations, fire training sites, and airports, are a major point source of contamina-tion to surface and groundwater.74,75 Other point sources of PFAS include release from suboptimal landfills into groundwater76 and release from wastewater treatment plants.77 There are also concerns about emission from consumer use of PFAS-containing products, including textiles, housewares, and personal care prod-ucts.21 PFAS generally are highly mobile in the environment38 and may enter the boundaries of a community or watershed via precipi-tation, runoff, atmospheric deposition, and so on, which then becomes a burden on the people residing in that area. In this com-mentary, we focus on upstream regulation-restricting the production of new PFAS-while acknowledging that even a global embargo on PFAS manufacture would not guarantee that PFAS levelsin every community would stop increasing.

The countless routes of PFAS emission into the environment, combined with their environmental persistence, provide abundant opportunities for human exposure. PFAS have been found in human tissues across the globe, including in the blood of essen-tially all Americans tested.78 Major sources of exposure in non-occupationally exposed populations are diet, consumer products, and house dust.16,75 For populations living with contaminated water supplies, drinking water becomes the main source of PFAS exposure.16 Critically, even more than dioxin-like compounds, PFAS are incredibly persistent within the environment,79,80 resulting in people (and wildlife) being continually exposed, even in cases when new emissions are successfully eliminated.

The timeline of the dioxin-like chemicals has passed its hey-day; current research on the matter focuses on remediation, and media coverage is only an echo of what it once was.81 But the PFAS saga is actively unfolding, with stakeholders engaging in passionate debate over how to manage these chemicals. As we shall soon see, for dioxin-like chemicals that choice was informed by their mechanism of action, which is less well-defined for PFAS.

Mechanisms of Action

When health concerns warrant regulation of a group of chemicals, regulatory decisions can be supported by an understanding of the mechanism of action. The mechanisms of both dioxin-like chemicals and PFAS have been the subjects of intense research. But although the mechanism for dioxin-like chemicals was eluci-dated before the end of the 20th century, fully characterized mechanisms for PFAS still elude us due to their complexity.

Dioxin-like chemicals share a common molecular initiating event: binding and activation of the aryl hydrocarbon receptor (AhR). The evidence for AhR as the mediator of toxicity of dioxin-like compounds is unequivocal.2 We know that the binding affinity of a dioxin-like chemical to the AhR dictates its po-tency; those that bind AhR to a lesser degree require higher doses to achieve the same effect.82 The AhR is highly conserved among vertebrates, and although there are some differences in the toxic effects of these chemicals between species, there are notable overlapping effects, and the effects within a given test species are the same.83 Furthermore, AhR-knockout mice are mostly unaf-fected by doses of TCDD 10-fold higher than the acutely toxic dose in wild-type mice.84 The necessary and sufficient role of AhR in the toxic effect of dioxin-like compounds translated well to screening compounds and drawing conclusions about their tox-icity based on this one metric, and we believe this facilitated an expedited timeline between discovery and successful emissions reduction compared with PFAS.

The time between identification of the AhR and the first glob-ally harmonized regulatory strategy for dioxin-like compounds was just 21 y. The Ah receptor was first identified in 1976,85 and the first relative potency approaches were implemented in the late 1980s.86-88 By 1997, there were sufficient in vivo and in vitro data to establish globally standardized relative potencies for a core subset of dioxin-like compounds.34 However, the same mile-stones for PFAS are not yet reached. The mechanistic complexity of PFAS has stymied efforts to fully characterize the mechanism of action.

Unlike dioxin-like compounds, whose toxic effects are almost all mediated by a single receptor, the toxicity of any given PFAS is governed by multiple receptor and nonreceptor mechanisms. The first identified and best understood mechanism of action of PFAS is their ability to bind to the peroxisome proliferator- activated receptors (PPAR). The PPAR family was first identified in 1990,89 and research on mechanisms of action for PFAS did not begin until around the turn of the century; the first evidence that PFOA binds to PPARa was published in 1999.90 Since then, numerous studies have investigated the ability of different PFAS to bind and activate PPARs, particularly PPARa and PPARc.91-97 In the absence of exogenous ligands, PPARs bind to specific en-dogenous lipid ligands, translocate to the nucleus, and function as transcription factors. Activated PPARs affect expression of genes related to metabolism, including processing of fatty acids, lipopro-teins, and glucose homeostasis.98 Drugs that bind and activate the PPARs have effects on plasma levels of triglycerides and choles-terol,99 which has disturbing implications for the potential health effects of PFAS. Binding of PFAS to PPARa leads to liver tumors in mice, but liver tumors can also occur in PPARa knockout mice, signifying alternative mechanisms.91

Additional in vivo and in vitro research has identified the acti-vation of other receptors by PFAS, including the constitutive an-drostane receptor (CAR)100,101 and the pregnane X-receptor (PXR).101,102 Recent in silico evidence suggests that, to varying degrees, different PFAS interact with as many as 14 total nuclear receptors,103 including the androgen receptor (AR) and estrogen receptors (ERs). These receptors vary in their expression in different tissues and in various stages of development, further com-plicating the PFAS mechanism of action. For example, PPARa is highly expressed in the liver, heart, and small intestine, in contrast to PPARc, which is highly expressed in adipose tissue.99

Much research is still required on downstream effects of PFAS binding to nuclear receptors. To date, despite strong association of PFAS with health effects, including impairment of the immune system and some cancers,23,24 researchers have not drawn a clear line between any molecular initiating event of PFAS and the pathophysiology observed in epidemiological studies.22

Furthermore, unlike the dioxin-like compounds, PFAS also have multiple putative nonreceptor-based molecular initiating events that appear to have nontrivial effects. These include interfer-ing with lipid metabolism, partitioning into lipid bilayers, interfer-ing with mitochondrial function, causing oxidative stress, and interfering with protein-protein interactions and cell signaling pathways by directly binding to proteins.22 It is interesting to note that several putative mechanistic components of PFAS can be attributed to their structural resemblance to fatty acids or other am-phipathic linear lipids. The nuclear receptors mentioned above have endogenous ligands that are fatty acids or related lipids,104 and researchers have noted the structural resemblance between fatty acids and many PFAS compounds, which have long carbon chains and polar heads.105 Structural similarity of some PFAS to phospholipids has been confirmed by researchers who demon-strated partitioning into lipid bilayers.106 We still need to rigor-ously test how these contribute to the observed cellular and organismal effectsof PFAS.22

We will next discuss how the single molecular initiating event of the dioxin-like compounds makes them amenable to an effec-tive regulatory policy, although the multiple bases for biological effects of PFAS make it difficult to choose an ideal regulatory strategy.

