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Chapter

Multiple chemical sensitivityMalcolm Hooper

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INTRODUCTION

Multiple chemical sensitivity (MCS) is a complex, multi-symptom, multi-system multi-organ illness that is inducedby exposure to a wide variety of toxic environmentalinsults. It is often co-morbid with other overlapping syndromes and evokes a similar range of symptoms (Table 50.1).1–5

WHAT’S IN A NAME?

MCS goes under many names and overlaps with manyother syndromes and conditions (see Table 50.1). The mostfrequently used terms recognize that chemicals and theenvironment are understood by the affected people to beassociated with their disabling illnesses. Among the over-lapping syndromes are disorders, diseases and misdiagnosesthat any competent physician would be expected to iden-tify, for example coeliac disease, carbon monoxide poison-ing and hypothyroidism.

Other descriptors are drawn from particular locations, forexample ‘Gulf War syndrome’ (GWS) from the first GulfWar (1990–91) and ‘new buildings syndrome’ with new fur-nishings. Occupations such as carpet-fitting, commercialflying and cabin crew, and shepherding are associated withthe same constellation of symptoms. Other descriptors indi-cate the comprehensive nature of the illness and try toplace it within known clinical conditions such as allergy.More specific terms seek to identify the mechanism of theillness (e.g. toxicant-induced loss of tolerance, TILT) orcause of the illness (e.g. systemic candidiasis). An interest-ing inclusion in the list is electromagnetic sensitivity; thisoften follows chemical exposure but can be a primaryevent.6,7

The bewildering number and origins of so many namesreflects the problems of grappling with such a complex ill-ness and trying to understand it in order to effectively diag-nose and treat patients who have it.

The World Health Organization (WHO) classifies MCSunder chapters S00–T98 – injury, poisoning and certainother consequences of external causes, specifically at T66–78 – other unspecified effects of external causes and T78.4

– allergy, unspecified; hypersensitivity not otherwise speci-fied (NOS), idiosyncracy NOS. Among the exposures specif-ically listed are pesticides of various chemical types,fungicides and rodenticides, although the important chemi-cals polychlorinated biphenyls (PCBs) are not included(Table 50.2).8

This confusion is reflected in the prolonged and some-times acrimonious debate that surrounds MCS and involvesclinicians, patients and patient support groups, anddemands for recognition from governments, the chemical,pharmaceutical and insurance industries, and regulatoryauthorities in many countries.

DEFINITION AND DIAGNOSTICCRITERIA

DefinitionThe 1999 consensus is widely accepted and defines MCS asfollows:9

● A chronic condition● With symptoms that recur reproducibly● In response to low levels of exposure● To multiple unrelated chemicals● Improves or resolves when incitants are removed● Symptoms occur in multiple organ systems.

The major symptoms of MCS are summarized in Table50.1, but a more extensive list is given in Table 50.3.

Objective clinical signs have been identified in a widevariety of tissues and clinical systems in MCS (Box 50.1).

DiagnosisDiagnosis should be made in the light of the above criteria.A comprehensive paper by Heuser emphasizes the need forthe following:10

● A very thorough history● A thorough physical examination, with special attention

to the skin, blood pressure (orthostatic hypotension),movement and coordination

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794 Multiple chemical sensitivity

● The use of appropriate clinical, laboratory and psycho-logical tests.

Single-proton-emission computed tomography (SPECT),positron-emission tomography (PET), magnetic resonanceimaging (MRI)11 and quantitative electroencephalography(qEEG) all provide details of any abnormal lack of functionin the central nervous system. Magnetic resonance spec-troscopy (MRS) also provides a powerful tool that has iden-tified brain damage in veterans of the first Gulf War.12

Current perception threshold studies are especially impor-tant in investigating the peripheral nervous system, as they

assess the small but important C-fibres (see below).Autonomic function needs to be assessed with regard totemperature, perspiration, vascular tone, heart rate, smoothmuscle tone and other functions. The eyes are important,since dry eye syndrome is common in MCS. Ear, nose andthroat complaints are also common and need to be investi-gated fully, as nasal and pulmonary passages are frequentlydamaged or dysfunctional. Gastrointestinal problems occurregularly, with malabsorption and weight loss. Liver func-tion tests are valuable, while low salivary immunoglobulinA (IgA) levels often indicate an impaired mucosal defencemechanism. Kidneys and the urinary tract may be

Table 50.1 Names used to describe multiple chemical sensitivity (MCS) and overlapping syndromes

Aspects of environmental sensitivities Commonly overlapping conditions

State of heightened reactivity to the environment Fibromyalgia

Total allergy syndrome Myalgic encephalomyelitis (ME), chronic fatigue syndrome

Universal allergy Postviral fatigue syndrome

Toxicant-induced loss of tolerance (TILT) Post-infectious neuromyasthenia

Multiple chemical sensitivity(ies) (MCS) Yuppie flu

Multiple chemical hypersensitivity(ies) Chronic pain

Chemical intolerance(s) Migraine

Chemical acquired immunodeficiency syndrome (AIDS) Arthritis

Gulf War illness/syndrome (GWI/S) Allergies

Idiopathic environmental intolerance (IEI) Rhinitis

Environmental illness (EI) Asthma

Environmental irritant syndrome Food intolerance syndrome

Chemical injury/allergy Coeliac disease

Toxic injury Irritable bowel syndrome

Tight building syndrome Major depression

Sick building syndrome Anxiety or panic disorder

Twentieth-century disease Hypothyroidism

Chemically induced illness Aerotoxic syndrome

Chemical hypersensitivity syndrome Organophosphate poisoning

Chemophobia Sheep-dipper’s flu

Electromagnetic (hyper)sensitivities/intolerance Disorders of porphyrin metabolism

Toxic carpet syndrome Carbon monoxide poisoning

Systemic candidiasis

Multiple sensory sensitivity syndrome (MUSES)


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damaged; haematuria should be checked, together withother markers of kidney function. The skin is frequentlyaffected, with rashes, itching, welts, hives, flushing, bloodblisters and dermatitis. Immune function needs to bechecked and investigated, with immunoglobulin E (IgE) andeosinophil measurements, and specific cells (e.g. CD3,CD26) counted. Autoimmune disease markers should belooked for, for example phospholipids and nuclear antibod-ies. The endocrine system is commonly disabled or dysfunc-tional, and so thyroid, cortisol and dehydroepiandrosterone(DHEA) tests are important.

Psychological tests of motor activity, sensory function,memory and cognition are all valuable.13,14

Only when all this has been done may a psychiatric orpsychogenic diagnosis be considered in the light of possibleco-morbid emotional problems.15

INTERNATIONAL RECOGNITIONOF MCS

MCS is increasingly recognized by legal and medical sys-tems. It was first officially recognized in Germany anddescribed, using the WHO’s ICD, as ICD-10-SGB-V,November 2000, under the code T78.4, ‘allergy, otherwisenot specified’.16 Reports from Australia17 and Denmark18

have also been published. The Australian report includes aliterature assessment, evidence from 22 witnesses, and 167written submissions from Australia and overseas. It makes arecommendation for classification of MCS under its own

Table 50.2 World Health Organization International Classification of Diseases,10th revision (ICD-10) classification of various toxic chemicals

T60.0 Toxic effect of organophosphate and carbamateinsecticides

T60.1 Toxic effect of halogenated insecticides

T60.2 Toxic effect of other insecticides

T60.3 Toxic effect of herbicides and fungicides

T60.4 Toxic effect of rodenticides

T60.8 Toxic effect of other pesticides

T60.9 Toxic effect of pesticide, unspecified

X48 Accidental poisoning by and exposure to pesticides

X68 Intentional self-poisoning by and exposure topesticides

X-87 Assault by pesticides

Y-18 Poisoning by and exposure to pesticides

Note: ICD-10 does not have specific codes for disinfectants. To finddisinfectant poisonings, try T54, X49, X69, X87 and &19, which are codes forcorrosive and noxious substances.

Table 50.3 Symptom list* compiled by the JHU Multi-Center study of multiplechemical sensitivity (MCS) immunology

Cardiovascular 9

Digestive 18

Ears/hearing 7

Eyes/vision 12

Genitourinary 10

Head 6

Mouth/taste 14

Musculoskeletal 14

Neck 3

Nervous system 43

Nose/smell 10

Systemic/others 17

Vascular 5

Reproductive 17

Respiratory 6

Skin/touch 7

Throat 5

Total symptoms 203

*Number of symptoms associated with the different organs/systems listed.

Box 50.1 Objective clinical signs reported inmultiple chemical sensitivity

● Abnormal blood and plasma● Impaired circulation● Impaired heart function● Impaired detoxification pathways● Ear and hearing abnormalities● Endocrine deficiencies● Gastrointestinal impairment● Immune system activation● Increased mast cells● Mineral deficiencies● Musculoskeletal abnormalities● Neurocognitive deficiencies● Nose and smell abnormalities● Porphyrin enzyme abnormalities● Respiratory impairment● Sensory nerve impairment● Vestibular impairment● Vitamin deficiencies● Xenobiotics in fat, blood, urine and hair.



modification of the WHO codes as ICD-10-AM. The Danishreport is more limited, drawing largely on a publishedreview assessing the situation in the UK.19

In North America, MCS is widely recognized. In the USA,official recognition takes the form of reports from theDepartment of Justice, the Department of Housing andUrban Development, and the Department of Education,which accept MCS as a legitimate condition for their pur-poses. Medical resistance to MCS has begun to evaporateamong the American College of Physicians.20 The AmericanMedical Association and American Lung Association andEnvironmental Protection Agency state that ‘Claimantsshould not be dismissed as psychogenic and a thoroughworkup is essential ...’ Large population surveys report 16–33 per cent of people as being sensitive to everydaychemicals.

