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Introduction

The U.S. Environmental Protection Agency (EPA) has a mission and regulatory responsibility to protect human health and the environment. The Clean Air Act (CAA) is one of the major federal pollution-control laws through which EPA carries out its mission, and has as one of its main goals “To initiate and accelerate a national research and development program to achieve the prevention and control of air pollution” [USC 7401(b)]. The CAA also indicates that the EPA administrator “shall conduct studies, including epidemiological, clinical and laboratory and field studies as necessary to identify and evaluate exposure to, and effects of, air pollutants on human health” [USC 7403(d)].

EPA’s pursuit of that goal includes a variety of research activities involving human subjects, such as epidemiologic studies and surveys. Those research activities also involve studies of individuals who volunteer to be exposed to air pollutants intentionally in controlled laboratory settings so that measurements can be made of transient and reversible biomarker or physiologic responses to those exposures that can indicate pathways of toxicity and mechanisms of air-pollution responses. The results of those controlled human inhalation exposure (CHIE) studies, also referred to as human clinical studies or human challenge studies, are used to inform policy decisions and help establish or revise standards to protect public health and improve air quality.

In the CHIE study context, controlled refers to the aspect of experimental design intended to focus on exposure conditions (that is, the type of pollutant, concentration, and duration) and minimize the effects of other factors on the physiologic response measurements identified in the research protocol. The researcher varies the exposure conditions in a systematic way to assess the effect of changes in those conditions on the responses of interest.

A PRIOR NATIONAL RESEARCH COUNCIL REPORT ON CONTROLLED HUMAN EXPOSURE STUDIES

In 2004, the National Research Council (NRC) issued a report on Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues (NRC, 2004a). The report was prepared in response to a request from EPA to review the ethical and scientific issues posed by the agency’s possible use of third-party studies (conducted by organizations outside of EPA) that intentionally exposed humans to toxicants to identify or quantify their effects. The impetus for that study stemmed from the use of human studies to inform regulatory decisions concerning agricultural pesticides. There was concern that the companies conducting the health effects research had a financial stake in the outcome of the toxicity testing, resulting in a conflict of interest. Another concern was whether it is ethical to conduct research that involves the exposure of healthy volunteers to chemicals for the purpose of assisting EPA in setting regulatory standards for the general public.

The 2004 NRC report recommended that intentional exposure studies in humans be conducted and used for EPA regulatory purposes only if all the following conditions are met:

• The study is necessary and scientifically valid.
• The societal benefits of the study outweigh any anticipated risks to participants.
• There is reasonable certainty that participants will experience no adverse effects.
• All of the recognized ethical standards and procedures for protecting the interests of study participants are observed.

The committee is in agreement with that report. Selected recommendations that are directly relevant to this present study are provided in Box 1-1.

Subsequent to the 2004 report, EPA established the Human Studies Review Board to review third-party controlled human-exposure studies submitted by the Office of Pesticide Programs in the Office of Chemical Safety and Pollution Prevention (EPA, 2016a). The board was not chartered to review CHIE studies carried out by EPA. However, the agency has other processes in place to review CHIE studies, as discussed below and in Chapter 2.

CHIE STUDIES AT EPA

Research involving human subjects to study exposure to and effects of air pollutants on health is conducted by the National Health and Environmental Effects Research Laboratory (NHEERL) of EPA’s Office of Research and Development. EPA’s CHIE studies are carried out at EPA’s Human Studies Facility in Chapel Hill, North Carolina. EPA conducts CHIE studies involving subjects who are healthy individuals or those with mild medical conditions who are considered unlikely to have a serious adverse health response to the controlled exposures. The regulations that govern human research at EPA provide the general requirements for informed consent the agency must follow in seeking the involvement of human subjects in a CHIE study (40 CFR 26A). EPA CHIE studies cannot be conducted on children or pregnant or nursing women (40 CFR 26B). The potential effects to be observed in the individuals who participate in these studies are expected to be transient and reversible. Researchers use the results to help understand pathways of toxicity by which air-pollutant exposures might lead to illness or premature death in at-risk (or sensitive) groups in the U.S. population, such as individuals with heart or lung disease (EPA, 2016b).

According to EPA, the agency initiates CHIE studies when there is evidence that only reversible biologic changes will occur during and following a planned exposure based on prior data from one or more of the following types of research:

• Testing in laboratory animals,
• Observational research involving only naturally occurring human exposures (that is, exposures occurring as humans go about their normal activities in their regular environments), or
• CHIE studies of a very closely related substance or mixture.

As discussed in Chapter 2, EPA’s CHIE studies must comply with the “Common Rule,” a set of regulations that govern the ethical and scientific conduct of federally supported research with human subjects. Before a CHIE study can begin, the research must undergo multiple layers of review and approval, involving several officials within the agency, two outside scientists (usually research physicians), and an external Institutional Review Board (IRB). See EPA (2017a) for additional information on safeguards for human-subjects research.

