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Environmental Management and Health, Vol. 11 No. 3, 2000, pp. 250-262.#MCB University Press, 0956-6163
Toxic encephalopathy
William J. Rea and Yaqin Pan
Environmental Health Center, Dallas, Texas, USA
Keywords Pollution, Formaldehyde, Brain
Abstract Describes a study involving 30 non-smoking, white-collar patients (aged 25-50), 12 male, 18 female, chronically exposed (over 90 days) to non-lethal doses of solvents ± formaldehyde and chlorinated pesticides ± in their offices. They exhibited short-term memory loss, lack of concentration and balance, odor sensitivity and fatigue. When compared to control individuals, these people had objective brain dysfunction on triple camera brain (SPECT) CAT scan, brain mapping by multiple behavioral analysis, computerized balance testing, computerized Iriscorder for automatic nervous system measuring, inhaled double blind challenge, intradermal challenge and blood toxics. Toxic encephalopathy could then be diagnosed.
Introduction
Environmental physicians have observed that there is a subset of patients who have received chronic (over three months) exposure to non-lethal doses of pollutants such as exposures to solvents, formaldehyde and pesticides. There is a clinical syndrome that occurs in these patients characterized by short-term memory loss, inability to concentrate, imbalance, vertigo, dizziness or light-headedness, chronic fatigue, fibromyalgia and the adverse reactions to ambient doses of many chemicals (odor sensitivity). This study involves 30 non-smoking, white-collar patients (age range 25-50) (M-12, F-18) who developed this syndrome.
Materials and methods
Thirty (30) patients (ages 25-50, 20 female, ten male) chronically exposed (over three months) to non-lethal doses of solvents and pesticides, complaining of short-term memory loss, lack of concentration, vertigo, dizziness, chronic fatigue, fibromyalgia and sensitivity to the odors of many ambient chemicals and having a positive Romberg test, were studied. After an adequate history (including a 20-page system review environmental exposure questionnaire) a physical exam was performed.
The following tests were performed and compared with the control group. Triple camera computerized brain Tomography (SPECT) scans, by the method of Simon and Hickey (Fincher et al., 1996), brain mapping using a composite behavioral analysis profiled by the method of Butler and Didriksen (Didriksen, 1998), computerized balance testing by the method of Martinez (1990), blood toxic levels by the method of Laseter (Laseter and Dowry, 1977), and inhaled
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double blind ambient dose challenges (exposure for 15 minutes after four days' avoidance) under environmentally controlled conditions (less polluted clean environment that is solvent and pesticide free), intradermal skin titration tests by the method of Rinkle (1949) and Lee (1961) and autonomic nervous system evaluation using an Iriscorder (Hamamatsu) by the method of Ishikawaet al. (1970).
Results
All patients had a history of over three months' non-lethal chronic exposure to solvents (benzene, toluene, xylene, tetra- and trichloroethylene, trichloroethane, chloroform, pentane, hexane or heptane) from the construction and inside finishing material. In addition, they were exposed to the ambient doses of formaldehyde emanating from new carpet, pressboard, plywood, and other synthetics. All were white-collar workers who were exposed to monthly sprayings of chlorinated pesticides or solvents used for cleaning of printing machines, copy machines, cleaning of carpets or use in graphics. On physical examination, all patients had positive tandem Romberg tests and also usually had intracellular edema, acne, spontaneous bruising and Raynaud's phenomenon. Complaints were short-term memory loss, lack of concentration, vertigo, dizziness, fatigue, fibromyalgia and odor sensitivity to ambient doses of many chemicals.
Triple Camera SPECT Brain Scans
Figures 1a-d show the triple camera SPECT brain scans compared with the control. Tables I-IV show the 30 exposed patients compared with the controls. The normal controls had smooth, uniform brains, all scans had a uniform consistency and color. Blood flow and brain cell dye uptake indicated that function was equal. The patients with neurotoxicity showed a pattern of discrepancy between flow and function, hot and cold areas throughout the brain, unequal temporal lobes, often soft tissue dye involvement and unequal coloring.
Brain mapping by multiple behavioral analysis showed objective short-term memory loss, 50 percent verbal and 30 percent visual, 51 percent general memory loss, 46 percent had below average attention and concentration and 49 percent delayed new concept formulation, new problem-solving, abstract reasoning and new learning ability, especially numbers, loss of equilibrium 100 percent, loss of IQ, loss of innovation and/or judgment (Table V).
Computerized balance testing
Table VI shows that 93 percent of the 27 patients tested with objective balance abnormalities compared with the control group.
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Figure 1a.
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Figure 1b.
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Figure 1c.
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Figure 1d.
