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. .\4 S T 0 8 52592 MEDICAL RESEARCH COUNCIL INDUSTRIAL HEALTH RESEARCH BOARD REPORT NO. 80 (Revised Edition, 1952) TOXICITY OF INDUSTRIAL ORGANIC SOLVENTS (Revised in consultation with the Toxicology Committee) By ETHEL BROWNING LONDON: HER MAJESTY'S STATIONERY OFFICE 1953 ST0852593 Crown Copyright Reserved PUBLISHED BY HER MAJESTY'S STATIONERY OFFICE To be purchased from York House, Kingsway, London, w.c.2 423 Oxford Street, London, w.l P.O. BOX 569, LONDON, R3.1 13a Castle Street, Edinburgh, 2 1 St Andrew's Crescent, Cardiff 39 King Street, Manchester, 2 Tower Lane, Bristol, 1 2 Edmund Street, Birmingham, 3 80 Chichester Street, Belfast or from any Bookseller 1953 Price 1 15d. Od. net ST 0852594 MEDICAL RESEARCH COUNCIL The Right Hon. the Earl of Limerick, K.C.B., D.S.O. (Chairman) Sir Geoffrey Vickers, V.C. (!Treasurer) Group Captain C. A. B. Wilcock, O.B.E., A.F.C., M.P. Sir Percival Hartley, C.B.E., M.C., D.Sc., F.R.S. Professor J. McMichael, M.D., F.R.C.P. Professor W. E. Le Gros Clark, M.D., D.Sc., F.R.C.S., F.R.S. Professor F. G. Young, D.Sc., F.R.S. Professor G. L. Brown, C.B.E., M.Sc., M.B., F.R.S. Professor Sir James Learmonth, K.C.V.O., C.B.E., Ch.M., F.R.C.S. Professor G. R. Cameron, D.Sc., M.B., F.R.C.P., F.R.S. Professor Aubrey J. Lewis, M.D., F.R.C.P. Sir James Spbnce, M.C., D.Sc., M.D., F.R.C.P. Sir Harold Himsworth, K.C.B., M.D., F.R.C.P. (Secretary) A. Landsborough Thomson, C.B., O.B.E., D.Sc. (Second Secretary) 111 S T 0 8 5 2595 TOXICOLOGY COMMITTEE Professor E. J. King, D.Sc. (Chairman) A. J. Amor, C.B.E., M.Sc., M.D. Professor J. H. Gaddum, Sc.D., M.R.C.S., F.R.S. R. A. E. Galley, Ph.D., F.R.I.C. Donald Hunter, M.D., F.R.C.P. E. R. A. Merewether, C.B.E., M.D., F.R.C.P. W. D. M. Paton, M.A., B.M. Sir Rudolph A. Peters, M.C., M.D., F.R.S. J. Davidson Pratt, C.B.E., B.Sc. Professor J. R. Squire, M.D., F.R.C.P. J. Walker, D.Sc. Professor R. T. Williams, D.Sc. J. M. Barnes, M.B. {Secretary) ST 0852596 PREFACE TO THE SECOND EDITION In response to a request from the Home Office in 1935, the Council undertook to investigate the possibility that various volatile substances, used industrially as solvents and often in enormous quantities, might injure the health of the workers handling them. A special Committee on the Toxicity of Industrial Solvents, under the chairmanship of Sir Joseph Barcroft, was appointed to advise on this matter. At the time when the Committee was formed, there was, to quote the Preface to the First Edition of this Report, " a clear need for research into the possible effect of substances that seem open to suspicion, either through having a chemical constitution closely allied to that of compounds already proved to be dangerous or through complaints of ill-health among those who constantly use them. As a first step, however, it was plainly desirable to take stock of existing knowledge of the subject." The Committee therefore asked Dr. Ethel Browning to compile a summary of the available information on such solvents as were then in general use. Issued in 1937 as No. 80 in the Council's Series of Industrial Health Research Board Reports, it was almost the only publication of its kind in existence and, although not exhaustive, was for practical purposes sufficiently detailed to show the extent of the problem and to indicate the most suitable points of attack. Requests for copies came from all parts of the world, and the demand continued for some years after the edition had gone out of print. Consequently, in 1946 it was decided that the Report should be re-issued, having first been revised and also enlarged to include those solvents which had come into use since the first edition was prepared. Fortunately, Dr. Browning was willing to undertake the formidable task of revision, and die Council would like to take the opportunity of expressing their thanks to her for the care with which she has completed it The original Committee had not met during the War, and the responsibility for supervising the new edition, on which Dr. Browning was already working, fell to the Toxicology Committee, appointed in 1947 under the chairmanship of Professor G. R. Cameron. In discussing what additions or changes might be made, the Committee decided that the new edition, like the old, should be limited to substances used primarily as solvents, and that the Report should retain its original form as a compendium of information rather than attempt a critical review of the published literature. In recent years a number of new books dealing with industrial toxicology have been published. Most of them cover a wider field than this Report, but do not deal so comprehensively with the industrial solvents. This new edition, with its extensive bibliography covering the years up to 1948, should be a valuable source of references for medical officers and others responsible for the health of workers concerned with the manufacture, transport and use of organic solvents. Medical Rbsbarch Council, 38 Old Queen Street, London, S.W.l. December 2, 1952. ST 0852591 CONTENTS INTRODUCTION CHAPTER I: Hydrocarbons 1. Benzene.......................... 2. Toluene.......................... 3. Xylene.......................... 4. Ethylbenzene 5. Cumene.......................... 6. Tetrahydronaphthalene .. 7. Decahydronaphthalene .. 8. Methylated naphthalenes 9. Coal tar solvent naphtha PAGE 3 46 55 63 64 65 68 69 70 10. Petroleum spirit .. 11. Benzine .. 12. White spirit 13. eycfoHexane 14. Methylcyc/ohexane 15. Turpentine 16. Dipentene 17. cyc/oPentadiene .. 18. Dicyc/opentadiene PAGE 74 79 93 94 98 100 106 106 107 CHAPTER II: Chlorinated Hydrocarbons 1. Methylene dichloride 2. Chloroform 3. Carbon tetrachloride 4. jym.-Dichloroethane 5. Tetrachloroethane 6. Pentachloroethane 7. Dichloroethylene 122 8. Trichloroethylene 124 9. Perchloroethylene 128 10. Propylene dichloride 149 11. Amyl chloride 154 12. Amylene dichloride 163 13. Monochlorobenzene 165 14. o-Dichlorobenzene 169 182 185 186 187 187 189 CHAPTER HI: Alcohols 1. Methyl alcohol 2. Wood spirit 3. Ethyl alcohol 4. /j-Propyl alcohol 5. uoPropyl alcohol 6. n-Butyl alcohol 7. sec.-Butyl alcohol 8. iroButyl alcohol 9. fert.-Butyl alcohol 10. Amyl alcohol 202 11. Methylisobutylcarbinol 236 216 12. cyc/oHexanol 236 217 13. Methylcyc/ohexanol 239 222 14. Allyl alcohol 241 224 15. Benzyl alcohol 242 227 16. Diacetone alcohol 244 230 17. Ethylene chlorohydrin 246 231 18. Monochlorohydrin 250 231 19. Dichlorohydrin .. 251 232 CHAPTER IV: Ethers 1. Ethyl ether 2. j9j3'-Dichloroethyl ether.. 3. troPropyl ether 4. Propylene oxide 261 266 267 268 5. Dioxan 6. Methylal 7. Acetal 8. Paraldehyde 268 274 , , 274 276 CHAPTER V: Esters 1. Methyl formate .. 2. Ethyl formate 3. n-Butyl formate 4. Amyl formate 5. Benzyl formate 6. Methyl acetate 281 281 284 285 286 286 vii 7. Ethyl acetate 8. n-Propyl acetate .. 9. iroPropyl acetate 10. n-Butyl acetate .. 11. rec.-Butyl acetate 12. iroButyl acetate .. 289 293 294 295 298 298 CHAPTER V: Esters--continued 13. Amyl acetate 14. sec.-Hexyl acetate 15. cyc/oHexyl acetate 16. Methylcyc/ohexyl acetate 17. Butoxyl .. .. 18. Benzyl acetate 19. n-Butyl propionate 20. Amyl propionate 21. n-Butyl butyrate S T 08 52598 CONTENTS PAOB 299 306 306 308 308 309 311 311 312 PAOB 22. Methyl benzoate 312 23. Ethyl benzoate .. 313 24. Ethyl lactate 313 25. Butyl lactate 314 26. Amyl lactate 314 27. Ethyl hydroxyirobutyrate 315 28. Diethyl carbonate 315 29. Dialkyl carbonates 316 30. Diethyl oxalate .. 316 CHAPTER VI: Ketones 1. Acetone.......................... 2. Methyl acetone 3. Acetone oils 4. Methyl ethyl ketone 5. Methyl uobutyl ketone .. 320 327 328 328 331 6. Mesityl oxide 331 7. cyc/oHexanone .. 333 8. Methylcyc/ohexanone .. 334 9. Isophorone 335 CHAPTER VII: Glycols and Their Derivatives 1. Ethylene glycol .. 2. Ethylene glycol mono methyl ether 3. Ethylene glycol monoethyl ether .......................... 4. Ethylene glycol monoethyl ether monoacetate 5. Ethylene glycol diethyl ether 6. Ethylene glycol mono-n- butyl ether 340 345 348 351 352 353 7. Ethylene glycol mono acetate 8. Ethylene glycol diacetate 9. Diethylene glycol 10. Diethylene glycol mono ethyl ether 11. Diethylene glycol mono-n- butyl ether 12. Diethylene glycol mono acetate .......................... 13. Dipropylene glycol 355 356 356 358 360 360 361 CHAPTER VIII: Amines and Coal Tar Bases 1. cyc/oHexylamine 2. Dicyc/ohexylamine 3. Ethanolamines .. 365 4. Pyridine.......................... 365 5. Picoline.......................... 366 367 371 CHAPTER IX: Nitro-compounds 1. Nitromethane 2. Nitropropanes 373 373 3. Nitrobutanes 4. Nitrobenzene 375 376 CHAPTER X: Miscellaneous Compounds 1. Carbon disulphide 2. Acetic acid 3. Acetic anhydride 4. Cresols.......................... 380 392 392 393 5. Dimethyl sulphate 6. Silicones and silane inter mediates 395 397 viii ST0852599 OE TOXICITY OF INDUSTRIAL ORGANIC SOLVENTS 12 13 13 INTRODUCTION 14 14 15 Thb following Report summarizes the existing available information about the effects on animals and man of the various solvents used in industry. The 15 16 16 literature from which the Report has been compiled is widely scattered in various books and scientific periodicals, and although much trouble has gone towards its composition, completeness of the references cannot be vouched for. More over, new work is being published at frequent intervals, and the bibliography must rapidly cease to be up to date. The main object in the collection tuid publication ofthese data is the avoidance 31 of poisoning from the use of these solvents, some of which are used on a vast 33 scale in industry. To suggest the ease with which intoxication could occur, and 34 to emphasize the importance of finding appropriate measures for its prevention, 35 the following figures are quoted from statistical records. The Annual Abstracts of Statistics shows that in the United Kingdom in 1950 the consumption of ethyl alcohol as 68 O.P. spirit was 36-8 million gallons; that of methyl alcohol was 72,000 tons. The Ministry of Fuel and Power's Statistical Digest records that, in 1951, the total production of different fractions of benzol, excluding 55 56 >6 motor and aviation spirits, was 15-2 million gallons, of which 9-2 million gallons were the `pure' solvent; the total production, of toluol was, .8-7 million gallons, of which 4-9 million gallons were 'pure'. Similar figures for other solvents are not readily available, but these f$w are surely impressive enough to indicate 58 the need for investigation. . It is often difficult to determine, phoyld illness occur in a worker or group 50 of workers, whether or not this is due to the toxic action of chemical agents, and, if so, which particular agent is responsible. This difficulty is often in 50 creased by the slow development of symptoms which may occur after pro 51 longed or intermittent exposure to low concentrations. The direct method of determining the possible and relative toxicity of a substance to man is by experi ments with that substance on man himself, under conditions as nearly as possible parallel to those under which a worker is exposed. Experiments on man, 57 however, are not justified, and the indirect method using experiments on n animals in the laboratory must therefore be adopted. Owing to the expense and difficulties of housing large animals, preliminary investigations are nearly always made on large numbers of small animals, although no general rules can be laid down which relate the sensitivities to poisons of small rodents and of man. There are many poisons which '5 6 produce completely different effects in different species of animals, but it is very exceptional for a substance which is toxic to various species of rodents to be innocuous to man, and vice, versa. It is to be anticipated that there will exist qualitative and quantitative differences in response to any poison between man 5 and the lower animals, just as they are known to exist between different species of lower animals themselves. Nevertheless, there can be no.'doubt that 7 experiments on small animals are of value in giving an indication of the type of .toxic action as well as the relative toxicity of the substance under investig ation. Thus the fact that butyl cellosojve (ethylene glycol mono-n-butyl ether) is five times as toxic to mice as ethylene glycol at least gives a warning that the former compound may have greater potential dangers for man than the latter. 1B 2 INTRODUCTION ST 0852600 In attempting to'relate experimentally determined effects on small animals to probable or suspected effects on man, certain factors have to betoken into consideration. The first of these is the size of the animal. As regards the systemic actions of poisons, depending as they do mainly upon the concentration of the poison which occurs in the blood and tissues, it is generally true that a given amount of poison will produce greater effects in a small than in a large animal. No entirely satisfactory method is known for correlating accurately dosage and body weight, but a useful approximation is obtained by the usual method of stating the dosage as per kilogramme of body weight; however, it will be readily understood that if the minimum lethal dose of a solvent for a rat weighing 0*2 kg. is 1 ml., it does not fallow that the corresponding dose for a man weigh ing 70 kg. will be 350 ml. Even such an approximate relation does not hold good for the local effects of poisons, before they are absorbed. For example, a given concentration of a volatile solvent in air may produce local effects on the lungs, the intensity of which hears no relation to the weight of the animal. It is now known that individual variation is found in response to all drugs and in all populations of aninials. Measurements of toxic effects on animals usually express the average or median toxic dose or concentration, i.e., the quantity that produces the observed effect in half the population studied. Unfortunately the range over which individual variation is scattered differs widely in the case of different drugs. Some individuals will be less, some more, sensitive to a toxic action than the majority. This is of especial importance in human beings when it is necessary to a$oid producing toxic effects on any particular individual. There is also the important question of exceptional sensitivity or idiosyncrasy to poisons. It has been found that certain drugs, which have been widely used for many years without apparent danger, can nevertheless produce very serious toxic effects in certain exceptional individuals. It is possible that cases of personal idiosyncrasy would occur with all drugs though they may be only recognized with those that are widely used. Similar cases of idiosyncrasy will no doubt arise from the use of substances in industry, and slight signs of intoxi cation occurring with any new solvent should consequently be regarded seriously, even if other individuals have sustained greater exposuie without any apparent injury. Consideration of the available literature on the actions of solvents has shown that many experiments have been made with little direct relation to the condi tions that may possibly occur in industry. For example, the effect of the sub cutaneous injection of a large dose of substance may be entirely different from, and have little bearing upon, the effects which may be produced by prolonged inhalation of small quantities. The Committee had some hesitation in including an account of such experiments, but for some substances they were the only ones available. The results have therefore been included partly for completeness and partly for such evidence as they afford. One other difficulty should be mentioned. The number of chemical compounds used as solvents is large, but unfortunately the number of proprietary names is much larger, and a toxic substance may be concealed under such a name. It has not been possible to give a glossary of proprietary names, and although many are mentioned in the text and appear in the index, this report will, in general, only be of service in judging the safety of a solvent in those cases where the chemical composition of the solvent is known. ST085260 I CHAPTER I HYDROCARBONS 1. Benzene (Benzol) CgH,, i.e. PROPERTIES Benzene, or benzol, a hydrocarbon of the aromatic series, and a coal tar product, is to be carefully distinguished from benzine, a mixture of varying and uncertain proportions of hydrocarbons, chiefly hexane and heptane, which is a distillate of petroleum. A certain amount of confusion has arisen from time to time in reports of cases of toxic injury due to benzine, e.g. the case of fatal aplastic anaemia in a cellulose sprayer in 1934 (Special Article, Lancet), in which the toxic agent was referred to as benzine, when benzol was meant Simonin (1934) points out that the distinction between benzene and benzine is not merely one of theoretical importance. He quotes as an instance the occurrence of a severe collective intoxication in a boot factory in 1932, involving forty-four workers, eight of whom died, caused by the misinterpretation of an order for benzine, benzene being delivered instead (Merklen and Israel, 1934). The effects of chronic poisoning by these two substances, especially with regard to the blood picture, are clearly distinguishable, while the acute narcotic effect of benzine on animals has been shown to be less than half that of tenzol (Bamesreiter, 1932). It has been-suggested by some French workers, notably Duvoir (1922), that benzinp should be called petrol essence and that the word benzinism should be replaced by petrolism. Benzol is graded commercially as crude or refined, according to the percentage which distils below 100 C. Pure benzol should be the pure substance strictly designated as benzene (C,Hg), B.P. 80 C., Sp. Gr. 0-884 at 15 C., M.P. 5 C., soluble in water to the extent of 0-082 g. per 100 ml. at 22 C. It is an excellent solvent for rubber, gums, resins, and fats of all kinds. Commercial benzol is practically never pure; it contains traces of xylene, toluene, phenol, thiophene, carbon disulphide, acetonitrile, and, according to Ellis and Meigs (1921), probably pyridine, and many other substances. (For method of analysis see Gooderham, 1935). A process for removing thiophene by the action of acidified hypochlorite solution with only a small attendant loss of benzene has been described by Ardagh and Bowman (1935). There are three usual commercial types. (a) Commercial crystallizable. 100 per cent benzene, B.R. 80-81 C., Sp. Gr. 0-879 at 20 C. This variety appears to produce very severe toxic effects, many cases of poisoning having been reported from its use. A typical example is the series recorded by Heim de Balsac and Agasse-Laforit (1933), of which eight cases were fatal, and by Merklen and Israel (1934) who describe their cases as "haemorrhagic aleukaemia'' from the use of crystallizable benzene. These investigators urge that the use of crystallizable benzene should be prohibited. (b) Commercial 90 per jent benzol. 90 per cent by volume distils below 100 C. It contains 13-15 per cent toluene, 2-3 per cent xylene, and sometimes, traces of olefins, paraffins, sulphuretted hydrogen, and other bodies. 3 S T 08 52602 4 TOXICITY OF INDUSTRIAL ORGANIC SOLVENTS (c) 50 per cent benzol. 50 per cent of constituents distil below 100 C. and 90 per cent below 120 C.--a highly mixed product. The usual commercial 90 per cent benzol is a colourless, mobile, refractive liquid, with a not unpleasant odoyr. It burns with a luminous but smoky flame; it is extremely volatile, especially if slightly heated. Its relative time of volatiliza tion compared with that of ethyl ether is 3 :1 (I. G. Farbenindustrie, 1930). It is a good solvent for a number of cellulose esters and ethers, especially ethyl cellulose, for most oils, ester gums, benzyl abietate, copal ester, coumarone, benzyl resin, and many other resins. It does not dissolve cellulose acetate or nitrate, copal, or shellac. MANUFACTURE Benzol is given off during the distillation of coal in a closed vessel, part remaining in the tar and part occurring in the gas. The chief means of recovery is by "stripping" the benzol from the coke oven gas, a method which has of recent years largely superseded distillation of the tar from gas works and coke ovens. During 1934, of the total production of crude benzol at coke'ovens, gas works, low temperature carbonization works and tar distilleries, about %0 per cent was obtained from the gas, and 20 per cent from distillation of tar (Secretary for Mines, 1934). A full description of the distillation method was given by Lehmann (1910) and of the "stripping" process in the Final Report on Benzol of the National Safety Council (1926). r USES AND APPLICATIONS The use of benzol received a great impetus during the 1914-18 war, and since that time its extension has been wide and rapid. While in 1922,68 million gallons were used in..America, by 1928 the figure had reached 115 million gallons (McCord, 1929). During the 1939-45 war, benzol was again increasingly used owing to the scarcity of other solvents. Benzol may be regarded as having two more or less distinct fields of applica tion in industrial processes: (a) Where it is handled in large quantities in closed mechanical systems. (1) The distillation of coal and coal tar in the production of benzol. (2) The blending of motor fuels. (3) The chemical industries, including oil extraction, the manufacture of dyes and dye intermediates, paints, varnishes and stains, and paint and varnish removers. (b) Where it is used as a solvent or diluent. (1) The rubber industry, in solutions for rubber cement in the manufacture of straw hats, cardboard boxes, waterproof goods, shoes, cameras, and the sealing of cans; in the manufacture of rubber tyres, the metal case on which the tyre is built being usually coated with rubber cement in which considerable quantities of benzol are used. (2) The manufacture of artificial leather; textiles are spread with a coating of a viscous liquid consisting essentially of a solution of nitrocellulose, benzol in amounts up to 60 per cent being added as a diluent. (3) In the dyeing and cleaning industry for degreasing, mordanting and removing grime from clothing and other articles; also generally for cleaning HYDROCARBON? ST0852603 5 purposes in workshops. In many dyeing and cleaning establishments, however other solvents have largely replaced benzol. (4) In the paint and varnish industry as a diluent for lacquers, a constituent of quick-drying paints, in bronzing and gilding pottery, in varnishing reservoir vats, ships, motor cars, etc., and in floor and woodwork stains and floor waxes. (5) In the aviation industry as a constituent of the dope solution, to the extent of about 20 per cent. (6) In the linoleum and celluloid industries. (7) In artificial manure and glue manufacture. (8) In electrical fitting and accumulator works: (9) In chemical laboratories as a solvent. (10) In the alkaloid industry for the extraction of atropine, hyoscine, codeine, etc. (11) In the photogravure printing process. BENZOL VAPOUR Concentration in Air of Factories The actual concentrations of benzol in air to which workers have been exposed have been found to vary greatly. The earliest figures, given by Lehmann (1910), ranged from 25 to 106 p.p.m. of the air in benzol washing and distillation plants. Legge (1919-20) found the quantities in the atmosphere of a balloon fabric spreading room to range from 210 to 1,050 p.p.m. in different parts of the room, and in a pneumatic tyre manufacturing room from 800 p.p.m. with an exhaust fan in operation to 2,800 p.p.m. with the windows open. In a Milan raincoat factory, where three fatal cases occurred, Pugliese (1922) found 1,000 p.p.m.; in the printing works referred to by Saita and Domp6 (1947) they found the con centration of benzol varied from 188 to 908 p.p.m. In the National Safety Council Report of 1926, examination of the air of 18 different workrooms, representative of the various processes in which benzol is used in rubber, artificial leather, wire insulating, dry cleaning, and sanitary can manufacture, revealed a very wide variation of its benzol content, 0 to 4,140 p.p.m., the latter in a dry cleaning process .during the summer when ho other solvent than benzol was used. It should be noted that the method used for the estimation of benzol in the survey failed to distinguish between benzol and other solvent vapours such as alcohol, methyl acetone, etc., but the figures for solvent vapours were all computed in terms of benzol. These studies brought out the importance of local exhaust ventilation in reducing the atmospheric content of benzol. The Report concludes that "rooms in which benzol is evaporated into the air without local exhaust ventilation will in most cases show high concentration of the fumes in the air of the rooms. With ideal local exhaust ventilation on the other hand even large quantities of benzol can be used without heavy atmospheric con tamination". After the occurrence of two fatal cases in Edinburgh in 1918, it was found that without ventilation the concentration of benzol in the room reached 16,800 p.p.m., and with 30 changes of air per hour was reduced to 550 p.p.m. Risk of Explosions The vapour of benzol, which has a flash point (F1.P.) of 10 F. (--12 C.), forms an explosive mixture with air in proportions from 5 to 8 per cent. Escape of the vapour or liquid may occur through faulty design of the plant or faulty ventilation, and ignition may be produced by the presence of naked lights, the , ST085260U 6 TOXICITY OF INDUSTRIAL OROANIC SOLVENTS production of sparks by the use of tools or appliances, such as electric fans and motors, and by iron-shod boots on stone floors, trolley wheels, etc. Precautions to avoid these dangers are described in the Chemical Works Regulations Reg. 4 b (1922), also in Safety Circulars Nos. 29,43, and 51 of the Association of British Chemical Manufacturers (1929, 1931) and in Quarterly Safety Summary (1930, 1931, 1932). Concentration in relation to Toxic Effects The maximum allowable concentration above which toxic symptoms may be expected to occur was estimated by the National Safety Council (1926) as 100 p.p.m., and this figure was again taken by the American Standards Associa tion in 1941. It has been suggested by Greenburg and Moskowitz (1945) with regard to the war-time use of benzene as a solvent for synthetic rubber that 50 p.p.m. is a safer desirable maximum, since, they state, "death may occur with exposures to only 25 p.p.m., and at least one such case has been observed". The concentration which produces fatal results in a very short time appears to be 19,000 to 20,000 p.p.m. In a report made by McNair to the Home Office* on a fatal case of benzol poisoning occurring in 1930, he states that to form a mixture which would be fatal would required volumes in 100 of air, representing 7 oz. of benzol per 100. cubic feet. He also states that 1 volume in 100 of air can be recognized by smell, while Safety Circular No. 51 states that more than 1 mg. per L (0-029 per cent) is necessary before the smell is distinctly perceived. The concentrations of benzol and their effects and time of exposure (Table 1) are taken from the table drawn up by Sayers and Dallavalle (1935). TABLE 1 Effects from different concentrations of benzol vapour Concentration in air (p.p.m.) Effects 19,000 3,000 3,130-4,700 1,570-3,130 100 Fatal in very short time Dangerous with exposures of I to 1 hour Maximum concentration for exposures of I to 1 hour Slight symptoms with exposures of several hours Maximum concentration allowable More recently (1949) the standard limit suggested has been lowered to 35 p.p.m. (Congress of American Hygienists). Estimation in Air Numerous methods for the determination of the amount of benzol in air have been described. The majority of the earlier ones are reviewed by Tausz (1924) and include the nitration method, introduced by Harbeck and Lunge (1898), used by Lehmann (1910) and adapted by Smyth (1931) for concentra tions as low as 30 p.p.m., and the method of activated charcoal considered superior to all others by Tausz himself, and used by the National Safety Council in 1926. More recent methods include those of Ficklen and Cook (1933) and of * References to cases reported to the Home Office are taken from confidential records, to which the author had access, of the Factory Department, Home Office, later transferred to the Ministry of Labour and National Service. HYDROCARBONS S T 0852605 7 Cook and Ficklen (1935); the former, the pernitric method, has since been found not applicable because of the interference of toluene; the latter, the oxidation method with peroxide in presence of iron salts, is described below. A simple test, involving the absorption of the benzene vapour in formaldehyde-sulphuric acid, has been devised by the Department of Scientific and Industrial Research (1939). (1) The nitration method. The method described by Smyth (1929) consisted in catching the benzene vapours in a mixture of sulphuric and nitric adds, neutralizing, separating the dinitro benzene formed in the adds by steam, distillation from a .buffered solution when toluene was present in the air, and then titrating the nitro compound with titanous chloride. This method was shown to be 93-1 per cent correct for pure benzene vapour at 11,000 p.p.m., and 99*2 per cent correct at 200 p.pjn. In order to adapt the method for concentrations as low as 30 p.p.m., Smyth (1931) took larger samples of air for analysis than formerly, so as to obtain enough dinitrobenzene for titration. He found the method 99-100 per cent correct with pure benzene vapours at concentrations of from 30 to 383 p.p.m., even in the presence of various aliphatic alcohols and acetates. In the presence ofnotmore than three times as much toluene as benzene, the accuracy was over 83 per cent down to a concentration of 30 p.pjn. of benzene. It is pointed out by Cook and Ficklen (1933) that the method requires transportation of air samples to a central laboratory for determination of the' amounts of benzene present. A modification of it is, however, described by Schrenk, Pearce and Yant (1933) by which small samples of air can be used and as little as 0-001 mg. of benzene can be determined, and further modifications by Dolin (1943), and by Duvoir and Fabre (1945). The latter claimed that a variation in the technique serves to distinguish benzene from toluene with an error of less than 10 per cent. The titrating reagent used is methyl ethyl ketone in a 40 per cent solution which gives a violet colour not given by the higher homologues of benzene. Dolin's technique has been still further elaborated by Milton (1943), making the reaction still more specific for benzene in the presence of xylene and toluene. (2) The activated charcoal method (National Safety Council 1926). Special precautions to render the sampled air moisture-free before passing it into the charcoal absorption tube con sisted in the provision of a first tube filled with soda-lime for the absorption of acid vapours and a second with calcium chloride for absorption of water vapour. The charcoal tube itself contained approximately 7 g. of 8-14 mesh activated charcoal. The charcoal was also dried overnight in a constant temperature oven at 103 C. The charcoal tubes were equilibrated before use by the passage ofcompressed air, flowing at the rate ofapproximately 61. per minute, through a chain composed of the following elements: cotton-wool tube, soda-lime tube, calcium chloride tube, glass tubing manifold and six charcoal tubes. A sample of the air of the work room, usually 201. in amount, was aspirated through the prepared charcoal, and the increase in weight of the charcoal was taken to represent the approximate amount of solvent vapours in the atmosphere sampled. Where benzol is the only solvent used, this increase in weight represents that due to benzol vapours only, but since the charcoal absorbs other solvent vapours also the method is not specific for benzol. (3) The oxidation method with hydrogen peroxide in presence of iron salts (Cook and Ficklen, 1935). In this method the air to be sampled is streamed at the rate of 21. per minute on to the surface of glass beads in a U-tube packed round with solid carbon dioxide; the tube is later removed and immersed in hot water when the collected benzene is volatilized, passed through a bubbler unit containing 25 ml. of water for the removal of the more watersoluble vapours, and thence into a trap immersed in a solid carbon dioxide and acetone cooling bath, the benzene and a small portion of less water-miscible solvents being frozen out in the trap. For the estimation of the benzene, 5 ml. of 0-5 per cent ferrous sulphate followed by 2 ml. of 1 per cent hydrogen peroxide is directed down the inlet tube of the trap, the contents of which are then shaken and transferred to a test-tube. If benzene is present in an amount of 0-005 ml., a characteristic brown coloration is produced in 2 to 5 minutes; if in amounts of 0-010 mL to 0-030 ml., a black amorphous precipitate also appears. Upon the addition of 1 ml. of 2N nitric acid the black amorphous precipitate will dissolve and the solution may then be diluted with water and compared with standards in a colorimeter. A number of other solvents, having boiling points relatively near that of benzene (toluene, xylene, methanol, ethyl acetate, trichloroethylene, carbon tetrachloride, cellosolve, acetone) were tested, and did not give the reaction when no benzene was present Carbon disulphide gave a greenish amorphous sulphur precipitate, which, if benzene is being simultaneously estimated, must be filtered from the solution after the addition of nitric add, the benzene being then estimated from the coloration of the filtrate. ST 0852606 8 TOXICITY OF INDUSTRIAL ORGANIC SOLVBNTS Ficklen and Cook (1933) observe >ht, owing to the complicated nature of the reaction, the method is only approximately quantitative, but sufficiently so to permit estimation of the concentration of benzene in air within the limits required in an industrial hygiene investigation. (4) The formaldehyde-sulphuric acid test (Department of Scientific and Industrial Research, 1939). A sample of the air to be tested is drawn through a tube containing the reagent --concentrated sulphuric add containing a trace of formaldehyde--by means of a hand pump of definite capacity. From the number of strokes of the pump required to produce the standard orange-brown colour, the concentration of benzene vapour present is obtained by reference to a given table. The colour with the formaldehyde-sulphuric reagent is also given by the vapours of toluene and of coal-tar naphthas. Crude benzols, which may contain compounds such as thiophene and unsaturated hydrocarbons, might give a slightly different, yellow or red shade of colour, but the quantities of such substances usually present in commercial grades of benzenes should not interfere with the comparision of the depth of colour of the reagent and standard. (5) The interferometer. Data on the use and value of this instrument are supplied by the United States Bureau of Standards, and by the catalogue of the Arthur H. Thomas Co. It is stated (Answer to a letter, S. Arner. med. Ass., 1935) that the instrument is of restricted value under many industrial circumstances, owing to thq fact that benzene, benzine, naphtha, toluene, and xylene are rarely used as single entities, but as mixtures with various esters, acetates alcohols and glycols. This Act precludes any ready standardization of the apparatus to meet the diversity of vapour conditions likely to be encountered. ESTIMATION IN BLOOD AND IN TISSUES The chief methods of estimating the amount of benzol in the blood and tissues of animals or human beings subjected to exposure to benzol vapour have been described by Peronnet (1934). (1) Method ofLazarew, Brussilovtskaja and Lawrow (1931a, b). The benzol is extracted by a current of air flowing over a sample of blood, and the amount present in the air measured by the method described,by Matveev, Pronin and Frost (1930), which consists in combustion of the air in an electric oven and titration of the CO, formed by conductivity. (2) Method of Gadaskin (1923). The oxalated blood is nitrated by means of sulphuric and nitric add and the merodinitrobenzene formed is reduced to me/ophenylenediamine, which by oxidation with dimethylparaphenylenediamine gives a violet colour. (3) Method of Peronnet (1934). The benzol extracted from a slightly heated sample of blood is nitrated to me/odinitrobenzeDe, which is then diluted with distilled water, neutralized and rendered alkaline. Alcohol is added, followed by a solution of laevulose in 70 per cent alcohol and soda. The violet colour formed is compared in a colorimeter with that produced by a benzene solution of known concentration. This method is not applicable in the presence of xylene or toluene. A modification of-this method has been used by Koppenhbfer (1935) in estimating the benzol content of the blood and tissues in a fatal human case of benzol poisoning, and by Duvoir and Fabre (1946) in estimating separately benzene and toluene in the blood. TOXICITY As an acute poison benzene is a narcotic, producing severe, or even fatal, depression of the central nervous system. Its chronic toxic effect is that of injury to the bone-marrow, producing great variety in the blood picture, with the salient feature of aplastic anaemia. It is clearly apparent, both from the study of cases of benzol poisoning in human beings, and from experimental work on animals, that acute and chronic benzol poisoning are two entirely distinct phenomena. "In acute benzol poisoning the symptoms are due to a severely irritant and destructive effect upon the central nervous system, whereas in chronic benzol poisoning the relatively slight effects on the central nervous system are not at all comparable with the severity of the degenerative changes occurring HYDROCARBONS S T 0 8 5 2 6p 7 in the haematopoietic system. In acute poisoning benzol thus acts as a convulsive neurotoxin and later as an asphyxiant narcotic." (Batchelor, 1927.) Chronic poisoning presents a wide variety of subjective symptoms, both in number and in degree of severity, and although the classical picture of anaemia of aplastic type is still the most widely recognized example of benzene poisoning, extensive investigations of recent years have tended to bring out the salient fact that this is by no means the invariable one. This concept of expected variation tends to alter the value of the criteria of benzene poisoning, or benzene absorp tion, such as those laid down in the Report of the National Safety Council on Benzol, 1926. Toxicity in Industrial Processes In the earlier literature, cases were reported with some frequency of acute, sometimes fatal, poisoning from swallowing benzol. Such were the two cases recorded in St. George's Hospital Reports for 1877-78, and those of Averill (1889), Simonin (1903) (in this case the patient survived, but developed swelling and oedema of the skin), Hetzer (1922), in which the poisoning was followed by intense toxic gastritis and later pyloric stenosis, and Nick (1922), in which recovery followed the injection of 5 mL of a 10 per cent lecithin emulsion. Although it has been stated by Hamilton and Johnstone (1943) that "acute benzol poisoning is of little importance under modem industrial management", owing to unforeseen imperfections of plant, or neglect of the precautions provided, severe and even fatal cases do occur. During the last seven years thirty-one cases, nine of them fatal, have been reported to the Factory Depart ment Most of the total number of fatalities recorded in the literature have been caused by the entry of workmen into tanks containing benzol, or having contained it at some time. With regard to the possibility of reducing the incidence of acute benzol poisoning from this cause, Marian-Wolfen (1925) suggests certain measures for the cleaning of benzol containers. He states that removal of benzol residues from tanks is not possible by means of water alone, that in fact such a method increases the danger, since the benzol, being of comparatively low'specific gravity and scarcely soluble in water, forms a layer on the walls of the vessel which is later vaporized. The passage of steam through the container, however, with the provision of several openings for the escape of the steam and volatilized benzol, and of an exit at the lowest level of the container for the escape of the benzol-containing water of condensation will, he claims, constitute an entirely successful procedure for cleaning out vessels containing benzol and removing the residue; this method should, if carried out universally, much reduce the danger of severe and fatal cases of benzol poisoning. It may be mentioned, however, that though the number of acute fatalities has certainly decreased since the need for adequate protection has been realized and acted upon, one of the nine cases reported to the Factory Department occurred in 1945 during the steam-cleaning of a condenser, the procedure advocated by Marian-Wolfen. According to Pfeil (1932), cases of poisoning reported from the exhaust gases of machines in which benzol is used as a motor fuel are not actually due to the benzol but to carbon monoxide, since exhaust gases contain no benzol. In the rubber industry four cases of poisoning, two of which were fatal, from the use of shoe cements containing a large proportion of benzol Were reported by Hunter and Hanflig in 1927. With regard to the sealing of cans, Hamilton .. ST0852608 10 TOXICITY OF INDUSTRIAL ORGANIC SOLVENTS (1931) remarks that since the introduction in 1926 of rubber latex as a substitute for rubber dissolved in benzol, many works have substituted latex for the benzol rubber sealing mixture, but that no less than one third of all food cans are still sealed with benzol. In tyre-building, five cases (three fatal) of poisoning with aplastic anaemia and haemorrhages occurred (Harrington, 1917). Six deaths and twelve severe and several slighter cases of poisoning occurred in a rubber factory in Vienna in 1932, although all the apparatus used was of the closed type. The trouble arose apparently from the transportation of goods moist with benzol from one room to another (Fischer, 1932). An Austrian Government Order of May 1, 1934, prohibited workers in processes using benzol, toluol, xylol, or trichloroethylene from working more than 4 hours a day, and, when large quantities are used, not more than 2 hours a day. The processes covered by the more stringent restrictions include the cold vulcanization of rubber and the production of rubber substitutes. Two of six cases of benzol poisoning reported by Hunter and Hanflig (1927) and a fatal case mentioned by Hamilton (1928a) occurred in the manufacture of patent leather. In connexion with quick-drying paints, it is emphasized by Flury and Zernik (1931) that the use of benzol is attended with special danger from the fact that it volatilizes quickly from the painted surface, especially when the surface is warm, as in metal parts of machines, or when the paint is sprayed on. Details of the conditions and risks of this process are given by Smyth and Smyth (1928) summarizing the findings of the Pennsylvania Department of Labor and Industry (1926) and of the National Safety Council Committee on Spray Coating (1927). It was finally recommended by the Committee that no lacquers be used for spraying which contain over 0-5 per cent of benzol. An investigation by Kranenberg and Peeters (1928) of workers in an aeroplane factory showed great and characteristic changes of the blood picture in a large number. In one case, after six years' exposure, there was a relative lymphocytosis of 62 per cent and a reduction of haemoglobin to 65 per cent. Attention has been drawn by Bloomfield (1928) to the possibility of poisoning in laboratories where tests are conducted with rubber, paint, varnish and oil products, and involve centrifuging the material to be tested with benzol. He found a considerable amount of benzol in the air of such laboratories, 28 to 223 p.p.m., and examination of workers revealed in three cases a change in the ratio of polymorphonuclear leucocytes to lymphocytes. Nine cases of chronic benzol poisoning in workers in the alkaloid industry were reported by Mitnik and Genkin (1931). In England benzol is'rarely used in high concentration in printing inks, but an investigation made by Saita and Domp6 (1947) in Italy revealed that the percentage of benzol in the ink solvents and diluents varied from 66 to 93 per cent. Of the fifty-five operatives examined, 67-3 per cent showed some abnor mality of the blood picture, and at one of the factories there had been two serious cases of benzene poisoning, one of which was fatal. In England also a series of cases of severe intoxication has occurred during recent years (p. 42). \ TOXIC BFFBCTS IN ANIMALS Absorption Absorption and Excretion (a) Through the lungs. Rabbits, according to the investigations of Lehmann (1910), have a smaller capacity for absorption of benzol through the lungs than HYDROCARBONS ST 0852609 11 human beings. Whereas men absorbed 80 per cent of the benzol vapour inhaled, rabbits absorbed only 63 per cent. No definite ratio between the relative amount absorbed and the total amount present in the air was found, but Robinson and Climenko (1941) have since observed that rabbits exposed to about 1,000 p.p.m. for 2 hours show a blood concentration of 25 to 30 mg. per 100 ml. i {b) Through the skin. The investigations of Lazarew, Brussilowskaja, Lawrow and Lifschitz (1931c) have shown that benzol in the form of vapour, as well as in liquid form, can be absorbed through the skin of animals. In liquid form, benzol produced great irritation. Immersion of the ears of rabbits for 2J to 3 hours was followed by inflammation and oedema, then pus formation, and finally by mummification of the ear, while immersion of the whole body of a mouse was followed by death after about 3 hours. When animals were kept in a chamber filled with benzol vapour, their heads being passed outward through an opening so that inhalation of the vapour was impossible, no general symptoms of intoxication were observed. Evidence of absorption through the skin, however, was obtained in three ways: '(1) The hydrocarbon content of the air expired by tracheotomized rabbits with one foot immersed in benzol was estimated. The estimation was carried out by the method of Matveev, Pronin and Frost (1930). The benzol appeared in the expired air after 3 or 4 minutes in amounts of 1 -2 to 1 -5 mg. per 1., the total amount expired in the course of 115 minutes' immersion of the foot being 138 mg. The speed of absorption of benzol through 1 sq. cm. of skin was there fore calculated as more than 0-016 mg. per minute (0-013 to 0-76 mg. in a later investigation by Lazarew et al., 1931c). (2) Phenol, an oxidation product of benzol in the urine, was estimated. The urine of animals kept as described above in a chamber filled with benzol vapour showed a strong phenol reaction (Millon's reagent). (3) The amount of benzol in the blood of rabbits after immersion of the ear in benzol was estimated by Lazarew et al. (1931a, b), and the average amount during 30 minutes' immersion plotted as a curve, which rose to between 50 and 100 mg. per kg. of blood taken from the external jugular vein. Lazarew and co-workers correlate the absorption of benzol through the skin with its water solubility as well as its fat solubility. They estimate its water solubility as 0-033 to 0-040 g. per 1. and explain its greater speed of absorption as compared with that of benzine by the lower water solubility of the latter (0-007 to 0-015 g. per 1.). (c) Distribution in the body tissues andfluids after absorption. The experiments of Yant, Schrenk, Sayers, Horvath and Reinhard (1936), and Schrenk, Yant, Pearce, Patty and Sayers (1941) have shed much light on the biochemical action of benzene. Of special importance is the partial explanation they afford of the injurious effect of benzene on the haematopoietic system--the predilection of benzene for fat, of which the bone-marrow essentially consists. The con centration of benzene in the fat, bone-marrow and urine of the exposed animals was approximately twenty times that in the blood. Other conclusions reached were: (1) The initial rate of absorption of benzene by the blood was extremely rapid, a matter of minutes. (2) The final equilibrium value was attained very gradually, after several hours of exposure. (3) The final elimination took place very slowly, the time increasing as the length of exposure increased. In some cases complete elimination had not ,, ST08526I0 taken place until about 13 hours after termination of exposure. The fat, acting as a reservoir, is saturated slowly, and also loses its benzene slowly. (4) The red blood cells contained approximately twice the concentration of benzene found in the plasma, and the muscles and vital organs about one to three times that in the blood. (3) Benzene absorbed into the body by inhalation was apparently excreted into the stomach, and the high benzene concentration in the urine indicated that the benzene is concentrated by the kidneys. Excretion While the greatest amount of benzene is excreted unchanged by the lungs, a certain amount is oxidized in the body and excreted in the urine in the form of phenol, catechol, hydroquinone, and muconic acid (Jost, 1932): In animals the excretion of benzene in the urine has usually been estimated by the amount of phenol excreted. The phenol excretion of rabbits after 2 hours' daily inhalation of benzene in a concentration of 13*6 mg. per 1. has been estimated by Sartorius and Sudhues (1933). The average phenol excretion rose almost immediately from a normal level of 2 mg. per day to 30 mg., and later to nearly 100 mg. When inhalation was stopped the phenol excretion sank to the normal level only after 4 or 3 days. This finding appears to indicate, according to Sartorius and Sudhues, that many cell systems must constitute special storage centres for benzene, or its ethereal sulphates. Change in sulphates in urine. Some investigations by Yant et al. (1936) show that a change in the normal ratio of inorganic to organic sulphates, i.e. a decrease in inorganic sulphates, in the urine is a constant and early sign of benzene poisoning in animals. The analysis of urine specimens from 79 dogs exposed to concentrations of from 100 to 800 p.p.m. of benzene vapour for periods of 100 to as long as 1,000 days in one instance showed that a rapid and marked decrease occurred in the percentage of inorganic sulphates in the total sulphates in the urine. Single examples of their figures will suffice to show the quantitative aspect of this decrease (Table 2). TABLE 2 Decrease in urinary inorganic sulphates after exposure to benzene Concentration (p.p.m.) Daily exposure (hours) 100 8 500 8 800 1 800 8 Exposure period (days) Percentage of inorganic sulphates Before exposure (average) After exposure (average) 42 89-4 57-0 317 94-7 28-8 17 86-7 62-5 192 96-5 6-3 A distinct decrease in the percentage of inorganic to total sulphates occurred even with conditions of exposure which did not produce anaemia or leucopenia. With conditions which produced benzene poisoning a great decrease occurred weeks and months in advance of anaemia, leucopenia,and the common signs and symptoms of benzene poisoning. The mechanism of the response is believed to be dtie to oxidation of the benzene to phenol or phenolic derivatives, which in ST08526I I HYDROCARBONS 13 turn are conjugated in the liver with sulphate ions to form ethereal sulphates, thereby causing a shift to the right in the system: inorganic sulphates X con jugated sulphates. The shift or decrease in inorganic sulphates is related quantit atively to the severity of the exposure to the point of complete elimination of the inorganic, sulphates (p. 26). Acute Poisoning It has long been known that benzene in large doses produces in animals a severe narcosis, often accompanied by symptoms of irritation of the central nervous system, tremor, muscular twitching, etc., and, above the minimum lethal dose, followed by death. It was believed that the cause of death was invariably respiratory paralysis, but some investigations by Nahum and Hoff (1934) suggest that, although death may occur from respiratory failure during the stage of narcosis, it may also occur suddenly from myocardial failure produced by the action of benzol, both by causing the liberation of adrenaline and at the same time sensitizing the