In 1998, 25 US federal and 28 US state authorities werelisted and summaries of medical and legal/compensationpapers and cases provided. Canada has recognized MCS inten state authorities21 and has published a major review ofthe evidence linking its recognition to human rights.22

In contrast, official sources in the UK have been resistantto any recognition of chemical sensitivity. The BritishSociety for Allergy, Environmental and NutritionalMedicine (BSAENM; now the British Society of EcologicalMedicine, BSEM) has published substantial evidence inrecognition of MCS as an organic illness that can be diag-nosed and treated effectively.23,24 Although MCS does not fitcomfortably into current views on allergy, the RoyalCollege of Physicians’ report Allergy: The Unmet Needrecords a huge increase in allergy in the UK.25 Currently oneperson in three in the UK has some form of allergy, a totalof 18 million people; of these, some 3 million have severeallergies. The Royal Commission on EnvironmentalPollution identified the need for a proper understanding ofthe health effects of novel chemicals used widely and dis-tributed ubiquitously in the environment.26 A further reportby the Royal Commission endorsed the validity of GWS,myalgic encephalomyelitis (ME; chronic fatigue syndrome,CFS) and MCS in its appendices.22 The Research AdvisoryCommittee on Gulf War Veterans’ Illnesses from the USAsummarized epidemiological studies indicating that 28–32per cent of veterans from the first Gulf War are now ill withsymptoms, including MCS.27

Veterans of the first Gulf War represent large cohorts offit, young, mainly male military personnel from the USA (n= 697000) and the UK (n = 53 000) who were exposed to awide variety of biological and chemical toxins.28 Such largenumbers of personnel allow considerable statistical analysisof their illnesses (GWS). There is extensive evidence ofdamage to the central, autonomic and peripheral nervoussystems, to the cardiovascular system, and to other organsand bodily systems, and there is evidence of birth defects insome offspring.

In Sweden, electrosensitivity is officially recognized butis seen as a condition rather than a disease.

PREVALENCE OF MCS ANDESTIMATED COSTS IN THE USA

The confusion and lack of uniformity in trying to assess theprevalence of MCS in various communities makes any fig-ures open to questioning; however, various large popula-tion surveys report 16–33 per cent of people being sensitiveto everyday chemicals, with the best estimates coming fromstudies and reports in the USA (Table 50.4).29

Table 50.4 Prevalence of multiple chemical sensitivity (MCS)

Reference % with MCS

Bell et al.31 15

Bell et al.32 17

Meggs et al.33 33

Voorhees34 17

Bell et al.35 30 (Gulf War veterans)

Kreutzer et al.36 15.9 (doctor diagnosed 6.3)

Caress and Steinemann37 12.6

Caress and Steinemann38 11.2

Caress and Steinemann39 11.2 (doctor diagnosed 7.4)

All studies report MCS as more common in women but not associated withsocioeconomic status.

Source: Centers for Disease Control and Prevention.30

A surprising number of people report sensitivity to ordinaryeveryday chemicals. The figures range from an average of elevento seventeen percent, with spikes as high as thirty percent ofsubjects who report reactions to multiple chemical incitants.The figures reveal that at least two percent, and as many as sixpercent, have been so bothered by chemical exposures that theysought medical care and received a doctor-diagnosis of multiplechemical sensitivity (MCS). Applying the case definition criteriato the average reported chemical sensitivity, it appears that 1.5out of 10 people suffer from MCS. Health care utilization costsdirectly related to MCS have been estimated at approximately$1581 annually per patient. The United States population isestimated to be 302.8 million. Prevalence studies predict thatapproximately 15% of the United States population, now esti-mated at 302.8 million, suffers from MCS; therefore, directhealth care utilization costs amount to a staggering $71.8 bil-lion dollars per year. Estimated costs for MCS and other disor-ders linked to neurotoxicity amount to an additional $81.5 to$167 billion annually in lost productivity. Cumulative social andeconomic costs identified in four case studies of illnesses thatare candidates for environmental causation totalled between$568 billion and $793 billion dollars per year.30


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By any criteria, the impact of MCS on individual andcommunity health and the cost to the nation (healthcarebudgets) and those directly concerned with the illness(carers and dependants) is considerable.

CHEMICALS INVOLVED

The number and nature of chemicals associated with MCS is huge and covers many different chemical classes, bio-logical activities and sources. Table 50.5 summarizes themajor chemicals, their sources and their biological activi-ties.21,29,40–43 American national studies commenced in 1999,but so far these cover only 148 different compounds.30,44

There are important concerns about how to interpret thedata and the need to avoid a one-size-fits-all approach. It isnecessary to take into account individual factors, includingabsorption, distribution, metabolism, excretion, genetics,age, sex, environment and nutritional status.45

Various studies have found extensive chemical contami-nation of people throughout the world.46–48 Of particularinterest is the identification of hundreds of toxic com-pounds in cord blood, indicating that even in utero, whencellular replication is at its greatest, there is no protectionagainst many very toxic compounds.49,50

Of special note is a report that identified 287 differentchemicals in cord blood from newborns. Of these chemicals,217 were toxic to the brain and nervous system, 208 couldcause developmental problems, and 108 cause cancer inhumans and animals.50 American organizations haveemphasized the connection between mental retardation andother developmental disorders, including autism-spectrumdisorders, and learning and developmental conditions inchildren,48,51 and they stress the lack of any testing of indi-vidual chemicals and mixtures for these disorders. Chronicneurological and neuropsychiatric conditions are increasingin older people, possibly as a result of the massive increasein environmental toxins.52

The problem was first highlighted in Rachel Carson’sgroundbreaking work Silent Spring,53 which was then fol-lowed by other publications.54 Many compounds have beenwithdrawn but, because of their persistence in the environ-ment and people, contamination is now widespread. Forexample, PCBs were banned in 1979 in America, but peopleborn after that date are commonly contaminated with thesecompounds.

A comprehensive study provides considerable data onextensive biological damage to fertility, intelligence andsurvival as a result of the untrammelled use and irresponsi-ble spread of numerous untested environmental chemicals.55

Table 50.5 Major classes of chemicals associated with multiple chemical sensitivity (MCS)

Chemical class Known biological activities Common sources/uses

Highly substituted, poly- or per-halogenated Carcinogenic, mutagenic, kidney and Household and agricultural pesticides as organic compounds with chlorine, bromine or liver damage, endocrine disruption sprays and dusts, electrical insulation, fluorine atoms*, e.g. DDT, DDE, lindane, flame-retardants, non-stick kitchen utensils, hexachlorobenzene, hexachlorocyclohexanes, stain-resistant fabricsPCBs, aldrin, dieldrin, PBDEs, perfluorooctanoic acid polymers and derivatives

Organophosphates, nerve agents Nerve toxins, immune dysregulation, Various pesticides in agriculture, fisheries, inhibition of key enzymes herbicides, engine oils

Phthalates, nonylphenol, bisphenol A and B* Endocrine disruption Polymers, plasticizers, toys, babies’pacifiers, dialysis tubing

VOCs, aliphatic and aromatic compounds*, Disruption of brain function, nerve Ubiquitous in fragrances, perfumes, formaldehyde, aldehydes, esters, ketones, damage, carcinogenic household goods, solvents, fuels, paints, acids, alcohols, toluene polymers

PAHs Carcinogenic, mutagenic Burning fuels, exhaust fumes, powerstations

Heavy metals: mercury*, lead, cadmium, Neurotoxicity, tissue damage, endocrine Anti-fouling paints, fuels, preservatives, arsenic, organometallics, tributyltin* disruption pesticides, electrical goods, crematoria

*Bioaccumlative and biomagnified through the food chain.

DDT, dichlorodiphenyltrichloroethane; DDE, dichlorodichlorophenylethene (major metabolite of DDT); PAHs, polyaromatic hydrocarbons; PBDEs, polybromodiphenylethers;PCBs, polychlorobiphenyls; VOCs, volatile organic compounds.



The challenge is to understand:

● how such diverse chemicals can provoke very sensitiveresponses to chemically unrelated compounds – thisraises new question about drug and chemical receptorsand how they operate;

● how very low levels of exposure well below those affect-ing the majority of people can provoke such extensiveand profound biological effects – this questions the basicunderstanding of toxicology, particularly the relation-ship between dose and response and genetics;

● how the damage to one generation can be transmitted tosucceeding generations.

In response to these challenges, new mechanisms of drugand chemical action have been proposed, coupled withtechnologies that provide hidden details of bodily systems,particularly the brain. A further challenge is to understand:

● how so many different chemicals, which have not beenevaluated for adverse biological effects, have come to bereleased for general use;

● how novel chemicals can be assessed effectively beforerelease into general use.

In response to these challenges, new regulatory systemshave been advocated, particularly Registration, Evaluation,Authorisation and Restriction of Chemical Substances(REACH) in Europe.56 In the USA, action is being demandedto establish a similar regulatory authority.57

Estimates from various sources indicate that 80 000–100 000 compounds currently used commercially and dis-tributed in a wide variety of products have never beenassessed toxicologically or have been assessed only assingle entities and not in the complex mixtures in whichthey are delivered in most products.58–60

Clearly, in addition to the concerns about health, thereare important commercial, political and economic consider-ations around the use and development of chemicals intoday’s world. There is no doubt that there is considerablevested interest and even secrecy when MCS is being consid-ered, not unlike the activities and attitudes around tobacco-smoking, nuclear power, and genetically modified (GM)crops. A big divide lies between those espousing a purelypsychogenic, psychiatric or psychological understanding ofthe illness and those seeking to understand the illness as anorganic illness with a clear biological basis.

PSYCHOGENIC, PSYCHIATRICAND PSYCHOLOGICAL VERSUSTHE BIOLOGICALUNDERSTANDING OF MCS

This is well exemplified by the following titles:

● ‘Allergic to life: psychological factors in environmentalillness’61

● ‘In search of non-disease’.62

In marked contrast are the following:

● Stop the 21st Century Killing You63

● Chemical Exposures: Low Levels and High Stakes64

● Chemical Sensitivity, a large medical publication in fourvolumes with an allied website.65

The website ‘Chemical sensitivity in mainstream medicaldocumentation’ considers all aspects of the debate aboutMCS, with a strong emphasis on the implications for peoplewho are affected by MCS.66

A major two-stage population study of MCS found thatonly 1.4 per cent of the population studied had emotionalproblems before exposures occurred, but that after thedevelopment of MCS 37.7 per cent of the population hademotional problems, indicating that MCS had a biologicalrather than psychogenic origin.25 This is hardly surprising,since any chronic illness is likely to precipitate emotionalproblems.

