Chemical Intolerance

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."

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."

OCCUPATIONAL HAZARD

Are Anesthesiologists Unwitting Addicts?

Anesthesiologists comprise only 5% of the physicians in Florida, but they account for about 20% of the doctors there who become addicted to narcotics. After undergoing treatment, formerly addicted anesthesiologists have the highest relapse rate--15%--of any medical specialty and are often forced to leave the profession. The relapse rate for all specialties is just 6%.

Mark S. Gold, professor of psychiatry, neuroscience, community health, and family medicine at the University of Florida College of Medicine, hypothesized that repeated operating-room exposure at low levels to the anesthetic propofol and the synthetic analgesic fentanyl--both commonly used in surgical procedures--may inadvertently cause anesthesiologists to become addicted to those drugs and to relapse after undergoing treatment. In the operating room, patients receive propofol and fentanyl intravenously but breathe out some of the drugs. Also, many anesthetic machines are leaky. "Opioids used in the operating room have become more potent recently, but air-handling systems designed in the 1980s are still in place," he told attendees at a recent meeting on chemical intolerance and addiction. Fentanyl has an analgesic potency about 80 times that of morphine.

Gold and his colleagues took air samples in various parts of an operating room and had them analyzed for fentanyl and propofol with liquid chromatography and tandem mass spectrometry. He found the highest levels of these drugs near the patient's head--where the anesthesiologist sits or stands. "We have routinely detected fentanyl in excess of 1 nanomole/L in the exhaled patient's breath, effluent gas from the cardiopulmonary bypass machine, and workspace of the anesthesiologist," he said. "We know that intermittent exposure would sensitize the brain to drugs of abuse and make it more, not less, responsive to them."

Some anesthesiologists compensate for their propofol or fentanyl cravings by becoming addicted to narcotics or alcohol, Gold explained. For example, they sometimes feed their addiction with fentanyl painkiller lollipops designed to speed relief to cancer patients.

"Environmental exposure may explain why there are such high rates of addiction among anesthesiologists and why their recovery often necessitates changing medical professions," Gold concluded.

"There is hardly a department chairman who doesn't know an anesthesiologist who died of a narcotic overdose," Gold observed.

When Gold proposed this hypothesis while speaking at an anesthesiologists' conference a few years ago, the audience was highly skeptical of the idea that operating-room exposures could play some role in addiction. They believed that stress and easy access to narcotics are responsible.

Gold's research shows that low levels of some substances probably can cause addiction without any awareness on the part of those who are becoming addicted, said Claudia S. Miller, professor of environmental and occupational medicine at the University of Texas Health Science Center, San Antonio.

ANOTHER LINK between intolerance and addiction shows up in research on brain structure. Studies show that amphetamine and cocaine addiction affect dendritic branching in rat brains, said Terry E. Robinson, professor of psychology at the University of Michigan, Ann Arbor. He placed rats in cages where they could self-administer amphetamine or cocaine for a few weeks to a month, and then the drugs were removed from the cages for weeks to months before the rats' brains were examined. He found that both drugs increase dendritic branching and spine density in the nucleus accumbens and medial prefrontal cortex of the rats' brains. In other words, the drugs changed brain structure in a way that reflects a reorganization of brain circuitry.

Rats that live in a complex environment usually develop more dendritic branches in the parietal cortex than rats kept in a simple cage. However, if they are treated with amphetamine, cocaine, or nicotine before they are placed in a complex environment, rats fail to develop more branches, Robinson said. The drugs seem to block the ability of experience in a complex environment to increase dendritic branching.

He concluded from his studies that "amphetamine, cocaine, and nicotine reorganize patterns of synaptic connectivity in many rat brain regions and influence the ability of other experiences to do the same." The brain systems that were changed include those involved with motivation, decision-making, and other cognitive processes, he said. "They undergo a fundamental reorganization as a consequence of being exposed to drugs," which persists for months after exposure.

In human and rat brains, the subcortical regions--those involved with core motivational functions--are similar, Robinson said. If human brains respond to drugs in the same way as rat brains, then "if you've had drugs in the past, it may change your brain's ability to respond to challenges in the future," he said. "In other words, structural plasticity--the ability of the brain to restructure--may decrease because of prior drug exposure. The normal brain changes its wiring all the time as the person encounters new experiences, so it is important not to impair this capacity."

Robinson's study raises the question of whether exposure to drugs like amphetamines in the past would produce brain changes, making the person more susceptible to chemical intolerance, he said. Or the converse might be true--chemical intolerance might strengthen adverse reactions to drugs of abuse, he observed.

In a rat model for chemical intolerance, similar methods could be used to study brain changes as the rats are exposed to environmental chemicals, such as pesticides and solvents, which often initiate chemical intolerance in humans, Robinson said.

David H. Overstreet, professor of psychiatry at the University of North Carolina, Chapel Hill, developed a strain of rats that could perhaps be used as an animal model for chemical intolerance. He selectively bred cholinergically susceptible and resistant strains of rats, called the Flinders Sensitive Line (FSL) and the Flinders Resistant Line based on their responses to the organophosphate pesticide diisopropylfluorophosphate (DFP). He used the resistant line as control rats, because they are very similar to normal rats.

FSL rats are similar in many ways to chemically intolerant patients and to depressed individuals, Overstreet said. First, they are sensitive to DFP, and organophosphate pesticides are one of the most common triggering exposures reported by the chemically intolerant. Also, FSL rats react negatively to nicotine, ethanol, and structurally unrelated drugs, including serotonin agonists and dopamine antagonists. Chemically intolerant patients report adverse responses to nicotine, alcohol, and many of the same drugs, he said.

FSL rats are also similar to humans suffering from depression, and individuals with chemical intolerance have a higher incidence of depression, Overstreet noted. The rats show reduced activity and appetite and increased REM (rapid eye movement) sleep, just as many humans are inactive, eat little, and experience intermittent sleep when depressed. FSL rats also exhibit increased gut permeability and airway reactivity when exposed to egg protein following sensitization by injection, he said. This could be an animal model for the food intolerance and asthma reported by chemically intolerant individuals.

"Further study of FSL rats, chemically intolerant patients, and depressed patients by using diverse approaches is needed to obtain a clear picture of the mechanisms that may underlie chemical intolerance," Overstreet said. FSL rats need to be tested with more of the chemicals, such as volatile solvents, that chemically intolerant individuals react to, he added.

Barbara A. Sorg, professor of neuroscience at Washington State University, Pullman, is another researcher who has been developing a rat model for use in studying chemical intolerance. She hypothesized that the process occurring in some humans may be similar to the behavioral sensitization to addictants seen in rodents. Because there is much evidence that the limbic system in the human brain is involved in chemical intolerance, the animal models are based on amplification of behaviors controlled by limbic circuitry.

In rats, repeated doses of cocaine sensitize the mesolimbic dopamine pathway in the brain, leading to addiction. Using rats that had never been exposed to cocaine, Sorg repeatedly exposed them to low levels of formaldehyde vapor. Later, when she administered cocaine to these rats, they responded as if they had been previously sensitized to cocaine, suggesting that the mesolimbic pathway may have been sensitized by the formaldehyde exposure. She concluded that the sensitized rats "may be analogous to individuals who become chemically sensitive after long-term low-dose, or single high-dose, exposures."

Sorg also paired an aversive odor with a foot shock. Rats that had been exposed to formaldehyde had a greater fear response than the unexposed control animals. Based on these laboratory studies, Sorg concluded that "amplification of limbic output after exposure to environmental chemicals and drugs of abuse might make the animals react more strongly to the stimuli." Sorg's research protocol could be applied to FSL rats, Overstreet said.

ALTHOUGH THE results from genetic research and animal studies are important, some researchers say that the best way to make progress in treating and understanding chemical intolerance is to construct special hospital rooms where patients can be isolated from pollutants and tested with individual substances. In the 1950s, several such hospital rooms were set up in the U.S. and used for about 30 years to diagnose tens of thousands of patients, said William J. Meggs, professor of toxicology at the Brody School of Medicine at East Carolina University, in Greenville, N.C.

In these units, patients fasted for about five days, receiving only water so they had a chance to withdraw from the effects of any chemicals and foods they were reacting to. Then foods were introduced one at a time, and the patients were monitored for adverse reactions. After food testing was complete, they were exposed to common pollutants, such as tobacco smoke, to measure reactions. At the end of the period, the patients usually knew what foods and other substances triggered their illness and could modify their home and work environments to avoid them.

NIAAA Director Li told C&EN that setting up similar isolation units in hospitals would be an important way to make progress in understanding chemical intolerance. Several isolation units have recently been constructed in Japan.

Because research on chemical intolerance is at an early stage, it will take at least several years before cross-fertilization of ideas between NIEHS and NIAAA might produce useful results. The conference gave the participants ideas for joint research but no surefire paths to rapid progress. The ultimate aim of the collaboration is to develop preventive and treatment strategies for chemical intolerance, said Samuel H. Wilson, deputy director of NIEHS.