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Jan 11 -- The Agency for Toxic Substances and Disease Registry (ATSDR), Department of Health and Human Services (HHS), invites comment on a proposed information collection project titled Human Health Effects of Drinking Water Exposures to Per- and Polyfluoroalkyl Substances (PFAS): A Multi-site Cross-sectional Study (The Multi-site Study). The purpose of this research is to use sound study methods to see if drinking water exposure to PFAS is related to health outcomes. ATSDR must receive written comments on or before March 13, 2023.

Per- and polyfluoroalkyl substances (PFAS) are a family of chemicals used in industrial applications and consumer products. PFAS contamination of drinking water is widespread in the U.S. Some estimates indicate that at least 60 million residents were served by 66 public water supplies that had at least one sample at or above the U.S. Environmental Protection Agency (EPA) Lifetime Health Advisory for perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) (individually or combined), which is 70 nanograms per liter (ng/L) of water. Industrial facilities that manufacture or use PFAS have contaminated drinking water in surrounding communities in several states. In addition, PFOS, PFOA, perfluorohexane sulfonic acid (PFHxS) and other PFAS chemicals are constituents in aqueous film-forming foam (AFFF), used to extinguish flammable liquid fires. The use of AFFF at military bases and other sites may have resulted in the migration of PFAS chemicals through soils to ground water and/or surface water sources of drinking water for the bases and/or surrounding communities around the country. . . . Currently, the study is funded through section 337 of the William M. (Mac) Thornberry National Defense Authorization Act for fiscal years 2019 through 2023 (Pub. L. 116-283).

The Multi-site Study builds on research methods and activities developed for the proof-of-concept study at the Pease International Tradeport in Portsmouth, New Hampshire (the Pease Study) (OMB Control No. 0923-0061, Discontinued 08/31/2022). These methods and activities included developing data management systems and community engagement materials, modifying the childhood neurobehavioral test battery, adjusting blood collection volume, and modifying data collection materials such as the childhood questionnaire and medical records abstraction forms.

ATSDR is conducting this cooperative research program under Notice of Funding Opportunity (NOFO) No. CDC-RFA-TS-19-002, titled “Multi-site Study of the Health Implications of Exposure to PFAS-Contaminated Drinking Water.” The seven research recipients are University of Colorado School of Public Health, Michigan State Department of Health and Human Services, Pennsylvania Department of Health and RTI International, Rutgers School of Public Health, Silent Spring Institute, SUNY at Albany and the New York State Department of Health, and the University of California at Irvine.

Under the cooperative agreement, each recipient proposed candidate study sites at communities whose drinking water was impacted by AFFF use or by industrial PFAS releases. Site selection considered the documented levels of PFAS drinking water concentrations. The aim was to include sites so that a wide range in PFAS exposures levels were included in the study. This will enable the evaluation of exposure-response trends including effects at the lower range of exposures. Ground water contaminant fate and transport models and water distribution system models may be necessary to identify the areas with contaminated drinking water, to determine the period when the drinking water was contaminated, and to reconstruct historical PFAS contaminant concentrations.

The Multi-site Study is designed to aggregate data across all recipient sites. The main goal of this cross-sectional study is to evaluate associations between measured and reconstructed historic serum levels of PFAS including PFOA, PFOS, and PFHxS, and selected health outcomes. The health outcomes of interest include lipids, renal function and kidney disease, thyroid hormones and disease, liver function and disease, glycemic parameters and diabetes, as well as immune response and function in both children and adults. In addition, the study will investigate PFAS differences in sex hormones and sexual maturation, vaccine response, and neurobehavioral outcomes in children. In adults, additional outcomes of interest include cardiovascular disease, osteoarthritis and osteoporosis, endometriosis, and autoimmune disease.

For exposure estimation, participants will be categorized based on their measured serum concentration of PFAS compounds or on modeled estimated historical serum levels (e.g., referent or low, medium, high). Measured and estimated PFAS serum levels will also be evaluated as continuous variables. At sites with prior PFAS biomonitoring data, the study will evaluate changes in PFAS concentration over time.

Each recipient is reconstructing historic serum PFAS concentrations. This is being done by estimating half-lives and elimination rates as well as by water contamination modeling to inform pharmacokinetic (PK) or physiologically based pharmacokinetic (PBPK) models. Historical serum PFAS reconstruction will enable the evaluation of exposure lags and vulnerable periods as well as statistical analyses that can control for confounding and reverse causation due to physiological factors. Over the first three years of the five-year cooperative agreement program, the recipients have prepared working group support documents describing the methods used by sites for the historical reconstruction and for the whole consortium for the PBPK modeling. Both documents that are undergoing external peer review as required by ATSDR.

