Summary

The Clean Air Act calls for the U.S. Environmental Protection Agency (EPA) administrator to “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.” In carrying out that mandate, EPA’s Office of Research and Development recruits human volunteers to participate in studies in which they are intentionally exposed to pollutants by inhalation under controlled experimental conditions.¹ EPA conducts controlled human-inhalation exposure (CHIE) studies, also referred to as human clinical studies or human challenge studies, at its Human Studies Facility on the campus of the University of North Carolina at Chapel Hill. The information is used primarily to inform the periodic review of the National Ambient Air Quality Standards (NAAQS) for criteria pollutants.

The objective of EPA CHIE studies has been to produce transient and reversible biomarker or physiologic responses (such as a temporary change in lung function) that inform about biologic mechanisms of pollutant effects but do not cause clinical effects. EPA uses the results to help understand pathways of toxicity by which air-pollutant exposures might lead to illness or premature death in sensitive groups in the U.S. population, such as groups of people who have heart or lung disease. The agency also uses the results to inform its air-quality management decision making.

In response to a congressional request in 2012, EPA’s Office of Inspector General (OIG) assessed whether the agency followed applicable requirements when it exposed human subjects to concentrated airborne particulate matter (PM) or diesel exhaust particles. The request pointed to concerns about the intentional human exposure to those pollutants, given evidence of causal relationships between ambient exposures and human health effects or premature mortality. The OIG assessment concluded that EPA followed applicable regulations in conducting the studies. The OIG also made several recommendations to EPA, for example, that it define “reasonably foreseeable risks” and provide examples of them to study participants and that it develop procedures for ensuring that participant consent forms present exposure information and short- and long-term risks, including cancer risks, in a consistent manner.

THE COMMITTEE’S STUDY

In addition to implementing corrective actions in response to the OIG’s recommendations, EPA asked the National Academies of Sciences, Engineering, and Medicine to establish a committee to assess the value of CHIE studies for informing and reducing uncertainties in setting air-pollution standards to protect public health. The committee also was asked to assess health risks to study subjects who had participated in recent EPA CHIE studies. And the committee was asked, if it supported the continued conduct of such studies, to provide further guidance on methods for estimating risks posed to study subjects and on characterizing reasonably foreseeable risks when seeking consent from people to participate in CHIE studies.²

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THE DEVELOPMENT OF CONTROLLED HUMAN INHALATION-EXPOSURE STUDIES

In carrying out its task, the committee considered general requirements for ethical research and the previous 2004 National Research Council report Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues, which presented conditions under which it is ethically acceptable to involve humans in studies that expose them to chemical toxicants that would result in somewhat higher risks than studies that pose no identifiable risks or for which there is a reasonable certainty of no harm.

CHIE study designs are developed by EPA scientists and reviewed by other agency staff and two outside experts to evaluate aspects of the safety of study subjects, scientific rigor, adherence to ethical principles, and the extent to which expected study results would support air quality–related decisions. All CHIE studies are required to receive prior approval from the University of North Carolina Institutional Review Board (IRB). IRB approval means that the net risks posed to the subjects have been determined to be justified by the study’s expected social value. The IRB of record has the additional responsibility of monitoring the progress of the study and, if necessary, withdrawing its approval.

Study subjects are enrolled after it is determined, through EPA’s preexposure health evaluations, that there is no reason to believe that their participation in the study will lead to an adverse event.³ EPA applies a broad set of criteria when selecting study subjects. The health status of subjects is monitored shortly before, during, and immediately after the exposure studies and usually again about 24 hours later. If during a study there is any evidence that a person is being or has been harmed, the person is referred for medical observation or treatment. EPA investigators also are responsible for addressing adverse effects that become apparent only after a study is completed (see Chapter 5).

The committee concludes that EPA’s procedures are consistent with and indicative of ethical approaches to human-subjects research; this conclusion is consistent with conclusions of the EPA OIG’s report. The committee also concludes that CHIE studies have by design been limited to exposures of subjects that are highly unlikely to exhibit responses of adverse clinical significance by screening of potential subjects and selecting pollutants and concentrations that are not expected to produce adverse short-term responses. The latter selection is usually based on reports of associations in observational epidemiologic studies in larger populations or in studies of laboratory animals at comparable concentrations.

