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Is multiple chemical sensitivity a clinically defined entity?
Toxicology Letters 128 (2002) 99 – 106 www.elsevier.com/locate/toxlet
Review article
Is multiple chemical sensitivity a clinically defined entity? Hermann M. Bolt *, Ernst Kiesswetter Institut fu¨r Arbeitsphysiologie an der Uni6ersita¨t Dortmund (IfADo), Ardeystr. 67, D-44139 Dortmund, Germany Dedicated to the late Philip Chambers
Abstract In 1996 a WHO/IPCS Workshop has suggested to use as an appropriate descriptor of MCS the broader term ‘‘Idiopathic Environmental Intolerances (IEI)’’, in order to incorporate ‘‘a number of disorders sharing similar symptomatologies’’. Research was strongly encouraged. The following points have been put forward as a precondition to define MCS as a clinical entity: (a) establishment of diagnostic criteria, (b) identification of pathogenic mechanisms, together with, (c) an explanation of relationship between exposures and symptoms. Against this background, progress made in the fields of sensory physiology and neurobehaviour research must be debated. In particular, recent results on processing of cognitive stimuli have to be considered. IEI/MCS patients exhibited differences vs. controls in their reactions to intranasal challenge, consistent with changes in cognitive processing of suprathreshold chemosensory information. Trait anxiety and focus of attention have clearly been identified as major components in eliciting neurobehavioural MCS symptoms. Hence, the question as to whether MCS should be regarded as a clinically defined entity remains controversial, but important progress can be noticed in elucidating and defining the nature of this phenomenon, by a combined effort of several disciplines (toxicology and behavioural toxicology, psychology and psychophysiology, and clinical medicine). The new situation will call for a re-evaluation of traditional positions. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Multiple chemical sensitivity (MCS); Idiopathic environmental intolerance (IEI); Mechanisms of MCS; Dose-dependence
1. Introduction The thesis ‘‘Multiple Chemical Sensitivity (MCS) is a Clinical Entity’’ was selected as Debate topic for the IXth International Congress of Toxicology (Brisbane, QLD, Australia, July 8 – 12, Theses Presented at the IUTOX Debate, IXth International Congress of Toxicology, Brisbane, Australia. * Corresponding author. Tel.: + 49-231-1084-348; fax: + 49-231-1084-403. E-mail address: [email protected] (H.M. Bolt).
2001. See: Wright, 2001; Thier and Bolt, 2001). Debaters were Robert H. Loblay and Hermann M. Bolt. The present paper provides a summary of theses and major discussion points. There is a specific background, in Australia and New Zealand as well as in other anglophone industrialised countries, regarding the eccentric ideas of ‘‘Clinical Ecologists’’ (Loblay, 1993, 1995). Problems of semantics were addressed in the general discussion. Terms like ‘‘20th Century Allergy’’, or the medical subculture of ‘‘Clinical Ecology’’ are typical for Anglo-Saxon countries.
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Also, the question as to whether MCS and other manifestations of so-called ‘Idiopathic Environmental Intolerance’ must be called ‘illness’ or ‘disease’ (Lloyd et al., 2000) is linked to the specific vocabulary of the English language. Such distinctions do not exist in other languages, which is an important aspect, as all expressions of symptoms in human behavioural toxicology are closely connected with language. As defended by Loblay, these manifestations, in the absence of a clear understanding of the underlying pathophysiology, should be described as ‘‘illness’’ rather than a disease (Jennings, 1986). ‘‘Illness’’ is understood as a subjective state of suffering— physical, psychological and social—and can only be understood and defined with reference to the sick individual (Cassell, 1991). In this sense, people with MCS are mostly regarded as being ill, independent of the question as to whether an underlying disease process has been identified (Lloyd et al., 2000). There is overwhelming consensus within the scientific community that patients labelled with MCS are clearly distressed, and that many are functionally disabled (Sparks et al., 1994a,b).
2. MCS as a clinically defined disease? In 1996, a WHO/IPCS workshop in Berlin arrived at the following conclusion (Anonymous, 1997): ‘‘The term MCS should be discontinued because it makes an unsupported judgement on causation. Although there exist several definitions of what has been called MCS, it cannot be regarded as a clinically defined disease. There are neither accepted theories of underlying mechanisms nor validated clinical criteria for diagnosis. A relationship between exposure and symptoms is unproven.’’ This calls for fulfilment of the following three points to define MCS as a clinical entity, and we have to put forward the question whether these points are now being met: establishment of diagnostic criteria, identification of pathogenic mechanisms, together with an
explanation of relationship between exposures and symptoms.
