Response to the letter to the editor regarding the article “Weight of evidence evaluation for chemical-induced immunotoxicity for PFOA and PFOS: findings from an independent panel of experts” by Garvey et al. (2023)

Dear Editor-in-Chief Dr. Roger O. McClellan

Thank you for the opportunity to respond to Dr. Post’s letter (Post 2023) regarding our recent publication. We are pleased that our paper and the work of the independent panel of experts is gaining such attention and we appreciate the opportunity to respond and correct the record.

Dr. Post suggests there are “inaccuracies” in our statements regarding the use of immune system effects as the critical endpoints for toxicity factors for perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). We divided her comment letter into three sections and provide responses below.

1. “The statement by Garvey et al. (2023) that few toxicity factors for PFOA and PFOS are based on immune endpoints does not accurately reflect the information presented in Post (2021). Specifically, Table 3 of Post (2021) shows that of the eight states whose drinking water guidelines and RfDs for PFOS were reviewed, most (six) states used an immunological endpoint as the critical effect for their PFOS RfDs, one state used a database uncertainty factor to account for potentially more sensitive effects (specified in the state’s supporting documentation as immune system effects), and one state did not derive its own RfD but rather used the RfD based on developmental effects developed by the U.S. Environmental Protection Agency in 2016. Additionally, Post (2021) discusses that the European Food Safety Authority’s (EFSA 2020) Tolerable Daily Intake for PFOA, PFOS, and two other long-chain PFAS is based on immune system effects (decreased antibody response to vaccination) in breastfed children.”

The full sentence in Garvey et al. (2023) is: “Currently, there are few examples of use of immune endpoints as critical effects for deriving toxicity values (e.g. RfDs). Some regulatory agencies have used other critical effect endpoints (e.g. developmental) to derive toxicity values for PFOA and PFOS, often accounting for the immune endpoint in the database uncertainty factor (see review in (Post 2021)).” It is not clear what is “inaccurate” with this statement, which applies to both PFOA and PFOS. Of the eight (8) states with risk-based toxicity values for PFOA reviewed by Post (2021), none use the immune endpoint (see Table 2 in Post (2021)) and of the eight (8) states with risk-based toxicity values for PFOS reviewed by Post (2021), six (6) use the immune endpoint as the critical effect (see Table 3 of Post 2021). Therefore, based on the data presented in Post (2021), 6 out of 16 U.S. state values for either PFOA or PFOS are based on the immune endpoint as the critical effect. It should be noted that only four of the six states that use the immune endpoint as the critical effect for PFOS (but not for PFOA) conducted their own independent review of available toxicity data - Minnesota, Michigan, New Hampshire, and New Jersey. Washington and New York reviewed risk-based values previously derived by other agencies to select a value for their state agency; they did not derive their own toxicity values (NYSDEC/NYSDOH 2021; WADOH 2021). We cited Post (2021) in Garvey et al. (2023) as a useful reference for understanding how states have derived toxicity values for PFOA and PFOS. Due to the rapidly changing regulatory landscape for PFOA and PFOS, we do encourage readers to always consult each agency’s documentation as the authoritative source of information related to the associated toxicity values derived. Since Dr. Post published her review, additional U.S. states and international agencies have derived toxicity values for PFOA and PFOS, and most continue to select alternative critical effect endpoints.¹

• “Post (2021) also discusses that the Agency for Toxic Substances and Disease Registry (ATSDR 2021) did not use immune system effects as the primary basis for its PFOS MRL (analogous to an RfD), but instead incorporated a modifying factor (i.e. uncertainty factor) of 10 to account for potentially more sensitive immune effects.”

This comment by Dr. Post is, in fact, in agreement with the second part of the full quotation from our publication, “Some regulatory agencies have used other critical effect endpoints (e.g. developmental) to derive toxicity values for PFOA and PFOS, often accounting for the immune endpoint in the database uncertainty factor.”

• “It is also noted that Garvey et al. does not cite Pachkowski et al. (2019) a highly relevant peer reviewed publication on the derivation of an RfD for PFOS based on an immune endpoint (for which I am a co-author).”

Pachkowski et al. (2019) was not among the body of literature identified by the panel as necessary for their deliberation. As stated in the Methods section of Garvey et al. (2023), the independent expert panel was provided with a wide range of published literature and agency guidance documents, including USEPA’s technical support documents related to PFOA and PFOS, to facilitate the review and response to charge questions. Panelists were encouraged to identify additional literature, publications, and reports during their deliberations. As can be seen in the transcript of expert questions, responses, and interactions, several additional relevant publications were brought up for discussion by the panelists throughout the deliberation process (see Garvey et al. Supplemental Material). Moreover, the panelists were explicitly asked if they were aware of additional studies that should be considered as part of their review (see Questions 2.4 and 3.5). The panelists targeted publications that provide new study data or analysis, rather than reviews of other studies. None of the experts identified Pachkowski et al. (2019) as a publication that provides substantive new data or analysis that would inform their deliberations.

We appreciate the opportunity to contribute to the discussion of this important class of chemicals and of our approach to seeking a dispassionate assessment of the evidence.

Declaration of interest

All authors of Garvey et al. (2023) had complete control over this response to Post (2023) and agree to this response. No authors received funding for preparing this response to Post (2023). The sponsor of the original manuscript had no input or review of this response.

Notes

1 Notably, the Draft for Public Comment U.S. Environmental Protection Agency’s (USEPA) revised technical support documents for PFOA and PFOS maximum contaminant level goals, released in March 2023, still considered the immune endpoint for the point of departure derivation for both compounds, however, this endpoint was no longer used by the agency as the ultimate critical effect for PFOS and was used only in combination with developmental and cardiovascular effects for PFOA (see https://www.epa.gov/system/files/documents/2023-03/MAIN_Proposed%20MCLG%20for%20PFOA%20in%20Drinking%20Water_3.9.23_For%20Proposal.pdf and https://www.epa.gov/system/files/documents/2023-03/MAIN_Proposed%20MCLG%20for%20PFOS%20in%20Drinking%20Water_3.9.23_For%20Proposal_0.pdf).