J Occup Health 2002; 44: 1–7 

### Journal of Occupational Health



# Neurological Disorders in Three Workers Exposed to 1-Bromopropane

Gaku I CHIHARA 1 

## , Joseph Keith M ILLER 2 

## , Aldona Z IOLKOWSKA 3



## , Seiichiro I T OHARA 1 

## , Yasuhiro T AKEUCHI 1

1 

### Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine,

2 

### Department of Neurology, Johnson Neurological Clinic, High Point, North Carolina and

3 

### High Point Regional Hospital, High Point, North Carolina, USA

Abstract: Neurological Disorders in Three Workers Exposed to 1-Bromopropane: Gaku I CHIHARA , et al. Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine —A 35-yr-old female worker developed sore throat, stumbling, dysphagia, incontinence of urination and numbness with a burning sensation in the legs, thighs, hips and lower back as well as numbness in the perineum. She was spraying a glue to compose a cushion with polyurethane foam parts. One year after beginning to use a glue containing mainly 1- bromopropane, she became unable to stand up by herself. The second case, a 30-yr-old female worker developed a staggering gait, paresthesia, urinary incontinence, slurred voice, dysphagia, numbness or paresthesia in the hands, legs, lower back, hips and perineum, six months after beginning the same task. The third case, a 50-yr-old female worker showed signs of staggering, and numbness and paresthesias in the feet, thighs, lower back and hips, and headache, two months after starting the work. The daily time-weighted average of exposure concentrations ranged from 60 to 261 ppm (mean 133, N=11) after the ventilation was improved. The common signs in the three workers were staggering, numbness with paresthesia/dysesthesia, as well as a remarkable decrease in vibration sense in the legs and various symptoms in the central nervous system. Abnormal sensation was distributed to the area covered by pantyhose, rather than glove-stocking. Not only peripheral nerves, but also the spinal cord or brainstem was suspected to be impaired, given the paresthesia/dysesthesia and the distribution of sense deficits. Their diarrhea, incontinence of urination and abnormal sweating also suggested disorders in the

Received Oct 17, 2001; Accepted Dec 12, 2001 Correspondence to G. Ichihara, Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan autonomous nervous system. 1-Bromopropane might induce neurological disorders in the peripheral nerves and/or the central nervous system in humans. (J Occup Health 2002; 44: 1–7)

Key words: Intoxication cases, Neurological disorders, 1-Bromopropane, Alternative solvent to ozone-layer depleting, Intoxication

1-Bromopropane is a new alternative to ozonedepleting solvents. It is less destructive to the ozone layer, but nonflammable and moderately volatile, which are important properties for metal cleaning agents. Otheralternatives have been phased out because of their ozonedepleting potency or toxicity, so the demand for 1- bromopropane as a solvent is now increasing in industry, but it was recently revealed to have neurotoxicity and reproductive toxicity in animal experiments 1–4) . Although one case report suggests the neurotoxicity of 1- bromopropane in a worker 5) , its neurotoxicity in humans is generally not well understood. We report neurological disorders in three workers exposed to 1-bromopropane in a cushion company, because we consider these cases very important in understanding the neurotoxicity of 1- bromopropane in humans.



### Case Reports

Three workers, who used 1-bromopropane as a solvent with a spray gun, showed abnormal neurological symptoms or signs. In a cushion company in North Carolina in the U.S., 1-bromopane was introduced in the workplace to replace dichloromethane as a solvent in glue in July 1999. The workers sprayed glue on polyurethane foam parts, then pressed them together by hand to form a bond as a part of the cushion production process. Fifteen workers were engaged in spraying glue in the same
workroom at the time that case 1 became ill in June of 

