TOLUENE SENSITIVITY AS PART OF THE
CHEMICAL SENSITIVITY SYNDROME - CASE REPORT
Linda Livingston, Ph.D.
Mansour R. Sanjar, M.D.
William J. Rea, M.D.
Scientists are exposed to much higher levels of a variety of toxic chemicals in their work environment than would be found in most environmental situations. When ventilation and building construction are inadequate to correct for these high exposure levels, severe illness may occur even to the point of total incapacitation. The following case history involves toluene and other chemical sensitivities. Toluene, a lipophilic solvent, produces many effects in the body including decreases in plasma concentrations of tyrosine, tryptophan, and other amino acids. When an individual is overcome by a chemical reaction, many chemical sensitivities become apparent and recovery may take years. Toluene, prolactin, tryptophan, phenylalanine, tyrosine, serotonin.
In the medical community, especially academia, many personnel are exposed to high concentrations of certain chemical compounds. The construction of new medical schools in this country during the 1970s may have resulted in many buildings suffering from the "tight building" syndrome. Sealed windows, enclosed laboratories, construction in high traffic and delivery areas, compounded with inadequate ventilation, can produce profound illness.1 The epidemic of "Legionnaire's Disease" helps in understanding some of the implications. The general adaptation, syndrome,2-4 which explains physical and mental stress, is understood by most medical faculty members and physicians in the United States. Unfortunately, what is less well understood is the variety of disturbances in the body's homeostatic mechanisms produced by exposure to chemicals. Total body load is often ignored, as is biochemical individuality of response.
The chemical sensitivity syndrome was first described by Randolph as an adverse reaction to an
ambient dose of toxic chemicals.5,6 Phenolated, chlorinated, and other hydrocarbon compounds can distort the body's homeostatic mechanisms and cause immune suppression and/or dysregulation.7,8 Environmental assaults are often mistaken for viral illnesses.9 Many physicians have recognized that their own personal illnesses have been produced by an exposure to environmental chemicals.10 This case history illustrates how a medical scientist became totally disabled following exposure to toluene and other toxicants in a medical school environment and the difficult road to recovery.
MATERIALS AND METHODS
The patient is a 47-year-old Caucasian female. She has been on a medical leave of absence for the last four years, following a collapse at work triggered by prolonged exposure to toluene and other toxicants in her immediate work environment. She has been unable to return to work and has been forced to receive social security disability benefits.
The patient had worked continually in a medical school environment for twenty-three years prior to collapse, during which time she had been highly productive and healthy. A few months before the collapse, her family physician of many years detected an elevated blood pressure, gastritis, and extreme fatigue. This was followed by metrorrhagia of three weeks duration. The fatigue worsened until viral-like symptoms occurred in early January, 1986. Many other individuals in her immediate work environment complained of similar symptoms and reported a heavy odor of toluene in the hallways. Her office was located above a passageway for automobile traffic. In addition, the positron emission tomography building, immediately adjacent to her building, was being repaired and heavy black smoke was released from the lines into the air. Her physical and mental exhaustion became so severe that bed rest at home for a week had little effect. She was admitted to a hospital for tests (cardiovascular, gastrointestinal, and pulmonary function) and prescribed amitriptyline (25 mg at bedtime) to correct her insomnia. There were two additional hospital stays within the year following collapse. During this time many physicians were seen and medication prescribed, i.e., thiothixene (10 mg/day) and chlorpromazine (100 mg/day), that more often than not worsened her condition. Gradual recovery followed a thorough endocrinological evaluation (pituitary, thyroid, adrenal, and ovarian function), while psychiatric management and counseling corrected the severe insomnia, using 25 mg of imipramine at bedtime. Stabilization was accomplished during an eighteen-month period but the patient still did not feel well.
The laboratory and office building where she worked had inadequate ventilation with little fresh air in certain areas and an outside air intake received air from an incinerator. Only half of the laboratories were equipped with hoods and these were often inadequate.1 An environmental evaluation was conducted utilizing gas chromatography analysis to determine the presence of volatile hydrocarbons. Many toxic chemicals were found in the air. Blood chemical analysis confirmed the presence of many chemicals, including high levels of 2- and 3-methyl pentanes, hexane, and toluene. Intradermal, oral, and inhalant challenges for food, chemical, and inhalant sensitivities, and blood analyses for vitamin, mineral, and trace element levels were performed. A stringent environmental control program consisting of avoidance of inciting agents, exercise, sauna treatment to facilitate removal of chemicals, antigen injections, and an amino acid fast (70 gms/day free-form amino acids, Medifast) produced marked improvement in her health and well-being. The patient is currently feeling well on a maintenance diet with preservative- and additive-free food (four-day rotation cycle) and using the other environmental controls.
