/TOC Art Abstract Per- and polyfluoroalkyl substances (PFAS) are a class of synthetic organic substances with diverse structures, properties, uses, bioaccumulation potential s and toxicities. Despite this high diversity , all PFAS are alike in that they contain perfluoroalkyl moieties that are extrem ely resistant to environmental and metabolic degradation. PFAS are therefore either non -degradable or transform ultimately into stable terminal transformation products (which are still PFAS ). Under the European chemicals regulation this classifies all PFAS as very persistent substances (vP). We argue that this high persistence is sufficient concern for their management as a chemical class, and for all “non - essential” uses of PFAS to be phased out. The continual release of highly persistent PFAS will result in increasing concentrations and increasing probabilities of the occurrence of known and unknown effects . Once adverse effects are identifie d the exposure and associated effects will not be easily reversible. Reversing PFAS contamination will be technicall y challenging, energy intensive, and costly for society , as is evident in the efforts to remove PFAS from contaminated land and drinking water. Environmental Relevance Recent scientific publications and regulatory actions suggest that PFAS should be managed as a class. This Perspective article supports a broad scope in restricting the use of PFAS in society based on the extremely high environmental persistence of all PFA S. Our previous work (cited below) has highlighted the particular concern of high environmental persistence and noted that high persistence is the root cause of most of the serious cases of environmental contamination in the last 50 year s. The field of gre en chemistry also recognizes the particular issue with persistence and recommends that chemical manufacture rs incorporate “design for degradation”. We are of the opinion that h ighly persistent PFAS are incompatible with green chemistry principles and futur e visions of sustainable development. Phasing out “non -essential” uses of PFAS from society and replacing them with suitable alternatives will benefit environmental and human health , now and into the future . Unfortunately, as PFAS are non -mineralizable red uction of environmental exposure to PFAS will be a slow process even if their uses are phased out. Perspective article The national authorities of five European states have agreed to prepare a joint REACH restriction proposal to limit the risks to human and environmental health associated with per- and polyfluoroalkyl substances (PFAS ).1 The exact scope of the restriction proposal for P FAS will be determined during the development phase of the project , but it will initially aim for a broad inclusion of substances (the aim is to include “substances that contain at least one aliphatic -CF2- or -CF3 element”2) and uses to be restric ted. A recent commentary by Kwiatk owski et al.3 outlined the scientific basis for managing PFAS as a chemical class. This was an important contribution towards efforts to regulate4, 5 and group6 PFAS . In this Perspective article , we would like to voice our support of a broad scope in the restriction proposal for PFAS, based largely on concerns regarding their high persistence. A precedent for this exists in the recent action by the European Union (EU) to restrict intentionally added microplastics based largely on concerns regarding their high persistence .7 PFAS are a class of fluorinated synthetic organic substances with diverse properties that have been used in a wide variety of industrial and consumer applications.8, 9 The Organisation for Economic Co - operation and Development (OECD)/United Nations Environment Programme (UNEP) compiled a list of PFAS with over 4700 CAS numbers that may have been on the global market.10 More recently, t he United States Environmental Protection Agency (US EPA)11 has compiled a list of more than 7000 PFAS entrie s.12 As noted in the Supplement of the recent paper by Johnson et al.,13 the PFAS class comprises distinct substances with very different structures and properties: high molecular weight polymers and low molecular weight non-polymers; neutral, anionic, cationic and zwitterionic substan ces; solids, liquids, and gases; highly reactive and non-reactive ( inert ) substances; soluble and insoluble substances; and volatile and involatile substances. In the environment , some PFAS are mobile14 and others immobile , and some bioaccumulat e while others do not. PFAS display a wide range of environmental and human health hazards. Some PFAS are considered of low concern (e.g., certain fluoropolymers, perfluoroalkanes and perfluoroalkylamines3), whereas others are associated with adverse health effects in humans or wildlife at current environmental exposure levels .15 It is important to note that even if some PFAS are considered of low concern, there may be starting materials , breakdown products and/or other PFAS by-products of higher concern released during their lifecycle (e.g. in the case of certain fluoropolymers)6. Our current understanding of PFAS toxicity is based on a relatively small number of compounds , and little is known about the properties and behaviour of most of the thousands of PFAS as individual chemical s or as the much more commonly present complex mixture s. It is likely that additional health concerns will be identified as research continues on this class of chemicals.16 It is also important to note that new findings will undoubtedly be made in toxicology that will change the current hazard and risk perspective of certain PFAS. For ex ample, o ver the last two decades advances in the understanding of the human toxicology of perfluorooctanoic acid (PFOA) has caused US state level drinking water guidelines to be steadily lowered (from 100,000 ng/ L in West Virginia in 2002 down to 10 ng/ L in multiple states in 2019) .17 The diversity in PFAS structures, properties and behaviour is often used by the PFAS manufacturing industry18,19 to argue that PFAS cannot be treat ed as a single class . We acknowledge the diversity of PFAS in terms of many properties, behaviour, hazards and risks , and that statements such as “ all PFAS are bioaccumulative and toxic” are overgeneralized and debatable . However, d espite their diversity, PFAS do share one common structural feature that ma kes them highly problematic, namely the presence of perfluoroalkyl moieties, resulting in the ir shared resistance to environmental and metabolic degradation.16 PFAS are either non -degradable or degrade to form terminal products (which are still PFAS; e.g. fluorotelomer alcohols degrade ultimately to PFCAs) .16 The extreme resistance to degradation of the perfluoroalkyl moiety is due to; (i) the strength of the C -F bond, (ii) multiple C-F bonds (“perfluorination”) on the same carbon , lead ing to the shortening (i. e., increased strength) of the C -F bond , and (iii) t he atomic radius of a C -F bond and the extreme electronegativity of the fluorine atom , which facilitate “shield ing” of perfluorinate d chains from nucleophilic attack .20 Environmental persistence is often expressed by half -lives of a chemical in various environment al medi a (typically; water, soils and sediments) based on the kinetics of dominant abiotic and biotic degradation processes .21 Although the concept of environmental persistence is simple to understand , its assessment for a given chemical in a given environmental medium can sometimes be a challenging task because of the difficulty in measuring and estimating environmental degradation half-lives for chemicals.22 But this challenge does not exist in the case of PFAS because scientists have reached consensus that PFAS are resistant to any form of environmental degradation that results in complete mineralization under natural conditions .16 Indeed, to our knowledge , PFAS are the most environmentally persistent substances in the universe of synth etic organic chemicals , which is why they have earned the moniker in the popular press of “forever chemicals” .23 Therefore, under the REACH definition of persis tence, which include s persistent degradation/transformation products, all PFAS are very persistent (vP).24 Unfortunately, not all jurisdictions include persistent degradation/transformation products in their definition of persistence , and this h as given the manufacturing industry some basis to claim that not all PFAS are persistent. In a recent paper by Cousins et al.25, the concerns regarding the high persistence of chemicals were explained . In summary, the se concerns are: • The continuous release of highly persistent chemicals will necessarily lead to widespread, long -lasting, and increasing contamination. • Increasing concentrations will result in increased exposures and therefore increas ed probabilities for known and unknown health effects, be it by individual PFAS and/or in a mixtur e with other substances. • Once adverse effects are identi fied, it will be technically challenging, energy intensive, and thus costly, to reverse the chemical contamination and therefore effects. Even with extensive efforts, removal will be only partially ef fective , and some level of contamination and some adverse effects will be irreversible. It was argued in Cousins et al.25 that high persistence alone should be established as a sufficient basis for management of a chemical, which w as term ed the “P -sufficient approach” . Logic dictates that evidence of bioaccumulation or some type of effect (biological or otherwise) is not required , given that the occurrence of an effect is of increasing probability and ultimately inevitable if emissions continue. Using current technology, it is not feasible to develop full toxicological profiles for all PFAS. Managing these compounds as a highly persistent class is a clear benefit to society because otherwise a large number of resource -intensive and time -consuming toxicity and other tests would need to be conduct ed. Howe ver, on the basis of plausible reasoning, for continually released, highly persistent organic chemicals, a harmful effect (known or unknown) is likely in the future based on ever expanding exposures . This view may be controversial for some. For example, major regulatory bodies such as the US EPA are instead following the traditional risk assessment paradigm of testing as many PFAS as possible for adverse effects. Because traditional animal testing is costly and considered unethical , the US EPA is instead conducting a large number of high -throughput toxicity tests ( in vitro assays) on 150 novel and emerging PFAS (2% of known PFAS) for multiple endpoints .26 Such appro aches are, however, uncertain and not comprehensive in their coverage of chemical or biological space and are not, therefore, reliably protective of human and environmental health. A conservative approach of not using highly persistent synthetic organic su bstances is more protective and also less costly for society , both in terms of fewer tests and reduc tion in externalized societal costs including the expected costs of health care , loss of biodiversity , loss of ecosystem services and remediation. The argument s for not using highly persistent organic chemicals in society are not new and ha ve been made for nearly 50 years, early on by Jensen in 197227 and Stephenson in 197728 and reformulated later in concepts such as “late lessons from early warnings”,29 “planetary boundar y threats from chemical pollution ”30-32 and recently in the “P -sufficient approach”.25 As well as not being new, the argument s have always been simple to understand for scientists and non -scientists alike, and ha ve never been convincingly challenged. Arguments against the “P-sufficient” approach often point to inert substances such as some inorganic minerals that are also highly persistent and often in a non -bioaccessible form (e.g. sand and rocks ). However, apart from their similar high persistence, PFAS are distinct from inert inorganic mineral s in that PFAS (i) are synthetic organic substances and not naturally present (i.e. there are few known biogenic sources of PFAS) (ii) continue to be manufactured, leading to ongoing accumulat ion in the environ ment , and (iii) are often bio accessible . With regard to biogenic sources of PFAS; it has been estimated that there are only about 20 biogenic organofluorine substances33 and even fewer PFAS are known to have biogenic sources (one is trifluoroacetic acid34)). There are finally encouraging signs that regulators are taking notice of the problems with high persistence (e.g. in the case of intentionally added microplastics) and that the European Green Deal will hopefully introduce regulatory provisions for highly persisten t substances. It is further encouraging that i n recent years concepts such as “green chemistry ”35 and “cradle -to-cradle ”36 are gaining momentum . For example, o ne of the 12 prin ciples of green chemistry is : “design for degradation ”,35 i.e. chemical products should be designed so that at the end of their fun ction they break down into innocuous degradation products and do not persist in the environment . Highly persistent substances such as PFAS are incomp atible with green chemistry principles and future visions of sustainable development (e.g. the European Gre en Deal) . The concept of essentiality has been put forward as a tool for guiding the phase out of hazardous substances such as PFAS37 and efforts have already begun to address this challenging, but not insurmountable, task in the EU and elsewhere. We are of the opinion that the EU restriction proposal1 for PFAS should have a wide scope grounded in the one completely consistent feature of PFAS: their persistence , based on the arguments presented in this Perspective article . Regulation alone is not sufficient to phase out PFAS . Innovation will also be needed by chemical and product manufacturers to develop safer chemical and func tional alternatives to PFAS. There is cause to be optimistic about the future , given the innovations and changes implemented in recent years (e.g. the transition to fluorine -free aqueous film forming foams in South Australia38 and elsewhere, the wider availability of fluorine -free durable water repellent outdoor equipment ,39 the banning of fluorinated ski waxes in international competition ,40 the phasing out of PFAS in cosmetics by multiple retailers ,41 the banning of PFAS in paper and board used in food contact materials in Denmark42), but the work is far from finished . In summary, although PFAS have diverse structures and behaviour, the high persistence of PFAS is sufficient cause of concern for all “non-essential ” uses of PFAS to be phased out. Unfortunately, there has until very recently been no legal precedent in any jurisdiction for regulation on high persistence alone. Promisingly, t he idea of regulating highly persistent chemicals and intentional ly added microplastics is being explored within the EU . We hope that this idea will spread around the world. Acknowledgement s The authors thank the Global PFAS Science Panel (GPSP) and the Tides Foundation for supporting this cooperation (grant 1806 -52683). The authors appreciate the valuable suggestions of Xenia Trier. In addition, R. Lohmann acknowledges funding from the US National Institute of Environmental Health Sciences (grant P42ES027706); DeWitt from the US Environmental Protection Agenc y (83948101), the US National Institute of Environmental Health Sciences (1P43ES031009 -01) and the North Carolina Policy Collaboratory; C. Ng from the National Science Foundation (grant 1845336) and D. Herzke thanks the Norwegian Strategic Institute Progra m, granted by the Norwegian Research Council “Arctic, the herald of Chemical Substances of Environmental Concern, CleanArctic”, 117031).