If feasible, each recipient is identifying and enumerating all households served by the contaminated drinking water supply in the selected community to recruit potential participants and to meet the sample size requirements for children and adults. If the selected community is served by a PFAS-contaminated public water system, then the recipient will obtain a list of households served by the water purveyor from its billing records. If the community is served by contaminated private wells, then the recipient will obtain a list of households with contaminated wells from the local and/or state health and environmental agencies.

Statistical sampling methods (e.g., a two-stage cluster sample) may be used for recruitment of study participants if all the affected households can be enumerated. If the PFAS drinking water concentrations vary widely across the community, then the recipient can use targeted sampling approaches—including oversampling of areas with higher PFAS concentrations—to ensure a sufficiently wide distribution of exposure levels among study participants to evaluate exposure-response trends. If enumeration of all households is not feasible, or if participation rates are expected to be low, then the recipient can consider non-probabilistic sampling approaches such as “judgment” and “snowball” sampling approaches.

The recipients should consider requesting assistance from local and state health departments in their recruitment efforts. In addition, the recipients should engage community organizations to assist in conducting outreach about the study and recruitment of participants and consider establishing a community assistance panel (CAP). The CAP could provide comments on any additional investigator-initiated research questions and hypotheses and facilitate the involvement of the affected community in decisions related to outreach about the study, participant recruitment strategies, and study logistics. The CAP could also assist the recipient in the dissemination of study findings to the community.

In total, ATSDR seeks to cumulatively enroll approximately 9,100 participants (7,000 adults and 2,100 children and their parents) from communities exposed to PFAS-contaminated drinking water. In total, each recipient will attempt to meet a target recruitment of 1,000 adults and 300 children. Annualized estimates are 3,033 participants (2,333 adults and 700 children). Over the first three years of the five-year cooperative agreement program, the recipients have enrolled over 3,000 adults and over 300 children (as of 11/17/2022). The enrollment of children has been especially challenging during and following major closures and access to schools and other educational facilities due to the COVID-19 pandemic.

To restrict this study to drinking water exposures, adults occupationally exposed to PFAS are not eligible for the study (e.g., ever firefighters or ever workers in an industry using PFAS chemicals in its manufacturing process). Likewise, children whose birth mothers were occupationally exposed will not be eligible.

Assuming a 95% eligibility rate and a 40% response rate, ATSDR estimates that the recipients will screen 7,982 people (6,140 adults and 1,842 children) each year across all sites in order to recruit the target sample size of 3,033 participants (2,333 adults and 700 children). At enrollment, each recipient will obtain adult consent, parental permission, and child assent before data collection begins. For each participant, the recipient will take body measures, collect blood samples to measure PFAS serum levels and several effect biomarkers such as lipids, and thyroid, kidney, immune and liver function. Recipients will also obtain urine samples from participants to measure PFAS levels and kidney function biomarkers. The study will archive leftover serum and urine samples for additional analyses of PFAS chemicals and specific effect biomarkers. The National Center for Environmental Health (NCEH) laboratory will perform blood and urine PFAS analyses for all Multi-site Study participants. Thus, issues of inter-laboratory variability for exposure measures will be eliminated.

Adult participants and a parent of child participants will complete a questionnaire that includes residential history, medical history, occupational history, and water consumption habits (n=3,033 adults and 700 children per year). Ideally, the parent will be the child's birth mother, as ATSDR will ask details about the child's exposure, pregnancy, and breastfeeding history. ATSDR assumes that 20% of parents (n=140 per year) will also enroll as adults and can take the child short form questionnaire; therefore, 560 parents will take the child long form questionnaire per year. Parents and children, with administration by trained professionals, will also complete neurobehavioral assessments of the child's attention and behaviors (n=700 per year).

To facilitate access to medical and school records, each recipient will reach out to local medical societies, public school systems, and private schools, to enlist their cooperation with the study. The recipient will ask for permission to verify participants' medical conditions to confirm self-reported health outcomes. Recipients will also seek permission to obtain information from the children's school records to supplement their behavioral assessment results.
ATSDR PFAS: https://www.atsdr.cdc.gov/pfas/
Draft data collection instruments and technical documentation: https://www.dropbox.com/scl/fo/0tys52uqndurhus3e90xe/h?dl=0&rlkey=d0yn4412icfiq44r85pkof0b1
FRN: https://www.federalregister.gov/d/2023-00333

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