Chlorine-Induced Damage Documented by Neurophysiological, Neuropsychological, and Pulmonary Testing

Chlorine-Induced Damage Documented by Neurophysiological, Neuropsychological, and Pulmonary Testing

Kaye H. Kilburn

CHLORINE is ubiquitous in the United States, ranging from trace amounts in culinary water to tank car loads transported to water- and sewage-treatment plants. In addition, in industry it is used to bleach paper and cloth and to make chemicals. Chlorine poisoning was studied intensely after its use caused deaths of Allied solders in World War I.[1,2] Widespread use of chlorine implies a potential for toxic exposures at swimming pools and at water- and sewage-treatment plants. Transport of chlorine in tankers on the road and rail contributes to this problem. Recognized acute human effects are respiratory tract burning, cough, and shortness of breath. Bherer et al.[3] reported that airways obstruction is evidenced by pulmonary function tests.

Respiratory effects (with no mention of central nervous system [CNS] damage)were summarized in 1993.[4] Brain impairment has been demonstrated in individuals exposed to chlorine gas.[5,6] A group of 13 women were damaged as gas evolved from a chlorinated bleach they used to clean an institutional kitchen.[7] Subsequent to 1993, 22 patients with exclusive exposure to chlorine were examined and tested, and they comprised a series. They represented 6% of 384 patients who were evaluated for effects of chemical exposure. The results of the examinations and tests are reported herein.

Method

Central nervous system performance of 22 chlorine-exposed individuals was measured with a battery of tests. Eight workers were exposed during unloading of chlorine from a tanker truck at a sewage-treatment plant, 5 were neighbors of an industrial leak, 4 were exposed in a gymnasium by a defective swimming pool chlorinator, 2 were exposed individually from water chlorinating systems, and 3 used liquid chlorinated bleaches with other cleaning agents. In no instance was the chlorine concentration in air measured. In all cases, duration of exposures ranged from seconds to a few minutes, the result of which were tearing, burning of the nose, throat and chest symptoms, and other symptoms. Discomfort made all these people leave the exposure area. The exposures were not simply “whiffs” of chlorine.

The duration of chlorine exposures ranged from 1 or 2 min to a few hours. Airway and eye pain, tearing, and secretion occurred and were immediately followed by headache and nose and throat congestion. Most patients described these effects as “flu-like” symptoms. The symptoms persisted for months. Impaired recall, difficulty concentrating thoughts, and difficulty in following directions occurred days to months after exposure. Problems with balance also appeared for several months. Intervals between exposure and evaluation were 7 to 48 mo.

Exposure. Chlorine odor is detected at levels between 0.2 and 3.5 ppm. The occupational limit is 1 ppm as a time-weighted average, and the National Institute of Occupational Safety and Health (NIOSH) recommendation is no more than 0.5 ppm for 15 min. Thirty ppm of chlorine produces immediate chest pain, dyspnea, cough, and vomiting; 50 ppm causes pulmonary edema; 1,000 ppm is rapidly fatal; and 430 ppm is fatal within 30 min.[8] Exposure concentrations were unavailable for these brief incidents. When such releases occurred, priority had been evacuation of patients and emergency care. A brief episode of exposure is difficult to measure.

Unexposed subjects. Exposed subjects were followed during the course of several years. Each test for each person was compared with individually predicted test values calculated with equations derived from nearly 300 individuals who were unexposed to chemicals from two communities.[9] A total of 296 unexposed subjects (except for household cleaners and pesticides) had been recruited randomly from voters’ registration rolls: 66 from Springfield, Louisiana, and 230 from Wickenburg, Arizona. Ages of the subjects ranged from 18 to 83 y (mean = 45 y), and attained educational level averaged 12.9 y. The Springfield and Wickenburg group scores on each test were similar; therefore, the groups were combined. Thereafter, the author developed prediction equations for each test by stepwise linear regression. The unexposed group’s scores for each test were examined for symmetry of distributions and transformed to log, reciprocal, etc., when transformation improved the symmetry. Age, sex, educational attainment, and other factors that affected results were therefore adjusted in the comparisons.[9] Means of transformed data were compared by analysis of covariance (ANCOVA).

