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September 01, 2023

PFAS toxicological risk status–A topic of much debate

Caron Koll and Jack Sheldon

The toxicological risk status of per- and polyfluoroalkyl substances (PFAS) is currently uncertain and evolving, and it has affected how PFAS might be regulated at both the federal and state levels. While there are thousands of toxicological studies on PFAS, many of these have low levels of confidence or are based on animal, not human, studies. Although perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) are by far the most studied PFAS compounds, the strength of evidence for their health effects varies. Toxicological assessments for PFAS are still in an early stage; much is still unknown about the risks associated with these compounds, and there are tens of thousands of PFAS.

Despite the varying strength of evidence of adverse health effects of different PFAS compounds, there is a consensus among independent studies on certain health outcomes. However, there are significant data gaps related to PFAS in mixtures, which is a significant source of uncertainty in the current state of PFAS toxicology research. Toxicologists are struggling to demonstrate causality from a single PFAS compound, let alone mixtures of PFAS. Mixtures are important, as seldom is a single PFAS compound detected alone in environmental media, raw materials, or consumer products.

Despite this uncertainty, the current toxicological stance is that there is consensus and corroborating evidence from limited independent studies on the following PFAS health outcomes, as summarized by Alan Ducatman et al. in the National Library of Medicine and U.S. Environmental Protection Agency (EPA):

  1. Immunity. According to the U.S. National Toxicology Program, PFOA and PFOS are “presumed to be an immune hazard to humans.” In June 2022, EPA referenced doses for PFOA and PFOS that are based on lowered human antibody responses to administered vaccines, noting that human epidemiological studies are generally consistent with an association between PFOA or PFOS exposure and immunosuppression in children.    
  2. Liver and lipids. “Multiple adult human population studies also show alterations in liver functions associated with PFAS exposure, and notably with PFOA, including all studies in large populations with a wide range of exposure levels."
  3. Breastfeeding. As a result of early studies on elevated PFAS exposure to infants from breastfeeding, early termination of breastfeeding is recommended, despite the known advantages of breastfeeding.
  4. Testicular and kidney cancer. The International Agency for Research on Cancer (IARC) classified PFOA as a possible human carcinogen based on testicular and kidney cancer data. “The human population evidence is strongest for kidney cancer and supportive for testicular cancer.”
  5. Kidney and liver cancer. Recently, PFOS was classified as a likely carcinogen by EPA. On March 14, 2023, EPA’s science advisory board took a systematic review of available human epidemiological and animal toxicity studies for PFOS, and EPA determined that both PFOA and PFOS are likely to cause cancers (e.g., kidney and liver cancer). Additionally, there is no dose below which either chemical is considered safe. The State of California has already classified PFOS as a carcinogen in 2021.

These health outcomes are supported by the scientific community. Regardless, there appears to be significant miscommunication by government health agencies that minimizes or over-generalizes health risks of PFAS to affected communities, medical practitioners, and the judicial system. The miscommunications stem from one big data gap—PFAS in mixtures.

EPA has recognized the need for toxicological methods for PFAS mixtures, and efforts are currently underway to develop methods for evaluating their toxicology. However, this is a complex and time-consuming process that will take years. In the meantime, toxicologists are using the best available practices and standard methods for evaluating PFAS on an individual basis.

In addition, as of November 2022, EPA has reopened the door for toxicological methods for other chemical family mixtures such as polynuclear aromatic hydrocarbons (PAHs), phthalates, disinfection by-products (DBPs), and others. Eleven educational institutions are funded to research predictive toxicology methods to evaluate environmental chemical mixtures; the studies are expected to run for two to four years. 

In the meantime, for litigation cases in which parties are trying to either prove or disprove causality, toxicologists use available best practices for evaluating PFAS on an individual PFAS chemical basis. Toxicologists are often struggling to demonstrate causality from a single PFAS compound. A recent study by the Keck School of Medicine of USC reported findings that “Exposure to a mixture of chemicals called PFAS leads to alterations in biological processes associated with a broad range of diseases.”

It is too soon to make risk-based decisions about PFAS without additional study and vetted toxicological methods for evaluating PFAS mixtures other than PFOA and PFOS and perhaps a handful of other PFAS and their salts. Therefore, there is a significant level of uncertainty surrounding the toxicological risk status of PFAS, and this uncertainty will likely persist for several years as research efforts continue. EPA and other global agencies’ focus on PFAS health effects on an individual chemical basis and mixtures are slowly filling those gaps.

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    Caron Koll and Jack Sheldon


    Caron Koll leads Antea Group's PFAS service offerings with nearly 40 years of experience in the environmental business serving private and public clients globally. She is a subject-matter expert on contaminant fate and transport PFAS and co-contaminants.

    Jack Sheldon, a senior remediation specialist for Antea Group, has over 41 years of experience in environmental consulting. He leads Antea Group's Site Assessment & Remediation service line and provides expertise in PFAS risk management, investigation, and remediation.