Bette Hileman

Chemical intolerance, or as it was once known, multiple chemical sensitivity, continues to be a serious health issue. Up to 6% of the U.S. population may react so seriously to chemical exposures that the quality of their day-to-day lives is affected. What causes this condition it still largely a mystery, and there is no effective way to treat the problem.

Researchers have begun to recognize, however, that there are similarities between peoples' response with chemical intolerance and withdrawal symptoms from chemical addictions. This parallel was the topic of a recent joint meeting of two federal research institutions, the National Institute of Environmental Health Sciences (NIEHS) and the National Institute on Alcohol Abuse & Alcoholism (NIAAA). It was the first time chemical intolerance and addiction researchers have come together to explore the interface between their fields.

The aim of the conference was to see if some of the research methods used to study addiction could be employed to investigate chemical intolerance. Other important issues included exploring the idea that people who are addicted to drugs or alcohol may be more likely to become chemically intolerant and whether certain genetic variances make individuals more susceptible to chemical intolerance. Participants at the conference also considered whether the disease mechanisms operating in alcoholism or drug addiction also apply to chemical intolerance.

Chemically intolerant individuals are those who, after exposures to often high concentrations of compounds--such as pesticides, solvents, cleaning agents, toxic molds, or volatile organic compounds--begin to experience adverse effects from exposures to low levels of these substances. As time goes on, they begin to react to exposures that never bothered them before, such as fragrances, cleaning agents, tobacco smoke, alcoholic beverages, medications, caffeine, and traffic exhaust.

In key respects, "chemical intolerance looks like the flip side of addiction," said conference organizer Claudia S. Miller, professor of environmental and occupational medicine at the University of Texas Health Science Center, San Antonio. "Addicted individuals seek repeated hits of a substance," she explained, "while the chemically intolerant shun many of the same substances. But the reason for these seemingly opposite behaviors may well be the same--to avoid unpleasant withdrawal symptoms." Further, she said, "similar neurotransmitter pathways and pathophysiology may underlie both addiction and chemical intolerance."

Epidemiological studies show that 3-6% of the U.S. population suffers from chemical intolerance severe enough to be disabling or compromise their quality of life, Miller said. A 1994 report prepared for the European Commission concluded that chemical intolerance is found in at least nine European countries as well, though no studies have been done to determine its prevalence in Europe.

The chemically intolerant have one or more of a wide variety of symptoms. These include skin disorders, memory and concentration difficulties, depression, debilitating fatigue, arrhythmias, headaches, asthma, and digestive problems. The condition affects people from all walks of life, including hairdressers, pesticide applicators, homemakers, chemical plant workers, office workers, and Gulf War veterans.

SO FAR, there is no generally effective way to treat chemical intolerance, except by avoidance of the chemicals, foods, and other substances that trigger symptoms. But sometimes it is impossible to identify the precise substances. To regain their health, some severely affected patients totally disrupt their lives, such as moving to a house with few sources of toxicants in a rural area where exposures to factory emissions and traffic exhaust are minimal.

A phenomenon called masking makes it difficult for the chemically intolerant to know what is triggering their symptoms, Miller said. If people are sensitive to a variety of substances, they can go through the day reacting to fragrances, hair spray, vehicle exhaust, foods, and other substances that create a confusing array of symptoms. The response to each substance overlaps with the next, and the effect of any single exposure is not apparent.

A decade ago, many physicians claimed chemical intolerance did not exist--that patients who believed they suffered from low-level chemical exposures have a psychosomatic illness. Now, there is widespread recognition that the vast majority of these patients are indeed sick and that their symptoms have something to do with chemical exposures.

"Most people seem to have a natural ability to tolerate a wide variety of exposures," both natural and synthetic, Miller said. The chemically intolerant have lost that natural resistance.

"From a toxicologist's point of view, this sort of response to structurally unrelated substances is difficult to understand or believe," Miller continued. "The exposure levels that cause symptoms are orders of magnitude below established safety limits. We may be dealing with a new paradigm for environmentally induced illness--in fact, perhaps, an entirely new disease mechanism."

McKeown-Eyssen Li Miller

THE SPEAKERS at the meeting presented studies that illustrate how some of the research methods employed in addiction studies might be used to study chemical intolerance. They also discussed research that shows similarities between addiction and chemical intolerance.

Gail E. McKeown-Eyssen, a professor in the department of public health sciences and nutritional sciences at the University of Toronto, matched 203 chemically intolerant women with 162 women as controls. Blood samples from patients and controls were analyzed for variants of six genes. She found significant variations, called polymorphisms, of three genes--CYP2D6 (cytochrome P4502D6), NAT2, and PON1--in the intolerant cases compared with the controls. All of these genes are involved with metabolism of environmental contaminants, she said.

