s c i e n c e / t e c h n o l o g y

BREATHER BEWARE? Chemical sensitivity may result from stress, learned behavior, or a new disease process

Ear, nose, and throat • Sinusitis • Polyps •Tinnitus • Recurrent otitis

Sophie L. Wilkinson C&EN Washington

From the ACS meeting

I s hypersensitivity to low levels of vola­tile chemicals a genuine medical prob­lem? Or is it simply a construct of some

overly stressed imaginations? Such dispar­ate views have sometimes engendered in­flamed debate, but that wasn't the case at last month's Agrochemicals Division sym­posium on multiple chemical sensitivity (MCS) at the American Chemical Society national meeting in Boston.

The session instead served as a forum for researchers to dis­cuss their current """ —--— work and to obtain ideas for future inves­tigation, according to symposium organizer Amy E. Brown, an as­sociate professor in the entomology de­partment at the Uni­versity of Maryland, College Park. Brown, a toxicologist, is co­ordinator for the uni­versity's pesticide ed­ucation and assess­ment program.

ACS asked the staff at the hotel where the symposium took place to hold off on using pesticides, de­odorizers, and disin­fectants in the room for two weeks before­hand and to increase the ventilation rate. Brown said some of the attendees with MCS who arrived at the session wearing dust masks and respi­rators felt comfortable enough to remove them after a short while. And some stayed in the room to

eat lunch rather than leave it for the less congenial conditions outside.

Despite the civil nature of the pro­ceedings, consensus on the condition has not yet been achieved. Some people believe that medical proof of MCS's exist­ence is elusive simply because the condi­tion represents a new class of disease, and researchers haven't yet found the right markers to search for. Others be­lieve that the symptoms are real but psy­chosomatic, brought on, for example, by a Pavlovian, conditioned response to the odor of chemicals or by previous physi­cal or mental abuse. It's possible that a combination of biological and psycholog-

Chemical sensitivity may affect many physiological systems

Neuropsychological 1 Multiple chemical sensitivity Attention deficit hyperactivity disorder Depression Migraines Cardiovascular Seizures χ ' .

• Arrhythmias Hypertension Hypotension Raynaud's phenomenon

Respiratory • Asthma • Reactive airways

dysfunction syndrome

• Toluene diisocyanate hypersensitivity

Skin

Miscellaneous • Chronic fatigue syndrome • Implant syndromes • Gulf War syndrome

Connective tissue, musculoskeletal • Fibromyalgia • Carpal tunnel syndrome • Temporomandibular joint

dysfunction syndrome • Arthritis • Lupus

ical factors are involved in MCS. Still oth­ers claim that MCS doesn't even exist.

Regardless, the fallout can be far-reaching for people who believe they have the condition (C&EN, July 22, 1991, page 26). To avoid exposure to ex­acerbating chemicals, they may need to alter their diet, clothing, personal care, and home-furnishing selections; change their work environment; and limit travel, recreational, and cleaning activities, ac­cording to Claudia S. Miller, assistant pro­fessor of environmental and occupation­al medicine at the University of Texas Health Science Center, San Antonio.

This enforced fastidiousness along with the medical symptoms can have a devastating impact on the patient's fami­ly, social, and work life. Miller noted that 80% of 112 MCS patients she surveyed were unable to work or could work only part time, compared with 80% working full time before their exposure.

Substances typically associated with ini­tiating or exacerbating chemical intoler­ances include insecticides, fragrances,

cleaning products, ===™~~~"™~== gasoline vapors,

vehicle exhaust, to­bacco smoke, paint, paint thinner, fresh tar and asphalt, nail polish and remover, hair spray, new cloth­ing, and outgasses from new furnishings such as carpets, Mil­ler said.

Some of the peo­ple exposed to such substances develop intolerances "not only for the chemi­cals they were ex­posed to but also for chemically unre­lated substances, in­cluding foods and medications," Miller said. These might include alcohol, caf­feine, chlorinated tap water, and even newspaper ink.

Unfortunately, there is no "gold stan­dard" to diagnose MCS, according to Karen I. Bolla, associ­ate professor of neu­rology, Johns Hop­kins Bayview Medical Center, Baltimore.

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58 SEPTEMBER 21, 1998 C&EN

science/ technology

And an MCS diagnosis may actually obscure other problems, she told C&EN.

"A lot of these people probably have things like multiple sclerosis, lupus, or a neuropsychiatrie disorder, and they don't get diagnosed and treated," Bolla said. "They go to the people that see MCS in everybody and don't even con­sider another diagnosis."

