PKG00249584-instructions.pdf

Centers for Disease Control

Agency for Toxic Substances and Disease Registry Extramural Research Program Office

Multi-Site Study of the Health Implications of Exposure to PFAS-Contaminated Drinking

Water

RFA-TS-19-002

Application Due Date: 05/30/2019

Multi-Site Study of the Health Implications of Exposure to PFAS-Contaminated Drinking

Water

RFA-TS-19-002

TABLE OF CONTENTS

Part 1. Overview Information Key Dates Required Application Instructions Executive Summary

Part 2. Full Text Section I. Funding Opportunity Description Section II. Award Information Section III. Eligibility Information Section IV. Application and Submission Information Section V. Application Review Information Section VI. Award Administration Information Section VII. Agency Contacts Section VIII. Other Information

Part 1. Overview Information Participating Organization(s) Centers for Disease Control Components of Participating Organizations Agency for Toxic Substances and Disease Registry Extramural Research Program Office

(ATSDR ERPO)

Agency for Toxic Substances and Disease Registry (ATSDR) Notice of Funding Opportunity (NOFO) Title Multi-Site Study of the Health Implications of Exposure to PFAS-Contaminated Drinking Water Activity Code Applications in response to this Notice of Funding Opportunity (NOFO) will be funded using the U01 activity code.

Notice of Funding Opportunity Type New Agency Notice of Funding Opportunity Number

RFA-TS-19-002

Assistance Listings (CFDA) Number(s) 93.070 Category of Funding Activity:

Health NOFO Purpose The Agency for Toxic Substances and Disease Registry (ATSDR) is soliciting research to commence a multi-site study on the human health effects of exposures to drinking water contaminated with per- and polyfluoroalkyl substances (PFAS). Proposed study sites must include communities using PFAS-contaminated private residential wells or public water systems. Exposure assessment will be based on measured PFAS serum levels as well as estimated PFAS serum levels derived from pharmacokinetic modeling of reconstructed PFAS drinking water concentrations over time. Effect biomarkers such as lipids and tests of immune and thyroid function derived from pharmacokinetic modeling of reconstructed PFAS drinking water concentrations over time will be evaluated.

ATSDR intends this research to be a two-part program consisting of (1) a mandatory core research protocol to allow ATSDR to aggregate the core data and to compare laboratory and statistical analyses across sites, and (2) each successful awardee will have the option to propose additional investigator-initiated research questions and hypotheses related to the overall goals of this NOFO.

Key Dates Publication Date: To receive notification of any changes to RFA-TS-19-002, return to the synopsis page of this announcement at www.grants.gov and click on the https://www.grants.gov

"Send Me Change Notification Emails" link. An email address is needed for this service.

Letter of Intent Due Date: 05/03/2019 A letter of intent is not required to apply to this NOFO, is not binding, and does not enter into the review of a subsequent application. However, the information that it contains allows ATSDR staff to estimate the potential review workload and plan the review.

Application Due Date: 05/30/2019

On-time submission requires that electronic applications be error-free and made available to CDC for processing from the NIH eRA system on or before the deadline date. Applications must be submitted to and validated successfully by Grants.gov no later than 5:00 PM U.S.

Eastern Time. Applications must be submitted using the Application Submission System & Interface for Submission Tracking (ASSIST) module which is a web-based service used for the preparation and submission of grant applications to CDC through Grants.gov. ASSIST provides the ability for applicants to prepare their applications online, and offers the applicant additional capabilities including the ability to preview the application image, validate the application against required business rules, and prepopulate data from an applicant organization's records, therefore identifying issues earlier in the application submission process.

Note: HHS/CDC grant submission procedures do not provide a grace period beyond the application due date time to correct any error or warning notices of noncompliance with application instructions that are identified by Grants.gov or eRA systems (i.e., error correction window).

Scientific Merit Review: 07/24/2019 This is an estimated date.

Secondary Review: 09/06/2019 This is an estimated date.

Estimated Start Date: 10/01/2019

Expiration Date: 06/28/2019 Due Dates for E.O. 12372: Due no later than 60 days after the application receipt date.

Required Application Instructions

**ELECTRONIC APPLICATION SUBMISSION VIA ASSIST IS PREFERRED**

It is recommended that applicants use ASSIST for the electronic preparation and submission of applications through Grants.gov to CDC. ASSIST is an alternative method to prepare and submit applications, and provides many features to facilitate the application submission process which improves data quality (e.g., pre-population of organization data, pre-submission validation of business rules, and preview of the application image used for review). Use of the Grants.gov downloadable Adobe application packages and submission process will still be supported.

It is critical that applicants follow the instructions in the SF 424 (R&R) Application Guide except where instructed to do otherwise in this NOFO. Conformance to all requirements (both in the Application Guide and the NOFO) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.

Note: The Research Strategy component of the Research Plan is limited to 20 pages.

Applications that do not comply with these instructions may be delayed or not accepted for review.

