Addressing the environmental and health impacts of microplastics requires open collaboration between diverse sectors

Public concern over the environmental and public health impacts of the emerging contaminant class “microplastics” has recently prompted government agencies to consider mitigation efforts. Microplastics do not easily fit within traditional risk-based regulatory frameworks because their persistence and extreme diversity (of size, shape, and chemical properties associated with sorbed chemicals) result in high levels of uncertainty in hazard and exposure estimates. Due to these serious complexities, addressing microplastics’ impacts requires open collaboration between scientists, regulators, and policymakers. Here we describe ongoing international mitigation efforts, with California as a case study, and draw lessons from a similarly diverse and environmentally persistent class of emerging contaminants (per- and polyfluoroalkyl substances) that is already disrupting traditional regulatory paradigms, discuss strategies to address challenges associated with developing health-protective regulations and policies related to microplastics, and suggest ways to maximize impacts of research.


Introduction
Recent polls suggest the public is aware of and concerned about the effects of plastic pollution on the environment and public health [1][2][3]. Microplastics (typically defined as plastic particles smaller than 5 mm [4]) are found virtually everywhere, including in aquatic and terrestrial ecosystems [5,6], air [7], drinking water [8], food [9], and even remote alpine and polar settings [10,11]. Adverse impacts of plastic pollution, particularly microplastics, are becoming better understood in aquatic ecosystems [12,13], with exceedances of risk thresholds documented in several ecosystems [14]. However, uncertainties regarding impacts remain, largely due to uncharacterized hazards and sampling bias towards larger-sized particles (which are believed to be less toxic) [12,15]. Greater uncertainties remain in assessing impacts to humans, which have received far less research attention than ecological receptors [16].
Generally, the public relies on the government to address environmental issues and often promotes policy and regulatory actions through citizen's groups and nongovernmental

Microplastics challenge traditional risk-based regulatory paradigms
Innovations in risk assessment frameworks and regulatory approaches may be required to protect environmental and public health from complex contaminant classes and mixtures with vast uncertainties in their environmental fate and transport, exposure, and hazards. The traditional framework for assessing risk is by comparing exposure amounts with known hazard thresholds [28]. Many regulatory frameworks are based on this traditional risk assessment framework and set regulatory thresholds (e.g., maximum contaminant levels in drinking water, effluent limits in wastewater discharge) based on estimated exposures which would theoretically exceed certain risk thresholds [29,30]. While this traditional risk assessment-based regulatory framework works well for single-chemical contaminants or relatively simple mixtures of contaminants with known chemical structures, compositions, and biological activities (e.g., dioxins and dioxin-like polychlorinated biphenyls (PCBs) [10]), it may be inadequate to address risks from more complex contaminants. The term "microplastics" encompasses a vast universe of particles that present unique challenges in estimating risks due to their extreme diversity (e.g., size, shape, solubility, polymer composition, sorbed chemicals and biota, etc.) [19]. Even defining the contaminant class has been a matter of lengthy debate [4,31]. In order to estimate risks and regulate microplastics using traditional frameworks, recent innovative efforts have tried to reduce complexities associated with the high number of variables used to classify microplastics (i.e., size, shape, polymer types) [32]. However, such simplification efforts are unlikely to satisfactorily capture the full variability of shapes of microplastics, leading to underestimates of risk [32].
A recent study on wild-caught, commercially important fish found that microplastics ingested by the fish likely transferred bisphenol A (BPA) and related analogues into their tissue at high enough quantities to exceed risk thresholds in adults and children at mean ingestion rates of the fish [33]. Notably, the study would not have estimated an exceedance of risk threshold if the authors had used the United States Environmental Protection Agency's (US EPA) risk value for BPA [34], which is 12.5 times higher than the European Food Safety Authority's value [35]. This study highlights both the importance of characterizing plasticassociated chemicals in microplastics (a key hazard trait) [36][37][38][39] and assessing hazards of endocrine-disrupting chemicals (e.g., BPA, di-2-ethylhexyl-phthalate) commonly added to plastics [37,40]. Assessing hazards for some endocrine-disrupting chemicals may be complicated due their exhibiting nonmonotonic dose-response effects (i.e., effects observed at low concentrations are not predicted by and/or observed at higher concentrations) [41][42][43]. When such nonmonotonic effects are considered, such compounds may be considered substantially more toxic [44].
