58ournal ofNeurology, Neurosurgery, and Psychiatry 1993;56:538-542

N-hexane neuropathy in offset printers

C M Chang, CW Yu, K Y Fong, S Y Leung, TW Tsin, Y L Yu, T F Cheung, S Y Chan

AbstractIn an offset printing factory with 56workers, 20 (36%) developed sympto-matic peripheral neuropathy due toexposure to n-hexane. Another 26 work-ers (46%) were found to have subclinicalneuropathy. The initial change in thenerve conduction study was reducedamplitude of the sensory action poten-tials, followed by reduced amplitude ofthe motor action potentials, reduction inmotor conduction velocities and increasein distal latencies. These changes indi-cate primary axonal degeneration withsecondary demyelination. Sural nervebiopsy in a severe case showed giantaxonal swellings due to accumulation oflOnm neurofilaments, myelin sheathattentuation and widening of nodal gaps.The development of neuropathy bore nodirect relationship to the duration ofexposure, hence factors such as individ-ual susceptibility may be important.Optic neuropathy and CNS involvementwere uncommon and autonomic neu-ropathy was not encountered.

( Neurol Neurosurg Psychiatry 1993;56:538-542)

University ofHongKong, Hong KongDepartment ofMedicineC M ChangKY FongYLYuT F CheungDepartment ofPathologySY LeungOccupational HealthDivision, LabourDepartment, HongKong Government,Hong KongCWYuTW TsinS Y ChanCorrespondence to:Dr Chang, Department ofMedicine, University ofHong Kong, Queen MaryHospital, Hong KongReceived 23 March 1992and in revised form10 July 1992.Accepted 20 July 1992

N-hexane, present in many commonly usedorganic solvents, is known to cause peripheralneuropathy.' Outbreaks have been reported inlaminating,2 3 pharmaceutical,4 sandal andshoe making,'9 furniture production'0 andadhesive bandage manufacturing" industries.

In the printing industry, n-hexane is usedto remove residual colouring agents on theroller and has caused two outbreaks of neu-ropathy in the past.'2 13 We report our investi-gation on the clinical, electrophysiological andpathological features of n-hexane neuropathyin a printing factory.

Materials and methodsFollowing the diagnosis of peripheral neu-ropathy in the index case, the factory wasinspected by a team of occupational healthexperts. Samples of commonly used chemi-cals and solvents were obtained. Under nor-mal operating conditions, air samples werecollected on two different days, each over 60to 90 minutes (about four to six job cycles) bystandand charcoal tube method with low flowsampling pumps. All liquid and air sampleswere analysed by high performance gas chro-

matography. The Time Weighed Average(TWA) air concentration of organic vapourswere computed from the amount determinedby gas chromatography and the calculatedvolume of the air sampled. All staff membersof the offset printing department were seen byan occupational health physician and then bya neurologist. Standard questionnaires wereadministered, general and neurological exami-nations were performed, full blood counts,ESR, renal and liver function tests, and bloodglucose were checked in all. Serum lead leveland red blood cell delta aminolaevulinic acid(d-AIA) dehydratase activity were measuredin the first three affected workers only.Standard nerve conduction study of the rightupper and lower limbs and pattern reversalvisual evoked potential study (VEP) were per-formed in all. The results were comparedwith 20 age and sex matched normal controls.Statistical analysis was carried out on a stan-dard personal computer, using the StatisticalPackage for Social Sciences. Dunnett's t testwas employed after analysis of variance. A p-value of

N-hexane neuropathy in offset printers

Table 1 Sympwms and signs in 20 patients with n-hexane neuropathy

Number (%)

Upper Limbs Lower Limbs

Numbness 8 (40) 14 (70)Paraesthesiae 5 (25) 13 (65)Pain 2 (10) 9 (45)Cramp 1 (5) 8 (40)Weakness 7 (35) 15 (75)4Pain 2 (10) 6 (30)4Light Touch 1 (5) 4 (20)4Vibration 1 (5) 5 (25)JJoint position 0 (0) 1 (5)Proximal wasting 1 (5) 2 (10)Distal wasting 2 (10) 4 (20)Proximal weakness 1 (5) 3 (15)Distal weakness 3 (15) 5 (25)Hyporeflexia 9 (45) 9 (45)

air intakes from passive air inlets. Only twolocal exhausts and one window mounted fanwere installed.The offset machine workers worked 12

hours per day, 6 days per week. The meanduration of employment was 2-6 years (range1 month to 12 years) in this printing factoryand 6-4 years (range 1 month to 30 years) inthe printing trade. Using cloths or sponges