Telecommunications for the Hearing Impaired: TTY 1-888-232-6348

Executive Summary The Agency for Toxic Substances and Disease Registry (ATSDR) is committed to protecting people's health from environmental hazards by investigating the relationship between environmental factors and health, developing guidance, and building partnerships to support healthy decision making. The intent of the ATSDR extramural research program is to fund research that promotes healthy community environments by assessing the available scientific data to determine whether or not people are at risk because of their exposures to harmful chemicals in the environment.

Purpose: The Agency for Toxic Substances and Disease Registry (ATSDR) is soliciting research to commence a multi-site study on the human health effects of exposures to drinking water contaminated with per- and polyfluoroalkyl substances (PFAS). Proposed study sites must include communities using PFAS-contaminated private residential wells or public water systems. Exposure assessment will be based on measured PFAS serum levels as well as estimated PFAS serum levels derived from pharmacokinetic modeling of reconstructed PFAS drinking water concentrations over time. Specifically, grant awardees will be required to conduct historical reconstruction/water modeling in order to determine the PFAS concentration.

Effect biomarkers such as lipids and tests of immune and thyroid function derived from pharmacokinetic modeling of reconstructed PFAS drinking water concentrations over time will be evaluated.

ATSDR intends this research to be a two-part program consisting of (1) a mandatory core research protocol to allow ATSDR to aggregate the core data and to compare laboratory and statistical analyses across sites, and (2) each successful awardee will have the option to propose additional investigator-initiated research questions and hypotheses related to the overall goals of this NOFO.

Successful awardees will be expected to send all serum and urine samples to an ATSDR facility or an ATSDR-designated facility for analysis. ATSDR will provide recipients with details regarding sample transfer within the first six months post award. All data resulting from the sample analysis will be stored by ATSDR. ATSDR will share each site's sample testing results with them in addition to additional de-identified data for all sites.

Research Notice of Funding Opportunity (NOFO) RFA-TS-19-002 aligns with the National http://grants.nih.gov/grants/funding/424/SF424_RR_Guide_General_VerC.pdf

Center for Environmental Health (NCEH)/ATSDR 2014-2016 strategic plan, available at https ://www.atsdr.cdc.gov/about/mission_vision_goals.html, and supports the specific ATSDR goal to identify, characterize, and monitor health outcomes and environmental exposures to guide actions that protect and promote health. Research under this NOFO also aligns with the specific ATSDR goal to ensure safe drinking water. Additional information about ATSDR priorities is available at https://www.atsdr.cdc.gov/about/docs/NCEHATSDR_priorities_2014_final.pdf.

Mechanism of Support The funding mechanism for this Notice of Funding Opportunity (NOFO) will be a cooperative agreement research grant.

Funds Available and Anticipated Number of Awards.

ATSDR intends to commit approximately $6,500,000 in FY 2019 to fund up to six applications.

Awards issued under this NOFO are contingent upon availability of funds and a sufficient number of meritorious applications. Because the nature and scope of the proposed research will vary from application to application, it is also anticipated that the size and duration of each award may also vary. The total amount awarded and the number of awards will depend upon the number, quality, duration and cost of the applications received and approved.

Budget and Project Period.

The maximum award amount will be $3,000,000 per award for the first 12 month budget period. This includes both direct and indirect costs. An applicant may request a project period of up to five years. The maximum total project funding amount is $32,500,000 (including both direct and indirect costs) over the expected project period length, with a maximum of $3,000,000 per award per year. The project period for this award is expected to run from 10/01/2019 to 9/30/2024.

Throughout the project period, ATSDR's commitment to continuation of awards will be conditional on the availability of funds, evidence of satisfactory progress by the recipient (as documented in required reports), and the determination that continued funding is in the best interest of the Federal government.

Application Research Strategy Length: Page limits for the Research Strategy are clearly specified in Section IV. Application and Submission Information of this announcement.

Eligible Institutions/Organizations. Institutions/organizations listed in Section III. 1 are eligible to apply.

Eligible Project Directors/Principal Investigators (PDs/PIs). Individuals with the skills, knowledge, and resources necessary to carry out the proposed research are invited to work with their institution/organization to develop an application for support. NOTE: CDC/ATSDR does not make awards to individuals directly.

Number of PDs/PIs. An application may name more than one PD/PI; their names must appear on the face page of the application. However:

One (1) principal investigator must be designated as the contact PI for all correspondence related to the application.

All PD/PIs must include their eRA Commons Identification in the Credential Field of the Senior/Key Person Profile Component of the SF424 (R&R) Application Package.

https://www.atsdr.cdc.gov/about/mission_vision_goals.html https://www.atsdr.cdc.gov/about/mission_vision_goals.html https://www.atsdr.cdc.gov/about/docs/NCEHATSDR_priorities_2014_final.pdf http://grants.nih.gov/grants/guide/pa-files/PAR-11-022.html#SectionIV

Institutions/organizations proposing multiple PDs/PIs must visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF 424 (R&R) Application Guide.

Number of Applications. Applicant organizations may submit more than one application, provided that each application is scientifically distinct. However, applicant institutions can submit only one grant application with the same principal investigator in response to this NOFO. Only one application per principal investigator will be funded under this NOFO.

