Engaging with Multiple Chemical Sensitivity (MCS)- London 2003

 

Malcolm Hooper PhD, B Pharm, C Chem, MRIC

Chief Scientific Advisor to the Gulf War Veterans

 

Introduction

 

Multiple chemical sensitivity, MCS, was first officially recognised in Germany and is now included in its edition of the WHO’s International Classification of Diseases, ICD-10, under the code T 78.4. Interestingly, this code is for “allergy, otherwise not specified”.

The recent report “Allergy the Unmet Need”, Royal College of Physicians, June 2003, records the huge increase in allergy in the UK with 1 person in 3 suffering some form of allergy, a total of 18 million people. Of these 18 million some 3 million suffer from severe allergies which can be life-threatening and require emergency treatment.

The release of the Royal College of Physician’s report coincided with the publication of, another very large report, the Royal Commission on Environmental Pollution, 24^th Report, “Chemicals in Products: safeguarding the environment and human health.” This report identifies the need for a proper understanding of the health effects of novel chemicals widely used in society and distributed ubiquitously in the environment. Some 30,000 chemicals with little or no toxicology now need to be assessed, an enormous undertaking.

I do not think these reports are unrelated. The rise of allergy, chemical toxicity and MCS are consistent with the disturbing data in these reports. The Germans have surely embarked on the right course. If we are to engage with MCS as a feature of health care in our modern societies and even more so in the developing economies of what is sometimes referred to as the third world then we need new ways of diagnosing and treating MCS and related illnesses. Otherwise there will be a legacy of ill-health added to the burden of third world countries and the poor in all societies.

 

In the USA official recognition has come in the form of reports from the Department of Justice, the Department of Housing and Urban Development, and the Department of Education, which accept MCS as a legitimate condition for their purposes, CFIDS Chronicle, 1997. Medical resistance to MCS has begun to evaporate among the American College of Physicians. The American Medical Association and American Lung Association and Environmental Protection Agency state that, “Claimants should not be dismissed as psychogenic and a thorough workup is essential….” . large population surveys report from 16-33% of people being sensitive to every day chemicals.

A consensus report by 89 physicians, University of Illinois at Chicago, 2001, defines MCS as a chronic condition in which symptoms-

 

1.        recur reproducibly

2.        in response to low levels of exposure

3.        in response to multiple unrelated chemicals

4.        improve or resolve when incitants are removed

5.        occur in multiple organ systems.

 

In the UK MCS has been resisted by the medical establishment generally, with some honorable exceptions. A major review by Gravelling et al, 1999, and a monograph from the British Society for Allergy, Environmental and Nutritional Medicine, 2001, provide substantial evidence for recognition of MCS an organic illness that can be diagnosed and treated effectively. A major textbook has appeared that provides a comprehensive understanding of MCS, Ashford and Miller, 1998.

 

The triggering event for MCS is often associated with exposure, usually at a high level, to a single chemical entity, or a commercial product formulated in a complex mixture which is frequently thought to be inert. There then develops widespread sensitivity to very low dose exposures to a wide variety of quite different chemicals. This poses a significant puzzle for clinicians, toxicologists, allergists, and medicinal chemists.

 

Our own work, Figure 1, identifies MCS is one of several recognised overlapping syndromes, Merck 1999; Hooper, 2000, 2003; see also Donnay 1997, which share a common core of biochemical dysfunctions involving the gut, nervous, immune and endocrine systems.

 

??? many other syndromes can be added here. IBS (irritable bowel syndrome), Carbon monoxide poisoning, other pesticide poisoning eg pyrethroids; post polio syndrome, post viral fatigue syndrome.

Key: OCs = organochlorine pesticides; OPs = organophosphate pesticides; FMS = Fibromyalgia Syndrome; HPA = Hypothalamus-Pituitary-Adrenal axis

 

Figure 1. Overlapping syndromes sharing a common core of biochemical deficits.

 

It is interesting to note that many Gulf War Veterans, Proctor, 2000; Wessely et al, 20001, OP and pesticide poisoned, Richardson, 2001, and ME-CFS, fibromyalgia, Donnay, 1997, patients report increased and disabling chemical sensitivities.

The symptoms shared by some overlapping syndromes are listed in Table 1. Although there is confusion and sometimes heated debate about the existence of CFIDS, the American description of ME-CFS, MCS, and OP poisoning there is no argument today about the neurological illness, MS, multiple sclerosis, or the immunological illness, HIV-AIDS. This data underlines the multiple system nature of these chronic illnesses.

 

Table 1. Common Symptoms shared by Seven different Chronic Illnesses

 

 

OP = Organophosphate Poisoning; GWS/I = Gulf War Syndrome/Illness; MCS = Multiple Chemical Sensitivity; FMS = Fibromyalgia Syndrome; CFIDS = Chronic Fatigue Immune Dysregulation  Syndrome = ME/CFS; MS = Multiple Sclerosis; HIV/AIDS = Acquired Immune Deficiency Syndrome.

+ Literature   Reported ie. Anecdotal              Adapted from Jackie Burkhead

 

Some agencies and doctors who insist on a psychiatric diagnosis have developed a terminology that confounds questions around MCS and the other overlapping syndromes. Usually the battery of standard tests provided to support clinical investigations yield little or no positive results leading to the false conclusion that there is “nothing wrong with the patient”. Absence of evidence is taken as absence of evidence. No regard is given to the limited nature of the tests. The standard thyroid test(s) are particularly limited and recent work from Holland, European Laboratory of Nutrients, Baiser et al, 2000; Downing, 2000, has shown that an older test, involving a 24 hour urine sample, provides much more accurate and reliable tests. Nutritional deficits, particularly in selenium, have a major impact on the conversion of thyroxine (T4) to the much more active 3,5,3’-iodothyronine (T3).

New acronyms are invented to cloak medical ignorance of and unwillingness to engage with these chronic illnesses. Hence, SSIDC, signs and symptoms of ill-defined conditions, favoured by the War Pensions Agency, PUPS, persistent unexplained physical symptoms, MUPS, multiple unexplained physical symptoms, used by the Medical Assessment Panel of the Gulf Veterans Illness Unit, Lee et al, 2000, 2002, 2003.

 

CHEMICAL EXPOSURES

The Royal Commission report acknowledges the failure of self-regulation in the chemical industry and provides examples of lessons not learned from investigations in the past. These include the enormous problem of the organochlorine compounds first used as potent insecticides. The extensive worldwide impact of these compounds, first made public in Rachel Carson’s ground breaking book, Silent Spring, 1962, should have alerted the chemical industry and related industries producing pharmaceuticals, herbicides, and pesticides, particularly DDT. But no! Now we have organochlorines ubiquitously distributed in human fat to such an extent that we are literally unfit to eat. Our  flesh could not be sold in the market place- it would be banned as too heavily laden with toxic materials. The biological half-life of these compounds is of the order of 50 years, so once we are contaminated we are marked for life. The Inuits whose diet involves fatty meat from seals and fish carry one of the highest loads of organochlorines and breast feeding is limited by such contamination since the mother is feeding toxic compounds to her new born baby! The contamination of our food chain by organochlorines now limits the harvesting of essential omega-3 fatty acids from fatty fish, salmon, trout, mackerel, sardines and the like. In a cruel irony the recommended consumption of fish oils may prove toxic because of the level of contamination. When purchasing such oils it is important to know if organochlorine compounds are contained in them- ask and if no information is forthcoming then buy elsewhere. Despite this toxic compounds continued to be released.

The dioxin story is another salutary example. These organochlorines, 2,3,7,8-tetrachlorodibenzo[b,e][1,4]dioxin is the best known, are by-products from the manufacture or incineration of chlorophenols used in agriculture and as antiseptics. The growing awareness of the toxicity of dioxins has lead to a progressive reduction in the exposure levels to these compounds, from nanogram, 10^-9 g  to picogram, 10^-12 g quantities. This has not stopped the American military from contesting the excessive illnesses, varying from cancers to birth defects and the non-specific symptoms in Table 1, among Vietnam veterans resulting from the use of Agent Orange. Only after 20 years was it conceded that the use of Agent Orange a defoliant which contains only traces of dioxins as by-products of the manufacturing process, Bertell, 2000, Brown, 2001. The endocrine disrupting properties of dioxins released in an explosion of a manufacturing plant at Seveso in N. Italy were responsible for the change in the ratio of female to male human births which increased to 3:1 over the early birth cohorts. Birth ratios now appear to be normalising. But still there is a deficit of male children which is a world wide phenomenon and associated with chemical exposure of the mother whilst the child is in utero, Montague, 1998.

