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Environmental Management andHealth, Vol. 11 No. 3, 2000,pp. 250-262. # MCB UniversityPress, 0956-6163

Toxic encephalopathyWilliam 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), 12male, 18 female, chronically exposed (over 90 days) to non-lethal doses of solvents ± formaldehydeand chlorinated pesticides ± in their offices. They exhibited short-term memory loss, lack ofconcentration and balance, odor sensitivity and fatigue. When compared to control individuals,these people had objective brain dysfunction on triple camera brain (SPECT) CAT scan, brainmapping by multiple behavioral analysis, computerized balance testing, computerized Iriscorderfor automatic nervous system measuring, inhaled double blind challenge, intradermal challengeand blood toxics. Toxic encephalopathy could then be diagnosed.

IntroductionEnvironmental physicians have observed that there is a subset of patients whohave received chronic (over three months) exposure to non-lethal doses ofpollutants such as exposures to solvents, formaldehyde and pesticides. There isa clinical syndrome that occurs in these patients characterized by short-termmemory loss, inability to concentrate, imbalance, vertigo, dizziness or light-headedness, chronic fatigue, fibromyalgia and the adverse reactions to ambientdoses of many chemicals (odor sensitivity). This study involves 30 non-smoking, white-collar patients (age range 25-50) (M-12, F-18) who developedthis syndrome.

Materials and methodsThirty (30) patients (ages 25-50, 20 female, ten male) chronically exposed (overthree months) to non-lethal doses of solvents and pesticides, complaining ofshort-term memory loss, lack of concentration, vertigo, dizziness, chronicfatigue, fibromyalgia and sensitivity to the odors of many ambient chemicalsand having a positive Romberg test, were studied. After an adequate history(including a 20-page system review environmental exposure questionnaire) aphysical exam was performed.

The following tests were performed and compared with the control group.Triple camera computerized brain Tomography (SPECT) scans, by the methodof Simon and Hickey (Fincher et al., 1996), brain mapping using a compositebehavioral analysis profiled by the method of Butler and Didriksen (Didriksen,1998), computerized balance testing by the method of Martinez (1990), bloodtoxic levels by the method of Laseter (Laseter and Dowry, 1977), and inhaled

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Research supported by a grant from The American Environmental Health Foundation and theEnvironment Health Center, Dallas. The authors wish to thank Drs Theodore Simon, DavidHickey, Nancy Didriksen, John Laseter, Daniel Martinez and Satoshi Ishikawa for theirgenerous time and resources for running the objective tests and controls and criticisms fordeveloping and instituting these complete testing tools.

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double blind ambient dose challenges (exposure for 15 minutes after four days'avoidance) under environmentally controlled conditions (less polluted cleanenvironment that is solvent and pesticide free), intradermal skin titration testsby the method of Rinkle (1949) and Lee (1961) and autonomic nervous systemevaluation using an Iriscorder (Hamamatsu) by the method of Ishikawa et al.(1970).

ResultsAll patients had a history of over three months' non-lethal chronic exposure tosolvents (benzene, toluene, xylene, tetra- and trichloroethylene, trichloroethane,chloroform, pentane, hexane or heptane) from the construction and insidefinishing material. In addition, they were exposed to the ambient doses offormaldehyde emanating from new carpet, pressboard, plywood, and othersynthetics. All were white-collar workers who were exposed to monthlysprayings of chlorinated pesticides or solvents used for cleaning of printingmachines, copy machines, cleaning of carpets or use in graphics. On physicalexamination, all patients had positive tandem Romberg tests and also usuallyhad intracellular edema, acne, spontaneous bruising and Raynaud'sphenomenon. Complaints were short-term memory loss, lack of concentration,vertigo, dizziness, fatigue, fibromyalgia and odor sensitivity to ambient dosesof many chemicals.

Triple Camera SPECT Brain ScansFigures 1a-d show the triple camera SPECT brain scans compared with thecontrol. Tables I-IV show the 30 exposed patients compared with the controls.The normal controls had smooth, uniform brains, all scans had a uniformconsistency and color. Blood flow and brain cell dye uptake indicated thatfunction was equal. The patients with neurotoxicity showed a pattern ofdiscrepancy between flow and function, hot and cold areas throughout thebrain, unequal temporal lobes, often soft tissue dye involvement and unequalcoloring.

Brain mapping by multiple behavioral analysis showed objective short-termmemory loss, 50 percent verbal and 30 percent visual, 51 percent generalmemory loss, 46 percent had below average attention and concentration and 49percent delayed new concept formulation, new problem-solving, abstractreasoning and new learning ability, especially numbers, loss of equilibrium 100percent, loss of IQ, loss of innovation and/or judgment (Table V).