THE DEBATE

MCS and other illnesses from a variety of medical special-ties have been described as functional somatic syndromes5

in order to provide a comprehensive scheme for under-standing these complex and little-understood conditions/illnesses. This approach has been severely criticized as adisguise for medical ignorance that seeks to label emergingillnesses as psychiatric when they present with symptomsvery different from those of established mental illnesses:

It must be noted that there is no proof that it is justified toapply the label somatisation to such conditions as chronicfatigue syndrome and several more illnesses that establishedmedicine has so far failed to explain scientifically... Don’t hesi-tate to ask questions about scientific evidence behind this talkabout somatisation. Be persistent, because a diagnosis of soma-tisation is definitely not an innocuous label. It will close variousdoors and lead (to) treatments that usually get nowhere.14

Somatization has a poor track record, being used at onetime to ‘explain’ diabetes, Parkinson’s disease, multiplesclerosis and Grave’s disease. All of these now have clear,well-established biological foundations.46–49,67

The biopsychosocial theory is now offered as the basis forunderstanding these complex illnesses/conditions. How -ever, although this appears to embrace a more holistic view,one of its major critics states: ‘The biopsychosocial theorylacks an intellectually sound basis, and spells the failureand possible imminent extinction of modern psychiatry.’15

The intellectual basis for the biological understanding ofMCS is found in the neuroendocrine–immune (NEI) para-digm (Figure 50.1). This integrated communication systemincludes messenger molecules that are released in responseto a wide range of challenges. Since these challengesinclude stress, it is important that the impact of stress isrecognized in patients with MCS, but not by denying the


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biological impact of chemical exposures. Many patientswith MCS report high levels of stress if they are disbelievedor falsely accused when seeking medical help for this syndrome.

A German multicentre study on MCS examined 291 con-secutive out-patients between 2000 and 2003 in consider-able depth and concluded that:50

● there was no characteristic set of symptoms for MCS,although many symptoms and clinical signs were identified;

● there was no systematic connection between complaintsand any triggers;

● there was no evidence for any genetic predisposition butonly metabolic variations in specific alleles;

● there was no obvious disturbance of the olfactorysystem;

● patients with MCS suffered more often from mental disorders that had commenced ‘many years before environment-related health complaints’;

● ‘overall the study did not support a toxicogenic-somaticbasis of the MCS phenomenon’.

These serious and comprehensive conclusions contradictmany other studies.21,25,27,28,30,43 However, the same studynoted some real problems when engaging with MCS:

● A lack of biomarkers, which are now being identified inspecific cases68,69

● A lack of clear-cut parameters of dysfunction

● Case criteria were usually formulated only vaguely andwere open to multiple interpretations

● ‘... despite all efforts of standardisation ... such attempts[were] very limited in clinical-based studies ... for eachindividual case completely different examination may beused which makes standardisation of diagnostic proce-dures much more difficult’.50

This final statement points to two different approaches toenvironmental medicine: (i) a one-size-fits-all approachwhen considering a patient population and (ii) an approachthat sees patients as unique individuals who require indi-vidualized medicine for their effective treatment and support.

The study was restricted to volatile organic compound(VOCs) and olfaction and used the 1987 Cullen criteriarather than the more widely agreed 1999 consensus.42 Evenhere, an important study involving capsaicin, a classicalvanilloid receptor agonist, has been ignored; this studyconcluded:

Upper and lower airway symptoms induced by chemicals andscents represent an entity of chronic disease, different fromasthma or chronic obstructive pulmonary disease, with persist-ent symptoms, a reduced health-related quality of life andunchanged sensory hyperreactivity.70

Other papers conclude that the combined environmentalannoyance, smells and electrical equipment is a better pre-dictor of chemical intolerance71 and that above-averageodour discrimination ability was associated with lower rat-ings of odour intensity and nausea.58,59

There was no consideration of any possible influence ofextensive and multiple contamination by xenobiotics.People from Central Europe were found to carry the highestburden of such compounds.48

Additive and synergistic effects of such contaminationwere not considered. There was no consideration of mutagenic and developmental effects of chemical exposure.46–50,58,59,68–71

There was no consideration of possible brain damagefrom other widely dispersed toxins such as pesticides.44,72,73

No psychometric tests45,51 appear to have been carried out.Sickness behaviour is well-known to be associated withchanges in levels of important cytokines that influence thebrain–immune axis,60 but this does not appear to have beeninvestigated.

Overall, the firm conclusions are less secure than theymay at first appear.

More recent papers report that exposure to VOCsincreases plasma levels of vasoactive intestinal peptide(VIP), substance P and nerve growth factors in self-reportedMCS patients (sMCS).74 Exposure to diesel fumes inducedboth Th-1 and Th-2 chemokines.75

A major conference hosted by the Chemical InjuryInformation Network (CIIN) provided a comprehensivesurvey of MCS with copies of important papers in the field.76

β-endorphins

Somatostatin

VIP

Substance P

Interferons, TNF-α

IL-1,IL-2, IL-6

Immune system

Circulating cellsCirculating molecules

GlandsTissues

Endocrine system

Circulating moleculesGlandsTissues

Central nervoussystem

Stationary cellsMessenger molecules

Tissues

CRH

ACTH

�-Endorphins

InterferonsThymic peptides

Interferons

and T

NF-α

IL�1,

IL�

6

Thym

ic pe

ptid

es�-En

do

rphins

ACTH

IL-2

Figure 50.1 The neuroendocrine immune comprehensive integrative defencesystem

ACTH, adrenocortiotrophic hormone; CRH, corticotropin-releasing hormone; IL,interleukin; TNF, tumour necrosis factor; VIP, vasoactive intestinal peptide.



possess tight cell junctions that severely restrict access ofcompounds from the blood into the brain. This is a protec-tive mechanism to restrict entry into the brain of biologicaland chemical toxins that may be ingested, inhaled or gener-ated by infection in other parts of the body or by injury.There are selective transport mechanisms that supply neu-ronal and other cells with essential nutrients.

Tight cell junctions occur in other tissues, particularly thegut and the lungs. This protection limits transport acrossthe gut wall (e.g. toxins and infections in food and water)and the lungs (e.g. inhaled toxins), but it is known to bebreached by many chemicals, including various pesti-cides.83–86 The blood–testes barrier is similarly breached.87

Microbial zona occludens toxins (ZOT) also open the tightcell junctions of the blood–brain barrier.88,89 Inflammatorycytokines90 and other peptide molecules are also effective.91

The bypassing of the blood–brain barrier by intraneu-ronal transport via the olfactory bulb allows toxins directaccess into the brain.79

A study in mice found that doses of parathion or perme-thrin at attomolar (10-18 molar) concentrations opened upthe blood–brain barrier and increased transport of a markercompound into the brain by about 20 per cent.92 These tinyquantities correspond to the amount of residue that wouldbe found on a single apple following spraying.

The blood–brain barrier is least efficient in the region ofthe paleolithic brain, and any leakage through the barrierwill be greatest in the basal ganglia, brainstem, thalamus,hypothalamus and pituitary gland.

Essential tissue barriers can be opened or bypassed byvarious mechanisms that are known to be associated withMCS and related overlapping syndromes.

CONCEPTS AND MECHANISMS

TriggeringMany people with MCS can identify an event when theyexperienced a large exposure to a toxic chemical, such as apesticide being sprayed outside or inside the house, a work-place exposure, an accidental spillage or an adventitiousagricultural spraying. This is followed by an increasing sen-sitivity to the same or related chemicals and then to quitediverse chemicals in very different situations. Gulf War vet-erans show an increased incidence of chemical sensitivityand MCS.66,77,78 More than 40 possible battlefield exposuresin 1990–91 have been identified,79 with the major onesbeing vaccines, pyridostigmine bromide (anti-nerve agentprophylaxis), pesticides (organophosphates, pyrethroids,lindane), nerve agents (sarin, tabun, VX), depleted uranium,oil and smoke.67 Frequently, veterans develop chemical sen-sitivity to perfume worn by their partners or children andpreviously enjoyed by the veteran, to alcohol and to petro-leum fumes, which previously was not a problem.66,80,81 Thechemistry of perfumes and petroleum products is extensiveand diverse and very different from that of pesticides, vac-cines and the major Gulf War exposures.

Chronic low-dose exposure to chemicals that may not beapparent to a person can also lead to MCS by a processknown as ‘kindling’.79 Rowat, as part of his proposed inte-grative defence mechanisms, defines kindling as follows:

Kindling refers to neural processes that mediate lasting changesin brain function in response to repeated, temporally spacedapplication of neurobehaviorally active agents.

Partial limbic kindling is a progressive and persistent lowering ofthe threshold for eliciting electrical after-discharges, but notmotor seizures, in certain brain structures such as amygdala andhippocampus; behavioral consequences include increasedavoidant behaviors.

The range of physical action for kindling includes various brainstructures, e.g. the cortex and especially the limbic brain includ-ing the olfactory bulb and amygdala. Changes in brain chemistryare found, including a decrease in acetylcholinesterase enzymeactivity that parallels the increase in sensitivity. Calcium- binding protein and tyrosine hydroxylase activity are reportedlyreduced, and there are changes in b-noradrenergic binding.Benzodiazepine receptor binding is modified, as are transmitterGABA [g-aminobutyric acid] and N-methyl-D-aspartate[NMDA] functions. Zinc may be implicated through GABA.Superoxide dismutase may also be involved. These changesmay be irreversible.15

The blood–brain barrierThe blood–brain barrier is the barrier of endothelial cellslining the blood vessels in the brain (Figure 50.2). The cells

Brain capillary

Endothelial cells

Water, oxygen,and glucose

Astrocyte

Neuron

Cerebrospinalfluid

Blood flow

Figure 50.2 Blood–brain barrier

Reproduced with permission from ref. 82


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Toxicant-induced loss of toleranceThe concept of TILT was proposed as a useful alternative toMCS in 199879 and was fully developed later.93 A commonmechanism is postulated for both drug addiction and multi-ple chemical intolerance, but with opposite responses –addiction (a demand for regular and repeated doses) andabdiction (avoidance of a substance). In both cases, theintent is to avoid withdrawal symptoms associated with alack or presence of the substance. The basic idea is set outin Figure 50.3, in which the normal response to a stimulant(e.g. caffeine) involves stimulation followed by recovery.Loss of tolerance leads to an increased response, whichleads to alternative strategies, abdication (avoidance) oraddiction (persistent reinforcing doses).