Additionally, applicant institutions submitting applications with essentially the same proposed research to two or more CDC NOFOs will not be funded under more than one NOFO.

Application Type. NEW Special Date(s). A pre-application teleconference call will be conducted on April 29, 2019 to address questions from prospective applicants regarding NOFO RFA-TS-19-002, "Multi-Site Study of the Health Implications of Exposure to PFAS-Contaminated Drinking Water". The call will begin at 1:00 PM Eastern Standard Time (EST) and end at 2:00 PM Eastern Standard Time (EST), or sooner if all questions are addressed. Questions and answers from the discussion will be included in an amended NOFO approximately 2 weeks after the call.

Participant Access Information

Call Date: April 29, 2019 Call Start Time: 1:00 PM Eastern Standard Time (EST) Call End Time: 2:00 PM Eastern Standard Time (EST) Call Leader: Daniel Holcomb, Scientific Program Official Toll-Free Number: 1-866-916-0413 Conference Passcode: 52108552

Application Materials. See Section IV.1 for application materials.

Hearing Impaired. Telecommunications for the hearing impaired are available at: TTY: (770) 488-2783.

Part 2. Full Text Section I. Funding Opportunity Description

Statutory Authority This program is authorized by Section 316 of the National Defense Authorization Act for Fiscal Year 2018 (Pub.L. 115-91) as amended by Section 315 of the John S. McCain National Defense Authorization Act for Fiscal Year 2019 (Pub. L. 115-232).

ATSDR is authorized to conduct the PFAS multi-site study under Section 316(a) of the 2018 National Defense Authorization Act (Public Law 115-91) for research in general, under the 1980 Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA), as amended by the 1986 Superfund Amendments and Reauthorization Act (SARA) (42 U.S.C. 9601, 9604).

http://grants.nih.gov/grants/guide/pa-files/PAR-11-022.html#SectionIV1

1. Background and Purpose Background Per-and polyfluorinated substances (PFAS) are a family of more than 4,500 chemicals. They are used in a variety of industrial and consumer applications and products, including: fire-fighting foams; personal care and cleaning products; as well as oil, stain, grease, and water-repellent coatings on carpet, textiles, leather, and paper. Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) are the most extensively studied. There is little toxicity data related to other PFAS chemicals. Although the scientific evidence linking PFAS exposures with adverse health effects is rapidly growing, it is inconsistent for a variety of reasons, including differences in exposure levels, PFAS evaluated, PFAS mixtures, and the outcomes measured.

Finding a measurable amount of PFAS in serum does not imply that the levels of PFAS cause an adverse health effect. Biomonitoring studies on levels of PFAS provide physicians and public health officials with reference values so that they can determine whether people have been exposed to higher levels of PFAS than are found in the general population. Biomonitoring data can also help scientists plan and conduct research on exposure and health effects.

Due to past environmental contamination, PFAS have been detected in numerous public and private drinking water systems throughout the United States. As a result, public health agencies and community organizations are concerned about the possible health risks for communities exposed to these drinking water supplies as well as other sources of PFAS contamination (e.g.

dust, fish, food wrappers, etc.). In 2016, the EPA established a lifetime health advisory level (i.e.

“the level below which adverse health effects are not anticipated to occur over a lifetime of exposure”) of 70 parts per trillion (ppt) in drinking water for PFOA and PFOS, either separately or combined.

Epidemiological studies have been conducted to assess the relationship between PFAS exposure and adverse health effects in humans. These studies have been conducted in occupationally exposed populations, residential populations exposed to PFAS through contaminated drinking water, and the general US population. These studies have generated concerns among communities with identified exposures to PFAS. Although the scientific evidence linking PFAS exposures with adverse health effects is rapidly growing, only a limited number of studies currently exist for some health endpoints. Inconsistencies may also occur for some health endpoints such as kidney biomarkers and reproductive outcomes due to biases resulting from the use of cross-sectional PFAS serum measurements to determine exposure. Such biases can be minimized if PFAS serum levels are estimated (e.g., based on historical reconstruction modeling of drinking water PFAS contamination and pharmacokinetic modeling).

The C8 (PFOA) studies conducted in West Virginia and Ohio communities surrounding a chemical plant that contaminated drinking water included a large cohort of highly exposed workers and residents (60,000+) and provided extensive and high-quality information. However, the studies focused primarily on PFOA, and to a lesser extent, PFOS. Except for the C8 studies, there is scant information on the health effects of exposures to PFAS-contaminated drinking water. This research gap has led to the need for more epidemiological research on the health effects of PFAS exposures.

Purpose The Agency for Toxic Substances and Disease Registry (ATSDR) is soliciting research to commence a multi-site study on the human health effects of exposures to drinking water contaminated with per- and polyfluoroalkyl substances (PFAS). Proposed study sites must include communities using PFAS-contaminated private residential wells or public water systems.

Exposure assessment will be based on measured PFAS serum levels as well as estimated PFAS serum levels derived from pharmacokinetic modeling of reconstructed PFAS drinking water concentrations over time. Specifically, grant awardees will be required to conduct historical reconstruction/water modeling in order to determine the PFAS concentration.