MCS challenges researchers because it apparently results in such a broad spec­trum of symptoms affecting numerous or­gan systems. These symptoms are said to include mucous membrane irritation, gas­trointestinal complaints, joint pain and muscle aches, respiratory complaints such as asthma, fatigue, dizziness, depression, memory loss, and difficulty concentrating. For some, the condition is disabling.

The syndrome is also mystifying be­cause it strikes victims across demograph­ic lines—including workers in an Environ­mental Protection Agency office building, sheep dippers in the U.K., and casino workers in California—who attribute their illnesses to a whole range of disease-foster­ing conditions, according to Miller.

Such characteristics would be highly unusual for a single type of illness, she said. This view lends weight to Miller's theory that MCS is not just a single syn­drome but is in fact a new class of disease. "The common denominator may be expo­sure to various chemicals, with suscepti­ble individuals then going on to show sen­sitivities," she suggested. This "toxicant-in­duced loss of tolerance" results in "many different symptoms in different people af­ter a variety of exposures. There is not one single pattern of illness. "

Miller draws an analogy with infec­tious diseases. Such diseases are initiated by the same general disease mecha­nism—infection with germs—but there are numerous types of germs. And infec­tion results in all kinds of illnesses that cause an enormous range of symptoms affecting every organ system in the body.

Even when some symptoms overlap, studying patients as a group may not be very iUuminating, added Nicholas A. Ash-ford, professor of technology and policy, Massachusetts Institute of Technology. Pa­tients suffering from tuberculosis, AIDS, and syphilis "all may have fevers and chills, but that's where the similarity ends," he told C&EN.

Likewise, clumping chemically sensi­tive patients together to try to account for their symptoms hasn't been produc­tive, Ashford said, most likely because they "may have arrived at this condition through a variety of pathways."

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Miller: a new class of disease

Ashford—who has collaborated with Miller in MCS research and in coauthoring "Chemical Exposures: Low Levels and High Stakes" (see page 105)—stressed that future investigations to determine the cause of the disease must separate patients not on the basis of their symptoms, but on their type of exposure.

"Part of the problem is that doctors don't pay attention to the exposure his­tory," Ashford said. "They are only pay­ing attention to what makes these pa­tients ill now"—not to what originally initiated their sensitivity. "That's like coming in on the second half of the sec­ond act of a three-act play and trying to make sense of what's going on."

Ashford and Miller believe that chem­ical sensitivity is a two-step process, in which a substance such as a pesticide or solvent promotes loss of tolerance. That exposure is generally acute, as in a chem­ical spill, but it may simply be repeated or continuous lower level exposure. "Subsequently, extremely low levels of chemicals, levels that do not bother most people and were never a problem for that individual before, trigger symp­toms," Miller said. And the chemicals in­volved in this second step may or may not be related to the initial sensitizers.

Of particular concern to Ashford are or-ganophosphate, carbamate, and pyre-throid pesticides; some anesthetics; some drugs (particularly psychotropics); and some organic solvents such as toluene. "All these chemicals are neurotoxins, and as a rule, we have not factored neurotox­icity into the regulatory screening regime very much. We think that is a prime mech­anism by which this condition occurs."

hPhthalaldehyde

Studies in progress appear to show ir­regularities in metabolism and blood flow in the brains of MCS patients, Ashford said. However, he acknowledged that the work that has been done, which is based on single-photon-emission computed to­mography (SPECT) scans, is "not as good as it should be."

This brain damage may be tied to "lim­bic kindling" and time-dependent sensiti­zation, Ashford believes. This "causes a change in the brain, such that the brain af­ter that point interprets low levels of chemicals as if they were high levels."

The basic premise of this proposed limbic kindling or neural sensitization model is that "the nervous system, quite independent of the immune system, has the capacity to amplify responses to stim­uli that are perceived as dangerous to the organism," explained Iris R. Bell, associ­ate professor of psychiatry, psychology, and family and community medicine at the University of Arizona, Tucson, and di­rector of geriatric psychiatry at the Tuc­son Veterans Affairs Medical Center.

"The main property of a sensitizing agent—in addition to its initial foreignness

Ashford: look out for neurotoxins

to the individual—is that it [generally] has to be given on an intermittent, repetitive sche­dule," perhaps over a week or two. Some studies show that an intense, abrupt stimu­lus can also initiate sensitization, Bell said.

"After that, you have to stop the stimu­

lus, and then the nervous system initiates a process of amplification," Bell told C&EN. "The next time the organism encounters that stimulus, or anything that can cross-sensitize with it, even at a lower dose, you will see an amplified response."