Allergy, neurogenic inflammation andswitchingThe association of MCS with allergy has been the subject ofconsiderable debate, concerned mainly with the definitionof allergy. One common scheme recognizes four kinds ofallergy and hypersensitivity:94

● Type 1: mediated by immunoglobulin E (IgE) and almostimmediate (2–30 min). May lead to systemic anaphy-laxis, which can be life-threatening, or to more localizedanaphylaxis (e.g. insect bites, hay fever, asthma, hives,eczema, food allergies). IgE interacts with specific cells(basophils, mast cells), which are stimulated to releasepotent vasoactive mediators such as histamine and leucotrienes.

● Type 2: antibody-mediated. The antibodies immuno -globulin G (IgG) and immunoglobulin M (IgM) attacksites on cell walls, leading to total destruction of the cell.This process takes 2–8 h. The cell damage or loss can bevery serious. Examples include blood-transfusion reac-tions and some types of anaemia.

● Type 3: involves antigen–antibody (IgG) complex forma-tion and takes 2–8 h. The antigen–antibody complex pre-cipitates in various tissues and induces an inflammatoryreaction. Examples include a number of chronic illnesses,including glomerulonephritis, rheumatoid arthritis andsystemic lupus erythematosus (SLE). A delayed responseto insect bites or vaccines may operate by this mechanism.

● Type 4: cell-mediated. Hypersensitivity is slow (24–72 h).It involves sensitized immune cells, special T-cells thatrelease chemical messengers (cytokines) that activateother immune cells, causing direct cell damage. Contactdermatitis, tubercular lesions and graft rejection areexamples.

Not uncommonly, a single chemical or group of chemi-cals can induce more than one type of allergic response, forexample penicillins can cause types 1–4 reactions.

Normal response

TILT(loss of tolerance)

Avoid withdrawal(2 strategies)

Avoid substancealtogether

Take substanceregularly

Abdiction Addiction

Figure 50.3 Toxicant-induced loss of tolerance (TILT): relationship betweenabdiction and addiction

Figure 50.4 Limbic system, showing the olfactory tracts

Miller, in making a case for TILT, relies heavily on thedata from various studies involving Gulf War veterans.81 Inparticular, she draws attention to the concomitant develop-ment of a number of cravings for chocolate, sugar and caf-feine in these veterans. This phenomenon has not beencommented on previously.

Another aspect of the proposed relationship betweenabdiction and addiction is that dopaminergic, 5-hydroxy -trypamine (5-HT) and opioid neural pathways in the brainare associated with addiction and the response to addictivedrugs and food. These same pathways are damaged in GulfWar veterans.

Volatile or aerosolized inhaled substances may be carriedby intraneuronal transport along the olfactory tract directlyinto the limbic system (Figure 50.4). This bypasses theblood–brain barrier and introduces compounds directly intodeep (silent) brain structures where many basic bodilyresponses are controlled.



Meggs and colleagues define allergy as a type 1 reaction.They regard MCS as the opposite side of the coin, sharing asimilar mechanism to allergy:95,96

● The response to an allergen or a chemical irritant is notlimited to the immediate site of application or entry. Forexample, about 2 per cent of people with asthma havetheir asthma triggered by eating certain foods or alco-hol.97 The inoculation of the gut leads to a response inthe lungs: Meggs calls this ‘switching’. Bee stings maycause a generalized reaction involving the whole bodyand not only the local area affected by the sting itself.Similarly, chemicals that are generally inhaled can causediverse symptomatology associated with the centralnervous system, headaches, pain, rashes and gastroin-testinal disturbances.

● Adaptation is a key four-stage construct in chemicalexposures that has been known from the 1950s. Theremoval of the offending chemical(s) will lead to recov-ery, except at stage 3:● Stage 0: exposures are tolerated without illness.● Stage 1: exposure leads to multiple complaints, e.g.

headache, nausea, itching, flushing.● Stage 2: inflammation occurs in one or more organs,

e.g. rhinitis, asthma, arthritis, myositis (inflammatorymuscle disease). Continued low-dose exposure at thisstage will propagate the inflammatory condition(s).

● Stage 3: fibrosis with tissue damage, irreversible lungdisease, advanced asthma, deforming arthritis, etc.All the major systems can be affected, including mus-culoskeletal, respiratory, cardiovascular, gastroin-testinal, genitourinary and nervous.

● Conditioning is a feature of MCS. In chemical sensitivity,the most common classes of chemicals to trigger a reac-tion are volatile and odorous. The odour threshold ismany times lower than the chemical irritancy threshold,and this may explain the large difference in exposurelevels that develop in people with MCS.

● Essentially, chemical irritants bind to receptors onunmyelinated sensory nerve C-fibres, which are found inthe gut, airways, eye and genitourinary system and aremore numerous in patients with MCS. Binding triggersan inflammatory response via an axon reflex, leading torelease of substance P and subsequently other localizedmediators of inflammation by interaction with mast cells(Figures 50.5 and 50.6).

Central pathways also activate parasympathetic or sym-pathetic nerves with effects on more distant organs.98

Meggs and colleagues make much use of data from stud-ies on Gulf War veterans; they report extensive intoleranceto petrol, diesel, oils and exhaust fumes.99 Many veteransdescribe their response as loss of awareness (‘spaced out’),loss of motor control and ataxia. In some cases, this was somarked that driving became dangerous. Some veterans areunable to fill up their vehicle at a petrol station because thiswould render them incapable of driving safely. Mortality

studies on Gulf War veterans show that there is an excess ofdeaths from motor vehicle accidents in this group.27

Although this has been dismissed by the UK Ministry ofDefence (MoD) and the US Department of Defense (DoD) asa legacy of military service resulting in extravagant andrisk-taking behaviour and an inability to cope with a returnto civilian life, no other explanation has been forthcoming.MCS offers another explanation that better accords with theevidence and military training, which requires that extrav-agant risks be avoided and makes motor control and aware-ness paramount.

A useful summary of the varied responses to chemicalexposures is given in Figure 50.7. This includes the recogni-tion of the importance of perception and central integrationof the experience (Figure 50.8).

Smooth muscle

Epithelium

Neutralendopeptidase

Irritant receptors

Axon reflex

Sub PCGRPNKA

Parasympathetic

Vagus

Sympathetic

NorNPY

Vagus Brain

AchVIP Laryngeal

muscles

Chemosensitivenerves

Vessels

Glands

Neuropeptidereceptors

Figure 50.5 Axon and central reflexes initiated by triggering chemosensitivereceptors on C-fibres

Ach, acetylcholine; CGRP, calcitonin gene-related peptide; NKA, neurokinin A; Nor,noradrenaline; NPY, neuropeptide Y; Sub P, substance P; VIP, vasoactive intestinalpeptide.

P

Mast cell

P

P

P

H

Chemoreceptor

Histaminereceptors

Substance Preceptor

Antigen

Chemical

Substance P

Histamine

Immunoglobulin E(IgE) antibody

H H

Chemical

Sensory nerve C-fibre

Figure 50.6 Localized release of substance P triggered by chemical activation,leading to further release of inflammatory mediators from mast cells


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DAMAGE TO DEEP BRAINSTRUCTURES

Haley found clear evidence from MRS of cell death in thebasal ganglia and brainstem of sick American veteransfrom the first Gulf War (Figure 50.9).12 Later studies in ani-mals and from historical exposures found more areas of thebrain to be damaged, leading to the conclusion that ‘Whilepreliminary, such findings raise the concern that ill Gulf

War veterans may have neuronal damage in multipleregions of the brain’.27 Undoubtedly, the major chemicalsinvolved are inhibitors of acetylcholinesterase, organo -phosphate insecticides, the nerve agent sarin and pyri-dostigmine bromide – the so-called ‘cholinergic triplewhammy’.67 A useful paper analyses studies of sick veter-ans, agricultural workers and shepherds.100

Damage to the deep brain structures is consistent withpenetration of the blood–brain barrier by toxic chemicalseither via the bloodstream or by intraneuronal transport

Resp

onse

Normal

Time

Prolonged

Exposure

Resp

onse

Normal

(a)

(c)

(b)

(d)

Moresensitive

More reactive

Resp

onse

Time

Stimulus

Stimulus

Habituation

Adaptation

Resp

onse

ExposureS R T

Symptomthreshold

Figure 50.7 Summary of responses to chemical exposures. (a) More sensitive = a decrease in the magnitude of exposure required to initiate the response; more reactive =an increase in the slope or in the maximum level of the exposure–response curve. (b) The threshold for perceiving symptoms may occur in the mid-position of the exposure–response curve (T). As a result, the clinical report of increased sensitivity could mean that the individual has become more reactive (R) or more sensitive (S). (c) Recognition ofsymptoms may require the response to be present for a certain duration. The clinical report of increased sensitivity could mean that the response has become moreprolonged. (d) Habituation = decreasing responses with single repeat exposures; adaptation = progressive decrease in magnitude of response with prolonged exposure

Perceptual andcentral integration

Chemicalsensitivity

Neurogenicinflammation

Inflammation

Figure 50.8 Potential interactions between chemical sensitivity and the domainsof neurogenic inflammation, perceptual and central integration, and non-neurogenic inflammation

Figure 50.9 Basal ganglia wrapped round the thalamus, deep in the brain

Basal ganglia

Thalamus



(CYP450),93,102 which introduce oxygen atoms into organiccompounds that are largely lipid-soluble, creating highlyreactive intermediates. In phase 2, these intermediatesundergo conjugation with a variety of molecules to gener-ate water-soluble products that can be excreted in the urine(Figure 50.10).103 An important but secondary processinvolves excretion of some lipid compounds in the faeces.

