Toxicology: Per- and Polyfluoroalkyl Substances (PFAS) Testing

Number: 1067

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses toxicology: testing for per- and polyfluoroalkyl substances (PFAS).

1. Experimental, Investigational, or Unproven

   Aetna considers laboratory testing (e.g., blood, urine) for per- and polyfluoroalkyl substances (PFAS) (e.g., perfluorooctanoic acid [PFOA], perfluorooctane sulfonate [PFOS], PFAS (Forever Chemicals) Panel 2) experimental, investigational, or unproven for clinical evaluation and management of PFAS exposure or toxicity because the effectiveness of this approach has not been established.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
CPT codes not covered for indications listed in the CPB:
0394U	Perfluoroalkyl substances (PFAS) (eg, perfluorooctanoic acid, perfluorooctane sulfonic acid), 16 PFAS compounds by liquid chromatography with tandem mass spectrometry (LC-MS/MS), plasma or serum, quantitative
0457U	Perfluoroalkyl substances (PFAS) (eg, perfluorooctanoic acid, perfluorooctane sulfonic acid), 9 PFAS compounds by LC-MS/MS, plasma or serum, quantitative
0535U	Perfluoroalkyl substances (PFAS) (eg, perfluorooctanoic acid, perfluorooctane sulfonic acid), by liquid chromatography with tandem mass spectrometry (LC-MS/MS), plasma or serum, quantitative
0589U	Perfluoroalkyl substances(PFAS) (eg, perfluorooctanoic acid, perfluorooctane sulfonic acid), 24 PFAS compounds by high-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS), plasma or serum, quantitative
82542	Column chromatography, includes mass spectrometry, if performed (eg, HPLC, LC, LC/MS, LC/MS-MS, GC, GC/MS-MS, GC/MS, HPLC/MS), non-drug analyte(s) not elsewhere specified, qualitative or quantitative, each specimen
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
T65.91XA-T65.91XS	Toxic effect of unspecified substance, accidental (unintentional) [Evaluation and management of PFAS exposure or toxicity]
Z13.88	Encounter for screening for disorder due to exposure to contaminants
Z77.010 – Z77.098	Contact with and (suspected) exposure to hazardous, chiefly nonmedicinal, chemicals

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Background

Per- and polyfluoroalkyl substances (PFAS) are a family of thousands of manufactured, synthetic chemicals made up of a partially or fully fluorinated carbon chain. Their chemical properties include: oil and water repellency, temperature resistance, and friction reduction. As a result of having such desirable characteristics, PFAS have been used widely in industry and consumer products since the late 1940s. Their numerous applications include: use in surfactants in industrial processes and firefighting foams, chrome-plating, lubricants, insecticides, protectants for paper packaging products, carpets, cookware, and textiles that enhance water, grease, and soil repellency (ATSDR, 2024).

PFAS are extensively and persistently found in the environment and it for this reason they are referred to as "forever chemicals". Some PFAS build up and persist in the human body and environment, while others transform relatively quickly. Some PFAS change and become one or more other PFAS since their carbon-fluorine bond does not break naturally. Given their chemical characteristics and widespread use, PFAS levels persist in the human body and can continue even after exposure ceases. According to the National Academies of Sciences, Engineering, and Medicine (NASEM) (2022), estimated half-lives established from repeated serum measurements range from days (e.g., perfluorobutanoic acid [PFBA]) to years (e.g., perfluorooctanoic acid [PFOA], perfluorooctane sulfonic acid [PFOS]). A general assumption is that it takes five half-lives to eliminate PFAS from people's bodies after exposure has ended.

In the U.S., nearly all individuals have measurable amounts of PFAS in their blood. The National Health and Nutrition Examination Survey (NHANES) has been measuring certain PFAS (e.g., PFOS, PFOA, perfluorohexane sulfonic acid [PFHxS], and perfluorononanoic acid [PFNA]) in blood samples from individuals living in the U.S. Based on the data, declining levels of three prevalent PFAS (i.e., PFOA, PFOS, and PFHxS) are due, in part, to the U.S. Environmental Protection Agensy (EPA) enlisting major manufacturers to phase out production and reduce facility emissions of PFOA, PFOS, PFHxS, and PFNA. However, population blood levers of substitute PFAS (e.g., hexafluoropropylene oxide dimer acid [HFPO-DA] also known as GenX) are not well studied. Also, blood levels of these shorter-chain PFAS do not necessarily reflect total cumulative exposure because because they tend to have relatively short half-lives (ATSDR, 2024).