myocardium to its toxic action. The acute effects of benzene upon animals have been studied from results of intraperitoneal injections and of inhalation. The symptoms arising from irritation of the central nervous system are essentially similar in both modes of administration, hut the intense effect is most apparent when benzene is ad ministered intraperitoneally, owing to its rapid absorption. Effect of Intraperitoneal Injection Lethal dose. For guinea-pigs, 0-73 ml. per kg. body weight (Chassevant and Gamier, 1903); for rats, 1-5 to 1-75 ml. per kg. (Batchelor, 1927). Symptoms. Profound tremor and muscular convulsive twitchings were pro duced by doses as low as 0-25 ml. per kg. body weight, and in addition, a definite narcotic effect, with drowsiness, instability of gait, impaired equilibrium, weak ness, paresis, decreased susceptibility to pain stimuli, and cessation of voluntary movement; as the spinal cord was affected, loss of reflexes resulted. Post-mortem findings. Batchelor observed intense acute congestion of the peritoneum and abdominal viscera, with much fibrin deposit on these surfaces, considerable sero-sanguinous intraperitoneal exudate, injection of the gastric mucosa with small haemorrhages and ulceration, and acute congestion of the lungs. No appreciable effect was noted on the blood cell count. Effect of Inhalation In large doses, the effect of inhalation of benzol vapour upon animals is that of a nerve poison, with a characteristic neuro-irritant effect, as evidenced by muscle twitching, convulsions, general tremor (compared by Benech (1897) to that of paralysis agitans), and a state of hypertonicity of the body and musculature (Batchelor, 1927), shown in many cases by a peculiar rigid S-shaped formation of the tail (Lazarew, 1929a). A toxic action upon the heart is also postulated by Nahum and Hoff (1934), i.e. progressive anoxaemia of the myocardium, and a sensitization of the myocardium to the effects of adrenaline, so that death may occur from ventricular fibrillation. Different species of animals vary in their susceptibility to acute benzol poison ing, the rabbit bong more resistant than the mouse (Lehmann, 1912), while the cat appears to have a special sensitivity (Lederer, 1932; Engelhardt, 1931). A sinus arrhythmia, with ventricular asystoles, due to the action of benzene, either on the myocardium itself or on the vegetative nervous system has been observed by Caccuri (1940). ST0852612 14 TOXICITY OF INDUSTRIAL ORGANIC SOLVENTS According to Lehmann and others, animals of the same species, especially cats, also show a great variation in individual susceptibility, death occurring sometimes with relatively small dosage and short exposure, while on the other hand, feeble animals receiving large doses may show only slight weakness and others may recover from severe narcosis. It appears from the work of Nahum and Hoff (1934), and also that of Caccuri (1940) that some of these individual susceptibilities may be explained by variations in adrenaline response; periods of hyperexdtability being accompanied by increased liberation of adrenaline, to the action of which the myocardium is already sensitized by the action of benzol. Lethal and narcotic concentrations These are given in Table 3. TABLE 3 Lethal and narcotic concentrations of benzene by inhalation Animals Mice Cats Dogs Rabbits Guinea-pigs Lethal concentration (mg./L) (p.pjn.) 45 14,000 ---- 170 53,000 ---- 146 46,000 46 14,500 (after 3 hours) --- . -- Narcotic concentration (mg./l.) (p.pjm.) --_ 38 12,000 60 19,000 30 9,500 ---- --" 40 12,600 Author Lazarew (1929a) FOhner (1921b) Iehmann (1912) Bamesreiter (1932) Luig (1913) Lehmann (1912) Peronnet (1934) Symptoms The onset of acute symptoms is apparent at concentrations ranging from 15 mg. per 1. (4,700 p.p.m.) for mice to 22 mg, per 1. (7,000 p.p.m.) for cats (Bamesreiter, 1932). Table 4 taken from Lehmann (1912) shows the progress of effects with different concentrations in rabbits. TABLE 4 Effect of inhalation of benzene on rabbits Concentration Time of (mg./L) (p.pjn.) exposure 37 12,000 5 hr. 46 14,500 3 hr. 92 29.0Q0 70 min. Time before apparent effects Convulsions Lateral Light Deep position narcosis narcosis Further progress 2i hr. 80 min. 9 min. 35 min. -- 9 min. -- -- 40 min. 5 hr. . 2 hr. 50 min. Slow recovery. Death after 3 hr. Slow recovery. -(It should be noted here that the results obtained by Bamesreiter (1932) with regard to the narcotic symptoms produced by inhalation of benzol vapour by cats give a toxicity greater than that found by Lehmann. Lehmann, in a note appended to Bamesreiter's article, observes that the discrepancy is due to the fact that Bamesreiter has used a modification of the original Wurzburger apparatus, the new Ludwigshafen apparatus, described by Gross and Kuss (1931).) . 'j HYDROCARBONS ST 08526 13 15 Bamesreiter's results are summarized as follows: Lateral posture .. above 22 mg. per 1. after 6 hours' exposure Light narcosis .. above 28 mg. per I. after 6 hours' exposure. Deep narcosis .. above 30 mg. per 1. after 6 hours' exposure. Post-mortem findings. The organs of animals dying from inhalation of lethal concentrations of benzol vapour have not shown any specially characteristic changes; haemorrhage of the lungs has been observed in a few cases. The most outstanding feature was the fact that the blood remained fluid for a long time after death (Beinhauer, 1896; Lehmann, 1912; Heftier, 1915). No microscopic changes in the blood were found in Lehmann's animals; an odour of benzene could be detected in the lung cavity if opened promptly after death., Local irritant effect >' Mucous membranes'. In rats, irritation was caused by concentrations of 1,000 to 2,400 p.p.m. or even less (Batchelor, 1927). . Cornea. In rabbits, irritation with turbidity and a blister-like appearance after repeated exposure to 38*6 mg. per 1. Lungs. Histamine may be liberated (Garan, 1938). Effect on the blood The effect of a single exposure to 7,500 to 12,000 p.p.m. for 2 hours was found by Climenko and Macleod (1942) and Robinson and Climenko (1941) to be an immediate temporary leucopenia followed within 22 hours by a leucocytosis. There was no evidence of neutropenia, but on the contrary, varying degrees of neutrophilia, with a shift to the right. There was also a fall in the number of circulating erythrocytes. These investigators assume from the reaction of the white cells that the bone-marrow under benzol exposure is refractory to the normal endogenous stimuli which maintain the equilibrium of juvenile to senile cells; it proved, however, responsive to the more potent exogenous stimulus of sodium nucleinate. Effect on the Body Temperature According to Gaede (1944), the effect of administration of benzene to animals, orally, rectally, or intravenously, in doses of 5 to 20 drops, is an immediate rise of temperature. This, it is suggested, is due to stimulation of the temperaturferegulating centre of the brain. With narcotic doses, the temperature falls, this being due to paralysis of the centre. Inhalation of 100 p.p.m. causes a rise of temperature during the first half hour, followed by a rapid fall. Effect of Mixtures ofBenzene and other Solvents An investigation by Svirbely, Dunn and von Oettingen (1943), on the acute toxic effect of certain mixtures of solvents containing benzene, toluene and Xylene, has shown that so far as the lethal effect is concerned, benzene is less toxic than either toluene alone, or the blends of benzene, toluene and xylene. Pulmonary irritation was more predominant with benzene alone, but patho logical changes were not prominent owing to the short exposure and resulting early death of the animals. Chronic Poisoning Both by subcutaneous injection and by inhalation experiments on animals, the toxic effects of benzol have been investigated and described by a large number of workers beginning with Santesson (1897), Langlois and Desbouis ST08526I4 16 TOXICITY OF INDUSTRIAL ORGANIC SOLVENTS (1907), Lehmann (1910) and Selling (1916). It was chiefly Selling's extensive experiments, carried out by subcutaneous injection, that led to the clear con ception of benzol as a leucotoxin, destroying not only the circulating leucocytes in the blood, but also the parenchymatous cells of the bone-marrow, spleen and lymph glands. The destructive effect, he observed, was more pronounced on the myelocytic than on the lymphatic elements. In addition, Selling's experi ments brought out the following points: a less obvious effect on erythrocytes, due to injury of the erythroblastic tissue in the bone-marrow, an initial stimulat ing effect on the bone-marrow with a resulting initial leucocytosis, and regenera tion of the injured tissues when removed from the influence of benzol. In essentials these results have been confirmed by later workers, but'in some cases the details have not been reproduced. Thus Ferguson, Harvey and Hamilton (1933) were not able to produce in rats and rabbits a well-marked neutropenia with less effect on the erythrocyte system. In fact anaemia was even more evident than leucopenia, and an erythropoietic disturbance was even more manifest in the peripheral blood picture than a leucopoietic. According to a statement made by Hamilton (1934) these findings of Ferguson et al. are characteristic rather of the usual findings in human beings suffering from benzol poisoning than of those observed by most workers with experi mental animals. She states that animal experiments do not show the destruction of red blood corpuscles which in human beings is often more conspicuous than the destruction of white corpuscles. The discrepancy may be explained by the opinion expressed by Ferguson and others, and their agreement with a statement made by Selling which has been less emphasized than the main results of his investigation. Selling observed that "in general the'Tfesponse of the bone-marrow is not specific. It does not respond to a loss of white blood cells solely by production of granulocytes, nor to the loss of red blood cells solely by the production of erythroblasts." The conclusion of Ferguson and co-workers appears to be a confirmation of this observation. They state: ` `Our opinion indeed is crystallizing in the direction that the action of benzene or its homologues is not as singular in incidence upon the blood cells as it is generally made out to be, and that its effect is a varied one, not necessarily neutropenia, anaemia, nor thrombopenia, a stimulant as much as a destroying agent, and, generally speaking, more or less non specific." This also appears to be the opinion of McCord, Cox and O'Boyle, as the result of the extensive survey embodied in their report to the Industrial Health Conservancy Laboratories in 1932. Their general conclusions as to the toxic effects of benzol on animals may be summarized as follows*--leucopenia is not a consistent feature of benzol poisoning in animals and is not pathognomonic of it; no pathognomonic features absolutely characteristic of benzol poisoning' are to be found in life or post mortem; concentrations of 5 parts of benzol per 1,000 of air have set up signs of intoxication in rabbits equal to or more severe than 10 parts per 1,000; all grades of benzol, whether or not containing impuri ties, such as thiophene, carbon disulphide or acetonitrile' exert a toxic action on rabbits. Some of the intoxication produced in animals, both by subcutaneous injection and by inhalation, cannot strictly be labelled chronic since the doses used led immediately to more or less acute effects. In Batchelor's (1927) experiments, for example, doses of 1 ml. per kg. body weight were injected on successive days, and in some cases untoward general HYDROCARBONS ST08526 I 5 17 symptoms appeared early and resulted finally in death. Similarly the inhalation experiments of Ferguson and others can scarcely be regarded as illustrative of chronic poisoning, for the effect was acute and the exposure had to be short in . border to avoid the death of the animal. These investigators themselves suggest 7>tbat in this fact lies part of the explanation that the blood picture which followed, <*t least in the majority of cases, could not be called a neutropenia, or even an agranulocytic anaemia. Batchelor's inhalation experiments, however, included the inhalation of lower as well as higher concentrations of benzol, from 2,440 p.p.m. down to 460 p.p.m., and while no symptoms, except weakness, anorexia, / and loss of weight, resulted from concentrations of 800 and 460 p.p.m., definite injury to the haemopoietic and excretory organs was produced by these lower concentrations. The inhalation experiments of Lederer (1932) are of special interest in this .'connection, since apparently dogs are considerably less sensitive than other / Species to benzol poisoning, and Lederer was able to carry on the investigations 'bver a period of 2J years, with inhalations of 6 hours daily of concentrations of * 7 to 10 mg. per 1. (2,200 to 3,100 p.p.m.). tSymptoms The symptoms of poisoning by relatively small amounts of benzene in animals .are slight, e.g. weakness, anorexia and loss of weight. When, as in the case of . Lederer's dogs, symptoms of nervous instability, tremor, muscular hypertonicity, restlessness, appear at the beginning of the experiment, with the disappearance of gross pathological manifestations tolerance appears to be fairly rapidly established. \Ctymges in the Bone-marrow and Internal Organs Bone-marrow. Both in the more acute and in the strictly chronic intoxications, the changes in the bone-marrow are essentially those leading to aplasia affecting all cell types, but the appearances differ in individual animals according to Whether preliminary stimulation or regeneration has taken place. Thus, in some of the animals investigated by Engelhardt (1931) with inhalations of 10 to 25 mg. per L (approx. 3,000 to 8,000 p.p.m.), the bone-marrow showed very little change; in some there was degeneration and destruction of leucocytic elements, and in others irritative phenomena--new red cell formation, immature leucocytes, etc. The regenerative phase has perhaps been best described by Selling (1916) in his original series of animals. The regenerative process in the bone-marrow begins with the formation of small, circum scribed cell groups and islands, composed of large lymphocytes, granulocytes or erythroblasts. In any given island, after cellular differentiation has once begun, the type of cell, whether erythroblast or granulocyte, remains constant. The islands increase in size and num ber, fuse with each other and lead to a complete filling of the reticulum with parenchymal elements. In the earliest stages the younger cell types (myeloblasts and megaloblasts) are relatively abundant. In the later stages these cells are still present, but in comparison with more highly differentiated cells they are relatively scarce. These reparative changes have been further emphasized by Heitzmann (1931), who describes a preliminary atrophy of the bone-marrow followed by a hyper` plasia, especially of the leucocytic elements, in animals subjected to subcutaneous injection. Heitzmann, however, lays particular stress on the destruction of leucocytic elements in the bone-marrow as the characteristic effect of chronic poisoning by inhalation of benzol while the greater sensitivity of myeloid tissue has also been stressed by Larionow (1932). c S T 0 8 5 2 616 18 TOXICITY OF INDUSTRIAL ORGANIC SOLVENTS In Schillowa's (1933) experiments with rabbits receiving subcutaneous injec tions of benzol, the characteristic lesion of the bone-marrow was hyperplasia, chiefly of pseudo-eosinophils, megakaryocytes and erythroblasts. Spleen, The characteristic injury to the spleen appears to be aplasia (atrophy of Malpighian corpuscles and stroma) with pigmentation and increase in connective tissue, but myeloid metaplasia and hyperplasia have also been observed. Selling (1916) and Brandino (1922) recorded the occurrence of myeloid metaplasia as a regenerative phenomenon. In the more acute cases of intoxica tion in animals examined by Ferguson et al. (1933) no indication of myeloid metaplasia and no evidence of haemosiderin deposition were found, but in the animals subjected to chronic inhalation' by Engelhardt there was much deposi tion of blood pigment in the spleen, and Heitzmann, who examined them, states that this indicates a toxic action of benzol on the red blood corpuscles. Lignac (1932), who claims to have produced acute leukaemia in mice by injection of small doses of benzol, states that while the myeloid tissue in the spleen undergoes destruction, the lymphoid tissue is increased (hyperplasia follicularis lienis). Schillowa (1933) on the other hand emphasizes a marked hyperplasia of the reticulo-endothelial elements, especially the endothelial sinuses, as the charac teristic change in rabbits injected with benzol, and describes the formation of rhombic crystals, analogous to Charcot-Leyden crystals, as the result of phago cytosis of eosinophils. Liver, Among the earlier workers; Pappenheim (1913) reported the presence of a parenchymatous hepatitis, but this was not confirmed by Neumann (1915). In Batchelor's experiments the liver showed evidence of injury and focal necrosis with inhalation of concentrations as low as 815 p.p.m., but in Lederer's dogs the liver injury was comparatively slight, affecting chiefly the reticulo-endothelial cells, and'in Engelhardt's cats and rabbits the chief changes were congestion and deposition of haemosiderin. Silberberg reported negative findings (1928). Kidneys. Among the earlier workers only Pappenheim observed injury of any severity in the kidneys, while according to Batchelor's (1927) investigation, injury is slight with inhalations of low concentration; he observed cloudy swelling and tubular casts only with 440 and 815 p.p.m. McCord, Cox and O'Boyle (1932), however, lay great emphasis on nephritis as an outstanding characteristic. They state that the special point of attack is the convoluted tubule. Bladder. McCord, Cox and O'Boyle also state that inflammatory conditions of the bladder, in which large numbers of pus cells may be present in tlie urine, are of fairly frequent occurrence in animals poisoned with benzol. Gastro-intestinal tract. Inflammatory reactions of the stomach and other parts of the intestinal tract are also recorded by McCord and co-workers. They state that in the stomach these reactions are preceded by purpura of the mucous meimbrane and may be followed by the formation of ulcers. Thymus. According to Lewin (1928), benzol produces atrophy of the thymus in rabbits, the histological changes being those of accidental involution, An increase of interlobular connective tissue is accompanied by the new formation of a network of collagenous bundles within the lobules. Regeneration is possible only if complete inversion of the gland has not taken place. Lymph glands. Only slight hyperplasia with pigmentation and phagocytosis was found with fairly high concentrations (Batchelor, 1927), though Brandino (1922) recorded a notable destruction of lymphocytes. Schillowa (1933) noted a ST08526I1 HYDROCARBONS 19 . - diminution of lymphoid tissue and phagocytosis of pseudo-eosinophils but no ' nuclear pyknosis or necrosis of the lymphoid nodules. Muto (1931), however, reported complete atrophy of the lymph follicles. Lungs. Lesions of the lungs--catarrhal bronchitis, emphysematous areas, W.: ^jf&crease in the lypiphatic tissue and thrombosis of vessels--have been described ''' Yty Schmidtmann (1930), pneumonic processes, bronchial catarrh of a desquama tive nature and commencing cirrhosis of the lung by Mgebrow (1930), and fatty emboli and emphysema by Schillowa (1933). > Brain. Degenerative processes in the vessels of the brain cortex and in the ganglion cells have been reported by Amenossow and Blinkow (1929). Genital organs. According to Barzilai (1933), the characteristic change in the genital organs of female mice was dilatation of the blood vessels of the endometrium. Jfffect on the Circulatory System .-; -paralysis of the vasomotor system, with resultant rapid lowering of the blood pressure, is recorded as an effect of benzol poisoning in animals by Dautrebande (1933, 1935b) and Dautrebande and Waucomont (1933), after inhalation of benzol vapour through the trachea. These workers believe that the site of action of benzol is upon the muscle fibres of the peripheral vessels, not on the nerve endings. Their opinion is supported by experiments with fragments of isolated organs, heart, intestine, ureter, which, when placed in Ringer's solution containing benzol, immediately cease contraction (Dautre bande and Waucomont), and by the negative results obtained bn applying known peripheral vasomotor stimulants, adrenaline, ephedrine, pituitrin, after benzol (Dautrebande, 1935a). . Y According to Litzner (1932), benzol produces on the heart progressive diminu tion of contraction, especially of the ventricles, while Dautrebande (1935b) states that benzol inhalation produces bradycardia, which appears even during -the occlusion of the two common carotids. This bradycardia is always increased by injection of adrenaline or hordenine, and after adrenaline, benzol intoxication may produce a fatal syncope by ventricular fibrillation. This conclusion can be well correlated with the results of Nahum and Hoff (1934) on the acute effects of benzol poisoning in animals (p. 13). Effect on the Blood The results of innumerable experiments on animals, mostly by subcutaneous injection of benzol, have, on the whole, confirmed Selling's original observation that the striking and characteristic effect of benzol poisoning is a reduction of leucocytes. The essential fact brought out by later researches, especially those of Wallbacb (1929, 1931), Weiskotten and co-workers (Weiskotten, Schwartz and Steensland, 1915, 1916; Weiskotten and Steensland, 1919; Weiskotten, Gibbs, Boggs and Templeton, 1920; Weiskotten, 1930) and others, is that the toxic action affects all forms of leucocytes rather than being specifically toxic to granulocytes. The striking effect on granulocytes is not so much their depres,'Sion as the appearance of immature forms (Hunt and Weiskotten, 1930; Weiskotten, 1930). In the later stages the red blood cells and platelets are also involved, and it is from these two marked differences between the condition of the blood in benzol poisoning and in true agranulocytosis that a conception of the mechanism of benzol poisoning has been evolved. This subject is discussed by McCord (1929), Dameshek (1929), Kracke (1932), and Kracke and Parker S T 08526 I 8 20 TOXICITY OF INDUSTRIAL ORGANIC SOLVBNTS (1935); the latter claimed to have produced true agranulocytosis in animals by subcutaneous iiyections of benzol, but the present position appears to be that summarized in the opinion of Reznikoff and Fullarton (1933): This "shift to the left" may be due to an attempt on the part of the bone-marrow to compensate for leucocytic destruction or to depression of maturation. The fact that bonemarrow studies do not show any hyperplasia and do show some depression for the most part indicates that the depressing action of benzol is on the formative and maturetive function of the marrow in addition to any possible leucolytic effect. ... In addition to eventual involvement of the red blood-cells and platelets which is present in true granulo cytopenia, the striking predominance of immature polymorphonuclears during the period of progressive leucopenia when benzol is administered suggests a different mechanism from that taking place during granulocytopenia. It may be that granulocytopenia affects primarily the formative functions of the granulocytogenic elements of the marrow and perhaps the delivery of granulocytes from the marrow into the circulation; whereas benzol injures the maturetive as well as the formative function. In the earlier investigations constant results were only obtained by sub cutaneous injections. Thus, while Langlois and Desbouis (1907) recorded a definite diminution of leucocytes and increase in erythrocytes after inhalation of benzol vapour, Luig (1913) obtained practically negative results with chronic inhalation of 5 to 10 mg. per 1. Later investigations, however, by Weiskotten and co-workers (1920), Engelhardt (1931) and Batchelor (1927), have shown that the typical leucopenia observed after subcutaneous injection can be reproduced after inhalation, though, according to Engelhardt, to a smaller degree. The results obtained by Ferguson, Harvey and Hamilton (1933), either by injection or inhalation, do not present the picture recorded by many workers, of a well-marked neutropenia, with less effect on the erythrocyte system. These workers tentatively explain the variability of their results as "one of phase", owing to the fact that the toxic action of benzol is not a specific action but operates according to circumstances on the stem cells of the myeloid leucocyte or the erythrocyte. The somewhat similar results obtained by Beyer (1933) in which the picfure was that rather of a terminal anaemia preceded by a leucocytosis than of a definite leucopenia are attributed by them to the fact that the doses given (0-01 g. per kg. by subcutaneous injection) were 100 times less than those used by the earlier workers. Susceptibility of animals of different species and of the same species. Many of the discrepancies in the findings of different workers in animal experiments are apparently to be ascribed to both individual and species susceptibility. Thus Wallbach (1931) was unable to produce in guinea-pigs and white mice the characteristic leucopenia obtained under similar conditions in rabbits, and states (1933) that only in man, dogs and rabbits is leucopenia an invariable result of benzol poisoning; other animals are refractory to the action. He also points out that underlying constitutional conditions, especially infection, e.g. infectiop at the site of injection of benzol solutions, may have a considerable effect on the leucocytic response. Schillowa (1933) lays special emphasis on the variation of susceptibility in animals of the same species, as judged by the blood picture and the degree of bone-marrow injury. She states that in the benzol-susceptible animal leuco penia and thrombopenia occur, with an aplasic condition of the bone-marrow and necrobiotic changes in