Human CYPs play an important part in the transforma-tion of many key endogenous compounds (e.g. steroidogen-esis) but they have been studied most widely in connectionwith drug metabolism and some carcinogenic compounds(e.g. polycyclic aromatic hydrocarbons, PAHs). The metabo-lism and elimination of xenobiotics is now an importantarea of toxicology.104,105 CYP450s are involved in the metab-olism of about 75 per cent of drugs and xenobiotics and arepresent in many important areas in the body, including themitochondrial membranes, the blood–brain barrier, the gas-trointestinal tract and the liver. Many xenobiotics distrib-uted widely in the environment are PAHs. Phase 1metabolism transforms PAHs via the introduction of activeoxygen species into very reactive compounds such as epox-ides, which in turn undergo phase 2 conjugation into morepolar compounds, which can be excreted in the urine. Ifoxidative phase 1 processes are not controlled carefully andcoupled with phase 2 reactions, then destructive reactiveoxygen species (ROS) are produced, leading to oxidativestress, which can cause considerable tissue damage – a fea-ture of all complex multi-system illnesses.2 Reliable data

along the olfactory tract, as suggested by Ashford andMiller.64 Undoubtedly, veterans of the first Gulf War wereexposed to a large number of diverse chemical and biologi-cal toxins and considerable electromagnetic radiation frommany sources. Some 25–30 per cent of these veterans arenow ill,27 and for this to happen to healthy young people inthe prime of life serves as a warning to the whole of societyabout taking care with the manner in which we exposeeven the healthiest people to novel chemicals. The counterview, that seeks to establish Gulf War illness (GWI)/GWS asa psychiatric illness,101 is typical of the debate that ragesaround MCS in the face of incontrovertible and replicatedevidence of significant brain damage in sick Gulf War vet-erans.99 It is important to examine the implications formental health rather than to claim that there is no such evidence.

METABOLISM AND CHEMICALS

The liver is the main but not the only organ of metabolismand is crucial in removing both endogenous and exogenouscompounds/xenobiotics from the body. Metabolic processesare generally well understood and involve a range of estab-lished chemical reactions. Of particular importance is atwo-stage process involving phase 1 and phase 2 metabo-lism. Phase 1 involves a large family of haem-containingenzymes, mono-oxygenases and cytochrome P450 enzymes

Endogenouscompounds

Free radicalgeneration

Reactive oxygenspecies

Tissue damage

Blood–kidney–

urine

Bile–faeces

Xenobiotics

Phase I

Biotransformedintermediatemetabolites

Excretoryderivatives

Phase IIconjugationpathways

P450 (CytochromeP450 isoenzymes)

Less polar

More polar

Figure 50.10 Phase 1 and phase 2metabolism. Cytochrome P450 (CYP450)enzymes generate free radicals and reactiveintermediates


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are available for ME/CFS,106,107 GWS,99,100 organochlorinepesticides108 and organophosphate pesticides, alone or incombination with other xenobiotics.109,110 Both mitochondr-ial function and the nervous system are affected.

Oxidative stress, defined as an imbalance between reac-tive oxygen species and free radicals and antioxidant com-pounds, can also arise from other defence processes such asinflammation, which are also tightly controlled undernormal circumstances.

This insight into multi-system illnesses suggests usefulways of providing treatment for patients with MCS.

Bioactivation can be a result of the metabolic conversionof xenobiotics (aflatoxins) and drugs (ethyl carbamate,troglitazone, terfenadine)104 to more toxic compounds. Incontrast, many persistent and bioaccumulative compoundspossess bonds that are resistant to cleavage in metabolicreactions. This is particularly true of carbon–halogen bondsattached to aromatic or ethylenic carbon atoms. Such com-pounds accumulate up the food chain, leading to increasingdoses in the organisms, including humans, that are at thetop of the food chain. Significant contamination of fish oilswith PCBs and dioxins111 and of tuna and swordfish withmercury112 have been reported, leading to advice to restrictthe intake of these foodstuffs. Mercury is both concentratedand bioactivated to methyl mercury when it passes up thefood chain, and this was the cause of the severe neuro-toxic/psychiatric Minamata disease.113,114

Phase 2 metabolism assists the elimination of many com-pounds by conjugation of reactive chemical groups presentin endogenous and exogenous compounds. The classicalexample is paracetamol. The metabolic pathway involvesconjugation with sulphate or glucuronyl groups, but whenthese become exhausted in patient who has taken an over-dose, a toxic quinoneimine is formed, which binds to glu-tathione, the primary cellular antioxidant molecule. Theprogressive removal of glutathione is responsible for theslow but often inevitable fatal effects of paracetamol.98

GENETICS

ME/CFS has been investigated extensively by Kerr and col-leagues, who have identified some 88 genes that are mainlyup-regulated in very sick patients with ME/CFS.19,115 Thelarger study identified seven clinical phenotypes forME/CFS.19,116 Although such studies have yet to be carriedout on patients with MCS, there is evidence of genetic sus-ceptibility in some studies.

The importance of genetic variations in drug- and xenobiotic-metabolizing enzymes was recognized at thebeginning of the twenty-first century:117,118

The underlying genetic predisposition of each patient will reflectcombinations of poor- and extensive-metabolizer phenotypes; ifthese enzymes cooperate in the same metabolic pathway forany given drug or environmental agent, such ecogenetic

variability might be synergistic and lead to as much as 30- or > 40-fold differences in activation or degradation. The endresult can be large interindividual differences in risk of environ-mentally caused toxicity or cancer.119

In one study, there was an 18-fold increase in the risk ofMCS when interactions between CYP2D6 and NAT2 metab-olizing enzymes occurred.120 Another study found that vari-ations in NAT2 and GST genes were linked to increasedchemical sensitivity.121 One study did not find any link withsome allele frequencies, but it considered only NAT1,NAT2, PON1 and PON2 and did not consider CYP2D6 orGST genes.122 Because of the large number of genetic vari-ants of the many enzymes involved in xenobiotic metabo-lism, this is a complex but urgent area of study that will bevery fruitful in understanding the widespread variations inMCS. Analogous studies to those of Kerr and colleagues areurgently needed.

Although traditionally the major concern has been withdrug metabolism (pharmacogenomics), the wider term ‘tox-icogenomics’123 has been introduced, and a paper describeshow exposures to arsenic in drinking water can alter thegene function in babies born to mothers exposed in thisway.124 This disturbing link of arsenic exposure to increasedinflammatory responses in the succeeding generationincreases the urgency to recognize and treat MCS, of whichit is a part.

The enzyme paraoxonase 1 (PON1) has been particularlywell studied. It plays a key role in protecting against oxida-tive stress associated with the oxidation of low-density lipidparticles. It is now recognized as a key enzyme in removingorganophosphates104,105 and nerve agents from the body. Itis important in GWS, where initially it was proposed thatgenetic variants Q and R, respectively involving the aminoacids glutamine or arginine at position 192 in the enzyme,were important;125 soon, however, it was found that it wasthe level of the enzymes and not their genetic form that wasimportant.126,127 The use of leaded petrol in the Gulf Warmay well have depressed the levels of PON1, making thetroops more susceptible to the toxic effects of organophos-phates and nerve agents.128 This illustrates the complexityof MCS where two apparently independent factors havebeen found to impact on the same biological system. Laterstudies indicated that there is genetic control of the levelsof the enzyme produced,109,129,130 particularly in connectionwith the recognition of organophosphates in aerotoxic syndrome.131

PolymorphismsPolymorphisms are defined as variations in gene structurethat are too common to be due merely to new mutations. Apolymorphism must have a frequency of at least 1 per centin the population. They have become the subject of intenseresearch, as small changes in gene structure can now beidentified that have been associated with the risk of devel-oping chronic diseases in later life and also predicting the



consequences of gene–environment interactions.132 Insingle-nucleotide polymorphisms (SNPs), a singlenucleotide change occurs that alters the function of thegene; for example, in the PON1 gene, the trinucleotidesequences for the key amino acids at position 192 in theenzyme are glutamine (CAG) and arginine (CGG) andinvolve the single exchange of adenine (A) for guanosine(G). However, it is now clear that almost 200 polymor-phisms have been found in PON1, although not all arefunctional. The direct measurement of the enzyme itself isthe most reliable way of investigating its role in disease:

We, along with other authors, would strongly suggest that allfurther epidemiological studies into the role of PON1 and dis-ease should include a measurement of the enzyme itself in addi-tion to the genetic polymorphisms.133

This conclusion is a measure of the difficulties of investi-gating complex multi-system illnesses such as MCS.

EpigeneticsEpigenetics concerns changes in the phenotypic expressionof inherited genes by chemical modification of DNA andchromatin, which results in changes of gene function (tran-scription, replication, translation, combination). Such modi-fications involve methylation of DNA or methylation,acetylation, phosphorylation, ribosylation or ubiquitinationof chromatin. These processes result in remodelling of chro-matin, with subsequent changes in gene expression. Genesmay be silenced or activated by these processes, which cancause permanent and heritable, or transient, changes in thephenotype.134 These changes can occur throughout life: pre-conceptually, in either parent; periconceptually; early or lategestation; and in neonates, children, young adults and older

adults. Animal and epidemiological studies have identifiedchanges in the reproductive organs, uterus and mammaryglands, including cancers in later life (diethylstilboestrol,DES; bisphenol A, BPA), prostate problems (methoxychlor),sperm-counts, fertility problems, hypospadias (phthalates),nutritional effects, obesity (DES, tributyltin (TBT), BPA) andearly-onset parkinsonism (paraquat, maneb).135 The majorfactors are presented in Figure 50.11.136

It is a matter for concern that the nutritional status of themother may have serious developmental outcomes for heroffspring when they reach adult later life (Figure 50.12).137

Combined with these adverse developmental effects, envi-ronmentally encountered heavy metals such as arsenic,manganese138 and lead119 will exacerbate the deficitsimposed on children, particularly in the developing world,where parents, especially mothers, are under prolonged

No developmental effects

Pharmacodynamic processes

Environmental factors Susceptibility factors

Infant

No developmental effectsDevelopmental effects

Developmental effect markers?

