By Dr Laura M. Labay and Dr Sherri L. Kacinko

The forever contaminants of our generation

 PFAS (perfluoroalkyl and polyfluoroalkyl substances) are synthetic chemicals that have a wide range of industrial and manufacturing applications because of their chemical and thermal stability and their hydrophobic and lipophobic characteristics. PFAS are persistent in the environment, bioaccumulate in wildlife and humans, and are associated with adverse health effects including cancer, immune dysregulation, and elevated cholesterol. Because several thousand PFAS chemicals exist, knowledge about critical health effects related to PFAS is constantly developing. Biomonitoring and increased medical surveillance, when appropriate, are useful to evaluate patient-specific health risks.

What are PFAS?

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are a heterogenous class of synthetic fluorinated compounds that have been used for decades (see Table 1 for the chemical names and abbreviations for the PFAS cited in this article). Although it is estimated that thousands of PFAS exist, two of the most well-known and widely studied are PFOA and PFOS [1]. PFOA was first mass-manufactured in the late 1940s. Use escalated in the 1950s for the purpose of chemically coating products to create nonstick, waterproof, noncorrosive, and nonreactive surfaces. Its related compound, PFOS, was discovered soon thereafter and used as an ingredient to make various textiles water and stain repellant [2]. Decades later, as awareness about the potentially harmful health effects associated with PFAS exposure grew within the scientific and medical communities, guidelines and policies addressing PFOA and PFOS use were formulated. In 2006, eight major companies using PFAS agreed to phase out production of PFOA and PFOA-related chemicals by 2015. In 2009, The Stockholm Convention on Persistent Organic Pollutants voted to eliminate the production and use of PFOS under most circumstances. A decade later, Stockholm Convention members banned the use of firefighting foams containing PFOA and removed exemptions for the use of PFOS [3]. However, PFOA and PFOS were replaced with alternative shorter-chain PFAS chemicals such as PFBS and GenX, the latter of which was marketed as a “sustainable substitute for PFOA” (Fig. 1). It was postulated that they were safer because the short-chain PFAS bioconcentrate to a lesser degree and are eliminated more quickly from the body compared to the longer-chain PFAS [4,5]. Examples of consumer products that may contain PFAS include rain gear, cosmetics, stain-resistant textiles, food package coatings and cookware. Their extreme persistence in the environment and long half-lives, estimated from days to years depending on the length of the PFAS chain, have earned them the name “forever chemicals” [6].

PFAS exposure

Several interconnected pathways exist for the release and circulation of PFAS into the environment (Fig. 2). Primary sources of contamination are manufacturing sites that produce or use PFAS and then discharge the chemicals into surface water, wastewater and soil. The presence of PFAS in waste streams affects surface and groundwater, the two primary sources of drinking water worldwide. PFAS are recalcitrant compounds in that they are not readily degraded by light or microbial organisms. Owing to their solubilities in water and resistance to breakdown, they are persistent, environmentally mobile and challenging to mitigate and remove. They are taken up by plants and animals throughout the food chain, which further leads to bioaccumulation in fish, wildlife and humans. It is estimated that 99% of the human population have PFAS in their blood [7]. Occupational exposure may also contribute to an increase of total PFAS body burden. Firefighters, as an example, can have significant exposure from direct contact, handling of contaminated equipment, managing foam waste, and working with foam concentrates. PFAS (e.g. PFHxS) can be present in some aqueous film-forming foam (AFFF) formulations that have been used for decades as a fire suppressant for extinguishing fires involving petroleum products or other flammable liquids. PFAS can also be present in personal protective equipment (PPE), which can carry PFAS-containing dust and particulates into firehouse work and living areas [8].

There are over 2100 PFAS hotspots (i.e. sites where the PFAS concentration reaches a level considered hazardous to health) in Europe and 2800 PFAS-contaminated public and private water systems in the United States of America [9,10]. Even though efforts have been made to reduce exposure through policies and regulations, complete success has been hindered. For example, oversight of environmental-toxicant regulations in the USA is not under ­the purview of a single authority – the Environmental Protection Agency (EPA) regulates public drinking water, the U.S. Food and Drug Administration (FDA) regulates bottled water, and private wells are not assigned to any federal agency. Furthermore, even though in March 2023, the EPA did announce the proposed National Primary Drinking Water Regulation that would limit PFAS in drinking water, this included only six PFAS (PFOA, PFOS, PFNA, Gen X chemicals, PFHxS and PFBS) [11].