3. Diagnostic criteria and relation between exposures and symptoms Very often, there is advocating of lack of ‘objective’ diagnostic criteria for MCS, such as laboratory tests (Sparks et al., 1994b). This alone does not seem to be a valid argument against existence of a clinical entity as this refers to many psychiatric diseases. Nobody would question depression or schizophrenia as clinical entities although there is no laboratory test supporting the diagnosis; the symptoms are entirely of behavioural and ‘subjective’ nature. Therefore, subjective symptoms are a legitimate basis of a clinical diagnosis when the pathogenic mechanisms are exclusively confined to the human brain. Based on the symptoms presented by the patient, there are commonly used ‘case definitions’ for MCS which are based on Cullen’s criteria (Cullen, 1987). These diagnostic criteria are also accepted by opponents of MCS being a clinical entity (e.g. Sparks et al., 1994b; Lax and Henneberger, 1995; Altenkirch, 2000), with the provision that Cullen attempted to define MCS primarily for research purposes: The disorder is acquired in relation to some environmental exposure, insult, or illness that is reported by the patient. Symptoms involve more than one organ system. Symptoms recur and abate in response to predictable stimuli. Symptoms are elicited by exposures to a variety of chemicals. Symptoms are elicited by exposures that are demonstrable. Exposures that elicit symptoms must be very low and are normally tolerated by others. Other likely causes of the observed symptoms are excluded. A cross-sectional survey by Nethercott et al. (1993) of 148 medical practitioners in Baltimore, MD, has revealed the following ranking of criteria selected as major for diagnosing the syndrome by more than 50% of the respondents:
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1. Symptoms are reproducible with exposure. 2. Condition is chronic. 3. Low levels of exposure result in manifestations of the syndrome. 4. Symptoms resolve with removal of incitation. 5. Responses occur to multiple, chemically unrelated substances. In this ranking reproducibility with exposure had been placed first, and this was considered ‘irrelevant’ by only 6% of the physicians. Both sets of criteria are based on two major sources of information: symptoms, generally of subjective nature, and exposure, of fictitious objective nature. Because in clinical diagnostic situations valid information on exposure is extremely rarely available, the dilemma of possible misdiagnosis has to be stressed. Relevant toxic exposures may be overlooked because the symptoms are similar to those commonly seen in psychic disorders. Conversely, subjective exposure information without a real toxicological background might lead to the misdiagnosis of a chemical-induced illness (Kiesswetter, 1998/1999). Whether the criteria tabled above, including ‘reproducibility with exposure’, are sufficient to diagnose MCS, remains an issue that has to be debated in view of specific models that could explain the relationship between exposures and symptoms.
4. Pathogenic mechanisms A central part of the Debate, from a toxicological point of view, was the question: which mechanisms of pathogenesis of MCS could be established. Models are straightforward that relate MCS to olfactory, especially trigeminal, stimuli, distinguishing between two stages of stimuli processing, sensory and nonsensory (Doty et al., 1988; Dalton and Hummel, 2000). Following this type of modelling, the way of cognitive processing, and not that of olfactory chemosensation, makes the differences between MCS patients and the rest of the population. The difference is related to a fundamental function of the brain the reduction of complex incoming information. During and after
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projection of sensory and environmental surrounding information upon the respective cortex regions, selection and interpretation processes are postulated, which are triggered by attention, the perceptional, behavioural and cognitive state, and by personal pre-existing traits (Dalton and Hummel, 2000). A key element in computation of the final output or decision is the memory that again is under influence of pre-existing states and traits (Fig. 1). Models of olfactory and cognitive–perceptual mediation allow explanation of why multiple, and chemically unrelated, compounds elicit similar MCS symptoms, subjective and physiological. If we reflect these mechanisms in terms of MCS, we can define two major factors in pathogenesis of the disease. On one hand, there are personal pre-existing traits (Kiesswetter et al., 1999), while on the other hand there is a specific stimuli anticipation and processing, being influenced by the perceptional, behavioural and cognitive state of the individual. Both induce a ‘pathological’ cognitive processing, finally leading to the evolvement of the behavioural and vegetative symptoms of MCS (Dalton and Hummel, 2000).
5. Pre-existing states and traits (‘‘s-MCS’’) For toxicological research purposes, we are able to define a specific subgroup within the population, which is susceptible to MCS development (Fig. 2). The specific susceptibility is related to a very stable personal trait, characterised by trait anxiety and negative affectivity (Kiesswetter et al., 1998, 1999), with a preponderance of the female gender (Fiedler and Kipen, 1997). The susceptible subgroup can be identified by means of psychological questionnaires (Kipen et al., 1995; Kiesswetter et al., 1997), and is now mostly being addressed as persons with ‘‘self-reported MCS’’, or ‘‘sMCS’’ (Kiesswetter et al., 1998, 1999). The questionnaire called ‘‘CAUS’’ in Germany (in English ‘‘Chemical and General Environmental Sensitivity, CGES’’) was developed in 1993 and covers 67 items (Kiesswetter et al., 1997). Operationally, a person is regarded as belonging
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to the sMCS group, if one of the critical items, regarding to extreme responses to defined olfactory stimuli, is answered positively. Alternatively, a quantitative ‘‘sMCS rating’’ based on a sum scale is applied, and the sMCS subpopulation is defined as persons with a rating above an explicit cut-off point. This refers to 10% of the normal population, and the percentage is only slightly higher in patients suffering from alcohol disease or psychosomatic disorders (Kiesswetter et al., 1998), which is also consistent with findings of others (Fiedler and Kipen, 1997). Interestingly, there is a high selection of the susceptible subgroup among patients in Germany coming to our institute with the question of compensation of the German Occupational Disease no. 1317, which inter alia comprises the psychoorganic syndrome due to solvents or other neurotoxic agents (Kiesswetter et al., 1999). In a laboratory experiment (van Thriel et al., 2000), groups of 12 persons rated ‘‘sMCS’’ subjects, as well as 12 non-sMCS controls were exposed to fluctuating concentrations of either 2-butanone, a ketone with irritating properties at
higher concentrations, or ethylbenzene, a hydrocarbon with a typical aromatic smell. The mean concentrations over time were equivalent to the German Occupational Exposure Limit, and the short-term excursion factor of the peaks was 2, also in compliance with current German workplace regulations. For comparison, ‘‘low exposures’’ were at 10 ppm for both compounds, which is higher than the olfactory threshold, but clearly below any toxicological effect. Inter alia, the time course, within the peak exposure periods, of nasal irritation ratings was recorded. Very strikingly, sMCS persons responded to both compounds with much higher reporting of irritation than the control group did. At the beginning of the peak exposure episodes, sMCS persons displayed slightly higher respiratory and heart rates than controls, indicative of influences on vegetative functions in this subgroup (Haumann et al., in press). In principle, this is consistent with earlier findings of Doty et al. (1988). After having completed the different exposures with 2-butanone or ethylbenzene, the nasal flow in the sMCS and control group was assessed by
Fig. 1. Psychophysiological characteristics of MCS.