On admission to the hospital in January, 1986, there was a marked fluctuation in blood pressure (140/95 to 106/64 mm Hg) while in a sitting position, elevated blood triglycerides (256 mg/dl, normal range 30-200) and white blood cell count (12.6 x 10, normal range 4.8 to 10.8.) Thyroid studies (T3 and T, levels), fluoroscopy of upper gastrointestinal tract, pulmonary function by spirometry and electrocardiogram were normal. X-rays of the chest showed granulomas in the base of the left lung. The patient was placed on 25 mg of amitriptyline at bedtime for insomnia. Weekly biofeedback and counseling sessions alleviated some of the physical and mental stress. However, during the next eight months, there were repeated bouts of metrorrhagia.
Upon readmission to the hospital in September, 1986, she reported that her blood pressure. temperature, sleep, etc. fluctuated and it took maximum effort for her to maintain balance. An electroencephalogram was reported as normal, although the amplitude was depressed and there was increased frequency of theta waves. Laboratory results revealed abnormal endocrine function: 26.3 mIU/ml for follicle stimulating hormone (normal range 5.9-17.2), 70.5 mIU/ml for luteinizing hormone (normal range 2.8-29.0), and 43 ng/ml for prolactin (normal range 0-20). A cerebral tomography scan showed a normal-sized pituitary gland with no evidence of microadenoma. During the three-week stay hospital stay, 10 mg of thiothixene at bedtime was prescribed. The insomnia worsened with an increased dazed state during the day. This required admission to a third hospital where she requested observation for any thiothixene-withdrawal reactions. During this one week stay, no tests were performed. She was prescribed chlorpromazine in increasing doses and kept in the intensive care unit until she was almost totally incapacitated and in very grave condition. The diagnosis at that time was schizophreniform reactions and paranoia-like disorder, even though the elevated blood prolactin results were presented upon admission by the patient.
After being dismissed from the hospital, she saw a different psychiatrist who prescribed 25 mg of amitriptyline at bedtime. Her sister, a registered nurse, cared for her at home in November, 1986. It took three weeks to correct the severe disturbance in sleep. The psychiatrist later prescribed 50 mg of imipramine at bedtime and then 0.5 mg of alprazolam at bedtime, which was continued for the next two years. A trial prescription of 2 mg of haloperidol produced jaw rigidity and tongue swelling.
A thorough endocrinological evaluation in November, 1986, including a prolactin response curve induced with thyrotropin-releasing hormone (TRH), confirmed an elevated prolactin level. The baseline prolactin was 11.2 with a peak response of 104.3 ng/ml (normal peak is less than 40 ng/ml). The TRH stimulation showed a normal thyroid stimulating hormone (TSH) response. Bromocriptine, a dopamine receptor agonist, was prescribed at 1.25 mg/day to stabilize the prolactin levels. Ovarian cysts detected by ultrasound were dispersed with 50 mg/day of clomiphene. Elevated testosterone levels (47.2 ng/dl, normal range 0-30.0) were corrected with dexainethasone (0.5 mg/day). The patient was not going through menopause: FSH = 3.7mlU/ml (reference range 1.0-12.0), LH = 9.5 mIU/ml (reference range 1.0-12.0) and DHEA = 112 ug/dl (reference range 60-150). The dexamethasone-suppression test (testosterone 46.6-13.3 ng/dl, reference range less than 30; DHEA 74.4-37.5 ug/dl, reference range 60-150; and cortisol 7.5-1.7 ug/dl, reference range 4-20) showed that according to depression evaluation criteria, the patient was normal and the "brain fog" was thought to be due to cerebral edema.
The patient continued to improve but functioned in a semidazed state that took maximum concentration to keep up with basic necessities. Visual disturbances (wearing contact lens was discontinued, trifocals were prescribed and up to four different pairs of glasses had to be worn during the day), tinnitus, paresthesia (two fingers were almost severed while mowing the lawn), and changes of smell and taste were noticed. Electroencephalography and magnetic resonance imaging investigations were reported as normal. However, decreased amplitude and increased frequency of theta waves in the electroencephalogram were again observed. Although somewhat improved, she was still unable to function normally and saw an environmental health physician in April, 1988. She was found to have the blood concentrations of toxic chemicals shown in Table 1, i.e., aromatic (toluene, xylene), aliphatic (cyclopentane, pentanes, and hexane), and chlorinated (trichloroethane and tetrachloroethylene) hydrocarbons. After a year, the levels of most of these volatile hydrocarbons had decreased. There were high levels of cryptopyrrole, methylnicotinamine and erythrocyte superoxide dismutase activity. The blood and urine concentrations of amino acids are shown in Tables 2 and 3. Levels of eight essential amino acids were low in the blood, four (leucine, threonine, tryptophan and valine) were low in the urine, while that of phenylalanine was elevated in the urine. Plasma protein and serum amino acid electrophoretic patterns were normal. The cell-mediated immunity test gave a positive reaction to tetanus only, suggesting some immune dysfunction.
