Disclosure of Unknown Harms in Magnetic Resonance Imaging Research

Abstract

Unknown harms are by their nature difficult to communicate. While magnetic resonance imaging (MRI) has known risks (e.g., metal projectiles, dislodgement of medical implants), this imaging modality also has potential unknown long-term negative health effects associated with its static magnetic fields. We carried out a research ethics board (REB) file review of previously approved MRI research studies and found that unknown risks were either left undisclosed or were inadequately disclosed to research participants and REBs. This article outlines issues raised by our REB file review and suggests steps that should be taken in order to satisfactorily communicate information about potential unknown harms of MRI.

Keywords:

• magnetic resonance imaging
• research ethics
• uncertainty
• unknown harms

INTRODUCTION

Magnetic resonance imaging (MRI) scanners of high strength are becoming ubiquitous in North America and around the world, increasing the exposure of the general public to high strength static magnetic fields. The International Agency for Research on Cancer (IARC, 2002) has categorized static fields as “not classifiable” because of inadequate evidence in humans for the carcogenicity of static electric and magnetic fields. For other health outcomes, the conclusion would have to be the same for the same reason, “inadequate evidence” (Feychting, 2005). The United States (U.S.) and Canadian regulations and guidelines for conduct in research do not explicitly discuss the disclosure of unknown harms, but there is an unspoken rule that they should be disclosed to research participants. Our group carried out a research ethics board (REB) file review study (see also Marshall and Hadskis, 2009). The results showed that researchers and REBs were struggling with unknown harms. Our purpose is not to raise alarm about these harms but to provide direction regarding their communication without misleading research participants and REBs or withholding information from them.

UNKNOWN HARMS OF MRI

The first magnetic resonance device was developed in 1938 and was able to provide data related to the magnetic properties of certain substances (Collins, 2008). After technological improvements, scientists used this technology to investigate biological tissues. Experimentation showed that magnetic resonance scans could distinguish between normal and cancerous tissues which lead to its development for medical applications (Moran, 1997). Researchers tested the modality in animal models and only a few years later the technology was used in humans.

When a new technology is first introduced for medical purposes, even beyond the preparatory observations carried out in laboratories and in animal models, many unknowns surround its performance in the clinic. Is it safe? Will it work in the greater population? With x-ray imaging, it was apparent quickly after the technology was introduced that there were serious health effects associated with the x-ray radiation. MRI has not manifested health effects in such an obvious manner. Some physical mechanisms of interaction between tissues and static magnetic fields could theoretically lead to pathological changes (Schenck, 2000). Static magnetic fields are capable of interacting with biological systems by exerting forces on tissues that have magnetic susceptibilities and can also affect enzyme kinetics and act on moving charges (e.g., blood flow) (Health Canada, 1987). Quantitative calculations of magnetic susceptibility indicate that the effects of the highest static magnetic fields now in use for MRI should not lead to long-term adverse harms in humans (Shellock, 2009). On the other hand, many qualitative studies have not been able to provide evidence of the absence of harm (see below). With the steady increase of the magnetic field strength of MRI, harms associated with the magnetic field could eventually arise at higher field strengths (Schenck, 2000).

MRI scanners use a strong magnet to generate images of the human body. Specifically, the unknown harms of MRI refer to potential long-term negative health effects caused by the static magnetic field of the MRI magnet. Most MRI systems in use today operate at fields ranging from 0.2 to 3 Tesla ¹ (Shellock, 2009). Four and 8 Tesla magnets are also used, though less commonly, and mostly for research purposes. The most powerful magnet in operation has 9.4 Tesla field strength (Atkinson et al., 2007) and a 12 Tesla magnet is presently being introduced (CEA, 2009).

The U.S. Food and Drug Administration has determined MRI examinations to be a “nonsignificant risk” ² if the field strength of the magnet is 8 Tesla or lower for adults and children, and 4 Tesla or lower for neonates (U.S. FDA, 2003). Health Canada's current position on the safety of high field strengths is considered outdated (Harding, 2000). Canadian researchers and REB members must, therefore, rely on the criteria established by the FDA (Marshall et al., 2007).

