About Human Subjects Research
On this page:
- Human Subjects Research defined
- About the type of research EPA conducts and funds
- Controlled exposure studies
- Currently enrolling controlled exposure studies
- How EPA protects human subjects
- Ethics of exposing humans to known toxic substances or carcinogens
- Approval process for human subjects research at EPA
- Requirements for Human Subjects Review Official (HSRRO) approval
- National Academy of Sciences (NAS) review of EPA's research studies
Human Subjects Research defined
EPA Regulation, codified at 40 CFR Part 26, defines the terms research and human subject as follows:
Research means a systematic investigation, including research development, testing, and evaluation, designed to develop or contribute to generalizable knowledge. Activities that meet this definition constitute research for purposes of this policy, whether they are conducted or supported under a program that is considered research for other purposes. For example, some demonstration and service programs may include research activities. [40 CFR 26.102(l)]. Human subject means a living individual about whom an investigator (whether professional or student) conducting research (i) Obtains information or biospecimens through intervention or interaction with the individual, and uses, studies, or analyzes the information or biospecimens; or (ii) Obtains, uses, studies, analyzes, or generates identifiable private information or identifiable biospecimens.
It is very important to make the human subjects research determination by proceeding in a particular order: research, and then if the project meets the definition of research per 40 CFR 26.102(l), then one must evaluate if human subjects (40 CFR 26.102(l)) are involved. This is because if your project does not constitute research, then it does not matter if the project involves human subjects! Only if a project is both considered research AND involves human subjects (both according to the federal definitions) is the project then considered human subjects research and subject to additional oversight. EPA does not allow investigators to make their own determinations regarding whether an activity involves human subjects research. Please refer to your institutions policies and procedures regarding these human subjects research determinations.
About the type of research EPA conducts and funds
EPA conducts and funds a wide variety of human subjects research (HSR). Some examples of HSR at the EPA include fish consumption surveys, surveys on household practices or demographics, analysis of biological specimens, use of focus groups, controlled exposure studies and epidemiology studies.
Each of the study examples listed above serves a particular research need. For example, epidemiology studies enable researchers to learn more about environmental exposure that individuals encounter in everyday life. The National Epidemiological and Environmental Assessment of Recreational (NEEAR) water study is an example of an epidemiological study in which researchers investigated the human health effects associated with exposure to pollutants at recreational swimming sites. The goal of the study was to evaluate whether real-time water quality measurement techniques could be utilized to alert and prevent beachgoers from entering the water and possibly becoming ill if high levels of pollutants were being recorded. Results were intended to enable EPA's Office of Water to develop new state and federal guidance for water quality indicators of fecal contamination.
Another category of human subjects research that is often utilized in EPA studies is survey research. Any time researchers administer a survey, questionnaire, or other data collection instrument, they are interacting with human subjects. If the data that researchers collect from subjects constitutes research per 40 CFR 26.102(l), and the data is about the subjects themselves, then the research meets the definition of human subjects per 40 CFR 26, and further review by the Human Research Protection Program (HRPP) is required. Even if a survey is completely anonymous, if people are providing information about themselves, it still may constitute human subjects research, and is subject to review by a member of the HRPP at the institution/agency. For example, if a researcher passes out anonymous surveys on a beach and asks about the individual's frequency of swimming at the beach or opinion about the cleanliness of the water, it qualifies as human subjects research since the researcher is systematically investigating swimming frequency and will generalize the knowledge gained, and the individual is answering questions about themselves. Often, survey research is just one component of a larger study, but it is still subject to review by the institution’s HRPP.
A final example of human subjects research at the EPA is controlled exposure research. EPA conducts controlled exposure studies for example, a study to evaluate the effects of particulate matter (PM) to understand the biological pathways by which air pollution particles exert their effects. Scientists can extrapolate the results from these studies to understand how PM may lead to illness in at-risk populations such as individuals with heart or lung disease. These studies help EPA fulfill its legal requirements to establish a National Ambient Air Quality Standard that protects Americans from the harmful effects of PM.
Controlled exposure studies
We can (and do) learn much from research in test tubes or using animal or computer models. But these are not all equally good predictors of ways the human body is affected by common pollutants. Even epidemiological studies rely heavily on statistical inferences and assumptions, and there are some things researchers can only learn by interacting directly with people, controlling variables and methods to allow firm conclusions to be drawn.
Over the years, scientific research with human subjects has provided much valuable information to help characterize and control risks to public health. This type of research enables investigators to test the effectiveness of insect repellants, measure the rates and pathways of human processing of environmental chemicals, measure occupational exposure of workers to chemicals, and measure the effects of a substance on exposed human subjects. EPA’s program offices use results from these studies to support decisions and set regulations such as National Ambient Air Quality Standards, water quality criteria and drinking water standards, cleanup levels, and pesticide registration.
Other types of human subjects research are intended to collect information about an individual’s behavior, opinions, and/ or characteristics in order to contribute to generalizable knowledge. Examples include surveys, focus groups, and interviews.