Computerized balance testingTable VI shows that 93 percent of the 27 patients tested with objective balanceabnormalities compared with the control group.

This Table also shows that 93 percent of the objective balance tests werealso abnormal for sensory or motor or a combination of the two suggestive ofcentral brain neuropathy.

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Figure 1a.Triple camera (SPECT)brain scans

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Figure 1b.Triple camera (SPECT)

brain scans

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Figure 1c.Triple camera (SPECT)brain scans

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Figure 1d.Triple camera (SPECT)

brain scans

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Table VII shows the blood toxic levels compared with normal ranges. Allpatients with solvent or pesticide exposures had multiple solvents forpesticides in their blood. Those exposed to chlorinated pesticides had them intheir blood. These levels were in the 0.1-100ppb.

Double blind ambient dose challenges of either an active ingredient orinhaled placebos were performed.

Table VIII shows the inhaled double blind challenges for 15 minutes underless polluted environmentally controlled conditions (after the patient had beendeadapted in a less polluted room for four days) to the ambient doses ofchlorine < 0.33ppm, phenol << 0.0050ppm, pesticide (2,4, DNP) < 0.0034ppm,petroleum derived ethanol < 0.50ppm and formaldehyde < 0.2ppm. Theambient doses of xylene and toluene were also challenged for 15 minutes.These were performed in a double blind manner using saline as placebos. Thegroup as a whole reacted overwhelmingly to the solvents and pesticides and

Table I.(SPECT) scan

30 patients had abnormal results25 controls with no history of illness, drug or medication intakeAll college age 20-30 years, non-smoking, most going for last two years of bachelor orMaster's degree

Table II.Frequencies and meansof early-tracer uptakefor each slice-triplecamera brain (SPECT)CAT scan

Level Group Minimum value Maximum value s.d. Mean

Temporal Controls 351959.0 933327.0 159883.3 595460.7Solvents 264945.0 773022.0 148042.1 466523.4

Frontal Controls 450686.0 1224653.0 198750.1 810389.3Solvents 362445.0 1066601.0 194957.3 650678.6

Thalamic Controls 507919.0 1269024.0 202352.5 849625.4Solvents 387667.0 1106120.0 202152.7 683304.5

Note: Courtesy of Simon and Hickey

Table III.Frequencies and meansof late-phase traceruptake 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 2580611.4Solvents 1283676.0 3769599.0 747145.6 2142243.3

Frontal Controls 2606279.0 5158952.0 703600.2 3639766.4Solvents 1988961.0 5340568.0 1065353.5 3144305.7

Thalamic Controls 1607362.0 5383333.0 835620.5 3730573.0Solvents 2102793.0 5606672.0 1102068.3 3284615.8

Notes: Values for the solvent group contained more extreme minimum and maximumvalues, indicating a wide range of tracer uptake; courtesy of Simon and Hickey

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Table V.Neuropsychological

data

Impairment (per cent)

I. Wechsler memory scale revisedBelow average verbal memory 55Below average visual memory 30Below average general memory 51Below average attention and concentration 46Below average delayed recall 49II. Comprehensive neuropsychologicalScreen 48Impairment in verbal memory over visual memory 57III. General neuropsychological deficit scaleOne standard deviation or below 96Halstead-Reitan battery 65IV. Category testImpaired 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 ofsolvent exposure and

controls for each of 12regions of interest and

combined totals

Variable Controls Solvents

Left basal ganglia 105194.80 161404.96Right basal ganglia 102826.36 159741.16Left thalamus 28159.52 26490.92Right thalamus 29643.40 30580.52Left frontal 281807.68 405902.56Right frontal 288186.96 414732.32Left occipital 276165.36 381485.92Right occipital 262607.56 389217.32Left parietal 335464.48 484096.84Right parietal 327106.32 482415.32Left temporal 177825.64 264277.12Right temporal 178441.52 262344.32Left total count 1204617.48 1723658.32Right total count 1188812.12 1739030.96Total 2393429.60 3462689.28

Notes: solvent group had significantly increased; t = ±3.61; p < 0.001;the comparison of the right hemisphere produced a significant t value (t = ±3.69, p < 0.001).The comparison of the left hemisphere was also significant (t = ±3.53, p < 0.001). In a posthoc analysis, each of the 12 regions was individually compared between the two groups. Ofthe 12 regions, significant differences were found in all of the regions at the p < 0.05 level,except for the right and left thalamus (p < 0.004 for left occipital lobe, p < 0.001 for theother nine regions, and p < 0.001 for the left and right basal ganglia). When the BonferroniCorrection was applied to control for a family-wise error rate, an adjusted a-value ofp < 0.003 was required for significance. Using this stringent criterion, all values remainedsignificant, with the exception of the left occipital lobe, which just missed significance

Source: Courtesy of Simon and Hickey

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only 8 percent to the saline placebos. The objective parameters measured forpositivity change were significant (< 20 percent) in pulse, blood pressure,respiration, peak pulmonary flow and symbol digit modality and subset brainfunction analysis. The patients had an average of five separate challenges. Notall 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 toan 8 percent placebo response. These challenges confirm sensitivity not only tothe solvents and pesticides but also to the odors of ambient doses of otherchemicals.

