Ozone-depleting solvents, such as specific

chlorofluorocarbons and 1,1,1-trichloroethane,

have been banned since 1996 in developed

countries. Because they were used in large

amounts in various industries, alternative compounds were introduced to the workplace.

One such alternative compound is 1-bromopropane (1-BP; n-propylbromide, CAS

Registry no. 106-94-5), which is used in the

United States and Japan as a cleaning agent for

metals, precision instruments, electronics, optical instruments, and ceramics (Ichihara, in

press). It is also used in spray form as an adhesive in the United States (Ichihara et al. 2002).

Environ Tech (2001) estimated the total

amount of 1-BP commercially available for sale

in the United States in the year 2000 was

1,967.9 metric tons (4,338,583 lb), which is

comparable to 9.0, 31.0, and 10.6% of the

amount of methylene chloride, perchloroethylene, and trichloroethylene used in adhesive/foam fabrication and metal cleaning in the

same year in the United States. In Japan, the

amount of 1-BP sold in 2003 was 1,125 metric

tons, which is about double the 645 metric tons

sold in 1998 (Association of Bromopropane

Producers of Japan, unpublished data). In

addition, in the workplace where cases of

neurotoxicity had been reported, 1-BP was

introduced as an alternative for methylene

chloride (Ichihara et al. 2002). The benefits of

using 1-BP instead of the chlorinated carbons

are not clear. However, under pressure to regulate the use of chlorocarbons, 1-BP has been

used as a surrogate, which is encouraged by the

lack of measures to define the exposure limits.

In this regard, previous animal studies revealed

neurotoxicity and reproductive toxicity of 1-

BP (Ichihara et al. 2000a, 2000b; Wang et al.

2002, 2003; Yamada et al. 2003; Yu et al.

1998, 2001). Exposure to 1-BP resulted in a

dose-dependent limb muscle weakness and

reduction of nerve conduction in rats (Ichihara

et al. 2000a). It also resulted in myelin degeneration of peripheral nerves and swelling of

preterminal axons in the medulla oblongata

(Ichihara et al. 2000a). It was also revealed that

1-BP exhibits reproductive toxicity in both

male and female rats (Ichihara et al. 2000b;

Yamada et al. 2003). Thus, animal studies preceded human studies and warned about the

potential neurotoxicity and reproductive toxicity of 1-BP in humans. The most recently

reported cases also confirmed the neurotoxicity

of 1-BP in humans (Ichihara et al. 2002; Sclar

1999). However, these case reports have limitations in terms of quantitative analysis. In

1999 we investigated a 1-BP factory, but this

investigation was also limited because it was

originally oriented to study the effects of

2-bromopropane (2-BP), which targets mainly

reproductive and hematopoietic systems

(Ichihara et al. 2004).

The aim of the present study was to assess

the neurologic function and other healthrelated changes in workers exposed to 1-BP

and compare the results with those of control

workers in a beer factory.

Materials and Methods

Factories and workers. The subjects were

female workers of a 1-BP production factory

located in Yixing, Jiangsu Province, China.

The survey was conducted 16–18 January

2001. The same factory mainly produced 2-BP

in 1996 (Ichihara et al. 1999), but shifted the

main production to 1-BP between 1996 and

1999 (Ichihara et al. 2004), and the product

was only 1-BP at the time of the present survey.

1-BP was synthesized by incubating n-propranolol and hydrogen bromide under concentrated sulfuric acid. The product was purified

by distillation and temporarily stored in

ceramic containers. The crude product was

then transferred to 20-L plastic vessels through

hose pipe from the cock of the container and

subsequently neutralized with hydrogen carbonate. The product was finally transferred to

1,000-L drums for storage and transport. The

Environmental Health Perspectives • VOLUME 112 | NUMBER 13 | September 2004 1319

Address correspondence to G. Ichihara, Field of Social

Life Science, Nagoya University Graduate School of

Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya

466-8550, Japan. Telephone: 81-52-744-2123. Fax:

81-52-744-2126. E-mail: gak@med.nagoya-u.ac.jp

We thank Z.-Q. Chen, School of Medicine, Fudan

University, and K. Yokoyama, Department of Public

Health, School of Medicine, Mie University, for their

help in conducting neurobehavioral tests. We also

thank Y. Koike, Department of Medical Technology,

Nagoya University School of Health Sciences, and

T. Kondo, Nihon Kohden Co. Ltd., for their support

in electrophysiologic examination. 

This study was supported by grants 13470088 and

14406015 from the Japan Society for the Promotion

of Science.

The authors declare they have no competing financial

interests.

Received 2 February 2004; accepted 30 June 2004.

Neurologic Abnormalities in Workers of a 1-Bromopropane Factory

Gaku Ichihara,1 Weihua Li,2 Eiji Shibata,3 Xuncheng Ding,2 Hailan Wang,1 Yideng Liang,4 Simeng Peng,5

Seiichiro Itohara,1 Michihiro Kamijima,1 Qiyuan Fan,2 Yunhui Zhang,2 Enhong Zhong,2 Xiaoyun Wu,2

William M. Valentine,6 and Yasuhiro Takeuchi7

1Field of Social Life Science, Nagoya University Graduate School of Medicine, Nagoya, Japan; 2Shanghai Institute of Planned

Parenthood Research, Shanghai, China; 3Department of Health and Psychosocial Medicine, Aichi Medical University, Aichi, Japan; 4Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; 5Yixing

Anti-Epidemic and Health Station, Yixing, China; 6Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee,

USA; 7Emeritus Professor, Nagoya University, Nagoya, Japan

We reported recently that 1-bromopropane (1-BP; n-propylbromide, CAS Registry no. 106-94-5),

an alternative to ozone-depleting solvents, is neurotoxic and exhibits reproductive toxicity in rats.

The four most recent case reports suggested possible neurotoxicity of 1-BP in workers. The aim of

the present study was to establish the neurologic effects of 1-BP in workers and examine the relationship with exposure levels. We surveyed 27 female workers in a 1-BP production factory and

compared 23 of them with 23 age-matched workers in a beer factory as controls. The workers were

interviewed and examined by neurologic, electrophysiologic, hematologic, biochemical, neurobehavioral, and postural sway tests. 1-BP exposure levels were estimated with passive samplers.

Tests with a tuning fork showed diminished vibration sensation of the foot in 15 workers exposed

to 1-BP but in none of the controls. 1-BP factory workers showed significantly longer distal latency

in the tibial nerve than did the controls but no significant changes in motor nerve conduction

velocity. Workers also displayed lower values in sensory nerve conduction velocity in the sural

nerve, backward recalled digits, Benton visual memory test scores, pursuit aiming test scores, and

five items of the Profile of Mood States (POMS) test (tension, depression, anxiety, fatigue, and

confusion) compared with controls matched for age and education. Workers hired after May 1999,

who were exposed to 1-BP only (workers hired before 1999 could have also been exposed to 2-BP),

showed similar changes in vibration sense, distal latency, Benton test scores, and depression and

fatigue in the POMS test. Time-weighted average exposure levels in the workers were

0.34–49.19 ppm. Exposure to 1-BP could adversely affect peripheral nerves or/and the central nervous system. Key words: 1-bromopropane, distal latency, nerve conduction velocity, neurobehavioral testing, neurotoxicity, ozone-depleting solvents, postural sway testing, reproductive

toxicity, vibration sense. Environ Health Perspect 112:1319–1325 (2004). doi:10.1289/ehp.6995

available via http://dx.doi.org/ [Online 30 June 2004]

Environmental Medicine Article
workers were at risk of exposure to 1-BP when

a) placing the chemicals into the reaction pots;

b) sitting close to the reaction pots to observe

and record the temperature; c) taking out the

crude product; d ) adding the hydrogen carbonate and stirring; and e) pouring the product

into the drums. In the final step, the workers

added the product with hand scoops to adjust

the product volume in the drum.

The surveyed factory has two similar-sized

manufacturing plants, each measuring 9.7 ×

24.4 × 7 m (width × depth × height). In each

plant, a ventilating fan was ineffectively

installed 6 m from the floor; no local ventilation fan was installed in the vicinity of the

areas where workers might be exposed to 1-BP.

The 27 surveyed workers who were engaged in

the production of 1-BP in the factory were all

female. As controls, we selected age-matched

(± 2 years) females at random from 202 female

workers in a beer factory in the same city. The

control workers lived in the same area.

In the analysis of paired t-tests between

1-BP workers and controls, four 1-BP workers

were excluded because no corresponding match

of control workers from the beer factory could

be recruited. However, the analysis by exposure

level or period of exposure included those 1-BP

female workers for whom no corresponding

age-matched controls could be recruited. All

workers who were hired after 1991 and for

whom corresponding age-matched controls

could be recruited were identified as 1991

workers. Among them, the workers who were

hired after 1999 and were exposed only to 1-BP

were defined as 1999 workers.

Medical examination. Signed informed

consent was obtained from each worker for all

examinations and interviews, according to the

Declaration of Helsinki (World Medical

Association 2002). All female workers in the

1-BP factory and the 23 age-matched beerfactory workers were clinically examined by a

trained Chinese neurologist who was conducting medical research at the Department

of Neurology, Nagoya University, Japan, and

had a good command of both Chinese and

Japanese languages.

The vibration sensation was evaluated

using a vibrating tuning fork (128 Hz); the

fork was placed on the dorsum of the

metatarsophalangeal joint of the big toe or the

dorsum of the metacarpophalangeal joint of

the thumb, and the worker was asked to

report when the vibration ceased. Immediately

after reporting, the tuning fork was moved to

the same site (big toe or thumb) of the examiner and the duration of the lasting vibration

after the worker’s report was recorded. It was

difficult to assess the actual time when the

delay time was < 2 sec, because it took some

time (but < 2 sec) to move the tuning fork

from the worker’s body to the examiner’s

body. In addition, one worker reported total

loss of vibration sense in the right toe.

Therefore, the value could not be treated as a

continuous value in the statistical analysis. The

examiner was a trained female (38-year-old)

neurologist who worked with every worker

throughout the investigation.

Electrophysiologic studies. We conducted

electrophysiologic studies in an air-conditioned

room maintained at 24°C. The workers were

acclimated to the room temperature for

30 min before the electrophysiologic studies.

We examined distal latency (DL), motor nerve

conduction velocity (MCV), F-wave conduction velocity (FWCV), and sensory nerve conduction velocity (SNCV). Electric stimulation

and recordings were performed with a

Neuropack evoked potential/electromyogram

measurement system (model MEB5508;

Nihon Kohden, Co., Tokyo, Japan). For

measurement of DL and MCV, the stimulation site was just behind the medial malleolus

(distal) and the center of poples (proximal),

and the recording site was fixed 11 cm distal

to the distal stimulation site on the abductor

hallucis muscle.

Blood tests. The following blood tests were

performed in each worker: red blood cell

(RBC) count, hemoglobin, hematocrit, white

blood cell (WBC) count, and platelet count,

using a hematocell counter (Coulter JT,

Coulter Electronics, Hialeah, FL, USA), as

well as fructosamine (colorimetric method),

blood urea nitrogen [urease ultraviolet (UV)

method], creatinine (enzyme method), total

protein (Biuret method), total cholesterol

(enzyme method), creatine kinase (UV

N-acetylcysteine method), aspartate aminotransferase (UV method), alanine aminotransferase (UV method), γ-glutamyl transferase

(L-γ-glutamyl-3-carboxy-4-nitroanilide substrate method), lactate dehydrogenase

(Wroblewski-LaDue method), alkaline phosphatase (p-nitrophenol substrate method),

serum creatinine (alkaline picric acid method),

vitamin B1 (HPLC method), iron [2-nitroso5-(N-propyl-N-sulfopropylamino)phenol

method], ferritin, thyroid-stimulating hormone [radioimmunoassay (RIA)], luteinizing

hormone (LH; RIA), follicle-stimulating hormone (FSH; RIA), and estradiol (RIA).