the granulocytes. In less susceptible animals the blood picture shows little change, while the bone-marrow may show considerable hyperplasia of myelogenous tissue. HYDROCARBONS ST08526 I r J it has already been observed that cats have been found to show a special sensitivity to acute poisoning by benzol. According to Sartorius and Sudhues (1933) they are not suitable for investigation of the results of chronic benzol poisoning because they are liable, even with comparatively small doses by i inhalation, to develop symptoms of irritation of the respiratory tract, leading j t6`secondary infection and purulent broncho-pneumonia. \ '"White cells Total count. The total white cell count, according to the great majority of observers, is reduced after both injection and inhalation of benzol, sometimes to a remarkable extent. In Batchelor's experiments with inhalations of low con centrations (460 to 815 p.p.m.) the reduction was as much as from 73 to 92 per cent. In one of Engelhardt's animals, a rabbit, after 13 injections of 0-5 ml. per : kg., me count reached the low level of400 per c. mm. Weiskotten and co-workers (1920), using concentrations of benzol in air which they describe as similar to those found in industrial conditions (average amount vaporized per hour 16-6 ml. in 3 L air), found that the lowest level reached (1,260 per c. mm.) was never as low as that reached after subcutaneous injections. An initial leucocytosis followed by the characteristic leucopenia was described ' by the earlier workers (Selling, 1916; Langlois and Desbouis, 1907) but was not confirmed by Neumann (1915). Later researches, however, appear to show that an initial leucocytosis may occur, but is not constant, and is to be attributed to an initial irritative effect on the haemopoietic system (Engelhardt, 1931). Schillowa (1933) found in all her animals a large increase of leucocytes during the1 first 3 months. ^ihphasic leucopenia, i.e. a secondary fall in the leucocyte curve following a primary rise after benzol injection is discontinued, has been observed by ^Weiskotten and Steensland (1919) and by Batchelor (1927) in the case of sub cutaneous injection. This phenomenon in the case of inhalation was not observed by Weiskotten and co-workers (1920). A permanent lower level of leucocytes (average 6,166, as compared with 11,302 before exposure) was reached when the inhalations were discontinued and no further "deuterophase" was observed. Lymphocytes. There have been differences of opinion as to whether a relative lymphocytosis is a characteristic feature. Batchelor, dividing the white cells into polynuclear (including polynuclear neutrophils, eosinophils and basophils) and mononuclear (including lymphocytes proper and large mononuclear forms) showed that there was a relative, as well as an absolute, decrease in the poly nuclear forms, and a relative increase in the mononuclear forms. This relative lymphocytosis has also been recorded by Selling, Fontana (1921) and others, and has been interpreted as an indication that the lymphocytes were more resis tant to the toxic action of benzol than the polymorphonuclear leucocytes. Among those who have found no relative lymphocytosis are Neumann (1915), Muto (1931), and Nicolajew and Schparo (1929), the latter stating that the lymphocytes are even more reduced than the polymorphonuclear leucocytes. Engelhardt's ^findings were variable, but on the whole a relative lymphocytosis was present in the majority of the animals. Sklawunos (1925), however, was able to produce a very marked leucopenia in animals without a corresponding diminution of lymphocytes, so that finally the white cell formation consisted almost entirely of lymphocytes. Lignfic (1932) claims to have produced leukaemia and allied diseases in white mice by subcutaneous injections of benzol. ST 0852620 22; TOXICITY OF INDUSTRIAL ORGANIC SOLVBNTS Eosinophils. An, increase of eosinophils, or rather "pseudo-eosinophils", has been described in animals, especially by Schmidtmann (1930) and Schillowa (1933). Beyer (1933) states that these constitute one of the differences in the normal blood picture of the human being and the rabbit; they are described as in the category of granulocytes, taking on Romanowsky-Giemsa stain with large light red granules. Degenerative changes. The degenerative changes in the white cells occurring in human benzol poisoning have also been observed in animals, but with similar differences ofopinion in the hands ofdifferent workers. Woronow (1929) recorded destruction of leucocytes but no basophil granulation due to benzol itself, this phenomenon only occurring with its homologues, a finding which is contradicted by Engelhardt (1931). Most workers, however, are agreed that the "shift to the left", indicating an immature polymorphonuclear response of the bone-marrow, is a character istic feature in the blood of animals at some stage (Hunt and Weiskotten, 1930; Wallbach, 1931; Engelhardt, 1931; Reznikoff and Fullarton, 1933, etc.); The findings of the latter, in a cat injected with benzol, are given in Table 5 as typical of this response when it does occur. TABLE 5 Effect on the blood of injection of benzol into cats Day of expt. Benzol subcut. (mL) Leuco Immature Mature cytes poly- poly Lympho Mono Eosino Baso (thou morphs, morphs, cytes cytes phils phils sands per (per cent) (per cent) (per cent) (percent) (percent) (percent) c. mm.) I 2 39.0 30 21 45 2 20 2- 2 44.4 73 18 6 3 00 3 2 20.2 60 18 12 8 20 i. 1 2 23.2 50 13 16 7 40 cat dead Changes designated by Gloor (1929) as "nuclear pyknosis"--disappearance of normal segmentation, concentration of the chromatin, clumping of the individual parts of the nucleus,' have been recorded in rabbits by Beyer (1933). He states that it is uncertain whether these changes are identical with the toxic granulation described by Naegeli (1931), but that they indicate a toxic affection of the bone-marrow elements. Red cells In inhalation experiments Engelhardt (1931) found the red cell count variable, sometimes remaining constant, at other times diminished or increased. In Batchelor's (1927) injection experiments the reduction in the red cell count (which ranged from 0 to 52 per cent) occurred considerably later than that of the white cells; the red cells usually began to fall off and reached a minimum several days after the discontinuance of the injections, and remained low for some time afterwards. Batchelor, and L6vy (1935), attribute the final anaemia partly to destruction of peripheral red blood cells, and partly to aplasia of the bone-marrow, and state that when the haematopoietic system is severely affected there may be a complete absence of immature forms. Silberberg (1928) and Orzechowski (1929) consider the variation in numbers ST 085262 HYDROCARBONS 23 /(., god fonnation of red cells of much less importance than some of the white '; > cell chanties. An initial increase, or hyperglobulia, in some of the experimental animals, ;toi noted by the earlier workers, as well as by Batchelor and by Orzechowski (1929) and others. This has been attributed to a preliminary stimulation of the bone-marrow. A secondary increase, 4 or more weeks after the cessation of ,v1^!fajections, was also observed by Batchelor. Anisocytosis and polychromato<\V philia were found in some cases, but normoblasts very rarely. Engelhardt (1931) observed normoblasts in only two cases. The appearance of reticulocytes, however, was a feature of the findings of Ferguson, Harvey and Hamilton (1933). They seem to have made their appearance irregularly, in "showers", and these workers suggest that they may indicate the state of bone-marrow or haematopoietic activity in this form of anaemia as in many others. i^-yTThe same phenomenon obseryed by Paul, Friedlander and McCord (1927) is /attributed by them to an irritant action of benzol on the haematopoietic m*^y:-" ' tissues. Robinson and Climenko (1941) observed with inhalations of 1,000 )p,p.m. for 2 hours an immediate fall in the number of red cells, followed by a sharp, brief rise and a return to normal in about 21 days. They also recorded a reticulocyte rise, up to 15 per cent, but do not attribute this to marrow hyperplasia. ... Haemoglobin level and colour index. A reduction in the haemoglobin content, corresponding more or less to the reduction of red cells, appears to occur in animals. Fontana (1921) noted reduction of haemoglobin to the extent of about one tenth, with a reduction of red cells to 3,000,000, as also did Secchi (1914) 1 and Mauro (1925). Engelhardt (1931), with subcutaneous injections, found a slow decrease of erythrocytes, accompanied in most cases by no essential decrease in haemoglobin, and in one case by an increase, so that the colour index remained ` fairly high. In inhalation experiments the two factors varied more or less simultaneously. . Resistance to haemolysis. In injection experiments Engelhardt (1931) found the resistance somewhat increased, but with inhalation, the findings were not characteristic. Sedimentation rate. A slight increase in the sedimentation rate, but not until late in the course of the toxic action, was observed by Engelhardt. Blood platelets A marked fall in the number of platelets, preceded in some cases by a rise, has been noted by some observers, but it does not appear to be so characteristic in animals as in human beings. Duke (1913) found that large doses (5 ml.) of benzol acted first as a stimulant, then as a poison, to the platelet-forming organs; the count first rose to 1,780,000 then fell rapidly to about 61,000. In small doses (2 ml.) it acted only as a stimulant, causing a gradual rise in platelet count, which later fell, but not below the normal. Orzechowski (1929) found no change in the thrombocyte count, but Hultgren (1926) and Hurwitz and Drinker (1915) confirmed the findings of Duke. The reduction of platelets observed by the latter workers approximated to that recorded by Duke, though wide variations .occurred, the average number following benzol injections in rabbits (average 2 ml. per kg. body weight) being 233,800 (normal average 683,400). They were unable to reduce the count below 31,000 and the animals showed no haemorrhagic symptoms such as occur after a more extreme lowering of the count. Where the platelets and leucocytes were much diminished in number the V,,'.; S T 0 8 52622 24 TOXICITY OF INDUSTRIAL ORGANIC SOLVBNTS marrow usually showed well-marked aplasia, but destructive changes were rarely noted without accompanying signs of regeneration. Hurwitz and Drinker (1915) were impressed by the fact that the blood platelets may remain at a high level at a time when the white cells have almost disappeared from the circulation. They suggest that this fact may be explained either by a very rapid regeneration of the megakaryocytes of the bone-marrow, forerunners of the blood platelets, or a higher resistance of these elements to the toxicity of benzol than of the forerunners of the polymorphonuclear leucocytes and erythro cytes. Schillowa (1933) also found that the number of blood platelets corre sponded with the number of megakaryocytes in the bone-marrow. Apitz and Hiihn (1942) have observed thrombopenia in rats poisoned by benzol. Factors of coagulation Although it has been observed by Duke (1913) that the blood of animals poisoned by benzol may clot at the normal rate even when the platelets are reduced to 10 per cent of the normal, it has also been shown that when the thrombocytes are at a very much reduced level the blood tends to show delayed coagulation, and the findings of the early observers, especially Santesson (1897), of symptoms of purpura haemorrhagica in clinical benzol intoxication gave* special point to investigation of this aspect of benzol poisoning in animals. The coagulation factors, prothrombin, antithrombin and fibrinogen, were in vestigated by Hurwitz and Drinker (1915). It was found that injections of benzol produced a diminution of circulating prothrombin, but that the antithrombin and fibrinogen were little changed from the normal. The reduction in pro thrombin is regarded as being due partially to the reduction of blood platelets, which contain prothrombin, but only partially. There was no parallelism between the extent of bone-marrow injury, the number of blood platelets, and the relative amount of prothrombin in the blood; therefore it appears that either some other tissue or organ in addition to the bone-marrow is concerned in prothrombin formation or that a minimum amount of myeloid tissue suffices to keep the quantity of prothrombin above a dangerous level. Immunity Reactions Many workers, including Rusk (1914), Schiff (1914), Simonds and Jones (1915), Hektoen (1916a), Wallbach (1933), Rich and McKee (1934) and Schnitzer and Goddard (1943), have described the inhibiting influence exerted by benzol on the natural immunity reactions of the body. Breakdown of Resistance to Infection Lowered resistance to pneumonia in rabbits has been observed by Wintemitz and Hiischfelder (1913) and Kline and Winternitz (1913), to tuberculosis in rabbits by White and Gammon (1914), to the common bacteria of inflammation, to the chemical irritants by Camp and Baumgartner (1915) and to streptococcal infection by Schnitzer and Goddard (1943). Most of the early investigators attributed this breakdown of natural resistance either to the reduction of phagocytic activity associated with the leucopenia produced by benzol poisoning, or to the inhibition of antibody formation. To these factors must now be added another--a profound modification of the inflammatory response in animals poisoned with benzol, postulated by Schnitzer and Goddard (1943). HYDROCARBONS S T0852623 25 . Phagocytic activity. Hektoen (1916a) and Wallbach (1933) found that in rabbits with benzene Ieucopenia the cytophagic index of the leucocytes for staphylococcus under the opsonic influence of normal rabbit serum fell to levels as low as 0*5 to 0*3, with leucocyte counts of about 1,800 per c.mm. Antibodyformation. Rusk (1914) recorded that the injection of benzol, either at the same time as or before the antigen, greatly reduced the formation of lysin for sheep corpuscles and ofprecipitin for horse serum. Simonds and Jones (1915) also observed a reduction of lysin for dog corpuscles, and of agglutinin and opsonin for typhuid bacilli. These findings were confirmed by Hektoen (1916a), ' but he, nevertheless, found that the toxic action of benzene on leucopoiesis did not interfere with a fully developed immunity. Modification ofinflammatory response. Schnitzer and Goddard (1943) observed a profound modification in the inflammatory response of tissues of benzol poisoned animals. The normal conditions of influx and outflow in the infected areas were reversed, so that the leucocytes, even if available, could not reach the " site of infection. This alteration in the inflammatory mechanism occurs only in tiifnkls which have not been immunized. In both actively and passively immun ised animals, localantibody formation appears to be sufficiently unimpeded to prevent the fatal outcome which occurs in non-immunized animals. 'fiffect on Metabolism 'y A.1deleterious effect of benzol on the general metabolism of animals seems to be indicated by the experiments of Underhill and Harris (1923). They found a sharp rise in the urinary elimination of both creatine and total nitrogen following subcutaneous injection of benzol into rabbits. Assuming that creatine is an index ofendogenous metabolism (Mendel and Rose, 1911), it would appear that benzol ..acts not only on the blood elements, but exerts a catabolic influence on body tissues as a whole. Alkali reserve According to Cavagliano (1932) no change takes place in the alkali reserve, estimated by the method of van Slyke, of animals in which the characteristic blood changes have been produced by chronic inhalation. . Vitamin C metabolism It appears from the investigations of Meyer (1937) that benzol intoxication in animals is associated with an increased consumption of vitamin C, though the evidence for this hypothesis was obtained only indirectly from the fact that the administration of large doses of vitamin C had a favourable influence on the symptoms induced by subcutaneous injection of benzene. The relation between benzene poisoning and the favourable effect of vitamin C administration is suggested by the researches of Frada (1937), Fischbach and Terbriiggen (1938), and others in the possible detoxicating effect of vitamin C in its stimulating action on liver function (see also p. 34). Phqsphatase activity ' According to AmbrOsio (1942), there is a perceptible diminution of phos phatase activity of the liver and kidneys in benzol poisoning in animals. He suggests that this may possibly be related to lesions of the liver and kidneys, and to endocrine and metabolic disturbances caused by benzol poisoning. ST0852624 26 TOXICITY OF INDUSTRIAL ORGANIC SOLVENTS Effect of Mixtures of Benzene and other Solvents Some experiments carried out by Svirbely, Dunn and von Oettingen (1944) appear to indicate that the chronic effect of benzene when mixed with its higher homologues, xylene and toluene, is more injurious to animals than that of benzene alone. Rats, dogs and monkeys were exposed for 7 hours daily for 5 days a week for 28 weeks to concentrations of 1,000 p.p.m. of mixtures con taining varied concentrations of benzene, xylene, toluene, and other hydro carbons. No significant differences were found in the blood picture following exposure either to the benzene or to the mixtures, but the pathological changes in rats, deposition of haemosiderin in the kidneys and toxic appearances in the spleen, were more severe with the mixed solvents. TOXIC EFFECTS IN MAN Absorption Absorption and Excretion Absorption of benzene takes place chiefly by inhalation. Whether there is any. absorption through the skin in human beings as in animals has been questioned, though litzner (1932) and, others believed it to be possible. An. experiment was carried out in 1947 by the Research Association of British Rubber Manufacturers, in which benzene liquid and vapour were applied to the thoracic skin of subjects prevented from inhaling the vapour. No detectable benzene was present in the expired air and the ratio of inorganic to total urinary sulphate was not changed. This confirms the observation of Cesaro (1946), that application of benzene to the skin was not followed by the disturb ance of the ordinary organic/inorganic sulphate ratio. In any case, absorption through the skin is less important than through the respiratory tract. According to Lehmann and Flury (1943), when benzene is inhaled by human beings 80 to 85 , per cent is absorbed within the first half-hour of exposure. Excretion Excretion of benzene takes place chiefly through the lungs (according to Feil (1933), nine tenths through the lungs, and scarcely one tenth in the urine). Benzene is not excreted as such in the urine, but is previously oxidized in the body to phenol, catechol, or hydroquinone, and is excreted in combination with sulphuric or glycuronic add (Nencki and Giacosa, 1880; Schmiedeberg, 1881; Jost, 1932). By oxidation of the benzene ring, a further portion is converted into muconic add (Jaffe, 1909), but according to Jost (1932), this substance is not of great importance in chronic benzol poisoning since it is only formed by rapid oxidation, and then only to a very small extent (Forssman and Frykholm, 1947). Jost has examined these constituents in the urine of workers in the printing industry, exposed to benzol, xylol and toluol, and in the case of benzol, he found a distinct increase in sulphuric and glycuronic adds, as well as in phenoL His actual figures, and the normal figures given by Tollens (1909) respectively, are given in Table 6. These results may be correlated with the findings of Yant, Schrenk, Sabers, Horvath and Reinhard (1936), and which have already been described in detail (p. 12). These investigators state that normally the total sulphates in the urine consist of85 to 95 per cent of inorganic sulphates, and 5 to 15 per cent conjugated. After exposure to benzol it is believed that phenolic products of oxidation or metabolism of the benzol become available, and that the conjugation reaction is HYDROCARBONS ST0852625 27 `increased with a shift of the system inorganic sulphates^conjugated sulphates to the right. TABLE 6 End-products in the urine after exposure to benzene Sulphuric acid........................... Glycuronic acid........................... Phenol: (1) Volatile phenol (phenol and cresol) ........................... (2) Non-volatile (dihydroxy- benzene) Normal dally average (g.) 018 0-62 Benzol poisoning daily average (g.) 0-407 1-08 0-03-0-07 0-015-005 0-17 007 ' It has been suggested by Yant and co-workers (1936), and by Kammer, Isenberg and Berg (1935) that the nature and reliability of the change in the sulphate ratio in the urine in animals is such that it could be taken as a measure in the exposure in workers before injury has occurred, and that estimation of the ratio would form a satisfactory method of medical supervision in a possible benzene hazard. Jephcott and Bulmer (1939) point out, however, that while the urinary sulphate test has some value in estimating the relative degree of exposure to benzene, it does not indicate the effect of exposure on the worker, and there is no invariable correlation between the haematological and urinary findings. This last statement was confirmed by Hamilton-Paterson and Browning (1944) during an investiga tion,Of women using rubber solutions containing benzene. Of seventeen women showing neutropenia, which these authors consider the earliest and most rdiable sign of benzene absorption, the partition of organic and inorganic Sulphates was in all cases within normal limits. Whether excretion of benzene takes place through the faeces is not certain, but an interesting point arising during the above-mentioned investigation by Hamilton-Paterson and Browning was the complaint by a number of the women examined that their faeces smelt strongly of benzene. Peacock (personal communication), on the basis of his work with fat-soluble substances, observes that these are to some extent excreted in the bile, and that some of the benzene may similarly find its way into the intestine and so be excreted with the faeces. Urinary sulphur analysis and laevorotation as a measure of benzene exposure. Owing to the discrepant values found by different authorities for the relative percentage of organic and inorganic sulphates in the urine, other criteria have been suggested by Gueffroy and Luce (1937). These percentages are obtained from estimations of the neutral sulphur in the urine and the increase of urinary laevorotation. An increase in the neutral sulphur is associated with the increased excretion of mercapturic acid characteristic of the metabolic disturbance caused by benzol poisoning; an increase of urinary laevorotation is said to indicate excessive excretion of phenylglycuronic acid. "? -Gueffroy and Luce found the urinary neutral sulphur to be up to 30 per cent in some workers exposed to benzol, as compared with the highest normal value Of 12 per cent, and these high values were in some cases associated with a lowered leucocyte total. ST0852626 28 TOXICITY OF INDUSTRIAL ORGANIC SOLVBNTS The polarization test showed no close agreement with the blood findings but is regarded as a sensitive indicator of the disturbed metabolism due to benzol absorption. A combination of both tests is suggested as being more reliable than the organic-inorganic urinary sulphate ratio. Blood phenol as a criterion of benzene absorption. Since estimation of the urinary sulphates does not take into account that part of the phenol which may be combined with glycuronic add during the detoxication by the liver of the toxic metabolites of benzol, Seghini (1941) suggests that estimation of the phenol compounds in the blood may be considered a more accurate index of benzol absorption. His method is based on the original technique of Theis and Benedict (1924) using a photometer with a scale of values corresponding to known quantities of phenol and giving the dosage in mg. per cent. The values given for twenty controls not exposed to benzol, and for thirty operatives employed in waterproof manufacture, are shown in Table 7. TABLE 7 Concentration ofphenol in the blood ofpersons exposed to benzene and a control group Free phenol Conjugated phenol Total phenol Controls (percent) 0-86-1-24 0-02-0-18 0-94-1-32 Exposed persons (per cent) 0-96-1-76 0-36-1-12 1-86-2-62 An increase in polyphenols and in urochrome A in the urine of workers exposed to benzene has also been noted by Forssman and Frykholm (1947), but these investigators consider that until there is more known about the factors which influence excretion of these substances, their analysis cannot be relied , upon as a criterion of benzene exposure. Acute Poisoning Lethal and Toxic Concentrations Flury (1928) gives the following figures: 20.000 p.p.m. (64 mg./l.) may be fatal if inhaled for 5 to 10 minutes; 7,500 p.p.m. (24 mg./l.) may be fatal if inhaled for 30 minutes to 1 hour; 3.000 p.p.m. (10 mg./l.) may be tolerated if inhaled for 30 minutes to 1 hour. Predisposing Factors The histories of the fatal cases, as described in the reports of the Benzol Poisoning Committee of the National Safety Council (1922), of McCord, Cox and O'Boyle (1932) and of Hamilton (1925), show great variation in individual susceptibility. Sometimes a man exposed for a short period died, while another, exposed for a longer period and more intensely, survived. Physical exertion associated with toxic conditions often ended fatally. In many instances members of a rescue party were fatally poisoned while the original victims, after a period of unconsciousness, survived. Such were the cases reported by Lewin (1907) and by Hamilton (1925), and they led to the belief that muscular exertion tends to increase the susceptibility to poisoning and to decrease correspondingly the prospects for recovery in acute cases. HYDROCARBONS ST 0852621 29 Emotional reaction has also been shown to be a factor in increasing the severity of the intoxication. In a case quoted by Feil (1933), the victim rushed suddenly out of the space where he had been working, cried out that he was burning and dropped dead, while a very