One explanation of these findings might be that the chemically intolerant metabolize environmental chemicals differently than do healthy individuals, McKeown-Eyssen said. Some specific enzymes--gene products of these polymorphisms--are likely associated with chemical detoxification, she said. For example, CYP2D6 is key to the metabolism of a wide variety of diverse substances, including therapeutic drugs, drugs of abuse, and neurotoxins. The arylamine transferases expressed by NAT2 metabolize aromatic amines, as well as other substances, and PON1 is essential for the metabolism of organophosphate pesticides, which several researchers have implicated in the initiation of chemical intolerance. Individuals with selected polymorphisms of both CYP2D6 and NAT2 were 18 times as likely to be among the chemically intolerant, suggesting that gene-gene interactions need to be considered, she said. But before firm conclusions can be drawn, "the study needs to be replicated because the numbers of cases and controls with some genotypes were quite small," she said.

NIAAA Director Ting-Kai Li described genetic differences in humans that make some people susceptible to excessive drinking of alcoholic beverages and lead others to avoid alcohol. He also discussed his work with rodents that shows marked differences in voluntary alcohol consumption and explained how the knowledge and techniques used to study alcoholism might be applied to chemical intolerance.

In the U.S., 8.5% of the adult population suffers from alcohol abuse or dependence, Li said. There is about a three- to fourfold difference in individual responses to alcohol, and about half of this is genetic, he said. Genetic predisposition to drink, he explained, depends to a large extent on variants of the alcohol dehydrogenase gene (ALDH2) and the aldehyde dehydrogenase gene (ADH).

When alcohol is consumed, it is first converted to acetaldehyde by the alcohol dehydrogenase enzyme and then to acetate by the aldehyde dehydrogenase enzyme, Li said. Ethanol is both a stimulant and a depressant; acetaldehyde is a stimulant and also a toxic compound that causes aversive reactions. Acetate is a depressant. Those who have genetic variants of the ADH gene that make it difficult to metabolize acetaldehyde generally find drinking unpleasant because they can't eliminate the toxic acetaldehyde, he explained. Drugs, such as Antabuse, developed to treat alcoholism, prevent the conversion of acetaldehyde to acetate. As a consequence, the drugs cause a highly unpleasant reaction when alcohol is ingested.

Because nearly all people with chemical intolerance feel sick when they consume even small amounts of alcohol, research on the biological mechanisms of alcohol in these patients might help elucidate why it causes such extreme reactions, Li said. Certain Gulf War veterans, who in the past could tolerate a great deal of alcohol, find that they can't drink even one beer after they become chemically intolerant.

"Another parallel is there are a variety of acetaldehydes and other aldehydes in the environment," Li said. They are in tobacco smoke, some foods, and traffic exhaust. The chemically intolerant may not be able to metabolize these aldehydes, just as they can't deal with the acetaldehyde metabolized from alcohol, he explained.

Roland R. Griffiths of the Johns Hopkins University School of Medicine discussed caffeine addiction and its relevance to chemical intolerance. "Caffeine is the most widely used mood-altering drug in the world," he said. In the U.S., 80-90% of adults are regular consumers, with a mean daily intake of 280 mg, mostly from coffee and soft drinks. A 6-oz cup of coffee has an average of 100 mg of caffeine, while a caffeinated 12-oz soft drink has about 40 mg.

"Chemically intolerant people have unusual sensitivity to low doses of caffeine and are more likely than those in the general population to be either addicted to or avoidant of caffeine," Griffiths said.

In most people, low doses of caffeine have primarily positive effects, producing a sense of well-being, increased energy, alertness, self-confidence, and decreased sleepiness, he said. "On the other hand, higher doses of 200-500 mg may produce anxiety, nervousness, and jitteriness."

"In prospective experimental studies, 13% of caffeine consumers had some kind of functional impairment, such as missing work or failing to complete daily responsibilities, if they went through caffeine withdrawal," Griffiths reported. "Avoidance of withdrawal symptoms plays a central role in the habitual consumption of caffeine."

Some people are able to detect doses of caffeine as low as 1.8 mg, and such low levels are physiologically active in those individuals, Griffiths observed. "Just as low doses of chemicals trigger negative reactions in the chemically intolerant, caffeine-susceptible individuals experience withdrawal symptoms after consuming surprisingly low amounts of caffeine for only a few days."

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