The patient was found to be sensitive to many chemicals by intradermal and inhalational challenges (Tables 4 and 5). She was also found to be sensitive to molds, lake algae, dust, dust mite, cat dander, feathers, histamine, serotonin, poison ivy, pine pollens, cigarette smoke, orris root, ethanol, formaldehyde, newsprint, perfume, diesel exhaust, mixed weeds, pine terpene, grass terpene, cotton, baker's yeast, brewer's yeast, cane sugar, chicken, cow's milk and egg. Antigen injections, rotation diet, and rigid environmental controls with amino acid supplementation produced a decrease in blood pressure (130/100-100/80) and improved stabilization of basal temperature within one month. When injections were missed for two weeks, symptoms returned and a three-day mineral water fast was necessary. Vitamin C (1000 mg per day) prevented bruising and peripheral cyanosis in her legs.
Basal temperature charts maintained throughout the course of treatment proved to be very informative (Figure 1). After two and one-half years of treatment, the menstrual cycle normalized- (Figure 1A). The patient had become markedly obese (at least forty pounds overweight) and an exercise program was initiated (aerobics classes started but not sufficient energy to continue, followed by bike riding and walking). Figure 1B shows the fluctuating basal temperature taken each morning upon awakening during the exercise program, which may represent toxicant release from fat tissue. Lipodystrophy with possible toxic poisoning was then diagnosed and a lipectomy was performed to remove fat samples (approximately 2 liters) for analyses. Unfortunately, the samples were spilled in transit to the laboratory and analysis was not possible. However, following the lipectomy (early August, 1988) the temperature became more stable (Figure 1C) and remained essentially the same unless the patient was reexposed to toxicants at which time the temperature decreased.
In September, 1988, the patient entered a three-month, physician-monitored free-form amino acid diet (Medifast) and moderate exercise (walking) program and lost forty pounds. During this time, she showed remarkable improvement in mental and physical function and in a feeling of well-being.
Because of the history of exposure to toluene, the demonstration of toluene in her blood, and the known cerebral and endocrinological effects of toluene exposure, she underwent double-blind inhalation challenge testing in a chemically-free booth to assess sensitivity to toluene. She was tested with two saline controls and toluene, in each case with a nasal clip in place to prevent any detection of odor from the substances. No reaction to the controls was observed (Table 4). On exposure to toluene she experienced head flushing, a dizzy sensation, complaints of flushed feelings in her arms, and appeared very distant and foggy in her thinking. Independent neurological assessment by a psychologist, before and after each inhalation challenge testing, showed significant worsening on neurological screening, and on visuoperceptual motor functioning with exposure to toluene. The patient also was perceived by the objective testor to be affected adversely by toluene exposure with clumsiness, tremulousness, and unsteady movement of hands and legs. These responses confirmed a sensitivity to toluene. These effects were not seen on the control challenges.
Nine months later, upon reexposure to toluene (1989), she deteriorated rapidly and again went on the amino acid liquid diet (70 grams/day). After three weeks on this program, the patient showed improvement. Another twenty-four hour amino acid analysis was conducted and, surprisingly, eight essential amino acids were decreased or absent from the urine (Table 3).
She is currently working on developing an uncontaminated, preservative- and additive-free diet plan for the future maintenance of her health.11, 12
Toluene is a lipophilic solvent that affects essentially all cells in the body, especially cellular membranes with their diverse physiological functions. Although toluene was not the only chemical present in the patient's blood, it will be used as a model. In fact, the patient had higher levels of 2- and 3-methyl pentanes and hexane, which are solvents which damage cellular membranes. Clearly, the total pollutant load is significant in inducing this patient's problems. However, toluene in the work place was pervasive, and she was aware of the odor when she collapsed, so this substance is likely to be the one that severely disturbed her homeostasis.