### Rapid Communication2 J Occup Health, Vol. 44, 2002

2000. The workbenches for the fifteen workers were arranged along one long side and one short side of a rectangular room. Each worker, including both case 1 and case 2, did their jobs, while facing a wall equipped with a ventilator, but the ventilators were operated only 15 min per hour in the summer of June, 2000. The ventilator in front of case 3 was not operating at all up through June. Some workbenches had no ventilators from the very start for other workers. The workers used spray guns, and the glue sometimes spattered on their faces. They wore only thin latex gloves for work, but no proper gloves or masks able to protect them from the solvents. The Material Safety Data Sheet (MSDS) indicated that the glue contained 1-bromopropane 55%, ethyl acetate 8% and aliphatic petroleum distillates 2%.
Case 1 : The patient, a 35-yr-old female was carried to the local emergency Room on June 30, 2000, because she could not walk by herself in the morning. She had dystaxia and dysesthesia with a burning sensation or tingling with numbness in both feet, legs, thighs and lower
back. On admission she could not walk without
assistance. It was difficult for her to use stairs. Dysesthesia was noted by touching. Her vaginal area felt numb both inside and outside, as if she had been given local anesthesia. She walked with a wide spread gait. She had been engaged in spraying glue in a cushion factory since 1998. From April to June, just prior to developing the above mentioned neurological symptoms, she went to the emergency room four times for a sore throat, earache, sinus irritation and hoarseness. Urinary incontinence was also noted during this period. She usually worked eight hours a day from Monday to Friday, but in June 2000, she worked nine hours per day. At the beginning of that month, she experienced difficulty in swallowing as if something was stuck in her throat. On June 23, she began to stumble, feel dizzy and lose her balance. She stayed home from work for two days, but the symptoms worsened. On June 26, she consulted her primary care doctor, because of the dizziness, sore throat, eyeache and numbness in the perineum. She was prescribed antibiotics and anti-allergic agents (Nasonex, mometasone furoate monohydrate) for ten d. On June 27–29, she worked for eight or nine h per d. The stumbling worsened, and her sore throat, earache and malaise in the sinuses failed to improve. She felt numbness and muscle pain in her feet, legs, thighs and lumbar area. Numbness in the thighs was more remarkable at the front than at the back, but in the legs, conversely, more remarkable at the back than at the front.
She also sometimes had headaches. She found it more difficult to walk with each passing day. She lost 11 pounds (about 5 kg) during the four days from 26 to 30 June, 2000.

Neurologic examination on admission revealed that the patient was alert and oriented with clear speech and sensorium. No intranuclear ophthalmoplegia was identified. The pupils were round and reactive to light. The left pupil seemed slightly larger than the right one, and there was some hippus noted bilaterally. Both tympanic membranes appeared clear. Tongue movements
were intact. No carotid bruit was noted and the heartbeat was regular. Tone did not increase and deep tendon reflexes were equal, symmetric and active throughout. There was no clear weakness in her upper and lower extremities. Plantar responses were flexor bilaterally. Her prick sensory level was about T6, and her vibration sense was distally diminished. The patient did not show any sings of spastic gait, but she was unsteady and had to hang onto the wall. Romberg sign was negative. There was no abnormality in the nose-finger-nose, heel-shin, line-drawing or pronation-supination test. Her spouse said that the patient was originally cheerful and active, but her mood had been changed to be depressive. The patient felt tired even after working for a short time. She was depressive but sometimes irritated and tended to get

angry.

Past and family history: Hypertension, migraine headaches. The patient was allergic to penicillin and codeine. She had had a tonsillectomy, bunionectomy, cholecystectomy and tubal ligation. Her family history included diabetes mellitus (grandfather and sister), heart attack (father) and ovarian cancer (sister). Drinking history: one or two glasses of beer per two wk. Smoking history: 20 cigarettes per d for 18 years. She felt recently
that she had become unable to drink much. Her cholesterol was 224 with HDL of 29 (mg/d l ). Her respiratory rate was sedate and 12. ANA was negative. The MRIs of the brain and cervical and thoracic portions of the spinal cord did not show any particular findings. No Lhermitte’s phenomenon was observed. On July 3 (3 days after admission), her walking had improved a little, but she still stumbled and her throat remained sore. On July 4, serum vitamin B12 was 442 mg/d l and Lyme disease antibody, IgG and IgM were negative. No urinary lead or mercury was detected and urinary arsenic was within normal limits (48.3 μ g/ l , 150.9