Regulatory Approaches

We believe the fundamentally different properties of the dioxin-like chemicals and PFAS-physicochemical, mechanistic, and otherwise-translate to a fundamental need for different regula-tory approaches. The characteristics of dioxin-like compounds we have discussed so far-their unified initiating mechanism of action and their persistence in the environment-make them suited to a special form of the relative potency factor approach called toxic equivalencies. This framework has four key criteria for inclusion as a dioxin-like chemical: a) it must be structurally related to TCDD; b) it must bind to the AhR; c) its biochemical and toxic responses are mediated by activation of the AhR; and d) it must be persistent and bioaccumulate.34 For each chemical that meets all criteria, the approach assigns a toxic equivalency factor (TEF) that summarizes the toxic effects across all toxic end points and multiple test species. The toxic equivalency (TEQ) approach can be applied to dioxin-like mixtures of known composition to establish their potency in terms of an equivalent amount of pure TCDD, the most toxic of the dioxin-like chemi-cals.34 At the inception of the TEQ method in the 1990s, the alternatives were limited; other approaches were to consider all these chemicals as equally toxic to TCDD, or on the opposite extreme, ignoring the congeners that lacked toxicological data.107 The TEQ approach was therefore a rational middle ground. Initially conceived as a placeholder, the TEQ approach has proven to be a useful framework for dioxin-like chemicals. These early relative potency values have undergone only minor changes since their initial publication,34,108,109 and the framework is still used today.35,110 An interesting feature of the dioxin-like chemicals is that TEQ values are used to quantify emissions12 as well as to determine the degree of contamination at a given site.111 Thus, our mechanistic toxicological knowledge of these chemicals, which includes 17 unintentionally produced dioxins and fur-ans, is tied to both upstream and downstream regulation.

PFAS, on the other hand, likely require a different approach. The cornerstone of the toxic equivalency approach for dioxin-like compounds is that they all agonize the AhR, but there is no evi-dence for an equivalent mechanism for PFAS, and this fundamen-tally prevents assignment of TEFs for PFAS.112 However, useful strides have been made with other approaches for screening and risk assessment. For example, relative potency factors (RPFs), which are related to toxic equivalency factors, may have use for PFAS. RPFs apply to the relative potency of a particular end point, such as hepatoxicity, immunotoxicity, or developmental toxicity, and are less generalized than TEFs, which summarize all toxicity end points in a single number. Bil et al. calculated RPFs for 22 PFAS based on liver toxicity in male rats and gave examples of how this approach might be used in risk assessment.113 They acknowledge, however, that the PFAS they studied have important end points outside of liver toxicity, illustrating a major limitation of the RPF approach. For example, although PFOA is a more potent activator of PPARa than is PFOS, PFOS is more potent as a developmental toxicant112; this is a clear example of how the higher potency of a given PFAS for one end point does not deter-mine a similar outcome for all end points. Analysis from another group demonstrated that the relative potency factor for PFOS rela-tive toPFOA depended on the end point measured (such aspup survival or pup liver glycogen in rats) and ranged more than 20-fold.114 This characteristic makes it inappropriate to use a single RPF for all PFAS.

Although the RPF approach has its limitations, it is an example of an alternative to the chemical-by-chemical approach. Rules that impose restrictionsononly one or a handfulof PFAS represent pro-gress, but we believe they are insufficient for a long-term solution. For example, in 2020 the US Food and Drug Administration (FDA) issued a voluntary phaseout of food contact substances con-taining a single PFAS, 6:2 FTOH.115 In the United States, the Unregulated Contaminant Monitoring Rules (UCMR) require monitoring of some currently unregulated chemicals in drinking water and are periodically updated. UCMR 3 included 4 PFAS (PFHpA, PFNA, PFBS, and PFHxS), and the upcoming UCMR 5 includes measurement of 29 individual PFAS in municipal drinking water.116,117 However, with thousands of PFAS posing a poten-tial threat, performing monitoring and toxicity testing on a chemical-by-chemical basis is impossible. Measuring and calculat-ing the toxic equivalency factors for dioxins was a challenging but finite endeavor. The monetary and time cost of such an effort for PFAS would beastronomical.

Efforts are underway to restrict production of some PFAS sub-classes and allow others to be produced. One ofthe largest examples of this approach has been a phaseout of long-chain PFAS in favor of shorter-chain PFAS, with the rationale that shorter-chain PFAS have shorter half-lives in biota16 and are therefore less toxic. For example, as part of the US EPA's 2010/2015 Stewardship Program, eight major manufacturers of PFAS phased out long-chain precursors of PFOA.118 However, for the handful of short-chain PFAS that have been studied, biological effects similar to those of long-chain PFAS have been found.119-122 Critically, short-chain PFAS are also highly persistent in the environment: They do not naturally degrade to non-PFAS substances. Continual, poorly reversible exposure123 may mean that the shorter biological half-lives of these chemicals are not sufficient to protect human health. We believe the transition from longer to shorter-chain PFAS is an example of why regulating only subgroups of PFAS may be insufficient in the long term. There is a tendency toward invention of replacement chemicals that are untested but have similar properties. And because PFAS are intentionally created but PCDDs and PCDFs were unin-tentional, we argue that PFAS are more challenging to regulate because of the potential for regrettable substitution.124

Mechanistic understanding for the thousands of PFAS in the environment currently eludes us and likely will continue to do so for some time absent paradigm-shifting innovations in toxicity testing. But we have enough data about PFAS to warrant concern for human health and to know how persistent PFAS are in the environment. Here, we argue that an important first step to get-ting ahead of this problem is broad, upstream restriction of PFAS production as a chemical class, an approach that has already gained significant support.15,124,125 For dioxin-like chemicals, governments and industry worked to successfully cut emissions. We believe the same urgency should be applied to stem the production of new PFAS, whose environmental persistence is even greater.

If PFAS are to be regulated broadly as a class, our previously mentioned discussion of the definition of PFAS becomes even more important. For instance, industry often cites some PFAS as deserving exceptions to a uniform approach, but they have prob-lematic life cycles. Fluoropolymers, for example, although toxi-cologically inert,126,127 require other, highly toxic PFAS for their production, and many fluoropolymers also break down during their lifecycle to release monomeric PFAS, including perfluor-oalkyl carboxylic acids (PFCAs).15,128 Thus, we argue that broad restrictions on PFAS as a class are appropriate.

A practical implementation of a classwide restriction would involve the concept of essential use. This model bans all PFAS within specified use categories, such as food contact materials, fire-fighting foam, and textiles, but allows other use categories that are considered critical for health or safety, such as fluoropolymers in some medical devices.129 A successful example of essential use has been the Stockholm Convention, which bans three key PFAS (PFOA, PFOS, and PFHxS) but allows limited acceptable uses.1

Stemming the flow of PFAS production is just part of the solu-tion. PFAS are already ubiquitous in the environment, with many communities suffering from serious contamination. This ubiquity raises the questions of how much PFAS are acceptable in various environmental media, and if levels are too high, how will they be remediated and who will pay for it? Although the complex chal-lenges ofcleanup and remediation are not the focus of this commen-tary, we issue a call to action for funding cleanup of contaminated communities, as well as advancing research on remediation of PFAS.

Conclusion

TCDD and related compounds that bind the AhR are infamous, with a storied history of public concern. These chemicals act at extremely low doses; the tolerable weekly intake from food is just 2 pg=kg body weight.14 Even though the generation of dioxin-like chemicals has waned thanks to a successful program of regulation and emissions reduction, most dioxins produced in the 20th century are still in the environment due to their slow rate of degradation.