The focus of controlled exposure research is to gain a better understanding of changes in the body that are associated with exposure to the substance that is being studied. By understanding exactly how commonly-occurring pollutants affect various people, the EPA can make appropriate recommendations to Congress and other State and Local governments about enacting laws that protect us and our environment.
Controlled exposure research also contributes to testing the effectiveness of insect repellents, measuring the rates and pathways of human processing of environmental chemicals, measuring occupational exposure of workers to chemicals, and measuring the effects of a substance on exposed human subjects. These studies advance the EPA’s understanding of the links between the environment and human health so that the Agency can carry out its mission of protecting human health and the environment.
What controlled exposure studies are currently enrolling?
How EPA protects human subjects
EPA follows strict safety protocols for all of its studies to protect the health and safety of volunteers, including engineering controls for the facility and protocols for the medical oversight of the exposures. In addition, all EPA research is conducted in compliance with federal regulations and best practices in ethics. The primary regulation that governs human subjects research at EPA is 40 CFR Part 26 Subpart A. It is known as the "Common Rule" because 18 federal departments and agencies have agreed to hold this regulation "in common."
All human subjects research is evaluated by an administrative body, known as an Institutional Review Board (IRB), which is designated with protecting the rights and welfare of human research subjects in research activities. IRB authority is codified at 40 CFR 26. The IRB has the authority to approve, require modifications in (to secure approval), or disapprove all research activities that fall within its jurisdiction.
In 2006, the EPA amended its regulation at 40 CFR Part 26 to include additional protections for vulnerable subjects within its subparts. Subpart B of the regulation is a ban on intentional exposure research involving pregnant women, nursing women, and children. Research involving intentional exposure of a human subject is defined in 40 CFR Part 26.202 as the “…study of a substance in which the exposure to the substance experienced by a human subject participating in the study would not have occurred but for the human subject’s participation in the study.”
Subparts C and D of 40 CFR Part 26 seek to ensure that vulnerable subjects are protected in observational research. Subpart C provides additional protections for observational research conducted with pregnant women as participants. Subpart D adds protections for observational research conducted or supported by EPA involving children as participants. Observational research is defined in 40 CFR Part 26.302 as any human research that does not meet the definition of research involving intentional exposure of a human subject.
The distinction between intentional exposure research and observational research is extremely important for EPA researchers in the development and approval process for studies involving human subjects. Since intentional exposure research involving pregnant women, nursing women, and children is banned, researchers must pay close attention to the details of their study in order to ensure that it does not meet the definition of intentional exposure if the study involves these protected populations.
EPA also added special regulations at 40 CFR Part 26, subparts K-Q, which are related to the review of third-party pesticide research involving human participants. These regulations were updated in 2013. For more information, please see the links below.
EPA holds a Federal-Wide Assurance (FWA), which is an assurance of compliance that covers the engagement of the Agency in any Human Subjects Research conducted or supported by any Common Rule agency, including EPA. This assurance covers all Agency components and therefore provides a basis for the participation of EPA personnel anywhere in the Agency in HSR under conditions that are compliant with applicable regulations.
EPA Order 1000.17 A (Policy and Procedures on Protection of Human Subjects in EPA Conducted or Supported Research) establishes EPA procedures and responsibilities for implementing the requirements set forth in 40 CFR Part 26. The Order requires that all human subjects research conducted or supported by EPA must either be approved or be acknowledged as exempt research by the EPA Human Subjects Research Review Official (HSRRO) before any work involving human subjects research can begin. Preliminary (or “conditional”) review by the HSRRO is not required, but can be requested, for any research project, contract, grant application, cooperative agreement, cooperative research and development agreement (CRADA), interagency agreement or any formal agreement involving EPA support of such studies. The Order describes the requirements for review, as well as the responsibilities of all parties involved in EPA research in protecting the rights and welfare of human research subjects.
EPA’s Office of Research and Development published SEAOES as a resource document for researchers to consult as they develop and conduct observational human exposure studies. EPA Order 1000.17 A requires that all human observational exposure studies conducted or supported by EPA adhere to the principles set forth in SEAOES. SEAOES provides information on regulatory requirements, sound scientific practices, and ethical issues to consider when performing observational human exposure studies.
Ethics of exposing humans to known toxic substances or carcinogens
The International Agency for Research on Cancer (IARC) has labeled outdoor air pollution and diesel exhaust as “carcinogenic to humans”, These classifications are based on studies examining the risk from high level lifetime cumulative exposures.
There are many factors considered under the IARC cancer classifications. A critical factor is the intensity and duration of exposure. It is important to make the distinction between lifetime (or long-term) exposure to uncontrolled levels of pollutants, and the very short-term exposure to controlled levels of pollutants that occurs in experimental studies. For example, the risk of smoking two packs of cigarettes every day for thirty years is very different from smoking a single cigarette which does not increase risk in any meaningful way.
The controlled human-inhalation exposure studies that EPA conducts last only a few hours. According to a recently released committee report from the National Academies of Sciences, EPA controlled exposure “studies add very little cumulative lifetime pollutant exposures … any increase in chronic disease risk, such as from lung cancer, resulting from experimental exposures would be vanishingly small”. At the same time, the NAS acknowledged the benefits from conducting these studies by providing unique information that cannot be obtained from other studies and impacting NAAQS reviews and regulations.