μ

g/g creatinine). On July 6, lumbar puncture produced clear, colorless fluid. Cell counts of cerebrospinal fluid (CSF) were all within normal limits (RBC 2, WBC 2,
L

ymphocyte 70, Monocyte-macrophage 30 but no other cells were found). The serum protein pattern was normal (total protein 7.2, albumin 4.19, alpha-1 0.46, alpha-2 0.75, beta 0.74, gamma 1.06 g/d l ). On July 19, a gynecologist found mild cystocele and rectocele, which suggested mild pelvic relaxation. In July, her menstruation began 2 wk earlier than usual. On August 23, an electrophysiological study showed values within normal limits in motor nerve conduction velocity on both sides of the peroneal nerve and left posterior tibial nerve, and sensory nerve conduction velocity on both sides of3 Gaku I CHIHARA , et al.: Workers Exposed to 1-Bromopropane

the sural nerve. On November 21, MRI of lumbar portions of the spinal cord showed only degenerative change with facet hypertrophy and mild central bulging
of the intervertebral disc at L5-S1.
Case 2 : The patient, a 30-yr-old female, worked in the same cushion company from February to June 30, 2000. On June 30, she developed a staggering gait as if she were in a drunken stupor. The patient was seen at the same local emergency room and was noted to have paresthesias. She had difficulty in noticing the need to defecate or void and could tell only by a sense of
discomfort in her abdomen. She had numbness in the perineum and lacked sensation during sexual intercourse. At first, there was some numbness in her hand, but it resolved later. She had some lower back pain, but no trouble with fever or chills. She had some difficulty in speaking, and her words were somewhat slurred. Her lower extremities usually felt tired. She lost 5 pounds (about 2 kg) in the last week of June.

Past illness: kidney infection (1998), cholelithotomy (1993), Family history: heart attack (grandmother), brain attack (grandfather), diabetes mellitus (mother) Smoking: forty cigarettes per week. Drinking: 2 times per yr. The former work: packing mail staples for four yr. She had a Cesarean section in the past. She was not allergic to any medications, nor was she taking any medications on a daily basis.

Neurological examination revealed her to be alert and oriented with clear speech and sensorium. The pupils were round and reactive to light. Extraocular muscle movements and tongue movements were intact. The patient had the full range of motion of the cervical spine. She had no Lhermitte’s phenomenon. There was no definite focal motor weakness in her upper or lower extremities. Plantar responses were flexor bilaterally. Deep tendon reflexes were equal, symmetric and active throughout. There was peripheral diminution to vibratory and pin prick sensation on the right lower extremity to the knee. The sensation was less impaired up toward the waist. It was less severe on the left side than the right side both in the legs and in the thighs. There was no spasticity, no fasciculations nor clear muscle atrophy. Finger-nose and heel-shin testing was normal. Gait and station were normal. Tandem gait was done without any difficulty. Romberg sign was negative. Rectal exam showed fair rectal tone. On July 19, 2000, the patient noted at times that her feet sensation easily changed from hot to cold. On August 9, 2000, the symptoms had improved, but she was still having paresthesias in both
her lower extremities. No focal motor weakness was identified. MRIs of cervical, thoracic and lumbar spine did not show any particular findings. On August 24, 2000, she still had urinary incontinence. She had difficulty in swallowing solid food. She had a very poor appetite and abdominal pain. She felt hot and sometimes cold in her feet. She felt hot but not really hot and just flushed. On 6 September 2000, the patient had some pain in her lower back, as well as in her stomach. She felt hot at night and her stomach sometimes felt hot in the morning. She felt her stomach bloated and also felt as if she were pregnant. She also had some repeated diarrhea and nausea/vomiting. Although there was nothing to void, she found herself repeatedly trying to do so. She suffered somewhat from insomnia. The patient also had bifrontal headache and at times her head felt like popping. Higher cortical functioning was normal. Funduscopic examination showed no particular findings. There was no abnormality in the line-drawing or pronation-supination test. Menstruation began one wk later than usual in June 2000. The patient tired easily and was misunderstood as lazy by her spouse. The patient was depressive, but sometimes irritated and tended to get angry. In June this patient fought with the former patient in case 1, though she had
never done so before.
Case 3 : The patient, a 50-yr-old female, started the work in March, 2000. She became aware of weight loss, staggering, numbness in the feet and pain in her wrists, elbows and shoulders from May to June, 2000. She also felt pain in the front of her thighs at night. During the week, she felt better on Monday, but on Tuesday she felt pain in her feet and shoulders, headache, and sore throat. On Wednesday and Thursday, rhinorrhea, and stumbling occurred, and her headaches became more severe. These symptoms were reduced over the weekend holidays. This change in symptoms was repeated every week. She could call up words, but sometimes felt difficulty in speaking.