When the pressure to control dioxin emissions came to a head in the 1990s, governments were able to mobilize and require alterations to the processes producing these harmful waste products. But unlike dioxin-like chemicals, PFAS are extremely valu-able and useful,26,27 and in our opinion, the pushback from industry against regulating them is intense because it acutely dis-rupts commercial and financial interests.130-132 Powerful litiga-tion campaigns from chemical manufacturers,60 combined with ambiguity and disagreement over best upstream regulatory strat-egies, are delaying attempts to rein in production of new PFAS. Because of their usefulness, their complex mechanisms that evade regulatory and toxicity screening strategies, and their extreme persistence in the environment, we argue that PFAS have the potential for a greater negative impact on environmental health than TCDD and the dioxin-like compounds, even though they are not as toxic on a molecule-for-molecule basis.

There are still lessons from the story of dioxins that can help us tackle the PFAS problem. The lingering effects of dioxin as microcontamination of the food supply and highly contaminated communities reveal the need for proactive funding of remediation research and allocating funds to communities for cleanup. This is especially true for PFAS because their environmental persistence surpasses dioxin-like chemicals5,16; even if we completely stopped creating new carbon-fluorine bonds immediately, absent sufficient remediation, exposures to forever chemicals would continue indefinitely.

Furthermore, because of the serious threat of PFAS to human health, and because of myriad barriers to successfully regulate PFAS individually or as subgroups, we favor regulatory approaches that restrict production of PFAS broadly. Although some have argued that this approach overestimates the hazard of PFAS, we maintain that the severity of the problem warrants a unilateral approach to protect human health and the environment. Efforts from multiple levels of government133,134 and from indus-try that target PFAS as a class are beginning to take hold, such as 3M's commitment to eliminating production of all PFAS by 2025.135 We hope that framing PFAS in the historical context of another group of challenging chemicals, the dioxin-like com-pounds, will offer an opportunity for reflection and inspire actions toward health-protective policies.

Acknowledgments

Research reported in this publication was supported by the National Institute of Environmental Health Sciences of the National Institutes of Health under Award Number T32ES021432 (Duke University Program in Environmental Health). The content is solely the responsibility of the authors and does not necessarily represent the official viewsof the National Institutes of Health.

References

References

1. UNEP (UN Environment Programme). 2019. Stockholm Convention on Persistent Organic Pollutants (POPS): Text and Annexes (A). https://www. pops.int/TheConvention/Overview/TextoftheConvention/tabid/2232/Default.aspx [accessed 19 September 2023].

2. DeVito MJ, Birnbaum LS. 1994. Toxicology of Dioxins and Related Chemicals. In: Dioxins and Health. Schecter A, ed. New York, NY: Plenum Press, 139-162.

3. Schecter A, Birnbaum L, Ryan JJ, Constable JD. 2006. Dioxins: an overview. Environ Res 101(3):419-428, PMID: 16445906, https://doi.org/10.1016/j.envres. 2005.12.003.

4. American Chemical Society. 1983. Dioxin report. Chem Eng News Archive 61(23):20. https://doi.org/10.1021/cen-v061n023.p020.

5. Alcock RE, Jones KC. 1996. Dioxins in the environment: a review of trend data. Environ Sci Technol 30(11):3133-3143, https://doi.org/10.1021/es960306z.

6. Eskenazi B, Warner M, Brambilla P, Signorini S, Ames J, Mocarelli P. 2018. The Seveso accident: a look at 40 years of health research and beyond. Environ Int 121(pt 1):71-84, PMID: 30179766, https://doi.org/10.1016/j.envint.2018.08.051.

7. SorgO, ZenneggM, Schmid P, FedosyukR, ValikhnovskyiR, Gaide O,etal. 2009. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) poisoning in Victor Yushchenko: identification and measurement of TCDD metabolites. Lancet 374(9696):1179- 1185, PMID: 19660807, https://doi.org/10.1016/S0140-6736(09)60912-0.

8. Consonni D, Sindaco R, Bertazzi PA. 2012. Blood levels of dioxins, furans, dioxin-like PCBs, and TEQs in general populations: a review, 1989-2010. Environ Int 44:151-162, PMID: 22364893, https://doi.org/10.1016/j.envint.2012.01.004.

9. Pham DT, Nguyen HM, Boivin TG, Zajacova A, Huzurbazar SV, Bergman HL. 2015. Predictors for dioxin accumulation in residents living in Da Nang and Bien Hoa, Vietnam, many years after Agent Orange use. Chemosphere 118:277-283, PMID: 25463251, https://doi.org/10.1016/j.chemosphere.2014.09.064.

10. Baccarelli A, Giacomini SM, Corbetta C, Landi MT, Bonzini M, Consonni D, et al. 2008. Neonatal thyroid function in Seveso 25 years after maternal exposure to dioxin. PLoS Med 5(7):e161, PMID: 18666825, https://doi.org/10.1371/journal. pmed.0050161.

11. Garabrant DH, Franzblau A, Lepkowski J, Gillespie BW, Adriaens P, Demond A, et al. 2009. The university of Michigan dioxin exposure study: predictors of

human serum dioxin concentrations in Midland and Saginaw, Michigan. Environ Health Perspect 117(5):818-824, PMID: 19479027, https://doi.org/10. 1289/ehp.11779.

12. US EPA (US Environmental Protection Agency). 2006. An Inventory of Sources and Environmental Releasesof Dioxin-Like CompoundsInthe U.S. For the Years 1987, 1995, and 2000. Washington, DC: US Environmental Protection Agency.

13. Marquès M, Domingo JL. 2019. Concentrations of PCDD/Fs in human blood: a review of data from the current decade. Int J Environ Res Public Health 16(19):3566, PMID: 31554236, https://doi.org/10.3390/ijerph16193566.

14. Knutsen HK, Alexander J, Barregård L, Bignami M, Brüschweiler B, Ceccatelli S, et al. 2018. Risk for animal and human health related to the presence of diox-ins and dioxin-like PCBs in feed and food. EFSA J 16(11):e05333, PMID: 32625737, https://doi.org/10.2903/j.efsa.2018.5333.

15. Cousins IT, DeWitt JC, Glüge J, Goldenman G, Herzke D, Lohmann R, et al. 2020. The high persistence of PFAS is sufficient for their management as a chemical class. Environ Sci Process Impacts 22(12):2307-2312, PMID: 33230514, https://doi.org/10.1039/d0em00355g.

16. Interstate Technology and Regulatory Council. 2022. Technical Resources for Addressing Environmental Releases of Per- and Polyfluoroalkyl Substances (PFAS). https://pfas-1.itrcweb.org/ [accessed 24 May 2023].

17. UNEP. 2019. Listing of perfluorooctanoic acid (PFOA), its salts and PFOA-related compounds. SC-9/12; Stockholm Convention on Persistent Organic Pollutants. https://www.pops.int/TheConvention/ConferenceoftheParties/Meetings/COP9/ tabid/7521/Default.aspx [accessed 23 April 2024].

18. UNEP. 2019. Perfluorooctane sulfonic acid, its salts and perfluorooctane sulfonyl fluoride. SC-9/4; Stockholm Convention on Persistent Organic Pollutants. https:// www.pops.int/TheConvention/ConferenceoftheParties/Meetings/COP9/tabid/ 7521/Default.aspx [accessed 23 April 2024].

19. UNEP. 2022. Listing of perfluorohexane sulfonic acid (PFHxS), its salts and PFHxS-related compounds. SC-10/13; Stockholm Convention on Persistent Organic Pollutants. https://www.pops.int/TheConvention/ConferenceoftheParties/Meetings/ COP10/tabid/8397/Default.aspx [accessed 23 April 2024].