Table 2 Nerve Conduction Study

Age (years)

Amplitudes of SAP (uV)Median

Ulnar

Sural

Amplitudes ofMAP (mV)Median

Ulnar

Posteriortibial

Commonperoneal

Distal Latency of SAP (ms)Median

Ulnar

Sural

Distal Latency of MAP (ms)Median

Ulnar

Posteriortibial

Commonperoneal

Motor Conduction VelocityMedian

Ulnar

Posteriortibial

Commonperoneal

Controln = 20

26-9 (4-4)(20-35)

37 (11)(20-65)15 (4)(8-22)24 (10)(12-45)

7 (2)(3-11)5-7 (2-1)(2 8-10)6-6 (2)(3-5-11)4-4 (1-5)(2-7)

2-3 (0 3)(1-9-28)2-1 (0 3)(1-7-2-8)3-3 (0-3)(2-8-3-6)

2-9 (0-4)(2 3-3 8)2-2 (0-3)(1-8-2-8)4-1 (0 6)(3 2-5-2)3.9 (0-5)(3-3-4-7)

(mls)59 (5*9)(48-68)61 (5 8)(44-69)50 (6-4)(41-66)51 (45)(43-63)

Asymptomatic

Healthyworkern = 10

25-8 (6-4)(16-37)

27 (6)*(20-40)14 (3)(10-18)22 (6)(15-35)

8 (3)(4-13)6-5 (1-9)(4-10)6-7 (2-3)(5-12)4-3 (1-4)(3-7)

2-3 (0-1)(2-1-2-5)2-1 (0-1)(1-9-2-3)3-1 (0-2)(2-8-3-3)

3-0 (0-2)(2-7-3-3)2-3 (0-3)(2-1-2-8)3-9 (0-6)(3-1-4-8)3-5 (0-4)(3-0-4-2)

57 (5)(48-65)59 (6)(52-71)46 (3-4)(41-51)46 (3-8)(40-53)

Subclinicaln = 26

26-7 (7)(17-43)

24 (8)*(11-41)12 (5)(5-24)18 (7)*(2-40)

6-7 (2 4)(3-2-12-5)4 (2-2)*(1-8)5-3 (2-5)(2-2-15)3-6 (1-4)(1-5-7)

2-6 (0.3)*(2 2-3.2)2-3 (0 3)(1-9-3-1)3-3 (0 3)(2 8-4-2)

3-6 (0.5)*(2 8-48)2-6 (0.5)*(2 0-3.9)4-4 (0-6)(3-2-5-8)4-2 (0-7)(3 0-5 5)

55 (6-7)*(43-73)55 (7.8)*(44-79)45 (4.7)*(36-55)45 (5-1)*(36-56)

Symptmaticn =20

28-2 (5-8)(16-38)

15 (5)*(5-24)7 (4)*

(0-15)11 (8)*(0-34)

4-6 (2-2)*(1-1-8)3-6 (1-5)*(0-9-6)2-9 (1-7)*(1-7)1-8 (1-4)*(0-25-6)

2-9 (0-3)*(2-4-3-8)2-7 (0-4)*(2-0-3-5)3-7 (0-6)*(2-3-4-6)

4-3 (1-2)*(2-6-7-2)3-0 (0-7)*(2-2-4-5)5-6 (1-2)*(3-4-8 4)5-4 (1-2)*(3 5-8 8)

46 (6 5)*(37-57)48 (7-5)*(38-69)38 (6-5)*(26-51)37 (7-1)*(26-54)

Mean (SD) (Range)*p < 0 05 compared with control.

soaked with cleaning solvents, they cleanedthe rubber roller blankets manually two tothree times every hour, each time lasting twoto five minutes.The background TWA air concentrations

were 30 to 110 ppm (mean 63 ppm) for n-hexane, 57 to 340 ppm (mean 130 ppm) forisopropyl alcohol (IPA) and 11 to 46 ppm(mean 26 ppm) for toluene. The TWA fig-ures were higher in the personal air samplesfrom the offset machine workers, 80 to 210ppm (mean 132 ppm) for n-hexane, 20 to680 ppm (mean 235 ppm) for IPA, and 20 to84 ppm (mean 50 ppm) for toluene.