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Fig. 2. Persons with ‘‘sMCS’’, characterising a specific subgroup susceptible for MCS.
anterior rhinomanometry (Wiesmu¨ ller et al., in press). Irrespective of the mode of exposure— high or low, 2-butanone or ethylbenzene— there was a general decrease of nasal passage in sMCS persons, pointing to a higher sensitivity with respect to this autonomic function. Current results of the studies at the Institute for Occupational Physiology in Dortmund are supplemented by those of the research team of F. Rist, University Muenster, with a strong focus on cognitive and psychosomatic aspects of MCS. Cognitive–behavioural models of psychosomatic disorders suggest attentional processes as a central element of pathogenesis. According to this approach, specific perceptional styles are responsible for ‘somatosensory amplifications’. To test this hypothesis, selected student samples with high and low sMCS scorings (according to CAUS: Kiesswetter et al., 1997) had to name, as fast as possible, the colour of single words displayed on a computer screen. The words were pre-selected and had either potentially threatening environmental (e.g. ‘‘insecticide’’) or neutral meanings (e.g. ‘‘towel’’). When solely referred to words with environmental threatening contents, the response time of the sMCS sample was significantly longer, compared to that of the non-sMCS sample (Nischk et al., in press). Although persons designated ‘‘sMCS’’ were not ill, from a theoretical point of
view they represent a risk group to develop environmental related disorders because of their selective attention.
6. Dose–response relationship If we put these and other findings into a perspective in terms of dose–response, we arrive at the dose– effect relationship shown in Fig. 3. It is evident that the classical pharmacological and toxicological dose–effect rules are not valid for MCS responses to chemical stimuli. Occupational exposure levels are set well below toxicologically defined NOAEL levels. As a general rule, the olfactory threshold is located much lower than the
Fig. 3. Olfactory threshold model for dose-dependence of MCS symptoms.
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NOAEL. As the eliciting of MCS symptoms is connected with chemosensory functions we arrive at an olfactory threshold model for the dose– response of MCS. There are obvious formal similarities between this type of dose–response and the dose– response towards allergens in sensitised persons: in both cases we realise a threshold model, but with the low threshold only for a subset of the general population. This subset reacts at concentrations that are normally tolerated. In relation to the criteria set by the initially mentioned WHO/IPCS workshop (Anonymous, 1997), it appears: We now start to realise the existence of a psychophysiological theory of mechanisms underlying MCS, which also explains the relationship between exposure and symptoms. There is diversity of opinions as to whether the criteria for diagnosis of MCS are sufficiently validated.
7. General toxicological and pharmacological perspective Argumentations on MCS at an International Congress of Toxicology would be incomplete without giving tribute to the contributions of the late Ernst Habermann who passed away early this year (Obituary, 2001). As professor of pharmacology and toxicology of the Justus-Liebig-University in Giessen, Habermann had put particular effort into developing and promoting his model of the ‘‘nocebo’’ (Habermann, 1998, 1999a,b; Fig. 4). On one hand, a substance may have either wanted or unwanted ‘‘chemical’’ effects which determine it to be either drug or poison. European pharmacology has called these: effects of the ‘‘verum’’. On the other hand, there are associated ‘‘psychosocial’’ effects, again wanted, characterising the eliciting compound as a placebo, or unwanted, making it a nocebo. All these effects, those of the placebo/nocebo and of the verum, are considered real. In terms of biomedical research, the 21st century has been called ‘the century of the brain’.
Fig. 4. The message of the late Ernst Habermann.