Another critical challenge in assessing risks of plastic-associated chemicals is that most plastic additives (approximately 80%) have their identities hidden from researchers, regulators, and the public, protected as "confidential business information" (CBI), or lack adequate documentation in public databases (see more on unknown chemicals in Box 1) [45,46]. Additionally, complex mixtures of chemicals on microplastics may exhibit mixture toxicity effects (i.e., additive, synergistic, antagonistic) [47], making their identification complicated [20].

Box 1. Unknown chemicals present never-ending challenges for risk assessors
There is an increasing worldwide trend of approving unknown chemicals and mixtures for use in commerce, thus providing scientists and regulators with a Sisyphean task in estimating risks for over 70,000 such chemicals/mixtures (>37,000 of which are polymers) [46]. This increasing trend is in spite of regulations that apparently intend to prevent the introduction of "regrettable substitutions" into the environment, such as the 2016-revised Toxic Substances Control Act (TSCA) in the United States (US) [48] and the European Union's more aggressive Registration, Evaluation, Authorisation, and Restriction of Chemicals [49]. Yet chemicals/mixtures protected as CBI lack information regarding chemical structure, composition and biological activities, and access to analytical standards [47], requiring innovative methods to determine hazardous chemical features within an unknown plastic chemical mixture, such as bioassay-guided chemical fractionation coupled with nontargeted analytical chemistry [20,45]. Such techniques are costly, however, and it remains unlikely that risks could ever be characterized with a high degree of certainty until full chemical compositions are known. Voluntary cooperation between industry and researchers in revealing the identity of some of these CBI chemicals provides a possible avenue for reducing such uncertainties [50].
In addition to complicating the assessment of risk for chemicals and mixtures already present in the environment, protections provided by CBI may lead to the continued introduction of potentially hazardous chemicals into the environment [51]. For example, in 2018, the identities, quantities produced, location of production facilities, and other data for 396 new PFAS was withheld by manufacturers on the basis that such information is CBI [52]. Such confidential compounds may eventually be characterized years later using nontargeted analytical chemistry, as demonstrated by the recent discovery of a new class of chlorinated PFAS (apparently used as a substitute for other banned PFAS [53])-chloroperfluoropolyether carboxylate compounds (ClPFPECAs) [54]. Most concerning, ClPFPECAs are considered to be safe for use in polymerized nonstick cookware by the European Food Safety Authority [55]-despite their similarities to other PFAS, and a complete lack of publicly available toxicity information [56]. ClPFPECAs are unregistered in both the US EPA's and the European Chemical Agency's inventories [56]. It's possible that ClPFPECAs passed EPA's review without much, or any toxicity testing, as under TSCA (pre-2016 amendment), EPA was required to produce evidence for potential risk in order to investigate a chemical further [48,49]-a catch-22 that allowed 90% of chemicals entering commerce between 1979 and 2016 to evade restrictions or testing orders [56].
The extremely diverse nature of microplastics is unparalleled; however, another emerging contaminant class may come relatively close and may provide insights for risk management. PFAS, like microplastics, are persistent, toxic, and largely unregistered in regulatory inventories [46,57,58]. The push to regulate PFAS in a timely manner has prompted some scientists and regulators to develop alternative methods to estimate their exposure and determine their hazards to estimate risk. A recent study estimated that there are over 4,700 PFAS chemicals distributed in the global market [59]-a multiplicity that makes developing analytical methods and determining toxicological effects for all constituents unachievable within reasonable timeframes. Novel, proxy-based approaches have been developed to estimate exposure (e.g., total fluorine [60,61]), and 21st century approaches are being applied to characterize hazards of PFAS (e.g., readacross [62]). Some of these approaches have proven, in some cases, to be health protective and simple, and are being considered for adoption by regulatory agencies [63][64][65]. While PFAS provide lessons for addressing extremely diverse and unique contaminant classes, microplastics are likely more complex and challenging (Box 2).