20. Mhaske ST, Mohanty JD, Chugh KW. 2023. Fluoropolymers: brief history, fun-damental chemistry, processing, structure, properties, and applications. In: Advanced Fluoropolymer Nanocomposites. Deshmukh K, Hussain CM, eds. Cambridge, UK: Woodhead Publishing, 1-27. https://doi.org/10.1016/B978-0-323-95335-1.00006-2.

21. Panieri E, Baralic K, Djukic-Cosic D, Buha Djordjevic A, Saso L. 2022. PFAS molecules: a major concern for the human health and the environment. Toxics 10(2):44, PMID: 35202231, https://doi.org/10.3390/toxics10020044.

22. Fenton SE, Ducatman A, Boobis A, DeWitt JC, Lau C, Ng C, et al. 2021. Perand polyfluoroalkyl substance toxicity and human health review: current state of knowledge and strategies for informing future research. Environ Toxicol Chem 40(3):606-630, PMID: 33017053, https://doi.org/10.1002/etc.4890.

23. National Academies of Sciences, Engineering, Health and Medicine Division, Division on Earth and Life Studies, Board on Population Health and Public Health Practice, Board on Environmental Studies and Toxicology, & Committee on the Guidance on PFAS Testing and Health Outcomes. 2022. Potential Health Effects of PFAS. In: Guidance on PFAS Exposure, Testing, and Clinical Follow-Up. Washington, DC: National Academies Press.

24. Zahm S, Bonde JP, Chiu WA, Hoppin J, Kanno J, Abdallah M, et al. 2024. Carcinogenicity of perfluorooctanoic acid and perfluorooctanesulfonic acid. Lancet Oncol 25(1):16-17, PMID: 38043561, https://doi.org/10.1016/S1470-2045 (23)00622-8.

25. Richter L, Cordner A, Brown P. 2018. Non-stick science: sixty years of research and (in)action on fluorinated compounds. Soc Stud Sci 48(5):691- 714, PMID: 30235980, https://doi.org/10.1177/0306312718799960.

26. Glüge J, Scheringer M, Cousins IT, DeWitt JC, Goldenman G, Herzke D, et al. 2020. An overview of the uses of per- and polyfluoroalkyl substances (PFAS). Environ Sci Process Impacts 22(12):2345-2373, PMID: 33125022, https://doi.org/ 10.1039/d0em00291g.

27. Wood Environment & Infrastructure Solutions UK Limited. 2020. Socio-Economic Assessment of the US Fluoropolymer Industry-Executive Summary. https:// fluoropolymerpartnership.com/wp-content/uploads/2020/03/Socio-Economic-Assessment-of-the-US-Fluoropolymer-Industry-Executive-Summary.pdf [accessed 21 May 2024].

28. Labadie P, Chevreuil M. 2011. Partitioning behaviour of perfluorinated alkyl contaminants between water, sediment and fish in the Orge River (nearby Paris, France). Environ Pollut 159(2):391-397, PMID: 21112680, https://doi.org/ 10.1016/j.envpol.2010.10.039.

29. Zhang L, Ren X-M, Guo L-H. 2013. Structure-based investigation on the inter-action of perfluorinated compounds with human liver fatty acid binding pro-tein. Environ Sci Technol 47(19):11293-11301, PMID: 24006842, https://doi.org/ 10.1021/es4026722.

30. Dassuncao C, Pickard H, Pfohl M, Tokranov AK, Li M, Mikkelsen B, et al. 2019. Phospholipid levels predict the tissue distribution of poly- and perfluoroalkyl substances in a marine mammal. Environ Sci Technol Lett 6(3):119-125, PMID: 33283018, https://doi.org/10.1021/acs.estlett.9b00031.

31. Cousins IT, DeWitt JC, Glüge J, Goldenman G, Herzke D, Lohmann R, et al.2020. Strategies for grouping per- and polyfluoroalkyl substances (PFAS) to protect human and environmental health. Environ Sci Process Impacts 22(7):1444-1460, PMID: 32495786, https://doi.org/10.1039/d0em00147c.

32. US EPA. 2024. PFAS National Primary Drinking Water Regulation. 89 Fed Reg 32532. https://www.federalregister.gov/documents/2024/04/26/2024-07773/pfas-national-primary-drinking-water-regulation [accessed 27 May 2024].

33. Ahlborg U, Becking G, Birnbaum L, Brouwer A, Derks H, Feeley M, et al. 1994. Toxic equivalency factors for dioxin-like PCBs: report on WHO-ECEH and IPCS consultation, December 1993. Chemosphere 28(6):1049-1067, https://doi.org/10. 1016/0045-6535(94)90324-7.

34. Van den Berg M, Birnbaum L, Bosveld AT, Brunström B, Cook P, Feeley M, et al. 1998. Toxic equivalency factors (TEFs) for PCBs, PCDDs, PCDFs for humans and wildlife. Environ Health Perspect 106(12):775-792, PMID: 9831538, https://doi.org/10.1289/ehp.98106775.

35. Wikoff D, Ring C, DeVito M, Walker N, Birnbaum L, Haws L. 2023. Development and application of a systematic and quantitative weighting framework to evalu-ate the quality and relevance of relative potency estimates for dioxin-like com-pounds (DLCs) for human health risk assessment. Regul Toxicol Pharmacol 145:105500, PMID: 37866700, https://doi.org/10.1016/j.yrtph.2023.105500.

36. US Congress. Toxic Substances Control Act. 1976. Pub L No. 15 U.S.C. § 2601. https://uscode.house.gov/view.xhtml?path=/prelim@title15/chapter53&edition= prelim [accessed 6 April 2024].

37. US EPA. Polychlorinated Biphenyls (PCBs). 1979. Manufacturing, Processing, Distribution in Commerce, and Use Prohibitions. Final Rule, 40 CFR Part 761 § Vol. 44 No. 106. https://www.ecfr.gov/current/title-40/chapter-I/subchapter-R/ part-761?toc=1 [accessed 6 April 2024].

38. Buck RC, Franklin J, Berger U, Conder JM, Cousins IT, de Voogt P, et al. 2011. Perfluoroalkyl and polyfluoroalkyl substances in the environment: terminol-ogy, classification, and origins. Integr Environ Assess Manag 7(4):513-541, PMID: 21793199, https://doi.org/10.1002/ieam.258.

39. OECD (Organisation for Economic Co-operation and Development). 2018. Toward a New Comprehensive Global Database of Per- and Polyfluoroalkyl Substances (PFASs): Summary Report on Updating the OECD 2007 List of Perand Polyfluoroalkyl Substances (PFASs), OECD Series on Risk Management of Chemicals, OECD Publishing, Paris, https://doi.org/10.1787/1a14ad6c-en.

40. OECD. 2021. Reconciling Terminology of the Universe of Per- and Polyfluoroalkyl Substances: Recommendations and Practical Guidance, OECD Series on Risk Management of Chemicals, OECD Publishing, Paris, https://doi.org/10.1787/ e458e796-en.

41. US EPA. 2022. PFAS structures in DSSTox. https://comptox.epa.gov/dashboard/ chemical-lists/PFASSTRUCTV5 [accessed 28 May 2024].

42. Washington JW, Rosal CG, McCord JP, Strynar MJ, Lindstrom AB, Bergman EL, et al. 2020. Nontargeted mass-spectral detection of chloroperfluoropo-lyether carboxylates in New Jersey soils. Science (6495):1103-1107, PMID: 32499438, https://doi.org/10.1126/science.aba7127.

43. Zheng G, Eick SM, Salamova A. 2023. Elevated levels of ultrashort- and short-chain perfluoroalkyl acids in US homes and people. Environ Sci Technol 57(42):15782-15793, PMID: 37818968, https://doi.org/10.1021/acs.est.2c06715.

44. Charbonnet JA, Rodowa AE, Joseph NT, Guelfo JL, Field JA, Jones GD, et al.

2021. Environmental source tracking of per- and polyfluoroalkyl substances within a forensic context: current and future techniques. Environ Sci Technol 55(11):7237-7245, PMID: 33983714, https://doi.org/10.1021/acs.est.0c08506.

45. Aylward LL, Hays SM. 2002. Temporal trends in human TCDD body burden: decreases over three decades and implications for exposure levels. J Expo Anal Environ Epidemiol 12(5):319-328, PMID: 12198580, https://doi.org/10.1038/ sj.jea.7500233.

46. Masuda Y, Kuroki H, Haraguchi K, Nagayama J. 1985. PCB and PCDF conge-ners in the blood and tissues of yusho and yu-cheng patients. Environ Health Perspect 59:53-58, PMID: 3921365, https://doi.org/10.1289/ehp.59-1568081.

47. Dwernychuk LW, Cau HD, Hatfield CT, Boivin TG, Hung TM, Dung PT, et al. 2002. Dioxin reservoirs in Southern Viet Nam-a legacy of agent orange. Chemosphere 47(2):117-137, PMID: 11993628, https://doi.org/10.1016/s0045-6535(01)00300-9.

48. National Academies of Sciences, Engineering, and Medicine, Health and Medicine Division, Board on Population Health and Public Health Practice, & Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Eleventh Biennial Update). 2018. Veterans and Agent Orange: Update 11 (2018). Washington, DC: National Academies Press.

49. Little J. 2020. A Town, a Flood, and Superfund: looking Back at the Times Beach Disaster Nearly 40 Years Later. https://www.epa.gov/mo/town-flood-and-superfund-looking-back-times-beach-disaster-nearly-40-years-later.

50. Needham LL, Gerthoux PM, Patterson DG Jr., Brambilla P, Turner WE, Beretta C, et al. 1997. Serum dioxin levels in Seveso, Italy, population in 1976. Teratog

Carcinog Mutagen 17(4-5):225-240, https://doi.org/10.1002/(SICI)1520-6866 (1997)17:4/5<225:AID-TCM5>3.0.CO;2-K.

51. US Congress. 1990. Clean Air Act Amendments of 1990. Pub. L. No. 101-549, 104 Stat. 2468. https://www.congress.gov/bill/101st-congress/senate-bill/1630 [accessed 8 May 2024].

52. US EPA. 1998. National Emission Standards for Hazardous Air Pollutants for Source Category: Pulp and Paper Production; Effluent Limitations Guidelines, Pretreatment Standards, and New Source Performance Standards: Pulp, Paper, and Paperboard Category. 40 CFR Parts 63, 261 and 430. https://www. federalregister.gov/documents/1998/04/15/98-9613/national-emission-standards-for-hazardous-air-pollutants-for-source-category-pulp-and-paper [accessed 20 September 2023].

53. Quass U, Fermann M, Bröker G. 2004. The European dioxin air emission inven-tory project-final results. Chemosphere 54(9):1319-1327, PMID: 14659425, https://doi.org/10.1016/S0045-6535(03)00251-0.

54. Dwyer H, Themelis NJ. 2015. Inventory of U.S. 2012 dioxin emissions to atmos-phere. Waste Manag 46:242-246, PMID: 26297638, https://doi.org/10.1016/j. wasman.2015.08.009.

55. Dopico M, Gómez A. 2015. Review of the current state and main sources of dioxins around the world. J Air Waste Manag Assoc 65(9):1033-1049, PMID: 26068294, https://doi.org/10.1080/10962247.2015.1058869.

56. Cao Z, Fiedler H, Wang B, Zhang T, Yu G, Huang J, et al. 2013. Economic status as a determinant of national PCDD/PCDF releases and implications for PCDD/ PCDF reduction. Chemosphere 91(3):328-335, PMID: 23280065, https://doi.org/ 10.1016/j.chemosphere.2012.11.054.

57. Ssebugere P, Sillanpää M, Matovu H, Mubiru E. 2019. Human and environmental exposure to PCDD/Fs and dioxin-like PCBs in Africa: a review. Chemosphere 223:483-493, PMID: 30784755, https://doi.org/10.1016/j.chemosphere.2019.02.065.

58. Zhao B, Zheng M, Jiang G. 2011. Dioxin emissions and human exposure in China: a brief history of policy and research. Environ Health Perspect 119(3): A112-A113, PMID: 21356622, https://doi.org/10.1289/ehp.1103535.

59. Hites RA. 2011. Dioxins: an overview and history. Environ Sci Technol 45(1):16-20, PMID: 20815379, https://doi.org/10.1021/es1013664.

60. Rich N. 2016. Rob Bilott v. Dupont. New York Times Magazine. 10 January 2016. https://www.nytimes.com/2016/01/10/magazine/the-lawyer-who-became-duponts-worst-nightmare.html?ref=magazine [accessed 12 May 2024].

61. Grandjean P. 2018. Delayed discovery, dissemination, and decisions on interven-tion in environmental health: a case study on immunotoxicity of perfluorinated al-kylate substances. Environ Health 17(1):62, PMID: 30060739, https://doi.org/10. 1186/s12940-018-0405-y.

62. Michaels D. 2020. The Triumph of Doubt: Dark Money and the Science of Deception. New York, NY: Oxford University Press.

63. Gaber N, Bero L, Woodruff TJ. 2023. The devil they knew: chemical docu-ments analysis of industry influence on PFAS science. Ann Glob Health 89(1):37, PMID: 37273487, https://doi.org/10.5334/aogh.4013.

64. Leach, et al v. E. I. DuPont deNemours and Co. No. 01-C-608, 2002 WL 1270121, at *1 (W. Va. Cir. Ct. April 10, 2002).

65. Gaines LGT. 2023. Historical and current usage of per- and polyfluoroalkyl substances (PFAS): a literature review. Am J Ind Med 66(5):353-378, PMID: 35614869, https://doi.org/10.1002/ajim.23362.

66. Barry V, Winquist A, Steenland K. 2013. Perfluorooctanoic acid (PFOA) expo-sures and incident cancers among adults living near a chemical plant. Environ Health Perspect 121(11-12):1313-1318, PMID: 24007715, https://doi.org/10.1289/ ehp.1306615.

67. CityofLake Elmov.3MCompany. 2017. No. 16-2557 ADM/SER 2017-02-15237. 237 F. Supp. 3d 877 (D. Minn. 2017). https://dockets.justia.com/docket/minnesota/ mndce/0:2016cv02557/157834 [accessed 12 May 2024].