Figure 2 illustrates the symptoms experienced by the patient. Although the patient had experienced no subjective feelings, an elevated blood pressure was an early symptom. This was followed by increasing fatigue accompanied by sensorial malfunction, decreased alertness and weight gain. Metrorrhagia, nerve fragility with forearm muscle rippling, and insomnia became progressively worse until the patient finally collapsed and was unable to continue working. The series of events clearly show the progression through adaptation to exhaustion. Since toluene and other solvents may be stored in fat tissues at several hundred times the concentration found in plasma, it is not surprising that the patient felt much worse when attempting to lose weight until the amino acid diet and sauna treatment was instituted.
Toluene and similar aromatic hydrocarbons, such as xylene and styrene, are highly toxic to all species at much lower levels than those established by the National Occupational and Safety Administration (100 ppm).13, 14 In animal studies, toluene at low levels (80 ppm) increased catecholamine levels and turnover rates, as well as increased serum prolactin levels.15 Short-term exposure to toluene alters monoamine receptors in the brain, as detected by biochemical receptor binding studies.16 Various other lipophilic agents also alter serotonin binding sites in whole brain membrane preparations from rats.16 Euler et al13 have developed the hypothesis that the primary action of toluene is on membrane fluidity, leading to changes in transmitter release and in transduction mechanisms. Intravenous injection of toluene into dogs produced neuronal shrinkage and pigmentation in the cortex, fragmentation of myelin, widespread petechial hemorrhage and loss of Purkinje cells.17 In patients toluene inhalation produces impairment in attention, memory, visuospatial function, and complex cognition.18 Aphasia was not found, although naming difficulty and impaired reading or writing were frequently encountered. Toluene produces decreased or absent sense of smell and bilateral sensorineural hearing loss. The toxicity of toluene has been well documented.19-23 Toluene and xylene are the most used aromatic hydrocarbon solvents in industry, with toluene being more toxic than xylene.24 Since both of these were found in the patient's blood, they may have had an additive or synergistic effect.
The effects of other lipophilic substances, such as ethanol, are quite similar.25-28 Electrophysiological changes, as measured by potential difference and electrical resistance, precede ion transport alterations, such as those of hydrogen and chloride ions in the stomach. These changes are followed by permeability changes before actual irreversible tissue damage occurs. It isn't surprising that many chemically-sensitive patients are hypo- or achlorhydric. Similar changes are also observed for small intestinal transport and renal function.
The extreme abnormalities in the blood and urine amino acid levels were very puzzling until the biochemical pathways and the chemical structures of the toxic chemicals were evaluated. Figure 3 illustrates the structures of toluene, tyrosine, tryptophan, and phenylalanine. These are the only amino acids that contain benzene rings in their structure. Urine levels of essential amino acids are often decreased in chemically sensitive individuals.29 Even though the patient was on what appeared to be an adequate nutritional regime, she was obese when the studies were initiated. The severe depression of amino acids in the blood, but elevation in the urine as with phenylalanine, indicates active transport defects. The elevated urine b -alanine, anserine, and carnosine indicate food intolerance. The elevated hydroxyproline, 1-methylhistidine, and 3-methylhistidine reflect poor renal conservation. Toluene decreases rat plasma concentrations of tyrosine and tryptophan, precursors of neurotransmitters and transported from plasma into the brain, both after intraperitoneal and inhalation treatments.30 The symptoms of chronically low phenylalanine and/or tyrosine according to Bionostics (Lisle, Illinois) are: enhanced sensitivity to changes in ambient temperature, low basal temperature, decreased physical activity and energy levels, possible mental depression, and weight gain. The symptoms of chronically low tryptophan, a precursor of serotonin and nicotinic acid, are: disordered sleep patterns, abnormal states of anxiety or depression, abnormal appetite and food cravings, hypersensitivity to various external stimuli (light, sound) and oversensitivity to pain (Bionostics; Lisle, Illinois). These are symptoms that had been reported by the patient. The psychological components of environmental illness have been documented and paranoia-like disorders may be present in some cases.31, 32 Toluene also decreases the amplitude and increases the frequency of theta waves of electroencephalograms as was experienced by this patient.33
Figure 4 illustrates the sequence of events by which phenylalanine is converted to tyrosine, then to dopamine and on to epinephrine. Disturbances in intestinal and renal transport of these primary amino acids would produce a multitude of effects throughout the body as seen in this patient.