Box 2. Microplastics are a more complex contaminant class than PFAS
While many similarities exist between PFAS and microplastics (e.g., persistence, diversity, unknown composition, bioaccumulative potential, toxicity), there are principal differences between these contaminant classes which make understanding risks of microplastics arguably more challenging. The principal difference is that PFAS (with the exception of polymers and anions) are generally soluble [66], while microplastics are (generally) insoluble [67]-thus having distinct physicochemical properties that may drive toxicological behavior as well as fate and transport characteristics-all of which are foundational in assessing exposure and risks. For other "conventional contaminants" (e.g., petroleum hydrocarbons), fate and transport characteristics are well studied [68]. Due to the diversity of the PFAS class and their unique characteristics (hydrophobic, lipophilic, and surfactant properties), traditional fate and transport models have proven inadequate in modeling their behavior-particularly in groundwater [68,69]. Even less understood are the environmental fate and transport behavior of microplastic particles, in which key determining factors are unique to insoluble particles (relatively less studied than soluble contaminants) and, in some cases, unique to synthetic polymers, such as: formation and emissions of microplastic particles; particle-particle interactions (e.g., aggregation and agglomeration); biological uptake and bioaccumulation; and transport

Plastics and PFAS are forever
In an effort to prevent irreversible damage from persistent chemicals with poorly known effects, some regulatory agencies in Europe and the US have departed from their traditional risk-based frameworks. They are doing so by taking a more precautionary approach, classifying certain chemicals as "nonthreshold contaminants" (i.e., "any release to the environment and environmental monitoring data regarded as a proxy for an unacceptable risk") [75,76]. A critical driver behind considerations of such precautionary management approaches is a chemical's ability to resist degradation in the environment (persistence) [77]-a trait which is shared by both microplastics and PFAS [55,75]. The combination of global environmental contamination, persistence, and uncertainties regarding effects on vital earth system processes satisfy the conditions for both PFAS and microplastics to be classified as "planetary boundary threats"-defined as factors that may irreversibly threaten the earth systems that allow humanity to thrive [78,79]. Indeed, PFAS are often referred to as "Forever Chemicals"-implying that their persistence should be worrying [80].
In 2019, Denmark banned all PFAS (known and unknown) in paper and cardboard food contact materials [81]. This broad, class-based restriction was aimed at preventing widespread, irreversible environmental contamination of persistent, bioaccumulative, toxic chemicals within the PFAS class [57]. In managing PFAS, the concept of "essential use" is integral to drafting sensible, risk-based restriction regulations [82]-an approach which has been considered by the European Chemicals Agency in restricting the use of intentionally added microplastics [75], and may also be useful in considering restrictions of single-use plastic products in a circular economy.
Like PFAS, microplastics are ubiquitous in the environment [83], and some particle types are known to be toxic and bioaccumulative [9,58], thus concerns over environmental persistence [84] are warranted [85,86]. With the continuous production and release of persistent chemicals, risk thresholds are likely to be exceeded over time, regardless of the chemical's properties [77]. This high likelihood of eventually exceeding risk thresholds renders traditional risk assessments inadequate, as they typically do not consider long-term impacts to future generations, or system-level effects at regional (or even global) scales.