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Table VII shows the blood toxic levels compared with normal ranges. All patients with solvent or pesticide exposures had multiple solvents for pesticides in their blood. Those exposed to chlorinated pesticides had them in their blood. These levels were in the 0.1-100ppb.
Double blind ambient dose challenges of either an active ingredient or inhaled placebos were performed.
Table VIII shows the inhaled double blind challenges for 15 minutes under less polluted environmentally controlled conditions (after the patient had been deadapted in a less polluted room for four days) to the ambient doses of chlorine < 0.33ppm, phenol << 0.0050ppm, pesticide (2,4, DNP) < 0.0034ppm, petroleum derived ethanol < 0.50ppm and formaldehyde < 0.2ppm. The ambient doses of xylene and toluene were also challenged for 15 minutes. These were performed in a double blind manner using saline as placebos. The group as a whole reacted overwhelmingly to the solvents and pesticides and
Table I.
(SPECT) scan
30 patients had abnormal results
25 controls with no history of illness, drug or medication intake
All college age 20-30 years, non-smoking, most going for last two years of bachelor or Master's degree
Level Group Minimum value Maximum value s.d. Mean Temporal Controls 351959.0 933327.0 159883.3 595460.7
Solvents 264945.0 773022.0 148042.1 466523.4 Frontal Controls 450686.0 1224653.0 198750.1 810389.3 Solvents 362445.0 1066601.0 194957.3 650678.6 Thalamic Controls 507919.0 1269024.0 202352.5 849625.4 Solvents 387667.0 1106120.0 202152.7 683304.5
Note:Courtesy of Simon and Hickey
Table III.
Frequencies and means of late-phase tracer uptake for each slice-triple camera brain (SPECT) CAT scan
Level Group Minimum value Maximum value s.d. Mean Temporal Controls 1789476.0 3708798.0 534404.6 2580611.4
Solvents 1283676.0 3769599.0 747145.6 2142243.3 Frontal Controls 2606279.0 5158952.0 703600.2 3639766.4 Solvents 1988961.0 5340568.0 1065353.5 3144305.7 Thalamic Controls 1607362.0 5383333.0 835620.5 3730573.0 Solvents 2102793.0 5606672.0 1102068.3 3284615.8
Toxic
I. Wechsler memory scale revised
Below average verbal memory 55 Below average visual memory 30 Below average general memory 51 Below average attention and concentration 46 Below average delayed recall 49
II. Comprehensive neuropsychological
Screen 48
Impairment in verbal memory over visual memory 57
III. General neuropsychological deficit scale
One standard deviation or below 96 Halstead-Reitan battery 65
IV. Category test
Impaired in executive function in judgment, concept formulation,
new problem solving, abstract reasoning, new learning ability *80
Note:*In impaired range, rest had isolated significant impairment
Source:Courtesy of Didriksen
Table IV.
Comparison of mean count for cases of solvent exposure and controls for each of 12 regions of interest and combined totals Variable Controls Solvents
Left basal ganglia 105194.80 161404.96 Right basal ganglia 102826.36 159741.16 Left thalamus 28159.52 26490.92 Right thalamus 29643.40 30580.52 Left frontal 281807.68 405902.56 Right frontal 288186.96 414732.32 Left occipital 276165.36 381485.92 Right occipital 262607.56 389217.32 Left parietal 335464.48 484096.84 Right parietal 327106.32 482415.32 Left temporal 177825.64 264277.12 Right temporal 178441.52 262344.32 Left total count 1204617.48 1723658.32 Right total count 1188812.12 1739030.96 Total 2393429.60 3462689.28
Notes:solvent group had significantly increased; t= ±3.61;p< 0.001;
the comparison of the right hemisphere produced a significanttvalue (t= ±3.69,p< 0.001). The comparison of the left hemisphere was also significant (t= ±3.53,p< 0.001). In apost hocanalysis, each of the 12 regions was individually compared between the two groups. Of the 12 regions, significant differences were found in all of the regions at thep< 0.05 level, except for the right and left thalamus (p< 0.004 for left occipital lobe,p< 0.001 for the other nine regions, andp< 0.001 for the left and right basal ganglia). When the Bonferroni Correction was applied to control for a family-wise error rate, an adjusted a-value of
p< 0.003 was required for significance. Using this stringent criterion, all values remained significant, with the exception of the left occipital lobe, which just missed significance
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only 8 percent to the saline placebos. The objective parameters measured for positivity change were significant (< 20 percent) in pulse, blood pressure, respiration, peak pulmonary flow and symbol digit modality and subset brain function analysis. The patients had an average of five separate challenges. Not all individuals reacted to the same substances but each reacted to enough (average three solvents per patient) to be highly significant.