Neurobehavioral tests and postural sway

test. Neurobehavioral testing [simple reaction

time, digit span, Santa Ana, digit symbol,

Benton, pursuit aiming test, Profile of Mood

States (POMS)] was conducted based on the

Chinese edition of the World Health

Organization Neurobehavioral Core Test

Battery (Chen 1988; Liang 1987) by trained

Chinese researchers. Because neurobehavioral

tests can be influenced by education level, we

also conducted analyses with controls matched

for age and education level. Postural balance

was measured with a Gravicorder GS-30

stabilometer (Anima Co., Tokyo, Japan). The

same instrument was used in all subjects

throughout the investigation. Postural sway

testing was performed as described previously

(Yamamoto et al. 2001; Yokoyama et al.

1997). Briefly, the subject was asked to stand

with big toes touching each other on the platform of the Gravicorder. The center of gravity

was recorded every 50 msec with both eyes

open for 1 min and closed for 1 min. The calculated values based on the center of gravity

were a) the total length of excursion; b) envelope area; c) length of excursion per envelope

area; d) rectangular area, representing the

product of the range of the x-component (lateral) and that of the y-component (anteroposterior); e) root mean square area; f) the mean

of x-axis or y-axis component of each recorded

point; g) the center of range of the x-axis or

y-axis component of points; h) power spectrum of the x-axis or y-axis at 0.02–0.2 Hz,

0.2–2.0 Hz, and 2.0–10.0 Hz, obtained by

frequency analysis, with both eyes open and

closed; and i) the Romberg quotient, representing the ratio of values measured with eyes

closed to the value with eyes open for items

a through h. 

Assessment of exposure to 1-BP. Individual

exposure levels during work shifts were evaluated with passive samplers (Sibata Scientific

Technology Ltd., Tokyo, Japan) using the

method described previously by Ichihara et al.

(2004). A passive sampler was attached to

each worker during one 8-hr shift and was

collected immediately after the shift and kept

in separate sealed bags at 4°C until analysis.

The absorbed solvent in the sampler was analyzed 2 weeks after the investigation. In our

previous study (Ichihara et al. 2004), we confirmed the stability of absorbed 1-BP in charcoal at 4°C for 2 weeks. For analysis, activated

charcoal particles were taken from the samplers

and then immersed in 2 mL carbon disulfide

(Wako Pure Chemicals, Osaka, Japan) in a

glass tube with a screw cap. The tube was

shaken vigorously for 5 min and left to stand

Environmental Medicine | Ichihara et al.

1320 VOLUME 112 | NUMBER 13 | September 2004 • Environmental Health Perspectives

Table 1. Characteristics of workers.

1-BP exposed Control

Characteristic (n = 23) (n = 23)

Age (years) 36.2 ± 5.7a 36.2 ± 5.2

Height (cm) 160.3 ± 6.6a 158.8 ± 5.9

Education

Elementary school 4 4

Junior high school 19 12

High school 0 6

University 0 1

Job duration (months) 27 ± 31 168 ± 67

Past job exposure to chemicals 0 4b

Previous medical condition 2c 8d

Data for age, height, and job duration are mean ± SD.

Other values are numbers of workers. 

aNot significantly different from the controls (paired t-test). bIncludes formalin (2), ammonia (1), alkaline (1). cIncludes

cholecystitis (1), contraceptive use (1). dIncludes anemia

(2), gastritis (2), hysteromyoma (2), oophoritic cyst (1),

cholecystitis (1), taking antihypertensive medications (1).
for 1 hr; the supernatant was then injected

into a gas chromatograph equipped with an

electron ionization detector (GCD system

G1800A, Hewlett Packard, Palo Alto, CA,

USA). The concentration of 1-BP was quantified by the selected ion mode. The detection

limit was 0.007 ppm by this method. The

time-weighted average (TWA) was calculated

based on the formula 

In our calculations, we used the value of 0.134

as the sampling rate of 1-BP. The value was

determined by the diffusing cell method.

Statistical analysis. We used the paired

t-test to compare continuous parameters of the

exposure group and controls matched for age

or age and education level. In this analysis, all

indices of electrophysiologic studies, neurobehavioral tests, POMS test, stabilometer testing, and blood tests were compared with the

age-matched controls, and the indices of

neurobehavioral tests and POMS were also

compared with controls matched for age and

education level. We used the Wilcoxon test

and Fisher’s exact test to compare the delay

time and abnormality of menstrual cycles,

respectively, of the exposure group and the

age-matched controls. In the analysis by exposure levels, the 27 exposed workers were classified into two groups: ≤ 2.64 ppm (n = 17) and

≥ 8.84 ppm (n = 7); data missing (n = 3). For

analysis by length of exposure, the 27 exposed

workers were again classified into two groups:

≤ 9.31 months (n = 10) and ≥ 16.33 months

(n = 16); data missing (n = 1). We selected

these cutoff values because they divided the

two peak distributions when the histograms

with column width of 2.5 ppm and 5 months,

respectively, were drawn, whereas no values

were found between 2.64 and 8.84 ppm and

9.31 and 16.33 months. In comparisons

between groups stratified with fructosamine

[≤ 246 μmol/L (n = 14) and 248–284 μmol/L

(n = 13)] or vitamin levels [20–30 ng/mL

(n = 13) and ≥ 31 ng/mL (n = 13); data missing (n = 1)], the groups were divided according to the median because there was no split in

the distribution that formed two peak distributions. The t-test was applied when comparing continuous variables (electrophysiologic

tests, neurobehavioral tests, POMS test, stabilometer tests, and blood tests) by exposure

levels or length of exposure as well as the levels

of fructosamine or vitamin B1. For the analysis

of delay time and frequency of menstrual

cycles, we used Wilcoxon test and Fisher’s

exact test, respectively, for comparison according to exposure levels, length of exposure, and

the level of fructosamine or vitamin B1. We

defined significance as the probability of

p < 0.05. 