At conceptionand pregnancywoman/fetus

Father atconception

Timing

Figure 50.11 Interaction of factors potentially leading to adverse healthoutcomes

Stages ofdevelopment

Folliculardevelopment andrecruitmentOocytedevelopmentand maturation

Cleavage, gastrulation,blastulation and maternal zygotictransition

Elongation, apposition, attachment,maternal recognition of pregnancy,placentation

Period of maternalundernutrition

Early gestation:

Late gestation:

Altered embryo growthAltered fetoplacental

growth trajectory

Hyperactivation of the HPAaxisPreterm labourIncreased blood pressureAltered cardiovascularfunctionAltered kidney growth

Physiologicalchanges

Adult healthoutcomes

Altered birth and weaningweights

Increased body mass

Poor perception of self-health

Hypertension

Cardiovascular and coronaryartery disease

Altered kidney growth

Metabolic adaptations

Periconceptional environmentand early gestation

Postnatal healthoutcomes

Preconception

Pre-implantation

Early gestation

Programming

Figure 50.12 Current understanding of howmaternal undernutrition during the periconceptualand early gestational windows of development mayprogramme pathophysiology and adult disease

HPA, hypothalamus–pituitary axis.


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socioeconomic stress.139 This avoidable loss of humanpotential is a grievous loss to the world community.

Mitochondrial DNAMitochondrial DNA is derived only from the mother and isknown to more readily undergo mutations and damagecompared with nuclear DNA. Pathogenic mutations inmitochondrial DNA have been reported to be common.140

The question arises as to what effects environmental toxinshave in this process. Are epigenetic changes involved?Since oxidative stress, a feature of MCS, is associated withcompromised mitochondrial function, these latest findingsmay be very important for the future.

THE NO/ONOO HYPOTHESIS

Pall brought together a long series of papers and reviewsconcerning the NO/ONOO (nitric oxide/peroxynitrite)hypothesis (Figure 50.13).141 This provides a comprehensivedisease paradigm for ME/CFS, MCS, fibromyalgia, post-traumatic stress disorder (PTSD), GWS and related illnesses.

interleukin 6, IL-6), which also stimulate iNOS. At the sametime, ionic calcium is released from intracellular stores,which stimulates the activity of neuronal nitric oxidasesynthase (nNOS) and endothelial nitric oxidase synthase(eNOS). Oxidative stress and superoxide further stimulatethe vanilloid receptor, VR1, which is a promiscuouschemoreceptor found on C-nerve fibres. The vanilloidreceptor and NO evoke stimulation of the excitatory NMDAglutamate receptors. These interacting positive-feedbackcycles provide vicious and destructive biochemical cyclesthat afford a comprehensive understanding of the charac-teristic signs and symptoms of all the overlapping syn-dromes, including MCS. This explanation means that theso-called ‘unexplained illnesses’ are to a large degreeexplained – the controversy is at an end. However, amongthe stressors for ME/CFS are severe psychological stress andtrauma. In an interesting presentation, Perry described howprior brain injury or damage (e.g. in people withAlzheimer’s dementia) followed by a modest systemic infec-tion leads to a massive inflammatory response in the cen-tral nervous system in experimental animals and, fromlimited studies, in elderly people.142 This work addresses oneof the conundrums of MCS: how can small events provokesuch large and extensive adverse effects found in patientswith ME/CFS and MCS? Since organophosphates provokesignificant but delayed brain damage via NO,143 it is likelythat toxicant exposure coupled with a mild systemic infec-tion may also provoke significant inflammation in thebrain.

THE CHALLENGE TOTOXICOLOGY

Table 50.6 shows some conceptual shifts in toxicology.144

Low-level exposureThere are many examples of low levels of exposure havingsignificant effects on biological organisms and humanssome 100-fold lower than the no observable adverse effectslevel (NOEAL or NOEL) or allowed daily intake (ADI).Tributyltin, with a NOEL of parts per billion (ppb), causedsterility in dog whelks at 20 parts per trillion (ppt), whilepermethrin with an ADI of 0.7 parts per million (ppm) killedmost water invertebrates at 5–10 ppb.145 In mammalian sys-tems, endocrine-disrupting chemicals with oestrogenicactivity evoke responses at very low doses, comparable withthose found in the environment and consumed by people,but higher doses had contradictory effects, making it essen-tial to develop biological testing systems that will beresponsive to low doses of environmental toxins.146 Animportant aspect of testing chemically sensitive people isthe need to allow a period for adaptation before exposuresin order to ensure reliable and reproducible experimentalmeasurements.147

Nitricoxide

NMDA

Superoxide

Peroxynitrite

Ca2�

Oxidativestress

iNOS

nNOSeNOS

NF–κ B

IL–1β, IL–6IL–8, TNF–α

IFN–γ

Vanilloidreceptor

Figure 50.13 NO/ONOO (nitric oxide/peroxynitrite) cycle

eNOS, endothelial nitric oxide synthase; IFN, interferon; IL, interleukin; iNOS,inducible nitric oxide synthase; NMDA, N-methyl-D-aspartate; nNOS, neuronal nitricoxide synthase; TNF, tumour necrosis factor.

At the heart of this paradigm is the formation of thepotent free radical and oxidant, nitric oxide (NO). NO reactswith superoxide, which is generated mainly in mitochon-dria in small amounts, as part of the normal synthesis ofadenosine triphosphate (ATP), the body’s principal energymolecule. Nitric oxide and superoxide combine to form per-oxynitrite (ONOO), a very potent oxidizing molecule. This,in turn, generates oxidative stress, which is already a fea-ture of the overlapping syndromes that include MCS.Oxidative stress activates the gene transcription factorNFkB, increasing the activity of inducible nitric oxide syn-thase (iNOS) and the levels of inflammatory cytokines (e.g.



Additivity, antagonism, synergism, non-monotonic dose–response curves andhormesisEnvironmental toxicants are usually encountered in com-plex mixtures, but most are tested individually. The com-bined effects of such compounds might be expected to beadditive, antagonistic or synergistic. The study of theserelationships is complex and varied,148 but examples ofsuch interactions have been found experimentally in wholeanimals and in isolated biological in vitro systems:

● Additivity: using a yeast oestrogen screen, the effects offour different oestrogenic compounds (4-nonylphenol,4-octylphenol, o,p-dichlorodiphenyltrichloroethane(DDT), genistein) in two to four component mixtureswere found to be additive.149

● Antagonism: this was described in a study of the terato-genic effects of mixtures of PCBs.150 It was found thatthe immunotoxic effects of one PCB congener wereantagonized by another closely related conger.

● Synergism: this arises when the overall toxic effects of amixture are greater than the sum of those of the individ-ual components. This has been observed with acetyl-cholinesterase inhibitors and N,N-diethyl m-toluamide

(DEET), an insect repellent used in the first Gulf War in1990–91,151 in pesticide formulations152 and in herbicideformulations.153 The so-called ‘inerts’ in product formu-lations can increase toxicity and should be included inroutine testing of any products, which commonlyinvolves only a single active ingredient. These effectscan be very large, with increases in toxicity of more than100- or 1000-fold. Disturbingly, commonly used foodadditives also show synergistic increases in developmen-tal neurotoxicity tests.154

● Non-monotonic dose–response curves: classical toxicol-ogy uses linear dose–responses to estimate the limits forexposure to environmental toxins (Figure 50.14). Thiseffect involves the assumption that dose–response islinear and, at a sufficiently low dose, becomes zero – theNOEL. The data, usually from animal experiments, arethen adjusted arbitrarily by reducing the identified doseby one or more orders of magnitude in order to obtainthe reference dose. The reference dose is chosen toaccommodate possible differences between animal andhuman responses, and the different sensitivities of chil-dren and elderly people. The NOEL is, in this way,reduced to an estimated reference dose some 100–1000times lower than the observed experimentally deter-mined dose.

Table 50.6 Conceptual shifts in toxicology

Old concept New concept

High-level contamination overwhelms detoxification and other Low-level contamination hijacks control of developmentdefence mechanisms

The dose makes the poison Non-monotonic dose–response curves are common, in which low-levelexposure causes effects that disappear at higher levels

Only high levels of exposure matter Impacts caused at what had been assumed to be background levels

Focus on adults Periods of rapid growth and development (prenatal through puberty) aremost sensitive to exposure

A small number of ‘bad actors’ Many chemicals previously thought safe are biologically active andcapable of interfering with signalling systems

Immediate cause and effect Long latencies are common; fetal programming can lead to disease anddisabilities decades later

Examine chemicals one compound at a time In real life, mixtures are the rule; they can lead to effects at much lowerlevels than indicated by simple experiments with single chemicals

Focus on traditional toxicological endpoints such as Wide range of health endpoints, e.g. immune system dysfunction mutagenesis, carcinogenesis and cell death (hyper-/hypo-active), neurological/cognitive/behavioural effects,

reproductive dysfunction, chronic diseases

One-to-one mapping of contaminant to disease or disability Same contaminant can cause many different effects, depending uponwhen exposure occurs during development and what signals it disrupts;multiple contaminants can cause the same endpoint if they disrupt thesame developmental process


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Figure 50.14 shows that at doses below the NOEL, toxiceffects are found in a bell-shaped or inverted U-shapeddose–response curve. Note the large concentration differ-ences associated with the conventional linear part of thedose–response curve and those with the non-monotonicpart of the curve.

