Given that pharmacokinetics (particularly target organ distribution and elimination kinetics, metabolism of precursors) appear to be critical components for some of the PFAS (e.g., PFAAs and fluorotelomer alcohols), how should “certainty” or “variance” related to differences in study concentrations and durations be factored into extrapolation of data and PFAS grouping strategies. How can the “level of confidence” be defined?

I have mentioned the concerns regarding precursor exposure several times above. The presence of precursors to perfluoroalkyl acids (PFAAs) in exposure media will undoubtedly increase exposure. The total oxidizable precursor assay (TOPA) (e.g. example applied to external exposure media or even human blood) is not ideal because it does not simulate metabolism of precursors in the body, but it may be a means of making a rough estimate of potential additional exposure. Research is underway on this topic and maybe it is too early to come up with a definite recommendation on how to deal with precursors. It does suggest that we should be precautionary because we will likely underestimate exposure if we neglect precursors in the exposure considerations.

Differences in elimination kinetics between PFAAs are huge, if grouping multiple PFAAs. These differences can be accounted for using pharmacokinetic modelling or neglected if taking a precautionary approach. The differences in toxic potencies in liver hypotrophy for different perfluoroalkyl acids (based on external dose) can be largely explained by differences in elimination kinetics. For other effects, there may be differences in the toxic potencies of PFAAs as well as the elimination kinetics.

The level of confidence will be entirely dependent on the approach used. The assumptions and associated uncertainties must be clearly explained so the approach is fully transparent. If the approach is precautionary/conservative in its assumptions then I think the public can be convinced that they are safe, even if the margin of safety cannot be precisely calculated. The high uncertainly is the reason why some authorities have been willing to make scientifically-dubious (but precautionary) guidelines for drinking water thresholds (e.g. summing multiple PFAS with different elimination kinetics and toxic potencies). The level of precaution set has to reasonable, of course, and needs to be balanced with cost implications (for clean up, etc.,).

I am not sure I understand the question. In general, internal dose rather than administered dose must be considered, as well as controlling for species and gender differences in half-life through qualitative or quantitative pk models.

Some entities have developed and applied clearance factors to account for differences in half-life between humans and experimental models. Obviously to do so requires having information about pharmacokinetics in both experimental models and humans. However, it may be possible to reduce uncertainty by comparing available PK and half-life data across PFAS that have those data for both models and humans and using that comparison to develop clearance factors based on chain length, functional group, and/or other factors that delineate PFAS from one another.

A difficult question! Question 2.15 also addresses this point. There is probably no simple answer. Pharmacokinetic factors will need to be considered in PFAS grouping strategies, but it is not yet clear how to do this, so in all probability, the "level of confidence", however it is defined, will be low initially.

Differences in study concentrations and exposure durations are critical characteristics, the measurement of which is much simpler than the evaluation of their impact on outcome. Pharmacokinetics is a critical components of exposure, regardless of the chemical, but differences in PK between and within species can be more pronounced for some chemicals than others. Certainty and/or variance in PK data should be evaluated with respect to both dose (study concentration) and duration. Given that lower doses are anticipated in environmentally-exposed humans versus experimentally exposed test animals, the estimation of pharmacokinetic variance and certainty (confidence) surrounding lower doses/concentrations is more important/relevant than at high or higher doses. It might be expected that variability (variance) will be higher for lower doses/concentrations than for higher doses. But, this "variability" or "variance" is a specific measurement, and should be estimated for the measure of dose (the dose metric) that is most associated with risk, and at "humanly-relevant" concentrations (whatever that means). This may mean that variance of free (unbound) concentrations are more critical than variance of total plasma concentrations (combining both bound and unbound fractions). With some knowledge of the toxicologically active form of the dose (unbound versus total, parent versus metabolite, AUC versus Cmax measures of concentration, plasma concentration versus tissue concentration, etc), then we can understand which pharmacokinetic measurements should be evaluated for variance and certainty. The relationship between this/these pharmacokinetic measures (dose metrics) and exposure dose and duration should be characterized, focusing on dose and exposure durations that are most relevant to the human exposure scenario. There are numerous parameters identified in this proposal, and the level of confidence/certainty will be increased with an increasing knowledge of these and other parameters. Perhaps the best approach to defining a level of confidence is via a weight of evidence approach.

The pharmacokinetics of PFAS are complex and varies across chemicals and isomers. Long half-lives of legacy PFAS have been linked to reabsorption in the kidney and gut, lack of metabolism and high affinity for serum albumin. Whereas metabolism and binding to albumin can be carried out rapidly in vitro, other parameters may be harder to obtain. Again, TK would ideally be taken into account, it seems overly optimistic to think we will be able to characterize the TK of hundreds of PFAS in a timely manner.

I am not able to answer this question. Not my area of expertise.

This is true for many substances (I.e. ADME is important), so PFAS may not be any different from most other substances in this regard. Pharmacokinetic and pharmacodynamic differences between and within species are generally captured in the “default” uncertainty factors for inter- and intrapecies differences (usually 10 for each). When specific information is available, PK and PD differences can be addressed and reduce the reliance on uncertainty factors. Differences between PFAS compounds is currently harder to predict given how limited the data are. As for certainty - it may not be possible to define a level of confidence in quantitative terms. Some agencies use descriptors like “low”, “medium” and “high” in relation to confidence in toxicity reference values that are used to establish regulations.

The level of confidence in a study is based on the study design (that includes doses used, duration, animal model), dose-response, criticality of the end point, measured tissue concentrations, data interpretation, robustness of the study, among several other factors. Defining a level of confidence in a study should be based on expert advice and should be based on several criteria related to the study design.

Cannot answer.

There are many levels that need to be considered at the various steps (or users); they are not all necessary and they are not additive.
Needs a practical approach and not complex mathematical definitions.