How should potential risks to human health from PFAS for which there are no toxicity information be handled (check all that apply)?

Answer Explanations

• Read-across Use of high-throughout data QSAR

  Expert 8

  If there are no toxicity data then one would use everything possible to estimate the hazard and the dose-response. This might include read-across, QSAR, high throughput, as well as consideration of absorption potential and bioavailability.

• Read-across Use of high-throughout data QSAR

  Expert 1

  High-throughput data is the most useful, but we may have to rely on read-across and QSAR models because it is unrealistic to screen for thousands of PFAS in in vitro assays.

• Read-across Use of high-throughout data QSAR

  Expert 3

  The few results that scale toxic potency by chain length can be expanded upon and studied for generalizability.

  As a conservative default one could consider all PFAS to be equipotent, assume dose additivity, and calculate hazard indices for various exposure scenarios. As is always the case, this limits the PFAS included to those for which analytical methods exist. A discussion of treatment of non-detects (e.g. exclude, or `1/2 level of detection, etc.) would need to be included in the assessment.

• Other

  Expert 9

  Physical-chemical properties, i.e., persistence. Exposure will be continuous with persistence, eventually leading to toxicities that have not yet been identified.

• Read-across Use of high-throughout data QSAR

  Expert 6

  All of these techniques could potentially supply information on commonality of MoA/endpoints and relative potency that could be useful to inform risk assessment using conventional grouping techniques.

• Read-across Use of high-throughout data QSAR Other

  Expert 11

  I am not an expert in PFAS toxicity. But I would think that all of these tools would be considered for use. The challenge would be to calibrate read across and QSAR models with data that are relevant to PFAS.

• Read-across Use of high-throughout data QSAR

  Expert 5

  All the techniques should be considered. With caveats, among these approaches the read-across approach may be accompanied by the least amount of uncertainty.

  QSAR impacts both read-across and traditional QSTR approaches, somewhat differently. Among the approaches, a read-across based on structural similarity may provide a somewhat confident estimate of toxic potency, but QSAR findings to date seem to indicate that even subtle molecular structural differences can substantially impact predictions of toxicity; and can be the basis for somewhat striking differences in observed toxic potency among otherwise similar molecules. For that reason, a QSAR-based identification of potential surrogates for read-across application should be performed. When sufficient confidence can be placed in the representativeness of toxicological surrogates, then a read-across approach seems valid.

  A strict application of QSTR using computational chemistry approaches, like read-across, involves developing a library of toxicity (and, perhaps dose-response) data derived from enough chemical to develop a training set encompassing at least several chemicals each expressing a given molecular attributes. So, the identification of molecular attributes thought to impact PFAS toxicity should be determined, representing the PFAS chemicals fitting the definition of “PFAS Chemical” identified previously. Short of completing the daunting task of building the training set, the application of QSTR approaches should be straightforward.

  Short of a read-across approach, the development of high throughput data seems an inviting option. Success in this endeavor would require identification of a MOA, AOP or Toxicity pathway in which the event(s) studied in the high throughput approach are known to be both necessary and sufficient to either produce the apical endpoint, or to propagate the stream of further events involved in the pathway between the observed event and the apical endpoint. While it may be assumed that “any change” in an event observed in vitro and known to be a necessary and sufficient event in the MOA, AOP or toxicity pathway may be inviting, the concept of the “molecular tipping point” should also be considered. This concept addresses whether the observed perturbation occurs at a magnitude sufficient for effect propagation (or whether the event may be “corrected”).

• Read-across

  Expert 10

  There are not many good options here. QSAR has not been well-developed for PFAS to date although some limited efforts are underway. High-throughput toxicity data are not yet available although studies are underway. Precautionaty read-across is the only current option.

• Read-across Use of high-throughout data QSAR Other

  Expert 4

  Where possible, the data required information for the substance or mixture should be generated from a standard suite of toxicology studies.
  Where direct study is not possible, all of the other methods should be used together, to the extent supported by available data.
  The risks predicted from each method, and the confidence in each prediction, should be shared with risk managers who who must determine whether, how, and to what extent risks should be mitigated.