EPA’S OFFICE OF INSPECTOR GENERAL REPORT

In 2012, a congressional request for an Office of Inspector General (OIG) review was focused specifically on CHIE studies performed at the EPA Human Studies Facility in Chapel Hill, North Carolina (Broun, 2012). The review request asked whether the agency followed applicable laws, regulations, policies, procedures, and guidance when it exposed human subjects to concentrated airborne particulate matter (PM) or diesel exhaust particles. OIG reviewed the conduct of five studies that were carried out in 2010 and 2011 and found that the facility had complied with all applicable regulations, guidance, and policies (EPA, 2014a). OIG also identified some areas where clearer policies and guidance would enhance protection of study subjects, and suggested modifications to procedures involving obtaining approvals,

informed consent procedures, and monitoring adverse events. OIG’s report included these recommendations:¹

• Obtaining approvals. OIG recommended that NHEERL revise its human research guidance to indicate the review and approval process for significant study modifications, implement procedures to document that study investigators have met the requirement for annual ethics training, and develop management controls to ensure that reviews and approvals are documented and following NHEERL guidance.
• Informed consent. OIG recommended that NHEERL define and provide examples of “reasonably foreseeable risks” and develop procedures to ensure that consent forms present exposure information and short- and long-term risks, including cancer risks, in a consistent manner.
• Adverse events. NHEERL guidance should be revised to define adverse events and to clarify reporting time frames, and to establish clinical follow-up responsibilities after adverse events.

COMMITTEE’S STATEMENT OF TASK

In addition to implementing corrective actions in response to the OIG’s recommendations, EPA sought independent expert advice from the National Academies of Sciences, Engineering, and Medicine to address scientific issues and provide guidance on the conduct of CHIE studies. The committee was asked to assess the utility of CHIE studies to inform and reduce uncertainties in setting air-pollution standards to protect public health and assess whether continuation of such studies is warranted. The committee also was asked to assess the potential health risks to test subjects who participated in recent studies of air pollutants at EPA’s clinical research facility and comment on the degree of actual risk imposed by the exposures in those studies.

If the committee supports continued conduct of CHIE studies, it was asked to provide further guidance on methods for estimating levels of risk in CHIE studies. In addition, the committee was asked to provide advice on a template for characterizing reasonably foreseeable risks, which could be used in obtaining informed consent from potential study participants. (The committee’s formal statement of task is presented in Box 1-2.)

TERMS FOR REFERRING TO INDIVIDUALS EXPOSED IN CHIE STUDIES

This report uses the terms “participant” and “subject,” and occasionally “volunteer” or “healthy volunteer,” to refer to persons who enroll in EPA’s CHIE studies of environmental pollutants. Each term has assets and liabilities. “Subject” has been widely used for decades, and appears in most ethical codes and in the federal regulations. It correctly suggests that those who enroll are subjected to the requirements of a preapproved research protocol. Yet it can suggest passivity rather than active involvement. “Participant” has become more common in recent years both internationally and in the United States (NBAC, 2001). The National Bioethics Advisory Committee supported the use of the term “human participant” as a signal of respect for those who enroll in research and to emphasize that individuals should be active, not passive, in the decision to join research studies (NBAC, 2001). However, the participation of enrollees is quite limited; they have nothing to do with the design or conduct of the research. “Volunteer” or “healthy volunteer” implies that participation is a freely chosen decision, and that the research under consideration is not associated with medical care. Yet volunteers are paid for their participation. All three terms are of value, since each emphasizes an important feature of human-subjects research. Individuals involved in the EPA research described in this report volunteer to become participants and, in so doing, become subject to the requirements of the research protocol. Generally, this report considers these terms synonyms but sometimes uses them selectively, to emphasize a particular feature of enrollees.

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¹ EPA’s responses to OIG’s recommendations are provided in EPA, unpublished material, April 27, 2015.

ORGANIZATION OF THE REPORT

In Chapter 2, the committee provides the foundational context for the report in terms of language and concepts related to CHIE studies at EPA. That chapter also discusses the committee’s approach used in carrying out its study charge. Chapter 3 discusses the scientific value of CHIE studies for EPA decision making concerning air quality management. Chapter 4 discusses the risks of clinical adverse events posed to CHIE study participants in past studies. In addressing whether the continued conduct of CHIE studies at EPA is warranted, Chapter 5 considers the level of risk posed to study participants and whether CHIE studies are capable of filling relevant knowledge gaps, at least in part. Chapter 6 discusses methods EPA could use for characterizing short- and long-term risks to CHIE study subjects in the future for the purposes of informing IRBs and potential participants. Chapter 7 addresses communication to potential study participants about informed consent.