The intermittent nature of the initial exposures is a key factor that may ex­plain the failure of most lab tests to du­plicate MCS in animals. "In the real world, levels of chemicals fluctuate all the time," Bell explained. "In a work­place, you rarely have the kind of contin­uous, constant level of exposure that you'll see in an animal study testing for toxicity." As a result, the lab studies typi­cally turn up "either a direct toxic effect or a habituation effect, where you get a gradual reduction in responsiveness over time. But it is the intermittent exposures that will initiate sensitization."

Appropriately tested lab animals that go on to develop sensitivity share a num­ber of traits, Bell said. They are typically female, of specific genetic strains, and hyperreactive to novelty; they spontane­ously consume more sugar and have brain asymmetry (indicated by always go-

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s c i e n c e / t e c h n o l o g y »κ»"νννΐ'>^>^1;.

ing in one direction following a stimu­lus). She has found similar traits in chem­ically sensitive humans.

A number of pieces of circumstantial evidence implicate limbic and mesolim-bic system dysfunction in MCS, Bell said. Limbic kindling, which is a type of sensi­tization, is an animal model for temporal lobe epilepsy. This type of epilepsy in­volves abnormal firing in the limbic sys­tem, a part of the brain that has a "direct connection to the nose," she said. Fur­thermore, the amygdala, the particular region in the limbic system that is affect­

ed by this epilepsy, also sends input to the brain's dopaminergic mesolimbic sys­tem, Bell said. And exposure to solvents appears to affect dopamine.

"You begin to see some potential con­nections," she said. "Pesticides are capable of causing or facilitating limbic kindling." And solvent exposures can sensitize ani­mals' dopamine-mediated behavior.

"So the chemicals that are often iden­tified as things that might set off MCS are potentially the chemicals that could di­rectly alter nervous system function," she concluded. "An inhaled chemical

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could modulate the functioning of the mesolimbic system by way of changes bo th in the mesolimbic system and di­rectly in the amygdala."

Bell speculates that these chemicals could set off "subconvulsive" kindling of the amygdala or direct sensitization of the dopaminergic mesolimbic pathways or bo th—not enough to trigger epilepsy, but enough to interfere with smooth functioning of the nervous system.

As with epilepsy, this action wouldn't necessarily result in lesions or any other obvious damage to the brain, Bell said. "But the function of the cells is altered in a persistent way. And that is what we are postulating may go on in chemically sensi­tive people."

In other brain-related work, Bell found that the brain waves of people who consider themselves chemically sen­sitive were different from those who don't. In particular, their alpha-wave ac­tivity was higher than that of the con­trols, which may mean that their brains are less alert in a given situation. In addi­tion, animals show an increase in alpha activity when sensitized to drugs.

Many chemically sensitive people ex­hibit addictive behavior to particular foods, such as chocolate or coffee, be­fore they realize these substances are triggering attacks, Miller said. Once they cut back on eating large quantities of these foods, they go through intense withdrawal symptoms. And if they try to resume consumption, they may experi­ence an extreme reaction to even small amounts of the food, she said. For exam­ple, one alcoholic drink may cause ine­briation or lead to a severe hangover.

"In this regard, chemically sensitive pa­tients resemble certain reformed smokers or alcoholics who, after quitting their ad-dictants, report extreme sensitivity to minute amounts of the addicting agents," Miller wrote in a journal paper last year [Environ. Health Perspect, 105, 445 (1997)]. "One patient described the condi­tion as being 'like drug abuse without any of the fun.' "

Bell speculated that "perhaps there are people who are vulnerable to certain conditions such as sensitization, and de­pending on multiple factors, some may end up becoming substance abusers, and others become substance avoiders. It may involve somewhat the same path­ways, but with opposite results."

MCS may have ties to other ill-defined medical conditions whose symptoms in some cases are similar and whose causes have eluded researchers to date. These in-

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elude Gulf War syndrome, chronic fatigue syndrome (CFS), and the medical prob­lems of breast implant patients.

Miller, who has examined many Gulf War vets and is a member of the Depart­ment of Veterans Affairs' Persian Gulf Ex­pert Scientific Committee, has studied chemical intolerances in Gulf War vets, breast implant patients, MCS patients, and a healthy control group. Study participants rated the severity of their symptoms (affect­ing, for example, cognitive, neuromuscular, or gastrointestinal systems), intolerances (for such substances as insecticides, fra­grances, and caffeine), and the impact of their condition on their lives. In all cases, the control group scored considerably low­er on these scales than the other groups, Miller reported.