68. Harada K, Saito N, Inoue K, Yoshinaga T, Watanabe T, Sasaki S, et al. 2004. The influence of time, sex and geographic factors on levels of perfluorooctane sul-fonate and perfluorooctanoate in human serum over the last 25 years. J Occup Health 46(2):141-147, PMID: 15090689, https://doi.org/10.1539/joh.46.141.

69. Andersson EM, Scott K, Xu Y, Li Y, Olsson DS, Fletcher T, et al. 2019. High ex-posure to perfluorinated compounds in drinking water and thyroid disease. A cohort study from Ronneby, Sweden. Environ Res 176:108540, PMID: 31252203, https://doi.org/10.1016/j.envres.2019.108540.

70. Olsen GW, Burris JM, Mandel JH, Zobel LR. 1999. Serum perfluorooctane sulfo-nate and hepatic and lipid clinical chemistry tests in fluorochemical production employees. J Occup Environ Med 41(9):799-806, PMID: 10491796, https://doi.org/ 10.1097/00043764-199909000-00012.

71. US EPA. 2000. EPA and 3M Announce Phase Out of PFOS. https://www.epa. gov/archive/epapages/newsroom_archive/newsreleases/33aa946e6cb11f 35852568e1005246b4.html [accessed 3 September 2023].

72. Kotlarz N, McCord J, Collier D, Lea CS, Strynar M, Lindstrom AB, et al. 2020. Measurementof novel, drinking water-associated PFAS inblood from adults and children in Wilmington, North Carolina. Environ Health Perspect 128(7):077005, PMID: 32697103, https://doi.org/10.1289/EHP6837.

73. Ingelido AM, Abballe A, Gemma S, Dellatte E, Iacovella N, De Angelis G, et al.

2018. Biomonitoring of perfluorinated compounds in adults exposed to conta-minated drinking water in the Veneto Region, Italy. Environ Int 110:149-159, PMID: 29108835, https://doi.org/10.1016/j.envint.2017.10.026.

74. East A, Anderson RH, Salice CJ. 2021. Per- and polyfluoroalkyl substances (PFAS) in surface water near US Air Force bases: prioritizing individual chemicals and mixtures for toxicity testing and risk assessment. Environ Toxicol Chem 40(3):859-870, PMID: 33026654, https://doi.org/10.1002/etc. 4893.

75. Sunderland EM, Hu XC, Dassuncao C, Tokranov AK, Wagner CC, Allen JG. 2019. A review of the pathways of human exposure to poly- and perfluor-oalkyl substances (PFASs) and present understanding of health effects. J Expo Sci Environ Epidemiol 29(2):131-147, PMID: 30470793, https://doi.org/ 10.1038/s41370-018-0094-1.

76. Oliaei F, Kriens D, Weber R, Watson A. 2013. PFOS and PFC releases and associated pollution from a PFC production plant in Minnesota (USA). Environ Sci Pollut Res Int 20(4):1977-1992, PMID: 23128989, https://doi.org/10.1007/ s11356-012-1275-4.

77. Hu XC, Andrews DQ, Lindstrom AB, Bruton TA, Schaider LA, Grandjean P, et al. 2016. Detection of poly- and perfluoroalkyl substances (PFASs) in U.S. drinking water linked to industrial sites, military fire training areas, and waste-water treatment plants. Environ Sci Technol Lett 3(10):344-350, PMID: 27752509, https://doi.org/10.1021/acs.estlett.6b00260.

78. Kato K, Wong L-Y, Jia LT, Kuklenyik Z, Calafat AM. 2011. Trends in exposure to polyfluoroalkyl chemicals in the U.S. population: 1999-2008. Environ Sci Technol 45(19):8037-8045, PMID: 21469664, https://doi.org/10.1021/es1043613.

79. Sinkkonen S, Paasivirta J. 2000. Degradation half-life times of PCDDs, PCDFs and PCBs for environmental fate modeling. Chemosphere 40(9-11):943-949, PMID: 10739030, https://doi.org/10.1016/s0045-6535(99)00337-9.

80. Evich MG, Davis MJB, McCord JP, Acrey B, Awkerman JA, Knappe DRU, et al. 2022. Per- and polyfluoroalkyl substances in the environment. Science 375(6580):eabg9065, PMID: 35113710, https://doi.org/10.1126/science.abg9065.

81. Zhuang J, Cox JG, Chung M, Hamm JA, Zwickle A, Upham BL. 2019. Risk, stigma, trustworthiness, and citizen participation-a multifaceted analysis of media cov-erage of dioxin contamination in Midland, Michigan. Int J Environ Res Public Health 16(21):4165, PMID: 31671717, https://doi.org/10.3390/ijerph16214165.

82. Safe SH. 1986. Comparative toxicology and mechanism of action of polychlorinated dibenzo-p-dioxins and dibenzofurans. Annu Rev Pharmacol Toxicol 26(1):371-399, PMID:3013079, https://doi.org/10.1146/annurev.pa.26.040186.002103.

83. King-Heiden TC, Mehta V, Xiong KM, Lanham KA, Antkiewicz DS, Ganser A, et al. 2012. Reproductive and developmental toxicity of dioxin in fish. Mol Cell Endocrinol 354(1-2):121-138, PMID: 21958697, https://doi.org/10.1016/j.mce. 2011.09.027.

84. Fernandez-Salguero PM, Hilbert DM, Rudikoff S, Ward JM, Gonzalez FJ. 1996. Aryl-hydrocarbon receptor-deficient mice are resistant to 2,3,7,8-tetrachloro-dibenzo-p-dioxin-induced toxicity. Toxicol Appl Pharmacol 140(1):173-179, PMID: 8806883, https://doi.org/10.1006/taap.1996.0210.

85. Poland A, Glover E, Kende AS. 1976. Stereospecific, high affinity binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin by hepatic cytosol. Evidence that the binding species is receptor for induction of aryl hydrocarbon hydroxylase. J Biol Chem 251(16):4936-4946, PMID: 956169.

86. US EPA. 1987. Interim procedures for estimating risks associated with exposures to mixtures of chlorinated dibenzo-p-dioxins and -dibenzofurans (CDDs and CDFs). EPA/625/3-87/012. NTIS PB-90145756. https://cfpub.epa.gov/ncea/risk/ recordisplay.cfm?deid=54880 [accessed23May 2024].

87. US EPA. 1989. Interim procedures for estimating risks associated with exposures to mixtures of chlorinated dibenzo-p-dioxins and -dibenzofurans (CDDs and CDFs) and 1989 update. https://cfpub.epa.gov/ncea/risk/recordisplay.cfm?deid= 54880 [accessed23May 2024].

88. US EPA. 1991. Workshop report on toxicity equivalency factors for polychlorinated biphenyls congeners. https://nepis.epa.gov/Exe/ZyPURL.cgi?Dockey=20007VFR. txt [accessed 23 May 2024].

89. Issemann I, Green S. 1990. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 347(6294):645-650, PMID: 2129546, https://doi.org/10.1038/347645a0.

90. Maloney EK, Waxman DJ. 1999. Trans-activation of PPARa and PPAR? by structur-ally diverse environmental chemicals. Toxicol Appl Pharmacol 161(2):209-218, PMID:10581215, https://doi.org/10.1006/taap.1999.8809.