VALUE OF CONTROLLED HUMAN INHALATION-EXPOSURE STUDIES

The committee assessed the value of past CHIE studies by considering their scientific contributions and the societal benefit of providing a basis for NAAQS decisions. The Clean Air Act requires that EPA periodically review each of the NAAQS by evaluating the most recent evidence and uncertainties and then deciding whether the existing NAAQS are adequate to protect public health with an adequate margin of safety and whether they should be retained or revised in the light of new information. The committee focused primarily on the contributions of CHIE studies conducted by EPA and other organizations to the body of knowledge for the NAAQS of PM and the NAAQS for ozone (O₃) and related photochemical oxidants.

The committee concludes that CHIE studies have provided unique information that cannot be obtained from animal inhalation studies or from studies of people engaged in their normal daily activities (that is, through epidemiologic studies).

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³ An adverse event is any untoward or unfavorable medical occurrence in a human subject—including any abnormal sign (such as an abnormal physical examination or laboratory finding), symptom, or disease—that is temporally associated with the subject’s participation in the research, whether or not it is considered to be related to the subject’s participation in the research. A serious adverse event is one that is fatal or life threatening, results in substantial or persistent disability, requires or prolongs hospitalization, results in a congenital anomaly or birth defect, or indicates other important hazards or potentially serious harm to research subjects or others. (See Chapter 2 for formal definitions from the U.S. Department of Health and Human Services.)

The design of CHIE studies enables formal tests of hypotheses and less ambiguous assessments of short-term exposure–response relationships for specific laboratory-generated pollutants or mixtures. PM and O₃ CHIE studies have enabled investigators to separate the effects of exposure to individual criteria pollutants or specific groups of criteria pollutants from effects associated with exposures to ambient complex mixtures that are observed in epidemiologic studies. They have also enabled specific assessments of the timing of responses to short-term exposures to criteria pollutants.

Even though the generalizability of CHIE study results is limited by the studies’ narrow hypotheses and use of small numbers of study subjects, the studies have played a key role in evaluating and elucidating biologic or physiologic mechanisms through which air pollutants might lead to health effects (without the intent or need to observe clinical health effects in the CHIE studies). CHIE studies have provided assessment of multiple biomarker and physiologic responses to specific criteria-pollutant exposures and thus enabled evaluation of potential mechanisms of short-term actions. Developing and refining biomarkers of responses to short-term inhalation exposures to specific pollutants can lead to incorporation of the biomarkers in epidemiologic studies and animal inhalation studies. CHIE studies have also helped to determine the utility of the biomarkers in studies of disease progression.

CHIE studies involving short-term exposures to O₃ have contributed to clarification of exposure–response relationships. However, CHIE studies of PM have not focused on clarification of exposure–response relationships; they have involved the use of fairly uniform exposure concentrations of PM that have particles of different sizes (coarse, fine, or ultrafine). The difference between the O₃ and PM study designs is due in part to the complication of PM studies by the geographically and temporally variable composition of ambient PM, which makes it more difficult to characterize exposure–response relationships unambiguously at the national level. Such a complication is not an issue with CHIE studies of single gaseous pollutants, such as O₃.

Combination of CHIE study results with information from epidemiologic and toxicologic studies can facilitate a holistic evaluation of the evidence and thereby provide a well-considered scientific basis for establishing or revising a NAAQS. Although the EPA CHIE study design generally precludes inclusion of subjects who have serious health conditions, the studies have helped to define an adequate margin of safety, as required in the Clean Air Act, and have begun to define the groups that have substantial risk factors associated with air-pollution exposures, including people who have heart or pulmonary disease and people of low socioeconomic status.

CHIE studies of O₃ have been of critical importance for the NAAQS by providing a number of advances, including

• A basis for EPA’s decision to move from a 1-hour to an 8-hour averaging time for the O₃ NAAQS level (concentration), and
• Demonstrations of the importance of considering susceptibility factors and variability among individuals in human physiologic responses (such as changes in lung function) and biologic responses (such as increases in biomarkers of pulmonary inflammation) to exposure to O₃ and other oxidant pollutants.