Hence, if a disease is regarded as ‘psychogenic’, we have to look at brain physiology and psychophysiology; and major breakthroughs are to be noticed in these fields. We currently witness a clear process that the traditional paradigm of a dichotomy between the antipodes psyche and soma is fading. In his last publication on this issue, Habermann (2000) has made particular reference to a publication by Ploghaus et al. (1999). The experience of pain is subjectively different from the fear and anxiety caused by threats of pain. Functional magnetic resonance imaging (fMRI) was used in this paper to dissociate neural activation patterns associated with acute pain and its anticipation. Twelve healthy volunteers underwent fMRI while being presented with a pseudo-random sequence of two intensities of thermal stimulation (either painful ‘‘hot’’ or non-painful ‘‘warm’’). Coloured lights signalled in advance the two kinds of stimuli, and the subjects learned during the imaging session which colour signalled pain and which signalled warmth. Interviews after the experiment confirmed that all subjects were aware of the relation between the light colour and the intensity of the stimulation. Brain regions with functional activities characteristic of pain were identified by comparison with those of the ‘‘warm’’ situation, and regions with functional activities characteristic of pain anticipation were identified in comparison with those of anticipation of warmth. Within the entire network of activation, particular brain
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regions were identified where responses to pain could be differentiated from those to anticipation of pain, on the basis of neuroanatomical localisation and the time course of the fMRI signal change. These regions were located in the medial frontal lobe, the insular cortex and the cerebellum (Ploghaus et al., 1999). Based on this very recent piece of work, Habermann (2000) made the point that an objective comparison between a verum effect, the thermally induced nociception, and a nocebo effect, the anticipation of nociception, has been achieved. In the experiment described by Ploghaus et al. (1999) the brains of the test persons used ‘‘identical programmes to process the differing data sets of verum and nocebo’’. Habermann (2000) commented this as being indicative of the current convergence of psychology and neurophysiology that make the 21st century the ‘‘century of the brain’’. This aspect seems fundamental to a pathophysiological understanding of MCS and related diseases. It also sheds new and a very modern light on what had been expressed by William Shakespeare some 390 years ago (Zilker 1999). In ‘‘The Winter’s Tale’’, 2nd act, 1st scene, King Leontes of Sicily tells the image of the spider: ‘‘There may be in the cup A spider steep’d, and one may drink, depart, And yet partake no venom ( for his knowledge Is not infected); but if one present Th’ abhorr’d ingredient to his eye, make known How he hath drunk, he cracks his gorge, his sides, With violent thefts. I have drunk, and seen the spider.’’
8. Conclusion The question as to whether MCS should be regarded as a clinically defined entity is controversial. However, important progress can be noted in elucidating and defining the nature of this phe-
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nomenon. This progress requires a combined effort of different disciplines (toxicology and behavioural toxicology, psychology and psychophysiology, and clinical medicine). MCS is not a conventional toxicological phenomenon, according to Paracelsus. It has a distinct psychophysiological background that explains the lack of classical dose-dependency. But it also explains, in responding individuals, its reproducibility with exposure. Not the venom of the spider is causing this effect: it is the anticipation of the venom, the ‘‘infection of the knowledge’’ according to Shakespeare (vs.), or the nocebo according to Habermann.
Acknowledgements The authors acknowledge the assistance of the Behavioural Toxicology group of IfADo Dortmund: A. Seeber, Ch. Van Thriel, M. Zupanic, B. Sietmann, and K. Golka.
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Habermann, E., 1998. Facts and fallacies of alternative medicine. Satellite to IUPHAR XIII. Biomarkers Environ. 2, 26 – 29. Habermann, E., 1999a. The convergence of biosciences. Futura (BIF) 14, 272 – 279. Habermann, E., 1999b. Gift und Nocebo: Zwei Aspekte der Toxikologie. In: Mu¨ cke, W. (Ed.), Chemikalien-Syndrome— Fiktion oder Wirklichkeit?, Institut fu¨ r Toxikologie und Umwelthygiene der Technischen Universita¨ t Mu¨ nchen, ISBN 3-932108-07-8, pp. 23 –43. Habermann, E., 2000. Abbildung eines Nocebo-Pha¨ nomens im menschlichen Gehirn durch fMRI. DGPT Forum. Mitteilungen der Deutschen Gesellschaft fu¨ r experimentelle und klinische Pharmakologie und Toxikologie, No. 26, Feb., p. 63. Haumann, K., Kiesswetter, E., van Thriel, C., Blaszkewicz, M., Seeber, A., Psychophysiological functions of subjects with self-reported multiple chemical sensitivity (sMCS) during experimental solvent exposure, Int. J. Hyg. Environ. Health, in press. Jennings, D., 1986. The confusion between disease and illness in clinical medicine. Can. Med. Assoc. J. 135, 865 –870. Kiesswetter, E., 1998/1999. ’Multiple Chemical Sensitivity’, the relevance of toxic, neurobiological and psychic effect mechanisms. Zbl. Hyg. Umweltmed. 202, 191 – 205. Kiesswetter, E., Sietmann, B., Golka, K., Zupanic, M., Seeber, A., 1997. Discriminant validity of a new questionnaire for chemical and general environment sensitivity. NeuroToxicology 18, 902 –903. Kiesswetter, E., Sietmann, B., Zupanic, M., van Thriel, Ch., Golka, K., Seeber, A., 1998. ’’Multiple Chemische Sensitivita¨ t’’ (MCS): Berufliche Exposition und individuelle Merkmale. Verh. Dtsch. Ges. Arbeitsmedizin (Rindt-Druck, Fulda) 38, 315 – 319. Kiesswetter, E., Sietmann, B., Zupanic, M., van Thriel, Ch., Golka, K., Seeber, A., 1999. Verhaltenstoxikologische Aspekte der Pra¨ valenz und A8 tiologie ‘‘multipler chemischer Sensitivita¨ t’’. Allergologie 22, 719 –735. Kipen, H.M., Hallman, W., Kelly-McNeil, R., Fiedler, N., 1995. Measuring chemical sensitivity prevalence: a questionnaire for population studies. Am. J. Public Health 85, 574 – 577. Lax, M.B., Henneberger, P-K., 1995. Patients with multiple chemical sensitivities in an occupational health clinic: presentation and follow-up. Arch. Environ. Health 50, 425 – 431. Loblay, R.H., 1993. Allergic to the 20th century. Aust. Family Physician 22, 1086 – 1997. Loblay, R.H., 1995. Chronic fatigue syndrome: what’s in a name? Med. J. Australia 163, 285 – 286.