Results

There were no differences in age and height

between 1-BP workers and the age-matched

controls (Table 1). The control group had a

higher education level than the exposure

group. Job duration of the exposure group

was shorter than for the controls, probably

because the area where the workers lived had

been developed quite recently, so they had

engaged in agriculture before employment in

the factory. Four workers in the beer factory

(controls) had been exposed to various chemicals (formalin, n = 2; ammonia, n = 1; alkaline

reagent, n = 1) in occupational settings before

their present jobs. None of the workers investigated was a smoker, and only one exposed

worker and one control worker were alcohol

drinkers. None of the workers investigated

had a history of diabetes mellitus, which could

cause polyneuropathy. Individual exposure

levels ranged from 0.34 to 49.2 ppm (median,

1.61 ppm; geometric mean, 2.92; Figure 1).

Bromopropane workers, all of whom were

hired after 1991 (1991 workers), had significantly longer DL and lower SNCV than did

the age-matched controls (Table 2). Because

the main product in the factory had shifted

from 2-BP to 1-BP between 1996 and May

1999 (Ichihara et al. 2004), we also analyzed

data for 1999 workers to examine the effects

of exposure to 1-BP only. Examination of

these workers showed the only significant

change to be an increase in the DL compared

with age-matched controls. However, the

extent of the change in any electrophysiologic

parameter in the 1999 workers tended, in general, to be similar to that of the 1991 workers.

Reduced vibration sensation as tested on the

right toe, left toe, right finger, and left finger

was detected in 15, 13, 4, and 4 female workers, respectively (Tables 3 and 4). One worker

showed complete loss of vibration sense on the

right toe by tuning fork stimulation. The exposure level for this worker was 1.10 ppm, and

she had a relatively high DL (8.8 msec) and

low MCV (43.1 m/sec), FWCV (53.7 m/sec),

and SNCV (38.8 m/sec). In contrast, none of

the age-matched beer workers showed any

abnormalities in vibration sensation in the toe

and finger. The Wilcoxon test showed significant differences in the delay time bilaterally

both in the feet and in the fingers between

1991 workers and controls. Analysis of

1999 workers also showed significant prolongation of the delay time on the toes bilaterally

but not in the fingers. The percentage of

1999 workers who showed reduced vibration

sensation (delay time ≥ 2 sec) on both sides of

the foot and in the fingers was similar to that

of 1991 workers.

Neurobehavioral tests showed lower values

for the forward and backward digit span,

Benton visual memory test, pursuit aiming

test, POMS test (scores for tension, depression, anxiety, fatigue, and confusion) in the

1-BP workers than in the controls (Tables 5

and 6). Because the education level of 1-BP

workers was different from that of the agematched controls and because the education

level could affect the results of neurobehavioral tests, these tests were analyzed after

matching both education level and age

(Tables 5 and 6). 1-BP workers had lower levels of backward digit span; correct scores in

the Benton visual memory test; completed

response in the pursuit aiming test; and tension, depression, anxiety, fatigue, and confusion in the POMS test than did controls

matched for age and education level. Further

analysis was conducted for these neurobehavioral tests on 1999 workers (Tables 5 and 6).

Significant differences with the controls were

found only in the Benton visual memory test

and in POMS depression and fatigue. 

The postural sway tests showed significantly lower power spectrum of the x-axis at

2.0–1.0 Hz with eyes open and y-axis at

0.02–0.2 Hz with eyes closed and significantly

TWA absorbed solvent g

sampling rate g

ppm

sampling time

= μ

μ

( ) ×





 



 ×

( )

min (min)

Environmental Medicine | Neurologic abnormalities due to 1-bromopropane

Environmental Health Perspectives • VOLUME 112 | NUMBER 13 | September 2004 1321

Figure 1. Exposure levels of each worker in a 1-BP

factory (TWA for 8-hr shift). Values were obtained

with passive samplers from workers who had agematched controls (n = 23). Maximum = 49.19; minimum

= 0.34; median = 1.61; geometric mean = 2.92 ppm.

Workers

60

50

40

30

20

10

0

Exposure level (TWA for 8 hr)

●

●

●●

●

●

●

●●●

Table 2. Electrophysiologic indices of workers exposed to 1-BP and of the controls.

Age-matched Age-matched

1991 workers controls for 1991 1999 workers controls for 1999

No. of pairs 23 12

DL of nervus tibialis (msec) 8.05 ± 2.17* 5.96 ± 1.38 8.36 ± 2.38* 6.06 ± 1.43

MCV of nervus tibialis (m/sec) 49.8 ± 10.3 49.9 ± 8.2 51.3 ± 12.0 51.7 ± 10.7

FWCV of nervus tibialis (m/sec) 52.8 ± 3.5 55.1 ± 3.2 51.8 ± 2.8 55.0 ± 2.9

SNCV of nervus suralis (m/sec) 39.2 ± 3.5* 46.2 ± 6.6 39.2 ± 2.6 47.5 ± 8.5

Data are mean ± SD. 

*p < 0.05 compared with age-matched controls (paired t-test).
higher power spectrum of the y-axis at

0.2–2.0 Hz with eyes closed (Table 7) in the

1999 workers than in the age-matched controls, but other parameters were not significantly different between the two groups

(Table 7; Romberg quotients for all items,

which also did not show any statistical difference, are not shown). The comparison of the

1999 workers and age-matched controls did

not show any significant differences in postural

sway tests (Table 7; Romberg quotients not

shown).

Laboratory tests did not show any significant differences between the 1991 workers

and age-matched controls (data not shown)

except for significantly lower levels of

vitamin B1 (31.0 ± 5.6 vs. 34.3 ± 5.4 ng/mL)

and low WBC count (5.7 ± 1.7 × 103/μL vs.