The San Francisco Bay Regional Monitoring Program, which ranks contaminants of emerging concern monitored in water, sediment, and biota into tiered, risk-based categories (based on occurrence and hazard ratios) [76], initially classified microplastics as a constituent class of "Possible Concern" based on uncertainties regarding toxicity, but later elevated microplastics to "Moderate Concern," despite a noted lack of certainty regarding hazard thresholds [87]. The San Francisco Bay Regional Monitoring Program justified this departure from their established risk-based framework based on the EU's decision to classify microplastics as a nonthreshold contaminant for risk assessment purposes [75]; uncertainties regarding toxicities [87]; an via air and oceanic circulation [70]. Significant challenges for testing the toxicity of dispersed particles in aqueous systems remain [71], and extrapolating effects of exposure at high concentrations to lower, environmentally relevant concentrations may not be appropriate [70]. Further challenges in assessing microplastics toxicity are the lack of standardized, environmentally realistic mixture samples, and the selection of natural particles as controls [72]. Finally, determining the drivers of microplastics toxicity (e.g., physical, chemical) is difficult [73], as exemplified by the association of PFAS with plastic [74]. upward trend in both plastic production and environmental detection [88][89][90]; and persistence [75,87]. These decisions are in congruence with conclusions made by the Science Advice for Policy by European Academies, which state that while risk thresholds are exceeded at some locations (i.e., predicted or measured concentrations are greater than predicted no-effect levels), it is unlikely that exceedances of risk thresholds are geographically widespread [12]; however with expected increases in exposure to microplastics [91], widespread ecological risk may arise within the next century [12]. In other words, while traditional regulatory frameworks typically focus on short-term risks from chemicals with known hazards, highly complex, persistent contaminants with unknown hazards are being recognized as potential irreversible global scale threats and are being precautionarily evaluated by regulators and scientists.
A case study for intersector collaboration: California legislation as a regulation, policy, and science driver California Senate Bills (SB) 1422 and SB 1263 outline initial steps to address microplastics in drinking water and the ambient marine environment, respectively [26,27]. In response to initial findings of widespread contamination of drinking water with microplastics [86] and considerable uncertainties regarding their health risks to humans at the time [92], the California Legislature passed SB 1422 in 2018, which requires the State Water Resources Control Board (State Water Board) to adopt a definition for "microplastics in drinking water" by July 1, 2020 (see Box 3 for more), and to adopt a standard methodology for detecting microplastics in

Box 3. Lessons learned from PFAS in developing a regulatory definition for microplastics
After the discovery of some fluorinated chemicals in food contact materials (e.g., perfluoropolyether dicarboxylic acid) that were not formally recognized as PFAS under their definition at the time (-C n F2 n+1 -) [59,99], the Organisation for Economic Co-operation and Development (OECD) expanded their definition (-C n F2 n -) [59]. Meanwhile, other organizations (e.g., Interstate Technology Regulatory Council) more narrowly define perfluoroalkyl substances as having two or more fully fluorinated carbons (-C n F2 n+1 -), and polyfluoroalkyl substances as having a nonfluorine atom (typically hydrogen or oxygen) attached to at least one, but not all, carbon atoms, with at least two or more fully fluorinated carbons (-C n F2 n+1 -), with a further explicit exclusion of aromatic carbon ring substances [66]. In the case of extremely environmentally persistent chemicals like PFAS, the exclusion of certain chemicals from the contaminant class has resulted in a systematic lack of focus on their existence-resulting in sparse monitoring data (e.g., aromatic carbon ring PFAS) [100].