The main route of PFAS exposure is through the ingestion of food and water. For communities not affected by PFAS-contaminated drinking water, the relative contribution of exposure sources can vary. PFAS ingestions sources can include: drinking water from PFAS-contaminated municipal sources or private wells, eating food (e.g., meat, dairy, and vegetables) produced near places where PFAS were used or made, eating fish caught from water contaminated by PFAS (PFOS, in particular), eating food from some types of grease-resistant paper or packaging (e.g., popcorn bags, fast food containers, pizza boxes, and candy wrappers), and swallowing contaminated soil. Ingestion of residue and dust from PFAS-containing consumer products (e.g., stain resistant carpets, upholstery, and other fabrics, water resistant clothing, cleaning products, personal care products and cosmetics, and paints, varnishes, and sealants) can also be a source of exposure. PFAS exposure is greater in children compared with adults since children eat and drink more relative to their body weight and can ingest dust or dirt containing PFAS from mouth objects and hand to mouth behaviors. Other sources of PFAS exposure for children include: drinking formula mixed with PFAS-contaminated water, and drinking breastmilk from persons exposed to PFAS. Some PFAS can pass through the placenta and enter the umbilical cord blood. Inhalation of PFAS is not a common route of exposure for the general population but can occur in people living near facilities that incinerate PFAS and PFAS-containing materials or with use of some PFAS-containing consumer products (ATSDR, 2024).

In humans, the most well-studied PFAS have the following pharmacokinetic properties: intestinal and lung absorption with limited dermal absorption; distribution through serum protein binding, and to a lesser extent, tissue protein binding (e.g., liver, kidneys, and brain); most not metabolized and some metabolized to other PFAS; elimination mainly in urine (clearance rate varies by sex and kidney function) and can include defecation, menstruation, breastfeeding, and placental transfer; and a half-life of a few days to 8 years or more, depending on the specific PFAS (ATSDR, 2024). 

The 2021 Toxicological Profile of Perfluoroalkyls (The Agency for Toxic Substances and Disease Registry [ATSDR]) provides a comprehensive review of toxicological information for 12 different PFAS. Based on ATSDR's evaluation of the available epidemiological data, the preponderance of the evidence suggested associations between exposure to individual PFAS and certain health effects. Most of the studies have focused on PFOA and/or PFOS. Fewer studies have evaluated a smaller number of potential health outcomes for the remaining 10 perfluoroalkyls included in this toxicological profile. Most of the studies used serum perfluoroalkyl level as a biomarker of exposure. The three main sources of this information include: occupational exposure studies, studies of communities living near a PFOA manufacturing facility with high levels of PFOA in the drinking water, and studies of populations exposed to background levels of perfluoroalkys (referred to as general population studies). Most of the epidemiological studies examining the potential of perfluoroalkys to induce adverse health effects are cross-sectional in design and do not establish causality. A number of factors in the available epidemiological studies point to associations between perfluoroalkyl exposure and several health outcomes; however, cause-and-effect relationships have not been determined for the following outcomes: pregnancy-induced hypertension/pre-eclampsia (PFOA, PFOS); increases in serum hepatic enzymes, particularly alanine aminotransferase (ALT), and decreases in serum bilirubin levels (PFOA, PFOS, PFHxS); increases in serum lipids, particularly total cholesterol and low-density lipoprotein (LDL) cholesterol (PFOA, PFOS, PFNA, PFDA); decreased antibody response to vaccines (PFOA, PFOS, PFHxS, PFDA); small (<20-g or 0.7-ounce decrease in birth weight per 1 ng/mL increase in either PFOA or PFOS blood level) decreases in birth weight (PFOA, PFOS).

The International Agency for Research on Cancer (IARC) concluded that PFOA is possibly carcinogenic to humans, and the United States Environmental Protection Agency (EPA) concluded that there was suggestive evidence of the carcinogenic potential of PFOA and PFOS in humans. Increases in testicular and kidney cancer have been observed in highly exposed humans (ATSDR, 2021).