Reference subjects were reimbursed for time and mileage. All subjects provided informed consent, and the protocol was approved by the Human Studies Research Committee of the University of Southern California School of Medicine.

Subjects completed questionnaires that were checked for omissions by computer-guided reading and rectified by each individual. They marked frequencies of 35 common health complaints arrayed from 1 to 11 (i.e., rare to daily, respectively) in Table 1,[10] thus enabling the author to compare group means. Subjects also completed a standard respiratory questionnaire[11] and a history of occupational and other exposures to chemicals (i.e., pesticides, herbicides, tobacco, alcohol, and drugs [prescription and illicit]). Histories were obtained for unconsciousness, anesthesia, head trauma, and neurologic and medical disorders.[10,12,13] The questionnaires and the neurophysiological and neuropsychological test batteries had evolved through studies of (a) histology technicians,[12] (b) firemen exposed to thermolysis products of polychlorinated biphenyls (PCBs),[10] (c) individuals exposed to toluene-rich chemical wastes, and (d) groups of unexposed reference subjects.[9,13] Alcohol was measured in air expired after a 20-s breath hold with a fuel-cell analyzer. No values approximated 0.1 [micro]g/dl, so the author excluded its effects. Testing required approximately 4 hr.

Table 1.–Symptom Frequencies Scaled from 1 to 11 for 22 Chlorine-Exposed Subjects, Compared with National Referents

Symptoms

frequencies

Symptom Exposed Unexposed p

Skin irritation 3.8 3.1 .536

Deformed fingernails 2.5 1.9 .416

Chest tightness 5.8 2.2 .0001(*)

Palpitations 5.4 2.1 .0001(*)

Burning-tightness of chest 4.8 2.0 .0001(*)

Shortness of breath 7.5 2.5 .0001(*)

Dry cough 5.9 2.6 .0001(*)

Cough with mucus 5.0 3.0 .015(*)

Cough with blood 1.9 1.2 .025(*)

Dry mouth 4.6 3.2 .117

Throat tight 4.5 2.8 .021(*)

Eye irritation 5.0 2.8 .01(*)

Decreased smell 3.9 2.1 .01(*)

Headache 7.0 4.1 .004(*)

Nausea 4.1 2.4 .014(*)

Dizziness 7.9 2.1 .0001(*)

Lightheadedness 8.4 2.5 .0001(*)

Exhilaration (unusual) 1.3 1.7 .435

Loss of balance 9.0 2.3 .0001(*)

Loss of consciousness 2.0 1.3 .059

Extreme fatigue 6.1 3.2 .003(*)

Somnolence 3.3 2.5 .346

Insomnia 5.4 3.0 .01(*)

Wake frequently 7.0 2.8 .0001(*)

Sleep few hours 5.4 2.9 .012(*)

Irritability 8.1 3.5 .0001(*)

Loss of concentration 9.0 3.5 .0001(*)

Loss of recent memory 9.3 3.5 .0001(*)

Long-term memory loss 7.1 2.5 .0001(*)

Unstable moods 7.5 2.6 .0001(*)

Loss of libido 6.5 3.2 .0008(*)

Decreased alcohol tolerance 4.9 2.5 .024(*)

Indigestion 4.4 3.2 .145

Loss of appetite 5.4 2.6 .0003(*)

Swollen stomach 5.8 2.7 .0005(*)

(*) Statistically significant.

Neurophysiological tests. Simple reaction time and visual two-choice reaction time were measured with a computerized instrument.[14] Body balance was measured with the subject standing erect with feet together. The position of the head was tracked by two microphones from a sound-generating stylus on a headband, processed with a computer and expressed as the mean speed of sway in cm/s.[15] The minimal sway speed of 3 consecutive 20-s trials was counted with the eyes open and with the eyes closed. The blink reflex latency was measured bilaterally with surface electromyographic (EMG) electrodes from lateral orbicularis oculi muscles[16,17] stimulated by tapping the right and left supraorbital notches with a light hammer, which triggered a recording computer. The author averaged 10 firings of R-1 to determine the mean response for each site, and failures were recorded.[17]

Color confusion index was measured with the desaturated Lanthony 15-hue test under constant illumination[18] and was scored in accordance with the method of Bowman.[19] Threshold testing of visual fields was conducted with a computerized Med Lab Technique automated perimeter that mapped the central 30 [degrees] of right and left eyes individually. Hearing was measured in each ear with standard audiometers (model ML-AM Microaudiometrics [South Daytona, Florida]) at frequency steps from 500 to 8,000 Hertz. The sum of deficits in each ear was the hearing scores.

