Archives of Environmental Health: An International Journal
ISSN: 0003-9896 (Print) (Online) Journal homepage: http://www.tandfonline.com/loi/vzeh20
Toxicity of Methyl n-Butyl Ketone Robert L. Raleigh MD , Peter S. Spencer PhD & Herbert H. Schaumburg MD To cite this article: Robert L. Raleigh MD , Peter S. Spencer PhD & Herbert H. Schaumburg MD (1975) Toxicity of Methyl n-Butyl Ketone, Archives of Environmental Health: An International Journal, 30:6, 317-318, DOI: 10.1080/00039896.1975.10666709 To link to this article: http://dx.doi.org/10.1080/00039896.1975.10666709
Published online: 02 May 2013.
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=vzeh20 Download by: [University of Florida]
Date: 06 June 2016, At: 22:09
Archives of Environmental Health: An International Journal 1975.30:317-318.
Letters to the Editor
o-Aminolevulinic Acid Dehydratase
To the Editor.- We have been very much interested in K. Tomokuni's report, "o-Aminolevulinic Acid Dehydratase," that appeared in the November issue of the ARCHIVES (29:274-281, 1974). We also undertook to find a modification of the enzyme pH optimum when inhibited by lead, and likewise used this phenomenom to carry out screening for lead intoxification. We found a very significant difference of enzyme activity between a standard and intoxicated population at pH 6.9 but not at pH 5.9. 1 However, we cannot agree on three other points: 1. We were not able to separate accurately the two populations because of the great dispersion of our values. The use of Tomokuni's test (activity ratio) did not improve our dispersion, possibly because our patients were more intoxicated. Indeed, the average blood lead value of Tomokuni's patients was lower than 40J..tg I 100 ml. From our results, we were inclined to think that two enzymatic fractions were present in red blood cells; one (A), greatly inhibited by lead, had a pH optimum of 6.8, and another (B), not very much affected by lead, had a pH optimum of 6.1. In presence of a low blood value (lower than 40J..tg/lOO ml), the activity ratio at pH 6.8 and 6 is lowered by inhibition of enzymatic fraction A only; however, when the blood lead level value was increased, the fraction E too became affected by lead and thus the activity ratio came to a normal or even increased value. In fact, these results may be found also in Tomokuni's report (Fig 8). 2. Unlike the author, we found a biphasic pH curve for the standard 2
Arch Environ Health/Vol 30, June 1975
population, thus agreeing with the original work of Nikkanen. 3. We also found that heating did not entirely restore the enzyme activity as we could not find the typical biphasic pH curve afterward. However, by addition of glutathione in the incubation mixture, we did succeed in restoring the 8-aminolevulinic acid dehydratase integrity and activity in red blood cells. B. DINGEON A. ROULLET Laboratoire de Biochemie Hopital Jules-Courmont Pierre-Benite, France G. PROST F. TOLOT Institut Universitaire du Medecine du Travail Lyon, France References 1. Dingeon B, Prost G, Tolot F: Sensibilite et valeur pratique de l' A.L.A. dehydrase pour la surveillance des sujets exposes au pJomb. J Int Meditwr Med TTa1Jaii 29:30-34, 1974. 2. Tolot F, Prost G, Dingeon B, et al: Contribution a l'etude du mecanisme de l'inhibition de l'A.L.A.D. erythrocytaire par la plomb. Soc Med Travail Ergonom Lyon 13:12, 1974.
In reply.-I am grateful to Dr. Dingeon et al for their interest in my report. The pH activity curve of erythrocyte ALA-D in normal and leadexposed subjects can be influenced by kinds of anticoagulants used. Therefore, the activity ratio in my test may also be affected by the anticoagulants. These findings are more striking when an anticoagulant containing a small volume of edetic acid (EDT A) salts is used instead of heparin or oxalic acid salts. For instance, the pH activity curve of ALA-D obtained from normal blood containing EDTA salts as an anticoagulant has extremely high activity level in more alkaline
solution. The difference between heparin and oxalic acid salts can be slightly observed also. On the other hand, I think their hypothesis that two enzymatic fractions may be present in red blood cells is very interesting. When this hypothesis is supported by investigations, the activity ratio in my ALA-D test could be useful for detecting lead effects in occupational exposure to a low concentration of lead. In addition, in my recent results, the blood samples of lead-exposed workers containing not EDT A salts, but oxalic acid salts or heparin as an anticoagulant, showed that the ALAD activity at pH 6.8 is almost completely restored by not only heating the hemolysate for five minutes at 60 C but also incubating in the presence of dithiothreitol (DTT). KATsuMARo TOMOKUNI, MD, MS Okayama, Japan Toxicity of Methyl n·Butyl Ketone
To the Editor.- In February of 1974, Dr. J. R. McDonough, Director of the Laboratory of Industrial Medicine of Tennessee Eastman Company, division of Eastman Kodak Company, reported in the ARCHIVES (29:120, 1974) our preliminary findings in regard to the effects on rats of exposure to methyl n-butyl ketone (MEK). We respectfully request that the following be published as a follow-up to our previous communication. The Health and Safety Laboratory of Eastman Kodak Company and the Department of Pathology (Neuropathology) of Albert Einstein College of Medicine have been conducting experiments on the effects of MEK in animals of various species by different routes of administration. It was Letters to the Editor
317
Archives of Environmental Health: An International Journal 1975.30:317-318.
previously reported that rats exposed by inhalation to MEK at an atmospheric level of 1,300 ppm for six hours a day, five days a week, for four months developed nerve changes characteristic of peripheral neuropathy. In our latest tests, cats and rats exposed by inhalation to this solvent at concentrations of 330 ppm and 100 ppm for six hours a day, five days a week, for approximately five months have not shown evidence of clinical neuropathy. However, minimal histological changes were observed in nerve fibers supplying interosseous muscles in biopsy specimens from cats, following approximately 4112 months of inhalation of MEK at concentrations of 330 ppm. No such changes were observed in the nerve fibers of cats so exposed to a concentration of 100 ppm. Histological examination of nerve fibers of the rats exposed to 330 ppm and 100 ppm has not been completed. Exposure at each of these levels is continuing. In cats, twice daily subcutaneous injections of 150 mg/kg of MBK, five days a week for two months; and in dogs, twice daily subcutaneous injections of 150 mg/kg of MBK, five days a week for two to four months produced neuropathy. Clinical neuropathy was not produced in guinea pigs subject to repeated applications of MBK to the skin over a period of approximately eight months. We found 2,5-hexanedione to be a major metabolite of MEK in experimental animals of several species. Peripheral neuropathy was observed in rats exposed to 2,5-hexanedione in two independent experiments: at Albert Einstein College of Medicine by subcutaneous injection, and at the
318' Arch Environ Health/Vol 30, June 1975
Health and Safety Laboratory, Eastman Kodak Company by administration in the drinking water of rats. By the subcutaneous route, an average dose of 340 mg/kg was injected daily, five days a week, for 19 weeks. The dose rate of drinking water was an average of 25 ml of a Q.5% solution; 520 mg/kg/day for approximately two months. Further studies are in progress. ROBERT L. RALEIGH, MD Director Health and Safety Laboratory Eastman Kodak Company PETER S. SPENCER, PHD HERBERT H. SCHAUMBURG, MD Department of Pathology (N europathology) Albert Einstein College of Medicine "Degreasers' Flush"
To the Editor.-The ~~Degreasers' Flush" described by R. D. Stewart ot al in the .J uly issue of the ARCHIVES (29:1, 1974) is probably an ethanol. of a chemical substance's ability to sensitize the body to ethanol. The dermal response found by Dr. Stewart is a typical sign of a reaction to ethanol known to occur in sensitized individuals. Various substances have been reported as possessing this sensitizing property; many are listed by Weissman and Koe. 1 The best known is, of course, disulfiram (Antabuse-tetramethylthiuram disulfide). The effect on rubber workers of tetramethylthiuram disulfide was first reported in 1937 by an American factory physician. 2 This was before the post war
Scandinavian publications on the ethyl derivative. The unpleasant response to ethanol experienced by workers exposed to trichlorethylene has been previously reported. In summarizing this German article in English, Pullar-Strecker4 says: Authors mention that they recently came across a workman handling trichlorethylene who become queer and then collapsed after taking a small amount of alcohoL Apparently this reaction is known to industry, for the man had been warned not to touch alcohol on taking up his employment.
The cause of the dermal response and other symptoms of a disulfiram ethanol reaction (DER) has never really been determined. While many authors incriminate the toxic effects of acetaldehyde, some" consider a quaternary ammonium compound to be responsible. It would be interesting if Dr. Stewart could measure acetaldehyde levels in his reacting patients. MILES T. MALCOLM, MD, MRCPsych, DPM Chester, England References 1. Weissman A, Koe BK: Drugs and deterrence of alcohol consumption, in Smith (cd): Topics in Biu/oUY. New York, Academic Press Inc, 1968, pp 246-258. 2. Williams EE: Effects of alcohol on workers with carbon disulfide. JAMA 109:1472-1473,
1937. 3. Von Schiller 0, Solms W; Neue Methoden in der Behandlung des chronischen Alkoholismus. Wi!' n I(/in W.~ch r 61:536-539, 1949. 4. Pullar-Strecker H; A review on the 1949/ 1950 literature of addiction. Br J Addict 48:8-87, 1951. 5. Casier H, Merlevede E: Mechanism of the disulfiram-ethanol intoxication symptoms. 111' J Addir:t 59:105, 1963.
Letters to the Editor
ISSN: 0003-9896 (Print) (Online) Journal homepage: http://www.tandfonline.com/loi/vzeh20
Toxicity of Methyl n-Butyl Ketone Robert L. Raleigh MD , Peter S. Spencer PhD & Herbert H. Schaumburg MD To cite this article: Robert L. Raleigh MD , Peter S. Spencer PhD & Herbert H. Schaumburg MD (1975) Toxicity of Methyl n-Butyl Ketone, Archives of Environmental Health: An International Journal, 30:6, 317-318, DOI: 10.1080/00039896.1975.10666709 To link to this article: http://dx.doi.org/10.1080/00039896.1975.10666709
Published online: 02 May 2013.
Submit your article to this journal
Article views: 1
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=vzeh20 Download by: [University of Florida]
Date: 06 June 2016, At: 22:09
Archives of Environmental Health: An International Journal 1975.30:317-318.
Letters to the Editor
o-Aminolevulinic Acid Dehydratase
To the Editor.- We have been very much interested in K. Tomokuni's report, "o-Aminolevulinic Acid Dehydratase," that appeared in the November issue of the ARCHIVES (29:274-281, 1974). We also undertook to find a modification of the enzyme pH optimum when inhibited by lead, and likewise used this phenomenom to carry out screening for lead intoxification. We found a very significant difference of enzyme activity between a standard and intoxicated population at pH 6.9 but not at pH 5.9. 1 However, we cannot agree on three other points: 1. We were not able to separate accurately the two populations because of the great dispersion of our values. The use of Tomokuni's test (activity ratio) did not improve our dispersion, possibly because our patients were more intoxicated. Indeed, the average blood lead value of Tomokuni's patients was lower than 40J..tg I 100 ml. From our results, we were inclined to think that two enzymatic fractions were present in red blood cells; one (A), greatly inhibited by lead, had a pH optimum of 6.8, and another (B), not very much affected by lead, had a pH optimum of 6.1. In presence of a low blood value (lower than 40J..tg/lOO ml), the activity ratio at pH 6.8 and 6 is lowered by inhibition of enzymatic fraction A only; however, when the blood lead level value was increased, the fraction E too became affected by lead and thus the activity ratio came to a normal or even increased value. In fact, these results may be found also in Tomokuni's report (Fig 8). 2. Unlike the author, we found a biphasic pH curve for the standard 2
Arch Environ Health/Vol 30, June 1975
population, thus agreeing with the original work of Nikkanen. 3. We also found that heating did not entirely restore the enzyme activity as we could not find the typical biphasic pH curve afterward. However, by addition of glutathione in the incubation mixture, we did succeed in restoring the 8-aminolevulinic acid dehydratase integrity and activity in red blood cells. B. DINGEON A. ROULLET Laboratoire de Biochemie Hopital Jules-Courmont Pierre-Benite, France G. PROST F. TOLOT Institut Universitaire du Medecine du Travail Lyon, France References 1. Dingeon B, Prost G, Tolot F: Sensibilite et valeur pratique de l' A.L.A. dehydrase pour la surveillance des sujets exposes au pJomb. J Int Meditwr Med TTa1Jaii 29:30-34, 1974. 2. Tolot F, Prost G, Dingeon B, et al: Contribution a l'etude du mecanisme de l'inhibition de l'A.L.A.D. erythrocytaire par la plomb. Soc Med Travail Ergonom Lyon 13:12, 1974.
In reply.-I am grateful to Dr. Dingeon et al for their interest in my report. The pH activity curve of erythrocyte ALA-D in normal and leadexposed subjects can be influenced by kinds of anticoagulants used. Therefore, the activity ratio in my test may also be affected by the anticoagulants. These findings are more striking when an anticoagulant containing a small volume of edetic acid (EDT A) salts is used instead of heparin or oxalic acid salts. For instance, the pH activity curve of ALA-D obtained from normal blood containing EDTA salts as an anticoagulant has extremely high activity level in more alkaline
solution. The difference between heparin and oxalic acid salts can be slightly observed also. On the other hand, I think their hypothesis that two enzymatic fractions may be present in red blood cells is very interesting. When this hypothesis is supported by investigations, the activity ratio in my ALA-D test could be useful for detecting lead effects in occupational exposure to a low concentration of lead. In addition, in my recent results, the blood samples of lead-exposed workers containing not EDT A salts, but oxalic acid salts or heparin as an anticoagulant, showed that the ALAD activity at pH 6.8 is almost completely restored by not only heating the hemolysate for five minutes at 60 C but also incubating in the presence of dithiothreitol (DTT). KATsuMARo TOMOKUNI, MD, MS Okayama, Japan Toxicity of Methyl n·Butyl Ketone
To the Editor.- In February of 1974, Dr. J. R. McDonough, Director of the Laboratory of Industrial Medicine of Tennessee Eastman Company, division of Eastman Kodak Company, reported in the ARCHIVES (29:120, 1974) our preliminary findings in regard to the effects on rats of exposure to methyl n-butyl ketone (MEK). We respectfully request that the following be published as a follow-up to our previous communication. The Health and Safety Laboratory of Eastman Kodak Company and the Department of Pathology (Neuropathology) of Albert Einstein College of Medicine have been conducting experiments on the effects of MEK in animals of various species by different routes of administration. It was Letters to the Editor
317
Archives of Environmental Health: An International Journal 1975.30:317-318.
previously reported that rats exposed by inhalation to MEK at an atmospheric level of 1,300 ppm for six hours a day, five days a week, for four months developed nerve changes characteristic of peripheral neuropathy. In our latest tests, cats and rats exposed by inhalation to this solvent at concentrations of 330 ppm and 100 ppm for six hours a day, five days a week, for approximately five months have not shown evidence of clinical neuropathy. However, minimal histological changes were observed in nerve fibers supplying interosseous muscles in biopsy specimens from cats, following approximately 4112 months of inhalation of MEK at concentrations of 330 ppm. No such changes were observed in the nerve fibers of cats so exposed to a concentration of 100 ppm. Histological examination of nerve fibers of the rats exposed to 330 ppm and 100 ppm has not been completed. Exposure at each of these levels is continuing. In cats, twice daily subcutaneous injections of 150 mg/kg of MBK, five days a week for two months; and in dogs, twice daily subcutaneous injections of 150 mg/kg of MBK, five days a week for two to four months produced neuropathy. Clinical neuropathy was not produced in guinea pigs subject to repeated applications of MBK to the skin over a period of approximately eight months. We found 2,5-hexanedione to be a major metabolite of MEK in experimental animals of several species. Peripheral neuropathy was observed in rats exposed to 2,5-hexanedione in two independent experiments: at Albert Einstein College of Medicine by subcutaneous injection, and at the
318' Arch Environ Health/Vol 30, June 1975
Health and Safety Laboratory, Eastman Kodak Company by administration in the drinking water of rats. By the subcutaneous route, an average dose of 340 mg/kg was injected daily, five days a week, for 19 weeks. The dose rate of drinking water was an average of 25 ml of a Q.5% solution; 520 mg/kg/day for approximately two months. Further studies are in progress. ROBERT L. RALEIGH, MD Director Health and Safety Laboratory Eastman Kodak Company PETER S. SPENCER, PHD HERBERT H. SCHAUMBURG, MD Department of Pathology (N europathology) Albert Einstein College of Medicine "Degreasers' Flush"
To the Editor.-The ~~Degreasers' Flush" described by R. D. Stewart ot al in the .J uly issue of the ARCHIVES (29:1, 1974) is probably an ethanol. of a chemical substance's ability to sensitize the body to ethanol. The dermal response found by Dr. Stewart is a typical sign of a reaction to ethanol known to occur in sensitized individuals. Various substances have been reported as possessing this sensitizing property; many are listed by Weissman and Koe. 1 The best known is, of course, disulfiram (Antabuse-tetramethylthiuram disulfide). The effect on rubber workers of tetramethylthiuram disulfide was first reported in 1937 by an American factory physician. 2 This was before the post war
Scandinavian publications on the ethyl derivative. The unpleasant response to ethanol experienced by workers exposed to trichlorethylene has been previously reported. In summarizing this German article in English, Pullar-Strecker4 says: Authors mention that they recently came across a workman handling trichlorethylene who become queer and then collapsed after taking a small amount of alcohoL Apparently this reaction is known to industry, for the man had been warned not to touch alcohol on taking up his employment.
The cause of the dermal response and other symptoms of a disulfiram ethanol reaction (DER) has never really been determined. While many authors incriminate the toxic effects of acetaldehyde, some" consider a quaternary ammonium compound to be responsible. It would be interesting if Dr. Stewart could measure acetaldehyde levels in his reacting patients. MILES T. MALCOLM, MD, MRCPsych, DPM Chester, England References 1. Weissman A, Koe BK: Drugs and deterrence of alcohol consumption, in Smith (cd): Topics in Biu/oUY. New York, Academic Press Inc, 1968, pp 246-258. 2. Williams EE: Effects of alcohol on workers with carbon disulfide. JAMA 109:1472-1473,
1937. 3. Von Schiller 0, Solms W; Neue Methoden in der Behandlung des chronischen Alkoholismus. Wi!' n I(/in W.~ch r 61:536-539, 1949. 4. Pullar-Strecker H; A review on the 1949/ 1950 literature of addiction. Br J Addict 48:8-87, 1951. 5. Casier H, Merlevede E: Mechanism of the disulfiram-ethanol intoxication symptoms. 111' J Addir:t 59:105, 1963.
Letters to the Editor
