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The Role of Environmental Factors in Medically Unexplained Symptoms and Related Syndromes: Conference Summary and Recommendations Howard M. Kipen and Nancy Fiedler Environmental and Occupational Health Sciences Institute, University of Medicine and Dentistry–Robert Wood Johnson Medical School, Piscataway, New Jersey, USA arise, particularly, how do we best distinguish This monograph of peer-reviewed articles is based on presentations at the conference “Environmental for individuals and groups between medically Factors in Medically Unexplained Physical Symptoms and Related Syndromes” held 10–12 January unexplained physical symptoms related to an 2001 in Piscataway, New Jersey, USA. The purpose of the conference was to determine research pri- environmental exposure and those relatively orities for elucidating the role of environmental factors in medically unexplained symptoms and unrelated to exposure. symptom syndromes. These include conditions such as chronic fatigue syndrome, multiple chemical • What experiments or epidemiologic sensitivities, sick building syndrome, Gulf War illness, and the like. Approximately 1 1/2 days were studies would best clarify or refute exam- devoted to plenary talks and 1 day was devoted to break-out sessions to discuss epidemiologic, ples of the above distinction between con- psychosocial, and experimental research. Recommendations were made for a series of epidemiologic, ditions related to the environment and psychosocial, and experimental research approaches, with acknowledgment that nosology issues are those that exist relatively independent of clearly fundamental to advancing understanding of these conditions. Key words: environment, indoor environmental influences? air, psychology, research, symptoms. Environ Health Perspect 110(suppl 4):591–595 (2002). Each invited expert made a presentation http://ehpnet1.niehs.nih.gov/docs/2002/suppl-4/591-595kipen/abstract.html and submitted a manuscript reflecting her/his own research interests. During the course of the 2 1/2-day meeting, discussion groups were Recommendations these dissimilar causal agents show remark- held in which the focus was on responding to This Environmental Health Perspectives able similarity; and to the extent they have the three questions above, although explicit monograph is a compilation of peer- been studied, the victims of one disorder fre- answers were not generated for all questions, reviewed articles based on presentations at quently qualify, on the basis of symptoms, for and all answers to date are incomplete. the conference “Environmental Factors in other disorders as well. Thus, consideration of Presentations were made and then manu- Medically Unexplained Physical Symptoms these symptoms and syndromes in concert is scripts were submitted, which summarized or and Related Syndromes” held 10–12 long overdue, and this was the overriding expanded upon the oral remarks. January 2001 in Piscataway, New Jersey, rationale for this conference. Epidemiology of Unexplained USA. The conference focused on the devel- opment of a research agenda to help investi- Objectives and Organization Physical Symptoms Attributed gators understand the role of environmental of the Conference to the Environment factors in a diverse, yet strikingly similar The primary objective of this meeting was to The first group, encompassing seven papers, group of illnesses and syndromes. These may convene a diverse group of expert researchers addresses the epidemiology and phenome- present either endemically, such as chronic from the United States, Canada, and Europe nology of unexplained symptom disorders fatigue syndrome (CFS), multiple chemical to address the relationships between med- widely attributed to, and named after, envi- sensitivities (MCS), fibromyalgia, post- ically unexplained physical symptoms and ronmental factors. Lyme disease, electromagnetic sensitivity, environmental exposures. In our overview of the problem, we cited and somatization; or epidemically, includ- The experts were asked to consider the evidence supporting both an overlap in the dis- ing outbreaks of sick building syndrome following questions in formal presentations orders and the important role for environmen- (building-related illness), systemic com- and group discussions: tal factors in many of these constructs of illness. plaints associated with breast implants, and • What are the nature and mechanism of the The logic of intertwining psychosocial with Gulf War illness. All these entities are relationship(s), if any, between environmen- environmental investigation was emphasized. remarkably similar in symptomatic presen- tal exposures (both acute and chronic) and Richard Kreutzer (1), a medical/environ- tation and in the limited approaches symptoms without apparent disease? mental epidemiologist outlined the epidemi- employed by scientists to investigate them. • How do we determine an optimum nosology ologic challenge of linking chemical The similarity of the complaints across these to classify these symptom complexes as they exposures to symptoms from a health syndromes has not been widely acknowl- edged nor has this commonality been This article is part of the monograph Environmental Factors in Medically Unexplained Physical Symptoms and exploited by the scientific community to Related Syndromes. advance our public health and therapeutic Address