Neuropsychological tests. Immediate verbal memory or recall was measured with stories from Wechsler’s Memory Scale (revised).[20] Culture Fair (battery 2A) and vocabulary were completed in groups. Culture Fair tested nonverbal, nonarithmatic intelligence based on the selection of designs for similarity, difference, completion, pattern recognition, and transfer.[21,22] Culture Fair resembles Raven’s progressive matrices.[23] The 46-word vocabulary test was derived from the multidimensional aptitude battery.[24] Digit symbol was from the Wechsler Adult intelligence Scale-Revised (WAIS-R),[25] and it tested attention and integrative capacity. Long-term (embedded) memory was tested with information, picture completion, and similarities subtests from the WAIS-R. Time required for each subject to place 25 pegs in the Lafayette slotted pegboard was measured. Trail making A and B and fingertip number writing, both of which measure dexterity, coordination, decision making, peripheral sensation, and discrimination, were from the Halstead-Reitan battery.[26,27] The profile of mood states (POMS)[28] was used to appraise the moods of subjects who responded to 65 terms that described feelings for the week.

Respiratory flows and vital capacities were measured standing with a nose clip from a full inspiration into a volume-displacement (Ohio) spirometer until two forced expirations agreed within 5%.[29] The author used prediction equations to adjust for height, age, sex, and years of cigarette smoking.[30] Volume and flow were traced from records with a digitizer and measured with a computer.

Statistical analysis. All scores and computed data were entered into a IBM compatible microcomputer. Measurements and scores were converted to percentage predicted–adjusted for differences in age, education, gender, and height–and were based on stepwise linear-regression modeling (Stata Statistical Software, Stata Corporation [College Station, Texas]). Other factors, such as family income, hours of general anesthesia, history of alcohol intake, and POMS score, were examined but excluded because they lacked significant coefficients defined as p [is less than] .05.

Results

The ages and education levels of the women and men exposed to chlorine and the referent unexposed group were similar (Table 2), implying that a simple analysis of variance (ANOVA) would detect differences between measurements. Nevertheless, adjustment for sex, age, educational attainment, and other factors–when applicable–were made, and the groups were compared as a percentage of their predicted values. Group differences between exposed and unexposed are also described.

Table 2.–Demographics and Exposure Data for 22 Chlorine-Exposed Subjects

Subject Age Education Site and/or type of

no. (y) (y) Sex exposure

1 30 10 M Home–atmospheric

2 27 12 F Home–atmospheric

3 19 12 M Home–atmospheric

4 35 12 F Home–atmospheric

5 45 11 M Home–atmospheric

6 34 14 M Las Vegas casino

7 54 16 M Chlorinator leak

8 43 12 F Jail/Chlorox + acid

9 59 10 F Chlorine tablet

10 51 12 M City water tank

11 41 16 F Gym

12 34 18 F Gym next to pool

13 45 19 M Gym

14 37 13 M Gym working out

Dallas, Texas, Group

15 33 12 M Chlorine transfer leak

16 32 12 M Chlorine transfer leak

17 36 12 M Chlorine transfer leak

18 58 9 M Chlorine transfer leak

19 35 12 M Chlorine transfer leak

20 40 12 M Chlorine transfer leak

21 53 11 M Chlorine transfer leak

22 46 12 M Chlorine transfer leak

Subject Interval

no. Exposure duration (mo)

1 Several hr 33.5

2 Several hr 33.5

3 Several hr 32.5

4 Several hr 41

5 Several hr 41

6 15 min 7

7 Mins 17

8 5 hr 54

9 Mins on 2 occasions 32

10 1-2 min 28

11 4 hr 13

12 5 hr 13.5

13 4-1/2 hr 11

14 1-2 hr 19.5

Dallas, Texas, Group

15 5-20 min 48

16 5-20 min 48

17 5-20 min 48

18 5-20 min 48

19 5-20 min 48

20 5-20 min 48

21 5-20 min 48

22 5-20 min 48

Chlorine-exposed persons had significantly faster sway speeds than referents, both with eyes closed and with eyes open (Table 3). Simple and choice reaction times were greatly prolonged and abnormal. Blink reflex latency R-1 was delayed bilaterally. Color confusion index was increased, and visual field performance was decreased in both eyes. There was no hearing loss. Grip strength was reduced bilaterally.