Nancy L. Fiedler, associate professor of the Environmental & Occupational Health Sciences Institute and Robert Wood Johnson Medical School, Piscat-away, N.J., compared healthy people with civilians and Gulf War vets who have chronic fatigue or chemical sensitiv­ity. She found that "for both civilians and veterans with MCS and CFS, psychologi­

cal distress and psychiatric disorders oc­cur at a significantly higher rate com­pared to healthy controls." She noted, however, that psychiatric disorder does not account for all MCS and CFS cases.

She also found that MCS and CFS in both civilians and veterans were associated with "increased rates of psychological stress, per­sonality styles associated with increased vul­nerability to stress, and self-reported expo­sures to chemicals that produce illness."

Possibly, stress or other nonchemical input may be enough to initiate the illness, according to Bell. And several studies of chemically sensitive people show that they report high rates of past sexual, phys­ical, or emotional abuse. However, other work has shown that the brains of people who have been sexually abused are differ­ent from those of chemically sensitive indi­viduals, she pointed out.

"Sensitization is involved in psychiat­ric disorders, it's involved in substance abuse, and it may be involved in chemi­cal sensitivity, so that may be one expla­nation why you see more psychiatric dis­orders. But it has no cause-effect relation­ship," Bell said.

"The trouble in talking with people about this issue is that they are desperate­ly trying to [show] that either it's caused by psychogenic factors or it's caused by toxic factors," Bell said. "I think that is an extremely incorrect view."

On the other hand, if MCS patients are treated with "lots of intensive psy­chotherapy, they get better," Bolla ar­gued. "If it is an immune disease or a dis­ease of the brain, you wouldn't expect them to get better" through psychologi­cal treatment.

But Bell said that many neurological and psychiatric disorders involve both psycho­logical and biological mechanisms, and "both psychological and biological therapies are helpful. The implication in MCS is that if you find a psychological factor, or even that a psychological treatment helps, that proves it's only psychogenic, and that's a fallacy."

Bolla nevertheless believes that MCS symptoms are psychosomatic and in many cases are rooted in prior abuse in the pa­tients' lives. People whose jobs may be in jeopardy or who have little control over their jobs are also susceptible. "People in assembly-line work will get 'mass hysteria'

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that they have been exposed to a chemi­cal they perceive to be toxic," Bolla said. In these cases, "the pattern is that a leader will become the first one affected, and then other people will follow." Bell noted, however, that MCS cases often occur in individuals outside of group settings.

On the basis of such evidence, Bolla concludes that MCS is "a psychological manifestation of a person's inability to han­dle stress very well. The predominant view in the medical and scientific commu­nity is that MCS [involves] the conversion of anxiety into physical symptoms." The Centers for Disease Control & Prevention, the American Medical Association, and several other medical groups do not recog-ni2e MCS as a disease, she noted.

But she doesn't dispute that the con­dition exists. "People who have the dis­order are really sick," Bolla said. "They are not saying, 'What symptoms can I de­velop so I can get out of work?' They re­ally have this fear of chemicals, and they really develop these symptoms to the point that they become incapacitated. They believe that all chemicals are dan­gerous and very scary things, and they

attribute every little bodily sensation to chemical exposure."

Unlike some of the other speakers, Bolla thinks chemical exposure must be long term, perhaps over a period of years—or very high, if the exposure is acute—to result in neurological harm. "When somebody is exposed for a short period of time to low levels of irritants, it is not biologically plausible that the ner­vous system has been damaged," she said. "Just because they are exposed to a chemical doesn't mean it is a toxic chem­ical and it produces health effects. We are exposed to chemicals every day."

Other evidence suggests that MCS symptoms may have a psychological com­ponent. People may learn to associate un­related bodily ills with coincidental chemi­cal exposure, much like Pavlov's dogs, ac­cording to Shepard Siegei, professor of psychology, McMaster University, Hamil­ton, Ontario. A subsequent encounter with that same chemical or others with a strong odor may trigger "an inappropriate response"—much as an individual who happened to eat a particular food just be­fore coming down with a stomach virus

may find that the smell or taste of that in­nocent food later induces aversion.

Likewise, someone who eats a partic­ular food prior to receiving chemothera­py treatment will later dislike that food and associate it with nausea, "even though they know the food doesn't cause the nau­sea," Siegei said. "They have this associa­tion that has been acquired. There is an in­evitability to it."

Even allergic reactions can be condi­tioned. One example Siegei cited con­cerns a patient who was allergic to roses and sneezed when presented with an ar­tificial rose. And guinea pigs sensitized to egg albumin administered in what he termed a "distinctive injection environ­ment" equipped with a mirror later showed signs of allergic reaction when they were returned to that environment even without being exposed to albumin.