Effect biomarkers such as lipids and tests of immune and thyroid function derived from pharmacokinetic modeling of reconstructed PFAS drinking water concentrations over time will be evaluated.

ATSDR intends this research to be a two-part program consisting of (1) a mandatory core research protocol to allow ATSDR to aggregate the core data and to compare laboratory and statistical analyses across sites, and (2) each successful awardee will have the option to propose additional investigator-initiated research questions and hypotheses related to the overall goals of this NOFO.

Successful awardees will be expected to send all serum and urine samples to an ATSDR facility or an ATSDR-designated facility for analysis. ATSDR will provide recipients with details regarding sample transfer within the first 6 months post award. All data resulting from the sample analysis will be stored by ATSDR. ATSDR will share each site's sample testing results with them in addition to additional de-identified data for all sites.

References:

ATSDR. Feasibility Assessment for Epidemiological Studies at Pease International Tradeport, Portsmouth, New Hampshire, November, 2017. Available at: https://www.atsdr.cdc.gov/sites /pease/documents/Pease_Feasibility_Assessment_November-2017_508.pdf ATSDR. Per- and Polyfluoroalkyl Substances (PFAS) and Your Health, November, 2018.

Available at: https://www.atsdr.cdc.gov/pfas/index.html ATSDR. Toxicological Profile for Perfluoroalkyls, August, 2018. Available at: https://www.atsdr .cdc.gov/toxprofiles/tp.asp?id=1117&;tid=237 Centers for Disease Control and Prevention, National Biomonitoring Program. Per- and Polyfluorinated Substances (PFAS) Factsheet, April, 2017. Available at: https://www.cdc.gov /biomonitoring/PFAS_FactSheet.html Sunderland EM, Hu XC, Dassuncao C, Tokranov AK, Wagner CC, Allen JG. A Review of the Pathways of Human Exposure to Poly- and Perfluoroalkyl Substances (PFASs) and Present Understanding of Health Effects; J Expo Sci Environ Epidemiol; 2018; Nov 23, (Epub ahead of print)

Healthy People 2020 and other National Strategic Priorities ATSDR is committed to achieving the health promotion and disease prevention objectives of https://www.atsdr.cdc.gov/sites/pease/documents/Pease_Feasibility_Assessment_November-2017_508.pdf https://www.atsdr.cdc.gov/sites/pease/documents/Pease_Feasibility_Assessment_November-2017_508.pdf https://www.atsdr.cdc.gov/pfas/index.html https://www.atsdr.cdc.gov/toxprofiles/tp.asp?id=1117&tid=237 https://www.atsdr.cdc.gov/toxprofiles/tp.asp?id=1117&tid=237 https://www.cdc.gov/biomonitoring/PFAS_FactSheet.html https://www.cdc.gov/biomonitoring/PFAS_FactSheet.html

"Healthy People 2020" and to measuring program performance as stipulated by the Government Performance and Review Act (GPRA). This research NOFO directly supports the United States Department of Health and Human Services (DHHS) Healthy People 2020 goals and objectives as described in: http://www.healthypeople.gov/.

The proposed program of research addresses the Healthy People 2020 priority area of environmental health infrastructure and surveillance and is in alignment with ATSDR's performance goal to conduct a targeted program of research to identify, characterize, and monitor health outcomes and environmental exposures to guide actions that protect and promote health.

Specifically this research NOFO supports the Healthy People 2020 goal for promoting high-quality, longer lives free of preventable disease and Healthy People Objective EH-21 to improve the quality, utility, awareness, and use of existing information systems for environmental health.

Public Health Impact The results of this study will add to the body of literature regarding the association between PFAS exposure in drinking water and health outcomes. Since the study will evaluate PFAS serum levels and adverse health outcomes, the study findings are expected to be generalizable among individuals with similar PFAS serum levels who have been exposed to PFAS contaminated drinking water, as well as those potentially exposed from other sources (e.g., diet, workplace exposures).

Relevant Work NCEH/ATSDR provides ongoing technical assistance to affected state/city/local health departments in conducting PFAS exposure investigations on an as-needed basis. NCEH/ATSDR has initiated a proof of concept research study to inform the approach outlined here. That proof of concept will be conducted at Pease International Tradeport in Portsmouth, NH. NCEH/ATSDR also plans to conduct PFAS exposure assessments in no less than eight sites with PFAS contaminated drinking water which are yet to be determined.

ATSDR also has extensive experience in modeling the fate and transport of contaminants in groundwater from the source of the contamination to drinking water supply wells and distribution system (i.e. from previous work performed under the USMC Camp Lejeune project and the Toms River study). ATSDR has reconstructed historical concentrations of trichloroethylene, tetrachloroethylene and other volatile organic chemicals in the drinking water systems at Camp LeJeune, North Carolina and in Decatur, Alabama. ATSDR has experience using a pharmacokinetic model to estimate chemical half-lives of per fluoro octanoic acid (PFOA), perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonic acid and its salts (PFHxS) in serum. ATSDR will use this modeling expertise to advise and assist recipients in reconstructing historical PFAS concentrations in drinking water and serum levels.