This debacle demonstrates the importance of starting with a broad definition as a common departure point for further definitions for microplastics and other emerging contaminant classes with significant uncertainties. Failure to start with a broad definition and consider all constituents within the class has resulted in the likely human exposure to short-(4 to 7 carbons) and ultrashort-chain (2 to 3 carbons) PFAS through food packaging in the US (e.g., 1,1,1,2-tetrafluoroethane, which is "generally recognized as safe" by the nation's Food and Drug Administration) [101]. With regulatory agencies focused on long-chain PFAS (8+ carbons), industry has increased production of short and ultrashort alternatives [102], even though they were included in the once commonly accepted definition of PFAS (-C n F 2n+1 -). Learning from mistakes made with PFAS, if regulatory definitions of microplastics are too narrow, risks may be underestimated due to their drinking water by July 1, 2021 (Fig 1). Additionally, the bill requires 4 years of testing and reporting of microplastics in drinking water, public disclosure of the results, and possible issuance of a health-based guidance level to interpret results [26]. SB 1263 requires the California Ocean Protection Council to adopt a statewide microplastics strategy (Strategy) [27]. The Strategy shall include the development of standardized methods for sampling, detecting, and characterizing microplastics, development of a risk assessment framework for microplastics, and the use of that risk assessment framework to identify data gaps, and effective policy changes to reduce risks due to microplastic pollution in the ambient marine environment (Fig  1) [27].
To meet unprecedented challenges in addressing perhaps the most complex, diverse, and publicly visibly contaminant suite (plastics pollution; including microplastics), California is partnering with an international network of researchers, local, state, and federal agencies, nongovernmental organizations, water purveyors, and engaged citizens. For example, the California State Water Board has a long history of working with citizen scientists regarding characterizing trash and microplastics in water, reporting some of the earliest findings of persistent organic pollutants on preproduction plastics pellets along California's beaches in 2005 [93]. Starting in 2018, the California State Water Board began hosting annual, multiday, immersive "Trash Data Dives" where researchers (data scientists and trash/microplastic experts) work alongside municipalities, policy writers, regulators, nongovernmental organization leaders, community leaders, and others to develop a, "trash management picture informed by open and accessible data, to identify and understand trends, data gaps, and priorities" [94]. Similarly, the California Ocean Protection Council (which has made policy recommendations to reduce plastic pollution since 2007 [95]) partnered with the National Oceanic and Atmospheric Administration in 2018 to incomplete characterization and lack of consideration for the vast possibilities within the contaminant class.
A challenge in implementing California's legislative requirements to address microplastics in drinking water (SB 1422) was the apparent lack of a consensus definition for "microplastics." Despite calls for a unified, internationally agreed-upon definition for "microplastics" [103], it seems that no such definition had emerged due (in part) to the lack of both standardized methods and regulations. Due to the regulatory impacts (i.e., monitoring and reporting and communicating health effects to consumers) associated with adopting a definition of microplastics in the context of drinking water, California's State Water Board recognized that the definition they adopted in June 2020 would likely be used for nondrinking water purposes and by other government agencies and scientific bodies [104]. In drafting an initial regulatory definition for microplastics (which have extreme uncertainties in regards to exposure and hazards for humans [105]), a principal consideration was to use terms that broadly encompass particle sizes (1 nm to 5 mm), types (e.g., theoretically soluble plastics), and polymers (e.g., including biodegradable polymers, for which limited toxicity information is available [106]) to avoid inappropriately restricting risk assessments based on regulatory definitions [70], as well as research, monitoring, and collection of data-at least until the adoption of a more narrow definition can be justified [31]. Drawing lessons learned from PFAS, subcategories of microplastics may be grouped for strategic purposes for monitoring and regulations [107], however should be distinguished from a broader class-based definition, with exclusions and limitations acknowledged wherever possible [108].
develop the California Ocean Litter Prevention Strategy, which outlines actions that California and interested stakeholders can take to address ocean litter through 2024 [96]. The Ocean Litter Prevention Strategy laid out critical needs in microplastics research, such as standardized methods, which were later included in SB 1263 [96].
