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The Continued Conduct of Controlled Human Inhalation Exposure Studies by EPA

The committee was asked to assess whether continued conduct of controlled human inhalation exposure (CHIE) studies by the U.S. Environmental Protection Agency (EPA) is warranted. To carry out that assessment, the committee evaluated past CHIE studies with respect to the requirements for determining whether a research trial is ethical (see Table 2-3 of Chapter 2). The requirements and relevant aspects considered by the committee include the following:

• Scientific validity: The committee considered the collective contributions of past CHIE studies to the body of scientific information as assessed systematically through the Integrated Science Assessments (ISAs) process to inform EPA’s review of National Ambient Air Quality Standards (NAAQS) (see Chapter 3) and, secondarily, through peer-reviewed literature, including “state-of-the-art” medical journal reviews.
• Fair subject selection, independent review, informed consent, and respect for potential and enrolled subjects: The committee considered the protocols of eight recent CHIE studies, including consent forms and participant monitoring procedures (see Chapters 4 and 7).
• Social or scientific value: The committee considered the potential benefits to society that could result from future studies designed to address key knowledge gaps with appropriate informed consent and protection of human subjects.
• Favorable risk–benefit ratio: Taking into account the designs, protocols, reported adverse events, and contributions of previous CHIE studies, the committee assessed qualitatively whether the risk–benefit ratios were favorable.

In this chapter, we summarize our evaluations of scientific contributions of previous CHIE studies, societal benefits of previous studies, safety-related aspects of the study protocols, and the potential for future benefits.

SCIENTIFIC CONTRIBUTIONS OF PAST CHIE STUDIES

Review of the contributions of past CHIE studies to the ISA process is presented in detail in Chapter 3. The committee considers the ISA process to be one of the key ways EPA provides communities, individuals, businesses, and state, local, and tribal governments with access to accurate information regarding air quality and potential human health effects on the general public and sensitive subgroups. The committee also considered potential contributions of CHIE studies for informing other decision making by EPA, and to scientific understanding of biomarker and physiologic effects of ambient pollutants.

The detailed documentation of eight recently completed or ongoing CHIE studies and other materials provided by EPA (see Chapter 4) comprised adequate material for an in-depth assessment of current practices and protocols employed in CHIE studies, and current administrative and scientific review processes. The documents from the eight studies also gave some perspective on scientific priorities of EPA investigators for future CHIE studies and their rationale for these priorities. Because not all of the eight studies were completed at the time of the committee’s review, and the completed studies were performed recently, the committee did not attempt to conduct a full assessment of their scientific merit, as most of the actual contributions of those eight studies to ISAs or other EPA functions would occur in the future.

To obtain a fuller understanding of the past role of CHIE studies, and potential for future contributions, the committee studied the contributions of CHIE studies conducted by EPA and other organizations to the 2009 ISA for Particulate Matter (PM) (EPA, 2009), the 2013 ISA for Ozone and Related Photochemical Oxidants (EPA, 2013), to earlier ISAs of these criteria pollutants, and to more recent professional society (such as the American Heart Association; Brook et al., 2004, 2010) scientific reviews and consequent position statements on air pollution health effects.

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 panel studies and other epidemiologic studies). The committee also concludes that no one type of study is sufficient for developing comprehensive ISAs of ambient pollution health effects. Appropriately, EPA and its external scientific reviewers have considered multiple sources of complementary exposure–response information (that is, epidemiologic, animal toxicologic, CHIE, and in vitro toxicologic testing and modeling studies) as they have addressed the challenging task of reviewing and potentially revising NAAQS or carried out other decision making.

Air pollution health-effects research is iterative by nature—one discipline’s results inform the development of hypotheses, designs, and methods of the other disciplines’ next studies. Large observational studies have demonstrated associations between adverse health outcomes and exposures to ambient pollutants or pollution traceable to emission source categories. However, when those studies have lacked biologic data or physiologic response data to support the specificity, precise temporality, or biologic plausibility of these associations, the likelihood that the associations can be used to help estimate real health effects in the U.S. population sometimes has been challenged. Those challenges have been addressed by using complementary approaches, including animal studies and CHIE studies, with an awareness of their study design strengths and weaknesses (see the EPA ISAs). Even though the generalizability of CHIE study results is limited by the studies’ narrow hypotheses and use of small numbers of study subjects, they 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 from the CHIE studies).