When harms are not observable, epidemiological studies can be carried out to generate knowledge about potential unknown risks. But, sometimes the science cannot provide definitive answers. A recent review of epidemiological studies looking into the potential health effects (e.g., cancer risk, reproductive outcomes) of static magnetic fields found that the evidence was inconclusive (Feychting, 2005). The review listed methodological limitations, such as small sample sizes, crude exposure assessments, and limited control of confounding as reasons for questioning the reliability of the data. Few of the studies were designed to examine the effects of static magnetic fields specifically. The pool of epidemiological studies that have attempted to correlate magnetic field exposure and health effects is not large. These kinds of studies are extremely difficult to design and a degree of uncertainty about future health risks may continue to surround MRI.

MRI researchers often point to the vast number of MRI examinations that have been carried out as evidence of its safety. Indeed, there have been well over 100 million MRI exams performed worldwide since its first use with no evidence that commonly used field strengths are unsafe (Shellock and Crues, 2002). While this is a useful gauge for the safety of MRI, an insufficient number of validated studies have been carried out to demonstrate the safety of high strength static magnetic field exposure (Shellock, 2009). While MRI has been used for many years in the clinic, at higher Tesla levels (over 3 Tesla) the technology is relatively novel. Even less information about potential negative health effects exists for specific populations such as pregnant women and children. Pregnant women are often excluded from MRI research due to potential unknown harms to the fetus. Children are often excluded from MRI research mostly for reasons other than unknown harms, but there is limited experience of use in this population at high Tesla levels.

RISK DISCLOSURE AND COMMUNICATION REQUIREMENTS

The key federal regulatory instrument that applies to most human MRI research conducted in the United States is Title 45, Part 46 of the Code of Federal Regulations (CFR). The rough equivalent to these regulations in Canada is the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (TCPS). Both the CFR and the TCPS require researchers to provide participants (or their substitute decision-makers) with all relevant information concerning the research project, which includes, according to the CFR, “a description of any reasonably foreseeable risks or discomforts to the subject” (45 CFR 46.116(a)), and the TCPS, a “description of reasonably foreseeable harms and benefits that may arise from research participation” (TCPS, Art. 2.4(c)). Researchers must also present the information to participants in a way that is comprehensible (45 CFR 46.116; TCPS, Art. 2.4).

The Canadian Medical Protective Association (CMPA) recently decided that the “as yet unknown complications” of vaccines need not be disclosed, based on the premise that doctors are not required to discuss potential unknown harms with their patients (CMPA, 2009). Yet, some organizations recommend the discussion of uncertainties regarding treatment or other clinical interventions (Politi et al., 2007). With respect to research, the CFR and TCPS do not explicitly require the disclosure of unknown harms. The CFR requires “when appropriate” that research participants be informed of procedures that “may involve risks to the subject (or to the embryo or fetus, if the subject is or may become pregnant) which are currently unforeseeable” (CFR 46.116 (b)). The TCPS does not have a similar statement. Yet, adding a caveat to the consent form that some risks of research may be unknown is considered acceptable and common (Ells and Gutfreund, 2006).

In addition, it is plausible that research participants may want to know about potential unknown harms related to MRI. Lay people often have legitimate concerns that may be omitted from expert risk assessments (Slovic, 1987). According to the TCPS, a research participant-centered approach recognizes “that researchers and research subjects may not always see the harms and benefits of a research project in the same way” (TCPS, i.7). The TCPS encourages researchers and REBs to see research studies from the point of view of research participants. The CFR focuses more on a protective perspective in that Institutional Review Boards (IRBs) shield research participants from harm and assure that they receive all pertinent information about risk in order to make informed decisions.

UNKNOWN HARMS AND RISK PERCEPTION

Potential unknown harms can provoke anxiety because they are not easy to appraise or control. Risk perception research has shown that both experts and lay people have difficulty understanding probabilistic information (Politi et al., 2007) and employ mental strategies to attempt to bring order to uncertainty (Slovic, 1987). These strategies can lead to persistent biases and misjudgments about risks and unknowns. Ambiguities surround all types of unknown harms including those associated with novel technologies or new therapies and could be due to lack of experience of use or potential unknown side-effects.

Investigations into the optimal methods of communicating risk have been carried out by many groups, but there is little information available regarding the optimal methods of communicating unknown harms and uncertainty to research participants (and patients with regards to clinical risk communication) (Politi et al., 2007). Risk communication studies have found that hard numerical data or pictorial descriptions aid in understanding (Edwards et al., 1999). But unknown harms may not always be amenable to these kinds of descriptors.