References:

Maslia, ML; Aral MM; Ruckart, PZ; Bove, FJ. Reconstructing Historical VOC Concentrations in Drinking Water for Epidemiological Studies at a U.S. Military Base: Summary of Results. Water (Basel) 2016; 8(10):449.

Maslia, ML; Reyes, JJ; Gillig, RE; Sautner, JB; Fagliano, JA; Aral, MM; Public Health Partnerships Addressing Childhood Cancer Investigations: Case Study of Toms River, Dover

Township, New Jersey, USA. Int J Hyg Environ Health; 2005; 208(1-2):45-54.

Worley, RR; Yang, X; Fisher, J; Physiologically Based Pharmacokinetic Modeling of Human Exposure to Perfluorooctanoic Acid Suggests Historical Non-drinking-water Exposures are Important for Predicting Current Serum Concentrations. Toxicol Appl Pharmacol; 2017; 330:9- 21.

2. Approach This is cooperative research program will include several research components (core, optional, and future). First, all recipients must conduct research at their sites following the ATSDR core protocol. This core protocol has been submitted for final approval, but a link to the current version is provided in this document for applicants' planning purposes. Uniform collections under the core protocol will allow ATSDR and recipients to aggregate data and analyze results across sites.

At each selected site, the core research activities will focus on assessing health outcomes among adults and children exposed to PFAS-contaminated drinking water. As part of the core activities, the successful applicants will obtain blood samples from participants to measure PFAS serum levels and effect biomarkers. Applicants will be expected to describe how they intend to characterize the participants’ exposures based on the measured serum concentrations of PFAS compounds and on modeled estimated current and historical PFAS serum levels (e.g., referent or low, medium, high). Successful awardees will be required to conduct historical reconstruction(s) of PFAS concentrations in drinking water and pharmacokinetic modeling. Specifically, grant awardees will be required to conduct historical reconstruction/water modeling in order to determine the PFAS concentration.

As part of the core activities, applicants should also plan to obtain urine samples from participants to measure urinary PFAS levels and kidney function, as they are identified during the program period, and to archive these blood and urine samples in order to provide for the possibility to conduct subsequent analyses of additional PFAS chemicals and effect biomarkers.

Successful grantees will be expected to send all serum and urine samples to an ATSDR facility or an ATSDR-designated facility. ATSDR will provide recipients with details regarding sample transfer within the first 6 months post award. All data resulting from the sample analysis will be stored by ATSDR. ATSDR will share each site's sample testing results with them in addition to additional de-identified data for all sites.

Applicants may propose their own site-specific modules to investigate their own research interests related to the required core activities.

Applicants should plan to obtain consent from participants to archive leftover blood and urine samples in order to provide for the possibility to conduct analyses of additional PFAS chemicals and effect biomarkers. Successful grantees will be expected to send all serum and urine samples to an ATSDR facility or an ATSDR-designated facility. ATSDR will provide recipients with details regarding sample transfer within the first six months post award. All data resulting from the sample analysis will be stored by ATSDR. ATSDR will share each site's sample testing results with them in addition to additional de-identified data for all sites.

Applicants should describe a community engagement plan in their application and consider requesting assistance from local and state health departments in their proposed recruitment efforts, and plan to engage community organizations to assist in conducting outreach about the study and recruitment of participants. In addition, the applicant should consider engaging with the affected community in decisions related to outreach about the study, participant recruitment strategies, study logistics, and dissemination of study findings.

Approach Considerations for Achieving Primary Outcomes Applicants will be required to describe how they plan to conduct historical reconstruction/water modeling in order to determine the PFAS concentration in the drinking water and the exposure estimation. In order to determine the level of complexity of modeling necessary to historically reconstruct PFAS drinking water contamination, the successful applicants should collect all the available historical and current information on the water system (e.g., distribution system characteristics and sources of water, supply well construction and production logs, well capacity, and years of operation, water demand and pipe network, etc.) and/or private wells. The successful applicants should also collect all available information on the source and migration of the PFAS contamination (e.g., information on the historical use of AFFF or PFAS in industrial processes, information on PFAS emissions to soil, ground water and surface water, hydrogeological reports, and information on groundwater plumes, etc.) and PFAS sample data from supply wells, private wells, monitoring wells, surface water, and the distribution system.

Child and adult studies proposed should be cross-sectional with separate evaluation of children (ages 4-17 years) and adults (aged ≥18 years). The participants should be recruited from areas served by PFAS-contaminated drinking water. The study goal is to recruit, at least 2,000 children and 6,000 adults at a minimum in total.

Required sampling frame – Please refer to the draft ATSDR core study protocol document located https://www.atsdr.cdc.gov/PFAS/PFAS-Research-NOFO.html For sites with a contaminated public water supply, the successful applicants should request, at a minimum:

information from the water purveyor on the distribution system characteristics, in particular, whether the PFAS concentrations can be assumed to be relatively uniform throughout the system or whether the system had specific areas with considerably higher or lower PFAS concentrations, and a list of residences served by the water purveyor, including the name of the person on the residential account and the street address of the residence.