interesting account of a "Massenver- 'tung" by benzol in a Russian factory was described by Dworetsky (1914) ^where the medical authorities considered that of the 230 persons involved, the :: greater number were affected by hysteria only, and that a few suffered from benzol poisoning together with hysteria. The interesting results of the experiments carried out by Nahum and Hoff - (1934) on the mechanism of sudden death in animals intoxicated with benzol appear to shed much light on this question of individual susceptibility in human beings. They point out that in muscular exercise there is a reflex cardio-acceleradon with a liberation of sympathin, while in excitement there is also a well" marked liberation of adrenaline into the blood stream. Their experiments on animals showed that benzol effects the liberation of adrenaline and sensitizes the myocardium to its action. The adrenaline and sympathin contribute to the production of ventricular extra-systoles, and the amount liberated determines the ' severity of the attack. Thus the danger of death from ventricular fibrillation is in. creased by either muscular exertion or emotional excitement or both, and Nahum and Hoff consider that many of the individual variations in susceptibility reported , in the literature may be due largely to variations in the adrenaline response. Symptoms The gravity of the symptoms of acute benzol poisoning is generally in accord with the amount absorbed and the length of exposure. In the cases reported .to the Factory Department since 1935, the fatal cases had been exposed, for ; .periods varying from 45 minutes to 3 hours, to concentrations which must have been very high, since practically all of them took place in closed spaces contain ing the vapour evaporating from residues of benzol. Feil (1933) describes several ' forms of acute benzol poisoning. '. (a) Mildform. A state of euphoria is followed, if the subject is not removed .from exposure, by giddiness, headache, nausea, vomiting, staggering gait, sensa tion of tightness in the chest,'and inability to escape from the site of the poison ing. Of the twenty non-fatal cases reported to the Home Office between 1921 and 1939, twelve might be regarded as in this class, eight of the patients were rendered partially unconscious, and four complained only of dizziness, headache or nausea. (b) Severeform. After inhalation of large amounts of the vapour, the principal symptoms, convulsive movements, paralysis, unconsciousness with dilated and , non-reacting pupils, are related to the central nervous system, and in the most severe cases are followed by death. Of the twenty-eight cases that from 1921 to 1939 were reported to the Home Office, eight were fatal, and eight other patients were rendered completely unconscious. According to Fischer (1932) this form of intoxication is not unlike that produced by other fat-soluble narcotics; he notes especially that there is no blue-grey colour of the face as in poisoning by nitrobenzene, though Hamilton observed cyanosis of mucous membranes and finger tips in some cases. (c) Atypicalforms. Intoxication is preceded by either coma or a state of violent excitement and delirium. Such is the case described by Feil (1933), and also one reported by Harrington (1917) of a man who is described as having acted "as if he had gone crazy", becoming wildly excited and jater unconscious. ST0852628 30 TOXICITY OF INDUSTRIAL ORGANIC SOLVBNTS After-effects in Non-fatal Cases In the majority of patients who recover from acute intoxication there are no immediate after-effects, except temporary symptoms such as pain in the head and chest,- shortness of breath, giddiness, loss of appetite, sometimes nausea, and even vomiting; late manifestations and sequelae have, however, been recorded. The most severe case is probably that recorded by the Chief Inspector of Factories and Workshops in 1918 of an ex-patient who, 2 nights after his return to work, relapsed into unconsciousness from which he never recovered. The chief sequelae of acute poisoning recorded are: (a) Dizziness and uncertain gait lasting about 12 days, as in the cases reported by Genhard (1910) and Wyss (1910). (b) Respiratory catarrh and pleurisy (Genhard, 1910; Schaefer, 1909; Robert, 1906). (c) Nervous disorders, depression, insomnia, bad dreams (Wyss, 1910), nervous exhaustion (Lewin, 1907). (d) Skin changes; a residual yellow pallor was observed in one of Lewin's cases (1907); Genhard (1910) reported an exanthem over the back. (e) Cardiac distress; spells of cardiac distress lasting 4 weeks after recovery were reported by Cronin (1924) and by Lewin (1907), who also observed a blowing murmur. Post-mortem Findings The earliest record of an autopsy on a case of acute benzol poisoning is that of Sury-Bienz (1888), in which the chief findings were bright red spots on the body and a dark red, fluid condition of the blood, which remained fluid for a long time after death. The chief results of post-mortem examinations since that time, including the very complete and detailed examination of a case made by Koppenhdfer (1935), may be summarized as follows: (1) Petechia! haemorrhages. The findings of Sury-Bienz in this respect were confirmed by Brinhauer (1896). Minute haemorrhages in the pleural, gastric and intestinal mucosa, and in the pancreas, were also noted by these two workers, by Buchmann (1911) in the brain and pericardium, in the lungs by Heffter (1915), Binder (1921) and Ziel (1925), in the subcutaneous fatty tissue and serous membranes by Floret (1926), in the brain, pleura, gastro-intestinal mucous membrane, kidney, pelvis, ureter and bladder by Koppenhofer. (2) Fluidity of the blood. The observations of a dark or cherry red fluid condition of the blood by the earlier workers was confirmed by Binder (1921), Heffter (1915) and Floret (1926). Heffter remarked (hat in spite of the blood remaining fluid for a long time after death, there was no evidence of haemolysis. The result of a test for methaemoglobin in the blood made in a case reported by Martland (quoted by Hamilton, 1931) was negative, but Carter (1928) stated that the spectroscopic appearances of the fluid blood in a fatal case were those of oxyhaemoglobin and that reduction was easily effected by ammonium sulphide. Koppenhdfer (1935) also demonstrated the presence of oxy- but not of methaemo globin. (3) Congestion or cyanosis of the Internal organs. Floret (1926) describes ithe phenomenon as "all the organs bring full of blood", as also does Ziel (1925). Cyanosis of the liver, spleen and kidneys in one case, and of the brain in another, was observed by Martland; in another case, cited by Hamilton (1931), there was fluid blood in the right side of the chest with marked distension. Koppenhbfer (1935) observed hyperaemia of all the internal organsand an albu minous fluid exudate in the liver and lungs. (4) Changes In the respiratory organs. Small areas of interstitial emphysema in the lungs, ' reddened and irritated bronchi (Martland), oedema of the lungs (Binder, 1921; Koppenhflfer, 1935), and "bloody mucus" in the air-passages (Heffter, 1915; Sury-Bienz, 1888) are among the findings reported, while in a case reported to the Home Office in 1925; the lungs showed HYDROCARBONS ST0852629 31 pent adheuoia and cyanoiis. In this cue, trace* of pyridine (0-5 per cent) were present in the 'vapour to which the man, a worker in a dye factory, waa exposed. (*T) Benzene in the Internal organs. There has been some difference of opinion as to whether benmoecan be detected, either by the odour, or by chemical analysis, in the organs after 'dwth. Martiand noted a distinct odour on section of the hrngi, while in the Home Office case - talready mentioned, the trachea, larynx and liver smelt of benzene. In another case .by Martiand (quoted by Hamilton', 1931), there was no distinctive odour in the lung cavity, or in the brain, although the autopsy was performed while the body was still warm. In Koppenhfifer's case (1935), the post-mortem examination was made 24 hours after death, and he states that a strong typical aromatic odour issued not only from the muscles as they were cut, and from the body cavity, but even more decidedly from the brain and spinal cord. With regard to the actual estimation of benzene in tbe tissues, and in spite of the state ments of Heffter (1915), Beinhaner (1896), and Buchmann (1911), that benzene could not be detected chemically in the bodies of subjects dying from acute poisoning, Koppenhdfer . has been able to ectimate its, pretence, not only qualitatively but quantitatively. He used a modification of tbe method,described by Peronnet (1934), obtaining needle-shaped crystals -pf, dinitrobenzene, and producing the intense violet coloration by adding a 1 per cent solution of laevuloee to an alkaline alcoholic solution of these. In contrast to the opinion of Heffter (1915) and of Jdachjmqghi (1915), that the greatest amount of benzene should be present in tbe brain, and that this should denote a special affinity of benzene for the lipoid tissue of the brain and spinal cord, KoppenhSfer found the highest percentage of benzene to be in the blood (Table 8). He calculated that the whole blood of the body of this man weighing 72 kg. would contain approximately lmL of benzene. He believes that in the most severe cases :pf.benzene poisoning, at any rate, the essential lesion is a colloid-chemical disturbance of the Mood rather than a disturbance of the lipoidal tissue of the central nervous system. TABLE 8 percentage ofbenzene in different organs (Koppenhofer, 1935) Organ Blood Spinal cord R. kidney Spleen Brain R. lung Liver Benzene (mg./100 g.) 140 126 10-3 9-4 7-5 5-5 5-3 . (6) Changes in the urine. No benzene was detected in the urine taken from the bladder after death by Heffter or by Martiand, but both, as well as Beisele (1912) and Simonin (1903), found an increased amount of "phenol bodies" (phenylsulphuric add in Hester's case). Heffter states that in cases which are rapidly fatal, phenol bodies are not usually found, since the change to conjugated adds is fairly slow. Urobilin, diminished urea and diminished chlorides were observed by Simonin (in a case of poisoning by accidental ingestion of benzol). No blood, albumin or haematoporphyrin were detected by Beisele. Treatment The usual measures are artificial respiration, administration of oxygen, etc., but intravenous injections of lecithin have been claimed by Nick (1922) to have saved life in ones case. ' v.-4. ... .. Chronic Poisoning ad iWbil animal experiments have undoubtedly elucidated sopie of the problems -of benzol poisoning in human beings, their results cannot be said to be applicable in all respects to human intoxication. The variation of individual and species. susceptibility, and the liability to infection of animals injected with benzol are .only two of the factors which make the complete picture of benzol intoxication ST0852630 32 TOXICITY OF INDUSTRIAL ORGANIC SOLVENTS unlike that found in human beings. Among the facts which have emerged from the more recent researches on the subject, perhaps the most outstanding is the variability in the clinical syndrome and blood picture hitherto regarded as typical. Undoubtedly the incidence of symptoms is a less reliable indication of poisoning than the blood picture, since there is often a striking variation between the two. Hamilton (1925) quotes a case where, with the typical symptoms of bleeding from the gums and nose, retinal haemorrhage and purpura haemorrhagica, the only abnormal feature of the blood picture was the absence of blood platelets. Much more frequent, in Browning's experience, is the comparative absence of symptoms when the blood picture reveals a very definite evidence of benzol poisoning. The blood picture of a woman, whose case is described on p. 39 as one of delayed benzol poisoning 2 years before the fatal outcome, revealed severe leucopenia and anaemia, but at the time she did not complain of any disturbance of health. In rare cases, such as that described by Friemann (1936), deterioration may even be so rapid that serious, or fatal, illness may set in very shortly, even after a blood examination has revealed no abnormality. Related Factors Sex, pregnancy and age. It has been rather generally believed that young subjects, particularly women, are specially liable to chronic benzol intoxication (Feil, 1933; Pulford, 1931; Meda, 1922; and others). Whether women are. actually more susceptible than men appears to be uncertain, since groups of opposite sexes working under exactly similar conditions do not seem to have been investigated. In Dimmel's investigation (1933) both men and women were affected, and though the conditions of work in this rubber factory were such that it was impossible to say definitely that both sexes were equally exposed, Dimmel found no grounds for believing that women showed more susceptibility 'than men. According to Danysz (1942), women invariably show a slight deterioration of the blood picture after 8 to 12 weeks' exposure, especially with regard to a fall in the total red cells, which men often escape. That women may suffer more from subjective symptoms than men having an equal degree of leucopenia is suggested by records secured by Smith (1928) in a camera-manufacturing factory, where among a group of thirty-five women only six made no complaint of symptoms such as headache, dizziness, nervous ness, weakness and great fatigue, and where eleven positive cases and one suspected case of benzol poisoning were found. Of fifteen men exposed under the same conditions, whose white cell counts were below 5,625, only one had symptoms associated with the work. An increased susceptibility in pregnant women has been definitely observed (Meda, 1922; Hamilton, 1925; Smith, 1928). The latter author quotes a case in which no symptoms appeared until the woman became pregnant; she then suffered from severe nausea, vomiting, bleeding from the nose, gums and rectum, and into the skin. After the birth of a premature child she had a severe uterine haemorrhage and died. According to Feil (1933) pregnancy should constitute an absolute contra-indication to the use of benzol. Youth, especially in women, was stated in the Report of the National Safety Council (1926) to be a predisposing factor, but this was not found to be the case by the New York State Department of Labor, 1927. The percentage of positive cases was lowest in the youngest group and highest in the oldest. Smith remarks that the opinion of earlier workers in this respect may have been due to the extreme youth of the women whom they studied. In the factory from which HYDROCARBONS ST 0 8 526 Selling'8 cases came for instance, all the fourteen girls exposed were between 14 and 16 years of age, whereas in the factories studied in the Department of Labor Report the average age was 28. length ofexposure. The findings of the Department of Labor seem to indicate X.. .that where susceptibility to poisoning exists it tends to develop during the first year, the percentage of positive cases being lowest in the group with an exposure t " bf 3 months or less, but showing little difference in groups with an exposure of 3 to 12 months, 1 to 4 years, and 4 years and over, respectively. According to L6vy (1935) a latent period may extend from 3 weeks to 6 months or even up to 3, 6 or 12 years. Among the cases reported to the Home Office since 1926, the time of exposure seems to have had little relation to the severity of the intoxication. Three cases exposed for 1}, 2 and 4$ years, respectively, were . comparatively little affected, while two cases of 4 months and 31 years exposure, respectively, both proved fatal. Feil (1933) emphasizes the fact that longcontinued exposure may result in a progressive hypersensitivity, while Danysz (1942) states that the critical period of evidence of deterioration of the blood picture arises 2 to 3 years after the first exposure. .. intensity of exposure. The actual amounts of benzol in the air of factories in which cases of benzol poisoning have been reported have already been discussed. In the fatal cases reported by Legge in 1918 the average amount was 550 p.p.m. It is interesting to observe that in the factory in which one of the . deaths occurred, that of a man employed for 6 months in coating the metal rims of tyres with a benzol solution of rubber, the ventilation had been diminished during the last 2 months by the carrying out of structural altera tions. The Report of the National Safety Council (1927) states that benzol poisoning occurs with greater frequency in cold weather when natural ventilation is usually reduced to a minimum by closed windows and doors so that the concentration in the atmosphere reaches a maximum. Atmospheric conditions of temperature and humidity also play an important part. At times of heat and high humidity, other things being equal, spontaneous and sporadic out breaks are most apt to appear. In an investigation of photogravure operatives in Milan, Saita and Domp6 (1947) considered that the abnormalities of the blood picture found in thirty-seven of the fifty-five workers examined were more or less closely correlated with the period of exposure, and also with the kind of work performed, the atmospheric concentrations varying in different parts of the room from 188 to 908 p.p.m. According to Ldvy (1935) and Merklen and Israel (1934), the intensity of exposure determines to some degree the type of blood picture. The latter states that the "classical aleukaemia" is only produced with long exposure and lack of individual resistance, while short and moderate exposure produces theformes frustes. Individual predisposition. According to L6vy this is the most important factor in determining whether a given time and intensity of exposure will produce symptoms of poisoning among a group of individuals. Weil (1935) has gone so far as to call it the "sol himatique"--an innate constitution of the haemopoietic tissues predisposing to their injury. - An apparent family susceptibility has been noted by Reifschneider (1922). He found three cases in one family; two of these proved fatal, the third patient with secondary anaemia was removed before other symptoms developed. Conditions of ill-health. General lowering of vitality, respiratory diseases, especially tuberculosis, alcoholism by virtue of its effect on the liver and brain, D ST0852632 34 TOXICITY OF INDUSTRIAL ORGANIC SOLVENTS heart disease, nervous disorders, nephritis by reducing the elimination of toxins, and obesity, are among the predisposing factors listed by the National Safety Council and by Feil (1933). Vitamin C deficiency. On the basis of animal experiments already described on p. 25, and the observations of Friemann (1936) and Meyer (1937) that workers exposed to benzene show a decreased urinary excretion and an increased con sumption of vitamin C, it has been suggested that toxic avitaminosis may be a factor in benzene poisoning. Many French observers believe that lack of vitamin C is an important predisposing factor in benzene poisoning. Roubinet (1939), for example, states that vitamin C deficiency appears to damage the liver and suprarenal glands; he urges, as a prophylactic measure, that vitamin C satura tion should be maintained in all workers exposed to benzene. Seyfried (1942) recommends vitamin C as a therapeutic measure, and states that there is a "slight haemorrhagic diathesis" among benzene workers which varies with the seasonal vitamin C intake, and that the therapeutic effect of vitamin C in their condition is rapid and complete. Blood group. According to Chevallier and Ddsoille (1947), statistics on the incidence of benzol poisoning in persons with various blood groupings suggest that individuals of Group A are the most susceptible and should therefore not be exposed. Symptoms Most common form The development of a syndrome pointing to damage of the blood-forming organs is preceded by slight preliminary symptoms--headache, giddiness, drowsi ness, lassitude, loss of appetite, nausea, even vomiting. Sometimes more definite symptom&appear at this stage, pallor, anaemic condition, metrorrhagia or menor rhagia in women, ecchymoses. L6vy (1935) states that at this stage tan examina tion of the blood would show Ieucopenia and neutropenia. Generally it is the occurrence of haemorrhages which reveal the condition as one of benzol poison ing--epistaxis, bleeding from the gums, persistent and heavy metrorrhagia, subconjunctival and retinal haemorrhages, ecchymoses and purpuric eruption, Haemoptysis, or even haematemesis, may occur; in a case reported to the Home Office in 1929 other symptoms (lassitude and oppression in the chest) were comparatively slight, and the changes in the blood picture were not of great severity (leucocyte count 4,800, with neutrophils 50 per cent and lymphocytes 39 per cent), but were preceded by haematemesis. Ulcerations of the buccal and tonsillar mucosa, scorbutic in appearance, are not uncommon, though according to Pulford (1931) they never progress to the gangrenous and sloughing condition found sometimes in agranulocytosis. The patient appears characteristically pale, dyspnoeic and anxious, has a rapid pulse and often a raised temperature. Neurological symptoms. Smith (1928) considers the symptoms related to the nervous system found in a number of women examined (Table 9) as evidence of the neurotoxic action of benzol. Similar evidence was provided in a case, also a woman, reported by Faur6-Beaulieu and L6vy-Bruhl (1922). The nervous symptoms took the form of increased tendon reflexes, bilateral clonus, positive Babinski reflex, impairment of deep sensitivity, pseudo-tabetic lesions with paraesthesia, ataxia and paraplegia and motor impairment, signs indicating lesions of the posterior columns and pyramidal tracts. Such lesions, according to the National Safety Council Report, were probably the combined effects of the prolonged and persistent anaemia, and of the possible direct action of the benzol ST 0852633 HYDROCARBONS 35 on the central nervous structure, inasmuch as it has been found that benzol is excessively held by these tissues. TABLE 9 Frequency of symptoms of benzene poisoning among women Complaint Headache Excessive fatigue Dizziness Nausea.......................... Anorexia Weakness Nervousness Numbness and tingling Frequent urination Nose bleeding .. Disturbed sleep Indigestion Frequent menstruation Shortness of breath Skin eruptions Vomiting Pain in abdomen No. Percentage 18 <50-0 14 46-7 13 43-3 10 33-3 9 300 8 26-7 6 200 3 16-6 4 13-3 4 13*3 4 13-3 4 13-3 3 10O 2 6-7 2 6-7 2 6-7 2 6-7 Neuritis of the median nerve and retrobulbar neuritis with dimness of vision and headache in a worker in spray lacquering have been observed by Land6 and Kalinowsky (1928) and by Goldmann (1930). Epilepsy has also been related directly to benzol poisoning by Korvin (1933). , She quotes the case of a female worker exposed to benzol who developed typical epileptic attacks after some months. No other clinical symptoms of benzol poisoning, except lassitude and loss of appetite were present, but she states that the diagnosis was strongly supported by the presence of a typical blood picture, a leucopenia of 2,000 and a relative lymphocytosis of 50 per cent. She also mentions a rather similar case reported by Albrecht in 1932, which was at first diagnosed as a brain tumour, but in which the diagnosis of benzol poisoning was made more probable by the favourable progress after removal from exposure. Localized myelitis in a benzol worker has also been observed by Saenger (1914). Spastic paresis, nystagmus and a positive Babinski reflex were present and recovery took place on removal from exposure. Frequency of urination was mentioned by Stair (1922) as a common symptom among the milliners whom he examined, and was attributed by him to the possible excretion of phenols in the urine. This symptom was also observed by Smith (1928) as a transient phenomenon. More severe form Many cases prove fatal in spite of removal from exposure to benzol. The picture is that of a progressive severe anaemia, ushered in .by purpuric manifesta tions; death occurs from a feW days to one or two weeks after the appearance of the purpuric symptoms. This was the type of case which first drew attention to the existence of benzol poisoning in industry, as in the famous cases of Santesson (1897) and in those reported by Le Noir and Claude (1897), Selling (1916), Hogan and Shrader (1923), Legge (1919-20, the first cases reported in Great ST 085263U 36 TOXICITY OF INDUSTRIAL ORGANIC SOLVENTS Britain), Harrington (1917), Flandin and Roberti (1922), and many others. It was the typical syndrome in a series of cases reported by Heim de Balsac and Agasse Lafont (1933) in workers using an adhesive where benzol was the solvent. Forty operatives were affected, eight of whom died; thirty-six showed purpuric manifestations,, eruptions, haemorrhage from the gums and nose, ecchymoses, and metrorrhagia. A feature of this outbreak was the delay in the onset of the purpuric symptoms, which appeared some days after the initial slight symptoms of headache, giddiness, digestive troubles, anorexia and asthenia. Cause of the purpuric manifestations. Although variations in the condition of the blood itself, such as thrombopenia or anaemia, are regarded as having some influence on the tendency to haemorrhage in benzol intoxication, they are appar ently not the whole cause (Litzner, 1932). Mitnik and Genkin (1931) have in fact observed no haemorrhage in the presence of severe thrombocytopenia, but con versely, haemorrhage in the presence of a normal blood platelet count; they also found no diminution in the fibrinogen and thrombin content of the blood. Injury to the capillary vessels has been put forward as an important factor in the cause of the haemorrhage by Santesson (1897), Land6 and Kalinowsky (1928) and Mitnik and Genkin (1931). Santesson related this injury to fatty degeneration of the capillary endothelium, and Mitnik and Genkin postulate a preliminary functional disturbance, in the sense of a strong vasomotor spasm with long continued stasis. Litzner (1932) also states that the Rumpel-Leeds sign, (pro duction of capillary haemorrhage by means of stasis) is an early symptom of benzol poisoning, and that this phenomenon, together with a lengthening of the time of bleeding