In implementing SB 1422 and SB 1263, the California Ocean Protection Council and California State Water Board are collaborating with a wide range of stakeholders to accomplish the ambitious objectives required by the bills. The public research and development agency, the Southern California Coastal Water Research Project (SCCWRP) plays a pivotal role in the State's microplastics-related projects, coordinating more than 35 laboratories based in 7 different countries to standardize microplastics monitoring methods in aquatic environments, and serving as facilitator for the development of a consensus statement on the human health effects of microplastics in drinking water [97]. Additionally, the Ocean Protection Council is collaborating with an independent science-based nonprofit, The Ocean Science Trust, to convene an internationally recognized expert panel to develop a microplastics risk assessment framework as part of their Strategy [98]. Intersector working groups, such as the Pacific Northwest Consortium on Plastics and San Francisco Estuary Institute Microplastics Working Group, play key roles in coordinating local and regional research efforts that directly inform decision makers, and serve as exemplary models for constructive interactions between policymakers, scientists, regulators, and industry representatives.

Making microplastics research "actionable": Standardized methods and beyond
Scientific organizations have long called for the standardization of microplastic analysis methods [109,110]; the legislative requirements for California to adopt standard methodologies to monitor microplastics provides an impetus and requisite funding to develop such methods [26,27]. Standardization of microplastic monitoring methods will allow for direct comparisons between studies, may reduce uncertainties in assessments of risk, and reliably inform management strategies. It is important to keep in mind that unintended consequences may result if practical considerations of enacting regulations inhibit broader research investigations. For example, standardized methodologies may miss certain components (e.g. < approximately 10 μm particles, black particles) due to technical and economic barriers-a phenomenon that has caused a significant mismatch in the size ranges of particles used in toxicological assessments and monitored in the environment [15]. Therefore, as regulatory agencies adopt standardized methods for analyzing microplastics, the academic community should continue to improve detection methodologies [111], and regulatory agencies should consider regularly updating their standardized methods.
In addition to developing standardized methods for monitoring microplastics in the environment, food, and water, further research is necessary to develop evidence-based policies and regulations. The policy and regulatory communities need actionable research that focuses on (a) addressing gaps in the understanding of the ecological and human health hazards and exposure of microplastics; (b) identifying and prioritizing sources (e.g., packaging, tire wear, textiles) and pathways (e.g., washing machines, stormwater, wastewater, biosolid agriculture application) that may be candidates for regulatory intervention; and (c) developing cost-effective technologies to reduce economic impacts of policy and regulatory interventions (e.g., analysis methods, water treatment, reusable or truly biodegradable materials). Moreover, quantitative toxicological risk assessments may be necessary under certain regulatory paradigms to effectively regulate microplastics as a water quality contaminant [112]. A useful strategy to accurately assess and convey risks associated with plastic without downplaying the potential of uncertain risks is to focus on known particle-and species-specific effect mechanisms (e.g., adverse outcome pathways) [112]. These adverse outcome pathways allow for the separation of hazards of plastic-associated chemicals with the physical particles themselves [112], allowing for a more simplistic understanding and communication of risks and development of risk-based regulations and policies. Most regulatory paradigms will prioritize highrisk microplastic morphologies-thus research should focus on reducing toxicological dimensions of complex mixtures to simplify sampling and monitoring plans [32]. Finally, research findings should be written so that they can be easily summarized and distilled into fact sheets and talking points, which are useful for both general media inquiries and policy briefings.

Conclusion
Microplastics as a contaminant class are unmatched in their magnitude of complexity, diversity, and persistence (with PFAS likely being the closest in all 3 categories), presenting significant challenges for scientists in developing analytical methods, fate and transport models, characterization of exposure pathways, and assessment of toxicological hazards. Considering unprecedented uncertainties associated with risks to humans and ecosystems, governmental organizations are reconsidering the appropriateness of applying traditional frameworks in mitigating risks of microplastics (and PFAS), opting in some cases for more precautionary approaches that give additional weight to uncertainties and environmental persistence. To address such challenging and complex emerging contaminant classes, governments should coordinate closely with researchers, citizens, industry representatives, and commercial monitoring laboratories, and should actively promote transparency, data accessibility, and civic engagement. California's pioneering efforts in addressing microplastics in drinking water and aquatic ecosystems serves as a model for developing open collaborations between diverse sectors.