Lloyd, A.R., Hickie, I.B., Loblay, R.H., 2000. Illness or disease? The case of chronic fatigue syndrome. Med. J. Aust. 172, 471 – 472. Nethercott, J.R., Davidoff, L.L., Abbey, H., 1993. Multiple Chemical Sensitivities syndrome: toward a working case definition. Arch. Environ. Health 48, 19 – 26. Nischk, D., Rist, F., Weinbrenner, B., Selektive Aufmerksamkeitslenkung auf bedrohliche umweltbezogene Stimuli bei Probanden mit selbstberichteter MCS. (Selective attentional focussing on threatening environmental stimuli in subjects with self-reported MCS), University of Muenster, Germany, in press. Obituary, 2001. Prof. Dr. Ernst Habermann. DGPT Forum. Mitteilungen der Deutschen Gesellschaft fu¨ r experimentelle und klinische Pharmakologie und Toxikologie, No. 28, Feb. 2001. Ploghaus, A., Tracey, I., Gati, J.S., Clare, S., Menon, R.S., Matthew, P.M., Rawlins, J.N.P., 1999. Dissociating pain from its anticipation in the human brain. Science 284, 1979 – 1981. Sparks, P.J., Daniell, W., Black, D.W., Kipen, H.M., Altman, L.C., Simon, G.E., Terr, A.I., 1994a. Multiple Chemical Sensitivity syndrome: a clinical Perspective. I. Case Definition, theories of pathogenesis, and research needs. J. Occup. Med. 36, 718 – 730. Sparks, P.J., Daniell, W., Black, D.W., Kipen, H.M., Altman, L.C., Simon, G.E., Terr, A.I., 1994b. Multiple Chemical Sensitivity syndrome: A clinical Perspective. II. Evaluation, diagnostic testing, treatment, and social considerations. J. Occup. Med. 36, 731 – 737. Thier, R., Bolt, H.M., 2001. The new era of toxicology. Trends Pharmacol. Sci. 22, 549 – 550. van Thriel, C., Blaszkewicz, M., Kiesswetter, E., Seeber, A., 2000. Irritative und olfaktorische Symptome unter experimenteller Exposition gegenu¨ ber Ethylbenzol und 2-Butanon. Verh. Dtsch. Ges. Arbeitsmedizin (Rindt-Druck, Fulda) 40, 454 – 456. Wiesmu¨ ller, G.A., van Thriel, C., Steup, A., Bachert, C., Blaszkewicz, M., Kiesswetter, E., Seeber, A., Nasal function in self-reported chemically intolerant individuals, Arch. Environ. Health, in press. Wright, P.F.A. (Ed.), 2001. Toxicology and Sustainable Development — Meeting the Challenge. Abstracts of the IXth International Congress of Toxicology, Brisbane, Australia, July 8 – 12, 2001. Toxicology 164, 1 – 266 Zilker, Th., 1999. Multiple Chemical Sensitivity (MCS) — psychiatrische Aspekte. In: Mu¨ cke, W. (Ed.), ChemikalienSyndrome — Fiktion oder Wirklichkeit?, pp. 45 – 56. Institut fu¨ r Toxikologie und Umwelthygiene der Technischen Universita¨ t Mu¨ nchen, ISBN 3-932108-07-8.
Review article
Is multiple chemical sensitivity a clinically defined entity? Hermann M. Bolt *, Ernst Kiesswetter Institut fu¨r Arbeitsphysiologie an der Uni6ersita¨t Dortmund (IfADo), Ardeystr. 67, D-44139 Dortmund, Germany Dedicated to the late Philip Chambers
Abstract In 1996 a WHO/IPCS Workshop has suggested to use as an appropriate descriptor of MCS the broader term ‘‘Idiopathic Environmental Intolerances (IEI)’’, in order to incorporate ‘‘a number of disorders sharing similar symptomatologies’’. Research was strongly encouraged. The following points have been put forward as a precondition to define MCS as a clinical entity: (a) establishment of diagnostic criteria, (b) identification of pathogenic mechanisms, together with, (c) an explanation of relationship between exposures and symptoms. Against this background, progress made in the fields of sensory physiology and neurobehaviour research must be debated. In particular, recent results on processing of cognitive stimuli have to be considered. IEI/MCS patients exhibited differences vs. controls in their reactions to intranasal challenge, consistent with changes in cognitive processing of suprathreshold chemosensory information. Trait anxiety and focus of attention have clearly been identified as major components in eliciting neurobehavioural MCS symptoms. Hence, the question as to whether MCS should be regarded as a clinically defined entity remains controversial, but important progress can be noticed in elucidating and defining the nature of this phenomenon, by a combined effort of several disciplines (toxicology and behavioural toxicology, psychology and psychophysiology, and clinical medicine). The new situation will call for a re-evaluation of traditional positions. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Multiple chemical sensitivity (MCS); Idiopathic environmental intolerance (IEI); Mechanisms of MCS; Dose-dependence
1. Introduction The thesis ‘‘Multiple Chemical Sensitivity (MCS) is a Clinical Entity’’ was selected as Debate topic for the IXth International Congress of Toxicology (Brisbane, QLD, Australia, July 8 – 12, Theses Presented at the IUTOX Debate, IXth International Congress of Toxicology, Brisbane, Australia. * Corresponding author. Tel.: + 49-231-1084-348; fax: + 49-231-1084-403. E-mail address: [email protected] (H.M. Bolt).
