Considerations for toxicity experiments and risk assessments with PFAS mixtures
Open accessAbstract
Per- and polyfluoroalkyl substances (PFAS) have been around for decades and have been the subject of laboratory and field research studies for nearly as long. Although attention to PFAS has grown in recent years, many unanswered questions remain. Accordingly, the number of research projects designed to improve our understanding of PFAS toxicity, bioaccumulation, and biomagnification, and to improve our ability to predict the interactions of PFAS mixtures, is also increasing. The growing number of ongoing and future research projects focusing on these chemicals will benefit from lessons learned in previous studies. This perspectives article discusses available approaches to mixture risk assessment with specific focus on application to PFAS mixtures. We discuss ongoing research as well as lessons learned from approaches to handling mixtures of other groups of chemicals. Many of these approaches require some detailed understanding of a manageable number of representative chemicals, yet only limited toxicological data are available for most PFAS. With the limited amount of published data currently available, the need for single-chemical and binary-mixture studies persists. Based on our previous work with single-chemical exposures for understudied PFAS, we explored some of the challenges of trying to design and interpret an aquatic concentration–response experiment for a binary mixture of two commonly detected PFAS: perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonic acid (PFHxS). Based on our findings, we propose that addressing risk from PFAS mixtures will likely require combinations of approaches incorporating findings from traditional whole-organism toxicity studies and novel methods relying on in vitro assays, read-across, or quantitative structure activity relationships. Complicating a limited understanding of PFAS mixture toxicity is that relative concentrations of PFAS mixtures vary across sites and time, even at one site. Thus, reliance on empirical data, such as site-specific toxicity sampling or community structure studies, may be needed to fully understand potential impacts of mixtures. Integr Environ Assess Manag 2021;17:697–704. © 2021 SETAC KEY POINTS Due to their ubiquity, PFAS exist commonly in mixtures and it is important to consider PFAS mixture effects in risk assessments. Some studies with PFAS mixtures have been published or are ongoing, but more field and laboratory studies are still needed to adequately support the risk assessment of PFAS mixtures. Previous approaches for assessing the risk of adverse effects from mixtures of other chemicals provides an excellent starting point to unravelling the challenges associated with mixtures of PFAS. Understanding and managing PFAS mixtures is complex and will likely require multiple approaches.
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Mechanism-based and in-silico studies are starting to fill gaps in knowledge about the cellular and molecular pathways that cause PFAS toxicity.
“Mechanism-based studies and in-silico approaches are beginning to fill data gaps pinpointing the cellular and molecular pathways resulting in toxicity (136, 137).”
From Per- and polyfluoroalkyl substances in the environment (2022) · cites this paper as [137]
The Introduction (page not provided) describes major gaps in knowledge of PFAS modes of action and reports evidence that some PFAS interact with nuclear receptors. The Conclusions (page not provided) suggest that invertebrate testing, including multi-omics testing, could help fill knowledge gaps. The paper does not say that in-silico approaches are beginning to pinpoint the cellular and molecular pathways causing PFAS toxicity. (LLM, conf=0.77)
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- Authors
- McCarthy, C. J., Roark, S. A., & Middleton, E. T.
- Affiliations
- Jacobs Engineering Inc., Boston, Massachusetts, USA
- Jacobs Engineering Inc., Denver, Colorado, USA
- NiPERA Inc., Durham, North Carolina, USA
- Venue
- Integrated Environmental Assessment and Management
- Publisher
- Oxford University Press (OUP)
- Published
- 2021-03-01
- Volume
- 17
- Issue
- 4
- Pages
- 697-704
- ISSN
- 1551-3777 (ISSN-L)
- 1551-3793
- OpenAlex
- W3136699231
- Semantic Scholar
- f2f520dd6ebad30cb8b41aba134051e52c6ffab5
- Cited by
- 46
- References
- 30
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 15 · 2023: 3 · 2022: 9 · 2021: 5
- FWCI
- 3.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Integrated Environmental Assessment and Management (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Strategic Environmental Research and Development Program
- Topics
- Physical Sciences › Environmental Science › Environmental Chemistry › Per- and polyfluoroalkyl substances research
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Environmental Toxicology and Ecotoxicology
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
- Keywords
- per- and polyfluoroalkyl substances, PFAS mixtures, mixture risk assessment, binary mixtures, PFOS, perfluorohexane sulfonic acid, bioaccumulation, biomagnification, read-across, QSAR, in vitro assay
- MeSH terms
- Fluorocarbons, Alkanesulfonic Acids, Risk Assessment, Quantitative Structure-Activity Relationship
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