What is the most toxic chemical you can think of? Dioxin, PCBs, perhaps lead? You may be surprised to learn that perfluorohexanesulfonic acid (PFHxS), a member of the per- and polyfluoroalkyl substances (PFAS) chemical class, has recently emerged as a frontrunner.
One of the newest chemicals assessed under the U.S. Environmental Protection Agency’s Integrated Risk Information System (IRIS), PFHxS currently has the lowest non-cancer oral toxicity value of any chemical in its database. In the final toxicological review, published January 13, 2025, the derived reference dose (RfD) for PFHxS is reported at 0.0000000004 mg/kg/day, and is based on a decreased immune response to vaccines in children. This RfD is the amount of daily chemical exposure (by kilogram of body weight) that is considered to be unlikely to result in serious health effects over the course of a lifetime.
Implications of the new RfD
Reference doses are used by USEPA to develop screening levels for soil and water, are considered in the derivation of standards, and are also used at contaminated sites to perform human health risk assessments. Thus, this new IRIS RfD will likely change screening level and risk calculations for PFHxS. Screening levels are used to identify contaminants of potential concern at Sites, including for risk assessment evaluation.
The current EPA Regional Screening Levels (RSLs) are based on an RfD that is based on thyroid effects and 50,000 times higher (less stringent) than this IRIS value. Lowering the toxicity value for screening levels from 2×10-5 to 4×10-10 mg/kg/day will reduce PFHxS RSLs by five orders of magnitude. This change will increase the number of sites identified with PFHxS contamination and complicate precise measurement of such low concentrations.
The table below presents RSLs for soil and tap water as of November 2024. It also includes the predicted RSL based on the new IRIS RfD and typical reporting limits for PFHxS in the associated medium.
Potential changes to USEPA Regional Screening Levels (based on hazard quotient of 0.1)
µg/kg: micrograms per kilogram
µg/L: micrograms per liter
pg/L: picograms per liter
The predicted RSLs for PFHxS are too low to measure in soil and water. When screening levels are below reporting limits, it creates uncertainty in site investigations and risk assessments. Thus, any PFHxS detection in soil or water, especially potable water, may require remediation. Cleanup goals might also fall below measurable levels, triggering non-detectable concentrations or local ambient background levels as remediation targets.
Why so low?
The low value of the IRIS RfD is based on “decreased serum anti-tetanus antibody concentration in children” who were exposed to PFHxS to a degree where the immune response was not considered sufficiently protective. This effect was observed in one of several studies considered; other studies also indicated effects to the thyroid. The RfD derived for immune effects turned out to be the lowest among the calculated values.
The key elements that resulted in such a low value as the final RfD were the concentration of PFHxS that was estimated as the dose that could cause the antibody effect (the benchmark dose), and the rate at which PFHxS is eliminated from the body (the clearance rate). In both cases, the values are very low, which, when combined, results in an even lower RfD. The benchmark dose from the study, conducted with young children as sensitive receptors, applies to people of all ages.
At the request of other USEPA programs and regions, IRIS has now completed toxicity assessments for four of five PFAS: PFHxS, perfluorohexanoic acid (PFHxA), perfluorobutanoic acid (PFBA), and perfluorodecanoic acid (PFDA). The fifth assessment for perfluorononanoic acid (PFNA) is currently in the final stages of development.
Further information on the IRIS assessment of PFHxS is available on the IRIS website, including a table summarizing the information about the RfD, the toxicological review, and the IRIS summary for the chemical.
Get ready for RSLs
Overall, this new toxicity value is likely to result in PFHxS becoming a driver of risk and site cleanup at locations where it is found. Because this RfD has not yet been directly incorporated into the screening levels, there are no compliance actions required at this time, however there are steps site managers can take to stay ahead of potential future regulatory requirements.
Prudent actions could include comparing site data to the predicted RSLs to understand the potential implications of the forthcoming screening levels on sampling and analytical requirements, provide an indication of the extent to which PFHxS may drive risk and the need for response actions, and consider how the change may affect the positioning of a site for closure. It will also be important to stay on top of any additional regulatory developments that may arise from this new PFHxS value, which could include standards for drinking water and other matrices.
Woodard & Curran is available to support you with extensive experience in emerging contaminants and a deep bench of nationally recognized expertise in site assessment, management, risk assessment, and regulatory support. Please reach out to a member of our team with any questions or if you wish to talk about your situation and understand your options.
