A Report on Multiple Chemical Sensitivity (MCS)

The Interagency Workgroup on
Multiple Chemical Sensitivity

August 24, 1998

Predecisional Draft

NRC Workshop on Multiple Chemical Sensitivities, 1991

AOEC Workshop on Multiple Chemical Sensitivity, 1991

Report on Biologic Markers in Immunotoxicology, 19923

ATSDR Expert Panel on Multiple Chemical Sensitivity, 1993

Chemicals and Neurobiologic Sensitivity, 1994

California Department of Health Services, 199454

NIEHS, MCS: Controlled Exposure Studies, 19955

EOHSI/NIEHS Conference, 199656

DHHS Report to Congress, 19987

Summary

Table of Contents

VII. Key Panels, Workshops, and Reports: Recommendations

Since 1990, Federal Government agencies have sponsored or cosponsored a number of expert panels and workshops concerning MCS. These meetings have been important, because key researchers on chemical sensitivity and related areas have participated in the development of recommendations pertinent to the condition. MCS patient advocates and persons with MCS have also participated in some of the panels and workshops. The workgroup recognizes the expertise used to develop the recommendations from these meetings and is concerned that they not be lost to time. Moreover, it is important to compare the status of the key recommendations to assess whether they are still relevant for a better understanding of MCS. The key recommendations from federally sponsored panels and workshops on MCS are given in Table 5. The key recommendations from individual panels and workshops are described in the following sections.

NRC Workshop on Multiple Chemical Sensitivities, 1991

In March 1991, at the request of EPA, the National Research Council (NRC) conducted a workshop to develop an MCS research agenda. The participants included a wide range of scientific disciplines and philosophical views. The meeting reported its findings and recommendations through three working groups: Research Protocol for Clinical Evaluation, Exposures and Mechanisms, and Epidemiology.

Key Recommendations:

Clinical Evaluation working group:

  • Prospective longitudinal studies of exposure-based events are very important and should be performed.
  • A research priority should be the study of the adaptation-deadaptation hypothesis, and the study should be pursued using an ECU. In addition, a second approach should evaluate individuals, over time, in their usual environment.
  • Selection of research subjects should be based on the specific hypothesis to be tested (e.g., symptom-based, exposure-based, and population-based).
  • Development of a database of chemicals, foods, drugs, and signs and symptoms reported to be associated with MCS is important.

Exposures and Mechanisms working group:

  • Studies should include a comprehensive history, including exposures, physical examination, and appropriate laboratory testing. Endpoints for response should include immunologic, neurologic, endocrinological, psychological, social, and other markers or measures.
  • Dose-response relationships should be examined.
  • Animal models should be developed that mimic the human syndrome.
  • Tissues obtained by biopsy and necropsy from patients, animals, and their controls should be evaluated for signs of pathologic change.

Epidemiology working group:

  • The magnitude of the problem caused by MCS in the general population should be determined.
  • Multi-center, clinical case-comparison studies in occupational/environmental medicine clinics should be an early priority.
  • A broad set of symptom prevalences should be utilized that will allow flexible construction of a variety of case definitions.
  • Population-based methods, including construction of survey instruments, should be used to determine the basic descriptive epidemiology of certain multiorgan disorders that have been linked to MCS (e.g., systemic lupus erythematosus, scleroderma, multiple sclerosis, and somatization disorder).
  • Prompt studies of defined populations subjected to discrete and sudden chemical exposures should be enacted to assess the initiation and natural history of sensitivity syndromes involving environmental chemicals.
  • Normal ranges for new test modalities, including the sensitivity and specificity of screening techniques and biomarkers, should be determined.

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AOEC Workshop on Multiple Chemical Sensitivity, 1991

In September, 1991, the Association of Occupational and Environmental Clinics (AOEC) held an MCS workshop in Washington, D.C. The workshop format included plenary sessions and four work groups that focused on research needs in characterizing patients, events, developing treatment strategies, and exploring possible mechanisms.