Five managerial staff were examined andfound to be unaffected clinically or electro-physiologically. Fifty seven offset machineworkers were investigated, but one workerwith peripheral neuropathy was excludedbecause of alcoholism and diabetes mellitus.The remaining 56 workers were males with amean age of 27 years (range 16 to 43); onlyone was aged over 40. Twenty five weresmokers and 15 (27%) had mild alcohol con-sumption (one to two cans of beer daily).None of them had a history of alcoholism ordiabetes mellitus. Fifty one workers (91%)wore gloves but none wore respirators atwork.Twenty workers (36%) had both clinical

and electrophysiological evidence of peripher-al neuropathy. Thirty six workers wereasymptomatic and normal on examinationbut 26 (72%) had abnormalities in their NCSand hence subclinical neuropathy. There wasno correlation between the development ofneuropathy and the length of employment inprinting. Nine workers (16%) developed neu-ropathy just a few months after exposurewhile five (9%) remained healthy four toeight years after exposure.

In the 20 patients with symptomaticperipheral neuropathy (table 1), the initialsymptoms were most frequently numbness,followed by paraesthesiae, pain and weaknessof the feet and distal part of the legs. Sensorydisturbances usually preceded motor distur-bances and lower limbs were affected earlierthan upper limbs. However, in four workerswho did not wear gloves, the earliest symp-tom was numbness in the hands and fingers.Symptoms developed retrogradely andascended the limbs as the neuropathy pro-gressed. Fourteen workers with mild neu-ropathy had only sensory disturbances whilefive with moderate and one with severe neu-ropathy had weakness and muscular atrophyin addition. The coasting phenomenon (ini-tial deterioration of the neuropathy even afterremoval from exposure) was present in threeworkers.

In the electrophysiological evaluation(table 2), the control subjects and workerswere males and their ages were comparable.In the asymptomatic healthy workers, theabsolute values of the NCS were within nor-mal ranges. However, the mean median nervesensory action potential (SAP) was signifi-cantly reduced when compared with controls,while mean SAP amplitudes of the ulnar and

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Chang, Yu, Fong, Leung, Tsin, Yu, Cheung, Chan

Table 3 Number (%) ofworkers with other abnormalities

Symptomatic Subclinical Asymptomaticperipheral petipheral healthyneuropathy neuropathy workern = 20 n = 26 n = 10

Systemic upset* 11 (55) 5 (19-2) 0 (0)Subclinical optic neuropathy** 2 (10) 3 (11-5) 0 (0)Autonomic neuropathy*** 0 (0) 0 (0) 0 (0)CNS symptoms**** 5 (25) 0 (0) 0 (0)CNS signs***** 2 (10) 0 (0) 0 (0)Abnormal liver function test 0 (0) 1 (3 8) 1 (10)

*Weight loss >5 lb, anorexia.**Delayed P100 latency in VEP.***Postural hypotension, impotence, urinary difficulty, constipation, diarrhoea, anhidrosis,hyperhidrosis.****Headache, deteriorating memory, drunken feeling, vertigo.*****Hyperreflexia.

sural nerves and mean motor conductionvelocities (MCV) also showed a decrementaltrend.

In the asymptomatic subclinical group,more marked reduction in mean SAP ampli-tudes and MCV was encountered. In addi-tion, mild reduction in mean motor actionpotential (MAP) amplitudes and mild prolon-gation in mean distal latencies (DL) of SAPand MAP were also found.

In the symptomatic group, reduction inmean SAP, MAP amplitudes and MCV weremarked while prolongation in mean DL ofSAP and MAP were also obvious.

Other neurological and systemic abnormal-ities were listed in table 3. Most of theseabnormalities occurred in workers with symp-tomatic neuropathy. Full blood picture, ESRblood glucose and renal function tests werenormal in all 56 workers. Serum lead and redblood cell d-ALA dehydratase levels werenormal in the three workers studied.