Neurological examination revealed her to be alert and oriented with clear speech and sensorium. The pupils were round and reactive to light. Extraocular muscle movements and tongue movements were intact. She had no definite focal motor weakness in her upper or lower extremities. Plantar responses were flexor bilaterally. Deep tendon reflexes were equal, symmetric and active throughout. There was peripheral diminution of response to vibratory and pin prick sensation in both lower extremities to about the level of the thighs, hips and lower back, but tactile sense was lowered only in the toes and was comparatively well preserved in the upper levels. She could not maintain a standing position when her knees were bent even slightly by others. Romberg sign wasnegative. There was no abnormality in the nose-fingernose, heel-shin, line-drawing or pronation-supination test.
She said that she could stare but could not concentrate.

The exposure level of the worker to 1-bromopropane was estimated with a passive sampler (passive gas tube for organic solvents, Sibata Scientific Technology Ltd.,
T

okyo, Japan). A passive sampler was attached to the worker for eight h during work on October 23–26, 30 and 31, 2000. Immediately after each day’s work, the sampler was sealed in an aluminum bag and kept at 4 ° C4 J Occup Health, Vol. 44, 2002

until analysis. On analysis, coal particles were taken from the samplers and then immersed in 2 m l carbon disulfide (Wako Pure Chemicals, Osaka, Japan) in a glass tube with a screw cap. The tube was shaken for 5 min and leftfor 2 h and the supernatant liquid was injected into GCMS (GCD system G1800A, Hewlett Packard). 1- Bromopropane was quantified by the single-ion mode at 43.1 (m/z) with a qualifier at 41.15 (m/z). The value of 0.134 was used in calculation as the sampling rate for 1- bromopropane. The daily time-weighted average ranged from 60 ppm (min.) to 261 ppm (max.). The average of the daily values and the standard deviation (S.D.) for eleven d (N=11) was 133 ± 67 (mean ± S.D.) ppm.

Questionnaire to three workers

Three workers were interviewed based on the check up form for organic solvent intoxication at Nagoya University School of Medicine (Tables 1 and 2). The common symptoms or signs of the three workers were staggering, weakness in legs, and numbness and paresthesia with a similar distribution in their feet, legs, thighs, lower back and hips, along with various symptoms in the central nervous system such as headache, dizziness, nausea, insomnia, anxiety, irritation, light headedness, muddle-headedness, forgetfulness, difficulty in concentrating and listlessness. They also complained of weakness in the legs, tremor in the legs, dizziness when standing up, thirst, indigestion, diarrhea, weight loss, rough skin, a strange feeling in throat and frequent cough.



### Discussions

The three workers showed the common symptoms of staggering, numbness and paresthesia/dysesthesia with a similar distribution in their feet, legs, thighs, lower back and hips as well as a remarkable decrease in vibration sense, along with various symptoms of the central nervous system and autonomic symptoms. There were no laboratory data supporting Lyme disease, multiple sclerosis, Guillan-Barre syndrome, lack of Vitamin B12 or metal intoxications in Case 1, but no such data were available in the other cases. Although other causes were not completely ruled out, common work-related causes were suspected in the three cases. This is because common symptoms and signs were found in these three among the fifteen workers engaged in the same work almost at the same time and during the busiest months. The weekly changes in neurological symptoms in case 3 also strongly suggested solvent involvement.

Our previous animal experiments showed 1- bromopropane exposure induced myelin degeneration in the peripheral nerves, swelling of preterminal axons in the gracile nucleus in the medulla oblongata at 800 ppm or

over 1, 3, 4) and pyknotic shrinkage of Purukinje cells in the cerebellum at 1000 ppm 3) , as well as electrophysiological changes in the peripheral nerves and weight loss of the brain at 800 ppm 1) . Recent animal studies also revealed a decrease in neuro-specific γ-enolase in the brain 6, 7)

. These animal studies, which provide definite evidences of the neurotoxicity of 1-bromopropane, suggest the involvement of 1-bromopropane in the cases under study.