in the presence of a normal coagulation time, constitutes further evidence of capillary injury. Terminal infection. Thus is often the cause of death in cases of grea^severity; it is believed to be due to a decrease in the leucocytic defences, as shown in the case of animals. Gangrenous periostitis and osteomyelitis were observed in a fatal case by Ldwy (1926), and severe haemorrhagic ulcerative gingivitis by Laignel-Lavastine, L6vy and Desoille (1928). This feature was also shown in two fatal cases (1934) reported to the Home Office. In the first subject, a leather sprayer, the anaemia was so severe as to arouse suspicions of pernicious anaemia, and at autopsy there was found a terminal sepsis of the tonsil and lower end of the oesophagus. In the second, a female worker in leather cloth and lacquers, death was due to aplastic anaemia with septicaemia, the latter arising from a septic endometritis. Slighter forms Cases of less severity with slight symptoms and no very great disturbance of the blood picture may recover under treatment and with removal from exposure. Such were the cases reported by Teleky and Weiner (1924) occurring in the manufacture of rubber goods. The symptoms were variable, headaches, nausea, eructation, vomiting, tendency to bleed from membranes, irritation of conjunctivae, menstrual irregularities and anaemia with reduced platelets and inversion of the leucocyte-lymphocyte formula. Substitution of benzine for benzol resulted in definite improvement both of the symptoms and of the blood picture. Latent form Falconer (1931) quotes a case where after 15 years' exposure the only demon strable sign of benzol poisoning was a reduction of blood platelets to 100,000 per c.mm. The patient was removed from exposure and 2 years later developed an HYDROCARBONS S T 0 8 5 2 f73 5 acute respiratory infection, followed by the full picture of benzol poisoning, which proved fatal. Falconer states that an infection such as influenza may precipitate frank benzol poisoning with leucopenia, anaemia, purpura, and haemorrhages several months after exposure. Cases of progress of the disease without further exposure have also been reported by Santesson, four of whose cases developed symptoms only after they had left the factory, and by Rohner, Baldridge and Hansmann (1926). In one of the cases reported by the latter authors, eye irritation was the only symptom during exposure, but haemorrhage and a fatal aplastic anaemia developed a month later. Duration of Symptoms after Removalfrom Exposure From the observations of Gounelle and Dumas (1935) it appears that benzol intoxication produces a lasting effect on the organism, manifested both by Symptoms existing for long periods after removal from exposure and by the persistence of an abnormal blood picture. Examination of four women, 16 to 18 months after removal from exposure because of purpuric manifestation and typical blood changes (Dumas, 1934; Israel, 1934), showed that they were still suffering from asthenia, fatigue, pallor, slight attacks of purpura, gingivitis with loss of teeth, and in two instances metrorrhagia and menorrhagia. Gounelle and Dumas (1935) remark that the metrorrhagia prolongs the injurious effect of the benzol and tends to produce a chronic hypochromic anaemia, which they have found resistant to iron therapy, except in so far as it produces a purely palliative result. Effect on the Skin Although a chronic toxic effect of benzol on the skin, of an eczematous nature, has been described by Lande and Kalinowsky (1928) and Oppenheim (1930), these are regarded by most workers when they occur as probably allergic in nature, or because of innate or acquired susceptibility, according to Engelhardt (1931). Land6 and Oppenheim have described them as characterized by follicu litis, comification of the seborrhoeic glands, hyperkeratosis and hyperpigmenta tion, and have regarded them as arising from the fat-solvent action of benzol on the superficial layers of the skin, leading to irritation and inflammation of the deeper layers. No such changes were observed by Dimmel (1933) in any of the sixty-six cases of benzol poisoning recorded by him. Effect on the Blood Picture While the most characteristic blood picture in benzol poisoning remains that described by the earlier writers, a leucopenia with neutropenia, thrombocyto penia and some anaemia, it becomes increasingly evident that this is by no means the invariable picture. Wide variations, such as hyperchromic anaemia of pernicious type, myeloid leukaemia with splenomegaly, and typical leu kaemia have been described by Weil (1933; 1935), Delor6 and Borgomano (1928), Loeper, Fabre and Borreau (1946), Lechelle, Coste, Thieffrey and Cuadrano (1940) and by others. Marked deviations in the red cell picture have also been observed; for example, L6vy (1935) states that anaemia is a much less constant, and much later feature, than disturbance of the white cell count, while Schwartz and Teleky (1941) state that "the maintenance of a normal count of red cells in the presence of other signs of damage in the blood is better explained by a stimulated compensating regeneration than by an uninjured erythropoiesis". ST 0852636 38 TOXICITY OF INDUSTRIAL ORGANIC SOLVBNTS Side by side with the undoubted destructive effects of benzol on the bonemarrow, there evolves a regenerative activity, and the resulting picture in any individual case is a reflection of the balance of these two opposing processes. It has been pointed out by Schwartz and Teleky (1941) that "there is no greater stimulus for regeneration than the products of decaying cells of the same kind.... Either the stocks of new-formed cells are time and again destroyed, in which case the result will be a hypo- or aplastic bone marrow, or regeneration surpasses destruction and the result is a gradual transformation of aplastic into hyperplastic bone marrow." This process has been specially emphasized by Jackson, Parker and Lemon (1940), Mallory, Gall and Brickley (1939) and by Bowers (1947). Although the histological picture was not that of a true leukaemia, the bonemarrow in Bowers' fatal case was grossly hyperplastic and there were extensive areas of extra-medullary haemopoiesis. Similar appearances observed by Jackson have been stated by him to be characteristic of the condition which he calls "agnogenic myeloid metaplasia". If, for instance, the regenerative, or stimulative process is uppermost, a leucocytosis or hyperglobulia may be present, which, according to the accepted criteria of "white cells not less than 5,000", and "red cells decrease of 25 per cent", would mean that any worker showing these high values for white and red cells should not be considered in any danger from further exposure. It may be, however, that these high values are evidence of excessive regeneration under the continuous stimulus of benzene, which, as in many other cases of biological over-stimulation, may be followed later by exhaustion and atrophy. In such a case further exposure would constitute a serious danger. Schwartz and Teleky (1941) suggest that another possible reason for the increase during recent years of atypical cases of benzol poisoning may be the greatly increased use of mixed solvents instead of benzene alone. It is possible that the effect on the blood of two or more substances may produce a different clinical picture from that of one acting alone, even though other consti tuents of the benzene mixture may be less destructive to haemopoietic activity than benzene itself. White cells Total count. The typical effect of benzol poisoning is a reduction of white cells, sometimes to a very low level. The lowest recorded appears to be 104 per c.mm. (Hogan and Shrader, 1923). In one of Selling's cases the total leucocyte count was 480, in Harrington's 500, and in Laignel-Lavastine's 600, while values from 1,000 to 2,000 are very frequently reported. It is stated by some authors, e.g. Livy (1935), that this reduction in white cells may go on to a complete agranulo cytosis, indistinguishable from true agranulocytic anaemia except by the history of exposure to benzol. In this connexion the work of Kracke and Parker (1934) on the effect of drugs containing the benzene ring is of interest. They state that such drugs, especially amidopyrin, may produce true agranulocytic anaemia, also caused by amytal, barbital, etc. Merklen and Israel (1934) point out that in man, as in animals (see Reznikoff and Fullarton, 1933), while hypogranulocytosis may result from the destruction of leucocytes by benzol, a liberation of immature granulocytic forms, myeloblasts, myelocytes, may be simultaneously provoked. So great was the leucopenia in the cases of benzol poisoning recorded by the earlier workers that in 1912 Koranyi suggested taking advantage of this leucopenic action of benzol by using it as a therapeutic agent in leukaemia. Favourable results from this treatment were reported by several workers, including Kiralyfi HYDROCARBONS ST 085263^ (1913), Billings (1913), Barker and Gibbes (1913) and others, but its dangers were pointed out by Pappenheim (1913) and Klemperer and Hirschfeld (1913); greatly varying results were reported in the hands of other workers such as Myers and Jenkins (1913). In later years, according to the Report of the National Safety Council (1926) "benzol therapy has more or less fallen into disrepute, due to lack of uniformity of action and the more or less transient nature of the results -.obtained.'' In view of the leukaemic effect of benzol reported by Weil (1932) (see below), the variation in the results of its administration is not surpris ing. In an investigation carried out by Hamilton-Paterson and Browning (1944), neutropenia was shown to be the commonest and earliest sign of benzene absorp tion, the leucopenia and a low polymorphonuclear count being concurrent. Atypical total counts. Leucocytosis has been reported by a few workers both as an initial phenomenon and as a consequence of intercurrent infection. Rabe and Hirschland (1920) observed an initial increase of leucocytes after administration of minute doses to men and women while Ldwy (1926) recorded an increase up to 16,000 in slight, fairly acute cases of poisoning. The presence of suppuration may also produce an increase of polymorphonuclear leucocytes (Paul, Friedlander and McCord, 1927; Meda, 1922). Leukaemia on the other hand has been reported by Delord and Borgomano (1928) and Weil (1933), and Loeper, Fabre and Borreau (1946). Weil describes two forms: (a) acute--as in Delord and Borgomano's case where a man, an employee in a chemical works, died within 3 weeks of the appearance of multiple enlarged glands, slightly enlarged spleen, anaemia with haemorrhages into the skin and mucous membranes, and gangrene of the palate; the white cells numbered 542,000, and myelocytes were present; (6) chronic--as in a case reported by Weil (1932), where a woman worker in a rubber factory died after 2 years of myelogenous leukaemia, with typical post-mortem findings. The white cell count in this case was 68,000. In the case recorded by Loeper, Fabre and Borreau, the leukaemia occurred 15 months after exposure to benzol had ceased. There was a profound anaemia and the white cell count was up to 58,000 per c.mm. Appreciable amounts of benzene were detected in the blood. A somewhat similar case was reported in 1947 to the Chief Inspector of Factories in which the leukaemia formed the terminal phase of an aplastic anaemia which had existed when the woman, employed in cementing rubber rings with a benzol rubber solution, was examined 2 years previously, but during these 2 years she had not been exposed. Saita (1945), describing a fatal case of aleukaemic leukaemia following exposure to benzol, considers that this syndrome should be regarded as a disease deserving compensation whether the terminal leukaemia follows directly or indirectly upon a primary benzol aplastic anaemia. Differential count. A relative lymphocytosis is found in most cases of benzol poisoning, the neutrophils being decreased in comparison with the lymphocytes. Instead of the normal ratio of 65 to 70 per cent polymorphonuclears to 20 to 30 per cent lymphocytes, values of 50 to 60 per cent polymorphonuclears and 40 to 50 per cent lymphocytes have frequently been recorded. Atypical differential counts, (a) Polynucleosis, a rise in the polymorphonuclear leucocytes (75 to 82 per cent) accompanying slight leucopenia, is postulated by Danysz (1942) and by Duvoir and D^robert (1946) as a sign of benzene absorp-' tion in a certain number of cases. (b) Lymphocytosis and monocytosis, not always accompanied by neutropenia, have been observed by Bernard (1942), Gamier and Cordier (1942), LaignelLavastine et al. (1928) and Brindeau (1931a). In a case described by Bernard, a ST0852638 40 TOXICITY OF INDUSTRIAL ORGANIC SOLVENTS female worker handling benzene, the total white cells were 15,300 with a lympho cytosis of 79 per cent (12,000 total). In this and other similar cases described by him, and also by Gamier and Cordier, the anomaly disappeared rapidly on removal of the patient from exposure. (c) Monocytosis, a rarer phenomenon, is regarded by Mazel, Picard and Bourret (1944) as not so much a direct consequence of benzol intoxication as an exaggeration of a disturbance of bone-marrow function found during recent years among workers exposed to other toxins, or even not exposed to any, .but possibly suffering from alimentary disequilibrium. These authors insist, however, that mononucleosis occurring in any benzol worker should be regarded as an indication for prohibition of exposure. (d) Immature white cells in the peripheral blood were noted by Mitnik and Genkin (1931), Jackson et al. (1940) and by Bowers (1947), who reports a fatal case showing hyperplasia of the bone-marrow with metamyelocytes 3 per cent, myelocytes 1 per cent and myeloblasts 2 per cent. (e) An increase in eosinophils has been recorded by some authorities, especially in France (Heim de Balsac and Agasse-Lafont, 1933; Dimmel, 1932, 1933; Duvoir and Derobert, 1942). Duvoir and Derobert, taking the lower limit of normal as 5 per cent, observed eosinophilia in 21-8 per cent in a series of 555 cases, the incidence being slightly higher in women than in men, and showing some correlation with time of exposure. No convincing explanation of this phenomenon is forthcoming, though some authorities appear to regard it as a sign of special resistance of the eosinophil cell to the toxic agent. This, Duvoir and Derobert remark, is somewhat paradoxical in view of the fact that the eosinophil granules are believed to consist of a protein-lipoid compound in which the lipoid constituent predominates. Dimmel (1932) regards eosinophilia as a favourable prognostic sign, but Duvoir and Derobert look upon it as a late mani festation. Other observers, including Teleky and Weiner (1924), and Browning have failed to observe any significant eosinophilia in chronic benzene poisoning. (f) An increase in basophil leucocytes has been recorded by Smith (1928). Red cells As a rule a reduction of red cells occurs during benzol poisoning, leading to a moderate degree of anaemia, but in certain cases anaemia of great severity is the outstanding symptom. Weil (1933) describes two forms of benzol anaemia: (a) slight, as described by Delarue (1919) and Chambovet (1921), with pallor of mucous membranes, fatigue, anorexia, dyspnoea on effort, and in women menorrhagia and metrorrhagia; (b) severe hyperchromic of the pernicious type, with a red cell count down to 1,860,000, and a colour index of T6. Similar cases have been described by Brindeau (1931a), Rivet and Gu6d6( 1928) and some fatal cases have been reported to the Home Office (1934). Total count. One of the lowest red cell counts recorded is that of a case of Brocher (1929)--630,000--while other very low values are 880,000 (Hogan and Shrader, 1923), 900,000 (Hayhurst and Neiswander* 1931) and 1,000,000 (Hamilton, 1925; Lande and Kalinowsky, 1928). The majority of cases, how ever, appear to range between 2 and 4 million per c.mm. Abnormalities. Degenerative changes, including anisocytosis, poikilocytosis (Rohner and co-workers, 1926; Schneider, 1930; Hayhurst and Neiswander, etc.), stippling, punctate basophilia, and even the appearance of nucleated red cells have been reported with some frequency (Hunter and Hanfiig, 1927; Ronchetti, 1922; von Oettingen, 1919; Brindeau, 1931a; Bowers, 1947). HYDROCARBONS ST 0852639 41 Resistance. According to Schneider (1930) the resistance of the red cells to haemolysis in benzol poisoning is never decreased and is sometimes slightly increased. Nucleated red cells. In a fatal case of benzene exposure, Bowers (1947) noted a progressive rise in nucleated red cells in the circulated blood. Reticulated cells. A slight reticulocytosis is recorded by Mitnik and Genkin (1931), also by Pulford (1931). Haemoglobin level and colour index. In most cases the haemoglobin level sinks concurrently with the red cell count so that the colour index is below 1, but in the severe cases, such as those described by Weil, etc., the haemoglobin remains relatively high and a colour index of above 1 results. In 2 of the fatal cases reported to the Home Office in 1934, the colour indices were 1 and 1-06 respectively. Dimmel (1932) found a high colour index to be a feature of the severe cases recorded in his investigation, lying between 1-1 and 1-3, and falling below 1 with improvement in the condition. Hamilton (1934) states that out of 75 cases the colour index was found to be low in 17, high in 22 and normal in 36 and that as a rule the lower the red cell count the higher the colour index. A case recorded by Selling (1916) was an exception to this rule, having very profound anaemia (640,000 red cells per c.mm.) with a low colour index (0-6). Blood platelets In nearly all cases where a platelet count has been made, thrombocytopenia has been recorded, the platelets sometimes falling to levels less than Vfr of the normal, e.g. 4,000 per c.mm. in a case of Mitnik and Genkin (1931), 600 in one of Brocher (1929). These low values usually occur in cases with severe purpuric manifestations but not always. Hamilton (1931), for example, observed no haemorrhage in a case with marked loss of platelets, and Mitnik and Genkin reported haemorrhage with a normal platelet count. Nikulina and Titowa (1934) agree that reduction of the number of blood platelets does not always result in haemorrhagic symptoms. They record one case with a thrombocyte count of 18,790 per c.mm. with no signs of bleeding, but state that with a high degree of thrombocytopenia the tendency to haemorrhage increases, and that this tendency is dependent also upon the length of exposure, i.e. it is present chiefly in persons exposed to benzol for a short period in spite of comparatively high thrombocyte counts, while amongst those exposed for a long period, a tendency to haem orrhage is only present with a high degree of thrombocytopenia. These workers found that when exposure to benzol is prolonged the thrombocyte count tends to increase, but they are unable to explain this finding. They have also attempted to correlate the degree of thrombocytopenia with the leucopenia, anaemia and relative lymphocytosis of typical chronic benzol poisoning, but have come to no more definite conclusions than that while no strict parallelism between these conditions can be postulated, thrombocytopenia is an earlier and more constant symptom than anaemia, that the number of thrombocytes tends to increase with a rising lymphocyte count, and that thrombocytopenia develops pari passu with leucopenia. According to Helmer (1944), thrombocytopenia is the most persistent feature of chronic benzene poisoning. In a series of serious cases in a factory manu facturing rubber raincoats in Sweden he found that after more than a year of work many of the workers showed a level not exceeding 200,000, though red cells, haemoglobin and leucocytes had long returned to normal. ST0852640 42 TOXICITY OF INDUSTRIAL ORGANIC SOLVBNTS Blood coagulation According to Simonin (1934) the coagulation time may be normal or delayed. Hayhurst and Neiswander (1931) found that the coagulation time was 4 minutes in a case with bleeding from the skin and mucous membranes. Brindeau (1931a) found it delayed in 2 cases with severe symptoms resembling pernicious anaemia, and Rohner and co-workers (1926) estimated it at 9 minutes in a fatal case, but Dimmel (1933) observed no delay in a series of 66 cases of varying severity. Coagulation itself, according to Simonin (1934), may be atypical, showing irretractability of the clot. Bleeding time is also variable, but is apparently more often normal than prolonged. It was prolonged (25 minutes) in the case recorded by Hayhurst and Neiswander, and those of Brindeau (1931b) and of Rohner and co-workers. Dimmel states that with extreme thrombocytopenia it is prolonged, otherwise normal or doubtful. Changes in the bone-marrow The changes in the bone-marrow described in the earlier literature of cases which came to autopsy were usually those of profound aplasia, affecting both the erythroblastic and leucoblastic elements. Selling (1911, 1916) described a bone-marrow practically depleted of leucocytes, and in cases recorded in the Home Office Reports for 1918 and 1931 respectively, the bone-marrow was des cribed as showing an aplastic anaemia identical with that produced by trinitro toluol poisoning and as "practically all replaced by yellow fat". However, later cases have shown that hyperplasia is by no means an infrequent sequela of chronic benzene poisoning. This was clearly shown in the series of cases des cribed by Mallory et al. (1939) whose observations included the histological examination of tissues from 14 autopsies and 45 biopsies. Of these exam inations only 6 showed hypoplasia of the bone-marrow while 9 showed hyperplasia. Extramedullary haemopoiesis was also found in the liver, spleen, and lymph nodes. Bowers (1947) describes a fatal case in which the bonemarrow hyperplasia . shown by sternal puncture during life was confirmed post mortem, and extramedullary haemopoiesis, both myeloid and erythroid, was also present. Persistence of benzene effect Studies by Goldwater and Tewksbury (1941) indicate that damage to the blood picture caused by benzene may persist for at least 2 years following cessation of exposure. Of 108 men re-examined 24 months after removal from exposure, 4 still had distinctly abnormal blood pictures. In a number of cases where re-examination was made after 2 months' interval of non-exposure, the finding that the blood picture showed further deterioration, even in spite of treatment with liver and vitamin B complex, suggested that the deleterious effect of benzene may continue to operate for some time after exposure has ceased. A similar observation was made by Browning in a number of photogravure process workers examined at intervals of 3 months after their first examination had been followed either by complete removal from exposure or continuance of work in conditions where exposure had been greatly decreased by improvement in exhaust ventilation and by the substitution of a solvent containing not more than 5 per cent of benzene (Table 10). HYDROCARBONS ST085264I 43 TABLE 10 Blood picture of two workers severely exposed to benzene Exam Exposure R.B.C. WJ.C ination x 10 per perejnm cunm. Hgb. per cent Colotu Poly- Lympho Eosino index morpbo- cytes phils nuclean percent percent percent Baso Large phils mono per cytes cent per cent No. 1 1 4 yean 4,472 2,250 86 2 2 months after 0-9 43 cessation 4,332 2,000 87 1-01 43 3 8 months after cessation 4,164 3,150 98 1-07 54-5 4 10 months after cessation 4,120 2,900 82 1 55 39 44-5 36 38-5 8 0 5 9-5 5-5 0-5 65 3 0 6-5 35 0 3 No. 2. 1 8 yean 2 2 months after con ditions improved 3 6 months later; con ditions further unproved 4 5 months later 3,990 3,676 3,648 4,360 3,425 3,400 3,350 ,3,400 70 72 66 76 0-9 39 1 49-5 0-9 32-5 0-9 42-5 49 5 43-5 62 51 3 1 7-5 1-5 0 ' 5-5 3-5 0-5 1-5 3-5 0 3 The "lag phenomenon", or appearance of symptoms long after exposure has ceased and in cases where no signs of intoxication were present during the period of exposure, has been reported by several observers. Usually the appearance of symptoms has coincided with some infectious disease, or with pregnancy, as in a fatal case reported to the Factory Department in 1945 and also one recorded by Perrault, Ddrobert and Tiret (1944). In a case described by Hunter (1939), symptoms occurred one year after cessation of exposure, following "heat stroke" and a septic infection of the leg; in a case reported by Smith (1943) the interval was 4 years, and in one reported by Meyer and Ginsberg (1942) the interval was 10 years. It may be assumed that the injury inflicted by exposure to benzol may not be apparent until extra demands upon the haematopoietic system are made by infection and disease. In the case recorded by Perrault et al. (1944), the presence of benzene was actually demonstrated in the bone-marrow at autopsy in amounts of 20 y per 100 g., 14 months after cessation of exposure, thus leading them to conclude that benzol, like many other chemical substances, may preserve its potential toxicity for long periods of time. The fact that in another fatal case investigated by Cachet, Jumi&re and D&obert (1944), no benzene was found in the bone-marrow does not, it is considered, invalidate the conclusion. The oxidation-reduction mechanism of the organism differs in individual cases, and these workers believe that in this case the local oxidation ST 0852642 44 TOXICITY OF INDUSTRIAL ORGANIC SOLVENTS was so intense that the benzol had completely disappeared after causing irreparable damage to the bone-marrow. Table 11 shows the features of the blood picture found in the chief investiga tions published. TABLE 11 Bloodpicture after benzene poisoning Author Haeao* R.B.C. Thrombo- W.B.C (lobin (millions eytet per (per cent) cm) (per e-mm.' (per um) Santeaaon (1897) .. Selling (1916) 80 20 8 3-7 0-6 0-64 __ Leueopenia Thrombo- 480 Diffenntlel count __ -- Other feature* __ -- McClure (1916) .. Harrington (1917) Horn* Office Report (191*) Newton (1920) PncUeee (1922) Hogen end Schrader (1923) Hamilton (1931) .. BrOckan (1923) 23 60 35 to -- __ 29 39 12 16 20 32 1-46 2*8 2*1 5-7 3-6 4-0 1-7 1-24 0-9 0-88 1-0 1-51 Thrombo penia _ _ __ Thrombo- __ -- 24,240 1,100 500 2.000 1,200 1,250 1,700 1,700 600 104 930 2,000 2460 ---- ---- -- __ ---- ___ -- ---- __ Lymphocytes 56 % Lymphocytes 52 % -- -- -- -- Lymphocyte* 42% Monocytes 10% Teleky end Weiner (1924) Rohnec f al. (1926) Window (1927) .. Smith (1928) Lendd end Krlinnwiky (1928) Leienet'Levutine tl al (1928) Brother (1929) Schneider (1930) .. Somntinl (1930) .. Pilcher (1932) AdUr-Herzmark (1930) Heyhurtt tl al. (1931) Brindeau (1931a) .. Ldwy (1926) Mitnik end Genkin (1931) Hepent and (1930) Kranenberg and Peeten (1928) Nikulina and Titowa (1934) Meriden end Isriel (1934) Pulford (1931) Newton (1920) Dimmel (1932) 55 60 fis 20 0-85 Under 30 08-3-4 Reduced 33 70 20 Slightly reduced 1-0 4-2 1-24 ii 0-63 47 2-2 56 2-34 80 2-6 __ 2-0 -- 3-0 10 0-9 50 1*638 22 0*9 30 26 33 63 69 73 Normal 65 1-3 1-6 2-4 3-9 4-1 4-85 Normal -- 70-79 70-79 60-83 21 80 18-110 3-5-4-0 3-3-4-0 2-S-4-5 1-2 4-7 0-78-5-3 -- 70.000 -- 34,000 -- 42,000 6,000 114,000 116_,000 -- 100,000 _ -- __ 4_,000 128,000 194--,000 -- 19,283 25,497 3,800230,000 94_,0_00 0-360,000 3.870 Lymphocytes 32% 3,500 Lymphocytes 42% -- 1.400 Lymphocytes 48% Anlio- and pofldlocytod* 1,450-6,140 lymphocytosis Leueopenia Lymphocytosis Myelocytes 2<x 3,200 600 Lymphocyte! 