environmental investigation toyuasa,kishi, eguchi, harabuchi, kawai,ikeda, et al supports the...

Occupational and Environmental Medicine 1996;53: 174-179

Investigation on neurotoxicity of occupationalexposure to cyclohexane: a neurophysiologicalstudy

Junko Yuasa, Reiko Kishi, Teruko Eguchi, Izumi Harabuchi, Toshio Kawai,Masayuki Ikeda, Ryouichi Sugimoto, Hiroyuki Matsumoto, Hirotsugu Miyake

Objectives-To examine the effect ofoccupational exposure to cyclohexane onthe peripheral nervous system.Methods-A nerve conduction study wasperformed on 18 workers exposed tocyclohexane in a luggage factory and onage and sex matched occupationallyunexposed controls. 12 workers had beenexposed to n-hexane (median 2-8 years)before the start of exposure to cyclo-hexane. To confirm the effect ofexposure,a follow up study was performed on nineworkers one year after the first study. Themean exposure to cyclohexane was 1 2years in the first study. A symptom surveywas performed. The exposure was mea-sured by air sampling of the breathingzone ofeach worker. The urinary metabo-lite cyclohexanol was also monitored.Results-The concentration of airbornecyclohexane ranged from 5 to 211 ppm.The urinary concentration of cyclohexa-nol ranged from 0-12 to 1 51 mg/I. Therewas a strong correlation between thecyclohexane exposure in personal air andurinary cyclohexanol. No differences werefound in nerve conduction velocities(NCV) between workers exposed to cylo-hexane and age and sex matched controls.The results of the follow up study showedsignificant improvements in peronealmotor NCV (P < 0.01) and sural sensoryNCV (P < 005) and in ulnar motor distallatency (MDL, P < 005) and peronealMDL (P < 005) compared with the firststudy. Although the past n-hexane expo-sure affected the first neurophysiologicalstudy, the effect had disappeared in thesecond study, one year later.Conclusion-Occupational exposure tothe concentrations of cyclohexane experi-anced in this study had no adverse effectson the peripheral nervous system.

(Occup Environ Med 1996;53:174-179)

Keywords: cyclohexane; neurophysiological study;occupational exposure

Cyclohexane has been considered to be a sol-vent of low toxicity and is recommended as asubstitute for other more toxic solvents such asn-hexane and benzene.' However, studies onhealth effects of cyclohexane and its metabo-lite, cyclohexanone, are scarce.2A Although itis reported that for cyclohexane the marginbetween narcosis and death is very narrow and

symptomatically barely recognisable,' we con-sidered that a neurophysiological study mightdetect the neurotoxicity of cyclohexane at alevel of exposure too low to cause narcosis ordeath. Adverse effects on the peripheralnervous system in humans were reported, butthis was not the case in rats. 6 However, theexposure was not exclusive in the human stud-ies; therefore, the adverse effect could not nec-essarily be attributed to cyclohexane.The primary aim of this study was to exam-

ine the neurophysiological effects of occupa-tional exposure to cyclohexane. This is thefirst study performed in a factory in whichworkers were exposed almost exclusively tothis solvent. To more accurately determine therelation between cyclohexane and neurophysi-ological effects, a follow up study was per-formed in some workers.The factory had used n-hexane in the past

and shifted to cyclohexane gradually. Thus,we studied the neurotoxicity of cyclohexaneconsidering the effects of past n-hexane expo-sure.

Materials and methodsThe survey was conducted in a luggage fac-tory. A glue containing 75-6% cyclohexane,12 0% toluene, and 0 9% n-hexane was usedin the factory.7 The workers were selected asfollows: (a) cyclohexane was found to be themain solvent to which the workers wereexposed, according to the individual exposuredata,7 (b) they had been engaged in the currentjob for more than half a year, and (c) informa-tion was available on working conditions, alco-hol, tobacco use, and subjective symptoms.Overall, 18 women met the requirements.Their ages ranged from 19 to 56, with a mean(SD) of 24-1 (8-5). They had been engaged inthe current job for 04-2 6 years (1 2 (0 6)years) at the time of our first study. On aver-age, they were exposed to cyclohexane vapourfor eight hours daily.

Twelve of the exposed workers had beenengaged in work with n-hexane for 0 3-20years (median 2 8 years), and stopped thework 0 7-2 6 years (median 1 3 years) beforethe first investigation (fig).