The present cases provided some implications as to vulnerable regions in the nervous system, which had not been found in previous animal studies. The neurological signs and symptoms suggesting abnormal regions are summarized from our three cases and the previous case 5) in Table 3. The present three cases showed abnormal sensation not only in distal portions of the lower extremities, but also in the thighs, back, hips and genitalarea. The present cases were not the typical glovestocking type neuropathy observed in hexane
intoxication 8, 9) , but as it were, pantyhose type. The paresthesia and dysesthesia like a burning sensation could Table 1. Worker symptoms while using organic solvent

Case 1 Case 2 Case 3 Working period 12 months (99.7–00.6) 5 months (00.2–00.6) 9 months (00.3–00.12)

Eye pain + – –
Nose stimulation + + –
Sore throat + + – Strange taste + + –
Hot face + + –

* Vertigo or dizziness + + +

* L ight-headedness + + +

* Feel intoxicated + + +

Heavy-headedness + – –

* H eadache + + +

*Items common to all three workers. No worker complained of “dim eyesight” or “strange smell” in answer to the questions regarding symptoms while using organic solvent.5 Gaku I CHIHARA , et al.: Workers Exposed to 1-Bromopropane

Table 2. Recent symptoms and signs after 1-bromopropane exposure in three workers

Case 1 Case 2 Case 3 Working period 12 months (99.7–00.6) 5 months (00.2–00.6) 9 months (00.3–00.12)

Heavy-headedness + + –

* H eadache + + +

* Vertigo or dizziness + + +

* Nausea + + +

Vomitting – + –

* Insomnia + + +

Frequent nightmares – + +

* Anxious about various things + + +

* Irritated by various things + + +

* L ight-headed + + +

* Feel muddle-headed + + +

* Forgetful + + +

* Difficulty in concentrating + + +

* T remor in hands or legs + (leg) + (leg) + (leg)

Cramp in hands or legs + (leg) – + (leg)

* Feel dizzy when standing up + + +

Palpitation – – + Feel as though chest is compressed + – – Feel as though choking or suffocating + + –

* L istlessness + + +

* H ands or legs feel heavy + + +

No appetite + + – Abdominal pain (Stomachache) – + –

* Thirsty + + +

* Indigestion (digestive trouble) + + +

* Likely to have diarrhea + + +

* Lost weight + + +

Changed the way you sweat + – – Irregular periods + + –
Lost sexual desire + + – Dim eyesight – – + Eye strain + – + Difficulty in hearing – – + Difficulty in speaking – – + Taste strange – + –

* Pain in joints or elsewhere + + +

* Numbness in hands and legs + + +

Chilly hands and legs + + –

* Smarting or abnormal feeling in hands and legs + (leg) + (leg) + (leg)

Weakened grip + + –
* W eakness in the hands or legs + + +

* Tend to stumble + + +

* Rough skin + + +

* Throat feels strange + + +

* Frequent cough + + +

Unable to drink much + + –

*Items common to all three workers. No worker complained of “Sometimes lose consciousness”, “Have convulsive fits”, “Likely to have constipation”, “Have a slight fever”, “Ringing or buzzing in my ears”, “Difficulty in smelling”, “Difficulty in tasting” or “Gums bleed easily”.6 J Occup Health, Vol. 44, 2002

indicate peripheral nerve, spinal cord or probably brainstem origin 10) . They also showed symptoms of the central nervous system such as memory loss, headache or mood changes. Sclar reported a patient 5) exposed to 1-bromopropane and with distal dominant neuropathy in the limbs, but there was no description of the presence of abnormal sensation in other areas or symptoms of the central nervous system. Nevertheless, the Sclar’s case showed abnormality of neural formina near the root ganglion and periventricular white matter of the brain in MRI. Somatosensory-evoked potential studies did not produce any cortical potentials, suggesting a lesion in the dorsal column or lemniscal level. These findings in Sclar’s case suggest possible deficits in more central regions of the nervous system than the distal peripheral nerve. Moreover, the abnormality near the root ganglion and the somatosensory-evoked potential studies might explain the distribution of abnormal sensation in the present cases. The three cases also suggested abnormality of the autonomic nervous system as indicated by diarrhea and the change in sweating. It was not clear if the urinary incontinence in cases 1 and 2 were the same as “urinary difficulty” in Sclar’s case, but this also suggested deficits in the autonomic nervous system. However, there could be other impaired regions; deficits in the somatic sensory nerves in the bladder, for example, were suggested by
the unawareness of urination in case 2.