76 % Aniaocytoeii Lymphocyte* 35 % PoUdlocytodi, basophilia Monocyte* 51 % 2000 Lymphocyte* 39 % __ 4.640 Lymphocyte* 44 % Nucleated R3.C. 1,320 3,000 1,000 Lymphocyte* 44 % Poikiiocytotls, basophilia __ _-- 2000-3,000 -- 850 -- Anisocytosis. Bleeding time 25 min. Coagula- 1,770 -- tion time 4 min. Monocytoei* 1,300 1.800 -- Aniso- and poOdlocytoris, --nucleated RJLC. Lymphocytes 38 % --1,600 Lymphocytes 82 % Punctate basophilia 3,800 Lymphocytes 24 % 4,000 Lymphocyte* 29% Reticulocyte* increased 4,300 Lymphocytes 29 % 4.500 Lymphocyte* 40 % Slight Lymphocyte* *"" leueopenia 32% and 50% More then Lymphocytes so % reduction 4,737 LymphocyteU -- 6,300 Lymphocytosis 2700-8,600 Lymphocytes Monocytes 3-22%. Mye- 20-55% loblasts, myelocyte* 1,940 1,200 --Lymphocytosis Slight retictuocytods Monocytes 39% 170-9,600 Lymphocyte* Monocytes up to 18%. 8-60% Eosinophils up to 33%. Degenerated and young leucocyte*; megslocytes Lesions of the Internal Organs In such lesions as have been observed in autopsies of fatal cases it is difficult, as pointed out by Litzner (1932), to decide whether they are due to direct injury by benzol or to secondary injury from severe blood changes. HYDROCARBONS ST08526U34S Heart. Myocardial infarcts (Le Noir and Claude, 1897) and fatty degeneration of the muscles (Selling, 1916) have been recorded, while in the two (1918) cases in the Home Office Reports haemorrhages were found under the endothelium of the heart. Liver. Fatty degeneration (Selling, 1916, Loeper, 1941) and areas of necrosis (Rohner and co-workers, 1926) are recorded and also enlargement with excessive iron deposition (fatal case, Home Office Report, 1931). - Spleen. The reports of post-mortem examinations of the spleen appear to show less change than in experimental animals. Lande and Kalinowsky (1928) found it small and anaemic with no demonstrable histological lesions. In the 1931 Home Office fatal case the spleen showed excessive iron deposition. A spleen removed therapeutically by Hegler (1933) was very little enlarged; the sinuses were filled with erythrocytes and reticulo-endothelial cells. Adrenals. Petri (1930) states that the adrenals in benzol poisoning are deficient in fat and show areas of necrosis. , Gastro-lntestinal tract. In both the 1918 Home Office cases submucous haem orrhages were found throughout the intestinal tract, in the 1931 case melanosis of the small intestine and ulcers of the large intestine, and in the 1934 case submucous haemorrhages of the stomach. Gastritis, demonstrable by endoscopy, in the form of a more or less intense irritation of the mucous membrane, is stated by Chevallier and Moutier (1947) to appear usually within the first few weeks of exposure. It shows no parallelism ,, with blood changes, and when tolerance is developed, even without removal from exposure, the gastritis disappears. Treatment Therapeutic measures of various kinds have been tried, but apparently with little success if the poisoning has become severe. Dimmel (1932) states that in cases of severe injury there are no means by which it is possible to save life. The following measures have been tried: (1) Blood transfusion has been found to have no permanent value in severe cases of poisoning. (2) Irradiation of the bone-marrow and spleen had no success in Dimmel's cases. (3) Splenectomy was followed by recovery in a case reported by Hegler (1933). (4) Liver therapy and a vitamin-rich diet have been recommended in cases with a tendency to hyperchromic anaemia (Schneider, 1930; Dimmel, 1932, etc.). (5) Protein shock and adrenaline therapy with a view to stimulating the bonemarrow was also tried by Dimmel but with no definite results. DIFFERENTIAL DIAGNOSIS OF POISONING In diagnosing benzol poisoning from the three chief conditions in which leucopenia and anaemia are found together, it appears that the only indubitable distinguishing feature is a history of exposure to benzol. The criteria of the National Safety Council (1926) for benzol poisoning were as follows:--"A history of exposure to benzol and a white blood count below 5,600 is accepted as reasonable evidence of poisoning." The three chief conditions from which benzol poisoning may have to be distinguished are: (1) agranulocytosis; (2) aplastic anaemia (idiopathic); (3) thrombocytopenic purpura. Dimmel (1932) adds also septic aleukaemia, from which, he states, benzol poisoning in its final stages is practically indistinguish able, if accompanied by secondary infection. > MISCELLANEOUS ST0852644 399 BIBLIOGRAPHY Abb, M. (1933). Beitrag zur pathologischen Anatomic der chronischer Schwefelkohlenstoff vergiftung. Jap, J. med. Sci., VIII. (Internal Medicine), 3,1. Alters, B. J. and Lewby, F. H. (1940). Change* in nervous system following CS, poisoning in ,animals and man. Arch. Neurol. Psychiat., Chicago, 44 725. ,AndrS, M. J. (1947). Quelquea aspects neurologiques du sulfocarbonisme. Brux. mid., 44 2398. Antoniou, E. (1942). Un caso di intossicazione da dimetisolfato. Med. d. Lavoro, 33, 138. Audo-Gianotti, G. B. (1932). Le Parkinsonisme sulphocarbon6 professionnel. Pr. mid., 40, 1289. Audo-Gianotti, G. B. (1932). Richerche anatomo-patologiche sul' intossicazione sperimentali da solfuro di carbonio. Reus. Med. Lav. industr., 3,434. AuDO-GiANorm, G. B. (1934). Sulla patogenesie di gastriche e duodenali nell' intossicazione solfocarbonka professional!. Rass. Med. Lav. industr., 5, 446. Aufpret, J. (1946). L'industrie des fibres artifidelles et des dangers. Arch. Mai. prof., 7,181. Baader, E. W. (i932). An Hirntumor erinnernde Vergjftungserscheinungen dutch Schwefel- kohlenstoff. Med. Klinik, 28,1740. BalAzs, J. (1934). Dimethylsulfat-Vergiftung. Samml. Vergiftungsf, 5, 47, A414. Barthelemy, H. L. (1939). Ten years' experience with industrial hygiene in connection with the manufacture of viscose rayon. J. industr. Hyg-, 21, 141. Bashore and Staley (1938). Survey of CS, and H,S hazards in viscose rayon industry. Occu pational Disease Prevention Bulletin, No. 46. Dept Labor and Industry, Pennsylvania. Bionaml G. (1925). Modificazioni del sangue nell' awelenamento da solfuro di carbonio. Boll. Soc. med. chir. Pavia, 37, 745. Binbt, L. and Bourli^rb, F. (1944). Sur les modifications du sang au cours du sulfo-carbon- isme chronique. Arch. Mai. prof., 6, 12. Bonhoeffer, K. (1930). Ober die neurologiscben und psychischen Folgeerscheinungen der Schwefelkohlenstoffvergiftung. Mschr. Psychiat. Neurol., 75,195. Burner. Cited by Lehmann and Flury, 1943, in Toxicology and hygiene of industrial solvents. Williams and Wilkins, Baltimore. Bourret, J. and Kohler, C. (1946). Deux cas de polyntvrites par sulfocarbonisme pro fessionnel. Arch. Mai. prof, 7, 294. Brieger, G. (1941). The effects of carbon disulfide on the blood corpuscles. J. industr. Hyg., 23, 388. Brina, A. (1946). Duo casi di intossicazione da solfatodimetilico. Med. d. Lavoro, 37,225. Cazeneuve, P., Morel, A. and de Leeuw, H. (1932). L*bygiine et l'industrie de soie artificielle. Chim. et Industr., 28,473. Constensoux, M. G. and Hem, M. F. (1910). Frequence relative des stigmates nerveux dans le sulfo-carbonisme chronique. Question VI. 2me Congr. int. Mai. prof., Brussels. Corcos, A. (1940). Contribution to the study of occupation poisoning by cieosols. Rass. Med. Lav. indiutr., 11, 55 (abstr. in/, industr. Hyg., 22,124). Creskoff, A. F. (1938). Survey of carbon disulphide and hydrogen sulphide in the viscose rayon industry. Pennsylvania, Dept. Labor and Industry. Occupation disease prevention division. Bull., 46. Davis, P. A. (1929). Toxic substances in the rubber industry. Rubb. Age, N. Y., 26, 83. Deichmann, W. B. (1949). Phenol and phenolic compounds: in Patty, F. A., Industrial hygiene and toxicology. Part II, p. 1023. Interscience Publishers, New York. Deichmann, W. B. and Witherup, S. (1944). Phenol studies VI. The acute and comparative toxicity of phenol and o-, m- and p-cresols for experimental animals. /. Pharmacol., 80, 233. Delpech (1856). Accidents produits par l'inhalation du sulfure de carbone en vapeur: ex periences sur les animaux. Gaz. hebd. Mid. Chir., 3, No. 1, 384. Departmental Committee on Certain Miscellaneous Dangerous Trades. Final Report. H.M. Stationery Office, 1899. Department of Scientific and Industrial Research (1939). Leaflet No. 6: Carbon disul phide vapour. H.M. Stationery Office. Devoto, L. (1934). Schwefelkohlenstoff und Nebenniere (Addisons Krankheit?). Arch. Gewerbepath. Gewerbehyg., 5, 429. Duvoir, M., Hazemann, R., Deruelle, H. and Fallot, P. (1938). Sur l'intoxication pro fessionnel du ph6nol. Bull. Soc. mid. H6p., Paris, 54,106. Floret, F. (cited by Krause, F., 1931. Beitrag zur Frage der Schwefelkohlenstoffvergiftung. Z. ges. Neurol. Psychiat., 134, 139). Flury, F. and Zernik, F. (1931). Schadlkhe Gase, DSmpfe, Nebel, Rauch- und Staubarten. Springer, Berlin. Foreman, W. (1886). Notes of a fatal case of poisoning by bisulphide of carbon; with post mortem appearances and remarks. Lancet, H, 118. Francine, A. P. (1905). Acute carbon bisulfide poisoning. Amer. Med., 9, 871. Goodman. H. (1933). Silk handlers disease of the skin, Dermatitis venenata, due to isomers of cresol. Med. J. Rec., 138, 349. ST0852645 400 TOXICITY OF INDUSTRIAL ORGANIC SOLVENTS Gordy, S. T. and Thumper, M. (1938); Carbon disulphide poisoning, with a report of six cases. J. Amer. med. Ass., 110, 1543. Gordy, S. T. and Thumper, M. (1940). Carbon disulphide poisoning. Report of 21 cases Industr. Med., 9, 231. Haas, G. and Heim, M. F. (1910). Manifestations oculaires du sulfocarbonisme professionneL 2me Congr. int. Mai. prof., Brussels. Harmsen, E. (1905). Die Schwefelkohlenstoff Vergiftung im Fabrikbetriebe und ihre Verhdtung. Vjschr. gerichtl. Med., 30, 149. Heufer, W. C. (1936). Etiologic studies on the formation of skin blisters in viscose workers J. industr. Hyg., 18,432. Home Office (Great Britain) Factory Department (1935). Memorandum on precautions against dangers of poisoning; fire and explosion in connection with use of carbon bisul phide in artificial silk, India rubber, and other works. H.M. Stationery Office. Jones, G. W., Scott, F. E. and Scott, G. S. (1943). Limits of inflammability and ignition temperatures of acetic anhydride. US. Bur. Mines, Rep. Invest., No. 3741. Jump, H. D. and Cruice, J. M. (1904). Chronic poisoning from carbon bisulphide. Univ. Pa. med. Bull., 17, 193. Kaspar, J. A.. McCord, C. P. and Frederick, W. G. (1937). Toxicity of organic silicon compounds. 1. Tetraethyl-ortho-silicate. Industr. Med., 6. 660. Kungbr, M. E. and Norton, J. F. (1945). Toxicity of cresylic acid-containing solvent. US. Nav. med. Bull., 44,438. Koster, E. F. (1943). Abscess of lung and of brain as complications of "lysol" poisoning. Ohio St. med. J., 39, 840. Kranenbbro, W. R. H. and Kessener, H. (1925). Schwefelwasserstoff- und Schwefelkohlenstoff-vergiftungen. Zbl. GewHyg., 12, 348. Krause, F, (1931). Beitrag zur Frage der Schwefelkohlenstoffvergiftung. Z. ges. Neurol. Psychlat., 134,139. Laudenhbimer, R. (1899). Die Schwefelkohlenstoffvergiftung der Gummi-arbeiter unter besonderer Berficksichtigung der psychischen und nerv&sen Stdrungen und der Gewerbehygiene. Veit, Leipzig. Lehmann, K. B. (1894). Experimentelle Studien fiber den Einfluss technisch und hygienisch wichtiger Gase und Dfimpfe auf den Organismus. Arch. Hyg., Berl., 20,26. Lehmann, K. B. (1908). Untersuchungen fiber die Absorption von Schwefelkohlenstoff. Arch. Hyg., Berl., 67, 93. Lehmann, K. B. and Flury, F. (1943). Toxicology and hygiene of industrial solvents. (Tr. by E. King and H. F. Snjyth, jr.) Williams ana Wilkins, Baltimore. Lewby, F. H. (1939). Vitamin B deficiency and nervous diseases. J. nerv. ment. Dis., 89,1,174. Lewey, F. H. (194i). Neurological, medical and biochemical signs and symptoms indicating chronic industrial carbon disulphide absorption. Ann. intern. Med., 15,869. Lewey, F. H., with the co-operation of Alpers, B. J., Bbllet, S., Creskoff, A. C., Drabkin, D. L., Ehrich, W. E., Frank, J. H., Jonas, L., McDonald, R., Montoomery, E. and Reinhold, J. G. (1941). Experimental chronic carbon disulfide poisoning in dogs; a clinical, biochemical and pathological study. J. industr. Hyg., 23,415. Luio, B. (1913). Beitr&ge zur Schwefelkohlenstoff- und Benzolvergiftirng in akuten und chroni- seben Versuchen. Dissertation, Wfirzburg. McDonald, R. (1938). Carbon disulfide poisoning. Arch. Ophthal., Chicago, N.S., 20, 839. MacGregor, R. D. (1892). Supposed poisoning by the daily use of CSa. Aust. med. J., 14,622. Mattei, C. and S4dan, J. (1SS4). Contribution a l'itude de l'intoxication par le sulfure de carbone. Ann. Hyg. publ., Paris, N.S., 2, 385. Monbrun, A. and Facquet, J. (1932). Nivrite optique rftro-bulbaire par le sulfure de carbone. J. Mid. Chir.prat., 103, 657. Monbrun, A., Richet, C. and Facquet, J. (1932). La nivrite optique ritro-bulbaire par sul fure de carbone. Arch. Ophtal., Paris, 49,697. Mutschlbchner, A. (1924). Seltenere Vergiftungen. 1. Schwefelkohlenstofftabes. Dtschr. med. Wschr., 50, 210. Nectoux, R. and Gallob, R. A. (1931). Quatre cas de nivrite rttro-bulbaire par le sulfure de carbone. Bull. Soc. Ophtal., Paris, p.750. Negro, F. (1930). Lea syndromes Parkinsoniens par l'intoxication sulfo-carbonic. Rev. neurol., 37, 518. von Nida, S. (1947). Tbdliches Glottisddem nach Dimethylsulfatveriitzung der oberen Ver- dauungswege. Klin. Wschr., 24, 633. Obttel, H. (1936). Einwirkung organische Fliissigkeiten auf die Haut. Arch. exp. Path. Phar- mak., 183, 641. von Oetitnoen, W. F. (1949). Phenol and its derivatives. Nat. Inst. Hlth. Bull., 190. Offret, A. (1906). Essai sur l'amblyopie par le sulfure de carbone. Thise, Paris. Paluch, E. A. (1948). Two outbreaks of carbon disulfide poisoning in rayon staple fiber plants in Poland. J. industr. Hyg., 30, 37. Peterson, F. (1892). Three cases of acute mania from inhaling carbon bisulphide. Boston med. surg. J., 127, 325. Pierre-Marie, M. (1888). Sulfure de carbone et hystirie. Bull. Soc. mid. Hdp., Paris, 5,445. ST 0852646 MISCELLANEOUS 401 Quaebt.ij, O. (1930). Intossicazione da solfuro di carbonio neila lavorazione della seta artifidale. Med. d. Lavoro, 21, 247. Quarterly Sapbty Summary (1938). 9, 57. Fire and Explosion. Acetic anhydride. Laboratory accident during acetylisatlon. Published by Association ofBritish Chemical Manufacturers. Quensel, F. (1904). Neue Erfahrungen Ober Geistesstfirungen nach SchwefelkohlenstofiVer- giftung. Mschr. Psychiat. Neurol., 16, 48. Ranellbto, A. (1931). Die berufliche Schwefelkohlenstoffvergiftung in Italien. Klinik und Experimente. Arch. Gewerbepath. Gewerbekyg., 2, 664. Ra*teuj (1941). (Cited by Antonioli, E,, 1942, in: Gazz. Oip. Clin., No. 48.) Redaelu, P. (1925). Sull' anatomia patologica dell' awelenamento cronico da solfuro di carbonio. Boll. Soc. med.- chir., Pavia, 38, 133. Rjchter, R. (1945). Degeneration of basal ganglia from chronic carbon disulphide poisoning in monkeys. J. Neuropath, exp. Neurol, 4, 324. ROdenacker (1931). Die Bedeutung der {Constitution fOr die Schwefetkohlenstofferkrankung. Zbl. GewHyg., 18,17. Rowe, V. K., Spencer, H. C. and Bass, S. L. (1948). Toxicological studies on certain commercial silicons and hydrolyzable silane intermediates. J. industr. Hyg., 30, 332. Schramm, H. (1940). Eine seltene Schwefelkohlenstoff-Vergiftung. Samml. Verglftungsf, 10, 213, A826. Smyth, H. F., jr. and Seaton, J. (1940). Acute response of guinea pigs and rats to inhalation of the vapours of tetraethyl ortho silicate (ethyl silicate). J. industr. Hyg., 22,288. Sterner, J. H. (1949). Aliphatic nitro, diazo and amino compounds in Patty, F. A., Industrial hygiene and toxicology. Part II. p. 967. Interscience Publishers, New York. Terrien, F. (1920). Deux cas d'amblyopie de sulfure de carbone. Paris mid,, 35, 317. Tomassia, A. (1882). De l'intoxication suraigue par le sulfure de carbone. Ann. Hyg. publ., Paris, 3me sir., 7, 292. Veucoona, A. and Viziano, A. (1932). La reazione della perossidasi nel solfo-carbonismo. Policlirdco, 39, 297. Viouani, E. C. (1946). L'intossicazione cronica da solfuro da carbonio. Med. d. Lavoro, 37, 165. Waldhecker, H. (1941). Ueber die chemischen Desinfektionsmittel. MUnch. med. Wschr., 88, 949. Walshe, F. M. R. (1929). Carbon bisulphide intoxication. Proc. R. Soc. Med., 23, 89. Warneceb, F. (1941). Die gewerbliche Schwefelkohlenstoff-vergiftung. Arch. Gewerbepath. Gewerbehyg., II, 198. Warnecke, F. (1941). Gesunderhaltung in der Gummiindustrie. Zbl. GewHyg., 28,1. Weber, S. (1902). uber die Giftigkeit des Schwefelsfiure-dimethylesters; Dimethylsulfates und einiger verwandter Ester der Fettreihe. Arch. exp. Path. Pharmak., 47,113. Weise, W. (1933). Magen-Darm Erlcrankungen durch chronische Schwefelkohlenstoff- und chronische Schwefelwasserstoff-Inhalation. Arch. Gewerbepath. Gewerbehyg., 4, 219. Wiener, J. (1908). Quoted by Lehmann. K. B. (1908). Arch. Hyg., Berl, 67, 93. Wiley, F. H., Hueper, W. C. and von Oetiinoen, W. F. (1936). Toxic effects of low concen trations of carbon disulfide. J. industr. Hyg., 18, 733. Woodard, G., Lange, S. W., Nelson, K. W. and Calvery, H. O. (1941). Acute oral toxicity of acetic, choracetic, dichloracetic and trichloracetic adds. /. industr. Hyg., 23, 78. Zangger, H. (1930). uber die modemen organischen Lbsungsmittel. Arch. Gewerbepath. Gewerbehyg., I, 77. Zangger, H. (1930). Weitere Mitteilungen Ober Vergiftungen durch flQchtige Gifte und deren Beziehung zu gewerblichen Vergiftungen. Schweiz, med. Wschr., 60,1193. Zeouo, P. (1942). Su di una complessa sindrome nervosa de intossicazione sulfocarbonica. Med. d. Lavoro, 33, 121. Zeguo, P. (1942). Le alterazioni della funzionaliti gastrica nel solfocarbonismo cronico. Med. d. Lavoro, 33,217. Zeguo, P. (1946). Sulla prognosi delle polineurite solfocarbonio. Med. d. Lavoro, 37, 288. ST0852647 INDEX Acetal, 274 properties of, 274 toxic effects of, 275 toxicity of, 275 uses of. 275 Acetic acid, 392 Acetic anhydride, 392 properties of, 392 toxicity of, 393 uaes of, 393 Acetic ester (see ethyl acetate), 289 Acetic ether (see ethyl acetate), 289 Acetone, 320 absorption of, by inhalation, 321, 325 --, through skin, 323, 326 accumulation of, in tissues, 325 concentration of, maximum permissible, 321 --, in blood, 326 elimination of, 325 estimation of, in air, 320 explosive risks of, 321 lethal dose of, 321 narcotic dose of, 322 production of, 320 properties of, 320 toxic effects of, in animals, 321 --, --, acute, 322 --, --, --, symptoms of, 322 --, --, chronic, 323 --, --, --, on internal organs, 324 --, in man, 324 --, --, acute, 325 --, --, --, on internal organs, 325 --, --, --, from skin absorption, 326 --, --, --, symptoms of, 325 --, --, chronic, 326 --, --, --, blood changes from, 327 --, --, --, eye irritation from, 326 --, --, --, symptoms of, 326 toxicity of, basic, 321 --, comparison with other solvents, 321 uses of, 320 Acetone oils, 328 Acetylene dichloride (see dichloroethylene), 165 Acetylene tetrachloride (see tetrachloroethane), 154 Actylol (see ethyl lactate), 313 Adronol (see cyc/ohexanol), 236 Adronol acetate (see cyefahexyl acetate), 306 "Alanol" (see tetrachloroethane), 154 Allyl alcohol, 241 absorption of, 241 properties of, 241 toxic effects of, 241, 242 toxicity of, 241 uses of, 241 Amyl acetate, 299 eosinophilia from, 306 estimation of, in air, 300 lethal dose of, 301 maximum permissible concentration of, 301 narcotic dose of, 301 post-mortem changes by, 303 properties of, 299 toxic effects of, in animals, 301 --, --, symptoms of, 302 --, on blood, 305 --, in man, 303 --, --, symptoms of, 304, 305 --, on mucous membranes, 302, 303, 305 toxicity of, 300 urobilinuna from, 305 uses of, 299 Amyl alcohol, 232 absorption of, through skin, 235 concentration of, lethal, 234 --, maximum permissible, 234 estimation of, m air, 234 metabolism of, 234 properties of, 232 toxic effects of, 234 toxicity of, 233 --, relative to other alcohols, 233 uses of, 233 varieties of, 232, 233 Amyl chloride, 186 properties of, 186 uses of, 187 Amyl formate, 285 Amyl lactate, 314 Amyl propionate, 311 Amylene dichloride, 187 Anol (see eyc/ohexanol), 236 Anon (see cycfohexanone), 333 "Avantine" (see iropropyl alcohol), 224 Benzene, 3 absorption of, by animals, 10 --, by man, 26 --, --, blood phenol in, 28 concentration of, in factories, 5 --, toxic, 6 --, maximum allowable, 6 distinction from benzine, 3 distribution in body tissues of, 11 effect of inhalation of, in animals, 13 effect of injection of, in animals, 13 estimation of, in air, 6 --, in blood and tissues, 8 excretion of, by animals, 12 --, by man, 26 --, urinary laevorotation in, 27 --, urinary sulphur in, 12, 27 explosive risk of, 5 lethal and narcotic concentrations of, for animals, 14 lethal and toxic concentrations of, for man, 28 manufacture of, 4 mixtures of, with other solvents, 15, 26 poisoning, acute, after-effects of, 30 , in animals, 13 --, effect of, on blood, 15, 19-24 --, --, on body temperature, 15 --, --, on metabolism, 25 --, --, on resistance to infectipn, 24 --, local irritation by, 15 --, post-mortem findings in, 15 --, symptoms of, 14 in man, 28 --, post-mortem findings in, 30 -, symptoms of, 29 predisposing factors in, 28 . treatment of, 31 in animals, susceptibility to, 13, 20 chronic, in animals, 15 -, anaemia in, 22 402 ST 08526U8 INDBX 403 Benzene,--continued Poisoning, chronic, in animals, effect of, on alkali reserve, 25 -- --. --. --, on blood circulation 19 --, --, --, --, on haemoglobin level, 23 ----. --. --, on red blood cells, 16,20,22 -- --, --, --, on white blood cells, 21 -- --, --, --, on immunity reactions, 24 --, --, --, --, on bone-marrow, 17 --, --, --, --, on internal organs, 18 --, --, --, leucocytosis in, 16 --, --, --, leucopenia in, 16 --, --, --, phosphatase activity in, 25 --, --, --, symptoms of, 17 --, --, factors related to, 32 --, --, in man, 31 --, --, --, anaemia in, 37 --, --, --, aplastic anaemia in, 39 --, --, --, blood groups in, 34 --, --, --, duration of symptoms of, 37 --, --, --, effect of, on blood, 37-44 --, --, --, --, on blood coagulation, 42 -- --, --, --, on blood platelets, 36, 41 --, --, --, --, on differential count, 39 --, --, --, --, on haemoglobin level, 41 --, --, --, --, on internal organs, 44 --, --, --, --, on red blood cells, 37, 40 --, --, --, --, on skin, 37 --, --, --, --, on white blood cells, 38 --, --, --, lag phenomenon, 43 --, --, --, leucocytosis in, 39 --, --, --, leucopenia in, 38 --, --, --, leukaemia in, 39 --, --, --, persistence of effect of, on blood, 42 --, --, --, purpuric manifestations in, 36 --, --, --, regeneration of bone-marrow in, 37, 38 --, --, --, symptoms of, 31 --, --, --, terminal infection in, 36 --, --, --, treatment of, 45 --, differential diagnosis of, 45 --, in man, susceptibility to, 29, 33 --, and vitamin C deficiency, 25, 34 properties of, 3 toxic effects of, in animals, 10-26 --, in man, 26-46 toxicity of, 8 uses of, 4 varieties of, 3 Benzine, 79 absorption of, 82 addiction to, 91 comparison of, with benzene, 80 composition of, 79 lethal dose of, 81 mixtures of, with other solvents, 86, 87 narcotic dose of, 82 poisoning (see toxic effects) properties of, 79 tolerance to, 85 toxic concentrations of, 93 toxic effects of, in animals, 81-88 --, --, on red blood cells, 84, 86, 87 --, --, symptoms of, 83 --, --, on white blood cells, 84, 86, 87 --, on blood, 83, 84, 86, 87, 91 --, on bone-marrow, 88 --, on fat metabolism, 88, 92 --, on internal organs, 88 --, leucocytosis, 84, 92 --, leucopenia, 84, 87, 91 --, lymphocytosis, 91, 92 --, lymphopenia, 84, 87, 91 --, in man, 88-92 --, --, on red blood cells, 91, 92 --, --, symptoms of, 89, 90, 91 --, --, on white blood cells, 91, 92 --, on mucous membranes, 91 --, on nerves, 90, 91 --, on permeability of spinal membrane, 83 --, on resistance to infection, 85 --, sequelae of, 90 --, tendency to thrombosis from, 87 toxicity of, 80 --, influence of temperature on, 81 --, relative to benzene, 80 uses of, 80 varieties of, 79, 82, 83, 84, 86, 87 Benzol (see benzene), 3 Benzoline (see petroleum spirit), 74 Benzyl acetate, 309 lethal dose of, 310 narcotic dose of, 310 properties of, 309 toxic effects of, in animals, 310 --, in man, 311 toxicity of, 310 uses of, 309 Benzyl alcohol, 242 properties of, 242 toxic effects of, 243 toxicity of, 242 uses of, 242 Benzyl formate, 286 Butanol (see n-butyl alcohol), 227 Butanol-2 (see secondary butyl alcohol), 230 Butanone (see methyl ethyl ketone), 328 "Butol " (see n-butyl butyrate), 312 Butoxyl, 308 iroButy! acetate, 298 n-Butyl acetate, 295 concentration of, maximum permissible, 296 --, toxic, 296 lethal dose of, 296 narcotic dose of, 296 properties of, 295 toxic effects of, in animals, 296 --, --, symptoms of, 297 --, in man, 297 --, --, symptoms of, 297 secondary Butyl acetate, 298 rioButyl alcohol, 231 n-Butyl alcohol, 227 concentration of, maximum permissible, 228 toxic effects of, 228 --, symptoms of, 229 toxicity of, 228 uses of, 227 secondary Butyl alcohol, 230 tertiary Butyl alcohol, 231 toxic effects of, 232 n-Butyl butyrate, 312 Butyl carbitol (see diethylene glycol mono-n- butyl ether), 360 iroButyl carbinol (see amyl alcohol), 232 secondary Butyl carbinol (see amyl alcohol), 232 ST 08526U9 404 IN! BX Butyl cellosolve (see ethylene