INDEX CASEA 30 year old male printer from MainlandChina came to Hong Kong in 1989. InAugust 1990, he was employed by the offsetprinting factory and his work involved regularcleaning of the rubber roller blanket with

Figure 1 Electron micrograph ofsural nerve showing a swollen axon with considerablyattenuated myelin sheath. Bar = lum 2800 x .

organic solvents. He did not wear protectivegloves or a respirator at work. Six monthslater, he developed numbness and painfulparaesthesiae in both legs, followed by weak-ness and muscle wasting. The upper limbswere also affected one month later. Despitestopping work, his symptoms deterioratedover the next two months. He did not con-sume alcohol or smoke and his past healthwas good. Some of his fellow workers experi-enced similar symptoms and the most severe-ly affected one was wheel-chair bound andhad returned to China.On examination, he had a typical sensori-

motor peripheral neuropathy, more severe inthe lower than the upper limbs. There weresevere distal and mild proximal wasting andweakness and glove and stocking sensoryimpairment to all modalities and hyporeflex-ia. The FBC, ESR, routine RFT, LFT, fast-ing blood glucose, serum and RBC vitaminB12 and folate levels, antinuclear and anti-DNA antibodies, serum complements, serumimmunglobulin levels and immunoelec-trophoresis, serum lead and other heavymetal screen, RBC d-ALA dehydratase activi-ty, urinary lead and porphyrins were all nor-mal or negative. Nerve conduction studyshowed very small median (10 uV), ulnar(1 uV) and sural (5 uV) SAP amplitudes,small and highly dispersed median (1 5 mV),ulnar (0-9 mV), posterior tibial (1 mV) andcommon peroneal (08 mV) MAPs. The DLof the MAP were mildly prolonged and theMCV were moderately reduced: median(38 m/s), ulnar (45 m/s), posterior tibial(28 m/s), common peroneal (26 m/s).Electromyography showed active denervationchanges in distal muscles. Somatosensory,visual and brainstem auditory evoked poten-tials studies were normal. Sural nerve biopsyshowed a normal number of myelinated andnon-myelinated fibres, mild thickening of theperineurium and giant axonal swellings inmany myelinated fibres. Electron micrographshowed that these swollen axons had consid-erably attenuated myelin sheaths (fig 1),accumulation of 10 nm neurofilaments in theaxoplasm and loss of neurotubules (fig 2).Teased fibre examination (fig 3) demonstrat-ed fusiform axonal swellings in the internodalregion, some of which were 50 um in diame-ter. The myelin sheaths were considerablyattenuated in the swollen areas and long seg-ments of myelin degradation leaving a nakedaxon was present. In other areas, there wasno axonal swelling but paranodal myelinattentuation resulting in a widened nodal gap.The result of the investigations in his factorywere as shown above. With physiotherapyalone, recovery started to occur in the proxi-mal limbs four months later. At the last fol-low up at 12 months, there was only milddistal weakness in the legs but he still hadpainful paresthaesiae in the feet and poorexercise endurance.

DiscussionIn our investigation, n-hexane was the only

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N-hexane neuropathy in offset printers

4~~~~~~~~~~~~~~~~~~~~~~~~~4

- tj wtFigure 2 Higher power electron micrograph showing accumulaton of 10 nmneurofilaments in the axoplasm. Bar = lum 30,000 x .

neurotoxic chemical present in the cleaningsolvents in considerable quantity. Other neu-rotoxic substances such as methyl n-butylketone,'4 methyl ethyl ketone (not itself neu-rotoxic but can potentiate n-hexane or methyln-butyl ketone induced neuropathy),'5organophosphate,'6 lead or mercury wereeither absent or present in trace amount only.Moreover, the TWA air concentration of n-hexane was well above the recommendedthreshold limit value of 50 ppm, while theconcentrations of other potential neurotoxicchemicals or gases were within internationallyacceptable limits.17 We concluded thereforethat the neuropathy was due to n-hexane.As the respiratory tract is the main site of

absorption for n-hexanel and since none ofour workers wore respiratory protection, it isnot surprising to find so many of themdeveloping peripheral neuropathy. N-hexanemay also be absorbed through intact skin 18and this may explain why upper extremity

numbness was the initial symptom in four ofthe workers who worked without wearinggloves.The symptomatology of our workers,

including the coasting phenomenon, is typicalof those described previously.' Comparedwith patients reported from Taiwan,19 ourworkers' neuropathy was milder, even thoughthe air concentrations of n-hexane were verysimilar in the two outbreaks. It is possiblethat our workers had a shorter duration ofexposure as they did not eat or sleep in thefactory as their Taiwanese counterparts. Also,skin absorption may be less because solventswith lower n-hexane content were used. It isvery likely, however, that many would devel-op more severe neuropathy if this outbreakwas not detected at an early stage.

Although the pathological evolution of n-hexane neuropathy has been well document-ed in experimental animals,20 this has notbeen possible in human disease because nervebiopsies have only been performed in themore severely affected patients. Our NCSdata, however, may be used to correlate withexperimental pathology. The earliest changein NCS was reduction in the SAP amplitudesas evidenced by the asymptomatic("healthy") workers. This electrophysiologicalchange is consistent with the pathologicalfinding of early distal axonal degenerationseen in experimental animals.20 In the sub-clinical group, the NCS was characterised byfurther reduction in the SAP amplitudes,mild reduction of MAP amplitudes andMCV, and mild prolongation in DL of SAPand MAP. These findings may suggest a milddegree of demyelination, probably secondaryto primary axonal degeneration.20 Finally, inthe symptomatic workers, all the abovechanges became much more obvious. In themost severely affected worker, there was evi-dence suggesting severe axonal degeneration(unrecordable SAP) and significant demyeli-nation (MCV of 26 m/s in the lower limbs),which was confirmed by sural nerve biopsy.The absence of SAP is likely to be related towidespread multifocal giant axonal swellings,

Figure 3 Two teasedfibres with internodalaxonal swellings, thinningof myelin sheath andwidening ofnodal gap inone (arrow) and myelindegradation leaving anaked axon in the other.Osmium tetroxide 100 x .

'I,IMwasommomme-

.- - I PI la i -11, -

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Chang, Yu, Fong, Leung, Tsin, Yu, Cheung, Chan

while slowing of MCV is likely to be due tosecondary myelin degeneration and wideningof nodal gaps.9 15 21As shown by other studies,'3 22 a direct rela-

tionship between the development of neu-ropathy and the duration of employment wasnot observed in this study. As n-hexaneinduces hepatic cytochrome p-45023 and ismetabolised to the neurotoxic 2,5-hexane-dione (2,5-HD),24 it is possible that individualdifference in this specific metabolism mayaccount for the difference in susceptibility.Analysis of serum 2,5-HD may shed light onthis apparent differential susceptibility but thetest was not available to us then.

N-hexane may cause maculopathy or opticneuropathy, as seen in a few of our workersand in other studies.5'1119 There is growingconcern whether it is also toxic to the CNS.We agree that symptoms such as headache,poor memory and a drunken feeling werenon-specific and therefore may not necessari-ly reflect CNS toxicity. However, theunmasking of hyperreflexia and spasticity onrecovery,25 electroencephalography26 andevoked potential abnormalities27 28 and degen-eration of CNS fibre tracts in experimentalanimals20 are good evidence of CNS involve-ment. As in other outbreaks, autonomic neu-ropathy was not encountered.The best way to avoid future outbreaks is

to use cleaning solvent with very low n-hexa-ne content, or better still, to find a non-toxicsubstitute for n-hexane. Short of this, safetyregulations and guidelines in handling n-hexane must be strictly adhered to. Workersshould be periodically screened for the devel-opment of toxicity. In this study, we haveconfirmed that standard NCS is reliable andsensitive.29 Other potentially useful methodsinclude multimodal evoked potential studies30and urinary 2,5-HD estimation.3" The exactprognosis of our patients is not yet knownbecause of the short duration of follow up,although some have already shown slow butdefinite improvement. Generally, an opti-mistic and encouraging attitude should beconveyed to the patients because the progno-sis is favourable and good recovery can beexpected within a few months to a fewyears.5 6 19

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20 Spencer PS, Schaumburg HH. Ultrastructural studies ofthe dyeing-back process, IV. Differential vulnerability ofPNS and CNS fibres in experimental central-peripheraldistal axonopathies. J Neuropathol Exp Neurol 1977;36:300-20.

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