91. Filgo AJ, Quist EM, Hoenerhoff MJ, Brix AE, Kissling GE, Fenton SE. 2015. Perfluorooctanoic acid (PFOA)-induced liver lesions in two strains of mice fol-lowing developmental exposures: PPARa is not required. Toxicol Pathol 43(4):558-568, PMID: 25398757, https://doi.org/10.1177/0192623314558463.

92. Cheng X, Klaassen CD. 2008. Perfluorocarboxylic acids induce cytochrome P450 enzymes in mouse liver through activation of PPAR-a and CAR transcription factors. Toxicol Sci 106(1):29-36, PMID: 18648086, https://doi.org/10.1093/ toxsci/kfn147.

93. Wolf DC, Moore T, Abbott BD, Rosen MB, Das KP, Zehr RD, et al. 2008. Comparative hepatic effects of perfluorooctanoic acid and WY 14,643 in PPAR-alpha knockout and wild-type mice. Toxicol Pathol 36(4):632-639, PMID: 18467680, https://doi.org/10.1177/0192623308318216.

94. Houck KA, Patlewicz G, Richard AM, Williams AJ, Shobair MA, Smeltz M, et al. 2021. Bioactivity profiling of per- and polyfluoroalkyl substances (PFAS) identi-fies potential toxicity pathways related to molecular structure. Toxicology 457:152789, PMID: 33887376, https://doi.org/10.1016/j.tox.2021.152789.

95. Takacs ML, Abbott BD. 2007. Activation of mouseand human peroxisome prolif-erator-activated receptors (<x, p/8, y) by perfluorooctanoic acid and perfluor-ooctane sulfonate. Toxicol Sci 95(1):108- 117, PMID: 17047030, https://doi.org/ 10.1093/toxsci/kfl135.

96. Vanden Heuvel JP,Thompson JT, Frame SR, Gillies PJ.2006. Differential activation of nuclear receptors by perfluorinated fatty acid analogs and natural fatty acids: a comparison of human, mouse, and rat peroxisome proliferator-activated receptor-a, -p, and -y, liverX receptor-p, and retinoid X receptor-a. Toxicol Sci 92(2):476-489, PMID: 16731579, https://doi.org/10.1093/toxsci/kfl014.

97. Evans N, Conley JM, Cardon M, Hartig P, Medlock-Kakaley E, Gray LE. 2022. In vitro activityof a panel of per- and polyfluoroalkyl substances (PFAS), fatty acids, and pharmaceuticals in peroxisome proliferator-activated receptor (PPAR) alpha, PPAR gamma, and estrogen receptor assays. Toxicol Appl Pharmacol 449:116136, PMID: 35752307, https://doi.org/10.1016/j.taap.2022.116136.

98. Mandard S, Müller M, Kersten S. 2004. Peroxisome proliferator-activated receptor atarget genes. Cell Mol Life Sci 61(4):393-416, PMID: 14999402, https://doi.org/10. 1007/s00018-003-3216-3.

99. Kersten S. 2008. Peroxisome proliferator activated receptors and lipoprotein metabolism. PPAR Res 2008:132960, PMID: 18288277, https://doi.org/10.1155/ 2008/132960.

100. Rosen MB, Das KP, Rooney J, Abbott B, Lau C, Corton JC. 2017. PPARa-inde-pendent transcriptional targets of perfluoroalkyl acids revealed by transcript profiling. Toxicology 387:95-107, PMID: 28558994, https://doi.org/10.1016/jtox. 2017.05.013.

101. BjorkJA, Butenhoff JL,Wallace KB. 2011. Multiplicity of nuclear receptor activation by PFOA and PFOS in primary human and rodent hepatocytes. Toxicology 288(1 3):8 17, PMID: 21723365, https://doi.org/10.1016/jtox.2011.06.012.

102. Bijland S, Rensen PCN, Pieterman EJ, Maas ACE, van der Hoorn JW, van Erk MJ, et al. 2011. Perfluoroalkyl sulfonates cause alkyl chain length-dependent hepatic steatosis and hypolipidemia mainly by impairing lipoprotein production in APOE*3-Leiden CETP mice. Toxicol Sci 123(1):290-303, PMID: 21705711, https://doi.org/10.1093/toxsci/kfr142.

103. Yu S, Ren J, Lv Z, Li R, Zhong Y, Yao W, et al. 2022. Prediction of the endocrine-disrupting ability of 49 per- and polyfluoroalkyl substances: in silico and epidemiological evidence. Chemosphere 290:133366, PMID: 34933031, https://doi.org/10.1016/j.chemosphere.2021.133366.

104. Kliewer SA, Sundseth SS, Jones SA, Brown PJ, Wisely GB, Koble CS, et al. 1997. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors a andy. Proc Natl Acad Sci USA 94(9):4318-4323, PMID: 9113987, https://doi.org/10.1073/ pnas.94.9.4318.

105. Zhao L, Teng M, Zhao X, Li Y, Sun J, Zhao W, et al. 2023. Insight into the binding model of per- and polyfluoroalkyl substances to proteins and membranes. Environ Int 175:107951, PMID: 37126916, https://doi.org/10.1016/j.envint.2023.107951.

106. XieW, Bothun GD, Lehmler H-J.2010. Partitioning of perfluorooctanoate into phos-phatidylcholine bilayers is chain length-independent. Chem Phys Lipids 163(3):300-308, PMID: 20096277, https://doi.org/10.1016/j.chemphyslip.2010.01.003.

107. Birnbaum LS, DeVito MJ. 1995. Use of toxic equivalency factors for risk assessment for dioxins and related compounds. Toxicology 105(2 3):391 401, PMID: 8571375, https://doi.org/10.1016/0300-483x(95)03237-a.

108. Safe SH, Kutz FW, Bottimore SP, North Atlantic Treaty Organization, Committee on the Challenges of Modern Society. 1988. Scientific Basis for the Development of the International Toxicity Equivalency Factor (I-TEF) Method of Risk Assessment for Complex Mixtures of Dioxins and Related Compounds. https://nepis.epa.gov/Exe/ZyPURL.cgi?Dockey=900F0800.txt [accessed 6 April 2024].

109. Van den Berg M, Birnbaum LS, Denison M, DeVito M, Farland W, Feeley M, et al. 2006. The 2005 world health organization reevaluation of human and mamma-lian toxic equivalency factors for dioxins and dioxin-like compounds. Toxicol Sci 93(2):223-241, PMID: 16829543, https://doi.org/10.1093/toxsci/kfl055.

110. Ring C, Blanchette A, Klaren WD, Fitch S, Haws L, Wheeler MW, et al. 2023. A multi-tiered hierarchical Bayesian approach to derive toxic equivalency factors for dioxin-like compounds. Regul Toxicol Pharmacol 143:105464, PMID: 37516304, https://doi.org/10.1016/j.yrtph.2023.105464.

111. Nhung NTH, Nguyen X-TT, Long VD, Wei Y, Fujita T. 2022. A review of soil conta-minated with dioxins and biodegradation technologies: current status and future prospects. Toxics 10(6):278, PMID: 35736887, https://doi.org/10.3390/ toxics10060278.