Table VI.Computerized balancetest (abnormal/tested =25/27 (= 92.6 percent)

Abnormal number Percent

Sensory organization 24 96Motor organization 16 64

Notes: 30 controls age 20-40 years; non-smokers, no drug or medication use or illness. Allof them had normal results (by method of Martinez)

Table VII.Blood toxic chemical

Compound Positive/tested Percent

Benzene 6/18 33.3Toluene 10/18 55.6Ethylbenzene 1/18 5.6Xylene 3/18 16.7Chloroform 1/18 5.61,1,1-Trichloroethylene 5.18 27.8Tetrachloroethylene 2/18 11.1Dichlorobenzene 2/18 11.1Trimethylbenzene 4/18 22.22-Methylpentane 23/24 95.83-Methylpentane 23/24 95.8n-Hexane 22/24 91.7n-Pentane 1/24 4.2Cyclopentane 1/24 4.2HCB 3/7 42.9DDE 7/7 100.0r-BHC 1/7 14.3Epoxide 1/7 14.3Beta-BHC 1/7 14.3Delta-BHC 1/7 14.3Oxychlordane 1/7 14.3Trans-Nonachlor 2/7 28.6Mirex 1/1 100.0

Notes: Measured by method of Laseter, J.; all were in the 0.1 to 100ppm

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Table IX shows the positive intradermal skin response confirming thesensitivity to chemical odors, some similar to the inhaled challenges and sometotally different. It also shows a widespread sensitivity to other toxics that hasbeen acquired in these patients. This method certainly confirms sensitivity toodors of many ambient chemicals.

Table VIII.Inhaled double-blindchallenge to ambient

dose chemicals*

Chemical Positive/tested number Percent

Formaldehyde (< 0.2ppm) 17/18 94Toluene (ambient) 13/16 81Xylene (ambient) 5/7 711,1,1-Trichloroethane (ambient) 7/8 88Ethanol (< 0.5ppm) 17/22 77Phenol (< 0.05ppm) 11/17 65Pesticide (2,4-DNP, < 0.0034ppm) 8/9 89Methylethyl ketone (ambient) 3/3 100Chlorine (< 0.33ppm) 11/12 92Benzene (ambient) 2/3 67Placebo (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 pollutedsolvent, 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 33.3Propane gas 2/12 16.7Cigarette smoke 16/23 69.6Chlorine 9/20 45.0Ethanol (petroleum derived) 14/22 63.6Formaldehyde 21/22 95.5Ladies' Cologne 14/23 60.9Men's Cologne 10/23 43.5Orrisroot 20/22 90.9News material 9/20 45.0Phenol 8/23 34.8Diesel 12/22 54.5Fireplace smoke 4/13 30.8Toluene 1/3 33.3Benzene 1/3 33.3Xylene 1/2 50.0Saline-placebo � 3 3/90 3.3

Notes: No more than one placebo positive in a single patient;dosage ± 0.05cc of the 1/100 dilution or more; test was under environmentally-controlledconditions ± positive indicated by a 2mm or more growth of the weal, reproduction of signsor symptoms

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Table X shows that 93 percent of the individuals with chronic exposure haddysfunction of their autonomic nervous system compared to the control group.

DiscussionIt is clear that overwhelming objective evidence exists to substantiatecomplaints of organic brain dysfunction in a subset of patients who receivedchronic non-lethal solvent or chlorinated pesticide exposure (for over threemonths) and having complaints of ambient odor sensitivity, short-termmemory loss, imbalance, loss of concentration and judgment and exhibiting apositive tandem Romberg test on physical examination.

However, the exact levels of the chronic exposures in the work environmentwere not known. These patients were studied in less polluted environments(pesticide and solvent free) and allowed to deadapt for four days, thus allowingtheir symptoms and signs to disappear. They were off all medication and werenon-smokers. With this experience of clearing away from work and since thesepatients were asymptomatic at home, it was obvious that the workenvironment was polluted to the extent of causing these patients chronicsymptoms. In addition once they were symptom free and returned to work,their symptoms would reoccur rapidly within the first day. When clear thesepatients could be given individual double blind inhaled challenges to verysmall doses of active substances as well as saline placebos. The activeingredients did reproduce their signs and symptoms, again confirmingexposure to the work-related solvents, formaldehyde and chlorinatedpesticides. When they are symptom free, it is much easier to acquire precisesymptoms and sign changes with inhaled challenge because the endpoints areacutely seen. In addition reactive vital signs and brain function tests such assymbol digit modalities and subsets could easily be plotted before and after thechallenges. These brain function tests along with recordings of pulse, bloodpressure, peak pulmonary flow, symptoms score and objective sign scorechanges allowed for precise diagnosis of the altered brain function. One couldactually confirm the observed brain dysfunction by the symbol digit tests,leaving little question as to cause and effect.