Figure 1. Chemical structures of (a) PFOA, (b) PFOS, (c) PFBS, (d) GenX, and (e) HFPO-DA

Table 1. PFAS abbreviations and names

Health effects

PFAS will remain in the body until exposure stops and they are eliminated. Their biological half-life has been extensively investigated, but the determinations vary somewhat depending upon the parameters of each study. Half-life estimates, however, range from days (e.g. PFBS) to years (e.g. PFOA, PFOS). Because it generally takes at least five half-lives for complete elimination, it is expected that some PFAS will remain in the body for at least a decade. The European Environment Agency (EEA) reports the following PFAS effects on human health with “high certainty”: thyroid disease, increased cholesterol levels, liver damage, and kidney and testicular cancers. Also reported with “high certainty” are developmental effects including lower birth weight, reduced response to vaccines and delayed mammary gland development. These conclusions are consistent with the determinations made by  The National Academies of Science, Engineering, and Medicine (NASEM) [12]. NASEM has categorized health outcomes based upon seven PFAS (MeFOSAA, PFHxS, n-PFOA and Sb-PFOA, PFDA, PFUnDA, n-PFOS and Sm-PFOS, PFNA) addressed in the Centers for Disease Control and Prevention (CDC)’s National Report on Human Exposure to Environmental Chemicals [12]. They concluded there is high confidence that there is an association between exposure to PFAS and decreased antibody response and dyslipidemia in adults and children, increased risk of kidney cancer in adults, and decreased infant and fetal growth. Increased risk of breast and testicular cancers in adults, thyroid disease and dysfunction in adults, increased risk of ulcerative colitis in adults, increased risk of gestational hypertension and preeclampsia, and liver enzyme alterations in adults and children were categorized as limited suggestive evidence of an association.

Figure 2. PFAS cycle

Biomonitoring and results interpretation

While no single standard method exists for PFAS determinations in biological samples, most are analysed by targeted techniques such as LC-MS/MS [13,14]. If the method is appropriately validated, this is an acceptable approach. The downside to a targeted approach is that not every PFAS present in the sample may not be accounted for or if new PFAS not within the analytical scope of the method are introduced into the ecosphere, they will remain unidentified, causing the total body burden to be underrepresented. Shifts from one PFAS to another by the chemical industry means that testing facilities must expend resources to maintain a relevant analytical scope. Even with this potential gap, laboratory testing is valuable in that it allows for biomonitoring. Biomonitoring is routinely performed by some health agencies, such as the CDC, in the interest of public health. This same type of testing, however, is not included in a routine or annual clinical visit unless it is necessitated for occupational exposure determinations. Although there can be some hesitancy for having a PFAS test because of the potential stigma and property devaluations associated with elevated results, NASEM concludes that the benefits of testing outweigh the potential harms in those who want to be tested.

Interpretation of biomonitoring results is complicated by several factors. Because of the ubiquitous nature of PFAS, it stands to reason that most people will test positive for PFAS [15]. However, as for other chemicals that undergo biomonitoring, a positive result does not necessarily equate to an adverse health event as clinical outcomes may be attributable to other risk factors such as genetic dispositions and lifestyle preferences (e.g. diet, exercise, exposure to other substances, etc.). How then are PFAS results best interpreted by patients and care providers? Overall, there are two main strategies for interpreting chemical concentrations for exposure biomonitoring: reference range based, and risk based. Reference range approaches compare the concentration of a chemical in the patient’s biological sample to a normal background range, whereas risk-based approaches categorize a patient’s biological concentration as below or above a value associated with tolerable, negligible, or minimal risk. The National Health and Nutrition Examination Survey (NHANES) is a population-based survey that collects individual, laboratory and physical examination data in the USA every 2 years [16]. NHANES has a huge repository of biomonitoring data pertaining to environmental chemicals including PFAS, which are available via the internet [17]. One limitation with the reference range approach is that interpretation relies upon data availability and its comparability to the population with which the patient result is being compared. Ideally, the reference population includes people with similar demographics (e.g. age, race, sex, pregnancy status, etc.) residing in the same geographic vicinity for comparable lengths of time to the person whose PFAS testing result is being interpreted. It is also important that reference ranges are available for the PFAS that are being reported in the tested biological matrix as a reference range in serum or plasma, for example, may not be applicable to blood. Given the large number of PFAS and the fact that humans are exposed to mixtures with varying proportions of chemicals, an approach that accounts for PFAS mixtures would most likely better inform clinical care than interpreting PFAS concentrations on an analyte-by-analyte basis. Figure 3 provides the NASEM recommendation for the risk-based approach regarding result interpretation [12].

Summary

PFAS use and subsequent environmental contamination has occurred for decades. Humans can be exposed to PFAS via contaminated water and food, occupational exposure, some consumer products, and through maternal exposure. Total PFAS body burden is dependent on variables such as PFAS-specific properties (e.g. PFAS have different half-lives), duration of exposure, medical conditions (e.g. kidney disease may limit excretion), and clinical status (e.g. PFAS can be eliminated during menstruation or through breastmilk). Adverse health outcomes associated with PFAS exposure include decreased antibody response, decreased fetal and infant growth, elevated cholesterol and lipids, and kidney cancer. PFAS concentrations can be measured in different biological matrices including blood and serum. Laboratory testing can inform care providers and patients about the need for follow-up biomonitoring or evaluation for PFAS-associated diseases or conditions.

Figure 3.
PFAS levels from The National Academies of Science, Engineering, and Medicine to advise clinical care

The authors

Laura M. Labay* PhD, F-ABFT, DABCC-TC and  Sherri L. Kacinko PhD, F-ABFT
Dept. of Clinical Toxicology, NMS Labs, Horsham, PA, USA

* Corresponding author
Email: Laura.Labay@nmslabs.com

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