Because of the small sample size of thisstudy, the short duration of exposure to cyclo-hexane and short duration without exposure ton-hexane, we performed the follow up studyone year after the first study to confirm thefindings in the first study (fig). However, nineworkers had moved to another department ofthe same factory or had left the job between

Department of PublicHealth, SapporoMedical University,Sapporo, JapanJ YuasaR KishiT EguchiH MiyakeJapan Railways,HokkaidoI HarabuchiOsaka OccupationalHealth Service Centre,Osaka, JapanT KawaiDepartment ofPublicHealth, KyotoUniversity Faculty ofMedicine, Kyoto,JapanM IkedaSugimoto Clinic,Akabira, JapanR SugimotoDepartment ofNeurology, SapporoMedical University,Sapporo, JapanH MatsumotoCorrespondence to:Dr Junko Yuasa, Departmentof Public Health, SapporoMedical University,Sapporo 060, Japan.Accepted 29 September 1995

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Investigation on neurotoxicity of occupational exposure to cyclohexane: a neurophysiological study

Table 1 Characteristics ofsolvent workers and controls

Solvent workers Controls(n = 18) (n = 18)Mean (SD) Mean (SD) P value

Age (y) 24 1 (8-5) 24-7 (8 2) NSEducation (y) 11-6 (1.0) 15 7 (2 2) < 0-01Height (cm) 154 6 (6-1) 158-7 (4 9) < 0-01Weight (kg) 47-2 (4-5) 51 2 (3 9) < 0 01Body mass index (kg/iM2) 19-7 (1.7) 20-3 (1 6) NSAlcohol (ml ethanol/week) 40-1 (69 9) 30-2 (46 7) NSCigarettes (/day) 4-7 (6 7) 0-1 (0 5) < 0 01Skin temperature (0G):Arm 33-6 (1-2) 33-7 (1 4) NSLeg 33-5 (13) 331 (14) NS

the first and second studies. For this reasonthe follow up environmental and neurophysio-logical study was performed in only nine work-ers.The control subjects (18 women) were

recruited from among medical students andclerical workers. They were matched to theworkers exposed to solvent by sex and age.Their mean (SD) age was 24-7 (8 2).

Table 1 shows the characteristics of sub-jects. Workers exposed to solvent were signifi-cantly shorter and lighter than matchedcontrols. The cigarette consumption of work-ers was higher than that of controls. All of thesubjects had no known neurotoxic risks suchas diabetes mellitus, alcohol or drug abuse, orneuropathy (including disk herniation).

SYMPTOM SURVEYThe questionnaire used in the symptom surveyincluded questions about subjective symptomsboth during work and when not at work in thepast six months. In the symptom survey, back-ground variables which could have influencedsymptoms and neurophysiological measures,as potential confounders, were investigated(drinking habits, smoking habits, height,weight, years of education, and age).Occupational history was also studied in thesurvey. Three of 18 controls did not partici-pate in the symptom survey. Among 61 symp-toms, 20 general (weight loss, general fatigue,etc) and neurological symptoms were com-pared. Details of this survey were describedpreviously.

EVALUATION OF EXPOSUREThe airborne cyclohexane of the breathingzone was collected for all workers with a diffu-sive sampler with activated carbon cloth (KF-1500, Tokyo Company, Osaka, Japan) fromthe start of the working day to its end,9 overthe whole eight hour shift. The urine at theend of the shift was collected and the concen-tration of urinary cyclohexanol was measuredby the enzymatic hydrolysis method. Thesebiological monitorings were performed in boththe first and follow up studies. A detaileddescription of the procedure can be found inYasugi et al.' The past data on personal cyclo-

Size of M = No of workers with past n-hexane and presentcyclohexane exposure

Size of C = No of workers with no n-hexane but withpresent cyclohexane exposure

Size of _ = No of controlsBM = Biological monitoringNCV = Neurophysiological studySS = Symptom survey

nh = No of exposed workers with past exposureto n-hexane

A Subjects and dates of examination

Cyclohexaneexposedworkers

Controls

B Solvents use in the factory

Use ofcyclohexane A It-

Use ofn-hexane

IS

n = 18 (nh = 12) n = 9 (nh = 8)

BM BM NCV \ N\CV

IIR\~ Loss of follow up

1992 11 1993 4 1993.7 1994.7

1989 1992 8 1992 11 1993.4 1993.7

Number of subjects, thedates of examinations, andthe history of use ofsolvents in the factory.

H= 10

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hexane exposure and urinary cyclohexanolmeasured by the same method used in the pre-sent study were available for some workers. Toconsider the relation between airborne cyclo-hexane and urinary metabolites, these datawere used for analysis. According to the pastand present exposure data, the workers weredivided into higher (n = 7) and lower (n =11) exposure groups and nerve conductionvelocities (NCVs) of each group were com-pared. The higher exposure group was thegroup whose mean cyclohexane exposureexceeded 100 ppm.The previous exposure data showed that

cyclohexane vapour is almost exclusively an aircontaminant and the exposures to other sol-vents-for example, toluene- and n-hexane-were much lower. The cyclohexane concentra-tion in air ranged froth 13-720 ppm (tnedian

Table 2 Comparison of neurophysiological measurements between cyddxawntktrsand matched controls (all results NS)

Solvent workers Cbnrnb(n = 18) 4 =8Mean (SD) Mt-as (SD)

Ulnar MNCV 65-6 (4 5) 66-3 (3 7)SNCVp 70 3 (4 7) 67-1 (4.3)SNCVd 53-2 (4 5) 51-7 (4-9)

Peroneal MNCV 51-6 (3 3) 53 8- (5w0)Sural SNCV 49-5 (8 4) 51 8 (6-7Ulnar MDL (ms) 3-2 (0 3) 3-2 (0p)Peroneal MDL (ms) 4 1 (0 7) 4.8 (1'2)Ulnar Amplitude (uV) 20-5 (10-3) 25 0 11-4)

Duration (ms) 1-5 (6 3) 1 5 <0,3)Sural Amplitude (uV) 25-7 (12-8) 288(141.)

Duration (ms) 1-8 (0 4) 1 8 (0 3)

Pairs were matched at the time of the first study.

Table 3 Comparison ofhigher and lower exposure groups and controls (al results wereNS)

Higher exposure Lower eposure GonrVls(n = 7) (n = 11) (n=-8)Mean (SD) Mean (SD) Meaw (SD)

Ulnar MNCV 64-5 (3 7) 66'3 (4J9) 66-3 (3.7)SNCVp 70-8 (5 4) 70 0 (4 4) 67-1 (4.3)SNCVd 53-1 (5 9) 53-3 (3-6) 51-7-(4.9)

Peroneal MNCV 49 7 (3 2) 53-0 (2'6) 53,8 (50)Sural SNCV 47-8 (5 6) 50-6 (9;9) 51 8 (6 7)Ulnar MDL (ms) 3-3 (0-4) 3-0 (-2) 3-2 (0.3)Peroneal MDL (ms) 4-2 (0-7) 3 9 (0-7) 4-8 (1.2)

Table 4 Summary of the results of regression analysis (stepwise, backward)NCVs of upper extremities NCVs oflower extremities(ulnar nerve) (sral nerve)

MNCVVariables MDL MNCV Duration (per~neal) Duration

Duration of exposureto cyclohexane (y) -(0 05)*

Duration of exposureto n-hexane (y) - (0-05)

Height (cm) -(0-01)Weight (kg) + (0-01)BMI (kg/m) -(0-01)Skin temperature (2C) -(0-01) -(0-01) (0-05)Cigarette consumption

(/day) + (0-05) -I01)Adjusted R2 0-51** 0-42 0-36 0-21 0-24

No significant relation was found for age or individual mean exposure to cydcloxnwe (ppm).*P value of regression coefficient listed only if P < 0 05; **result of analysis listed only ifadjusted R2 > 0-02; + = increase NCV or prolong MDL; -= decrease.NCV or shuon MDL.

88 ppm). The mean concentrations of tolueneand n-hexane vapour in the breathing zonewere 2-28 ppm (median 6 ppm) and notdetectable respectively.