There have never been any permanent adverse effects as a result of EPA research.
Approval process for human subjects research at EPA
Every project involving human subjects research conducted or supported by the EPA goes through multiple levels of approval. The specific path for review differs slightly depending on the origin of the research, but all human subjects research projects must be approved by the Human Subjects Research Review Official (HSRRO) before any work involving human subjects can begin.
EPA's approval process guidelines exceed what is generally accepted and required by universities, industry, and other government agencies. In those organizations, human subjects research is often proposed by an investigator, reviewed by a supervisor, and finally, reviewed by an Institutional Review Board (IRB). Research conducted or supported by EPA, on the other hand, has additional levels of oversight. For example, projects that are conducted or funded by the EPA are reviewed by the Program, Office, or Region’s Human Subjects Officer (HSO) prior to submission to the HSRRO for their review. HSRRO. Controlled human exposure studies conducted at EPA's Office or Research and Development (ORD) undergo multiple levels of both internal and external review.
Requirements for Human Subjects Research Review Official (HSRRO) approval
The HSRRO's responsibility is to ensure that all human subjects research conducted or supported by EPA are in compliance with EPA regulations for protection of human subjects in research. All human subject research conducted or funded by EPA must be approved by the HSSRO before work can begin.
The HSRRO makes certain that a variety of components are in place before giving their approval. For example, the HSRRO must review proof of external oversight of the study; specifically, IRB approval and documentation. The HSRRO also reviews the research plan to ensure that researchers are using best practices in study design and methodology. The HSRRO pays close attention to the description of subject selection to ensure that it is equitable and reviews the informed consent process to confirm that subjects are respected. The HSRRO is interested in ensuring that subjects will learn the goals of the project and expectations of participation before providing their voluntary consent to participate. Finally, the HSRRO confirms that the value of the research to society justifies the risk to research subjects and that researchers take precautions to minimize risks to subjects.
Please note that if pregnant women, nursing women, or children are likely to be included as subjects of a study, the HSRRO will closely review the study to determine whether it involves intentional exposure. Human subject research involving intentional exposure of pregnant women, nursing women, or children is prohibited pursuant to 40 CFR 26.203, "Notwithstanding any other provision of this part, under no circumstances shall EPA conduct or support research involving intentional exposure of any human subject who is a pregnant woman (and therefore her fetus), a nursing woman, or a child." Studies in which researchers intervene to reduce or mitigate the level of exposure to a substance that participants would otherwise experience, and do not administer a dose of a substance or deliberately cause or bring about participants' exposure to a substance, generally would not fall into the category of intentional exposure research. If the substance in question is not regulated by the EPA, then it will not constitute intentional exposure research as defined at 40 CFR 26. 202.
In addition to complying with the applicable federal regulations, EPA conducted or supported studies must also comply with EPA Oder 1000.17A, Policy and Procedures on Protection of Human Subjects in EPA Conducted or Supported Research.
To obtain approval or a concurrence of exemption by the HSRRO, researchers must submit the IRB-approved research package (including evidence of IRB approval) or documentation of exemption, and all correspondence between the IRB and the researcher(s).
If you are an EPA researcher, you can find more information about required documentation for each project type and instructions on how to submit your project for HSRRO review on the Program in Human Research Ethics and Oversight's (PHREO) intranet site.
If you are applying for a human subjects research grant you can find specific information on the request for agreement.
For other parties interested in requirements for human subjects review at EPA, please contact the HSRRO.
National Academy of Sciences (NAS) review of EPA's research studies
In 2015, the EPA sought independent expert advice from the NAS to address scientific issues and provide guidance on the conduct of EPA's controlled human exposure studies. NAS established the Committee on Assessing Toxicologic Risks to Human Subjects Used in Controlled Exposure Studies of Environmental Pollutants. The committee released its final report Controlled Human Inhalation-Exposure Studies at EPA on March 28, 2017.
The committee reviewed contributions to EPA’s Integrated Science Assessments for ozone and particulate National Ambient Air Quality Standards (NAAQS), Institutional Review Board (IRB) applications, informed consent forms, peer-reviewed publications, adverse event reports, and the presentations and materials provided by EPA and other interested parties. The committee report was peer-reviewed according to the procedures used by the NAS.
The committee report indicated that:
- EPA studies have provided unique and critical contributions to the science base supporting NAAQS decisions.
- Risks of serious adverse events posed to study subjects are unlikely to be large enough to warrant concern, but it is never possible to conclude there is no risk. Study exposures add very little to cumulative lifetime pollutant exposures and any increase in chronic disease risk, such as lung cancer, resulting from experimental exposures is vanishingly small.
- Controlled human inhalation-exposure studies should continue to be undertaken cautiously when a study is expected to provide additional policy-relevant knowledge that cannot be obtained by other means, and it is reasonably foreseeable that study subjects’ risks will not exceed transient and reversible responses.
- The committee report provided additional recommendations to EPA in the prioritization and conduct of future studies.
The report is available to the public at: