- Email: [email protected]
ULTRASTRUCTURAL EVALUATION OF TOXIC POLYNEUROPATHIES
1012 To assume that its presence in diseased reproductive organs is benign on the basis of finding it in normal reproductive organs as well ignores its potential role as a co-carcinogen and is similar to arguments voiced against many agents whch have already been proven carcinogenic. Not everyone exposed to carcinogenic materials gets cancer. Research into the Betiology of ovarian cancer must be vigorously pursued: the clues in this disease are not numerous. We are as sorry as Dr Roe about the tendency for certain scientific discussions to be distorted by the Press, but this is no reason to abandon the search for a scientific resolution of the issues.
cavity.
Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20014, U.S.A.
DAN L. LONGO ROBERT C. YOUNG
ULTRASTRUCTURAL EVALUATION OF TOXIC POLYNEUROPATHIES
SIR,-Evaluation of the effects of toxic substances on man is often difficult. Simultaneous exposure to more than one potential toxin and metabolic idiosyncrasies both may obscure the pathophysiology of a toxic agent’s effect. With solvent polyneuropathies investigations are further complicated by the similar light-microscopic features produced by many hydrocarbon solvents,’ the clinical effects of which may also overlap. Ultrastructural examination of the affected nerves, however, may be of value. We have described (Aug. 18, p. 363) a case of peripheral polyneuropathy after intensive exposure to spray paint containing acetone, dichloromethane, methyl isobutyl ketone (MiBK), methyl ethyl ketone (MEK), toluene, acetates, and butanol. The light-microscopic features of demyelination were those often seen with hydrocarbon solvent exposure. Ultrastructurally, however, the axonal degeneration with neurofilament accumulation seen in many cases of exposure to straightchained aliphatic ketones’.2 was not present; the primary effect appeared to be acute segmental demyelination. We attributed the neuropathy to MiBK because the other solvents have been inhaled in high concentrations for a long period without inducing peripheral neuropathies ;3 MiBK is further suspect due to the presence of MEK which is a potent potentiator of aliphatic ketone neuropathy. Dr Goldman (Oct. 6, p. 744) suggests that toluene played a vital role in our patient’s neuropathy. With simultaneous exposure to a known peripheral neurotoxin and toluene, toluene has been associated with peripheral neuropathy induction. In cases studied by electronmicroscopy, the axonal changes have been those which can be produced by the other solvents without the presence of toluene.’ There has been a case-report of vacuolar change accompanied by neurofilament accumulation after exposure to n-hexane and toluene.5 Inhalation of toluene without simultaneous exposure to a peripheral neurotoxin is not thought to damage peripheral nerves.3,6 Some early reports attributed the motor component of glue-sniffer’s polyneuropathy to toluene because n-hexane in glue was thought to cause primarily a -sensory disturbance; later, however, the n-hexane metabolite 2,5-hexanedione7 was shown to cause a marked motor neuropathy independently of toluene. 3,6 1.
Asbury AK, Johnson
PC.
Pathology
of
peripheral
nerve.
Maj
Probl Pathol
1978; 9: 1-311. K, Mendell JR, Weiss HS. Peripheral nerve changes induced by methyl n-butyl ketone and potentiation of methyl ethyl ketone. J. Neuropathol Exp Neurol 1976; 35: 207-25. 3. Altenkirch H, Mager J, Stoctenburg G, Helmbrect J. Toxic polyneuropathies after sniffing a glue thinner. J Neurol 1977; 214: 137-52. 4. Korobkin R, Asbury AK, Sumner AJ, Nielsen SL. Glue-sniffing neuropathy. Arch Neurol 1975; 32: 158-162. 5. Shirabe T, Tsudo T, Terao A, Araki S. Toxic polyneuropathy due to glue2. Saida
sniffing. J Neurol Sci 1974; 21: 101-13. 6. Boor JW, Hurtig Hl. Persistent cerebellar ataxia after exposure Ann Neurol 1977; 2: 440-42.
to
toluene.
Genetic differences in metabolism may cause idiosyncratic reactions to a variety of agents. The metabolism of six-carbon straight and branched chain ketones is along different pathways, the former terminating in the exotoxic 2,5-hexanedione which appears to be responsible for axonal degeneration with neurofilament accumulation.’ Branched chain ketones, such as MiBK, are not converted to this particular axotoxin, however.9 Thus it is not necessary to invoke metabolic idiosyncrasies to explain the presence of the primary acute segmental demyelination in our case. We wish to reaffirm the possible dangers of aliphatic ketone solvents. Their peripheral neurotoxicity seems to be independent of toluene. While simultaneous exposure to other solvents and the possibility of genetically determined alternate metabolic pathways may make it difficult to assign unequivocally a patient’s neuropathy to a particular toxin, ultrastructural studies may assist in delineating the class of the offending substance.
H.I.R. is
an
American Cancer
Departments of Pathology
and
Society fellow.
Oncology,
J. AUBUCHON
Clinical Science Center,
H. IAN ROBINS CHIRANE VISESKUL
University of Wisconsin, Madison, Wisconsin 53792, U.S.A.
ORIGIN OF RED-CELL-MEMBRANE DIFFERENCES IN MULTIPLE SCLEROSIS
SIR,-Seaman et al.,’.2 in their confirmation of theE-UFA (erythrocyte-unsaturated fatty acid) test3 for multiple sclerosis (MS), draw the far-reaching conclusion that "erythrocytes from MS patients do not possess an intrinsic membrane defect - instead the membrane differences arise reversibly from interaction with plasma". TABLE I-EFFECT OF PLASMA ON NATIVE RBC MEMBRANES
I-
..
_
.
1000.
-
_
Resuits expressed
as A%, the change in electrophoretic mobility in the presence of LA or AA expressed as a percentage of mobilities in absence of LA or AA (means all in range 0.990-0.998 fll11 s 1 V-’ cm). * Exposures to MS or control serum were for 1.5-2 h at 38°C. X=Normal subject; Y=OND ("stroke").
With well-washed, native RBC electrophoretic mobility in the presence of 80 tg/ml linoleic acid (LA) or arachidonic acid (AA) is increased in normals and OND (other neurological disease) and slowed in MS. We have found this in several hundred definite cases of MS. Low concentrations of LA and AA give reverse results.’ We have found that deliberate addi7. Couri D, Abdel-Rahman MS, Hetland LB. Biotransformation of n-hexane and methyl n-butyl ketone in guinea pigs and mice. Am Ind Hyg Assoc
J 1978; 39: 295-300. PS, Schaumburg HH. Experimental neuropathy produced by 2,5-hexanedione—A major metabolite of the neurotoxic industrial solvent methyl n-butyl ketone. J Neurol Neurosurg Psychiat 1975; 38: 771-75. 9. DiVincenzo GD, Kaplan CJ, Dedinas J. Characterization of the metabolites of methyl n-butyl ketone, methyl iso-butyl ketone, and methyl ethyl ketone in guinea pig serum and their clearance. Toxicol Appl Pharmacol 1976, 36: 511-52. 1. Seaman GVF, Swank RL, Taublyn CH, Zukorski CFIV. Lancet 1979; i: 8. Spencer
1138-39. 2. Seaman GVF, Swank RL, Zukorski CFIV. Lancet 1979;i: 1939. 3. Field EJ, Joyce G, Smith BM. J Neurol 1977; 214: 113-27. 4. Field EJ, ed. Multiple sclerosis: a critical conspectus. Lancaster:
1977: 245-61.
M.T.P.,
cavity.
Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20014, U.S.A.
DAN L. LONGO ROBERT C. YOUNG
ULTRASTRUCTURAL EVALUATION OF TOXIC POLYNEUROPATHIES
SIR,-Evaluation of the effects of toxic substances on man is often difficult. Simultaneous exposure to more than one potential toxin and metabolic idiosyncrasies both may obscure the pathophysiology of a toxic agent’s effect. With solvent polyneuropathies investigations are further complicated by the similar light-microscopic features produced by many hydrocarbon solvents,’ the clinical effects of which may also overlap. Ultrastructural examination of the affected nerves, however, may be of value. We have described (Aug. 18, p. 363) a case of peripheral polyneuropathy after intensive exposure to spray paint containing acetone, dichloromethane, methyl isobutyl ketone (MiBK), methyl ethyl ketone (MEK), toluene, acetates, and butanol. The light-microscopic features of demyelination were those often seen with hydrocarbon solvent exposure. Ultrastructurally, however, the axonal degeneration with neurofilament accumulation seen in many cases of exposure to straightchained aliphatic ketones’.2 was not present; the primary effect appeared to be acute segmental demyelination. We attributed the neuropathy to MiBK because the other solvents have been inhaled in high concentrations for a long period without inducing peripheral neuropathies ;3 MiBK is further suspect due to the presence of MEK which is a potent potentiator of aliphatic ketone neuropathy. Dr Goldman (Oct. 6, p. 744) suggests that toluene played a vital role in our patient’s neuropathy. With simultaneous exposure to a known peripheral neurotoxin and toluene, toluene has been associated with peripheral neuropathy induction. In cases studied by electronmicroscopy, the axonal changes have been those which can be produced by the other solvents without the presence of toluene.’ There has been a case-report of vacuolar change accompanied by neurofilament accumulation after exposure to n-hexane and toluene.5 Inhalation of toluene without simultaneous exposure to a peripheral neurotoxin is not thought to damage peripheral nerves.3,6 Some early reports attributed the motor component of glue-sniffer’s polyneuropathy to toluene because n-hexane in glue was thought to cause primarily a -sensory disturbance; later, however, the n-hexane metabolite 2,5-hexanedione7 was shown to cause a marked motor neuropathy independently of toluene. 3,6 1.
Asbury AK, Johnson
PC.
Pathology
of
peripheral
nerve.
Maj
Probl Pathol
1978; 9: 1-311. K, Mendell JR, Weiss HS. Peripheral nerve changes induced by methyl n-butyl ketone and potentiation of methyl ethyl ketone. J. Neuropathol Exp Neurol 1976; 35: 207-25. 3. Altenkirch H, Mager J, Stoctenburg G, Helmbrect J. Toxic polyneuropathies after sniffing a glue thinner. J Neurol 1977; 214: 137-52. 4. Korobkin R, Asbury AK, Sumner AJ, Nielsen SL. Glue-sniffing neuropathy. Arch Neurol 1975; 32: 158-162. 5. Shirabe T, Tsudo T, Terao A, Araki S. Toxic polyneuropathy due to glue2. Saida
sniffing. J Neurol Sci 1974; 21: 101-13. 6. Boor JW, Hurtig Hl. Persistent cerebellar ataxia after exposure Ann Neurol 1977; 2: 440-42.
to
toluene.
Genetic differences in metabolism may cause idiosyncratic reactions to a variety of agents. The metabolism of six-carbon straight and branched chain ketones is along different pathways, the former terminating in the exotoxic 2,5-hexanedione which appears to be responsible for axonal degeneration with neurofilament accumulation.’ Branched chain ketones, such as MiBK, are not converted to this particular axotoxin, however.9 Thus it is not necessary to invoke metabolic idiosyncrasies to explain the presence of the primary acute segmental demyelination in our case. We wish to reaffirm the possible dangers of aliphatic ketone solvents. Their peripheral neurotoxicity seems to be independent of toluene. While simultaneous exposure to other solvents and the possibility of genetically determined alternate metabolic pathways may make it difficult to assign unequivocally a patient’s neuropathy to a particular toxin, ultrastructural studies may assist in delineating the class of the offending substance.
H.I.R. is
an
American Cancer
Departments of Pathology
and
Society fellow.
Oncology,
J. AUBUCHON
Clinical Science Center,
H. IAN ROBINS CHIRANE VISESKUL
University of Wisconsin, Madison, Wisconsin 53792, U.S.A.
ORIGIN OF RED-CELL-MEMBRANE DIFFERENCES IN MULTIPLE SCLEROSIS
SIR,-Seaman et al.,’.2 in their confirmation of theE-UFA (erythrocyte-unsaturated fatty acid) test3 for multiple sclerosis (MS), draw the far-reaching conclusion that "erythrocytes from MS patients do not possess an intrinsic membrane defect - instead the membrane differences arise reversibly from interaction with plasma". TABLE I-EFFECT OF PLASMA ON NATIVE RBC MEMBRANES
I-
..
_
.
1000.
-
_
Resuits expressed
as A%, the change in electrophoretic mobility in the presence of LA or AA expressed as a percentage of mobilities in absence of LA or AA (means all in range 0.990-0.998 fll11 s 1 V-’ cm). * Exposures to MS or control serum were for 1.5-2 h at 38°C. X=Normal subject; Y=OND ("stroke").
With well-washed, native RBC electrophoretic mobility in the presence of 80 tg/ml linoleic acid (LA) or arachidonic acid (AA) is increased in normals and OND (other neurological disease) and slowed in MS. We have found this in several hundred definite cases of MS. Low concentrations of LA and AA give reverse results.’ We have found that deliberate addi7. Couri D, Abdel-Rahman MS, Hetland LB. Biotransformation of n-hexane and methyl n-butyl ketone in guinea pigs and mice. Am Ind Hyg Assoc
J 1978; 39: 295-300. PS, Schaumburg HH. Experimental neuropathy produced by 2,5-hexanedione—A major metabolite of the neurotoxic industrial solvent methyl n-butyl ketone. J Neurol Neurosurg Psychiat 1975; 38: 771-75. 9. DiVincenzo GD, Kaplan CJ, Dedinas J. Characterization of the metabolites of methyl n-butyl ketone, methyl iso-butyl ketone, and methyl ethyl ketone in guinea pig serum and their clearance. Toxicol Appl Pharmacol 1976, 36: 511-52. 1. Seaman GVF, Swank RL, Taublyn CH, Zukorski CFIV. Lancet 1979; i: 8. Spencer
1138-39. 2. Seaman GVF, Swank RL, Zukorski CFIV. Lancet 1979;i: 1939. 3. Field EJ, Joyce G, Smith BM. J Neurol 1977; 214: 113-27. 4. Field EJ, ed. Multiple sclerosis: a critical conspectus. Lancaster:
1977: 245-61.
M.T.P.,