Key Recommendations

Characterizing Patients group:

  • Develop a case definition for use in descriptive epidemiologic research and in challenge studies.

Characterizing Events group:

  • Determine incidence and prevalence of MCS, perhaps by using community-based studies and existing surveys such as the National Health and Nutrition Examination Survey.
  • Carry out prevalence surveys in specific occupational cohorts and cross-cultural studies of "naive" populations (i.e., groups who are unaware of MCS).
  • Perform longitudinal studies of populations exposed through "natural" situations (e.g., "sick building" exposures).
  • Develop case registries to follow the course of MCS patients.
  • Carry out double-blind, placebo-controlled challenge studies, primarily inhalation studies, including but not limited to chamber studies.

Treatment Methods group:

  • Study the effects of early intervention in an exposed population (e.g., critical incident counseling).
  • Perform randomized, controlled trials of therapies that have some reasonable theoretical basis.
  • Carry out studies of subjective outcomes, including belief structures of both patients and healthcare providers.

Mechanisms group:

  • Perform challenge studies, primarily inhalation studies, including (but not limited to) chamber studies.
  • Study olfactory function and the nasal-olfactory-limbic pathway.
  • Develop studies of neuroimaging techniques (e.g., PET and SPECT) and studies of pharmacologic probes.
  • Conduct prospective studies of cohorts of persons sensitive to chemicals and of families of MCS patients.

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Report on Biologic Markers in Immunotoxicology, 1992

In addition to the findings and recommendations from the March 1991 NRC Workshop, in 1992, the NRC Subcommittee on Immunotoxicology, through its Committee on Biologic Markers, published Biologic Markers in Immunotoxicology. The report endorsed the recommendations from the NRC meeting held in 1991.

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ATSDR Expert Panel on Multiple Chemical Sensitivity, 1993

In fiscal year 1993, Congress appropriated $250,000 to ATSDR "[f]or chemical sensitivity/low level chemical and environmental exposure workshops." The appropriation was in response to community concerns that chemical releases from hazardous waste sites and pesticide applications were associated with MCS. In response, ATSDR formed a 12-person panel to provide advice to the agency on projects that would fulfill congressional intent. The panel comprised representatives from academia, medicine, public health, and industry as well as several MCS patient advocates. Government and outside observers were also present. In April 1991, the panel developed and ranked ideas for MCS projects (Clean Sites, 1993).

Key Recommendations

  • Convene a neurologic workshop with clinicians and neuroscientists to compare clinical observations with animal and other neurologic research findings.
  • Conduct a cross-sectional/prevalence epidemiologic study.
  • Use a panel of experts with diverse interests to design and monitor a study that would use an existing ECU. The project would involve testing the usefulness of techniques such as double-blind, placebo-controlled challenge testing, provocation-neutralization, and deadaptation.
  • ATSDR should convene an interagency committee and obtain funds for an environmental unit. ATSDR should develop an educational workshop for other agencies to prepare them for membership on the interagency committee.
  • Convene a committee to define single or group phenomena to describe chemical sensitivity (i.e., MCS).
  • Convene an MCS panel to focus on developing a database, ways to piggy-back field-study research, and a registry.

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Chemicals and Neurobiologic Sensitivity, 1994

In April 1994, as a part of ATSDR activities that responded to the Congressional mandate to fund MCS workshops, and in response to the recommendations of the expert panel meeting held in April 1993, a national meeting was held in Baltimore, Maryland, to discuss low-level exposure to chemicals and neurobiologic sensitivity.

The conference did not formally adopt findings or recommendations. However, an overview was prepared and presented (Kipen, 1994); this overview pointed out that some overall recommendations could be made that do not necessarily represent consensus but may be useful to interested parties:

Definitions:

  • Establish a case definition with attention to its validity (e.g., content, criteria, and predictive value).

Populations:

  • Explore large populations for salient characteristics of chemical sensitivity.
  • Determine population prevalence of the various degrees of chemical sensitivity, with or without co-morbid medical or psychiatric conditions.
  • Undertake analytic epidemiology studies to ascertain risk factors and eventually design prevention strategies.