Heavy metal poisoning has also emerged as another major hazard worldwide. The recent large  increase in autism in the USA, especially in California, is strongly associated the increasing dose of thiomersal, a mercury containing preservative that liberates ethylmercury in the body, and is widely used in vaccines, Geier and Geier, 2003; Boyd Haley, DAN Conference, 2003. Mercury contamination of waters, even at low levels can have very serious health effects as inorganic mercury can be converted as it ascends the food chain into the much more neurotoxic organic mercury compounds, methyl and ethylmercury. Minamata disease was a consequence of just such a conversion together with a massive increase in concentration of methylmercury in shellfish which formed a significant part of the diet of people living around Minamata Bay, Tsubaki and Irukayama, 1997. Mercury contamination of tuna, swordfish and other large game fish is now a public concern and limits the consumption of these fish which provide a supply of essential omega-3 fatty acids.

Arsenic is much more widespread in the human environment than thought earlier. Water supplies are contaminated with high levels in many parts of the world and can reach toxic levels leading to all the classical symptoms of arsenic poisoning- this is especially so in places like Bangladesh, but arsenic levels are high in many countries including the USA. Recommended levels have been reduced downward to 10 ppb, parts per billion, WHO 2001.

Dr Dick Van Steenis has made several studies of releases from waste incinerators and crematoria that result in the release of toxic heavy metals and other particulates below 2.5 microns. These particulates enter the deep lung and effectively carry toxic material into the body. Carbon particulates also provide a potent source of destructive free radicals and are known to be very damaging to health, see inter alia, Van Steenis 1999, 2002.

Dr Chris Busby, 1995, 2000, 2003, of the low level radiation campaign, www.llrc.org ,in co-operation with scientists from all over the world has produced a major report, ECRR, 2003, that re-assesses the health effects of ionising radiation released from nuclear test programmes and the nuclear industry. The report calculates that the adverse health effects from such exposures to be responsible for 62 million extra deaths worldwide. A high price for the failed nuclear experiment.

 

 

 

 

 

 

            Deaths             

 

 

 

 

 

 

 

 

 

 

Figure 2. Numbers of Deaths from Medication Errors (wrong drug or dose) and from UNFORESEEN Adverse Effects of Drugs in England and Wales – 1990-2000.

 

The adverse effects from modern drugs are rapidly increasing and almost certainly under-

Reported, Eaton, 2002. Figure 2 shows a six-fold increase in deaths from unforeseen adverse effects for compounds that have been extensively investigated and for which considerable toxicological data will have been collected and trials on healthy and sick people carried out. Even with all this careful science unexpected and serious events can occur.

In summary, our environment is grossly polluted with a wide variety of chemicals and we have  virtually no understanding of the toxic effects of most of them. There is considerable evidence to show that many can cause adverse health effects and their use should be seriously limited or the compounds withdrawn. We continue to release novel chemicals into our environment as we seek ever more technological fixes for real or imagined problems. The latest involve potent broad spectrum herbicides, novel nucleic acids, and proteins associated with the production of GM crops.

It is important to recognise that usually only individual chemicals are usually tested. However, the exposure of the public is to the active chemical formulated in a finished product. This introduces further toxic possibilities. The other products in the formulation may be toxic themselves and/or act synergistically with the active compound to massively increase its toxicity. This was certainly the case with organophosphate pesticides which were formulated with known toxic compounds such as phenols, chlorophenols, epichlorhydrin, and organic aromatic hydrocarbons such as toluenes and  xylene. The phenols were withdrawn from the formulaton in 1993. Another example is the identification of the cardiotoxic properties of the surfactant used with glufosinate a herbicide which is widely used with some GM crops, Koyama et al, 1997, Very often it is impossible to discover the exact chemical nature of compounds used in formulations of an active compound- crude mixtures of compounds are commonly used, trace impurities are unknown and only the general properties of these compounds are known.  

MCS is one consequence of widespread distribution of numerous novel chemicals, usually in complex and often ill-defined mixtures, many of which may trigger a response either initially or following the development of full-blown MCS.

The whole environment, soil, water, air, and food, is contaminated and drastic action is required now to redress the present very unsatisfactory situation.

 

TRIGGERING MCS.