2001. See: Wright, 2001; Thier and Bolt, 2001). Debaters were Robert H. Loblay and Hermann M. Bolt. The present paper provides a summary of theses and major discussion points. There is a specific background, in Australia and New Zealand as well as in other anglophone industrialised countries, regarding the eccentric ideas of ‘‘Clinical Ecologists’’ (Loblay, 1993, 1995). Problems of semantics were addressed in the general discussion. Terms like ‘‘20th Century Allergy’’, or the medical subculture of ‘‘Clinical Ecology’’ are typical for Anglo-Saxon countries.
0378-4274/02/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 7 8 - 4 2 7 4 ( 0 1 ) 0 0 5 3 7 - 9
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Also, the question as to whether MCS and other manifestations of so-called ‘Idiopathic Environmental Intolerance’ must be called ‘illness’ or ‘disease’ (Lloyd et al., 2000) is linked to the specific vocabulary of the English language. Such distinctions do not exist in other languages, which is an important aspect, as all expressions of symptoms in human behavioural toxicology are closely connected with language. As defended by Loblay, these manifestations, in the absence of a clear understanding of the underlying pathophysiology, should be described as ‘‘illness’’ rather than a disease (Jennings, 1986). ‘‘Illness’’ is understood as a subjective state of suffering— physical, psychological and social—and can only be understood and defined with reference to the sick individual (Cassell, 1991). In this sense, people with MCS are mostly regarded as being ill, independent of the question as to whether an underlying disease process has been identified (Lloyd et al., 2000). There is overwhelming consensus within the scientific community that patients labelled with MCS are clearly distressed, and that many are functionally disabled (Sparks et al., 1994a,b).
2. MCS as a clinically defined disease? In 1996, a WHO/IPCS workshop in Berlin arrived at the following conclusion (Anonymous, 1997): ‘‘The term MCS should be discontinued because it makes an unsupported judgement on causation. Although there exist several definitions of what has been called MCS, it cannot be regarded as a clinically defined disease. There are neither accepted theories of underlying mechanisms nor validated clinical criteria for diagnosis. A relationship between exposure and symptoms is unproven.’’ This calls for fulfilment of the following three points to define MCS as a clinical entity, and we have to put forward the question whether these points are now being met: establishment of diagnostic criteria, identification of pathogenic mechanisms, together with an
explanation of relationship between exposures and symptoms.
3. Diagnostic criteria and relation between exposures and symptoms Very often, there is advocating of lack of ‘objective’ diagnostic criteria for MCS, such as laboratory tests (Sparks et al., 1994b). This alone does not seem to be a valid argument against existence of a clinical entity as this refers to many psychiatric diseases. Nobody would question depression or schizophrenia as clinical entities although there is no laboratory test supporting the diagnosis; the symptoms are entirely of behavioural and ‘subjective’ nature. Therefore, subjective symptoms are a legitimate basis of a clinical diagnosis when the pathogenic mechanisms are exclusively confined to the human brain. Based on the symptoms presented by the patient, there are commonly used ‘case definitions’ for MCS which are based on Cullen’s criteria (Cullen, 1987). These diagnostic criteria are also accepted by opponents of MCS being a clinical entity (e.g. Sparks et al., 1994b; Lax and Henneberger, 1995; Altenkirch, 2000), with the provision that Cullen attempted to define MCS primarily for research purposes: The disorder is acquired in relation to some environmental exposure, insult, or illness that is reported by the patient. Symptoms involve more than one organ system. Symptoms recur and abate in response to predictable stimuli. Symptoms are elicited by exposures to a variety of chemicals. Symptoms are elicited by exposures that are demonstrable. Exposures that elicit symptoms must be very low and are normally tolerated by others. Other likely causes of the observed symptoms are excluded. A cross-sectional survey by Nethercott et al. (1993) of 148 medical practitioners in Baltimore, MD, has revealed the following ranking of criteria selected as major for diagnosing the syndrome by more than 50% of the respondents:
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1. Symptoms are reproducible with exposure. 2. Condition is chronic. 3. Low levels of exposure result in manifestations of the syndrome. 4. Symptoms resolve with removal of incitation. 5. Responses occur to multiple, chemically unrelated substances. In this ranking reproducibility with exposure had been placed first, and this was considered ‘irrelevant’ by only 6% of the physicians. Both sets of criteria are based on two major sources of information: symptoms, generally of subjective nature, and exposure, of fictitious objective nature. Because in clinical diagnostic situations valid information on exposure is extremely rarely available, the dilemma of possible misdiagnosis has to be stressed. Relevant toxic exposures may be overlooked because the symptoms are similar to those commonly seen in psychic disorders. Conversely, subjective exposure information without a real toxicological background might lead to the misdiagnosis of a chemical-induced illness (Kiesswetter, 1998/1999). Whether the criteria tabled above, including ‘reproducibility with exposure’, are sufficient to diagnose MCS, remains an issue that has to be debated in view of specific models that could explain the relationship between exposures and symptoms.