correspondence to H.M. Kipen, UMDNJ–Robert Wood Johnson Medical, EOHSI - Occupational approaches to such vexing, persistent or Health Division, 170 Frelinghuysen Rd., Piscataway, NJ 08854 USA. Telephone: (732) 445-0123, ext. 629. recurrent, often disabling, and apparently Fax: (732) 445-3644. E-mail: [email protected] We are greatly indebted to all who gave so much of their creativity to allow these recommendations to be related issues. Currently, most of the made, and for the support of several U.S. government health agencies including the National Institute of demands for response are based on putative Environmental Health Sciences (NIEHS), U.S. Environmental Protection Agency, Centers for Disease etiologies for the symptoms of the various Control and Prevention (CDC) (grant U50CCU214463), and National Institute of Mental Health, as well conditions and often lead to specification of as private industry support from the American Petroleum Institute and ExxonMobil Biomedical Sciences. In a public health agency for response (environ- addition, N. Fiedler and H. Kipen were partly supported by CDC, National Institute for Occupational mental health agencies for MCS and Gulf Health and Safety (grant R01 0H03691), and NIEHS Center grant (Cooperative Agreement ES05022). This breadth of support for this conference augurs for increased recognition of the common challenges pre- War illness, infectious disease agencies for sented as we attempt to understand what lies beneath the enigma of Medically Unexplained Symptoms and CFS, and mental health for somatization). their relationship to the Environment (MUSE). Yet, the symptoms posited to result from Received 3 December 2001; accepted 8 April 2002.

Environmental Health Perspectives • VOLUME 110 | SUPPLEMENT 4 | AUGUST 2002 591 Unexplained Symptoms • Kipen and Fiedler department point of view. He emphasized physical symptoms other than environmental a high rate of susceptibility to panic attack problems with labeling, the need for case health problems. induction among patients with MCS (referred definitions, and consideration of alternative Javier Escobar (9), on the basis of his to in the paper as idiopathic environmental models for causation. extensive psychiatric research into somatiza- intolerances). This has both important thera- Anne Spurgeon (2), a psychologist, tion, provided an assessment of the frequency, peutic implications and interesting mechanistic proposed a biopsychosocial model of illness classification, research, and treatment for such implications for the relationship of MUS to in an attempt to leap over the “mind–body” symptoms in clinical settings, which pro- panic, which is well known to have both physi- dualism that bogs down so many debates on vided a valuable perspective on how environ- ologic and psychologic correlates. this issue with the often unanswerable ques- mental health investigators need to interact Benjamin Natelson and Gudrun Lange tion, “Is it real?” She gave an enlightening with and understand prevailing healthcare (16) summarized the work of their group example of some of her own perceptual and paradigms to effectively advance our and others in a search for underlying physio- neuropsychological investigative work into response to these problems. logic abnormalities among CFS patients. an outbreak of symptoms among farmers Carol North (10), a distinguished psychi- They discussed their promising investigations chronically exposed to pesticides. This out- atric epidemiologist studying the effects of recently using functional magnetic resonance break is known as “The UK sheep-dip story.” trauma, reviewed the pitfalls of doing post- imaging that seek to document that CFS Leonard Sigal (3), a rheumatologist, and trauma research and the need to carefully patients have an underlying mild encephalo- psychologist Afton Hassett, discussed Lyme evaluate symptom reports according to many pathy. They described cogently the potential disease as an example of a condition some- key methodologic criteria. for overlap of psychiatric diagnostic nomen- times characterized by medically unex- Charles Engel (11) an Army psychiatric clature with demonstrable, although rarely plained symptoms erroneously attributed to researcher, discussed the challenges that med- clinical, physiologic dysfunction. an infectious agent. ically unexplained physical symptoms present Simon Wessely (4) discussed his own to practitioners, especially in the setting of Research Recommendations prolific research and the current state of “contested” exposures and causation. He from the Conference knowledge on the nature and causes of the offered a number of therapeutic strategies for The recommendations presented below are symptomatic epidemic known as Gulf War improving outcomes based on a collaborative the work of all attendees at the conference syndrome 10 years after it first appeared. care concept. and are summarized by the authors. The This syndrome remains one of the quintes- responses and recommendations, some sential examples of a high profile outbreak in Biological Mechanisms for focusing on additional implicit issues as well which widespread assumptions of environ- Unexplained Symptoms as on the questions listed above, are summa- mental causation have not led to compelling The next section of articles begins to address rized under categories responsive to the data to support environmental causation. the third question on