Some writers have raised concerns about the possible dangers of discussing unknown harms with patients or research participants because it could lead to unwarranted fear, reluctance to enroll, and compromised consent (Illes and Chin, 2007). Also, if future unknown harms are considered to be overly speculative, researchers may be less vigilant in their disclosure of these potential harms to research participants.

Since there is insufficient guidance from the CFR and TCPS, and there is little information about the optimal method of communicating unknown harms, it is important to determine when to disclose unknown harms and whether they should always be disclosed. Also, should the possibility of generating unwarranted fear in research participants be taken into consideration? Or do research participants have the right to know when there are uncertainties about risk especially with respect to a continually changing technology? Is it possible to simply accept that there are unknown harms and rather than relying on scientific proof to demonstrate safety, the safety could be based on experience with a modality or therapy in the clinical setting?

REB FILE REVIEW STUDY

Methods

A questionnaire was sent by e-mail and post to 190 Canadian REBs that had been identified using a list compiled by Canada's National Council on Ethics in Human Research. Among other administrative issues, the questionnaire asked whether the REBs had reviewed any studies in which MRI was the principal subject of the research. Forty-six of the 115 REBs that responded indicated that they had reviewed such projects. The administrators and REB Chairs for these 46 REBs were then sent a letter asking whether an on-site review of their REB files could be conducted.

Nine REBs covering a span of four provinces permitted access to their MRI research files, which yielded a total of 37 files for review. All 37 MRI research projects had previously been approved by the relevant REBs. The vast majority of the studies were conducted after 2000. The REBs obtained the express permission of all of the MRI researchers to include their materials in the file review. The 37 files contained no identifying information regarding the research participants who had enrolled in the studies. From October 2006 to January 2007, the sites were visited, and all MRI research file material including, the research protocol, research summary prepared for the REB, participant consent/assent forms, all written communication between the REB and the MRI researchers, and REB minutes were reviewed. All information regarding MRI research risks was transcribed from the file materials. We obviously did not have any access to verbal communications between the MRI researchers and research participants during which the disclosure of unknown harms may have occurred.

RESULTS

In 30% of the files, the consent forms and protocols made no mention of any potential unknown harms of MRI. Of the consent forms and protocols that did discuss potential unknown harms, 46% contained statements such as, “no long-term adverse health effects of MRI have been reported” or “no long term harm to patients has been found from exposure to the magnetic field.” Nineteen percent of the consent forms and protocols had statements along the lines that, “there are no known side-effects or complications that have occurred during or following MRI examinations.” Other consent forms and protocols mentioned “there could be a small chance that an as yet unknown problem may occur” (8%). A few consent forms and protocols mentioned that there is an “insignificant risk” associated with human MRI exposure (4%).

Almost a quarter of the files had confusing and even possibly alarming explanations of potential long-term health effects of MRI (23%). The consent forms and research protocols in these files first noted, for example, that the magnetic fields of MRI carried “no known long-term health risks” or “no adverse side-effects.” These consent forms and protocols then included a discussion of the possibilities for risk, such as “we cannot rule out the possibility that in the future someone may discover that exposure to magnetic fields … may be harmful” or “magnetic fields … may increase your chances of obtaining some disease.” The researchers probably had good intentions and may have been trying to reflect some nuance around potential unknown harms, but the language was confusing, and sometimes descriptions were lengthy, seeming at times to magnify the potential unknown harms. From the REBs' communications with the MRI researchers, the language used in the consent forms (and research protocols) appeared to create apprehension amongst REB members. In the end, some of the MRI studies with these types of consent forms were delayed due to concerns raised about unknown harms. The REBs, whose mandate it is to be attentive to any future harm to research participants, were acting responsibly given the information they had in the MRI research files. However, it does appear that some of the delays could have been avoided if clearer language had been used.