NEUROPHYSIOLOGICAL STUDYThe following neurophysiological variableswere measured on the dominant arm and theleg of the same side by a standard method'0with an electromyograph (Sapphire 1P,Medelec, England). All the exposed workersand controls were examined from April to Julyin 1993 (the first study), and nine exposedworkers were examined again in July 1994 (thesecond study, fig). All neurophysiologicalexaminations were performed in an examina-tion room of the factory by the same techni-cian. The sensory ulnar nerve was stimulatedantidromically, to shorten the time requiredfor the study. Skin temperature was measuredwith a skin temperature indicator sticker(ProChecker, Kyowa Medex, Japan).Although the accuracy of the sticker was 10C,we used it for its simplicity.The following indices were used and are

defined as:(1) MNCV: maximum nerve conduction

velocity of the motor fibres of the ulnar nervebetween the wrist and elbow and commonperoneal nerve between the knee and ankle.

(2) MDL: motor distal latency of the ulnarnerve and common peroneal nerve.

(3) SNCVp: proximal conduction velocityof sensory fibres of the ulnar nerve betweenthe elbow and wrist.

(4) SNCVd: distal conduction velocity ofsensory fibres of the ulnar nerve between thewrist and 5th metacarpophalangeal joint andthe sural nerve between the calf and foot.

(5) Amplitude: amplitude of maximum sen-sory nerve action potential of the ulnar nerveand sural nerve.

(6) Duration: duration of sensory nerveaction potential of the ulnar nerve and suralnerve.The nerves were supramaximally stimulated

with a single pulse of 0 1 ms (for motornerves) or 0-2 ms (for sensory nerves) at a fre-quency of 2 Hz. The intensity of stimulationwas 200-300 V (for motor nerves) or 50-150V (for sensory nerves).

STATISTICAL CALCULATIONSStatistical analyses were carried out withStatview 4 0 procedures (Abacus Concepts).The X2 test was used for comparing subjectivesymptoms. The paired t test was used for com-paring the NCV variables between workersand age and sex matched controls andbetween the first and second studies. To com-pare the higher and lower exposure groupswith the controls, analysis of variance(ANOVA) was performed followed byScheffe's multiple comparison test." Multipleregression analysis (stepwise, backward) wasdone to consider the relation between expo-sure indices and NCV or motor distal latency(MDL), after adjustment for other confound-ing factors." Differences were considered sig-nificant at P < 5%.

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Table 5 Results ofcomparison between first and second studies

Exposed workersfollowed up (n = 9)

(Ist study) (2nd study) ControlsMean (SD) Mean (SD) (n = 9)

Time from the end of n-hexane (y) 1-2 (0 6) 2-3 (0-6)Ulnar MNCV 65-6 (3 9) 67-6 (4 2) 66-6 (3 0)

SNCVp 69-5 (5-1) 66-8 (4-4) 65-6 (3-8)SNCVd 53-4 (5 2) 52-0 (2 6) 50 7 (4-4)

Peroneal MNCV 50-9 (3-7) 54-9 (1-7)ft 55-5 (5 4)Sural SNCV 50 7 (6-1) 56-3 (3-7)t 49 7 (8-1)Ulnar MDL (ms) 3-3 (0-4) 2-9 (0.2)*t 3-3 (0 3)Peroneal MDL (ms) 3 9 (0 7)* 3-2 (0 2)**t 5-3 (1-3)Ulnar Amplitude (jV) 22-3 (10-0) 22-8 (8 7) 25-1 (15 2)

Duration (ms) 1-8 (0 5) 1-4 (0 1)*t 1-8 (0 3)Sural Amplitude (uV) 8-5 (3 0) 9-0 (3.2) 16-3 (7-1)

Duration (ms) 2-0 (0 4) 1-9 (0-4) 2-1 (0 3)

*P < 0-05 v controls; **P < 0-01 v controls; tP < 0 05 2nd v 1st study; ftP < 0-01 v 2nd v 1st study.One of the nine workers followed up had no history of exposure to n-hexane.Pairs were matched at the time of the first study.

ResultsWORKING CONDITIONS AND EXPOSUREMEASUREMENTSThe individual external cyclohexane exposureranged from five to 211 ppm, with a geometricmean (GM) of 28 ppm (GSD 22-35 ppm).The individual cyclohexane exposure mea-sured in the winter, six months before the firststudy, ranged from six to 720 ppm with a GMof 77 ppm (GSD 63-95 ppm). No improve-ment in equipment of the factory was madebetween that measurement and the presentstudy, which was performed in hot weather inJuly and ventilation was better than in the win-ter because of open windows and many elec-tric fans in the worksite.The urinary cyclohexanol concentration

ranged from 0-12 to 8-23 mg/l, with a GM of0 55 mg/l (GSD 045-068 mg/l).

SUBJECTIVE SYMPTOMSThere was no significant difference in subjec-tive symptoms between workers exposed tosolvent and matched controls. General fatiguewas mentioned by nine of 18 workers exposedto cyclohexane and four of 15 controls(P < 0 1). Headache and dizziness were com-plained of by 10/18 and seven of 18 workers,and seven of 15 and four of 15 controls,respectively. An uneasy feeling was com-plained ofby eight of 18 workers and five of 15controls. For other chronic symptoms, therewere smaller differences between workers andcontrols.

NEUROPHYSIOLOGICAL FINDINGSThe mean (SD, range) skin temperature was32-4 (1-6, 26-35) in the arm and 31-8 (1 9,26-34) in the leg.

Table 2 shows the means (SDs) of NCVsamong cyclohexane workers and matched con-trols. These NCVs were measurements of thelast study for each worker. There were no sig-nificant differences in MNCVs and SNCVsbetween 18 exposed workers and age and sexmatched controls. The ulnar and peronealMDLs were significantly shorter in workersthan in controls (P < 0-05). Analysis of vari-ance among different exposure levels did notshow significant differences in any neurophysi-ological variables. The mean exposures of the

higher exposure group ranged from 126 to384 ppm (median 156 ppm), and those of thelower exposure group ranged from 10 to 68ppm (median 51 ppm, table 3). The ages,heights, and skin temperatures of all thegroups were not significantly different.

Table 4 shows the summary of the results ofmultiple regression analysis. Eighteen workersexposed to cyclohexane and 18 age and sexmatched controls were included in the analy-sis. Dependent variables were neurophysiolog-ical indices, and independent variables wereage, height, weight, body mass index, cigaretteconsumption, skin temperature, exposureduration, and individual mean exposure tocyclohexane, and duration of exposure ton-hexane. Alcohol consumption (ethanolequivalent ml/week) was not included in theanalysis because of the multicollinearitybetween duration of exposure to n-hexane andalcohol consumption. Duration of exposure tocyclohexane had a significant negative relationwith ulnar MDL (P < 0 05). Individual meanexposure to cyclohexane, mean value of thepresent and past exposure data, did not havesignificant relations with any of the neurophys-iological indices.

Table 5 shows the results of the follow upstudy on nine workers. The MNCV andSNCV of the legs were significantly improvedin the second study compared with the firststudy (P < 0-01, P < 0-05) and MDLs of thearms and legs were significantly shortened inthe second study (P < 0-05). Comparison ofthe results of the second study with the mea-surements for age and sex matched controls(n = 9), showed that MDLs of workers inthe second study had significantly better con-duction.

DiscussionAs the main result, measurements ofNCV didnot show obvious or subclinical polyneuropa-thy under almost exclusive exposure to cyclo-hexane, the personal concentration of whichranged from 5 to 211 ppm (median 46 ppm).An experimental study in rats showed no

pathological changes in the tibial nerve, opticalnerve, and medulla oblongata under the 2500ppm, 30-week exposure to cyclohexane. This

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supports the validity of our study. On theother hand paralysis or neuropathologicalchanges under exposure to cyclohexane werereported in humans and chickens.56 In thosestudies the exposure to cyclohexane was mixedwith that to other solvents and the cyclo-hexane content of those solvents was less than20%. The airborne concentration of cyclo-hexane was also low, less than 10 ppm.6Whether the neuropathy is attributable tocyclohexane or not, further research is calledfor. Mutti reported a dose-dependent relationbetween the exposure of mixed solvents (n-hexane, cyclohexane, methyl ethyl ketone) andsubclinical neurophysiological changes.'2Although the mean exposure to cyclohexanewas over 70 ppm, the concentration of n-hexane was also over 60 ppm. The effect ofexposure to n-hexane could not be negligible.The exposure of the present study was lowerthan the time weighted average environmentallimit in the United States and Japan," 300ppm and 150 ppm, respectively.The improvement ofNCVs in the follow up

study was considered to be due to past expo-sure to n-hexane. Chang reported delayedMNCV of the arms and legs in workers notexposed to n-hexane for four years.'4 Delayedworsening ofMNCV was also found in five of11 workers five to 10 months after the end ofexposure to n-hexane.'4 In the present study12 workers had a history of exposure to n-hexane. The interval between the end of expo-sure to n-hexane and investigation was 0 3-2-6years, with a mean (SD) of 1 2 (0 7) years inthe first study. Therefore the first study wasconsidered to have occurred during the recov-ery from subclinical neuropathy caused by n-hexane.

Although the level of exposure to n-hexanewhich induces delay of NCVs was said to bemore than 100 ppm in some reports,'5"" a fewstudies reported that the delay of NCV wascaused by less than 100 ppm of n-hexane.'920According to the health checks, the mean uri-nary concentration of 2,5-hexanedione was9 03 (4-44) mg/l in winter and 2A4 (1-7) mg/lin summer, and 9 03 mg/l urinary 2,5-hexane-dione was equivalent to 87-8 ppm of n-hexaneas determined by Perbellini et al.21 Thus, weconsider it was possible for past exposure to n-hexane to cause neurophysiological changesand that the results of the first study wereaffected by past exposure to n-hexane.No neurophysiological indices were im-

paired at the second study. This agreed with areport describing the prognosis of n-hexaneneuropathy to be good.'4

Height, weight, body mass index, skin tem-perature, and cigarette consumption had inde-pendent significant relations with NCVs bymultiple regression analysis in the presentstudy. To detect effects of organic solvents onneurophysiological indices, these factorsshould be controlled as confounders. Skintemperature had significant relations withsome neurophysiological indices, andimproved nerve conduction in our study.Significantly positive relations between skintemperature and nerve conduction velocity

were described in some previous studies.22'Differences in skin temperature betweenexposed workers and controls, however, werenot significant. There are few reports on therelation between body build (height, weight,and BMI) and NCV other than in the mediannerve. Takano et al,24 Rivner et al, and Letzand Gerr reported a significant negative rela-tion between height and NCV."2 In ourstudy, height had a significantly negative rela-tion with ulnar MNCV as well (table 5) andexposed workers were significantly shorterthan matched controls (P < 0-01). UlnarMNCV could be slower in exposed workersthan in controls if there was no difference inheight between them. Studies that reported asignificant relation between cigarette con-sumption and NCVs could not been found.The urinary cyclohexanol concentration

was referred to as a good index of exposure tocyclohexane by the study,7 which was per-formed in the same factory on 33 workers atthe time of our first investigation. In particularurinary cyclohexanol measured by an enzy-matic method corrected for specific gravityand creatinine had a significant positive rela-tion with airborne cyclohexane. We examinedthe relation only in workers recruited for theneurophysiological study, but adding the dataof the first and the follow up study we foundthe same results (regression coefficient 0-8,P < 0000 1).

In conclusion, no evidence of neurotoxiceffects was found when almost the only occu-pational exposure was to cyclohexane for a rel-atively short time and at low concentrations(below the time weighted average thresholdlimit value of the United States)."3

We thank our colleagues of Sapporo Medical University,Department of Neurology for technical assistance. Thisresearch was partly supported by a grant from the JapaneseMinistry of Education, Science, and Culture.

1 Sandmeyer EE. Alicyclic hydrocarbons. In: George D.Clayton FEC, ed. Patty's industrial hygiene and toxicology,3rd ed. New York: John Wiley, 1981;2B:3227-9.

2 Perbellini L, Brugnone F. Lung uptake and metabolism ofcyclohexane in shoe factory workers. Int Arch OccupEnviron Health 1980;45:261-9.

3 Frontali N, Amantini MC, Spagnolo A, Guarcini AM,Saltari MC. Experimental neurotoxicity and urinarymetabolites of the C5-C7 aliphatic hydrocarbons used asglue solvents in shoe manufacture. Clin Toxicol 1981;18:1357-67.

4 Mutti A, Cavaorta A. Neurophysiological changes in work-ers exposed to organic solvent. Scand J Work EnvironHealth 1982;8(suppl 1):136-41.

5 Franchini I, Cavatorta A, D'Errico M, et al. Studies on theetiology of the experimental neuropathy from industrialadhesive (glues). Experientia 1978;34:250-2.

6 Franco G, Moglia A, Ghittori S. Polineuropatia profession-ale riferibile a cicloesano. Med Lavoro 1979;2:1 18-24.

7 Yasugi T, Kawai T, Mizushima K, et al. Exposure monitor-ing and health effect studies of workers occupationallyexposed to cyclohexane vapor. Int Arch Occup EnvironHealth 1994;65:343-50.

