Health and Environmental Effects Research
Controlled Human Exposure Studies
- Human studies involving populations and individuals contribute critically important environmental health data
- Controlled Human Exposure Studies fill a research gap
- EPA takes many precautions to ensure the safety of human participants
- Why EPA conducts Human Exposure Studies
- EPA assures that the study participants are fully protected.
- Particulate Matter Research at EPA
EPA is required by law to establish a National Ambient Air Quality Standard that protects Americans from the harmful effects of particulate matter (PM), an air pollutant mixture of solid particles and liquid droplets found in the air, which is a serious risk to public health.
Controlled Human Exposure Studies fill a research gap
Human exposure studies fill this gap by helping to explain how exposure to particulate air pollution can lead to adverse health events in people who are more susceptible because of significant heart or lung disease.
EPA conducts controlled exposure studies in healthy individuals or those with mild medical conditions, for example mild asthma who are at minimal risk to the effects of PM to understand the biological pathways by which air pollution particles exert their effects. The biochemical and physiological changes observed in the individuals who participate in these studies are transient and subtle. However, scientists can extrapolate the results to understand how PM may lead to illness or death in at-risk populations such as individuals with heart or severe lung disease.
EPA takes many precautions to ensure the safety of human participants
EPA controls human exposure studies to maximize safety and minimize risk for the study participants. Controlled human exposure studies do not study individuals who are at significant risk to short-term health effects but, instead, study healthy individuals or those with mild medical conditions like mild asthma.
EPA is one of many Federal departments and agencies, along with other research institutions, that conducts or supports research with human subjects under the governance of the Common Rule. All controlled human exposure studies conducted by EPA scientists are evaluated for safety and ethics by a special review board, which determines that risks to study participants are minimized, that each test subject gives informed consent to their participation, and that the research plan makes adequate provision for monitoring the data collected to ensure the study participants’ safety. EPA follows all laws and regulations concerning human studies research and has established internal guidelines that exceed those normally required by universities, industry, and other government agencies conducting human studies research.
Why EPA conducts Human Exposure Studies
Controlled human exposure studies are initiated only if there is evidence that only transient, reversible biological changes will occur following exposure and only if there is prior data from one or more of the following types of research:
- testing in laboratory animals,
- observational research involving only naturally occurring human exposures, or
- controlled human exposure studies of a very closely related substance.
In addition, at the direction of Congress, the National Academies of Science (NAS) wrote a series of four reports on PM research. In the fourth report released in 2004, Research Priorities for Airborne Particulate Matter IV , NAS included a recommendation to conduct controlled human exposure studies on PM. NAS report states, "Controlled human exposure studies offer the opportunity to study small numbers of human subjects under carefully controlled exposure conditions and gain valuable insights into both the relative deposition of inhaled particles and the resulting health effects."
EPA is one of many research institutions that conducts or supports research with human subjects to understand the effects of PM exposure. From 1999 to 2013, environmental research scientists in the United States and abroad published about 120 controlled human exposure studies related to PM in peer-reviewed scientific journals. These studies examined different sizes of PM and looked at many different responses related to the heart, blood vessels, blood, respiratory system, and other measures. EPA’s controlled human exposure studies have resulted in many significant research findings.
EPA assures that the study participants are fully protected.
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. EPA adheres to all of the recommendations of the NAS in their report Intentional Human Dosing Studies for EPA Regulatory Purposes.
Common Rule Compliance
EPA’s controlled human exposure studies are conducted in full compliance with the "Common Rule", a set of regulations followed by fifteen federal departments and agencies, including EPA, which governs the ethical and scientific conduct of federally-supported research with human subjects. Before any human controlled exposure research can begin, the research must be approved by an external Institutional Review Board and the Director of the Human Research Protocol Office (HRPO) in the EPA Office of Research and Development, the Director of the Environmental Public Health Division, the Associate Director for Health of the National Health and Environmental Effects Research Laboratory, and the EPA Human Subjects Research Review Official (HSRRO).
Institutional Review Board (IRB) review and approval
All human studies conducted by EPA undergo an extensive internal review and are additionally evaluated by an external Institutional Review Board (IRB) for safety and ethics. The University of North Carolina’s IRB reviews all studies that are conducted at the EPA research facility in Chapel Hill. The UNC IRB has the distinction of full accreditation from the Association for the Accreditation of Human Research Protection Programs, which offers assurance – to research participants, researchers, sponsors, government regulators, and the general public – that a Human Research Protection Program is focused first and foremost on safety for study participants followed by the soundness of the underlying science.