6.7 ± 1.8 × 103/μL) in the 1991 workers than

in age-matched controls. For 1999 workers,

only the WBC count was significantly lower

than in the age-matched controls. In only one

worker (42 years of age) in the control group,

the fructosamine level (286 μmol/L) was

above the upper limit of reference value

(205–285 μmol/L). This worker had rather

high DL (8.24 msec) and low levels of MCV

(42.5 m/sec), FWCV (49.8 m/sec), and SNCV

(39.5 m/sec) but did not show abnormal vibration sensation. This worker was not included

in the education-matched testing because she

had no education-matched individual in the

exposure group. Comparison between the two

groups stratified by fructosamine levels within

all exposed workers (n = 27) showed significant differences only in higher levels of total

protein (8.22 ± 0.53 g/dL), total cholesterol

(197.7 ± 32.1 mg/dL), choline esterase (ChE;

366.1 ± 86.7 IU/L), LH (14.3 ± 14.3 IU/L),

WBC (6.62 ± 5.15 × 103/μL), RBC (4.19 ±

0.38 × 106/μL), POMS confusion (5.31 ±

4.35), and lower estradiol level (35.4 ±

25.1 pg/mL) in the high-fructosamine group

compared with the low-fructosamine group

(total protein, 7.64 ± 0.24 g/dL; LH, 4.2 ±

3.4 IU/L; total cholesterol, 166.5 ± 28.7

mg/dL; ChE, 288.4 ± 37.8 IU/L; WBC, 5.16

± 0.97 × 103/μL; RBC, 3.84 ± 0.38 × 106/μL;

POMS confusion, 2.36 ± 1.91; estradiol, 63.2

± 38.3 pg/mL).

Fisher’s exact test did not show any difference between the 1991 and 1999 worker

groups and their corresponding age-matched

control groups with regard to the frequency

of menstrual abnormalities after starting

working in the 1-BP factory. Two workers

in the exposure group had a short menstrual

cycle. Similarly, one worker in the control

group had a short menstrual cycle, and

another reported a prolonged period of 

menstrual bleeding.

On the other hand, a comparison based

on the exposure levels (≤ 2.64 or ≥ 8.84 ppm)

showed that workers with high exposure levels

showed significantly high values of MCV

(56.4 ± 12.9 m/sec), FWCV (54.7 ±

2.8 m/sec), hematocrit (0.393 ± 0.032), and

POMS tension (5.14 ± 1.77) and lower values

of FSH (9.0 ± 6.3 mIU/mL) and POMS

vigor (18.6 ± 2.5), compared with the lowexposure group (MCV, 47.3 ± 8.3 m/sec;

FWCV, 52.0 ± 1.9 m/sec; hematocrit, 0.356

± 0.034; POMS tension, 2.73 ± 1.49; FSH,

27.7 ± 35.3 mIU/mL; POMS vigor, 24.3 ±

4.0) but did not show any significant association with other examined indices. In the comparison by the length of exposure (≤ 9.31 or

≥ 16.33 months), the longer-exposure group

had high levels of LH (13.5 ± 13.7 mIU/mL)

and FSH (34.9 ± 34.9 mIU/mL) and lower

levels of total protein (7.77 ± 0.30 g/dL)

and vitamin B1 (29.2 ± 5.1 ng/mL) than did

the shorter-exposure group (LH, 3.3 ±

1.8 mIU/mL; FSH, 5.5 ± 2.1 mIU/mL; total

protein, 8.18 ± 0.66 g/dL; vitamin B1, 33.2 ±

5.0 ng/mL) but did not show any significant

association with other examined indices.

Because the mean concentration of vitamin B1 was significantly lower in the exposure

group than in the controls, the values were

compared between the two groups stratified

by vitamin B1 level within all exposed workers

(n = 27). The comparison did not reveal any

difference in the frequency of low vibration

sensation or results of electrophysiologic tests,

apart from lower levels of alkaline phosphatase

(ALP; 129.3 ± 30.7 IU/L) and ChE (293.8

± 52.8 IU/L) in the low vitamin group than

high vitamin group (ALP, 169.5 ± 43.1 IU/L;

ChE, 361.8 ± 84.1 IU/L).

Discussion

In the tested factory, isopropanol, hydrogen

bromide, and sulfuric acid were also used as

materials in the process of producing 1-BP.

These chemicals are not considered to have

neurotoxic effects, so it is unlikely that the low

vibration sensation or change in DL is due to

these chemicals. In the last survey of the same

factory (Ichihara et al. 2004), we found that

the main product of this factory was shifted

from 2-BP to 1-BP. 1991 Workers include the

workers who were hired before May 1999 and

might have been exposed to not only 1-BP but

also 2-BP before 1999 (Ichihara et al. 1999).

In contrast, 1999 workers were exposed to

1-BP only. Therefore, the observed changes in

the DL, vibration sense in both feet bilaterally, Benton visual memory test score, and

depression and fatigue in the POMS test that

were noted in 1999 workers are considered to

be due to exposure to 1-BP. However, the

effects of 2-BP cannot be excluded in

1991 workers. The SNCV showed significant

changes in the analysis of 1991 workers but

not in 1999 workers with age-matched controls. This is most likely due to the lack of

power as a result of the reduction in the number of subjects, given the fact that the extent

of change in sensory nerve conduction, as well

as other electrophysiologic parameters, and

the percentage of workers who showed

reduced vibration sense among 1999 workers

was similar to that of 1991 workers. This

explanation might also be valid for other

parameters that showed significant change in

1991 workers but not in 1999 workers.

Environmental Medicine | Ichihara et al.

1322 VOLUME 112 | NUMBER 13 | September 2004 • Environmental Health Perspectives

Table 3. Number of workers with reduced vibration sensation in the foot.

1991 workers and age-matched 1999 workers and age-matched 

controls (n = 23 pairs) controls (n = 12 pairs)

Delay timea Right foot* Left foot* Right foot* Left foot*

(sec) 1-BP workers Controls 1-BP workers Controls 1-BP workers Controls 1-BP workers Controls

< 2 8 23 10 23 5 12 5 12

2 0 0 1 00 01 0

3 3 0 1 01 01 0

4 2 0 4 01 01 0

5 2 0 1 01 00 0

6 4 0 4 03 02 0

8 3 0 1 01 01 0

10 0 0 1 00 01 0

∞b 1 0 0 00 00 0

aDelay time for vibration sensation by tuning fork stimulation (see “Materials and Methods” for details); time 0 is the time

when the worker reported becoming unaware of the vibration. bOne worker felt no vibration sense in the right foot.

*p < 0.05, Wilcoxon test. 

Table 4. Number of workers with reduced vibration sensation in the finger.

1991 workers and age-matched 1999 workers and age-matched

controls (n = 23 pairs) controls (n = 12 pairs)

Delay timea Right finger* Left finger* Right finger Left finger

(sec) 1-BP workers Controls 1-BP workers Controls 1-BP workers Controls 1-BP workers Controls

< 2 19 23 19 23 10 12 10 12

2 3 0 2 0 2 0 20

3 1 0 2 0 1 0 00

aDelay time for vibration sensation by tuning fork stimulation (see “Materials and Methods” for details); time 0 is the time

when the worker reported becoming unaware of the vibration. *p < 0.05, Wilcoxon test.
Our animal studies (Ichihara et al. 2000a;

Yu et al. 1998) preceded human case reports in

revealing the neurotoxicity of 1-BP, which is

far more potent than that of 2-BP (Yu et al.

1999, 2001). However, the results of animal

studies had certain limitations in predicting

symptoms or signs in human cases; for example, animal studies cannot detect any subjective

symptoms that might reflect abnormalities of

sensation or the central nervous system. It is

sometimes difficult especially for morphologic

studies to substantiate the adverse effects on

the central nervous system because the structure of the central nervous system is far more

robust than that of peripheral nerves or other

organs. It is also difficult to evaluate imbalance

during walking in rodents because four-footed

animals are completely different from bipedal

humans regarding the clinical signs of imbalance. Thus, information from human cases

should help us understand the toxicologic targets of 1-BP. The first case was reported by

Sclar (1999), and three other cases were

recently reported by our group (Ichihara et al.

2002). All four cases showed diminished vibration sensation in the toe. Moreover, the present study showed that more than half of the

workers exposed to 1-BP suffered from

reduced vibration sensation. Considered

together, these results suggest that vibration

sensation in the toe might be susceptible to

exposure with 1-BP. The previously reported

cases also complained of urinary incontinence;

numbness in the perineum, low back, and

front of the thighs or buttocks; or headache

(Ichihara et al. 2002); however, our factory

workers did not report any such symptoms.

This difference might depend on the levels or

period of exposure to 1-BP because it is possible that our workers adapted to low levels but

longer periods of exposure, leading to unawareness of symptoms.

In comparisons with age-matched controls,

both the 1991 workers and 1999 workers

showed prolonged DL but no change in

MCV. This prolongation of DL without

decrease in MCV parallels the results of animal

studies, which showed earlier changes in DL

than MCV in the tail nerve (Ichihara et al.

2000a). Such a pattern of changes might indicate predominant deterioration of the distal

portion of the peripheral nerve or delay in

chemical transmission between nerve terminals

and muscle.

Comparison of data of 1991 workers with

age-matched controls showed that the exposure

group had lower levels of forward and backward digit span, Benton scores, pursuit aiming

test scores, and POMS tension, depression,

anxiety, fatigue, and confusion than did the

controls. Because education level could influence the results of neurobehavioral tests, the

results of the tests were reanalyzed after matching age and education levels. This reanalysis

also revealed changes in the above items

excluding forward digit span. When the analysis was limited to the 1999 workers, significant

differences were found only in Benton visual

memory test scores, POMS depression, and

POMS fatigue, which could reflect the lack of

power due to the small sample number. Digit

span, pursuit aiming test, and the POMS test

are considered the most sensitive indicators of

exposure to organic solvents or neurotoxic

agents such as lead (Zhou et al. 2002). Poorer

performance in the POMS test was also

observed in a Venezuelan study of workers

exposed to organic solvents (Escalona et al.

1995). The present results of neurobehavioral

tests could also suggest that 1-BP adversely

affects the central nervous system in humans.

Postural sway tests showed higher power of the

y-axis (anterior–posterior sway) at 0.2–2.0 Hz

and lower at 0.02–0.2 Hz with eyes closed,

although such significant differences were not

observed in 1999 workers. These results might

be important because the cases found in the

United States also showed unstable balance in

walking. Clinically, patients with cerebellar disease and anterior lobe atrophy show anteroposterior sway, often with a spontaneous

high-frequency body tremor of around 3 Hz

(Diener et al. 1984). This anteroposterior sway

might resemble the present result of the

increase in the power of the y-axis at 0.2–2 Hz.

However, the results of the postural sway tests

noted in our study await further confirmation

because the presence of cerebellar disorder in

the formerly reported cases or present workers

is not conclusive, and it is possible to attribute

the unstable balance to a disorder of the

peripheral nerves or spinal cord.

Diabetes mellitus could be a common confounding factor related to neurologic disorders

by solvent intoxication. HbA1C and fructosamine are used as long-term (Bunn et al.

1976) and intermediate-term (1–3 weeks)

(Baker et al. 1983) indicators of glucose levels

in clinical settings. In the present study, we

measured serum fructosamine levels. For the

measurement of HbA1C, the blood samples

had to be kept at 4°C but not frozen. However,

the long transportation from the factory site to

the laboratory could have potentially caused

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Environmental Health Perspectives • VOLUME 112 | NUMBER 13 | September 2004 1323

Table 5. Results of neurobehavioral tests in the 1-BP group and controls matched for age or for age and education (mean ± SD).

1991 workers 1991 workers 1999 workers

Test (age-matched controls) (age/education-matched controls) (age/education-matched controls)

No. (pairs) 22 12 6

Simple reaction time (sec) 0.38 ± 0.12 (0.36 ± 0.12) 0.38 ± 0.12 (0.36 ± 0.12) 0.40 ± 0.14 (0.39 ± 0.12)

Digit span (digits recalled) forward 10.6 ± 2.3* (11.7 ± 1.4) 10.8 ± 2.5 (11.8 ± 1.3) 10.2 ± 3.1 (12.0 ± 1.1)

Digit span (digits recalled) backward 4.5 ± 2.2* (5.8 ± 1.8) 5.0 ± 2.6* (5.6 ± 1.4) 4.2 ± 2.3 (6.2 ± 1.6)

Santa Ana preferred hand 35.2 ± 3.6 (36.6 ± 4.8) 35.3 ± 4.0 (36.1 ± 4.3) 36.0 ± 2.4 (35.8 ± 5.2)

Santa Ana nonpreferred hand 33.5 ± 4.6 (32.8 ± 5.1) 33.8 ± 5.2 (33.7 ± 5.6) 32.8 ± 4.4 (35.5 ± 5.9)

Digit symbol (no. completed) 47.0 ± 17.5 (54.0 ± 10.2) 48.6 ± 19.8 (55.5 ± 5.6) 45.3 ± 21.9 (56.7 ± 6.7)

Benton (no. correct) 7.2 ± 1.7* (8.3 ± 1.4) 7.8 ± 1.5* (8.2 ± 1.3) 7.3 ± 1.8* (8.3 ± 1.0)

Pursuit aiming test (no. completed) 103.1 ± 16.9* (119.9 ± 19.1) 101.6 ± 17.9* (119.3 ± 20.4) 98.0 ± 11.4 (125.7 ± 17.0)

*p < 0.05, paired t-test.

Table 6. Results of POMS tests in the 1-BP group and controls matched for age or for age and education (mean ± SD).

1991 workers 1991 workers 1999 workers

Test (age-matched controls) (age/education-matched controls) (age/education-matched controls)

No. (pairs) 20 12 6

Profile of mood state

Tension 4.4 ± 3.9* (7.7 ± 7.1) 4.1 ± 5.2* (10.2 ± 8.5) 6.8 ± 7.0 (9.6 ± 7.2)

Depression 4.8 ± 7.5* (10.5 ± 13.0) 5.6 ± 10.1* (13.3 ± 17.1) 10.0 ± 14.4* (12.8 ± 16.0)

Anxiety 4.1 ± 5.0* (10.2 ± 10.2) 4.7 ± 6.3* (12.6 ± 13.2) 7.0 ± 9.0 (13.4 ± 12.7)

Vigor 22.2 ± 4.3 (20.7 ± 6.7) 23.7 ± 3.9 (20.9 ± 6.9) 23.4 ± 4.5 (21.4 ± 9.2)

Fatigue 3.1 ± 2.6* (6.4 ± 4.0) 3.0 ± 3.4* (6.7 ± 5.2) 4.4 ± 4.8* (7.2 ± 3.8)

Confusion 3.7 ± 3.7* (7.1 ± 4.3) 3.3 ± 4.4* (7.7 ± 5.6) 5.0 ± 6.2 (5.6 ± 5.0)

*p < 0.05, paired t-test.
hemolysis of the collected blood and thus may

have resulted in marked variability and errors in

estimations. For this reason, HbA1C was not

measured in the present study. The comparison

between the exposed group and the controls did

not show any difference in the level of fructosamine, and the comparison between the

high-fructosamine group and low-fructosamine

group within the exposed group also did not

show any difference in indices related to the

nervous system.

The levels of vitamin B1 were lower in the

entire exposure group than in the controls and

in the longer-exposure group compared with

the shorter-exposure group. Lack of vitamin

B1 is known to cause polyneuropathy, but the

relatively low level of vitamin B1 in the 1-BP

factory workers could not fully explain the

neurologic abnormalities. First, the level of vitamin B1 in the exposed workers ranged from

20 to 43 ng/mL, which was within the normal

range (20–50 ng/mL). Second, the low-level

vitamin B1 group showed no neurologic

deficit such as vibration sensation or electrophysiologic indices, apart from a low score of

POMS confusion, which would be weak evidence in substantiating the adverse effects on

the nervous system.

Letz and Gerr (1994a, 1994b) investigated

the confounding factors that could affect nerve

conduction velocity and amplitude as well as

vibrotactile and thermal thresholds, based on

data from 4,464 subjects. Their studies

revealed that the major covariates were height,

examiner, skin temperature, and body mass

index for sural sensory nerve and height, examiner, age, and body mass index for peroneal

motor nerve conduction velocities. For vibrotactile threshold in toe, the major covariates

were height, examiner, age, and body mass

index. Our study design could control for the

effect of examiner-, sex-, and age-matching

pairs but not skin temperature-, body height-,

or body mass index-matching pairs. Although

body height was comparable on average

between the exposure group and the controls

and workers were acclimated to the room temperature before the electrophysiologic studies,

the lack of pair matching for height, skin temperature, and body mass index should be carefully noted as a limitation of this study.

Previous animal experiments demonstrated that

exposure to 1-BP disrupted the estrous cycle

and inhibited follicular development (Yamada

et al. 2003). Two patients who worked in a

cushion company in the United States also

reported temporary irregularities of menstrual

cycle (Ichihara et al. 2002). Although the exposure level for the two patients was not evaluated

directly, such levels would be higher than

60–261 ppm, which were determined with the

third case from the same factory after the former two cases were identified and ventilation

was improved in the workplace. On the other

hand, our study did not demonstrate significant differences in the prevalence of menstrual

cycle abnormalities between the two groups.

This might be due to the difference in exposure levels between U.S. cases (≥ 60–261 ppm)

and our Chinese 1-BP factory workers

(0.34–49.19 ppm).

Comparisons based on the exposure period

showed higher levels of FSH and LH in the

longer-exposure group than in shorter-exposure group. One explanation for this difference

is that our group included four elderly women,

who were excluded from the paired t-test

analysis because of the lack of matched controls and who had high levels of FSH

(42–100 mIU/mL) and LH (16–42 mIU/mL).

Analysis based on exposure level did not show

any relationship between exposure levels and

these parameters, which were different between

the exposure group and age-matched controls

(paired t-test). The present analysis by exposure

period and level has certain limitations. First,

the number of subjects was too small and did

not control for age. Second, the experimental

design allowed only a single measurement of

the exposure level, although the task of workers

was not fixed and thus the exposure levels

could vary. The exposure levels in 1999 in the

same factory ranged from 0.9 to 170.5 ppm

(geometric mean = 52.5 ppm) (Ichihara et al.