Imipramine and niacin have structures similar to serotonin and may facilitate sleep by directly acting on the serotonin receptors (Figure 5). Amitriptyline has also been found to be effective. In most situations, when the insomnia is not so severe, sleep can be induced with tryptophan and niacinamide. The patient markedly improved under proper psychiatric, endocrinological, and environmental health care, which is not surprising since elevated blood prolactin is due to decreased dopamine secretion by the hypothalamus. Thiothixene, which inhibits dopamine synthesis, and haloparidol and chlorpromazine, which are dopamine receptor antagonists, are frequently used in the treatment of schizophrenia. These pharmaceuticals decrease dopamine and thus would aggravate the condition of this patient. However, amitriptyline and imipramine both block the reuptake of serotonin and norepinephrine and thus prolong the action of serotonin while indirectly elevating the dopamine levels. Alprazolam potentiates these actions. Bromocriptine, a dopamine receptor agonist, directly decreases the prolactin levels.34 These results show the importance of a total approach, i.e., physical, mental, and environmental, in the thorough evaluation of a patient.
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2. Selye H. The General Adaptation Syndrome and the Diseases of Adaptation. J Allergy 1946:17:231-47.
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7. Rea WJ, Mitchell MJ. Chemical Sensitivity and the Environment. Immunology Allergy Practice 1982:9/10:21-31.
8. Rea WJ, Pan Y, Laseter JL, et al. Toxic Volatile Organic Hydrocarbons In Chemically Sensitive Patients. Clinical Ecology 1987:5:70-74.
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Blood Levels of Various Toxicant1
Compound April 27, 1988 Control2 May 3, 1989
ng/ml(ppb) (ppb) ng/ml(ppb)
Toluene 1.4 < 1.0 0.8
Xylene 1.7 < 1.0 2.1
Styrene < 1.0 < 1.0 1.5
n-Pentane 9.1 < 1.0 2.0
Cyclopentane 4.6 < 1.0 < 1.0
2 Methylpentane 26.7 < 9.6 12.0
3 Methylpentane 50.4 < 17.4 37.0
n-Hexane 15.5 < 8.3 18.0
1,1,1 Tricholoroethane 1.6 < 1.0 1.5
Tetrachloroethylene 1.5 < 0.5 1.0
1Tests for benzene, ethylbenzene, trimethylbenzenes, 2,2-dimethylbutane, n-beptane, dichloromethane, chloroform, trichloroethylene, and dichlorobenzenes were negative.
2Population segment tested by AccuChem Laboratories, Richardson, TX.
Amino Acid Concentrations in Blood
(June 13, 1988)
BLOOD LOW NORMAL
alanine 12.9 16-51
b -alanine nd
arginine† 2.8 3.8-13
asparagine 2.0 2.9-9
cystine 0.8 1.7-7
glutamine 14.0 38-75
histidine† 2.9 5.1-12
isoleucine† 2.6 3.5-10
leucine† 5.2 6.5-18
lysine† 7.2 8-25
1-methylhistidine 0.4 up to I
3-methylhistidine 0.1 up to .2
omithine 2.4 3-12
phenylalanine† 2.9 3.5-12
proline 7.8 5.5-35
serine 5.4 6.5-20
taurine 2.3 3.5-12
threonine† 4.2 7.5-20
tryptophan† 2.0 2.0-7.5
tyrosine 2.1 3.5-90
valine† 7.9 11-36
nd represents below detectable limits, no blood amino acids were high; amino acids not listed were within normal limits.
† essential amino acids
Amino Acid Concentrations in Urine
MCM/24 HRS Low Normal High Normal
cystathionine 5.3 15-75 b -alanine 43.7 up to 5
cystine 1.3 20-120 anserine 91.0 up to 55
glutamic acid 8.4 10-75 camosine 53.8 up to 20
leucine† 8.1 10-90 hydroxyproline 29.6 up to 15
phosphoethanolamine 4.2 20-95 1-methylhistidine 1932 130-930
threonine† 45.1 80-450 3-methylhistidine 306.4 30-300
tryptophan† 18.3 30-140 phenylalanine† 165.2 30-140
tryrosine 27.1 40-220
valine 8.4 10-55
*MCM represents micronoles.
†essential amino acids.
‡24-hour urine amino acid analyses done on May 25, 1989. Samples showed 8 out of 9 essential amino acids low, with none high. Valine was the only essential amino acid in the normal range. Phenylalanine was the only essential amino acid that was high in the urine.
Double-blind Inhalation Challenge:
Toluene* .002 ppm positive
*Symptoms produced -- flushing, brain dysfunction, clumsiness, shaking of hands and legs.
Double-blind Intradermal Challenge†
Chemical Amount Reaction
Ethanol, petroleum derived .05 cc 115 dil positive
Phenol .05 cc 115 di] positive
Formaldehyde .05 cc 1/25 dil positive
Normal saline .05 cc negative
†Performed in a controlled environment after a minimum of one day of adaptation.