experimental models spirit of the above questions: Policy and Raymond Neutra (5,6), a distinguished that may yield insight into the nature of med- Procedural Recommendations; Nosologic environmental epidemiologist, together with ically unexplained symptoms and contribu- Considerations; Recommendations for his colleague Patrick Levallois, provided two tions of environment to their genesis. Not Epidemiologic Research; Recommendations pieces on the phenomenon of electro- surprisingly, many of the models focus on the for Experimental and Mechanistic Research. magnetic hypersensitivity. The first, a gen- nose and upper respiratory tract. eral review of the published literature, Dennis Shusterman (12), an occupational Policy and Procedural concludes that there is a very limited scien- physician and upper airway researcher, Recommendations from tific database that could be used for risk reviewed the panoply of upper airway syn- the Conference assessment. The second was a survey, mod- dromes associated with either irritant, allergic, The necessity of interdisciplinary approaches eled after Kreutzer and Neutra’s ground- or odorant mechanisms. He provided an is recognized, and workshops facilitating such breaking epidemiologic work on chemical excellent outline, based on pathogenic mech- research are key to advancing this aim. A gov- sensitivities, exploring the population preva- anisms, from which to deconstruct a variety ernment agency or interagency working lence of symptomatic complaints related to of symptomatic complaints. These mecha- group is needed to to be responsible for this perceived EMF exposure, and also noting its nisms also guide the experimentalist in terms group of problems. A scientific society should relationship to correlates of sensitivity to of parameters needing control in controlled be identified as a focal point through which chemicals (7). exposure challenge experiments. relevant data could be regularly presented and Finally, Evelyn Bromet (8), a psychologist Glenn Greene (13), in conjunction with debated. This is not a small challenge because distinguished for her study of environmen- Howard Kipen, proposed a hypothesis of the apparent gap in interests and directions tal/occupational problems, described a explaining chemical sensitivity based on of organizations such as the Psychosomatic detailed study of the health concerns of interindividual differential function of the Society, the American Thoracic Society, the women evacuated following the Chornobyl controversial vomeronasal organ, situated in Society for Indoor Air Research, the power-plant explosion, concluding that long- the anterior nose. Neuroscience Society, and the International term health complaints did arise from the dis- Michael Hodgson (14), an occupational Society for Environmental Epidemiology, just aster and that they exert their greatest impact physician and indoor air quality expert, to name a few of those at which a number of in vulnerable and disadvantaged groups. reviewed the myriad exposures and stressors relevant papers are presented. Some regular associated with symptoms and commonly forum for presentation of relevant research, Psychosocial Mechanisms and known as sick building syndrome. He identi- such as the present ad hoc conference, needs Classification of Unexplained fied many likely mechanisms that may to be developed and made attractive to the Physical Symptoms explain unexplained symptoms in a number diverse group of researchers. The next section of articles was written by of settings and attempts to integrate this with One suggestion was that in order to mental health researchers, whose emphasis psychologic aspects of symptomatology. engage greater governmental interest, a formal has been on the psychosocial mechanisms Susan Tarlo (15), a pulmonologist, pre- thought exercise might be conducted, in and classification of medically unexplained sented an elegant investigation demonstrating which, after possible explanations for

592 VOLUME 110 | SUPPLEMENT 4 | AUGUST 2002 • Environmental Health Perspectives Unexplained Symptoms • Conference summary symptoms are identified, the consequent differ in individuals who have more severe Another example is The British Chemical policy options for prevention, treatment, and manifestations that lead to clinical presenta- Incident Registry. The registry may provide rehabilitation could be examined. Data gaps, tion for medical care. Such etiologic/mecha- an opportunity for researchers to study chem- including those that are fundamental, such as nistic considerations will have substantial ical release incidents that do not result in prevalence of various manifestations of impact on nosology and addresses a funda- widespread acclaim as well as those that do. unexplained symptoms and their syndromes, mental question common in medicine and This would enable investigators to examine— would need to be identified. Such an mental health as to whether certain disorders relatively independent of media influence— approach might empower a greater and more exist on a continuum or are truly discrete. the factors leading to greater individual and unified governmental stake in these problems. Novel and multifaceted research approaches population distress. are indicated to disentangle the relative, and Nosologic Recommendations perhaps simultaneous, contributions. Experimental/Mechanistic from the Conference When adequate peer-reviewed