4. Pathogenic mechanisms A central part of the Debate, from a toxicological point of view, was the question: which mechanisms of pathogenesis of MCS could be established. Models are straightforward that relate MCS to olfactory, especially trigeminal, stimuli, distinguishing between two stages of stimuli processing, sensory and nonsensory (Doty et al., 1988; Dalton and Hummel, 2000). Following this type of modelling, the way of cognitive processing, and not that of olfactory chemosensation, makes the differences between MCS patients and the rest of the population. The difference is related to a fundamental function of the brain the reduction of complex incoming information. During and after
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projection of sensory and environmental surrounding information upon the respective cortex regions, selection and interpretation processes are postulated, which are triggered by attention, the perceptional, behavioural and cognitive state, and by personal pre-existing traits (Dalton and Hummel, 2000). A key element in computation of the final output or decision is the memory that again is under influence of pre-existing states and traits (Fig. 1). Models of olfactory and cognitive–perceptual mediation allow explanation of why multiple, and chemically unrelated, compounds elicit similar MCS symptoms, subjective and physiological. If we reflect these mechanisms in terms of MCS, we can define two major factors in pathogenesis of the disease. On one hand, there are personal pre-existing traits (Kiesswetter et al., 1999), while on the other hand there is a specific stimuli anticipation and processing, being influenced by the perceptional, behavioural and cognitive state of the individual. Both induce a ‘pathological’ cognitive processing, finally leading to the evolvement of the behavioural and vegetative symptoms of MCS (Dalton and Hummel, 2000).
5. Pre-existing states and traits (‘‘s-MCS’’) For toxicological research purposes, we are able to define a specific subgroup within the population, which is susceptible to MCS development (Fig. 2). The specific susceptibility is related to a very stable personal trait, characterised by trait anxiety and negative affectivity (Kiesswetter et al., 1998, 1999), with a preponderance of the female gender (Fiedler and Kipen, 1997). The susceptible subgroup can be identified by means of psychological questionnaires (Kipen et al., 1995; Kiesswetter et al., 1997), and is now mostly being addressed as persons with ‘‘self-reported MCS’’, or ‘‘sMCS’’ (Kiesswetter et al., 1998, 1999). The questionnaire called ‘‘CAUS’’ in Germany (in English ‘‘Chemical and General Environmental Sensitivity, CGES’’) was developed in 1993 and covers 67 items (Kiesswetter et al., 1997). Operationally, a person is regarded as belonging
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to the sMCS group, if one of the critical items, regarding to extreme responses to defined olfactory stimuli, is answered positively. Alternatively, a quantitative ‘‘sMCS rating’’ based on a sum scale is applied, and the sMCS subpopulation is defined as persons with a rating above an explicit cut-off point. This refers to 10% of the normal population, and the percentage is only slightly higher in patients suffering from alcohol disease or psychosomatic disorders (Kiesswetter et al., 1998), which is also consistent with findings of others (Fiedler and Kipen, 1997). Interestingly, there is a high selection of the susceptible subgroup among patients in Germany coming to our institute with the question of compensation of the German Occupational Disease no. 1317, which inter alia comprises the psychoorganic syndrome due to solvents or other neurotoxic agents (Kiesswetter et al., 1999). In a laboratory experiment (van Thriel et al., 2000), groups of 12 persons rated ‘‘sMCS’’ subjects, as well as 12 non-sMCS controls were exposed to fluctuating concentrations of either 2-butanone, a ketone with irritating properties at
higher concentrations, or ethylbenzene, a hydrocarbon with a typical aromatic smell. The mean concentrations over time were equivalent to the German Occupational Exposure Limit, and the short-term excursion factor of the peaks was 2, also in compliance with current German workplace regulations. For comparison, ‘‘low exposures’’ were at 10 ppm for both compounds, which is higher than the olfactory threshold, but clearly below any toxicological effect. Inter alia, the time course, within the peak exposure periods, of nasal irritation ratings was recorded. Very strikingly, sMCS persons responded to both compounds with much higher reporting of irritation than the control group did. At the beginning of the peak exposure episodes, sMCS persons displayed slightly higher respiratory and heart rates than controls, indicative of influences on vegetative functions in this subgroup (Haumann et al., in press). In principle, this is consistent with earlier findings of Doty et al. (1988). After having completed the different exposures with 2-butanone or ethylbenzene, the nasal flow in the sMCS and control group was assessed by
Fig. 1. Psychophysiological characteristics of MCS.
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Fig. 2. Persons with ‘‘sMCS’’, characterising a specific subgroup susceptible for MCS.
anterior rhinomanometry (Wiesmu¨ ller et al., in press). Irrespective of the mode of exposure— high or low, 2-butanone or ethylbenzene— there was a general decrease of nasal passage in sMCS persons, pointing to a higher sensitivity with respect to this autonomic function. Current results of the studies at the Institute for Occupational Physiology in Dortmund are supplemented by those of the research team of F. Rist, University Muenster, with a strong focus on cognitive and psychosomatic aspects of MCS. Cognitive–behavioural models of psychosomatic disorders suggest attentional processes as a central element of pathogenesis. According to this approach, specific perceptional styles are responsible for ‘somatosensory amplifications’. To test this hypothesis, selected student samples with high and low sMCS scorings (according to CAUS: Kiesswetter et al., 1997) had to name, as fast as possible, the colour of single words displayed on a computer screen. The words were pre-selected and had either potentially threatening environmental (e.g. ‘‘insecticide’’) or neutral meanings (e.g. ‘‘towel’’). When solely referred to words with environmental threatening contents, the response time of the sMCS sample was significantly longer, compared to that of the non-sMCS sample (Nischk et al., in press). Although persons designated ‘‘sMCS’’ were not ill, from a theoretical point of
view they represent a risk group to develop environmental related disorders because of their selective attention.