CHIE studies of PM have been valuable in providing a number of advances, including

• Evidence on physiologic and biologic effects of exposures to high-PM mass-based concentrations, suggesting biologic plausibility of epidemiologic study results that demonstrate associations of ambient fine-PM mass-based exposures with clinical cardiovascular outcomes; and
• Confirmation in humans of PM-related biologic or physiologic effects observed in animal toxicity studies. Human studies and animal toxicity inhalation studies have been complementary in improving understanding of sources of sensitivity to PM mass-based exposures, and in exploring organ systems that are physiologically perturbed by PM exposure. As mentioned above, those studies have been complicated by the geographically and temporally variable composition of ambient PM.

POTENTIAL SOCIETAL BENEFITS OF FUTURE STUDIES

Well-designed CHIE studies could address needs in information relevant to the review of air-quality standards and the regulation of pollutant sources, such as information needed to fulfill the Clean Air Act mandate to protect public health, including the health of sensitive groups, with an adequate margin of safety. CHIE studies that address those gaps would have societal benefits by, for example, providing a greater understanding of the effect of PM composition on potential health responses and of the mechanisms by which people might exhibit sensitivity to air-pollution exposure.

RISKS TO PARTICIPANTS IN PAST CONTROLLED HUMAN INHALATION-EXPOSURE STUDIES

In assessing health risks to participants in recent EPA CHIE studies, the committee reviewed documents on the eight studies provided by EPA to illustrate current practices for articulating study objectives, rationale, and design with respect to the approaches and the substances being tested (see Box S-1). In addition, the committee assessed the adverse events reported to the University of North Carolina IRB for all CHIE studies for the period from January 2009 to February 2015.

Risks of adverse events temporally associated with a subject’s participation in a CHIE study might be affected by one or more of the following:

• Air-pollutant exposures occurring independently of the study several days before or during the multiday experiment,
• Intended pollutant exposures during the experiments,
• Subjects’ preexisting medical conditions or sensitivities to study pollutants,
• Other experimental procedures during the study (such as blood sampling or bronchoscopy), and
• Pathophysiologic events (such as a serious adverse cardiac or pulmonary event) that, although unrelated to air-pollutant exposures, might happen to occur in subjects during the study.

The biologic responses of CHIE study subjects that were anticipated by the study protocols dissipated after cessation of the exposures and were not known to have constituted any long-term adverse consequence for the health of any of the participants. For the period January 2009 to October 2016, the CHIE studies conducted at EPA’s Human Studies Facility involved 845 intentional exposures to pollutants and 555 exposures to clean air. Of those exposures, only one resulted in the hospitalization of a study subject. The subject experienced an unexpected serious event of paroxysmal atrial fibrillation a very short time after being exposed to concentrated ambient PM during the XCON study. The subject’s response reverted to normal sinus rhythm spontaneously without clinical sequelae about 2 hours after cessation of the pollutant exposure. The subject was observed overnight in the hospital after the event. The occurrence of one hospitalization, which corresponds to 0.1% of the pollutant exposures, illustrates that, despite substantial efforts to screen potential study subjects, some level of risk is present.

In light of its review of eight CHIE studies, the committee finds that the risk of a serious adverse event with long-term sequelae is unlikely to be large enough to warrant concern but recognizes that it is never possible to conclude that there is no risk.

Specific concerns have been expressed about CHIE-study risks of chronic diseases, such as lung cancer and ischemic heart disease, which correlate with long-term cumulative exposure to PM_2.5 (particles with an aerodynamic diameter less than or equal to 2.5 μm). However, because those diseases are considered to be associated with cumulative effects that develop over long periods, PM_2.5 exposures in the CHIE studies considered by the committee (for example, up to 600 µg/m³ for 2 hours) would add very little to the cumulative lifetime PM_2.5 exposures of many people in the United States. That suggests that any increase in chronic disease risk resulting from PM_2.5 CHIE exposures in the studies considered by the committee would be vanishingly small.