As discussed in Chapter 3, contributions of CHIE studies to ISAs can be described by using categories adapted from the Bradford Hill considerations (Hill, 1965) that have been used in the ISA process (and by other National Academies committees) in determining the strength of the causal evidence for effects of environmental exposures.

In addition, CHIE studies have contributed to the identification of sensitive subpopulations, which helps ensure that the NAAQS are set to provide an adequate margin of safety for those subpopulations and general populations. CHIE studies also complement observational studies by demonstrating a wide range of variability among individuals in their responsiveness to exposures to different criteria pollutants.

The committee concludes from findings in ISAs and other extensive reviews of pollution health effects in the literature that, although not all CHIE studies have contributed to every one of the categories mentioned above, many CHIE studies have contributed to one or more of them. PM and O₃ studies have contributed to elucidation of specificity, temporality, plausibility, and understanding of biologic or physiologic responses of the general population and sensitive subgroups. In addition, O₃ CHIE studies have contributed to an understanding of a biologic gradient, whereas PM CHIE studies have involved the use of fairly uniform target exposure concentrations of PM mass of different sizes (coarse, fine, or ultrafine) but have not focused on clarification of dose–response relationships. This study design difference results in part from the fact that PM CHIE studies have been complicated by the variable composition of PM, which is not an issue with CHIE studies of exposure to single gaseous pollutants, such as O₃.

PAST BENEFITS TO SOCIETY

The Clean Air Act requires EPA to set two types of NAAQS: primary NAAQS to protect public health, and secondary NAAQS to protect the public welfare from known and anticipated adverse effects (such as crop damage from pollutant exposure). The law requires primary NAAQS to be set to protect

public health with an adequate margin of safety, including the health of people whose profile of risk factors increases the likelihood of adverse effects from ambient air pollution exposure. In its review of the PM NAAQS that was completed in 2012, EPA found that currently available evidence indicated that groups with increased susceptibility to PM-related health effects include children, older adults, people with heart or pulmonary disease, and people of lower socioeconomic status (EPA, 2011).

CHIE studies that focused on the review and setting of primary NAAQS have helped to define an adequate margin of safety, as required in the Clean Air Act, and have begun to define the subgroups that have elevated risk factors associated with air pollution exposures. As documented in Chapter 3 and summarized below, the committee reviewed the contributions of the CHIE studies to the O₃ and the PM presented in ISAs.

Ozone CHIE Studies

O₃ CHIE studies have been of critical importance for the ISA and the subsequent NAAQS by providing

• A basis for EPA’s decision to move from a 1-hour to an 8-hour averaging time for O₃ NAAQS level (concentration).
• Demonstrations of the importance of considering susceptibility factors and variability among individuals in human physiologic and biologic responses to oxidant pollutant exposures:
  • Some participants in CHIE studies developed no change in pulmonary function while others had symptoms of cough and chest tightness and/or demonstrated up to a 30% decrease in pulmonary function after a 6.6-hour O₃ exposure, as well as symptoms of cough and chest tightness. The characteristic of responding to O₃ exposure with a decrease in pulmonary function was shown to be reproducible.
  • Some participants in CHIE studies responded to O₃ exposures with increases in biomarkers of pulmonary inflammation. These were not necessarily the same individuals who responded to O₃ exposure with a decrease in pulmonary function.
• An understanding of O₃ adaptation. For some subjects, pulmonary function responses to O₃ were reduced after repeated daily O₃ exposures, but the inflammatory response was sustained over repeated exposures.
• Evidence to support the plausibility of exposure to elevated outdoor O₃ concentrations causing increased asthma events in sensitive subgroups, such as individuals with mild asthmatic conditions.
• Biologic and physiologic evidence for O₃ effects in humans generated new hypotheses for animal studies addressing susceptibility factors with study designs for assessing the effects of O₃ inhalation on pulmonary inflammation, lung permeability, biomarkers, and particle clearance.