• Other

  Expert 7

  The value of an assessment shall not be valued or depend on speed, cheap costs, number of items or money spent, accountability and transparency, robustness are more important.
  Exposure pathways need to be established and then populated with present concentrations for a “model person” (and not too many scenarios).
  Lack of toxicity data may not be the only limiting factor.
  I object toward some of the papers provided since they do not constitute the “global” view; for example:
  • (USEPA, 2010b) must be replaced by (van den Berg et al., 2006)
  • (USEPA, 1986, 2000) WHO approaches should be considered
  • For carcinogenicty in humans, IARC classification to be used and not applied to chemicals that are not carcinogenic to humans. So far, only PFOA has been assessed. Should recommendation be given to IARC to assess at least PFOS? PFHxS? PFNA?
  • (USEPA, 2010a) is not an international approach. Limitations to be considered. In general should be noted that chemical analysis and biological systems do not deliver the same answer (TEF approach based on potency).

  Additional references:
  Deloitte, B.b. (2015). Technical assistance related to the review of REACH with regard to the registration requirements on polymer - Final report, pp. 235.
  Fiedler, H., Kennedy, T., and Henry, B.J. (2021). A Critical Review of a Recommended Analytical and Classification Approach for Organic Fluorinated Compounds with an Emphasis on Per- and Polyfluoroalkyl Substances. Integr Environ Assess Manag 17, 331-351.
  Han, X., Snow, T.A., Kemper, R.A., and Jepson, G.W. (2003). Binding of Perfluorooctanoic Acid to Rat and Human Plasma Proteins. Chemical Research in Toxicology 16, 775-781.
  Henry, B.J., Carlin, J.P., Hammerschmidt, J.A., Buck, R.C., Buxton, L.W., Fiedler, H., Seed, J., and Hernandez, O. (2018). A critical review of the application of polymer of low concern and regulatory criteria to fluoropolymers. Integr Environ Assess Manag 14, 316-334.
  UNEP (2017). Risk profile on pentadecafluorooctanoic acid (CAS No: 335-67-1, PFOA, perfluorooctanoic acid), its salts and PFOA-related compounds. UNEP/POPS/POPRC12/11/Add2.
  UNEP (2018a). Annex I: Decisions adopted by the Persistent Organic Pollutants Review Committee at its fourteenth meeting
  1. POPRC-14/1: Perfluorohexane sulfonic acid (PFHxS), its salts and PFHxS-related compounds 2. POPRC-14/2: Perfluorooctanoic acid (PFOA) its salts and PFOA-related compounds
  3. POPRC-14/3: Evaluation of perfluorooctane sulfonic acid, its salts and perfluorooctane sulfonyl fluoride pursuant to paragraphs 5 and 6 of part III of Annex B to the Stockholm Convention, F.m.o.t.P.O.P.R. Committee, ed. (Rome, Italy).
  UNEP (2018b). Perfluorooctanoic acid (PFOA) its salts and PFOA-related compounds, F.m.o.t.P.O.P.R. Committee, ed. (Rome, Italy).
  UNEP (2021a). Guidance on best available techniques and best environmental practices for the use of perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and their related compounds listed under the Stockholm Convention.
  UNEP (2021b). Technical guidelines on the environmentally sound management of wastes consisting of, containing or contaminated with perfluorooctane sulfonic acid (PFOS), its salts and perfluorooctane sulfonyl fluoride (PFOSF) and perfluorooctanoic acid (PFOA), its salts and PFOA-related compounds. In Technical guidelines, Addendum, Conference of the Parties to the Basel Convention, ed.
  USEPA (1986). Guidelines for the health risk assessment of chemical mixtures.
  USEPA (2000). Supplementary Guidance for conducting health risk assessment of chemical mixtures.
  USEPA (2010a). Development of a relative potency factor (RPF) approach for PAH mixtures.
  USEPA (2010b). Recommended toxicity equivalence factors (TEFs) for human health risk assessments of 2,3,7,8-tetracchlorodibenzo-p-dioxin and dioxin-like compounds, O.o.t.S. Advisor, ed.
  van den Berg, M., Birnbaum, L.S., Denison, M., De Vito, M., Farland, W., Feeley, M., Fiedler, H., Hakansson, H., Hanberg, A., Haws, L., et al. (2006). The 2005 World Health Organization reevaluation of human and mammalian toxic equivalency factors for dioxins and dioxin-like compounds. Toxicological Sciences 93, 223-241.