Figure 50.15 illustrates the different forms of non-monotonic curves that have been found for many environ-mental toxins.155 Among the earliest investigators of thisphenomenon was Frederick Vom Saal, who studied theoestrogenic effects of drugs and environmental toxins, par-ticularly BPA, in mice.133 In a paper published in 1997, VomSaal and colleagues wrote (author’s italics):

Our findings show for the first time that fetal exposure to envi-ronmentally relevant parts-per-billion (ppb) doses of bisphenolA, in the range currently being consumed by people, canalter the adult reproductive system in mice.156

Endocrine disrupters have been studied widely. Doses aslow 10-11 molar have evoked immune responses similar tothose caused by oestradiol that involve the release of hista-mine and cytokines from mast cells in cell culture,157

providing further evidence of the interrelationship betweenthe endocrine and immune systems.16

The situation is complicated by the discovery of twoclasses of oestradiol receptors, one in the nucleus and onethat is membrane-bound. The membrane-bound receptor isequally sensitive to oestradiol and bisphenol A, while thenuclear receptor is much less sensitive to bisphenol A.158

The crucial nature of the test systems must be consideredwhen determining the NOEL and reference doses.

HormesisHormesis is defined as low-dose stimulation and high-doseinhibition and follows a non-monotonic dose–responsecurve. It has been used to claim that low doses of environ-mental toxins should be regarded as beneficial and be thedefault position adopted by regulators and clinically. Therehas been a thorough evaluation of this view, which empha-sizes that:159

● underlying mechanisms of action, and not simply empir-ical data, must be considered;

● stimulatory effects are not always beneficial and may beharmful;

● all the induced effects of a toxicants, and not only thebeneficial ones, must be considered;

● any health decisions based on beneficial effects mustaddress interindividual differences, including suscepti-bility, genetic factors, life stage and health status;

● any health decisions based on beneficial effects mustaddress the fact that other environmental and workplaceexposures may alter the low-dose response of a singleagent.

This excellent paper puts all these considerations into ageneralized theoretical framework and includes manytelling experimental examples. For instance, 2,3,7,8-tetra-chlorodibenzodioxin (TCDD), an environmental carcinogen,has been quoted as having low-dose beneficial effects.Closer examination of the data shows this to be false, sincethe incidence of tumours of the liver, lung, tongue andnasal turbinates increased, while incidence of tumours ofthe pituitary, uterus, mammary glands, pancreas and adre-nal glands decreased.

In one study claiming the hormetic effects of cadmium, anon-statistical decrease in testicular cancer in rats wasaccompanied by a statistical increase in prostatic hyperpla-sia and an increase in prostate tumours per animal in thehormetic range.

Ethanol is cited as a classic hormetic agent, since benefi-cial outcomes – reduced risk of coronary heart disease anda reduction in mortality – have been identified with lowconsumption, in contrast to increases at higher doses of,among other things, neurological disorders, cancers andliver cirrhosis. However, small amounts of alcohol (0.5 unitsper day) in pregnancy have been associated with adversebehavioural outcomes such as aggression in children.

100

0

Tissue level of agent

Cell signaling disruption range (ppt–ppb) Pharmaceutical range (ppm)

0

Resp

onse

Risk assessmentDose–responseassumed linear

Assumedthreshold

No effect

Figure 50.14 Dose–response curves found in toxicology: inverted U- curve forcell signalling disruptors

Courtesy of Professor Vyvyan Howard.

Linear

Resp

onse

incr

ease

s

Non-linear

Dose increasesMonotonic Non-monotonic

U

Inverted U

Figure 50.15 Different linear and non-monotonic dose–response curves



Developmental effects of environmentalexposuresIntergenerational effectsDiethylstilboestrol (DES) is known to cause malformation ofthe uterus in daughters born to women who received DESduring pregnancy, predisposing the daughters to rare uter-ine cancers. In rats, androgen receptors were permanentlyraised in male offspring of females given DES during preg-nancy, with an increase in the size of the prostate gland.BPA caused similar changes.160,161 DDT lengthened the timeto pregnancy (fecundability) in the daughters of mothersexposed to DDT; the probability of pregnancy fell by 32 percent per 10 mg/L in maternal serum.164

Effects on the fetus and babiesThe most rapid multiplication of cells and differentiation oftissues occurs during fetal growth and development withinthe womb. This is when key biological processes are mostsusceptible to disturbance by xenobiotics. The notion thatthe developing fetus is protected during its growth anddevelopment within the womb has been shown to bewrong. Many xenobiotics cross the placental barrier andcan disrupt many crucial stages of development.

A ruling by the USA high court awarded damages of $4million to John Castillo, who was born without eyes(anophthalmia) following his mother’s exposure to the fun-gicide benlate when she was 6–7 weeks’ pregnant with herson. The exposure occurred on a single day when MrsCastillo was accidentally sprayed while walking. The initialcase was hotly contested by DuPont, the manufacturer ofbenlate, but the case was upheld and then lost on appealbefore the final ruling of the Florida supreme court in2003.163 The time of the exposure in the Castillo case corre-sponded to the time of maximum cellular replication andorganogenesis in the developing fetus. The company hadfunded a 2002 study that showed benlate to be concen-trated to the eyes in rats. This report was unpublished butreported by the Guardian newspaper.139 Benlate has beenthe subject of numerous other cases and has now beenwithdrawn, after 33 years on the market.

Cord blood studies identified hundreds of toxins to whichthe fetus had been exposed, many of them developmentalneurotoxins. This is of particular concern to the AmericanAssociation on Mental Retardation (AAMR; now theAmerican Association on Intellectual and DevelopmentalDisabilities, AAIDD), which stated: ‘The evidence is mount-ing that exposure to environmental pollutants and toxinsare contributing to poorer health and significant increasesin chronic disease and disabilities in our society’.43 Some17–18 per cent of Americans under age 18 years areclaimed to be affected.164

A scientific consensus statement on environmentalagents associated with neurodevelopmental disorders

brings together the most up-to-date information of a largegroup of concerned scientists in the USA and emphasizesthe following:36

● Children and young people cannot be considered as‘small adults’ and show marked differences in physiol-ogy and routes of exposure. They are often more suscep-tible to environmental exposures.

● Low doses of toxicants can alter gene expression andaffect learning and development.

● Effects can be delayed.● Genetic polymorphisms render some subgroups more

sensitive than others to certain chemicals.

Autism, attention deficit hyperactivity disorder (ADHD)dyslexia, mental retardation, lowered intelligence quotient(IQ) and other disorders of learning and behaviour arehighly prevalent among American children. These condi-tions appear to be rising, with presently 5–15 per cent of allchildren under the age of 18 years in the USA affected –more than 12 million children. ADHD has been shown to belinked to food additives used in children’s drinks andfoods.165 Autism-spectrum disorder appears to be ten timesmore prevalent now than in the 1980s. The costs of provid-ing special educational services in the USA have been esti-mated at $77.3 billion, twice the cost of regular education.In addition, there is the human cost for families and communities.

Agents definitely found to be associated with learningand development disabilities (LDDs) are alcohol, lead, mer-cury, manganese, arsenic, PCBs, polybromodiphenylethers(PBDEs), solvents, PAHs, pesticides and nicotine in tobaccosmoke. The damaging effects of these toxins have beenknown for many years, but the development of productscontaining them has been allowed to take place on eco-nomic grounds. A good example is lead. The toxic neuro -developmental properties of lead have been known foryears; however, its use in paints and in petrol was stoppedonly after much struggle. The failure of policy-makers toprotect young children by not acting quickly in response tothe science has laid waste countless young lives. The Centersfor Disease Control and Prevention (CDC) has not changedthe standard for acceptable blood levels of lead in childrensince 1985, although the most recent proposal for a level of2 mg/dL is some 12.5 times lower than the 1985 level.

Solvents and solvent-based products (Table 50.7) are fre-quently involved as neurotoxins and are ubiquitous in theenvironment.

Effects on elderly peopleThe Pritchard Report examined changing patterns of adult(age 45–74 years) neurological deaths in the major Westernworld in the period 1979–97 and found significant increasein chronic illnesses, for which the report suggested possibleenvironmental factors.37


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Delayed effectsOne of the most worrying aspects of chemical exposuresand MCS is the development of delayed neurotoxic effectsyears after the initial exposure, which may have been atlow levels. This has been found with GWS66 and in sur-vivors of terrorist attacks using the nerve agent sarin.129,166–

168 Such temporal relationships are easily missed without avery thorough history.

TREATMENT

A survey of 917 people with MCS enquired about illnessrating: the results were mild (7%), moderate (32%), severe(45%) or totally disabling (13%), with the respondents beingmainly white (95%) and predominantly women (82%).169 Atotal of 101 treatment and management techniques proce-dures, and their perceived efficacy, were assessed. Ahelp/harm ratio was devised that allowed comparison of thedifferent treatments tried by the respondents (Table 50.8).The higher the ratio, the more helpful the treatment, with aratio of 10 indicating that ten times more people found thetreatment helpful compared with those who found it harm-ful. The lower the ratio, the more harmful the treatment,with a ratio of 0.1 indicating that ten times more peoplefound the treatment harmful compared with those whofound it helpful. A ratio of 1 indicates that there was anequal balance between help and harm.

The three most highly rated treatments were:

● a chemical-free living space (ratio 155.2);● avoidance of chemicals (ratio 118.6);● prayer (ratio 48.3).