THE CONTINUED CONDUCT OF CONTROLLED HUMAN INHALATION-EXPOSURE STUDIES BY THE ENVIRONMENTAL PROTECTION AGENCY

Having evaluated the historical contributions of CHIE studies, human-subjects study protocols, the likelihood of serious adverse events with long-term sequelae, and the potential for societal benefits, the committee concludes that the continued conduct of EPA CHIE studies is warranted, with the improvements discussed in this report.

Selection of Study Subjects

In using CHIE studies to assess biologic plausibility of a pollutant-related effect or sensitivity to pollutant exposures, involvement of study subjects from groups with stable chronic conditions hypothesized to exhibit increased biomarker responses or physiologic effects of pollution (but not adverse events) might be more informative than involvement of healthy young adults. Therefore, the committee strongly supports EPA’s use of the process of medical screening of potential volunteers, thus ensuring that the health assessment is not limited to a volunteer’s knowledge of his or her own health status. In addition, the committee offers the following recommendations to ensure the continuation of various important activities and initiate several new ones regarding future CHIE studies. (See Chapter 5 for additional recommendations.)

Additional External Scientific Input

Documents on the eight studies allowed the committee to gain some perspective on scientific priorities of EPA investigators for future CHIE studies and their rationale for the priorities. Although the committee concludes that EPA CHIE studies are addressing important questions, it has concerns about the adequacy of the process for ensuring the most important CHIE study topics are selected and the external scientific input to maximize the rigor and value of each CHIE study. EPA would benefit by augmenting the process by which CHIE study topics are selected to obtain a broader array of input from the external scientific community on the importance and merit of the question being addressed and considerations that would ensure scientific validity. The external input could also help to strengthen coordination of EPA’s epidemiologic and toxicologic resources with those of its Human Studies Laboratory to ensure that scientific progress in each field informs future research plans and that understanding of participant risk factors and the potential value of the CHIE studies continue to be improved. The committee envisions that this external scientific input would be nonbinding on EPA or the reviewing IRBs, but the input would be provided in advance of IRB review and internal EPA review.

CHARACTERIZING RISKS TO SUBJECTS IN FUTURE STUDIES

Health risks to participants cannot be assumed to be the same for each CHIE study. Risks will vary according to study design (such as exposure agent, concentration, and duration) and the health status or risk profile of the individual participants. Once potential adverse outcomes are identified according to the principle of reasonably foreseeable risks and some decision is made about whether these outcomes are likely to be acute or chronic, risk characterization is necessary. There are two possible methods for characterizing risks of acute and chronic effects:

• Quantitative approaches that obtain a risk estimate from a published epidemiologic study of ambient-air exposures and adjusts the estimate according to the exposure duration of the CHIE study relative to the duration in the epidemiologic study, and
• The use of an exposure scenario comparator (ESC) approach, which involves comparing experimental exposure concentrations and durations with readily recognizable scenarios of real-world exposures at ambient concentrations of similar magnitude and duration experienced by a population in everyday life at a particular location.

Although EPA researchers and IRBs of record might seek quantitative estimates of risk of potential acute effects (for example, to estimate the increment that a CHIE study might add to the baseline risk associated with exposure to ambient air pollution), the committee considers the ESC approach to be the better alternative overall. Given the limited availability of appropriate data for risk calculations, the large attendant uncertainty in the results, (particularly that stemming from attempting to estimate risks from

very short-term low exposures from data in which subjects are exposed to higher levels for much longer periods of time) and uninitiated people’s potential difficulty in understanding the implications of the quantitative results in the context of controlled short-term exposures, the committee focused on the ESC approach. Such an approach would be useful to investigators, IRBs, and potential participants in characterizing acute and chronic risks.

An ESC approach would provide a useful context for considering chronic effects of the air pollutants being studied, which are thought to be associated with cumulated results of long-term exposures developed over long periods. In considering chronic effects, 2–4 hours of participation in a CHIE study would add only incrementally to the cumulative ambient background exposure over the life of a person, and calculating a risk estimate would involve so much uncertainty that the estimate would have little meaning. Therefore, the committee strongly prefers the use of an ESC approach for the characterization of risks related to participation in a CHIE study.

It is not advisable to compare a lower ambient concentration over a longer period with the CHIE study’s concentration and duration. Attempting to represent an equivalent ambient exposure in that way introduces more uncertainty as to whether the risk in the comparative scenario is greater than that in the CHIE study.