Table 3.–Chlorine-Exposed Subjects, Compared with Unexposed Subjects as Percentage Predicted

Exposed (n = 22)

Factors [bar] x SD

Age (y) 40.9 10.8

Education (y) 12.4 2.2

Simple reaction time (ms) 105.4 9.2

Choice reaction time (ms) 104.4 4.1

Balance sway speed (cm/s)

Eyes open 102.9 3.3

Eyes closed 105.2 4.4

Blink reflex latency (R-1 ms)

Right 104.7 12.7

Left 99.1 16.8

Hearing loss

Right 105.6 32.2

Left 109.3 44.1

Color score

Right 49.0 41.6

Left 51.9 47.3

Visual performance

Right 86.5 21.7

Left 84.6 21.5

Grip strength

Right 88.2 22.0

Left 83.5 23.1

Culture Fair A 93.2 21.8

Digit symbol 88.6 13.6

Vocabulary 65.8 31.0

Verbal recall

Immediate 86.8 28.3

Delayed 73.9 33.1

Pegboard 91.7 16.2

Trails A 104.9 11.0

Trails B 106.6 10.1

Finger writing

Right 100.5 9.2

Left 101.5 10.8

Information 73.2 35.1

Picture completion 89.6 34.4

Similarities 93.6 41.8

Unexposed

(n = 296)

[bar]

Factors [bar] x SD p

Age (y) 46.6 20.6 .202

Education (y) 12.9 2.3 .322

Simple reaction time (ms) 99.9 3.7 .0001(*)

Choice reaction time (ms) 100.1 2.5 .0001(*)

Balance sway speed (cm/s)

Eyes open 99.8 2.0 .0001(*)

Eyes closed 100.0 2.5 .0001(*)

Blink reflex latency (R-1 ms)

Right 96.2 13.2 .0068(*)

Left 95.0 13.6 .222

Hearing loss

Right 101.5 24.6 .547

Left 99.3 21.8 .158

Color score

Right 102.6 51.1 .0001(*)

Left 102.5 51.1 .0001(*)

Visual performance

Right 100.4 22.8 .023(*)

Left 101.1 21.7 .004(*)

Grip strength

Right 99.3 17.5 .007(*)

Left 99.1 17.5 .00072(*)

Culture Fair A 101.2 20.0 .078

Digit symbol 101.5 9.2 .0001(*)

Vocabulary 99.2 30.8 .0001(*)

Verbal recall

Immediate 99.8 31.1 .062

Delayed 99.9 41.3 .005(*)

Pegboard 101.7 25.7 .075

Trails A 101.3 8.3 .016(*)

Trails B 100.4 7.5 .00015(*)

Finger writing

Right 100.0 7.5 .812

Left 100.0 7.8 .473

Information 101.5 39.4 .001(*)

Picture completion 99.3 32.1 .184

Similarities 98.1 41.2 .626

Notes: SD = standard deviation, and [bar] x = mean.

(*) Statistically significant.

In the domain of cognitive function, digit symbol, and vocabulary were reduced, but this was not the case for Culture Fair or block design. Times required by subjects to perform trail making A and B were increased abnormally. Pegboard performance and fingertip number-writing errors were within normal ranges. The well-learned culture content tests that depend on embedded memory approximated predicted scores. This result was consistent with the premorbid ability of the chlorine-exposed group to be normal.

The ratio of forced expiratory volume in 1 s ([FEV.sub.1.0])/forced vital capacity (FVC) and vital capacity as percentage of predicted (adjusted for height, sex, age, and years of cigarette smoking) were reduced significantly. [FEV.sub.1.0], mid (i.e., [FEF.sub.25-75]) and late forced expiratory flows (i.e., [FEF.sub.75-85]) were not reduced (Table 4).