Other reports emphasize the importance of a chemical-free living space and avoidance of chemicals in health, edu-cation, legal and benefit provisions.21,22,27,28,40,61,62 It is clearlycommon sense to avoid known chemicals that cause thepatient problems and to avoid contact with other chemicalson the precautionary principle. Chemical-free living spaceis humane and less costly than attempting to provide long-term medical care for this complex condition. The inclusionof prayer is striking and indicates the need to consider

Table 50.7 Neurotoxins: common solvents and solvent-based products

Mostly solvent-based Partially solvent-based

Gasoline Glues

Diesel fuel Adhesives

Charcoal lighter fluid Oil-based paints

Lantern fuel Fingernail polish

Grease Furniture polishes

Lubricating oils Floor polishes and waxes

Degreasing agents Spot removers

Paint strippers Metal and wood cleaners

Paint thinner Correction fluid

Turpentine Computer disk cleaners

Nail-polish remover Varnishes and shellacs

Rubbing alcohol Wood and concrete stains

Table 50.8 Top 12 treatments tried in multiple chemical sensitivity (MCS)

Treatment tried n Harmed (%) No effect (%) Helped (%) Helped/harm ratio

Chemical-free living space 820 0.6 4.5 94.8 155.2

Chemical avoidance 875 0.8 4.7 94.5 118.6

Prayer 609 1.4 34.4 64.2 48.3

Meditation 423 2.8 43.3 53.8 19.2

Acupressure 308 4.5 28.3 67.2 14.9

Touch for health 75 3.8 41.8 54.4 14.3

Air filter (to prevent exposure) 786 6.0 11.8 82.1 13.7

Rotation diet 560 5.7 22.1 72.2 12.7

Acidophilus 661 4.1 44.0 52.0 12.7

Relocation 513 7.4 6.0 86.6 11.7

Reflexology 204 4.8 38.5 56.6 11.6

Personal oxygen to cope with exposures 326 7.3 14.2 78.4 10.6



people with MCS holistically. Prayer is not defined in anyspecific terms but excludes meditation, hypnosis and faithhealing. Cognitive-behavioural therapy (CBT) is not consid-ered specifically, but psychotherapy as a cure is rated as ofno noticeable effect (65.3%) or as very harmful (6.6%).However, as a coping procedure, 47.7 per cent of patientsfound psychotherapy somewhat helpful, with 24.1 per centof patients reporting no noticeable effect. Exercise isreported as causing harm (14.7%), of no noticeable effect(23.7%) or helpful (61.6%). Exercise is reported by severelyill people with ME/CFS to be positively harmful, with only 5per cent of patients finding it helpful.170,171

The interventions rated as more harmful than helpfulinclude:

● conventional medicines, particularly all antidepressantsand anxiolytics (tricyclics, selective serotonin reuptakeinhibitors (SSRIs), benzodiazepines) and anti-seizuredrugs (help/harm ratio 0.1–0.5);

● provocation-neutralization (P-N) testing for chemicalswith preservatives (help/harm ratio 0.9).

Since MCS includes heightened sensitivity to chemicals,it is not surprising that the response to drugs is also height-ened. When any drugs are given, it is imperative that theinitial dose is much lower (one-quarter to one-eighth) thanthe starting dose recommended in the formularies in orderto avoid any possible (severe) reactions. The drugs generallyfound harmful are those that work by modifying brainfunction, which is a major area of damage in MCS and partof the neuroendocrine immune paradigm.

More surprising was the inclusion of P-N among themore harmful treatments. P-N is used widely and com-mended among some practitioners of ecological/environ-mental medicine.61,62 P-N can take different forms, but thesewere not specified.

Initially, saunas were three to four times more helpfulthan harmful and feature among the recommended treat-ments that offer a means of detoxification.61,62,80 However,over a longer time, saunas proved less helpful. The type ofsauna used (wet or dry) was not specified. Reducing thetotal toxic load is seen as a desirable goal in treat-ment.61,62,80,96,172,173

Diet was also generally helpful. Only a rotation diet wasmentioned, although other exclusion diets, in which dairyand gluten are the first to be removed, using a fooddiary61,62,80 or following the Stone Age diet62 may also behelpful. Other aspects of diet modification include usingacidophilus to support gut flora, which, with related probi-otics, features in many diets.

Detoxification includes removal of dental fillings, with ahelp/harm ratio of 4.8, and the use of UltraClear®, a combi-nation product designed to comprehensively support thegut, with a health/harm ratio of only 1.

Many people had tried a range of mineral, vitamin andco-factor formulations, but the individual help/harm ratioscores varied between 8.6 and 4.1. No specific mineral,

vitamin and co-factor combinations were used. One studyfound that MCS was not associated with vitamin deficiencyor thyroid function, but lower lymphocyte counts suggestedimmune dysfunction with VOCs.160 The advent of specifictests that allow the identification of toxins permits moreprecision in designing treatments. Such tests identify block-ade of mitochondrial function, DNA adducts161,174–176 andanalysis of needle-fat biopsies. Pesticide load has beenreduced by choline and vitamin C.177 Vitamin B2 has longbeen used to treat neuropsychiatric disorders where noanaemia or macrocytosis is present.

Various combinations of supplements (vitamins, mineralsand other co-factors) in a wide variety of combinationshave been recommended. Among the most useful is onesupporting mitochondrial function – N-acetyl-L-carnitine,co-enzyme Q10, niacin, ribose and magnesium. A morecomplex mixture of potent antioxidants is being trialled inthe USA.2

An important question about the testing of adults forenvironmental chemical contamination is:

Could we be trying to correlate exposure and effect at thewrong time? If it is prenatal, or early life stage, exposure that iscritical to disease susceptibility, why are we measuring environ-mental chemicals in people once they have developed breastcancer? The critical exposure window may have been much earlier.178

This underlines the urgency to recognize many chemicalsas major developmental hazards, which must be addressedat the earliest possible moment in order to avoid longer-term and adverse consequences.

POLITICAL, SOCIAL ANDMEDICAL ACTION

The response of governments, global corporations, industryand society to the accumulating evidence of the hazards ofchemical contamination has been to minimize the observedeffects, to accuse the scientists involved of poor science,73

scare-mongering,161,179 unrealistic attitudes180 and, in anumber of extreme cases, vilification and character assassi-nation.181,182 Government activities and research fundinghave been dictated by policy and not open, independent,transparent science. In an article that called for research,not propaganda, the reluctance of the medical establish-ment to embrace change was challenged. US Representativeand physician Dave Weldon said:

Mind you, half of Dr. Wakefield’s theory has been proven correctand accepted in the medical community. Hundreds of childrenwith regressive autism and GI [gastrointestinal] dysfunctionhave been scoped and clinicians are seeing the inflammatorybowel disease he first described. The NIH [National Institutes ofHealth] is finally funding an attempt to repeat Dr. O’Leary’s find-ings of measles RNA in Wakefield’s biopsy specimens, though Iam disappointed it has taken this long.


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A similar story is described by Arpad Pusztai, whosework upset the establishment’s ideological commitment toGM crops and food.183

Evidence has been sought to support policy rather thanto design policy in response to medical and scientific evi-dence. Disturbing scientific and medical studies are beingdenied rather than replicated in order to establish theirvalidity.

The failure of government and regulators to act on areport on food colouring and ADHD in this matter is regret-table and symptomatic of the unwillingness to makechanges in our chemical environment that are resisted bythe industry, even in the light of good science.184 Both theFood Standards Agency (FSA)185 and the European FoodStandards Agency186 refused to endorse the precautionaryprinciple and withdraw the products immediately.

The phthalates reveal a similar story. These were bannedin some countries from 1977,187 but in the USA the toyindustry launched strong resistance to a ban in America.188

One study reports a positive association between urinaryphthalate metabolites and adult male (age 20–59 years)obesity.189 There were other positive associations withadverse health effects among young women and elderlypeople, but not in children.

The attitude to xenobiotics in the environment is reminis-cent of the fight against tobacco and smoking. It seems thatmany people and organizations are prepared to sacrifice thehealth of present and future generations in order to make afast buck or allow national tax income to be protected.

GULF WAR SYNDROME/ILLNESS

In November 2008, a second report on GWI was released bythe Congressionally mandated Research AdvisoryCommittee on Gulf War Veterans’ Illness (RACGWVI).190 The450-page report with some 1800 references validates theearlier conclusions of the 2004 report and states:

The illnesses suffered by veterans were a result of unique cir-cumstances in which they were exposed to a considerablenumber of toxic insults. The most important of these were:

● receiving multiple vaccines, some experimental;● pyridostigmine bromide, also experimental, in Nerve Agent

Pre-treatment Set (NAPS) tablets;● pesticides, especially organophosphates, used to keep down

disease vectors;● exposure to low levels of chemical warfare agents in the

form of nerve agents.

GWI has the following features:

● It is a chronic multi-system physical medical conditionwith a coherent pattern of symptoms.

● Many veterans show evidence of physical brain injury inthe form of neuropsychological impairment, whichcannot be detected by routine tests.

● It is not a stress-related condition.● There is a twofold increase in motor neuron disease and

brain cancer in people with GWI.

CONCLUSIONS

MCS is a medical, scientific, political, legal and social issuethat needs to be addressed within our society as a matter ofurgency. It is now beyond argument that xenobiotics havethe potential to damage present and future generations.

The role of psychiatry is to embrace the science and med-icine that provide the evidence of chemical and environ-mental damage and to support those people who have tocope with this condition.

The role of industry, science and medicine is to carry outcomprehensive and independent chemical, toxicological,pharmacological and clinical studies to ensure that allproducts in the marketplace are safe for widespread use inthe community. All data should be available for examina-tion in the same way that scientific papers are scrutinizedbefore publication by independent scientists and clini-cians.191 Vested interest should have no part in this process.

The role of politics is to protect its citizens with inde-pendent funding, coupled with robust and clear regulations,without any influence from vested interests that pay thou-sands of pounds in lobbying fees to exert control over thepolitical process.

Where people are physically, chemically or biologicallyexposed to any hazard and develop MCS and related condi-tions, their welfare should be put first and every provisionmade to ensure that they have the resources required tocope with the environment of the twenty-first century.

KEY POINTS

● MCS is a complex, chronic multi-system condition.● It is associated with exposure to a wide variety of novel chemicals,

environmental, agricultural and dietary.● It requires a much more responsible and careful assessment and

regulation of all novel chemicals in line with the precautionary principle.

● It requires recognition of the new understanding emerging fromrecent studies in toxicology, metabolism, genetics, epigenetics anddevelopmental biology.

● Recognition of the condition by clinicians, education, health authori-ties and government authorities is required for effective treatment,the most important of which is the removal of incitants and the pro-vision of a clean and controlled living environment.

● Research is needed in order to establish other treatments that mayhelp at various stages of the condition.

● There may be a need for subgrouping of people with MCS.



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