8 Kishi R, Harabuchi I, Katakura Y, Ikeda T, Miyake H.Neurobehavioral effects of chronic occupational exposureto organic solvents among Japanese industrial painters.Environ Res 1993;62:303-13.

9 Hirayama T, Ikeda M. Applicability of carbon felt to thedosimetry of solvent vapor mixture. Am Ind Hyg Assoc J1979;40: 1091-6.

10 Kimura J. Assessment of individual nerves. In: Kimura J,ed. Electrodiagnosis in diseases of nerve and muscle: principlesand practice. Philladelphia: FA Davis, 1989:103-32.

11 Kleinbaum D, Kupper L, Muller K. Applied regressionanalysis and other multivariate methods. Boston: PWS-KENT, 1988

12 Mutti A. Neurophysiological effects of long-term exposureto hydrocarbon mixtures. Arch Toxicol 1982;5(suppl):120-4.

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13 American Conference of Governmental IndustrialHygienists. Threshold limit values for chemical substancesand physical agents and biological exposure indices.Cincinnati: ACGIH, 1993-4.

14 Chang Y. An electrophysiological follow up of patients withn-hexane polyneuropathy. BrJIndMed 1991;48:12-7.

15 Herskowitz A, Ishii N, Schaumburg H. n-Hexane neuropa-thy. A syndrome occuring as a result of industrial expo-sure. NEnglJMed 1971;285:82-5.

16 Inoue T, Takeuchi Y, Takeuchi S. A health survey on vinylsandal manufactures with high incidence of "n-hexane"intoxication. Jpn J Ind Health 1970;12:73-84.

17 Paulson G, Waylonis G. Polyneuropathy due to n-hexane.Arch Intern Med 1976;136:880-2.

18 Yamada S. Intoxication polyneuritis in the workers exposedto n-hexane. jpn J7 Ind Health 1967;9:651-9.

19 Wang J-D, Chang Y-C, Kao K-P, Huang C-C, Lin C-C,Yeh W-Y. An outbreak of n-hexane induced polyneu-ropathy among press proofing workers in Taipei. Am JInd Med 1986;10: 11-8.

20 Sanagi S, Seki Y, Sugimoto K, Hirata M. Peripheral ner-

vous system functions of workers exposed to n-hexane ata low level. Int Arch Occup Environ Health 1980;47:69-79.

21 Perbellini L, Brugnone F, Silvestri R, Gaffuri E. Measure-ment of the urinary metabolites of n-hexane,cyclohexaneand their isomers by gas chromatography. Int Arch OccupEnviron Health 1981;48:99-106.

22 Letz R, Gerr F. Covariates of human peripheral nervefunction: I. Nerve conduction velocity and amplitude.Neurotoxicol Teratol 1994;16:95-104.

23 Halar EM, DeLisa JA, Brozovich FV. Nerve conductionvelocity: relationship of skin, subcutaneous and intra-muscular temperature. Arch Phys Med Rehabil 1980;61:199-203.

24 Takano K, Kirchner F, Steinicke F, Langer A, Yasui H,Naito J. Relation between height and the maximumconduction velocity of the uinar motor nerve in humansubjects. JpnJPhysiol 1991;41:385-96.

25 Rivner MH, Swift TR, Crout BO, Rhodes KP. Towardmore rational nerve conduction interpretations: the effectof height. Muscle Nerve 1990;13:232-9.

Occupational and Environmental Medicine and theelectronic age

OEM has an Email address which [email protected]. We wel-come contact by Email, including letters tothe editor. Some of our reviewers alreadysend us their reports by Email, helping tospeed up the peer review process.We are moving towards electronic pub-

lishing and for some months now we havebeen asking authors to send us their revisedpapers on disk as well as a hard copy. I amdelighted to report that nearly all ourauthors are managing to comply with this

request; far more than for other specialistjournals in the BMJ Publishing group.Oddly enough, the few authors who havenot sent us a disk version of their revisedpapers have been almost exclusively fromthe United Kingdom. I would be interestedin suggestions for why this might be.Perhaps United Kingdom based authorsread our correspondence and instructionsless assiduously? Watch for revisedInstructions to Authors.

The Editor

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environmental investigation toyuasa,kishi, eguchi, harabuchi, kawai,ikeda, et al supports the...

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