Table 4.–Pulmonary Function Tests, Expressed as Percentage Predicted

Exposed Unexposed

Pulmonary test [bar] x SD [bar] x SD p

FVC 89.7 13.2 101.6 15.1 .0006(*)

[FEV.sub.1.0] 88.7 12.3 93.6 15.8 .172

[FEF.sub.25-75] 100.1 32.3 88.1 35.0 .143

[FEF.sub.75-87] 82.5 37.3 78.1 52.7 .719

[FEV.sub.1.0]/FVC 49.7 39.6 72.8 9.5 .0001(*)

Notes: [bar] x = mean,

SD = standard deviation,

FVC = forced vital capacity,

[FEV.sub.1.0] = forced expiratory volume in 1 s,

[FEF.sub.25-75] = mid-forced expiratory flow, and

[FEF.sub.75-87] = late forced expiratory flow.

(*) Statistically significant.

Mood states scores of exposed subjects were elevated significantly (Table 5), with a mean score of 95.7, compared with 21.0 for unexposed individuals (p [is less than] .0001). Frequencies of 28 of the 35 symptoms assayed were elevated significantly in the exposed group, compared with the unexposed group (Table 1). Loss of recent memory, decreased concentration, loss of balance, and lightheadedness were found most frequently. In contrast, the frequencies of skin irritation, deformed nails, dry mouth, exhilaration, somnolence, and indigestion were not increased.

Table 5.–Profile of Moods Scores (POMS) of Chlorine-Exposed and Unexposed Subjects

Exposed Unexposed

Mood (n = 22) (n = 296) p(*)

POMS 95.7 22.9 .0001

Tension 21.5 9.3 .0001

Depression 24.8 8.9 .0001

Anger 21.4 9.5 .0001

Fatigue 18.8 7.3 .0001

Vigor 8.2 18.8 .0001

Confusion 18.2 6.8 .0001

(*) All p values were statistically significant.

No patient had a history of preexisting neurological or psychiatric illness. Drug use, including illicit ones, was absent. Exposure to anesthetic agents, alcohol, and other chemicals was not significantly different for patients and reference subjects. Only one patient had preexisting asthma associated with turkey farming and formaldehyde exposure. None had applied pesticides occupationally, and exposures at home were infrequent. Histories gleaned for each subject showed that there were no other chemical incidents, thus leaving chlorine exposure as the factor.

Discussion

Brief chlorine exposures in these 22 patients were associated with widespread CNS impairment. Included were balance, reaction time, color confusion index, visual field performance, blink latency R-1, cognition, verbal recall, and making trails.

Individual comparisons to predicted values for all tested functions were adjusted, when appropriate, for the effects from age, sex, and education. This strategy was necessary because the case series developed over several years. The strategy is more conservative and more flexible than group-to-group comparisons. Such comparisons have been accepted for pulmonary, cardiac, hepatic, metabolic, and renal function data.[9]

The subjects in this study resembled a chlorine-bleach-exposed group,[7] and they developed multiple and generalized adverse effects to the brain that resembled those following exposure to dibenzofurans,[10] toluene,[13] and trichloroethylene.[31] Chlorine effects differ from manganese, which affects the substantia nigra and the extrapyramidal system,[32] and from the dying back of peripheral nerves resulting from n-hexane.[33]

In light of these findings, why have the effects of chlorine on the CNS not been recognized previously? Plausible answers include the fact that clinicians have considered persistent flu-like symptoms, loss of memory, and concentration, fuzzy thinking, and sleep disturbances as separate illnesses and/or emotional problems. Second, such manifestations did not appear immediately or dramatically, but occurred in conjunction with persistent asthmatic pulmonary complaints. Third, CNS deficits were not obvious clinically. Finally, clinical tests commonly used in the past were not sufficiently sensitive to detect subtle CNS impairment.

The battery of tests that evaluate several complex functions, and thus survey functions of brain areas from the pons to the frontal cortices, appear in Table 6. Balance pathways are best known; blink is the most circumscribed; visual perception, though simple in concept, is complex; and distinguishing colors is particularly vulnerable to chemical damage.