Similar problems were seen in files regarding pregnancy and unknown harms of MRI. Four of the studies (11%) involved only infants; therefore, pregnancy was not mentioned in exclusion criteria, screening, or consent forms. In the rest of the studies, 88% excluded pregnant women from the MRI research via exclusion criteria or the screening process. Three of the files (9%) did not indicate whether pregnant women were excluded and 1 file (3%) included pregnant women. Thirteen files (40%) provided explanatory text in their consent forms relating to potential unknown harms of MRI magnetic field exposure and pregnancy, such as “although there are no known risks to the mother or unborn fetus associated with magnetic resonance studies, we cannot say with certainty that additional risks do not exist … for a research study such as this, we have chosen not to include pregnant women,” or “a few studies have linked long or high-level exposure to MRI with some bad effects on fetus development. However, there are an equal number of studies showing no harm is done. The MRI test we will do only uses a short-level exposure to MRI. No studies have shown that this has a bad effect.” Other files stated that pregnant women are excluded from the studies with no discussion of unknowns, such as “although there are no known adverse biological effects of MRI scanning, scanning will not be performed if you are pregnant,” or “there is no known risk to the fetus, but it is recommended that you do not become pregnant while you are in this study.”

Eleven files (30%) included children in the MRI research studies. Two of these files (18%) had information about unknown harms specific to children in the consent forms with text, such as “there is a small chance that an as yet unidentified problem may occur because of our relatively limited experience with the MRI exposure of children at these magnetic intensities. The intermediate and long term effects of exposure … to MRI at the intensities used in this study are unknown.” Except for one file that had no information about unknown harms, the rest of the files involving children (73%) used similar text to the adult consent forms.

DISCUSSION

The variability with respect to disclosure of the risks of unknown harms found in our review of MRI research files raised ethical concerns. It appeared that researchers and REBs were not sure how to deal with unknown harms or in some cases perhaps did not consider them at all. The omission of any mention of potential unknown harms of MRI in the consent forms (30%) is insufficient. The fact that negative health effects related to MRI exposure in humans have yet to be demonstrated might be a reason why researchers fail to mention potential long-term harms (Picano, 2004). However, this is not a justification for nondisclosure since this does not mean that there never could be harms associated with the static magnetic fields of MRI (Schenck, 2000). The type of disclosure would depend on the Tesla level of the magnet and study population, but some attention needs to be paid to unknown harms regardless.

Statements that “no long term harms of MRI have been reported” or “no long term harm to patients has been found from exposure to the magnetic field” are inaccurate. Some epidemiological studies published in the scientific literature have reported adverse effects in animals (Mevissen et al., 1994), aluminum workers, who are exposed to magnetic fields (Spinelli et al., 1991; Ronneberg and Andersen, 1995), and in MRI workers (Evans et al., 1993) though, as mentioned earlier, many of these studies' methodologies have been considered faulty (Feychting, 2005). Because of this, on the other hand, it would not be useful to refer to these studies as evidence of biological effects of MRI.

Those writing consent forms should note that there is a difference between stating that there are “no known harms” and there are “unknown harms” associated with static magnetic fields. Because there are no known harms associated with MRI does not mean necessarily that there are no unknown harms. In addition, consent forms that mention that there could be “a small chance that an as yet unknown problem may occur” (33%) are also inadequate. Based on the available evidence, the risk of unknown harms cannot be quantified particularly, again, for higher field strengths and for special populations.

To state that MRI exams pose an insignificant risk (4%) is also inadequate. As mentioned earlier, not enough useful epidemiological evidence has been gathered to support an unequivocal statement that there is insignificant risk associated with the static magnetic fields of MRI. Until there is sufficient scientific evidence about long-term harms of MRI (at all strengths and for all populations) or clear standards developed for unknown harms, researchers cannot make a blanket claim that there is insignificant risk associated with the static magnetic fields of MRI.

Of serious concern are those consent forms and protocols that could confuse or cause alarm in research participants. Participants could well be confused if told both that there are no known potential long-term harms and that as yet unknown problems may occur or participation may increase the chance of “obtaining some disease.” As mentioned above, the TCPS and the CFR state that disclosure must not only be complete, but it must also be comprehensible. Researchers also probably do not want to cause unwarranted worry in their prospective participants.

Based on the available evidence, it appears reasonable to draw the following conclusions:

1.

Some evidence of safety has accumulated based on the length of use of MRI at lower Tesla levels in the clinic. For MRI research using a field strength of 3 Tesla and lower, it is appropriate to say the following: “Based on the use of MRI in medicine for over 20 years, many radiologists believe that there are no long-term negative health effects caused by the magnetic field strength used in this study.”

2.