Particulate Matter CHIE Studies

PM CHIE studies have been valuable by providing

• Evidence for physiologic and biologic effects of exposures to elevated PM mass concentrations, suggesting biologic plausibility of epidemiologic studies demonstrating associations of ambient fine-PM mass exposures with clinical cardiovascular outcomes.
• Definition of sensitive subgroups with physiologic or biologic responses of study subjects to controlled exposures of concentrated ambient particle mass.
• Confirmation in humans of PM-related biologic or physiologic effects observed in animal toxicologic studies. Human studies and animal toxicologic inhalation studies have been complementary, in terms of understanding sources of sensitivity to PM mass effects, and in exploring organ systems biologically or physiologically perturbed by particle mass. Also, as mentioned previously,

• the generalizability of those studies has been complicated by the geographically and temporally variable composition of ambient PM.

• Input for regulatory decisions concerning the adequacy of the use of a single traditional metric (that is, PM mass without regard to individual constituents of the particles) for ambient PM, which comprises mixtures that vary considerably in chemical composition and/or particle size distribution. The 2009 PM ISA indicates that many different PM constituents are linked to adverse health effects and that evidence is not yet sufficient to identify the constituents or emission sources that are more closely related to specific adverse health effects.

STUDY PARTICIPANT SAFETY

To compare the risks and societal benefits of CHIE studies, the committee considered the contributions of past CHIE studies (presented in Chapter 3 and summarized above), the level of safety afforded by the study protocols, and the likelihood of serious adverse events with any long-term sequelae (see Chapter 4). Based on those considerations, the committee judges that the risk-to-benefit comparisons for EPA’s previous CHIE studies in Chapel Hill, North Carolina, have been favorable, such that the likely societal benefits are greater than the risks posed to the study participants, which are unlikely large enough to be of concern.

The short-term exposures (usually over 2 hours) to criteria pollutants used in these studies were similar to the highest ambient air concentrations that could be encountered for similar periods in the United States (EPA, unpublished material, July 14, 2005). (See Chapter 6 for a discussion of comparing CHIE study concentrations and durations to those encountered in the ambient environment.)

The biologic responses of study subjects that were anticipated by the study protocols dissipated following cessation of the exposures and were not known to have had any long-term adverse consequence to the health of any of the participants. The actual experience of participants in the studies over many years supported those assessments. For the period from January 2009 through October 2016, the CHIE studies conducted at EPA’s Human Studies Facility involved 845 intentional pollutant exposures and 555 clean-air exposures. Of those exposures, one resulted in the hospitalization of a study subject, which was for overnight observation following an unexpected adverse serious event of paroxysmal atrial fibrillation a very short time after being exposed to concentrated ambient particles (see Chapter 4). The subject’s response reverted to normal sinus rhythm spontaneously without clinical sequelae approximately 2 hours after cessation of the intentional exposure (see Chapter 4). The occurrence of one hospitalization over a period of almost 8 years, 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.

Medical Follow-Up Monitoring of CHIE Study Participants

After exposure sessions have been completed for a CHIE study, medical follow-up monitoring is often conducted as a routine part of the experiment. The length of the follow-up period is determined according to the study hypothesis and research protocol and the need to document the sequence of a transient and reversible biologic response. For example, the protocol might call for study subjects to return to the facility 24 hours after the final exposure to have blood drawn for analysis or to have their lung function assessed. When the study protocol contains no plans to obtain measurement data after the exposures have been completed and there is no indication of a reason for concern, 24 hours is often used as the point when medical staff might check on the status of the study subjects. However, the nature of the controlled exposures might warrant a follow-up period other than 24 hours.

Follow-up monitoring also is conducted in response to adverse events that might occur before the study subject leaves the facility at the end of the study or at some point afterward. Investigators have a responsibility for making certain that adverse events are treated, even after the study ends. If a person is judged to be clinically stable immediately after a study, but a symptom, such as a cough, arises afterward and then persists, the person is expected to report to the investigator.

The Food and Drug Administration (FDA, 2009) provides a useful overview of the responsibilities of researchers who conduct clinical investigations of a drug, biologic product, or medical device. See Box 5-1. According to FDA’s guidance, medical care should be provided to a subject for any adverse events related to the study until the symptom resolves. If the investigator is not able to provide the type of medical care needed, the investigator should make sure that the subject is able to obtain the necessary care from a qualified practitioner. However, the guidance does not specify the period after completion of a study when an investigator is no longer responsible for addressing a health concern that might be related to the study exposure. That decision usually is left to the judgment of the investigator to determine whether a health concern is attributable to a cause other than participation in the study or if the condition of the subject is considered to be stable.