Environmental Medicine | Ichihara et al.

1324 VOLUME 112 | NUMBER 13 | September 2004 • Environmental Health Perspectives

Table 7. Stabilometer test results of 1-BP exposure group and controls. 

Age-matched Age-matched

1991 Workers controls 1999 Workers controls

No. (pairs) 23 12

LNG (cm)

Eyes open 71.7 ± 15.5 69.9 ± 20.8 71.5 ± 19.3 74.0 ± 19.4

Eyes closed 100.4 ± 25.1 91.1 ± 27.3 106.3 ± 29.7 95.0 ± 26.0

E AREA (cm2)

Eyes open 3.38 ± 1.26 3.69 ± 2.86 3.60 ± 1.52 3.88 ± 2.64

Eyes closed 4.94 ± 2.27 4.56 ± 3.62 5.65 ± 2.67 4.80 ± 4.15

LNG E AREA (per cm)

Eyes open 22.9 ± 6.3 24.9 ± 10.9 21.8 ± 6.6 26.3 ± 13.7

Eyes closed 23.1 ± 7.9 26.3 ± 10.4 22.0 ± 8.8 28.8 ± 12.2

REC AREA (cm2) 

Eyes open 7.53 ± 2.76 8.26 ± 6.39 7.87 ± 3.42 8.51 ± 6.08

Eyes closed 10.5 ± 5.6 10.3 ± 8.6 12.8 ± 6.1 10.5 ± 9.6

RMS (cm2)

Eyes open 1.62 ± 0.70 1.98 ± 1.67 1.82 ± 0.91 2.09 ± 1.46

Eyes closed 2.05 ± 1.01 2.05 ± 1.65 2.30 ± 1.25 2.22 ± 2.01

Mx (cm)

Eyes open 0.019 ± 0.581 –0.123 ± 1.162 –0.166 ± 0.485 –0.008 ± 0.724

Eyes closed 0.010 ± 0.573 0.053 ± 1.228 –0.044 ± 0.557 0.217 ± 0.679

My (cm)

Eyes open –2.43 ± 1.15 –2.09 ± 1.37 –2.70 ± 1.05 –2.20 ± 1.41

Eyes closed –2.29 ± 1.06 –2.06 ± 1.28 –2.50 ± 0.95 –2.41 ± 1.07

XO (cm)

Eyes open –0.004 ± 0.621 –0.142 ± 1.170 –0.186 ± 0.627 –0.009 ± 0.756

Eyes closed 0.119 ± 0.657 –0.003 ± 1.347 0.106 ± 0.771 0.231 ± 0.788

YO (cm)

Eyes open –2.50 ± 1.15 –2.07 ± 1.39 –2.79 ± 1.14 –2.22 ± 1.41

Eyes closed –2.29 ± 1.01 –2.30 ± 1.42 –2.48 ± 0.86 –2.48 ± 1.09

Power spectrum of x-axis (lateral)

Eyes open (%)

0.02–0.2 Hz 61.1 ± 12.4 54.7 ± 17.0 62.5 ± 12.1 53.7 ± 14.5

0.2–2.0 Hz 38.5 ± 12.3 42.1 ± 13.6 37.1 ± 11.9 45.8 ± 14.4

2.0–10 Hz 0.36 ± 0.21* 0.46 ± 0.21 0.38 ± 0.24 0.46 ± 0.21

Eyes closed (%)

0.02–0.2 Hz 45.7 ± 17.3 47.9 ± 12.2 48.5 ± 17.8 46.1 ± 12.7

0.2–2.0 Hz 52.5 ± 19.7 49.2 ± 16.3 48.4 ± 21.8 49.2 ± 19.7

2.0–10 Hz 0.53 ± 0.37 0.59 ± 0.33 0.60 ± 0.44 0.58 ± 0.34

Power spectrum of y-axis (anteroposterior)

Eyes open (%)

0.02–0.2 Hz 66.6 ± 14.0 70.7 ± 11.4 73.5 ± 11.1 70.9 ± 10.1

0.2–2.0 Hz 32.4 ± 12.8 28.9 ± 11.4 26.1 ± 11.1 28.6 ± 10.1

2.0–10 Hz 0.97 ± 2.62 0.42 ± 0.28 0.35 ± 0.16 0.45 ± 0.35

Eyes closed (%)

0.02–0.2 Hz 51.6 ± 14.0* 61.2 ± 13.7 54.0 ± 11.6 55.0 ± 11.2

0.2–2.0 Hz 47.3 ± 13.0* 38.3 ± 13.7 45.4 ± 11.6 44.4 ± 11.2

2.0–10 Hz 1.03 ± 2.38 0.50 ± 0.28 0.56 ± 0.26 0.57 ± 0.25

Abbreviations: E, envelope; LNG, length of excursion; Mx, mean of x-axis (lateral) component of each recorded points;

My, mean of y-axis (anteroposterior) component of each recorded points; REC AREA, rectangular area; RMS, root mean

square area; XO, center of range of x-axis component of points; YO, center of range of y-axis component of points. Data

are mean ± SD. 

*p < 0.05, paired t-test. No significant difference was found between the exposed group and the controls in the Romberg

quotient for all items (the ratio of values measured with eyes closed to the values with eyes open; data not shown).
2004), which was far higher than in the present study. It is possible that the workers were

exposed to 1-BP at higher levels than those

measured in our study. Further assessment of

long-term exposure levels is required to determine the relationship between 1-BP and

exposure levels.

In summary, the present study suggested

that exposure to 1-BP produces adverse effects

on peripheral sensory and motor nerves and/or

the central nervous system in humans.

Estimation of long-term exposure levels is

required to confirm the precise association

between the health effects of 1-BP and exposure

levels.

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Environmental Health Perspectives • VOLUME 112 | NUMBER 13 | September 2004 1325

Correction

In the manuscript published online, the

numbers of workers listed in Table 1, especially in the footnotes, were incorrect; also,

the statistical significance of values for the

right and left fingers for 1999 workers and

age-matched controls was incorrect. These

errors have been corrected here.