Many people with MCS can identify an event when they suffered a large exposure to a toxic chemical such as a pesticide being sprayed outside or in the house. Sometimes it may be a result of treatment of and adjacent property or a roof space where assurances are given that the material “is safe”. This is followed by an increasing sensitivity to the same or related chemicals then finally to quite diverse chemicals in very different situations. Among Gulf War Veterans, GWVs, an increased incidence of chemical and multiple chemical sensitivity, Wessely et al 2001, Proctor, 2000. More than 40 possible battlefield exposures, 1990-1, have been identified, IOM, 2000, with the major ones being vaccines, pyridostigmine bromide (anti-nerve agent prophylaxis), pesticides (organophosphates, pyrethroids, lindane), nerve agents (sarin, tabun, VX), depleted uranium, oil and smoke, Hooper, 2000. Frequently chemical sensitivity developed to perfume, worn by wives, children, and girl friends and previously enjoyed by the veteran, and/or to petroleum fumes which had previously not been a problem, Miller, 2000; Meggs1999. The chemistry of perfumes and petroleum products is extensive and variable but very different from the chemistry of the pesticides and vaccines and other major Gulf exposures.

However, chronic low dose exposure to chemicals which may not be apparent to a person can also lead to MCS.

 

WHAT IS GOING ON?

The conundrums posed by MCS require new understandings of the processes in the body that handle foreign chemicals. Major considerations are-

1.        Metabolism of foreign compounds in the body.

a.  The liver is the main organ of metabolism which generally takes place in two stages. Other metabolic sites in the body include the gut wall and there are small contributions from other sites.

b.  Phase 1 proceeds by oxidative processes involving cytochrome P450 enzymes which can be induced to cope with a high load of a foreign compound or by some drugs or chemicals, eg. Barbiturates. They may also be inhibited by some chemicals or drugs, eg. Cimetidine – this may lead to increased toxic effects.

c.  These enzymes are under genetic control and this genetic variability, known as polymorphisms, provides an understanding of why some people are more susceptible to or handle some chemicals better than others.

d.  These enzymes generate highly reactive intermediates that are commonly free radicals with considerable potential for causing tissue damage.

e.  In Phase 2 metabolism these Phase 1 reactive intermediates rapidly combine with a variety of simple compounds, sulphate, amino acids, glucuronic acid to form compounds that are much less reactive and generally more water soluble that can be excreted in the urine. An important secondary route of excretion, especially for more fat soluble compounds, is via the bile and thence into the intestinal tract.

f.   If Phase 1 metabolism outstrips the capacity of Phase 2 metabolism there will be a build up of reactive oxygen species. The ensuing oxidative stress will have severe adverse health effects. Some 80% of ME-CFS patients suffer from oxidative stress as a result of major detoxification problems, Rigden, 1999.

g.  If the threshold triggering enzyme induction is raised, for whatever reason, then toxic compounds would accumulate in the body and removal would be slow, Mellish, 2001 and undated.

 

2.        Allergy and MCS

The association of MCS with allergy has been the subject of considerable debate mainly concerned with the definition of allergy. One common scheme recognises four kinds of allergic/hypersensitivity reactions, Kuby, 1997.

a.  Type 1- is mediated by immunoglobulin E. IgE and is almost immediate, 2-30 minutes, and leads to systemic anaphylaxis which can be life threatening or to more localised anaphylaxis, insect bites, hay fever, asthma, hives, eczema, food allergies. IgE interacts with specific cells, basophils and mast cells that arstimulated to release potent vasoactive mediators such as histamine, leukotrienes etc.

b.  Type 2- is antibody-mediated. The antibodies, IgG and IgM, attack sites on cell walls leading to total destruction of the cell. This process takes longer, 2-8 hours. The cell damage/loss can be very serious, examples include blood transfusion reactions and some types of anaemia.

c.  Type 3- involves antigen-antibody (IgG) complex formation and occurs in 2-8 hours. The antigen-antibody complex precipitates in various tissues and induces an inflammatory reaction, examples include a number of chronic illnesses, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus. A delayed response to insect bites or vaccines may operate by this mechanism.

d.  Type 4-cell-mediated hypersensitivity is slow, 24-72 hours, and involves sensitised immune cells, special T cells, that release chemical messengers, cytokines, which activate other immune cells causing direct cell damage. Contact dermatitis, tubercular lesions, graft rejection are examples of this type.

Not uncommonly a single chemical or group of chemicals can induce more than one type of allergic response, eg. penicillins can cause type 1-4 type reactions.