Stress may play a role here too. Animals that were stressed by handling before con­ditioning mounted an allergic response to a stimulus paired with the antigen bovine serum albumin, Siegei told C&EN. But ani­mals that weren't stressed did not.

Hence MCS patients may actually be

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SEPTEMBER 21, 1998 C&EN 65

science/ technology

suffering from a conditioned immune re­sponse "elicited by environmental stimuli present at the time of antigenic chal­lenge," Siegel concluded. That "antigen-paired cue may consist of the sensory qualities (for example, odor) of the anti­genic stimulation." Furthermore, concur­rent stress may enhance the link between the stimulus and the response to the anti­gen. (Bell countered that no evidence of immune abnormalities has been found.)

Siegel emphasized that a conditioned response is "not 'in your head,' any more than any other physiological or biochem­ical process is." Like other types of learn­ing, conditioned responses result in alter­ations in brain chemistry, specifically changes in neurotransmitters, he said.

Extensive literature on Pavlovian con­ditioning "suggests novel research and treatment strategies for MCS," Siegel said. One treatment option is "extinction," in which the odor or taste is repeatedly pre­sented. Another strategy is "countercon-ditioning," in which the odor or taste is paired with a stimulus designed to be pleasant rather than aversive.

Ample opportunities for further re-

A hospital-based environmental medical unit built and furnished with special air-filtration equip­ment and with materials that release minimal amounts of chemicals could serve as a tempo­rary residence and testing facility for a patient believed to have chemical sensitivity

search exist to clear up the confusion and disagreements over MCS. Scientists should gather data from people accidentally over­exposed to chemicals, Ashford suggested. These people could be tracked for a peri­

od of years to determine whether the ex­posure they experienced triggers chemi­cal sensitivity.

Researchers also need to develop im­proved animal models of chemical sensi-

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tivity, he said. And, to demonstrate wheth­er some people are actually responsive to parts-per-billion levels of chemicals, Ash-ford urged that tests be conducted in envi­ronmental medical units (EMUs), which are essentially clean rooms free of suspect chemicals. EMUs utilize special air-filtration techniques and construction ma­terials and furnishings that release almost no chemicals into the air so as to reduce background exposures to the lowest lev­els practical.

People could stay in these rooms for a few days and then be exposed to select­ed chemicals under double-blind, place­bo-controlled conditions and tested for initial signs of improvement and subse­quent sensitivity as compared with con­trol groups. Ashford noted that the Na­tional Academy of Sciences backs EMUs. The government allocated funds to use the method to study Gulf War vets, he said, but ultimately the money was used for other, unrelated purposes.

Progress in dealing with MCS is also required in the policy arena, Ashford said. Society must grapple with the ques­tion of "what we mean by 'reasonable

accommodation' " to make living and working conditions acceptable for MCS sufferers.

Some changes can be made without placing an undue burden on businesses and institutions, Brown noted. For exam­ple, pesticide use can be minimized by improving sanitation, vacuuming pests, and putting weather stripping on the bottoms of doors to keep bugs out.

Society must also come to terms with compensating people who are truly dis­abled, either through workers' compen­sation or Social Security, Ashford said. And he believes regulations should be put in place to protect the public from this possible hazard.

Scientific proof that MCS exists doesn't have to be indisputable before these steps are taken, in Ashford's opin­ion. "We have a history of regulating car­cinogens and other substances long be­fore the evidence is scientifically iron­clad," he told C&EN. MCS skeptics, on the other hand, "want the scientific stan­dard of evidentiary proof to be used be­fore justifying social action," Ashford said. "That is very good from the chemi­

cal industry perspective, but it's not very good from a public policy perspective."

Even if a goodwill effort is undertak­en, the extreme sensitivity of some al­leged MCS patients makes an appropriate response tricky. "There are people who are so sensitive—at the parts-per-billion level—that it challenges our regulatory system," Ashford acknowledged. "Short of banning a substance, it is very difficult to control things at the ppb level."

But perhaps the government won't have to go that far. "Just a handful of substances appear over and over again as the prime causes of initial sensitization," Ashford said. "If we regulated those suffi­ciently, we could prevent the creation of the next generation of chemically sensitive people.

"After all, it would make little sense to regulate chemicals at the ppb level if what was required was to keep people from becoming sensitized in the first place. Indeed, by understanding the true nature of chemical sensitivity and who is at risk, we may prevent unnecessary and costly overregulation of environmental exposures in the years to come."^

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