Deep sensation was diminished but the Romberg sign was negative. Since a positive Romberg sign requires a severe loss of deep sensation, the negative Romberg sign does not necessarily rule out ataxia due to lesions in the spinal cord or peripheral nerves. The decrease in deep sensation suggested ataxia due to spinal cord or peripheral nerve rather than cerebellular ataxia, but the possibility of cerebellular involvement was not disproved completely. In rats, pyknotic atrophy of Purukinje cells in the cerebellum was found at 1000 ppm for 4–5 wk, although this change was not remarkable below 800 ppm. Extrapolation of this result in the animal experiment to humans is difficult at this point. Dysphagia in cases 1 and 2, which was also reported in Sclar’s case, suggested a disorder in the glossopharyngeal or vagus nerve, or medulla oblongata. This disorder might also be suggested by articulatory disturbance in case 2 and possibly 3, though differential diagnosis was not completed. Case 1 did not demonstrate any abnormality in distal latency or nerve conduction velocity, nor did it show significant MRI findings explaining her symptoms, as different from the previous case 5) . This might be due to the difference in the degree of impairment or the Table 3. Neurological signs or symptoms suggesting abnormal regions of the nervous system

Case 1 Case 2 Case 3 (Sclar’s case) Working period 12 months 5 months 9 months 2 months (99.7–00.6) (00.2–00.6) (00.3–00.12) (98.1–98.2)

Weakness in limbs + (subjective) + (subjective) + (subjective) + Tremor in legs + + + ?

* Numbness in low back + + + ?

* Numbness in frontal thighs + + + ?

* D ecrease in temperature sensation in foot + + + ?

* Decrease in vibration sense in feet + + + +

* D ecrease in superficial sense in feet + + + +

Numbness in perineum + + – ?

* P aresthesia or dysesthesia + + + ?

Dysphagia + + – + Difficulty in speaking + + + ? Urinary difficutly + + – +
* Dia rrhea + + + ?

* D izziness when standing up + + + ?

* Thirsty + + + ?

* Memory loss + + + ?

* H eadache + + + ?

Dizziness + + + ?
Insomnia + + + ?
Brain and cervical MRI – – Not examined + Electrophysiology in legs – Not examined Not examined +

*Items common to cases 1–3.7 Gaku I CHIHARA , et al.: Workers Exposed to 1-Bromopropane

observation time, or whether gadolinium enhancement was applied.

Menstrual cycles were disrupted temporarily in cases 1 and 2. This might accord with the previous animal experiment 11)

.

The daily individual exposure levels were estimated to range from 60 to 261 ppm in case 3. As this evaluation was done after the ventilation was improved, the workers might have been exposed to higher 1-bromopropane than
the above levels in June.

In conclusion, 1-bromopropane might induce deficits in the peripheral nerves and/or the central nervous system in humans. The symptoms of diarrhea, abnormal sweating and urinary incontinence also suggested disorders in the autonomic nervous system.

Acknowledgements : Our sincere thanks to Dr. Thomas G. Braun, Department of Neurology, University of North Carolina, North Carolina, USA, Dr. Charles C. Goodno, Dr. Dennis Darcey, Division of Occupational and Environmental Medicine, Department of Community & Family Medicine, Duke University Medical Center, Dr. William M. Valentine, Dr. Holly L. Valentine, Department of Pathology, Vanderbilt University Medical Center, Dr. Sahoko Ichihara, Department of Internal Medicine, Nagoya University Graduate School of Medicine, Dr. Gen Sobue, Dr. Naoki Hattori, Dr. Yideng Liang, Department of Neurology, Nagoya University Graduate School of Medicine, Dr. Yasuo Koike, Department of Medical Technology, Nagoya University School of Health Sciences and Dr. Junzoh Kitoh, Professor Emeritus of Nagoya University.



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