 

3.        Meggs, 1999, sees allergy, defined as type 1 above, and MCS as opposite sides of the same coin which share a similar mechanism.

a.  The response to an allergen or a chemical irritant is not limited to the immediate site of application or entry. For example, about 2% of asthmatics will have their asthma triggered by eating certain foods. The inoculation of the gut leads to a response in the lungs- Meggs calls this switching. Bee stings may cause a generalised reaction involving the whole body and not just the local area affected by the sting itself. Similarly, chemicals that are generally inhaled can cause diverse symptomology associated with the central nervous system, headaches, pain, rashes,and gastrointestinal disturbances.

b.  Adaptation is a key four stage construct in chemical exposures that has been known from the 1950s.

i.          Stage 0 – exposures are tolerated without illness.

ii.        Stage 1– exposure leads to multiple complaints, headache, nausea, itching, flushing etc.

iii.      Stage 2- inflammation occurs in one or more organs, rhinitis, asthma, arthiritis, myositis (inflammatory muscle disease) etc. Continued low dose exposure at this stage will propagate the inflammatory condition(s).

iv.      Stage 3- fibrosis with tissue damage, irreversible lung disease, advance asthma, deforming arthritis etc. All the  major systems can be affected, musculoskeletal, respiratory, cardiovascular, gastrointestinal, genitourinary, nervous system.

The removal of the offending chemical(s) will lead to recovery except at stage 3.

c.  Conditioning is a feature of MCS. In chemical sensitivity the most common classes of chemicals to trigger a reaction are volatile and odorous. The odour threshold is many times lower that the chemical irritancy threshold and this may explain the large difference in exposure levels that develop in MCS sufferers.

d.  Essentially, chemical irritants bind to receptors on unmyelinated sensory nerve C-fibres which are found in the gut, airways, eye and genitourinary system and are more numerous in patients with MCS. Binding triggers the release of substance P (for pain) and other mediators of inflammation by interaction with mast cells, Figure 3 . The ensuing neurogenic inflammation can be switched to other sites in the nervous system, Figure 4.

 

 

 

Figure 3. Binding of chemicals to C-fibres triggers inflammatory response.

 

 

Figure 4.  Switching of response via the central nervous system, CNS.

 

Meggs make much use of  data from studies on GWVs and reports the extensive intolerance to petrol, diesel and oils as well as exhaust fumes. Many veterans describe their response as loss of awareness (‘spaced out’), loss of motor control and ataxia. In some cases this was so marked that driving became dangerous. Some veterans are now unable to fill up their vehicles at a filling station because this would render them incapable of driving safely.

Mortality studies on GWVs show that there is an excess of deaths from motor vehicle accidents. Whilst this has been dismissed by the MOD and DOD (Department ofDefence, USA) as a legacy of  military service resulting in extravagant and risk taking behaviour and an inability to cope with a return to civilian life no other explanation has been forthcoming. MCS offers another explanation that better accords with the evidence and military training which requires extravagant risks be avoided and makes motor control and awareness paramount.

 

4.        TILT- toxicant-induced loss of tolerance.

Ashford and Miller, 1998, and Miller, 2000, introduced this novel concept in which a common mechanism is postulated for both drug addiction and multiple chemical intolerance (their name for MCS) but with opposite responses- addiction (a demand for regular and repeated doses) and abdiction (avoidance of a substance). In both cases the intent is to avoid withdrawal symptoms that are associated with lack or presence of the substance. The basic idea is set out in Figure 5 in which the normal response to a stimulant (eg. caffeine) involves stimulation followed by recovery. Loss of tolerance leads to an increased response that leads to alternative strategies, abdication (avoidance) or addiction (persistent reinforcing doses).

Miller, in making a case for TILT, like Meggs relies heavily on the data from various studies involving Gulf War Veterans, GWVs. In particular, she draws attention to the concomitant development of a number of cravings for chocolate, sugar and caffeine etc. in GWVs. This phenomenon has not previously been commented on.

Another aspect of the proposed relationship between abdiction and addiction is that dopaminergic, 5-hydroxytrypamine, 5-HT, and opioid  neural pathways in the brain are associated with  addiction and the response to addictive drugs and food. These same pathways are damaged in GWVs – see below.

 

Figure 5.  TILT – relationship between abdiction and addiction

 

Ashford and Miller, 1998, also draw attention to the transport of volatile or aerosolised  inhaled substances by intraneuronal transport along the olfactory tract directly into the limbic system. This by-passes the blood-brain barrier and introduces compounds directly into deep (silent) brain structures where many basic bodily responses are controlled. This part of the brain is also called the ‘reptile’ or palaeolithic brain since similar structures with similar functions are found in many lower animals.

 

5.        The Blood-Brain Barrier.

This refers to the endothelial cells lining the blood vessels in the brain, Figure 6. The cells possess tight-cell jun