In a response to the OIG report (see Chapter 1), EPA indicated that the following language has been added to CHIE study consent documents:

The specification of a monetary upper limit for reimbursement of medical expenses is not included in the FDA guidance (Box 5-1). Also, the 2004 NRC report on intentional human dosing had recommended that participants receive needed medical care for research-related injuries, without cost to the participants (see Box1-1 in Chapter 1). The difference between EPA’s approach and the FDA guidance as well as the 2004 NRC recommendation provides a basis for EPA to reexamine its clinical follow-up responsibilities with respect to reimbursement for medical expenses.

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Regarding preexisting health conditions, the FDA guidance indicates the investigator should inform a subject when medical care is needed for conditions or illnesses unrelated to the study that are readily apparent or identified through the screening procedures and eligibility criteria for the study (see Box 5-1).

As part of EPA’s recordkeeping of adverse events associated with CHIE studies, it would be useful for future potential study subjects to know what serious adverse events associated with participation in previous CHIE studies had occurred and how those events had been addressed.

In addition to its IRB reporting, EPA should document all serious adverse events associated with participation in CHIE studies and the actions taken in response to them. That information should be accumulated and presented to future potential participants to illustrate that a study involves risks of serious adverse events that can be anticipated and that cannot be anticipated.

Selection of Study Subjects

In assessing for biologic plausibility or sensitivity in CHIE studies, involvement of study subjects from subgroups with stable chronic conditions hypothesized to increase sensitivity to the biomarker or physiologic effects of pollution (but not to adverse events) might be more informative than involvement of healthy young adults. 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 makes the following recommendations to ensure the continuation of various important activities and initiate several new ones:

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Communication with Potential Study Subjects and Informed Consent

After detailed review of the eight recent study protocols provided by EPA, the committee noted that there was inconsistency in approaches for explaining CHIE study risk and obtaining informed consent from potential study subjects. The committee also noted recent improvement in human subject consent forms related to EPA’s ongoing CHIE studies. Chapter 7 discusses the need for continued attention to updating the methods used for obtaining consent, and applying a consistent approach across studies. It is important to provide potential participants with accrued information on the occurrence of serious adverse events associated with previous CHIE studies and the resolution of those events.

POTENTIAL FUTURE SOCIETAL BENEFITS

As indicated at the beginning of this chapter, no one study and no one type of study is adequate to satisfy EPA’s regulatory needs. Epidemiologic studies have sometimes reported associations without clarity regarding specificity, temporality, or biologic plausibility. As the ISAs have concluded, well-designed CHIE studies have often provided such clarity, at least in part, despite the limited generalizability of their results. Therefore, CHIE studies can be expected to provide the future potential to assess specific biologic or physiologic responses to very well delineated exposures, particularly in sensitive subgroups. There are unresolved questions relevant to the review of air quality standards and the regulation of pollutant sources that well-designed CHIE studies could address in the future. This would include addressing important knowledge gaps in pursuit of the Clean Air Act mandate to protect public health, including the health of sensitive subgroups, with an adequate margin of safety. Addressing those gaps would enhance the potential societal benefits of future CHIE studies, for example, by providing a greater understanding of the effect of PM composition on potential health response and the mechanisms by which individuals might exhibit sensitivity to air pollution exposure.

Variability of Real-World PM Exposures

As discussed in Chapter 3, CHIE PM mass studies involve exposure to a complex mixture that varies temporally and spatially in the real world. The issue of the impact of PM chemical composition variability on human toxicity remains an important research topic that is highly relevant to EPA’s regulatory tasks. If a future ISA concludes there are identifiable regional differences in PM toxicity, then future regulatory approaches that differ by region might be warranted, rather than a single, nationwide PM mass-based standard.