research Recommendations In terms of research, attendees emphasized supports a case-definition change, it must be We agreed that the opportunity for experi- the desirability of flexible case definitions. done carefully so that comparison with his- mental science to contribute to our under- This means that the literature has demon- torical studies is not hampered. standing of the relationship between strated enough overlap between putatively medically unexplained symptoms and the separate entities, that it is desirable to think Epidemiologic environment was enormous (almost by defin- of any one definition in terms of various oth- Recommendations ition if environmental agents do make a non- ers. Further definition of the degree and Integrating with large scale prospective cohort perceptual contribution), although largely nature of such overlap can result from cross- studies such as has been done with the U.S. unrealized to date. Despite the numerous sectional (and cross-disciplinary) studies that National Collaborative Perinatal Project (18) unsuccessful attempts of investigators to doc- incorporate more than one of the available was considered an optimal strategy. Creation ument a clinically or epidemiologically useful definitions, and researchers should strive to of new cohorts for longitudinal evaluation of marker (toxicologic, immunologic, or neu- incorporate standard definitions along with progression and natural history was recom- robehavioral) for these conditions, it is logi- any novel ones. Funding agencies should mended. For example, those individuals who cal and necessary to continue a search, acknowledge the greater burden of working have been identified in cross-sectional popula- perhaps using models that rely on a more with multiple candidate definitions. tion studies as having subclinical symptoms in integrative approach, with stress and central The conditions being considered need to the absence of a clinical presentation of ill- nervous system responses as a final common be rigorously evaluated for the extent to ness, could be followed prospectively. We rec- pathway. Thus, many of the recommenda- which they meet established criteria to be ognized as a limitation to this line of tions in this category refer to Figure 1, which considered as distinct nosolgic entities: The investigation that some large psychiatric epi- is a model of the exposure–outcome relation- Washington University criteria were specifi- demiologic studies now under way have cho- ship that passes through the systems of the cally recommended for evaluation: a) core sen not to include standard definitions of human stress response, and can apply to any characteristics, b) laboratory studies, c) family somatization, let alone the less well- of the conditions discussed at this confer- studies, and d ) follow up studies (17). It was established conditions we discussed. ence. Although this model fits for environ- recommended that CFS and fibromyalgia The prospective study of populations at mental exposures, it seems to be applicable to might be the best places to begin such a for- risk for exposure to chemical or other signifi- many external stressors that can challenge a mal exercise, because of the relatively greater cant stressors was deemed a high priority. person’s ability to respond appropriately and volume of peer-reviewed research investiga- Suggested examples, some of which have effectively. Researchers need to focus on tions available that directly address them already been studied cross-sectionally, identifying important susceptibility factors We recognized that various published include children living near industrial facili- and modifying factors, as well as ultimate scales for somatization have low levels of ties plagued with significant chemical changes in behavior, structure, and function. agreement, suggesting that if somatization is a releases; military recruits; police and fire Exposures and outcomes should be elabo- disorder, we have yet to isolate its most salient department recruits; children living in vio- rated across different unexplained illnesses, characteristics. We also recognized that per- lent inner cities; and children living in hurri- thereby defining common and illness-specific haps high levels of symptoms, somatic aspects cane-prone areas. Some of the various outcomes and triggers. of depression and anxiety, and hypochondria- populations enumerated by the Agency for For example, researchers should examine sis are not fully distinct. We felt that even in Toxic Substances and Disease Registry in whether the locus of sensory transduction (the the context of recognized psychiatric entities Atlanta, Georgia, USA, as living in proximity processing of a peripheral nervous system sig- such as obsessive-compulsive disorder, schizo- to hazardous waste sites may also be ripe for nal about the environment into a central ner- phrenia, and depression, debate continues exploration of the relationship of symptoms vous representation) is in the same brain about which ones qualify as disease entities, to the sites, and these may lend themselves in regions for various unexplained symptom syn- and thus continued nosologic research, incor- particular to longitudinal study. Use of dromes. More specifically, investigators should porating unexplained symptom syndromes, is quasi-experimental interventions with vari- probe the relationship, if any, between pre- a priority. able