Table 6.–Battery of Tests that Evaluate Several Complex Functions of the Brain

Test Portion of brain

Simple reaction time Retina, optic nerve, and cortex;

and visual two-choice integrative radiation to motor cortex.

reaction time

Sway-balance Inputs: ascending proprioceptive;

tracts, vestibular division 8th cranial

nerve, cerebellum, vision, visual

integrative, and motor tracts.

Blink reflex latency Sensory upper division trigeminal

nerves (V), pons, and facial nerves

(VII).

Color confusion index Center macular area of retina, with

optic cones, optic nerve, optic

cortices.

Visual fields Retina-optic nerve-optic cortex.

Hearing Auditory division of 8th cranial nerve.

Verbal recall memory Limbic system of temporal lobe,

smell brain.

Problem solving, Cerebral cortices: optic-occipital

culture fair, and parietal cortex.

digit symbol

Vocabulary Long-term memory, frontal lobes.

Information, picture Long-term memory, frontal lobes.

completion, and

similarities

Pegboard performance Optic cortex to motor cortex.

Trail making A and B Eye-hand coordination.

Fingertip number Parietal cortices, sensory area of

writing pre-Rolandic fissure.

Profile of mood Limbic system for emotional memory.

states (POMS)

In previous evaluations of chlorine exposure,[4] investigators used pulmonary function tests and respiratory questionnaires to assay airways disease and symptoms of asthma and chronic bronchitis–notably phlegm production. [3,34] They directed no attention to neurobehavioral function. This strategy was apparently an oversight because in 1933, Gilchrist[1] examined 96 chlorine-gassed American soldiers from World War I and confirmed Berghoff’s accounts of pain, headache, giddiness, and asthma in former British soldiers.[2] Therefore, 18 y after exposure, Gilchrist described one patient with epilepsy and “psychoneurosis” and another with shaking, jerking, stammering, and deafness whom he considered mislabeled as psychoneurotic.

The mechanisms for delayed CNS effects of chlorine are unclear. Chlorine added to water produces chlorine dioxide and hypochlorous acid, which decompose to liberate oxygen free radicals ([MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII]) and hydrochloric acid. Free radicals disrupt cellular proteins. Chlorine reacts with organic chemicals to make chloramines and other products.[35,36] Chlorine’s rapid absorption from the lungs into circulating blood disperses the reactive products and provides opportunities for further reactions. Blood flow to the brain transports these chlorinated byproducts, which damage astrocytes and neurons, cause toxic stimulation, and cell death.[37]

One “ultimate dysfunction” of the CNS[38]-temporal lobe seizures[38,39]–occurred in 3 of 35 patients, including 2 who were reported on previously.[7] Seizures began a few months after chlorine exposure and were characterized by staring and disorientation without loss of motor control, frothing at the mouth, incontinence, or tonic or clonic movements.

These mischance incidents of chlorine exposure should help generate hypotheses. It is hoped that other clinicians will test chlorine-exposed individuals and use appropriate methods (as suggested herein) to further document CNS impairment. Meanwhile, this warning of adverse effects of inhaled chlorine on the pulmonary and nervous system advises great care in the transport and use of chlorine. Dangerous concentrations of chlorine may be reached in and around water-treatment plants, swimming pools, sewage-treatment plants, and during floor cleaning and the sterilization of dishes and utensils. Massive releases, as occur during transport of compressed chlorine gas in cylinders or spheres on highways[41] and railways,[42] are a continuing hazard.

This study was peer reviewed by Drs. Rodney R. Beard and Janette D. Sherman.

Financial support was provided from patients and patients’ attorneys.

Submitted for publication March 12, 1999; accepted for publication May 5, 1999.

Requests for reprints should be sent to Kaye H. Kilburn, M.D., University of Southern California School of Medicine, Environmental Sciences Laboratory, 2025 Zonal Avenue, CSC 201, Los Angeles, CA 90033.

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[41.] Ill Wind. Dozens injured Alberton evacuated after derailment spills deadly chlorine. Missoulean (Montana); April 12, 1996.

KAYE H. KILBURN University of Southern California School of Medicine Environmental Sciences Laboratory Los Angeles, California

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