Do biomarker or cardiopulmonary physiologic responses to concentrated air particles vary by differing particle mass or composition or mixtures of gases? Relevant ongoing EPA CHIE studies that are evaluated in more detail in Chapter 4 include investigations of physiologic/biomarker effects of (1) ultrafine particles generated by vehicular traffic, (2) diesel-engine exhaust, (3) wood smoke, and (4) mixtures of NO₂ and O₃. However, the use of the CHIE study design to compare responses to different compositions of coarse or fine particles is challenging, as the variation in particle composition in a single location, such as Chapel Hill, is dissimilar to the particle composition in other parts of North America (see Chapter 3). While the implications of differences in PM composition for health outcomes is an active area of observational epidemiologic research, it would be impractical to use the CHIE study approach to

examine the impact of the full range of PM compositions and dose ranges on biologic perturbations associated with ambient PM exposure. To assess the contributions of different PM components to biomarker or physiologic responses and to help target future CHIE studies, EPA should consider conducting a systematic review of CHIE studies that had been conducted in North American and other parts of the world, in which study design and participant characteristics are sufficiently similar.

Sensitive Subgroups

Several ongoing EPA CHIE studies are seeking to identify sensitive “at-risk” subgroups and exposure responses that have not been well studied in the past. Those studies include evaluation of pollution effects on neurocognitive outcomes, the potential of wood smoke to modify biologic responses to influenza vaccine, and genomic markers and oxidative stress genotypes as sources of sensitivity to pollution. As the results of those studies are analyzed, it is important to consider what information gaps might remain that future CHIE studies might address. For example:

• Are older adults at greater risk of neurocognitive responses to air pollution?
• If air pollution influences immune response to immunization, what does that imply about the effectiveness of vaccines, the response to infection, or the timing of vaccine administration in areas with seasonal variation in air pollution levels?
• Can genomic responses to criteria pollutants or pollution from particular sources help identify sensitive individuals or biologic pathways through which air pollution influences health?

As discussed in Chapter 3, a CHIE study (Kahle et al., 2015) involving sequential 2-hour exposures to clean air and O₃ at 22°C and again at 32.5°C showed an interaction between high temperature and O₃ that may activate the fibrinolytic pathway and help to explain the adverse effect of O₃ on cardiac mortality and morbidity. That finding raises important questions concerning how temperature and pollutant exposures interact. This has relevance for warning systems (such as EPA’s Air Quality Index for daily air quality) as well as regulation. Review of multiple CHIE studies with a core of harmonized physiologic or biomarker outcomes might be useful when increased statistical power is needed to assess interactions of short-term exposure effects and changes in environmental conditions.

ADDITIONAL EXTERNAL SCIENTIFIC INPUT

As discussed earlier in this chapter, several of the key considerations in determining if a CHIE study is ethical involve considerations of scientific validity and potential scientific value. While the committee concludes that EPA CHIE studies are currently addressing important questions, there are 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 impact of each CHIE study. Currently, external scientific advice is provided by EPA’s Clean Air Scientific Advisory Committee and its Board of Scientific Counselors through their review of the Office of Research and Development’s strategic research action plans. However, those plans do not indicate specific research topics to be addressed by future CHIE studies. EPA would benefit by augmenting the process by which CHIE study topics are selected to obtain a broad range of input from the external scientific community on the importance and merit of the question being addressed, and considerations to ensure scientific validity. The external input also could help strengthen coordination of EPA’s epidemiologic and toxicologic resources with those of the agency’s Human Studies Laboratory to ensure that scientific progress in each area informs their future research plans in order to continue to improve understanding of participant risk factors and the potential value of the CHIE studies to be performed. The committee envisions that the input provided by the advisory panel would be nonbinding on EPA or the reviewing IRBs. However, the panel’s input would be provided in advance of IRB review or internal EPA review. EPA should convene an external scientific advisory committee of ex-

perts on a regular basis to review the agency’s progress and provide advice on the creation of a portfolio of CHIE studies with the objective of breaking new scientific ground relevant to Clean Air Act mandates and ensuring protection of human subjects.

CONCLUSION AND RECOMMENDATION

Having evaluated the historic contributions of past CHIE studies, human-subjects study protocols, the likelihood of serious adverse events with any 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 chapter and in Chapters 6 and 7. Improvements are needed in (1) future human-subjects oversight, protocols, risk characterization, study subject consent processes and forms, and communications with potential participants during the informed consent process; and (2) with broader scientific oversight to maximize the potential for additional societal benefits conferred by continuing to conduct CHIE studies. Chapter 6 presents the committee’s recommendations regarding characterizations of risk to inform IRBs, EPA, and potential study subjects. Chapter 7 discusses ways to improve communication with potential subjects about the study protocol, risks, and potential societal benefits.