Introduction and Overview

University of Medicine and Dentistry of New Jersey--Robert Wood Johnson Medical School, Piscataway, New Jersey

-- Environ Health Perspect 105(Suppl 2):405-407 (1997)

Unlike previous conferences, this conference was conducted as a workshop in which experienced MCS clinicians who could document patient characteristics worked with experimental investigators from scientific disciplines related to MCS to develop experimental approaches. This supplement is a compilation of papers given by invited speakers, both clinical and methodologic, along with assigned commentaries in response to some of the papers. These papers reflect the background and the diversity of opinion that exists in this area of inquiry.

The paper by Fiedler and Kipen (3) is an overview of published studies that have characterized patients with chemical sensitivity and highlights differences in case definition and subject selection criteria between studies. We summarize the peer-reviewed literature on the psychiatric, neuropsychologic, immunologic, and olfactory function of patients reported to have chemical sensitivity, and offers suggestions for subject selection and experimental approaches based upon the limited published experience with individuals who have this syndrome.

The series of clinical papers offers a summary of patient characteristics from both the research that has directly evaluated patients with chemical sensitivities and from clinical experience. The purpose of these talks and papers was to provide background to those researchers with limited previous access or knowledge of MCS.

Ross (4), and Ziem and McTamney (5) describe case studies of patients who are unable to tolerate low-level chemical exposures. Ziem and McTamney (5) further describe the use of various clinical tests for diagnosing chemical sensitivity. The patients discussed by these authors are good examples of the heterogeneity in exposure history and illness presentation among patients to whom the term chemically sensitive is applied. The tests and theories described, although different from those noted by Kipen and Fiedler (3), represent the breadth of clinical approaches and laboratory analyses used to characterize these patients, and challenge experimentalists looking for a homogeneous subject pool characterized by standardized methodology.

Kehrl (6) comments on the clinical surveys and emphasizes the inherent difficulties in using inadequately standardized laboratory assays or assays that are not validated for the conditions they are used to assess.

The next group of papers discusses divergent models to account for chemical sensitivity. Each model has a different experimental approach, and it is the use of these models that is the subject of the working groups.

Miller's model of chemical sensitivity proposes that MCS is explained by a loss in the ability to tolerate chemicals, which results after an exposure (7). Subsequently, low-level exposures trigger symptoms. This is an expansion and development of the concept of adaptation proposed by Rea (8), with less emphasis on putative metabolic explanations. Miller further explains that the only method by which these responses to exposures can be detected is by removing patients from all exposures for 3 to 5 days (deadaptation) and then exposing them to single chemicals. This paradigm provides substantial theoretical and logistical challenges for the design of experiments. MacPhail (9) comments on the model proposed by Miller, and notes that large interindividual differences commonly are found in animal studies, and that we should not be surprised that some individuals are more sensitive than others: "Variation in sensitivity has rarely been the focus of research, because scientists have been generally preoccupied with measures of central tendency." He recommends an approach that examines conditioning of adverse effects of airborne chemicals to provide a rigorous laboratory model for some aspects of MCS.

Bell et al. (10) review and present hypotheses suggesting that chemical sensitivity may be a neural sensitization phenomenon exemplified by time-dependent sensitization or limbic kindling. That is, patients become chemically sensitive following one toxic exposure or repeated low-level exposures separated in time. Subsequent responses may be triggered by very low-level exposures. Bell points out that sensitization is distinct from but interactive with other neurobiological learning and memory processes such as conditioning and habituation, both of which are emphasized in various other discussions in the monograph.

Sorg and Prasad (11) wonder whether nonelectrical kindling can occur. Sorg and Prasad examine the potential involvement of stress and temporal changes in the development of MCS from the perspective of behavioral sensitization and kindling in rodents. One model involves cross-sensitization between stress and drugs of abuse in looking for enhancement of response over time.