If uniform PFAS concentrations can be assumed, then a random sample of households may be conducted. Recruitment methods could include recruitment letters mailed to potentially affected households. If the system has areas with considerably higher PFAS concentrations, then the successful applicants could target (oversample) households in these areas for recruitment letters.

For sites with contaminated private wells, applicants should request information on the impacted residences and the results of PFAS sampling of their private wells from the state and/or local health and environmental agencies. Sampling should target households based on the magnitude of the PFAS concentrations in their private wells – i.e., wells with higher concentrations should be oversampled.

https://www.atsdr.cdc.gov/PFAS/PFAS-Research-NOFO.html

Partnerships between the applicant institution and outside entities may be necessary to complete the proposed work. However, a substantial portion of the proposed research work plan must be carried out by the applicant organization throughout the project period and the applicant organization cannot serve as a "pass through" to fund another entity to conduct the majority of the research. If partnerships are necessary, applicants are required to provide documentation that clearly describes how the partnership will allow the applicants to complete the proposed work (e.g., letter of support from institution or agency pledging access to data for outcome measures;

Memorandum of Understanding outlining partner commitment of or access to resources relevant to the application's research plan). Documentation describing working partnerships must clearly describe the existing working relationship, plans for the proposed research, the nature and extent of the involvement to be provided by the applicant institution and outside entity, including the roles and responsibilities of the Principal Investigator(s) and the outside entities or partner agencies, the outside entity's scope of work, and how the partnership will ensure implementation and sustainability of the proposed research plan.

Data Collection Methods The ATSDR core activities for data collection, at a minimum, are as follows:

Obtain adult consent, and parental permission and child assent (ages 7 years and older), to participate in this research study.

Obtaining and ensuring appropriate retention of identifiable study participant contact information for future research.

Administer adult and child questionnaires, and seek medical records verification of self-reported diseases. The adult participants and the parents of the child participant will be asked to bring documentation of all current prescription and over the counter medications.

Administer neurobehavioral test batteries to the children and their parent(s) and seek to abstract children’s school records (in particular, special education records).

Obtain a blood sample from each participant for analyses of PFAS and a number of effect biomarkers.

Seek consent to store residual blood samples for future analyses of other PFAS and/or relevant effect biomarkers yet to be identified.

Collect a urine sample from all participants to be stored for future analyses for PFAS and/or relevant effect biomarkers.

Determine whether study participants would be interested in being contacted for any future related studies.

Enrollment of study participants, including determining eligibility, verifying study participants current contact information for results reporting, and potential future contact, and obtaining informed consent.

Trained study staff will be required to perform the following measurements based on specific methods laid out in the ATSDR core sample study protocol, current draft available at https://www .atsdr.cdc.gov/PFAS/PFAS-Research-NOFO.html

Body measurements (i.e. height, weight, and waist and hip circumference) Blood pressure measurements Blood draws

Fasting blood specimen First morning urine void

Successful awardees will be required to coordinate with ATSDR staff on how and where to transfer samples for analysis. ATSDR will coordinate and house the data resulting from sample analysis (of the core) for all sites, and will provide individual site-specific data back to each site in addition to de-identified data collected from all sites.

Additionally, each adult participant and the parent of the child participant will be asked to verify and update their current contact information for results reporting and potential future contact.

ATSDR will provide a REDCap secure web application for building and managing online surveys and databases (at no cost to the awardee) that includes all ATSDR data requirements such as variable names, data types (numerical, text, drop-down list, etc.), controlled vocabulary, value range, and so on. The REDCap application provided by ATSDR will also contain a database for data storage, data entry forms for various study surveys/questionnaires, and data validation rules.

ATSDR strongly encourages the awardees to use the REDCap application provided by ATSDR for data management. This will help ensure that data sets from different study sites share a standard data structure (variable name, type, coding, etc.) and can be integrated into the ATSDR central database automatically. If the awardees choose not to use the provided REDCap application due to technical or other reasons, awardees will be responsible for making sure their delivered data sets to be in the same data structure adopted by the ATSDR REDCap application.

For more information on REDCap, please see https://www.project-redcap.org/.

Given the extent of ATSDR staff involvement in this research activity, it is anticipated that Office of Management and Budget (OMB) approval will be necessary before data collection can begin.

CDC/ATSDR may initiate a funding supplement to support additional activities in support of this research study. Pending availability of additional funds during the period of performance, successful applicants may have the opportunity to request supplemental funding for additional effort and/or innovative research intended to advance the science within scope of the approved research project, or a proposed change in scope. Such innovative research projects that may be funded with a supplement should be within scope of this NOFO, and may include research on PFAS exposure in relation to: sexual and neurodevelopment; bone density and osteoporosis measurements (such as ultrasound) in adults and children; liver disease imaging or biopsy in subjects with elevated liver enzymes other liver disease biomarkers (e.g. in addition to cytokeratin 18 (CK-18)); and reproductive health/fertility assessments. Any such supplements would be subject to review and approval by CDC/ATSDR staff.