As one can see, there was a positive active ingredient response compared to an 8 percent placebo response. These challenges confirm sensitivity not only to the solvents and pesticides but also to the odors of ambient doses of other chemicals.
Table VI.
Computerized balance test (abnormal/tested = 25/27 (= 92.6 percent)
Abnormal number Percent Sensory organization 24 96 Motor organization 16 64
Notes: 30 controls age 20-40 years; non-smokers, no drug or medication use or illness. All of them had normal results (by method of Martinez)
Table VII.
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Table IX shows the positive intradermal skin response confirming the sensitivity to chemical odors, some similar to the inhaled challenges and some totally different. It also shows a widespread sensitivity to other toxics that has been acquired in these patients. This method certainly confirms sensitivity to odors of many ambient chemicals.
Table VIII.
Inhaled double-blind challenge to ambient dose chemicals* Chemical Positive/tested number Percent
Formaldehyde (< 0.2ppm) 17/18 94 Toluene (ambient) 13/16 81 Xylene (ambient) 5/7 71 1,1,1-Trichloroethane (ambient) 7/8 88 Ethanol (< 0.5ppm) 17/22 77 Phenol (< 0.05ppm) 11/17 65 Pesticide (2,4-DNP, < 0.0034ppm) 8/9 89 Methylethyl ketone (ambient) 3/3 100 Chlorine (< 0.33ppm) 11/12 92 Benzene (ambient) 2/3 67 Placebo (saline) 2/35 6
Notes: *30 patients (12 male, 18 female, age range 35-63 years, mean age 43.9 years), exposed for 15 minutes at the ambient dose after four days' deadaptation in a less polluted solvent, formaldehyde and chlorinated pesticide free environment. Each patient acted as his/ her own control
Table IX.
Intradermal chemical tests Compound Positive/tested Percent
Natural gas 6/18 33.3 Propane gas 2/12 16.7 Cigarette smoke 16/23 69.6 Chlorine 9/20 45.0 Ethanol (petroleum derived) 14/22 63.6 Formaldehyde 21/22 95.5 Ladies' Cologne 14/23 60.9 Men's Cologne 10/23 43.5 Orrisroot 20/22 90.9 News material 9/20 45.0 Phenol 8/23 34.8 Diesel 12/22 54.5 Fireplace smoke 4/13 30.8 Toluene 1/3 33.3 Benzene 1/3 33.3 Xylene 1/2 50.0 Saline-placebo3 3/90 3.3
Notes:No more than one placebo positive in a single patient;
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Table X shows that 93 percent of the individuals with chronic exposure had dysfunction of their autonomic nervous system compared to the control group.
Discussion
It is clear that overwhelming objective evidence exists to substantiate complaints of organic brain dysfunction in a subset of patients who received chronic non-lethal solvent or chlorinated pesticide exposure (for over three months) and having complaints of ambient odor sensitivity, short-term memory loss, imbalance, loss of concentration and judgment and exhibiting a positive tandem Romberg test on physical examination.
However, the exact levels of the chronic exposures in the work environment were not known. These patients were studied in less polluted environments (pesticide and solvent free) and allowed to deadapt for four days, thus allowing their symptoms and signs to disappear. They were off all medication and were non-smokers. With this experience of clearing away from work and since these patients were asymptomatic at home, it was obvious that the work environment was polluted to the extent of causing these patients chronic symptoms. In addition once they were symptom free and returned to work, their symptoms would reoccur rapidly within the first day. When clear these patients could be given individual double blind inhaled challenges to very small doses of active substances as well as saline placebos. The active ingredients did reproduce their signs and symptoms, again confirming exposure to the work-related solvents, formaldehyde and chlorinated pesticides. When they are symptom free, it is much easier to acquire precise symptoms and sign changes with inhaled challenge because the endpoints are acutely seen. In addition reactive vital signs and brain function tests such as symbol digit modalities and subsets could easily be plotted before and after the challenges. These brain function tests along with recordings of pulse, blood pressure, peak pulmonary flow, symptoms score and objective sign score changes allowed for precise diagnosis of the altered brain function. One could actually confirm the observed brain dysfunction by the symbol digit tests, leaving little question as to cause and effect.
Table X.
Autonomic nervous system test via the Iriscorder (abnormal/ tested = 21/24 = 87.5 percent)
Reactive type Number Percent
Normal 3 12.5
Cholinergic 4 16.7 Sympatholytic 4 16.7 Sympathomimetric 1 4.2 Cholinergic + sympatholytic 3 12.5 Non-specific change 9 37.5
Notes: 30 controls age 20-40 years, non-smokers, no history of illness, medication or drug use. All of them had normal results.