Meggs (12), on the other hand, suggests that chemical sensitivity results through a process of neurogenic inflammation. He describes preliminary results from a study of nasal pathology in MCS as well as other patients in which defects in tight junctions, mucosal desquamation, glandular hyperplasia, lymphocytic infiltrates, and peripheral nerve fiber proliferation have been found. He describes how this inflammation suggests a model in which a positive feedback loop is set up between the inflammatory response to low-level irritants and the epithelial changes propagated by the inflammation, and that multi-organ symptoms can then be explained by the concept of neurogenic switching.

Lehrer (13) discusses analogies from the behavioral literature to propose hypotheses and strategies for exploring the contribution of psychological factors to MCS. Hypotheses are based on concepts of individual response stereotypy, situational response specificity, classical conditioning and psychophysiologic arousal in response to odor cues as models for chemical sensitivity. These strategies are tightly connected to the experimental psychology literature, and suggest immediately testable approaches.

Benignus (14) provides a brief and cautionary commentary to respect the canon of parsimony in generating theoretical constructs to explain MCS. He suggests careful work to connect explanatory hypotheses to the body of accessible scientific literature and compares the approaches of Rea (8) and Lehrer (13).

The final series of papers focus on experimental methods and dependent variables that could be employed in experimental studies suggested by the previous models.

Weiss (15) suggests that scepticism about MCS stems, in part, from a lack of supporting experimental data. Because of the apparent broad variations in sensitivity and the need to establish reproducibility, he strongly favors the single-subject design, emphasizing repeat observations on individual subjects combined with appropriate time series statistical tests.

Wetherell (16) comments from a perspective of psychopharmacology research and emphasizes good study design as the key to meaningful results when looking at neurobehavioral end points. Cognitive and psychomotor tests are examined from a perspective of sensitivity, reliability, and validity, and the Latin Square design is proposed as a way to resolve design issues. Difficulties with placebos are discussed.

Newlin (17) describes a behavior-genetic approach modeled after research on substance abuse to explore both the epidemiology and genetics of MCS. Opportunities to use twin registers and comparisons or contrasts with addiction are examined.

Eissenberg and Griffiths (18) describe elegant and well-developed protocols for assessing interindividual differences in sensitivity to or tolerance of caffeine. Although not the most prominent or challenging problem cited by MCS subjects, such intolerance is frequently reported and can be evaluated without developing new testing procedures, as inhalation studies would require. Thus, a window can be opened on the phenomenology of unusual sensitivity of some individuals to doses of agents usually well-tolerated by the rest of the population.

These manuscripts provide a rich insight into the wealth of clinical observation and scientific challenges offered by MCS. While two presenters were not able to submit papers for publication, we refer the interested reader to reviews to supplement this volume [Bascom (19) and Ader et al. (20)].

Following the plenary talks and commentaries, all presenters also participated in one of five working groups. The papers from these working groups reflect a synthesis of research questions, experimental approaches, and methods to test hypotheses generated by the proposed model of MCS (21-25). Each group was composed of both individuals who had experience with MCS patients and researchers who had developed research methods relevant to the model under discussion.

To summarize, these papers represent a rich source of hypotheses. The workshop brought together clinicians and researchers from divergent backgrounds and although controversies arose, their interactions produced many ideas and suggestions. We hope they will be of use to the research community as we endeavor to understand chemical sensitivities.

25. Bell IR, Rossi J III, Gilbert ME, Kobal G, Morrow LA, Newlin DB, Sorg BA, Wood RW. Working Group Report 5: Testing the neural sensitization and kindling hypothesis for illness from low levels of environmental chemicals. Environ Health Perspect 105(Suppl 2):539-547 (1997).

This paper is based on a presentation at the Conference on Experimental Approaches to Chemical Sensitivity held 20-22 September 1995 in Princeton, New Jersey. Manuscript received at EHP 27 December 1996; manuscript accepted 27 December 1996.

Last Update: March 18, 1997