MRI at higher Tesla levels (higher than 3 Tesla) have not been in use for as long a period in a similar high number of patients as lower Tesla MRI; therefore, consent forms and research protocols should reflect this. For MRI research using greater than 3 Tesla, it is accurate to say, “Based on the use of MRI in medicine for over 20 years, many radiologists believe that there are no long-term negative health effects caused by the magnetic strength. The MRI scanner used in this study has a higher magnetic field strength than MRI used in hospitals. The potential long-term health effects of higher field strengths are not yet known and so there is a possibility of unknown harms.”

With regards to special groups, most files did not provide any information in the consent forms specific to potential pregnant research participants and pediatric participants. Those files that did specifically address pregnancy should have provided accurate and comprehensible information. To attach a statement that there are no known risks or biological effects associated with the static magnetic fields of MRI to another statement explaining that pregnant women will be excluded from the study could lead to confusion. If the MRI exam is safe, why are pregnant women excluded from the study? In their disclosure, investigators should not discourage research participants who would otherwise be sanguine about potential unknown health effects. Confusing language and mixed messages in consent forms should be avoided to help research participants autonomously decide about MRI research participation. On the other hand, to go into detail about specific studies that have shown potential harm to the fetus and other studies that have not shown any harm, with no discussion of the context or the accuracy of the studies, could also lead to confusion.

Most of the files (73%) that involved children did not provide group specific information in consent forms to pediatric research participants or their substitute decision-makers. Therefore, more consistent disclosure would be needed.

Based on these observations, it would be reasonable to recommend that:

1.

Specific populations such as pregnant women need not be excluded from MRI research based on unknown harms; however, researchers must be clear to these participants that additional unknown risks could be associated with these populations. Regarding pregnancy and MRI research, the consent form should also include the following: “MRI is often used in hospitals and clinics during pregnancy to image the fetus or for other health reasons. Due to lack of research in pregnant women, the potential long-term health effects of strong magnetic fields on the fetus are not yet known and so there is a possibility of unknown harms.”

2.

Additional unknown harms are associated with children due to lack of experience of use in this study population at high intensities. This needs to be disclosed to the participants or their substitute decision-makers in the consent forms. For MRI research involving children, the consent form should also include the following: “Experience with the use of MRI in children is more limited than in adults. It remains possible that there could be unknown long-term harms related to the strong magnetic fields of the MRI.”

CONCLUSION

The REB file review study showed that researchers and REBs did wrestle with unknown harms of MRI, and this is understandable. Unknown harms are difficult to define, to study, and to measure; the regulations and literature are not clear about how to disclose unknown harms; researchers do not want to scare off research participants; and based on experience, researchers working with MRI on a daily basis probably believe that the static magnetic fields of MRI have no biological effects.

A degree of ambiguity about future unknown risk may continue to surround MRI; proving the absence of harm, in this and in many cases, is a difficult endeavor. While it is true that clinicians may not be the best observers of potential long-term harms from exposure to high static magnetic fields, based on a proven degree of reliability of clinical MRI at lower Tesla levels, coupled with quantitative evidence for human tissue tolerability at these levels, as well as the inherent difficulty of demonstrating lack of biological effect through qualitative studies, it could be possible to permit a degree of tolerability for the unknowns of MRI. For higher-level Tesla and in specific populations, the same point has not been reached, due to lack of experience of use and inconclusive scientific evidence. In these cases, we would still have to refer to potential unknown harms of MRI in consent forms and research protocols. Therefore, researchers would need to carefully distinguish between the higher and lower field strengths and different study populations. As Tesla levels continue to rise, it would be advantageous to establish routine disclosure of potential unknown harms of high static magnetic fields.

ACKNOWLEDGMENTS

The author is grateful to the Institute of Neurosciences, Mental Health and Addiction (INMHA) of the Canadian Institutes of Health Research (CIHR) for their generous financial support through the Neuroethics New Emerging Team (NET) grant. The author would also like to thank NET members for their thoughtful comments on earlier versions of this article.

Notes

1. Tesla is a unit measurement that refers to the magnetic field strength of the magnet. (1 Tesla is about 20,000 times greater than the Earth's naturally occurring magnetic field.)

2. Significant risk is defined in this guidance document as the “potential for serious risk to the health, safety, or welfare of a subject.” Nonsignificant risk is vaguely defined as “not meeting the definition of significant risk.”

CFR: Title 45 Code of Federal Regulations, Part 46.