112. Peters JM, Gonzalez FJ. 2011. Why toxic equivalency factors are not suitable for perfluoroalkyl chemicals. Chem Res Toxicol 24(10):1601-1609, PMID: 21913657, https://doi.org/10.1021/tx200316x.

113. BilW, SailmakerM,FrankyS, Lezen J, Verbruggen E, Bookers B. 2021. Risk assess-ment of per- and polyfluoroalkyl substance mixtures: a relative potency factor approach. Environ Toxicol Chem 40(3):859-870, PMID: 32729940, https://doi.org/10. 1002/etc.4835.

114. Conley JM, Lambright CS, Evans N, Medlock-Kakaley E, Dixon A, Hill D, et al. 2022. Cumulative maternal and neonatal effects of combined exposure to a mixture of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) during pregnancy in the Sprague-Dawley rat. Environ Int 170:107631, PMID: 36402036, https://doi.org/10.1016/j.envint.2022.107631.

115. US FDA(US Food and Drug Administration).2020. FDAAnnouncesthe Voluntary Phase-Out by Industry of Certain PFAS Used in Food Packaging. https://www. fda.gov/food/cfsan-constituent-updates/fda-announces-voluntary-phase-out-industry-certain-pfas-used-food-packaging [accessed27 May2024].

116. US EPA. 2012. Revisionstothe Unregulated Contaminant Monitoring Regulation (UCMR 3) for Public Water Systems. 40 CFR pt. 141 and 142. https://www. federalregister.gov/documents/2012/05/02/2012-9978/revisions-to-the-unregulated-contaminant-monitoring-regulation-ucmr-3-for-public-water-systems [accessed 31 August 2023].

117. US EPA. 2021. Revisions to the Unregulated Contaminant Monitoring Rule (UCMR 5) for Public Water Systems and Announcement of Public Meetings. 40 CFR pt. 121. https://www.federalregister.gov/documents/2021/12/27/2021-27858/revisions-to-the-unregulated-contaminant-monitoring-rule-ucmr-5-for-public-water-systems-and [accessed 31 August 2023].

118. US EPA. 2016. FactSheet:2010/2015PFOA Stewardship Program. https://www. epa.gov/assessing-and-managing-chemicals-under-tsca/fact-sheet-20102015-pfoa-stewardship-program [accessed 9 September 2023].

119. Gomis MI,Vestergren R, Borg D, Cousins IT. 2018. Comparing the toxic potency in vivo of long-chain perfluoroalkyl acids and fluorinated alternatives. Environ Int 113:1-9, PMID: 29421396, https://doi.org/10.1016/j.envint.2018.01.011.

120. Agency for Toxic Substances and Disease Registry. 2021. Toxicological Profile for Perfluoroalkyls. https://www.atsdr.cdc.gov/toxprofiles/tp200.pdf [accessed 21 May 2024].

121. US EPA. 2021. Final Human Health Toxicity Values for Hexafluoropropylene Oxide (HFPO) Dimer Acid and Its Ammonium Salt. https://www.epa.gov/ system/files/documents/2021-10/genx-chemicals-toxicity-assessment_tech-edited_ oct-21-508.pdf [accessed 21 May 2024].

122. US EPA. 2021. Human Health Toxicity Values for Perfluorobutane Sulfonic Acid and Related Compound Potassium Perfluorobutane Sulfonate. https:// cfpub.epa.gov/ncea/risk/recordisplay.cfm?deid=350888 [accessed 21 May 2024].

123. Brendel S, Fetter E, Staude C, Vierke L, Biegel-Engler A. 2018. Short-chain perfluoroalkyl acids: environmental concerns and a regulatory strategy under REACH. Environ Sci Eur 30(1):9, https://doi.org/10.1186/s12302-018-0134-4.

124. Kwiatkowski CF, Andrews DQ, Birnbaum LS, Bruton TA, DeWitt JC, Knappe DRU, et al. 2020. Scientific basis for managing PFAS as a chemical class. Environ SciTechnol Lett 7(8):532-543, PMID: 34307722, https://doi.org/10.1021/ acs.estlett.0c00255.

125. Blum A, Balan SA, Scheringer M, Trier X, Goldenman G, Cousins IT, et al. 2015. The Madrid statement on poly- and perfluoroalkyl substances (PFASs). Environ Health Perspect 123(5):A107-A111, PMID: 25932614, https://doi.org/10. 1289/ehp.1509934.

126. Henry BJ, Carlin JP, Hammerschmidt JA, Buck RC, Buxton LW, Fiedler H, et al. 2018. A critical review of the application of polymer of low concern and regulatory criteria to fluoropolymers. Integr Environ Assess Manag 14(3):316-334, PMID: 29424474, https://doi.org/10.1002/ieam.4035.

127. Korzeniowski SH, Buck RC, Newkold RM, Kassmi AE, Laganis E, Matsuoka Y, et al. 2023. A critical review of the application of polymer of low concern regulatory criteria to fluoropolymers II: fluoroplastics and fluoroelastomers. Integr Environ Assess Manag 19(2):326-354, PMID: 35678199, https://doi.org/ 10.1002/ieam.4646.

128. Lohmann R, Cousins IT, DeWitt JC, Glüge J, Goldenman G, Herzke D, et al. 2020. Are fluoropolymers really of low concern for human and environmental health and separate from other PFAS? Environ Sci Technol 54(20)12820-12828, PMID: 33043667, https://doi.org/10.1021/acs.est.0c03244.

129. Cousins IT, Goldenman G, Herzke D, Lohmann R, Miller M, Ng CA, et al. 2019. The concept of essential use for determining when uses of PFASs can be phased out. Environ Sci Process Impacts 21(11):1803-1815, PMID: 31204421, https://doi.org/10.1039/c9em00163h.

130. Chemsec. 2023. The top 12 PFAS producers in the world and the staggering societal costs of PFAS pollution. https://chemsec.org/reports/the-top-12-pfas-producers-in-the-world-and-the-staggering-societal-costs-of-pfas-pollution/ [accessed 28 May 2024].

131. Tabuchi H. 2024. Lawyers to Plastics Makers: Prepare for 'Astronomical' PFAS Lawsuits. New York Times. Late Edition (East Coast). 28 May 2024. https://www. proquest.com/docview/3061284418/citation/730FBBDBFDAD451FPQ/10 [accessed 31 May 2024].

132. Lerner S.2024. How3M ExecutivesConvinced a ScientisttheForever Chemicals She Found in Human Blood Were Safe. ProPublica. 20 May 2024. https://www. propublica.org/article/3m-forever-chemicals-pfas-pfos-inside-story [accessed 31 May 2024].

133. ECHA (European Chemical Agency). 2023. ECHA publishes PFAS restriction proposal. https://echa.europa.eu/-/echa-publishes-pfas-restriction-proposal [accessed 29 May 2024].

134. Balan SA, MathraniVC, Guo DF, Algazi AM. 2021. Regulating PFAS asa chemical class under the California safer consumer products program. Environ Health Perspect 129(2):025001, PMID: 33595352, https://doi.org/10.1289/EH P7431.

135. 3M Company. 2022.3M to Exit PFAS Manufacturing bythe End of 2025.3M News Center. https://news.3m.com/2022-12-20-3M-to-Exit-PFAS-Manufacturing-by-the-End-of-2025 [accessed 9 September 2023].