Common Rule Requirements On September 8, 2015, the Department of Health and Human Services (HHS) and 15 other federal departments and agencies published a notice of proposed rulemaking (NPRM) proposing revisions to each agency's codification of the Federal Policy for the Protection of Human Subjects, originally promulgated as a Common Rule in 1991. On January 19, 2017, HHS and other federal departments and agencies published a final rule revising the Federal Policy for the Protection of Human Subjects. (82 FR 7149). https://www.federalregister.gov/documents/2017 /01/19/2017-01058/federal-policy-for-the-protection-of-human-subjects https://www.project-redcap.org/ https://www.federalregister.gov/documents/2017/01/19/2017-01058/federal-policy-for-the-protection-of-human-subjects https://www.federalregister.gov/documents/2017/01/19/2017-01058/federal-policy-for-the-protection-of-human-subjects

The 2018 Common Rule Update has new requirements for cooperative research at Title 45 Code of US Federal Regulations, Part 46, and creates a requirement for U.S.-based institutions engaged in cooperative research to use a single Institutional Review Board (IRB) for that portion of the research that takes place within the United States, with certain exceptions. https://www.ecfr.gov /cgi-bin/retrieveECFR?gp=&;SID=83cd09e1c0f5c6937cd9d7513160fc3f&;pitd=20180719&;n =pt45.1.46&;r=PART&;ty=HTML Successful awardees under this cooperative agreement will be subject to the new rules, including the need to collaborate in selecting a single IRB to review and approve all non-exempt human subjects research activities conducted under this cooperative agreement.

Objectives/Outcomes Primary Outcomes to be achieved with this research:

This cooperative agreement will provide funding to successful awardees to to conduct data analysis and historical reconstruction, including water modeling, physiologically based pharmacokinetic (PBPK) modeling, and statistical analysis of the relationship between chemical exposure and health outcomes. Specifically, applicants should propose research designed to examine associations between exposures to PFAS compounds and lipids, and adverse health effects and/or outcomes on 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. All applicants should propose to investigate, at a minimum, the effect of PFAS exposures on differences in sex hormones and sexual maturation, vaccine response, and neurobehavioral outcomes in children. In adults, research on additional health outcomes of interest could include cardiovascular disease, osteoarthritis and osteoporosis, endometriosis, and autoimmune disease.

ATSDR will consolidate and integrate all data from successful grantees to support epidemiological and statistical analyses, including those above at a larger scale (i.e., across multiple sites). Consent forms must be written to achieve these goals. A publication review committee established by ATSDR will prioritize and coordinate dissemination of study findings in the scientific literature and to the communities. This committee will include representatives from the successful grantees.

Expected Timeline for Activities and Deliverables

Maximum Number of Months After Award

Completion of Expected Successful Awardee Activities

6 Obtain the single IRB approval and/or rely on CDC/ATSDR IRB approval.

12 -18 Protocol completed and reviewed by CDC/ATSDR, for core activities and beyond, if applicable.

24 Complete site-specific data and sample collection including questionnaires and https://www.ecfr.gov/cgi-bin/retrieveECFR?gp=&SID=83cd09e1c0f5c6937cd9d7513160fc3f&pitd=20180719&n=pt45.1.46&r=PART&ty=HTML https://www.ecfr.gov/cgi-bin/retrieveECFR?gp=&SID=83cd09e1c0f5c6937cd9d7513160fc3f&pitd=20180719&n=pt45.1.46&r=PART&ty=HTML https://www.ecfr.gov/cgi-bin/retrieveECFR?gp=&SID=83cd09e1c0f5c6937cd9d7513160fc3f&pitd=20180719&n=pt45.1.46&r=PART&ty=HTML neurobehavioral testing.

Send all samples to ATSDR and/or ATSDR-designated laboratory facility for analysis.

24-36 Complete historical water reconstruction.

36 Provide site-specific data to CDC/ATSDR; data management center at ATSDR creates combined/aggregated dataset from multi-site site specific datasets.

Commence statistical analyses by recipients and CDC/ATSDR (in collaboration) on site-specific and aggregated dataset.

Publication committee formed.

42 Complete statistical analyses of data; preliminary report prepared for CDC/ATSDR (review, clearance).

Provide reports on individual test results to study participants.

48-54 Draft final report/preparation in collaboration with CDC/ATSDR.

Number of Months After Award

Expected Deliverables from Successful Awardees to CDC/ATSDR

6 Provide evidence of institution’s IRB approval or rely on CDC/ATSDR IRB approval.

12 -18 Submit completed protocol for core activities and beyond, if applicable. Obtain approval from

CDC/ATSDR.

24 Submit dataset including participants contact information, questionnaire data, neurobehavioral testing data.

24-36 Analyses of site-specific PFAS exposure and clinical tests/biomarkers shared with recipients;

combined dataset created.

Provide evidence of historical water reconstruction.

Send all samples to ATSDR and/or ATSDR-designated laboratory facility for analysis.

42 Preliminary report on site-specific results.

48-54 Final report on site-specific result.