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Behavioral analysis compared to control groups confirmed short-term verbal and visual memory loss in all patients. Their intelligent quotients were usually low for the education level that was two years of college or above. Memory for numbers and delayed recall also seemed to be poor in most individuals who were solvent and pesticide exposed and odor sensitive. Their depressive scores were compatible with individuals who had toxic exposure, not of those with psychological problems. In addition, their executive functions for which they had been hired (i.e. judgment, concept formation, new problem solving, abstract and new learning ability) were objectively impaired. One would not expect this type of disability in a well-educated constantly working group of patients. These findings compared with Butler's in an earlier study at EHC-D when he showed that the IQ increased (sometimes by as much as 20 points) as chlorinated pesticides left the body (Laseteret al., 1983).
In the solvent exposed group one clearly sees defined criteria between the pathologic functional brain dysfunction and normal controls.
The contrast of the change between the patients in the triple camera (SPECT) CAT brain scans and those of the comparison group of complaint-free individuals was striking. Former studies had shown that double and single view scanners gave less than satisfactory changes. Only the three-dimensional scanners appeared consistent and accurate enough to consistently demonstrate toxic changes. Temporal lobes were always unequal in these patients complaining of short-term memory loss and this is apparently where short memory center either lies or integrates. The control group was selected from a group of graduate college students that had never been ill, on medication or drugs. The contrast was also clearly evident in the hot and cold uptake in the global brain as well as the discrepancy between flow and functions. These responses just did not occur in the control group but were consistent in the neurotoxic group.
Some objections could have been made to the blood toxic study since levels were lower than exposed industrialized solvent and pesticide workers. However, one would expect lower levels since the exposures were obviously less. However, it appears that the number of toxics in the blood were higher than the general population and this certainly holds some significance since they represented some of the substances the patients were exposed to. In addition, these substances are not supposed to be in individuals and certainly could cause adverse effects even in pharmacological doses. If nothing else, they certainly contributed to total body pollutant load. Certainly when given inhaled challenges of doses much smaller than found in the blood, these patients reacted.
In addition, since these solvents and chlorinated pesticides are lipophilic, a significant quantity may have shifted into the nervous system and other cells' lipid layers. This fact alone would explain the brain dysfunction complaints seen in these patients since they were chronically exposed and chronically ill.
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independent route of provocation. Signs and symptoms were produced in these patients by this technique which proved simple and efficacious. It appears that once neurotoxicity appears, patients develop secondary sensitivities to closely and then non-closely related chemicals. This secondary sensitivity can also account for their varied symptomatology.
Autonomic nervous system involvement appears to be an extremely positive and sensitive indicator of pollutant exposure in this group of patients. The positive results of this test correlated at 93 percent with the brain scan, balance test, and behavioral analysis data. Clearly some of the complaints of the patients could be correlated with autonomic nervous system dysfunction. These positive findings clearly show nervous system involvement in this group of patients.
Conclusion
There is a subset of chronically exposed patients who experience short-term memory loss, imbalance, chronic fatigue, dizziness, lack of concentration, odor sensitivity and fibromyalgia who have a neurotoxicity pattern on numerous objective tests. These tests included physical exam, triple camera (SPECT) CAT brain scans, computerized balance tests, blood toxics, double blind inhaled challenges, intradermal challenges, objective Iriscorder measurements of the autonomic nervous systems. Objective toxic encephalopathy was present in this small group of patients.
References
Didriksen, N. (1998), personal communication.
Fincher, C.E., Chang, T-S, Harrell, E.H., Kettlehut, M.C., Rea,,W.J., Johnson, A.R., Hickey, D.C. and Simon, T.R. (1996), ``Comparison of single photon emission computed tomography findings in cases of healthy adults and solvent-exposed adults'', American Journal of Industrial Medicine, Vol. 19, pp. 4-14.
Ishikawa, S., Naito, M. and Inabe, K. (1970), ``A new video pupillography'',Ophthalmologica, Vol. 160, p. 248.
Laseter, J.L. and Dowry, B.J. (1977), ``Association of biorefractories in drinking water and body burden in people'',Annals of New Academy of Sciences, Vol. 298, pp. 546-57.
Laseter, J.L., Deleon, I.R., Rea, W.J. and Butler, J.R. (1983), ``Chlorinated hydrocarbon pesticides in environmentally sensitive patients'',Clinical Ecology, Vol. 2, pp. 3-12.
Lee, C. (1961), ``A new test for diagnosis and treatment of food allergies'',Buchanan County Med. Bull., Vol. 25, p. 9.
Martinez, D.M. (1990), personal communication.
