Perfluorooctanoic Acid (PFOA) and Perfluorooctanesulfonate (PFOS) 

Peer Review

Background: 

PFOA and PFOS are environmentally persistent organic fluorocarbons that have been 

identified in ambient waters, ground water, drinking water, and biosolids. They are metabolically 

inert but have the ability to bind to and interact with a variety of biomolecules leading to 

responses in living organisms. Both compounds have a substantial database of epidemiological, 

pharmacokinetic, toxicological and mechanistic studies. 

The two documents submitted for peer review include health assessment chapters that 

will be used 1) to provide information to drinking water treatment plant operators regarding the 

significance of monitoring results with respect to potential health outcomes and 2) to determine 

whether the perfluorinated compounds currently being monitored at Public Drinking Water 

Systems require regulation. The health information at that time will be accompanied with 

chapters on environmental fate, occurrence at public drinking water systems and occurrence in 

other media. The quantitative aspects of the Health Assessment documents will also be used to 

develop lifetime Health Advisories for both compounds. 

 

Charge to the Peer Reviewers: 

1. Please comment on the strengths, weaknesses, and characterization of the studies selected as 

key for quantification. 

2 Please provide citations (and, where possible, pdfs or hard copies) for any references you 

suggest EPA consider adding to the document. Describe where you suggest these references 

be incorporated. 

3. The OW concluded that the human epidemiology data for PFOS/PFOA do not provide 

adequate quantifiable dose-response information for use as the basis of a candidate RfD 

because of uncertainty regarding the routes, levels and timing of exposures plus the 

confounding influences of other PFCs present in serum. Please comment of the OW 

characterization of the data.

4. Please comment on the transparency and characterization of the epidemiological data.

5. The OW has concluded that the cancer classifications for PFOA and PFOS are most 

consistent with respective classifications of suggestive evidence for carcinogenicity as 

described the EPA Guidelines for Carcinogen Risk Assessment (pp. 2-56, 2-57). Please 

comment on the strengths and weaknesses of this classification.

6. Significant interspecies differences in pharmacokinetics exist for both PFOA and PFOS. 

Adjusting for interspecies differences was an important step in developing candidate RfDs 

given the totality of the human and animal data. Please comment on the strengths and 
weaknesses of the pharmacokinetic model adjustments to accommodate the impact of 

albumin binding and renal tubule transporters in determining average serum values. 

7. Table 5-7 lists the parameters used for the ORD pharmacokinetic models that provide the 

final serum and AUC values for calculating the internal dose point of departure for the RfD 

calculation. Please comment on the strengths and weaknesses of the selected parameters. 

8. The volume of distribution (Vd) and half-life values are critical in the derivation of the 

interspecies uncertainty factor applied in derivation of candidate RfDs from a NOAEL, 

LOAEL or a BMDL. The available data for both values are provided in Section 3.5.2 and 

3.5.3 of both documents. Please comment the strengths and weaknesses of the values 

selected. 

9. A variety of endpoints and studies were used to compare points of departure and the resultant 

RfDs for both PFOA and PFOS. In addition, comparisons were provided across RfD 

outcomes based on the model outputs compared to those for the NOAEL, LOAEL and 

BMDL points of departure. The range of candidate RfDs derived from the different points of 

departure is fairly narrow. Please comment on the strengths, weaknesses and transparency of 

this analysis. 

10. The RfDs for PFOS and PFOA are derived from the modeled steady state serum 

concentrations and their association with effects that include short term and longer term 

exposures with associated diverse effects. The studies considered included effects due to 

exposure durations that ranged from 11 to 182 days, and occur at comparable human 

equivalent dose (HED) levels. The current, draft RfDs do not include an uncertainty factor 

for study duration because of the apparent concordance HEDs despite duration differences. 

Given this pattern of response, is it appropriate to conclude that the candidate RfDs are 

applicable to both short-term and lifetime exposures?

11. In addition to using the average serum values from animal studies to calculate internal doses 

for humans, the animal to human extrapolation can be accomplished by dividing animal 

average serum values by the human to animal clearance ratios to project a human average

serum point of departure in units of mg/L serum. Please provide recommendations for 

applying uncertainty factors to the extrapolated average human serum values to determine 

serum-based thresholds that are protective for humans. A NOAEL expressed in average 

human serum units would be useful in interpreting NHANES population monitoring data. 

 

12. Please describe any suggestions you have for improving the clarity, organization, and/or 

transparency of the draft documents.