6. Dose–response relationship If we put these and other findings into a perspective in terms of dose–response, we arrive at the dose– effect relationship shown in Fig. 3. It is evident that the classical pharmacological and toxicological dose–effect rules are not valid for MCS responses to chemical stimuli. Occupational exposure levels are set well below toxicologically defined NOAEL levels. As a general rule, the olfactory threshold is located much lower than the
Fig. 3. Olfactory threshold model for dose-dependence of MCS symptoms.
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NOAEL. As the eliciting of MCS symptoms is connected with chemosensory functions we arrive at an olfactory threshold model for the dose– response of MCS. There are obvious formal similarities between this type of dose–response and the dose– response towards allergens in sensitised persons: in both cases we realise a threshold model, but with the low threshold only for a subset of the general population. This subset reacts at concentrations that are normally tolerated. In relation to the criteria set by the initially mentioned WHO/IPCS workshop (Anonymous, 1997), it appears: We now start to realise the existence of a psychophysiological theory of mechanisms underlying MCS, which also explains the relationship between exposure and symptoms. There is diversity of opinions as to whether the criteria for diagnosis of MCS are sufficiently validated.
7. General toxicological and pharmacological perspective Argumentations on MCS at an International Congress of Toxicology would be incomplete without giving tribute to the contributions of the late Ernst Habermann who passed away early this year (Obituary, 2001). As professor of pharmacology and toxicology of the Justus-Liebig-University in Giessen, Habermann had put particular effort into developing and promoting his model of the ‘‘nocebo’’ (Habermann, 1998, 1999a,b; Fig. 4). On one hand, a substance may have either wanted or unwanted ‘‘chemical’’ effects which determine it to be either drug or poison. European pharmacology has called these: effects of the ‘‘verum’’. On the other hand, there are associated ‘‘psychosocial’’ effects, again wanted, characterising the eliciting compound as a placebo, or unwanted, making it a nocebo. All these effects, those of the placebo/nocebo and of the verum, are considered real. In terms of biomedical research, the 21st century has been called ‘the century of the brain’.
Fig. 4. The message of the late Ernst Habermann.
Hence, if a disease is regarded as ‘psychogenic’, we have to look at brain physiology and psychophysiology; and major breakthroughs are to be noticed in these fields. We currently witness a clear process that the traditional paradigm of a dichotomy between the antipodes psyche and soma is fading. In his last publication on this issue, Habermann (2000) has made particular reference to a publication by Ploghaus et al. (1999). The experience of pain is subjectively different from the fear and anxiety caused by threats of pain. Functional magnetic resonance imaging (fMRI) was used in this paper to dissociate neural activation patterns associated with acute pain and its anticipation. Twelve healthy volunteers underwent fMRI while being presented with a pseudo-random sequence of two intensities of thermal stimulation (either painful ‘‘hot’’ or non-painful ‘‘warm’’). Coloured lights signalled in advance the two kinds of stimuli, and the subjects learned during the imaging session which colour signalled pain and which signalled warmth. Interviews after the experiment confirmed that all subjects were aware of the relation between the light colour and the intensity of the stimulation. Brain regions with functional activities characteristic of pain were identified by comparison with those of the ‘‘warm’’ situation, and regions with functional activities characteristic of pain anticipation were identified in comparison with those of anticipation of warmth. Within the entire network of activation, particular brain
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regions were identified where responses to pain could be differentiated from those to anticipation of pain, on the basis of neuroanatomical localisation and the time course of the fMRI signal change. These regions were located in the medial frontal lobe, the insular cortex and the cerebellum (Ploghaus et al., 1999). Based on this very recent piece of work, Habermann (2000) made the point that an objective comparison between a verum effect, the thermally induced nociception, and a nocebo effect, the anticipation of nociception, has been achieved. In the experiment described by Ploghaus et al. (1999) the brains of the test persons used ‘‘identical programmes to process the differing data sets of verum and nocebo’’. Habermann (2000) commented this as being indicative of the current convergence of psychology and neurophysiology that make the 21st century the ‘‘century of the brain’’. This aspect seems fundamental to a pathophysiological understanding of MCS and related diseases. It also sheds new and a very modern light on what had been expressed by William Shakespeare some 390 years ago (Zilker 1999). In ‘‘The Winter’s Tale’’, 2nd act, 1st scene, King Leontes of Sicily tells the image of the spider: ‘‘There may be in the cup A spider steep’d, and one may drink, depart, And yet partake no venom ( for his knowledge Is not infected); but if one present Th’ abhorr’d ingredient to his eye, make known How he hath drunk, he cracks his gorge, his sides, With violent thefts. I have drunk, and seen the spider.’’
8. Conclusion The question as to whether MCS should be regarded as a clinically defined entity is controversial. However, important progress can be noted in elucidating and defining the nature of this phe-
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nomenon. This progress requires a combined effort of different disciplines (toxicology and behavioural toxicology, psychology and psychophysiology, and clinical medicine). MCS is not a conventional toxicological phenomenon, according to Paracelsus. It has a distinct psychophysiological background that explains the lack of classical dose-dependency. But it also explains, in responding individuals, its reproducibility with exposure. Not the venom of the spider is causing this effect: it is the anticipation of the venom, the ‘‘infection of the knowledge’’ according to Shakespeare (vs.), or the nocebo according to Habermann.
Acknowledgements The authors acknowledge the assistance of the Behavioural Toxicology group of IfADo Dortmund: A. Seeber, Ch. Van Thriel, M. Zupanic, B. Sietmann, and K. Golka.
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