glycol mono-nbutyl ether), 353 n-Butyl formate, 284 concentration of, toxic, 285 properties of, 284 toxic effects of, in animals, 284 --, in man, 285 uses of, 284 Butyl lactate, 314 n-Butyl propionate, 311 Carbitol (see diethylene glycol monoethyl ether), 358 Carbon disulphide, 380 absorption of, 384 concentration of, maximum permissible, 381 --, toxic, 380, 381, 382, 383 estimation of, in air, 382 --, in blood, 385 excretion of, 384 explosive risk of, 380 lethal dose of, 382 poisoning (see toxic effects) --, preclinical, 386 --, susceptibility to, 391 --, vitamin Bi deficiency and, 384 properties of, 380 toxic effects of, 382 --, on adrenals, 390 --, anaemia from, 386, 390 --, in animals, 382 --, on blood, 383, 390 --, on eyes, 383, 389 --, hysterical manifestations, 387 --, in man, 384 --, on nervous system, 383, 386, 387 --, Parkinsonian syndrome, 388 --, polyneuritic syndrome, 388 --, post-mortem findings, 382, 391 --, psychoses, 386, 387 --, --, mechanism of action of, 386 --, on sexual function, 391 --, on sulphvr metabolism, 384 --, symptoms of, 382, 385, 387 toxicity of, 380 uses of, 380 Carbon tetrachloride, 128 dangerous concentrations of, 130 estimation of, in blood, 132 impurities in, 129, 130 lethal dose of, 134 narcosis from, 141 narcotic dose of, 135 phosgene formation from, 129, 132, 141 poisoning (see toxic effects) --, methionine therapy in, 138, 140, 143, 148 --, persistent effect of, 143 --, post-mortem findings in, 140, 147 --, predisposing factors to, 131, 133 --, susceptibility to, 133, 149 --, tolerance to, 149 --, treatment of, 148 preparation of, 128 properties of, 128 toxic effects of, 133 --, acidosis from, 134 --, amblyopia from, 147 --, in animals, 133 --, --, on blood, 137 --, --, symptoms of, 135, 137 --, on blood calcium, 147 --, on blood urea, 141, 142, 145, .146 --, effect of diet on, 138 --, on internal organs, 133, 135, 137 --, on kidneys, 135, 137, 139,140, 142 --, --, regeneration of, 138 --, on liver, 133, 135, 136, 137, 145 --, --, regeneration of, 138 --, --, yellow atrophy of, 134, 135, 140 --, on lungs, 141 --, in man, 139 --, --, on blood, 147 --, --, symptoms of, 139, 140, 141, 144, 148 --, on metabolism, 134, 142, 146 --, on nerve tissue, 138 --, on nervous system, 136, 145 --, on skin, 147 --, on urine, 142, 146, 148 toxicity of, 130 --, relative to chloroform, 136 uses of, 130 --, in fire extinguishers, 132, 140, 141, 142 Cellosolve (see ethylene glycol monoethyl ether), 348 Cellosolve acetate (see ethylene glycol mono ethyl ether monoacetate), 351 Chlorex (see $S'-dichloroethyl ether), 266 Chlorobenzene (see monochlorobenzene), 187 Chlorobenzol (see monochlorobenzene), 187 2-ChloroethyI alcohol (see ethylene chloro- hydrin), 246 Chloroform, 124 absorption of, 127 addiction to, 128 as anaesthetic, 124 concentration of, maximum permissible, 125 estimation of, in brain, 127 excretion of, 127 lethal dose of, 125, 127 narcotic dose of, 125, 127 poisoning (see toxic effects) properties of, 124 tolerance to, acquired, 126 toxic effects of, in animals, 125 --, --, symptoms of, 126 --, hypoglycaemia, 126 --, on liver, 126 --, local irritation from, 126, 128 --, in man, 127 --, --, symptoms of, 128 toxicity of, 124 uses of, 124. Chloropropylene glycol (see monochlorohydrin), 250 Chlorosilanes, 398 Chlorylene (see trichloroethylene), 169 Coal tar solvent naphtha, 70 distinction of, from petroleum naphtha, 70 properties of, 70 toxic effects of, 71 toxicity of, 71 uses of, 71 Columbia spirit (see methyl alcohol), 202 Cresols, 393 absorption of, 395 excretion of, 395 ST 0852650 INDBX 405 Cresols,--continued lethal dose of, 394 metabolism of, 395 properties of, 393 toxic effects of, 394 --, local, 394 --, systemic, 394, 395 toxicity of, 394 --, relative to phenol, 394 uses of, 393 Cresylic acid (see cresols), 393 Cumene, 64 concentration of, "hazard index", 65 metabolism of, 65 poisoning (see toxic effects) properties of, 64 toxic effects of, in animals, 64 toxicity of, 64 uses of, 64 Decahydronaphthalene, 68 concentration of, lethal, 69 properties of, 68 toxic effects of, in animals, 69 --, in man, 69 toxicity of, 69 uses of, 69 Decalin (see decahydronaphthalene), 68 Diacetone alcohol, 244 concentrations of, lethal and narcotic, 244 properties of, 244 toxic effects of, in animals, 244 --, in man, 245 toxicity of, 244 uses of, 244 Dialkyl carbonates, 316 Diatol (see diethyl carbonate), 315 "Dichloren" (see under dichloroethylene), 168 orrAo-Dichlorobenzene, 189 concentration of, toxic, 191 estimation of, in air, 190 properties of, 189 toxic effects of, in animals, acute, 190 --, --, chronic, 191 --, on internal organs, 191 --, leucopenia, 191 --, in man, 191 toxicity of, 190 --, relative to other solvents, 190 uses of, 189 j^m.-Dichloroethane, 149 concentration of, maximum permissible, 150 distinction of, from a-dichloroethane, 149 --, from dichloroethylene, 149 lethal dose of, 150 narcosis due to, 150 narcotic dose of, 151 poisoning (see toxic effects) properties of, 149 toxic effects of, in animals, 150 --, --, symptoms of, 151 --, on cornea, 152 --, dermatitis, 153 --, effect of diet on, 152 --, on kidneys, 152, 153 --, leucocytosis, 153 --, on liver, 152, 153 --, in man, 152 --, --, symptoms of, 153 --, post-mortem appearances in, 152,153 --, on urine, 153 toxicity of, 150 --, relative to other solvents, 150 uses of, 149 ^'-Dichloroethyl ether, 266 concentration of, maximum permissible, 266 properties of, 266 toxic effects of, 266 --, symptoms of, 267 uses of, 266 Dichloroethylene, 165 concentrations of, lethal and narcotic, 166 properties of, 165 toxic effects of, 166, 168 toxicity of, 166 uses of, 166 Dichlorohydrin, 251 properties of, 251 toxic effects of, 252 toxicity of, 252 uses of, 251 Dichloromethane (see methylene dichloride), 122 1:2-Dichloropropane (see propylene di chloride), 185 1:3-Dichloropropan-2-ol (see dichloro hydrin, 251 Dichloroiropropyl alcohol (see dichloro hydrin), 251 Dicyc/ohexylamine, 365 Dicyc/opentadiene, 107 Dielene (see dichloroethylene), 165 Dioform (see dichloroethylene), 165 Diethanolamine, 366 Diethyl acetal (see acetal), 274 Diethyl carbonate, 315 Diethyl cellosolve (see ethylene glycol diethyl ether), 352 Diethyl ether (see ethyl ether), 261 Diethyl oxalate, 316 concentration of, toxic, 317 properties of, 316 toxic effects of, 317 --, on blood, 317 toxicity of, 317 uses of, 317 Diethylene dioxide (see dioxan), 268 Diethylene glycol, 356 absorption of, by skin, 357 properties of, 356 toxic effects of, in animals, 357 --, on bladder, 357 --, on kidneys, 357 --, on liver, 357 --, in man, 357 toxicity of, 357 --, relative to ethylene glycol, 357 uses of, 356 --, in cigarettes, 357 Diethylene glycol monoacetate, 360 Diethylene glycol mono-n-butyl ether, 360 Diethylene glycol monoethyl ether, 358 lethal dose of, 358 properties of, 358 toxic effects of, in animals, 358 --, from cosmetics, 358, 360 --, from ingestion, 359 406 INDEX ST085265I Diethylene glycol monoethyl ether--continued toxic effects of, on kidneys, 359 --, in man, 360 --, on nervous system, 359 toxicity of, 358 uses of, 358 Dihydroxydiethyl ether (see diethylene glycol), 356 Dimethoxymethane (see methylal), 274 Dimethylacetonylcarbinol (see diacetone alcohol), 244 Dimethylbenzene (see xylene), 55 Dimethyl carbinol (see isopropyl alcohol), 224 Dimethyl ketone (see acetone), 320 Dimethyl sulphate, 395 mode of action of, 396 properties of, 395 toxic effects of, 396 toxicity of, 395 uses of, 395 Dioform (see dichloroethylene), 165 Dioxan, 268 absorption of, by skin, 272 concentration of, maximum permissible, 269 lethal dose of, 269, 271 narcotic dose off 269, 271 properties of, 268 tolerance to, 271 toxic effects of, in animals, 269 --, on blood, 273 --, on internal organs, 270, 271, 273 --, on kidneys, 270, 271, 272, 273 --, in man, 272 --, post-mortem findings in, 271, 272, 273 --, symptoms of, 272 toxicity of, 269 uses of, 269 Dipentene, 106 Dipropylene glycol, 361 toxic effects of, 361, 362 Dissolvan C.A. and D.N. (see acetal), 274 "Dukeron" (see under trichloroethylene), 171 "Emaillet" (see tetrachloroethane), 154 "Enodrin" (see under dichlorohydrin), 252 Estisol (see ethyl lactate), 313 Ethanol (see ethyl alcohol), 217 Ethanolamines, 366 properties of, 366 toxic effects of, 367 toxicity of, 366 uses of, 366 2-Ethoxyethanol (see ethylene glycol mono- ethyl ether), 348 Ethoxysilanes, 398 Ethyl acetate, 289 concentration of, toxic, 292 lethal dose of, 291 narcotic dose of, 291 properties of, 289 toxic effects off in animals, 291 --, --, symptoms of, 291 --, on blood, 292 --, in man, 292 --, --, symptoms of, 292 toxicity of, 290 uses of, 290 Ethyl alcohol, 217 absorption of, by inhalation, 219 --, by skin, 220 concentration of, in internal organs, 220 --, toxic, 219, 220 estimation of, in air, 218 lethal dose of, 218 narcotic dose of, 218 oxidation of, 217 poisoning (see toxic effects) preparation of, 217 properties of, 217 toxic effects of, in animals, 218 --, --, symptoms of, 218 --, on internal organs, 219 --, in man, 220 --, --, symptoms off 221 toxicity of, 217 --, relative to methyl alcohol, 217 uses of, 217 Ethylbenzene, 63 concentration off dangerous, 64 metabolism off 64 toxic effects of, in animals, 63 --, in man, 64 toxicity of, 63 Ethyl benzoate, 313 Ethyl ether, 261 absorption of, 262 concentration of, maximum permissible. 262 decomposition of, products of, 261 "ether habit", 265 excretion of, 262 explosive risk of, 261 impurities of, 261 lethal dose of, 263 narcotic dose of, 263 properties of, 261 toxic effects of, in animals, 262 --on blood, 265 --, in man, 264 --, on metabolism, 263 --, symptoms of, 263,264,265 toxicity of, 262 uses of, 262 Ethyl formate, 281 concentration off toxic, 283 lethal dose of, 282 narcotic dose of, 283 properties of, 281 toxic effects of, in animals, 282 --, --, symptoms of, 283 --, in man, 284 toxicity of, 282 uses of, 282 Ethyl glycol acetate (see ethylene glycol monoethyl ether monoacetate), 351 Ethyl hydroxyriobutyrate, 315 Ethyl lactate, 313 Ethyl oxybutyrate (see ethyl hydroxyiio- butyrate), 315 Ethylene chlorohydrin, 246 absorption of, by skin, 247, 250 concentration of, maximum permissible, 246 poisoning by, conditions conducive to, 250 --, post-mortem findings in, 249 properties of, 246 toxic effects of, in animals, 246 --, --, symptoms of, 247 --, on internal organs, 248 ST 0852652 INDBX 407 Ethylene chlorohydrin--continued toxic effects of, in man, 248 --, --, symptoms of, 249 toxicity of, 246 uses of, 246 Ethylene dichloride (see sym.-dichloroethane), 149 Ethylene glycol, 340 concentration of, toxic, 344 lethal dose of, 342 properties of, 340 tOXIC effects Of, in animals, 342 --, on internal organs, 344 --, on kidneys, 343, 344 --, local irritation from, 343 --, in man, 344 --, post-mortem findings in, 344 --, symptoms of, 342, 344, 345 --, on urine, 344, 345 toxicity of, 340 --, relative, 341 uses of, 340 Ethylene glycol diacetate, 356 Ethylene glycol diethyl ether, 352 lethal and narcotic doses of, 352 Ethylene glycol monoacetate, 355 Ethylene glycol mono-n-butyl ether, 353 concentration of, toxic, 354 "hazard index" of, 354 lethal dose of, 353 properties of, 353 toxic effects of, in animals, 353 --, on blood, 355 --, on internal organs, 354 --, in man, 355 --, symptoms of, 354 --, on urine, 354 toxicity of, 353 --, relative, 354 uses of, 353 Ethylene glycol monoethyl ether, 348 concentration of, toxic, 349 lethal dose of, 350 properties of, 348 toxic effects of, in animals, 349 --, on blood, 350, 351 --, on internal organs, 350 --, on kidneys, 348, 350 --, in man, 350 --, on urine, 351 toxicity of, 348 --, relative, 349 uses of, 348 Ethylene glycol monoethyl ether mono acetate, 351 properties of, 351 toxic effects of, in animals, 351 --, in man, 352 Ethylene glycol monomethyl ether, 345 concentration of, in atmosphere, 345 estimation of, in air, 346 lethal dose of, 346 properties of, 345 toxic effects of, in animals, 346 --, on blood, 347, 348 --, on internal organs, 346 --, on kidneys, 346, 347 --, in man, 347 --, on nervous system, 347 --, on urine, 347 --, "toxic encephalopathy", 347 toxicity of, 345 uses of, 345 Ethylidene diethyl ether (see acetal), 274 Eusolvan (see ethyl lactate), 313 Formal (see methylal), 274 Gasoline (see petroleum spirit), 74 Glycol chlorohydrin (see ethylene chloro hydrin), 246 Heptanaphthene (see methylcyclohexane), 98 Hexahydrobenzene (see cyclohexane), 94 Hexahydrocresol (see methylcyclohexanol), 239 Hexahydrophenol (see cyclehexanol), 236 Hexalin (see cyclohexanol), 236 Hexahydrotoluene (see methylcyc/ohexane), 98 Hexalin acetate (see cyclohexyl acetate), 306 Hexamethyldisiloxane, 397, 398 Hexamethylene (see cyclohexane), 94 cycloHexane, 94 concentrations of, maximum permissible, 95 --, lethal and narcotic, 95 manufacture of, 94 properties of, 95 toxic effects of, in animals, acute, 95 --, --, on blood, 97, 98 --, --, chronic, 97 --, --, on internal organs, 97 --, --, on metabolism, 97, 98 --, --, symptoms of, 96, 97 toxicity of, 95 uses of, 95 cycloHexanol, 236 concentration of, maximum permissible, 237 lethal dose of, 237 narcotic dose of, 238 properties of, 236 toxic effects of, in animals, 237 --, in man, 239 --, on metabolism, 239 --, symptoms of, 238, 239 toxicity of, 237 uses of, 237 Hexanon (see cyclohexanone), 333 cycloHexanone, 333 concentration of, maximum permissible, 333 properties of, 333 toxic effects of, 334 --, on metabolism, 334 toxicity of, 333 uses of, 333 Hexone (see methyl irobutyl ketone), 331 cycloHexyl acetate, 306 concentration of, toxic, 307, 308 properties of, 306 toxic effects of, in animals, 307 --, in man, 308 toxicity of, 307 uses of, 306 secondary Hexyl acetate, 306 cyefoHexylamine, 365 Hydrolin (see methylcyclohexanol), 239 4-Hydroxy-4-methylpentanone-2 (see diace tone alcohol), 244 ST0852653 408 INDEX Industrial spirit (see ethyl alcohol), 217 "Inertol" (see under xylene), 62 Isophorone, 335 concentration of, maximum permissible, 336 properties of, 335 toxic effects of, 336 toxicity of, 336 uses of, 336 "Kalosche" (see under benzine), 81 Ketols (see acetone oils), 328 Ketone oils (see acetone oils), 328 Limonene (see dipentene), 106 LOsungsmittel C (see acetal), 274 Mesityl oxide, 331 concentration of, irritative, 333 --, toxic, 332 properties of, 331 toxic effects of, in animals, 332 --, on internal organs, 332 --, in man, 333 toxicity of, 332 uses or, 332 "Methone" (see under methyl acetone), 327 Methanol (see methyl alcohol), 202 Methoxybutyl acetate (see butoxyl), 308 2-Methoxyethanol (see ethylene glycol mono methyl ether, 345 Methyl acetate, 286 concentration of, toxic, 288, 289 lethal dose of, 287 narcotic dose of, 288 properties of, 286 toxic effects of, in animals, 287 --, --, symptoms of, 288 --, on blood, 289 --, in man, 289 --, --, symptoms of, 289 --, post-mortem findings in, 288 toxicity of, 287 uses of, 286 "Methyl acetone", 327 Methylal, 274 Methyl-adronol (see methyl cyc/ohexanol), 239 Methyl alcohol, 202 absorption of, by skin, 210, 213 acidosis from, 206, 210 amblyopia from, 212, 214 concentration of, maximum permissible, 205 --, toxic, 205, 210 decomposition products of, 204 estimation of, in air, 205 excretion of, 206 formaldehyde formation from, 206, 215, 216 lethal dose of, 207 metabolism of, 205, 215 narcotic dose of, 207 poisoning by (see toxic effects) --, industrial, 212 properties of, 202 susceptibility to, 211 toxic effects of, 205-216 --, in animals, 205 --, --, symptoms of, 208 --, on blood, 206, 210 --, on eyes, 208, 212, 214 --, on internal organs, 209 --, local irritation, 214 --, in man, 211 --, --, symptoms of, 213 --, on nervous system, 210, 215 --, on retina, 215 --, on urine, 206 toxicity of, 203 --, relative, 203, 206 uses of, 202 Methyl amyl alcohol (see methyl irobutyl carbinol, 236 Methyl anon (see methyl cyclohexanone), 334 Methylated naphthalenes, 69 toxicity of, 70 Methylated spirit (see ethyl alcohol), 217 Methylbenzene (see toluene), 46 Methyl benzoate, 312 Methylfjobutylcarbinol, 236 Methyl irobutyl ketone, 331 Methyl cellosolve (see ethylene glycol mono methyl ether, 345 Methylcyc/ohexane, 98 concentration of, maximum permissible, 99 lethal dose of, 99 narcotic dose of, 99 properties of, 98 toxic effects of, in animals, 99 --, --, symptoms of, 99 --, on internal organs, 99 --, on metabolism, 99 toxicity of, 98 uses of, 98 Methylcyc/ohexanol, 239 concentration of, maximum permissible, 240 properties of, 239 toxic effects of, 240 toxicity of, 239 uses of, 239 Methylcyc/ohexanone, 334 concentration of, maximum permissible, 335 Methylcyc/ohexyl acetate, 308 Methyl ethyl carbinol (see secondary butyl alcohol), 230 Methyl ethyl ketone, 328 absorption of, by skin, 330 concentration of, maximum permissible, 329 --, toxic, 330 estimation of, in air, 329 explosive risk of, 328 toxic effects of, in animals, 329 --, on cornea, 330 --, dermatitis, 330 --, symptoms of, 330 toxicity of, 329 uses of, 329 Methyl formate, 281 Methyl-hexalin (see methylcyc/ohexanol), 239 Methyl-hexalin acetate (see methyleyc/o- hexyl acetate), 308 4-Methyl-2-pentanone (see methyl irobutyl ketone), 331 2-Methyl-2-pentenone-4 (see mesityl oxide), 331 m-Methyl phenol (see cresols), 393 ST 085265U INDEX 409 o-Methyl phenol (see cresols), 393 p-Methyl phenol (see cresols), 393 Methylphenylsilicone, 397 2-Methyl-2-propanol (see tertiary butyl alcohol), 231 Methylpyridine (see picoline), 371 Methylene chlpride (see methylene dicblor- ide), 122 Methylene dichloride, 122 anaemia from, 124 as anaesthetic, 122 concentration of, maximum permissible, 122 lethal and narcotic doses of, 123 properties of, 122 toxic effects of, in animals, 122 --, on liver, 123 --, in man, 123 toxicity of, 122 uses of, 122 Methylene glycol dimethyl ether (see methylal), 274 Monochlorobenzene, 187 concentration of, lethal and narcotic, 188 --, maximum permissible, 188 toxic effects of, 188 --, symptoms of, 189 toxicity of, 187 uses of, 187 Monochlorohydrin, 250 properties of, 250 toxic effects of, 251 Monoethanolamine, 366 Naphthene (see cyclohexane), 94 Nitrobenzene, 376 absorption of, 377 properties of, 376 toxic effects of, 377 --, on blood, 378 --, on nervous system, 377, 378 --, methaemoglobinaemia, 376, 377, 378 --, symptoms of, 378 --, treatment of, 379 --, on urine, 378 toxicity of, 376 uses of, 376 Nitrobutanes, 375 1-Nitrobutane, 375 2-Nitrobutane, 375, 376 Nitromethane, 373 Nitropropanes, 373 1-Nitropropane, 374 2-Nitropropane, 375 "Novania" (see tetrachloroethane), 154 Oil of Mirbane (see nitrobenzene), 376 Oil of Niobi (see methyl benzoate), 312 Paraldehyde, 276 properties of, 276 toxic effects of, in animals, 276 --, in man, 277 --, post-mortem findings in, 277 --, symptoms of, 277, 278 toxicity of, 276 uses of, 276 Pentachloroethane, 163 concentration of, toxic, 164 estimation of, in animal tissues, 165 lethal dose of, 163 narcotic dose of, 164 properties of, 163 toxic effects of, 163 --, acute, 163 --, chronic, 165 --, on internal organs, 164 --, on mucous membranes, 164, 165 toxicity of, 163 --, relative, 163, 164,165 uses of, 163 cyc/oPentadieoe, 106 narcotic dose of, 107 properties of, 106 toxic effects of, in animals, 107 --, on internal organs, 107 --, in man, 107 --, symptoms of, 107 toxicity of, 107 Pentaline (see pentachloroethane), 163 A1: '-Pentamethylene (see cyclopentadiene), 106 "Pentasol" (see under amyl alcohol), 233 Pentol (see cyc/opentadiene), 106 cyetoPentylene (see eyc/opentadiene), 106 "Perawin" (see under perchloroethylene), 182 Perchloroethylene, 182 concentration of, maximum permissible, 183 lethal dose of, 183 narcotic dose of, 183 properties of, 182 toxic effects of, in animals, acute, 184 --, --, chronic, 184 --, in man, 185 --, symptoms of, 184, 185 toxicity of, 182 --, relative, 182, 183, 184, 185 uses of, 182 "Perspirit" (see isopropyl alcohol), 224 "Petrohol" (see isopropyl alcohol), 224 Petrol (see petroleum spirit), 74 Petroleum spirit, 74 concentration of, toxic, 75 distinction of, from benzine, 74, 76 properties of, 74 toxic effects of, in animals, 75 --, --, symptoms of, 76 --, in man, 76 --, --, on blood, 78 --, --, symptoms of, 77, 78 toxicity of, 75 uses of, 74 Phenylcarbinol (see benzyl alcohol), 242 Phenyl ethane (see ethylbenzene), 63 Pbenylmethanol (see benzyl alcohol), 242 Picoline, 371 Propanol (see n-propyl alcohol), 222 isoPropanol (see isopropyl alcohol), 224 Propan-2-one (see acetone), 320 Propenol (see allyl alcohol), 241 Propenyl alcohol (see allyl alcohol), 241 isopropyl acetate, 294 n-Propyl acetate, 293 concentration of, toxic, 293, 294 properties of, 293 toxic effects of, 293 isoPropyl alcohol, 224 absorption of, 226 ST 0852655 410 INDBX woPropyl alcohol--continued properties of, 224 toxic effects of, 225 --symptoms of, 225, 226,227 toxicity of, 224 --, relative to other alcohols, 225 uses of, 224 n-Propyl alcohol, 222 properties of, 222 toxic effects of, 222, 223 toxicity of, 222 uses of, 222 secondary Propyl alcohol (see iropropyl alcohol), 224 iroPropylbenzene (see cumene), 64 iioPropyl ether, 267 concentration of, maximum permissible, 268 properties of, 267 uses of, 268 Propylene dichloride, 185 concentration of, maximum permissible, 185 dermatitis from, 185,186 properties of, 185 toxic effects of, in animals, 186 --, --, on internal organs, 186 --, --, symptoms of, 186 toxicity of, 185 uses of, 185 Propylene oxide, 268 Pyranton-A (see diacetone alcohol), 244 Pyridine, 367 impurities in, 368, 369, 370 lethal dose of, 368 metabolism of, 369 properties of, 367 toxic effects of, in animals, 368 --, on kidneys and liver, 369 --, in man, 370 --, --, symptoms of, 368, 370 toxicity of, 368 uses of, 368 "Quittnerlack" (see tetrachloroethane), 154 Sextate (see methyicycfohexyl acetate), 308 Sextol (see cyclohexanol, methylcyc/o- hexanol), 236, 239 Sextone (see cyc/ohexanone), 333 Sextone B (see methylcyc/ohexanone), 334 Silane intermediates, 398 Silicones, 397 Solactol (see ethyl lactate), 313 "Solaesthin" (see under methylene dichlor ide), 122 Solvent G.C. (see ethylene glycol mono acetate), 355 Solvulose (see ethylene glycol monoethyl ether), 348 Spirits of wine (see ethyl alcohol), 217 Sulphuric ether (see ethyl ether), 261 Tetrachloroethane, 154 absorption of, 159 concentration of, maximum permissible, 157 estimation of, 157 lethal dose of, 157 narcotic dose of, 157 poisoning (see toxic effects) --, prophylactic measures against, 162 --, treatment of, 162 properties of, 154 tolerance to, 162 toxic effects of, in animals, 157 --, --, on blood, 158 --, --, on liver, 158 --, --, symptoms of, 157 --, ascites, 160 --, on internal organs, 158,160 --, in man, 159 --, --, on blood, 161 --, --, on liver, 160 --, --, symptoms of, 159, 162 --, --, toxaemic jaundice, 160, 161 --, on nervous system, 162 --, post-mortem findings in, 159, 160 --, on skin, 161 --, on urine, 158,160 toxicity of, in industrial processes, 155 --, relative, 156 uses of, 154 Tetrachloroethylene (see perchloroethylene), 182 Tetrachlorometbane (see carbon tetra chloride), 128 Tetrahydronaphthalene, 65 excretion of, 68 properties of, 65 toxic effects of, in animals, 66 --, --, symptoms of, 67 --, on kidneys, 67, 68 --, in man, 68 --, on metabolism, 67 --, on urine, 68 toxicity of, 66 uses of, 65 Tetralin (see tetrahydronaphthalene), 65 "Tetralix" (see under perchloroethylene), 182 Toluene, 46 absorption of, 48 excretion of, 48 lethal dose of, 49 manufacture of, 47 narcotic dose of, 49 poisoning (see toxic effects) properties of, 46 toxic effects of, in animals, 48 --, --, on blood, 51, 52 --, --, symptoms of, 50 --, on bone-marrow, 50 --, on immunity reactions, 52 --, on internal organs, 50, 54 --, local irritation, 54 --, in man, 52 --, --, on blood, 54 --, --, on liver, 54 --, --, symptoms of, 53 toxicity of, 47 --, in industrial processes, 48 --, relative, 47, 49 uses of, 47 Toluol (see toluene), 46 Trichloroethylene, 169 absorption of, 182 --, by skin, 174 addiction to, 177 decomposition of, 179, 181 estimation of, in air, 172 ST0852656 INDEX 411 Trichloroethylene--continued --, leucocytosis, 105 estimation of, in blood, 172 --, in man, 102 intolerance to, 181 --, --, symptoms of, 103 lethal dose of, 172 --, on mucous membranes, 103 metabolism of, 182 --, nephritis, 103, 104, 105 narcosis from, 170, 175 narcotic dose of, 173 poisoning (see toxic effects) properties of, 169 toxic effects of, in animals, 172 I --, --, symptoms of, 173 --, --, on blood, 174, 180 --, post-mortem findings in, 102,105 --, on skin, 103, 105 --, on urine, 103, 104 toxicity of, 101 uses of, 100 varieties of, 100 I ) f --, on internal organs, 173, 174, 177 --, in man, 175 --, --, symptoms of, 176 --, on mucous membranes, 178 --, nervous disorders, 176, 180 --, optic atrophy, 176 --, post-mortem findings in, 175 "Westron" (see tetrachloroethane), 154 White spirit, 93 properties of, 93 toxic effects of, 94 uses of, 93 Wood alcohol (see "wood spirit"), 216 --, on skin, 178, 181 Wood naphtha (see "wood spirit"), 216 toxicity of, in industrial processes, 171 "Wood Spirit", 216 --, relative, 170 trichloroacetic acid from, 182 Xylene, 55 uses of, 169 anaemia from, 60, 61 Triethanolamine, 366 Trilene (see trichloroethylene), 169 concentration of, in industrial processes, 56 Trimethylcaibinol (see tertiary butyl alcohol), 231 --, maximum permissible, 56 estimation of, m air, 56 l:l:3-Trimethylcyc/ohex-3-en-5-one (see isophorone), 335 excretion of, 57 lethal dose of, 57 Turpentine, 100 absorption of, 101 mixtures of, with other solvents, 61 narcotic dose of, 57 anaemia from, 104 properties of, 55 concentration of, maximum permissible, toxic effects of, in animals, 57 estimation of, 101 excretion of, 101, 104 lethal dose of, 101 --, --, symptoms of, 57 --, on blood, 58, 60, 61 --, on bone-marrow, 58 --, on internal organs, 58 poisoning (see toxic effects) properties of, 100 --, on kidneys, 58, 63 --, local irritation, 59 toxic effects of, in animals, 101 --, in man, 58 --, --, symptoms of, 101 --, on blood, 102, 105 --, --, symptoms of, 59, 62, 63 toxicity of, 56 --, haematuria, 103, 104 --, on internal organs, 102 --, on kidneys, 102, 103 --, comparative, 56, 57, 58, 60 uses of, 55 Xylol (see xylene), 55 ST 0852657 Printed in Great Britain under the authority of Her Majesty's Stationery Office by John Wright & Sons Ltd., at the Stonebridge Press, Bristol AO 1639. 3388. 3/53. J. W. & Sons Ltd. 1/518/0 K. 18. S.O. Code No. 46-2-82-52* /? / ? S e f / $. / f I U V0 % RECEIVED LIPB^ny APR 8 1954 The How Chemical Co. 1 ST 0852658 \ ST085259 I Toxicity of Industrial Organic Solvents Same Date