Table X.Autonomic nervoussystem test via theIriscorder (abnormal/tested = 21/24 = 87.5percent)

Reactive type Number Percent

Normal 3 12.5Cholinergic 4 16.7Sympatholytic 4 16.7Sympathomimetric 1 4.2Cholinergic + sympatholytic 3 12.5Non-specific change 9 37.5

Notes: 30 controls age 20-40 years, non-smokers, no history of illness, medication or druguse. All of them had normal results.By method of Ishikawa

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Behavioral analysis compared to control groups confirmed short-term verbaland visual memory loss in all patients. Their intelligent quotients were usuallylow for the education level that was two years of college or above. Memory fornumbers and delayed recall also seemed to be poor in most individuals whowere solvent and pesticide exposed and odor sensitive. Their depressive scoreswere compatible with individuals who had toxic exposure, not of those withpsychological problems. In addition, their executive functions for which theyhad been hired (i.e. judgment, concept formation, new problem solving, abstractand new learning ability) were objectively impaired. One would not expect thistype 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 heshowed that the IQ increased (sometimes by as much as 20 points) aschlorinated pesticides left the body (Laseter et al., 1983).

In the solvent exposed group one clearly sees defined criteria between thepathologic 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-freeindividuals was striking. Former studies had shown that double and singleview scanners gave less than satisfactory changes. Only the three-dimensionalscanners appeared consistent and accurate enough to consistently demonstratetoxic changes. Temporal lobes were always unequal in these patientscomplaining of short-term memory loss and this is apparently where shortmemory center either lies or integrates. The control group was selected from agroup of graduate college students that had never been ill, on medication ordrugs. The contrast was also clearly evident in the hot and cold uptake in theglobal brain as well as the discrepancy between flow and functions. Theseresponses just did not occur in the control group but were consistent in theneurotoxic group.

Some objections could have been made to the blood toxic study since levelswere lower than exposed industrialized solvent and pesticide workers.However, one would expect lower levels since the exposures were obviouslyless. However, it appears that the number of toxics in the blood were higherthan the general population and this certainly holds some significance sincethey represented some of the substances the patients were exposed to. Inaddition, these substances are not supposed to be in individuals and certainlycould cause adverse effects even in pharmacological doses. If nothing else, theycertainly contributed to total body pollutant load. Certainly when given inhaledchallenges of doses much smaller than found in the blood, these patientsreacted.

In addition, since these solvents and chlorinated pesticides are lipophilic, asignificant quantity may have shifted into the nervous system and other cells'lipid layers. This fact alone would explain the brain dysfunction complaintsseen in these patients since they were chronically exposed and chronically ill.

Intradermal titration skin tests confirmed the complaints of odor sensitivityto many substances in these patients. This technique of testing gave us another

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independent route of provocation. Signs and symptoms were produced in thesepatients by this technique which proved simple and efficacious. It appears thatonce neurotoxicity appears, patients develop secondary sensitivities to closelyand then non-closely related chemicals. This secondary sensitivity can alsoaccount for their varied symptomatology.

Autonomic nervous system involvement appears to be an extremely positiveand sensitive indicator of pollutant exposure in this group of patients. Thepositive results of this test correlated at 93 percent with the brain scan, balancetest, and behavioral analysis data. Clearly some of the complaints of thepatients could be correlated with autonomic nervous system dysfunction.These positive findings clearly show nervous system involvement in this groupof patients.

ConclusionThere is a subset of chronically exposed patients who experience short-termmemory loss, imbalance, chronic fatigue, dizziness, lack of concentration, odorsensitivity and fibromyalgia who have a neurotoxicity pattern on numerousobjective tests. These tests included physical exam, triple camera (SPECT)CAT brain scans, computerized balance tests, blood toxics, double blindinhaled challenges, intradermal challenges, objective Iriscorder measurementsof the autonomic nervous systems. Objective toxic encephalopathy was presentin this small group of patients.

References

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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 bodyburden 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 inenvironmentally 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.

Rinkel, H.J. (1949), `̀ Inhalant allergy I. Wealing response of skin to serial dilution testing'', Ann.Allergy, Vol. 7, pp. 625-50.