Target Population The suggested eligibility criteria for children is as follows:

Ages 4-17 years at the start of the study, Resided in areas with documented past or present PFAS drinking water concentrations at the tap, OR were exposed in-utero or during breastfeeding when the mother consumed contaminated drinking water

Last exposure occurred no more than 15 years prior to the start of the study Exclusion of children whose birth mothers were ever employed as a firefighter, ever participated in fire training exercises using Aqueous Film-Forming Foam Concentrates (AFFF), or were ever employed in industrial facilities that used PFAS chemicals in the manufacturing process

The suggested eligibility criteria for adults is as follows:

Ages ≥18 years at the start of the study Resided in areas with documented past or present PFAS drinking water concentrations at the tap, Last exposure occurred no more than 15 years prior to the start of the study, Exclude persons ever employed as a firefighter, ever participated in fire training exercises using AFFF foam, or ever employed at industrial facilities that used PFAS chemicals in the manufacturing process.

Collaboration/Partnerships ATSDR has taken several steps to ensure scientific credibility, consistency, and validity of the overall extensive sample testing and analyses of exposure and clinical/biomarker components required to fulfil core protocol requirements.

As part of their core activities, the successful awardees will be required to have exposure analytes (i.e. PFAS) in human samples analyzed by the NCEH Division of Laboratory Sciences laboratory. ATSDR will bear all costs related with these analyses.

To minimize extensive cost and efforts to coordinate the analyses of number of clinical tests and research biomarkers, or the need to implement an inter-laboratory quality control or comparison program to ensure comparability and external validity of performed analyses, ATSDR will engage and contract a commercial laboratory (to be determined/designated by ATSDR) to provide logistical support, handling/shipping and most importantly the analyses of all requested analytes. Successful applicants will not be responsible for the cost of biomarker testing/analysis;

ATSDR will directly fund a designated laboratory to complete this task.

Successful awardees will be required to use the same ATSDR-designated analytical laboratory to conduct the specific core clinical tests and research biomarkers listed in the ATSDR core study protocol (current draft available at https://www.atsdr.cdc.gov/PFAS/PFAS-Research-NOFO.html ) to ensure the comparability and quality control of the analysis of samples received from the various research sites. Successful awardees will be responsible for properly shipping all samples submitted for analysis to the ATSDR-designated laboratory. This will also assure the best possible analysis cost rates and effective use of funding. The cost of these analyses will be paid for by ATSDR.

The core activities also require conduct of an extensive battery of neuro-behavioral tests. It is not feasible to engage an outside entity to conduct all the tests at number of different sites. The successful awardees will be expected to coordinate and ensure that they use the same neuro-behavioral tests for comparison purposes among sites, as specified in the ATSDR study protocol.

Successful awardees must describe in their proposed research plan how they intend to engage and retain qualified personnel to administer such tests (current draft available at https://www.atsdr.cdc

.gov/PFAS/PFAS-Research-NOFO.html ).

Partnerships between the applicant institution and outside entities may be necessary to complete the proposed work. However, a substantial portion of the proposed research work plan must be carried out by the applicant organization throughout the project period and the applicant organization cannot serve as a “pass through" to fund another entity to conduct the majority of the research. Applicant organizations may include collaborators or consultants from foreign institutions. All applicable federal laws and policies apply. For applications that include collaborators or consultants from foreign institutions, the majority of the proposed research work plan (e.g. at least 80%) must be carried out domestically by the applicant organization throughout the project period.

If partnerships are necessary, applicants are required to provide documentation that clearly describes how the partnership will allow the applicants to complete the proposed work (e.g., letter of support from institution or agency pledging access to data for outcome measures;

Memorandum of Understanding outlining partner commitment of or access to resources relevant to the application's research plan). Documentation describing working partnerships must clearly describe the existing working relationship, plans for the proposed research, the nature and extent of the involvement to be provided by the applicant institution and outside entity, including the roles and responsibilities of the Principal Investigator(s) and the outside entities or partner agencies, the outside entity's scope of work, and how the partnership will ensure implementation and sustainability of the proposed research plan.

Applicants must describe all data sources and processes used to assure data access. Evidence of access to the data from outside entities may be demonstrated by data sharing agreements, Memoranda of Understanding or Letters of Support, detailing the data availability.

Documentation of collaboration/partnerships and data access must be included in the Letters of Support section of the application. Applications that do not include appropriate Letters of Support or Memoranda of Understanding between the applicant organization and every outside entity that will be participating in the research or providing data access will be considered non-responsive and will not be forwarded for peer review.

Evaluation/Performance Measurement Applicants should include analytic plans that describe the research design and hypotheses, data collection measures, and methods to evaluate whether the proposed research plan can effectively address the hypotheses. Outcomes to be evaluated should be clearly specified. Performance measures should include the number of participants (children/adults) recruited into the study and the participation rate, the number of participants who provided a blood and urine sample, and the number of children and parents who completed the neurobehavioral tests.

Translation Plan Applicants should provide evidence of the potential for widespread dissemination, implementation, and sustainability of the proposed strategy to ensure that the approach, if effective, is scalable without prohibitive costs or resources. Research findings should be disseminated through publications, including articles in peer reviewed journals and research briefs for diverse audiences, as well as presentations at professional conferences and other venues.