Mechanisms:

  • Focus on the olfactory system, both as a chemical sense organ and as an important receptor for psychological cues.
  • Focus on the immune system, especially its ability to be conditioned by psychological stimuli; include the field of psychoneuroimmunology.

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California Department of Health Services, 1994

To further address the recommendations from the ATSDR expert panel meeting held in 1993, a portion of the funds appropriated by Congress to ATSDR were used to fund a grant to the California Department of Health Services (CDHS). The grant's purpose was to develop a scientifically acceptable research design that could identify persons with physiologically-based susceptibility to low levels of chemical exposure. The grant included determining a case definition for MCS, designing survey instruments, and selecting appropriate biomarkers to characterize individuals who report sensitivities to multiple chemicals. In 1994, an expert panel was assembled by CDHS to provide advice on how best to carry out these goals. In 1996, CDHS released a final report on the project (CDHS, 1996).

Key Recommendations:

  • Rather than using a compromise definition, CDHS proposes the use of questionnaire data to assemble diagnostic scales describing various characteristics and attributes of the MCS syndrome.
  • Population-based determinations of prevalence of MCS are an important step in evaluating hypotheses about the mechanisms and etiology of this condition. Questions about the MCS syndrome have been included in the 1995 California Behavioral Risk Factor Survey (BRFS). CDHS has also proposed a more extensive study using the questionnaire they have developed.

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NIEHS, MCS: Controlled Exposure Studies, 1995

As part of NIEHS activities related to the Superfund Hazardous Substances Basic Research and Training Program, a workshop was held by the Environmental and Occupational Health Sciences Institute, the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, and Rutgers University. The objective of the workshop was to develop a multidisciplinary research agenda for elucidating possible mechanisms for MCS that involved investigators who realized the interactive nature of the problem. The relevant disciplines included neuroscience, immunology, epidemiology, exposure assessment, and environmental chemical engineering.

Key Recommendations:

  • Clear criteria are needed for the selection of subjects to participate in studies of chemical sensitivities, for example, the inclusion/exclusion of MCS subjects with co-morbid diagnoses. If subjects with other medical illnesses (e.g., asthma) are included, the number of co-morbid diagnoses should be limited in any given study and controlled in the analyses.
  • Controlled exposure studies in which a carefully defined set of MCS subjects are exposed to a chemical hypothesized to cause symptoms and in which objective and subjective responses are measured is critical. At present, no controlled study has demonstrated a relationship between chemical exposure and symptoms in this patient group.
  • Effects of conditioning and sensitization need to be considered in research studies of controlled exposure.
  • Consideration should be given to single case designs as an alternative to group comparisons, given the heterogeneity of subjects, symptoms, and chemical exposures.

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EOHSI/NIEHS Conference, 1996

In September 1996, the Environmental and Occupational Health Sciences Institute (EOHSI) and NIEHS sponsored the Conference on Experimental Approaches to Chemical Sensitivity, which was held in Princeton, New Jersey (Kipen and Fiedler, 1997). It was conducted as a workshop in which experienced MCS clinicians who could document patient characteristics worked with experimental investigators from MCS-relevant disciplines to develop experimental approaches to MCS elucidation. Five working groups addressed specific topics: empirical approaches for the investigation of toxicant-induced loss of tolerance, Pavlovian conditioning and MCS, psychoneuroimmunology, neurogenic inflammation, and testing the neural sensitization and kindling hypothesis. Each group was composed of both persons who had experience in trying to treat MCS patients and researchers who had developed research methods relevant to the MCS model under discussion. Each group produced recommendations, which included the following (Bascom et al., 1997; Bell et al., 1997; Cohen et al., 1997; Miller et al., 1997; Siegel et al., 1997):

Key Recommendations:

  • Studies should be initiated to test hypotheses in the domain of nonneurogenic inflammation, determining whether inflammation is present in symptomatic tissues of patients who have MCS and if it is associated with a heightened neurosensory response.
  • Conduct longitudinal studies to test hypotheses: (1) a psychoneuroimmunologic component is correlationally or causally associated with development of MCS and (2) stress is associated with MCS as a chronic disabling disease.
  • Conduct double-blind, placebo-controlled challenge studies performed in an environmentally controlled hospital facility coupled with rigorous documentation of both objective and subjective responses.
  • Conduct interviews with MCS patients to ascertain episodes consistent with a learning interpretation of their symptoms.
  • Conduct balanced placebo-controlled studies to separate the effects of chemical expectation from chemical effects in MCS.
  • Evaluate the possibility of olfactory hypersensitivity in MCS patients through further research.
  • Systematically evaluate the efficacy of systematic desensitization as a treatment for MCS disorders.
  • Consider single-case designs as an alternative to group comparisons, given the heterogeneity of subjects, symptoms, and chemical exposures.
  • Develop a generally accepted structured interview that is based on common patterns of patient symptoms.
  • One design for protocols to initiate and test for sensitization in MCS patients could involve the same sensitization procedures but compare outcomes under conditions of masking and unmasking.
  • Test the hypothesis that MCS patients are more susceptible to initiation of context-dependent sensitization than are control subjects.
  • Longitudinal studies with repeated measures would enable evaluation of fluctuations over time.
  • Conduct laboratory animal studies to assess neural time-dependent sensitization mechanisms.

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HHS Report to Congress, 1998

In January 1998, the Acting Assistant Secretary for Health, Department of Health and Human Services (HHS), submitted a report to Congress entitled "Report to Congress on Research on Multiple Chemical Exposures and Veterans with Gulf War Illnesses" (Eisenberg, 1998). The report was prepared in response to House Report 105-205, which accompanied the U.S. Departments of Labor, Health and Human Services, and Education and Related Agencies Appropriations Bill for fiscal year 1998. The appropriations language states, "[T]he Committee believes that there is need to conduct research as rapidly as possible into the possible links between chemical and biological exposures and the illnesses suffered by tens of thousands of Persian Gulf War veterans. The Committee believes it would be useful to support research in areas of multiple chemical sensitivity; the definition of individual genetic differences in the ability to metabolize environmental agents commonly encountered during the Persian Gulf War; and the development of a better understanding of how multiple exposures of chemicals interact to exert their toxicity on an organism. . . The Committee requests the Secretary to submit a report by December 31, 1997, describing the Department's proposed Gulf War illness research plan and a description of how funding will be allocated among the HHS agencies to implement the program."

The HHS report indicates that a representative will be located in the Office of Public Health, Office of Secretary, as the principal official for the research program stipulated by Congress. In fiscal year 1998, a consensus-building conference will be held to "[f]ully characterize the nature of multiple chemical exposures with the Gulf War veteran population and to relate this characterization to what is known about Multiple Chemical Sensitivity (MCS) and related conditions and disorders within civilian populations." CDC will be allocated $300,000 to conduct the conference. Also, in fiscal year 1998, $400,000 will be added to an NIH grant entitled "Chemical Mixtures in Environmental Health."

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Summary

Table 5 lists, in descending order of concordance, the recommendations from the seven meetings that are described in this section. There were four recommendations that had support from five or more meetings:

  • Conduct basic epidemiology,
  • Conduct case-comparison studies,
  • Develop a case definition for MCS, and
  • Conduct challenge studies.

The specifics of these four recommendations varied across the seven meetings. For example, all meetings recommended more research, although the specific types of research varied with the meeting. The need for more basic epidemiologic data on MCS was a mutual theme at all seven meetings.

This discussion of the previously held federally-supported meetings, while presenting the formal recommendations, should not diminish the serious consideration that was given to many other topics. The published proceedings should be reviewed for additional details. As will be evident in the next section, only limited progress has been made by Federal agencies on many of the recommendations listed in Table 5.

 

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