Some suggestive evidence for associations between perfluoroalkyls and additional health outcomes, albeit with less certainty in these associations due to inconsistencies across studies and/or a smaller number of studies looking at a specific outcome include the following: osteoarthritis in women under 50 years of age (PFOA, PFOS); decreased antibody response to vaccines (PFNA, PFUnA, perfluorododecanoic acid [PFDoDA]); serum PFOA and PFOS and decreases in glomerular filtration rate and increases in serum uric acid levels; serum PFOA, PFOS, PFHxS, and PFNA and increased early menopause (ATSDR, 2021). 

According to the EPA (2024), current peer-reviewed studies have shown that exposure to certain levels of PFAS may lead to the following: reproductive effects such as decreased fertility or increased high blood pressure in pregnant women; developmental effects or delays in children, including low birth weight, accelerated puberty, bone variations, or behavioral changes; increased risk of some cancers, including prostate, kidney, and testicular cancers; reduced ability of the body’s immune system to fight infections, including reduced vaccine response; interference with the body’s natural hormones; increased cholesterol levels and/or risk of obesity. 

The 2022 report Guidance on PFAS Testing and Health Outcomes (NASEM) categorizes the strength of evidence for various health effects for PFAS as a class. The NASEM also found epidemiologically-based associations with additional health effects.

Research for the association of health effects with PFAS exposure is ongoing with the following challenges noted: there are thousands of PFAS with potentially varying effects and toxicity levels; PFAS exposure in people can occur in different ways and at different stages of their life; and types and uses of PFAS change over time making it difficult to track exposure and assessment of effect (EPA, 2024).

There are no approved medical treatments available to remove PFAS from the body. PFAS toxicity does not present with characteristic signs or symptoms. The individual's PFAS exposure history and health history may serve as a basis guide the clinician in developing a collaborative and individualized care plan (ATSDR, 2024).

Systematic blood testing across the community can enable public health officials to investigate and respond to community-wide exposures. Test results can assess the types and blood levels of PFAS in the community. While blood PFAS in the accepted biomarker of exposure, some investigations also included urine testing (ATSDR, 2024). According the NASEM (2022), clinicians should offer PFAS testing to individuals likely to have a history of elevated exposure. All PFAS testing discussions should include: potential benefits and harms of testing and potential clinical consequences (e.g., additional follow-up); related social implications; and limitations of testing for informed decision making. Individuals who are likely to have a history of elevated exposure to PFAS include those who have: had occupational exposure to PFAS (such as those who have worked with fluorochemicals or served as a firefighter); lived in communities where environmental and public health authorities (Centers for Disease Control and Prevention [CDC], ATSDR, EPA, state and local environmental or health authorities), or academic researchers have documented PFAS contamination; or lived in areas where PFAS contamination may have occurred, such as near facilities that use or have used fluorochemicals, commercial airports, military bases, wastewater treatment plants, farms where sewage sludge may have been used, or landfills or incinerators that have received PFAS-containing waste.

The NASEM's guidance (2022) notes to consider confirmatory retesting when the result is much higher or lower than anticipated given exposure history. Individual should consider retesting if exposure changes because: public health actions (such as drinking water treatment programs or site cleanup are taken to reduce exposure); the individual takes action(s) to reduce exposure (such as installing water filters, moving from a community with known high levels of PFAS in drinking water, or modifying occupational exposures); or the individual moves into a community with known high levels of PFAS or otherwise has a suspected increase in exposure risk. For follow-up testing of PFAS with a long half-life, allow at least a year before retesting. Retesting offers limited or no value when the initial serum levels are low and exposure does not change. 

The NASEM (2022) also recommends that clinicians use serum or plasma concentrations of the sum of PFAS* to inform clinical care of exposed individuals. The following guidelines for interpretation can be used: adverse health effects related to PFAS exposure are not expected at less than 2 nanograms per milliliter (ng/mL); there is a potential for adverse effects, especially in sensitive populations, between 2 and 20 ng/mL; and there is an increased risk of adverse effects above 20 ng/mL.

*Simple additive sum of MeFOSAA, PFHxS, PFOA (linear and branched isomers), PFDA, PFUnDA, PFOS (linear and branched isomers) and PFNA in serum or plasma. Caution is warranted when using capillary blood measurements as levels may differ from serum or plasma levels.