In conjunction with EPA's internal review of a study, an external review is done by two outside scientists (usually research physicians). Following approval by the UNC IRB, EPA's internal procedures require that investigators also obtain EPA approval before a study can begin. This is a higher level of review than other agencies require. The process for obtaining this approval requires multiple steps. The investigator must prepare a Study Justification Document, which describes the relevance of the research to the Agency's mission, the value added by human studies, the value to society, any issues regarding subject safety. The IRB approved protocol and consent form, Study Justification document, copies ensuring the all personnel associated with the study have had ethics training, copies of outside peer reviews, and other relevant documents are then reviewed by an EPA Quality Assurance Officer to ensure that that data are collected in a sound and defensible matter and that protocols are in place to ensure safe and accurate delivery of pollutants to the participants. If approved, the package is then reviewed by the HRPO, the EPHD Division Director, the Associate Director for Health, and the EPA HSRRO. Only after signed approval is given by each of these individuals may a study begin. The CAPTAIN study received written approval from all of these individuals culminating in final approval by the EPA Human Subjects Research Review Official.
All potential participants are given an opportunity to read the consent form and then have an initial interview, ranging from 30 minutes to three hours, where EPA investigators explain the protocol and associated risks to them. Participants are encouraged to ask questions about anything that they do not understand about the study or any concerns they might have. They are told that everyone is exposed to PM continuously and that exposure to PM has been associated in epidemiological studies with increased illness and premature death in susceptible populations. Participants are told that the people most susceptible to experiencing illness and death or other adverse effects are those with pre-existing cardiac (heart) or severe respiratory (lung) disease such as COPD, and that no such individuals will be admitted to the study. Participants are told that, because they do not have any pre-existing cardiovascular disease or severe respiratory disease, the investigators do not believe they are at significant risk for experiencing an adverse health event related to a single two hour exposure to air pollution particles.
Participants are examined by EPA medical staff for any underlying medical conditions or medication use that might put them at increased risk. The interviewer discusses all criteria that would exclude a participant from enrolling in a study to make sure the participant does not meet any of them. The interviewer reviews the entire consent form, with the participant, paragraph by paragraph, explaining the procedures involved, the risks, the benefits (stating clearly that society is the beneficiary, not the participant), their rights as a participant and what is done to protect them. Participants are given ample opportunity to ask questions about all of this during the interview process, and are told that they can elect to end their participation in the study at any time.
The consent form, signed by each study participant and the study investigator, includes contact numbers for the investigators, physicians, the EPA Human Research Protocol Officer and the UNC IRB.
In order to further assure safety, study participants are continuously monitored throughout their time in the EPA facility. During exposures, participants are monitored continuously by closed circuit camera by trained EPA personnel stationed only a few feet away. The participants have a microphone near them and can always be heard by investigators. The investigators regularly talk to the participants to ensure that they are feeling fine, are not anxious and are in no discomfort. During training the investigators familiarize the participants with all the features and safe guards that are in place. Biological functions such as heart rate, oxygen and blood pressure, are monitored either continuously or at regular intervals. Study researchers carefully monitor the symptoms, if any, that participants may experience either during or immediately after exposure.
The EPA facility contains safeguards to respond to unanticipated events. These include emergency medical equipment, an overhead pager system, the presence of trained nurses to respond immediately and a dedicated on-call licensed physician who is always in the facility during any time a study participant is in the building.
Following any exposure the participant is observed for a period of time (typically 2 hours) to ensure that they have no symptoms and there is no discomfort. During that time vital signs are measured. Participants also are typically asked to wear a small recording device called a Holter monitor which documents their heart rate and rhythm. The participants wear this for 18 hours. The participants will return to the EPA the next day and they will undergo a medical evaluation to determine that there has been no change in symptoms or biological functions. The participants have the contact telephone numbers of EPA investigators, the EPA approval officer (who oversees research protocols), and the Institutional Review Board. They are told to call any of these numbers if they experience anything out of the normal or if they have any questions or concerns.