messages about risk being transmitted to existing and situational modifiers (Figure 1) Current cross-sectional data on preva- two similarly exposed populations was one and the CNS locus of sensory transduction. lence suggest substantial degrees of sub- specific recommendation. This mechanistic model of the relation- threshold (nonclinical) symptoms, which Development of rapid research response hip between exposure, susceptibility, and may become problematic in certain individu- capabilities, such as linking the Washington symptoms further suggests that for multiple als or certain situations (7). The relative con- University Disaster Study Group to a capabil- chemical sensitivity and other unexplained tributions to this subthreshold symptom ity such as that represented by the California illnesses that appear to involve sensation of prevalence of biological, psychological, or Department of Health’s chemical sensitivity the environment through olfaction, or even social factors are unknown. It is also not questionnaire, would be another example of other sensory modalities such as hearing known whether such relative contributions promoting cross-disciplinary investigations. and touch, classical conditioning

Environmental Health Perspectives • VOLUME 110 | SUPPLEMENT 4 | AUGUST 2002 593 Unexplained Symptoms • Kipen and Fiedler approaches should continue to be explored both patients and for practitioners. For multiple mechanisms ultimately combine to as important candidate mechanisms that example, exploration of why someone contribute to these expressions of illness: envi- can help explain the relationship of symp- considers himself/herself “unusually sensitive” ronmental stressors, misperceptions, and dis- toms to the environment. It is important would be useful and can be approached ordered brain biochemistry to name a but a for investigators to deliver rigorously con- through various qualitative research methods, few. Thus, the methods for understanding trolled and purified exposures to subjects, including anthropologicals approaches. MUS will ultimately require multidisciplinary in a blinded fashion. This is a substantial Blinded experimental research is indicated, approaches, bridging the gaps between those challenge, given the low odor thresholds of such as the double-blind randomized studies who investigate under an environmental cau- many compounds of interest. of electrical sensitivity (21). Because these sation paradigm and those who operate under We agreed that reliance on quantitative symptomatic conditions affect substantial a more traditional biopsychosocial paradigm measures of outcome that minimize suscep- numbers of individuals, and because reason- and are largely ignorant of the complex roles tibility to experimenter bias needs to be able efficacy has been shown for some of of environmental factors. We hope that the developed; validated and combined neu- them, further randomized controlled trials of breadth of support for this conference augurs roimaging techniques, discussed in the paper cognitive behavioral therapy as a symptom for increased recognition of the common chal- by Natelson and Lange (16), are one exam- management tool are indicated. lenges presented as we attempt to understand ple. Markers of effect that can be used both Animal models of unexplained illnesses what lies beneath the enigma of Medically in the laboratory and in the field need to be need to be developed. In addition, since Unexplained Symptoms and their relationship developed; for instance, common symptom psychiatric co-morbidity is often seen in to the Environment (MUSE). scales, computerized neurobehavioral persons with unexplained illnesses, there is a measures, and physiologic measures such as need for good animal models of depression REFERENCES AND NOTES cortisol, heart rate variability, and neuroen- and anxiety. docrine measures can be used in the field as 1. Kreutzer R. Idiopathic environmental intolerance: case Conclusions definition issues. Occup Med 15(3):511–517 (2000). well as in the laboratory. 2. Spurgeon A. Models of unexplained symptoms associated We agreed that the importance of Based on the recommendations of the experts with occupational and environmental exposures. Environ comparing and understanding individuals’ present at this conference, it is clear that Health Perspect 110(suppl 4):601–605 (2002). 3. Sigal LH, Hassett AL. Contributions of societal and geo- beliefs (something one holds consciously) as research must advance on many fronts to help graphical environments to “chronic Lyme disease”: the well as their mental models (how one us out of the quagmire that characterizes psychopathogenesis and aporology of a new medically processes information and stimuli, which many public health situations in which med- unexplained symptoms syndrome. Environ Health Perspect 110(suppl 4):607–611 (2002). may be conscious or unconscious), should be ically unexplained symptoms appear to be pre- 4. Wessely S. Ten years on: what do we know about the Gulf explored (19,20). This would be true for sent or are invoked. Perhaps we will find that War syndrome? Clin Med 1:28–37 (2001). 5. Levallois P, Neutra R, Lee G, Hristova L. Study of self- reported hypersensitivity to electromagnetic fields in Exposure/stressor California. Environ Health Perspect 110(suppl 4):619–623 (2002). Direct health effect 6. Levallois P. 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