EPA has compared the exposures to the various pollutants used in the eight CHIE studies with exposures to the pollutants that might be experienced by various groups of people living in the United States. However, many of the comparison exposure scenario comparators in the CHIE studies were undocumented, and ones that were documented were not all appropriate, for example, because of the substantial differences in exposure durations between the scenario and the CHIE study protocol.

Insofar as possible, the comparative scenario ought to be one that the participants in the CHIE study can readily identify with and understand. However, recent improvements in U.S. air quality might make it difficult to find recent ambient concentrations that are appropriate for use in an exposure scenario. Instead, the scenario could include a population at a U.S. location in the past or a present population in another country. If a particular exposure regimen has been used numerous times in previous CHIE studies without the occurrence of adverse effects, the accrued experience from those studies could be useful in developing a reasonable exposure comparator.

It is important to note that if a CHIE study is being proposed for which no appropriate ambient concentrations (past or present) can be found and no previous CHIE studies that found no adverse effects are applicable, it might be an indication that the CHIE study requires further explicit justification or should not be conducted.

COMMUNICATION WITH POTENTIAL STUDY SUBJECTS ABOUT INFORMED CONSENT

For a person considering participation in a CHIE study, information about the study is presented through a disclosure process. The potential participant considers the information in a deliberative process and decides to participate or not to participate. Some of EPA’s informed-consent documents reviewed by the committee contain complicated and technical language that requires high literacy and numeracy skills. In addition, comparative exposure scenarios presented in those documents might not be familiar or relevant to participants.

Characterization of reasonably foreseeable risks is an especially important part of disclosure to potential participants. The committee agrees with the approach taken by EPA in designating a risk as reasonably foreseeable if there is some credible evidence that harm might occur. However, an overdetailed list of all possibilities can result in a less valid consent process in that it groups the anticipated or likely risks with ones that are only distant possibilities.

In its report, the committee provides recommendations on consent-document development and on assessing participant comprehension of the documents (see Chapter 7). It provides the following recommendations for the development of consent documents with respect to reasonably foreseeable risks and other risks of possible concern. EPA should

• Provide accumulated information on the occurrence of serious adverse events associated with previous CHIE studies and on the resolution of the events to illustrate that a study involves risks of serious adverse events that can be anticipated and those that cannot be anticipated;
• Describe uniformly the risks from experimental procedures that are used often (such as bronchoscopy) and indicate how the risk profile of study subjects (such as mild asthmatic) has been taken into account; and
• Include and delineate all reasonably foreseeable risks and any risks likely to be perceived as important by the participants. CHIE studies typically impart a very small increase in the cumulative exposure to ambient air pollution over a person’s lifetime, and there is no credible evidence to suggest that chronic effects should be considered among the reasonably foreseeable risks in the studies. However, because of associations between long-term exposure to air pollution and chronic effects, the likelihood of chronic effects needs to be included in informed-consent communications, such as by using the recommended ESC approach for characterizing risks (see above). Allowing people to judge risks for themselves and determine if they are willing to assume those risks is essential in respecting the autonomy of participants.

CONCLUDING REMARKS

The committee concludes that CHIE studies have provided unique information that helps to enrich scientific understanding of underlying physiologic short-term responses to daily inhalation exposures to airborne pollutants or mixtures thereof. Such information is important for future NAAQS reviews. The committee judges that in the eight CHIE studies that it reviewed any risks of a serious adverse event with long-term sequelae were unlikely to be large enough to be of concern, although it should never be concluded that no risk was possible. The committee concludes that the continued conduct of EPA CHIE studies is warranted, with improvements in human-subjects oversight, protocols, consent forms, and commu-

nication with potential participants during the informed-consent process and improvements in scientific oversight to maximize the potential for the societal benefits of the studies. EPA CHIE studies should continue to be undertaken cautiously under two conditions: (1) only when a CHIE study is expected to provide additional knowledge that informs policy decisions and regulation of pollutants that cannot be obtained by other means and (2) when it is reasonably foreseeable that the risks for study participants will not exceed transient and reversible biomarker or physiologic responses.