In the UpToDate topic review on "Overview of occupational and environmental health", Goldman (2024) notes "we have been hesitant to advise routine blood testing, since it is difficult to interpret, or offer specific advice, other than to stop the exposure".

The PFAS (Forever Chemicals) Panel 2 by Quest Diagnostics is a blood test that measures the levels of 24 PFAS in the body, identifying exposure to these synthetic "forever chemicals" that can linger in the environment and body.  The test employs mass spectrometry (MS) and is designed to evaluate health risks associated with elevated PFAS levels, providing a physician-consulted report to help understand personal exposure and discuss potential next steps.  Clinical validation data showed that in a population survey of 1,023 specimens, 82.2 % had PFAS NASEM summations between 2 and less than 20 ng/ml, and 2.5 % had summations 20 ng/ml or higher.  The median PFAS NASEM summation was 4.65 ng/ml, lower than the 7.74 ng/ml median observed in NHANES 2017 to 2020, suggesting a decline in population PFAS levels or differences in exposure (Dui et al, 2024).  PFAS serum concentrations are useful for assessment of exposure but do not predict specific health outcomes, and there is no validated therapy for PFAS elimination.

Kee et al (2024) stated that PFAS are widespread environmental contaminants that have been demonstrated to contribute to human exposure; thus, raising a range of health concerns.  In this context, human bio-monitoring is crucial for linking exposure levels of PFAS with their potential health risks.  Mass spectrometry-based analytical techniques have been adopted for the assessment of PFAS levels across various cohorts.  However, challenges arising from the use of biological samples (e.g., plasma, serum, urine, etc.) necessitate ongoing research and refinement of analytical methodologies.  These investigators provided an overview of current trends in MS-based approaches for human bio-monitoring of PFAS, including sample collection and preparation, as well as instrumental techniques.  These researchers also examined analytical strategies to overcome challenges in obtaining PFAS-free blank matrices and discussed the risk of background contamination.  Moreover, the authors examined differing PFAS exposure patterns across regions by analyzing recent international cohort studies, specifically those conducted in the U.S. and China over the past 5 years.  Accordingly, they highlighted several key research gaps in bio-monitoring studies that need to be addressed moving forward.

The authors stated that this review had several drawbacks.  First, while the objective of this review was to summarize the latest analytical methods, it was important to note that a systematic review was not carried out; thus, some relevant studies or important information may not have been included in this analysis.  This drawback should be considered when interpreting the findings.  Second, since this review primarily focused on non-volatile PFAS, gas chromatography-MS-based analytical methods for several volatile PFAS in human samples were not extensively covered.  Third, as for human bio-monitoring data, by concentrating exclusively on recent findings from the past 5 years, these researchers may have overlooked significant earlier research in this field.  The regional comparisons were based on only 28 studies, which may not fully represent global patterns of PFAS exposure in humans.

Yang et al (2025) noted that PFASs have been widely used in the production of consumer products globally due to the excellent water and oil resistance and anti-fouling properties.  The multiple toxic effects of some PFASs also pose a threat to human health and ecosystem, and the frequent use of certain consumer products increased the risk of human exposure to PFASs.  More data on the occurrence, concentration, and migration of PFASs in consumer products is urgently needed to address the possible risks posed by exposure to consumer products.  These investigators reviewed the PFAS concentrations found, the migration characteristics known, as well as the exposure risks of PFASs arising from several types of consumer products over the past 5 years.  The types of consumer products considered here include food contact materials, textiles, and disposable personal hygiene products.  The influence of different factors on the migration process of PFASs from these products were summarized and discussed.  Furthermore, the main approaches and models of exposure assessment were evaluated and summarized.  The authors discussed current challenges and future research prospects in this field with a view to provide guidance for the future assessment and regulation of PFASs in consumer products.  Moreover, these researchers stated that while significant progress has been made in detecting PFASs and understanding their migration patterns, several challenges remain.  They stated that further investigations are needed to develop new detection techniques, migration experimental methods, as well as exposure assessment models to improve the accuracy and practicability of research, and to establish a global PFAS data-base to share detection, migration and toxicity data, and facilitate scientific research and policy development.

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References