Document 1OD4n8XBOaoZvRepQznXzbEo

. ..... ' .. API TO:\.'lCOLOGICAL REVIEW BENZENE SEPTEMBER 1948 Note: This review summari~ the best available iniQrma tiQn on the properties, characteristics, and toxicology of benzene. It offers suggestions and tentative recommenda tions pertaining to medical treatments, medical examinations, and precautionary measures for workers who ~ -,r. posed to benzene.. It was prepared at the Harvard School of Public Health, Boston. Mass., under the directiQil of Professor Philip Drinker. The review has been accepted for publication by the Medical Advisory Committee of the American Petroleum Institute.. Anyone desiring to submit additional information or proposed changes for considera tion prior to re-issuance of this review is requested to send them to the American Petroleum Institute. This re'\;ew was prepared by Marshall Ointon, ~L D . .-\:\IERICAN PETROLEUM INSTITUTE Dt::P.\RTMENT OF SAFI:.'TY 50 WEST 50Ttl STRF.ET NF.w Yon~ 20, N. Y. 2 . ' .' API TOXICOLOGICAL REVIEWS BNZ.NE TOXICOLOGICAL REVIEW ON BENZENE ( ..... Substance Benzene. Formula: C.H,. Structural formula: 0Molecular weight=78.11. Synonyms: benzol. phene. blended into motor gasolines. Some is used as a solvent in commercial processes such as the benzenemethyl ethyl-ketone dewaxing process, whereas mi.nor amounts are used in pilot plants and laboratories for solvent or reagent purposes. Exposure to benzene is usually limited to vapor exposure, although skin contact may occur. IL Properties and O:taracteristics 1 :. :a Boiling point =80.1 deg C (176.2 deg F). Melting point =5.5 deg C (41.9 deg F). Vapor pressure =74.6 mm of mercury at 20 deg C (68 deg F). Liquid density =0.899 g per milliliter at 0 deg C (32 deg F). Specific gravity =0.8787 at 15 deg C (59 deg F). Refractive index=1.5016 at 20 deg C (68 deg F). 1 mg per liter =313 ppm; 100 ppm=0.319 mg per liter. Benzene is a clear, colorless liquid with a char- -:teristic pleasant odor at low concentrations and a ( uisagreeable odor at higher concentrations. It forms a highly inflammable and explosive mixture with air at concentrations ranging rom 1.4 to 6.8 per cent benzene by volume. Puce .bcazene bums with a yellow, luminous, smoky flame. Benzene is relatively insoluble in water (0.08 g in 100 ml water at 22 deg C), but is readily miscible in :ill proportions with alcohol, ether, acetic acid, chloroform, carbon disulfide, carbon tetrachloride, and similar organic solvents. Commercial benzene is practically never pure, and usually contains vary- ing amounts of .ulene, phenol, and toluene; also traces of carbon disuillde (0.2 to 1.0 pet cent) , thiophene (0.1 to 0.2 per cent), olefuts, naphthalene, and similar substances. Chemic:1lly, benzene is the simplest of the aromatic hydrocarbons. It is relatively stable, but is capable of a variety of substitution reactions such as chlorination. nitration, sulfonation, and alkylation. Benzene is 311 excellent solvent for most organic substances. ~ I. Prob:1ble Sources of Contact 4 .. Benzene is used extensively in the petroleum industry. By far the greatest amounts of benzene are Figures refer to biblio!:f3PO}" on p. ~- IV. Toxicology I. Acute EJfectt .Acute benzene poisoning generally results from the inhalation of relatively high concentrations of the vapor. Exposure to air containing benzene in concentrations of 19,000 to 20,000 ppm (61 to 65 mg per liter of air) causes death within a few minutes, whereas concentrations of 7,500 ppm (25 mg per liter) are dangerous to life in ! to 1 hour. The maximum concentration which can be tolerated for 1 hour without serious disturbances is estimated at from 3,000 to 4,700 ppm (10 to 15 mg per liter). Mild symptoms supervene following exposure to 1,500 to 3,000 ppm (5 to 10 mg per liter) for a period of several. hours.~ The drinking of benzene produces symptoms similar to those following inhalation of like amounts of .-h~ ~n~tance, plus local evidences of acute irritation of the mouth, throat, esophagus, and stoma.ch.t .Acute exposure to benzene produces rapidly increasing symptoms of tightening of leg muscles, dizziness, excitation, and pallor, followed by flushing, "'eakness, headache, breathlessness, apprcllension of death, and constriction in the chest. The pulse becomes rapid, and the color blue. VlSUal disturbances, tremors, and muscular weakness are encountered. The victim may lose consciousness and pass into coma, or may develop acute mania and delirium. Convulsions are fairly frequent. Death may occur almost at once or several hours to several days following exposure.cs Recovery from acute benzene poisoning requires from 1 to 4 weeks. Immediately after e.'q'Osure there are temporary symptoms of chest and head pain, shortness of breath, giddiness, nause:t, and loss of appetite. Evidences of unsteady gait, nervous irritability, and breathlessness may persist for 2 or 3 weeks. whereas cardiac distress and :1 peculiar yellow - --------------~---- APt TOXICOLOGICAL R.EVWWS BENZENE ---. -- - pallor to the skin may last for as long as a month. proached within a ft:W minutes after exposure i: Recovery from acute poisoning is generally complete begun, and practic:illy complete elimination of ben after this period. although evidences of chronic ben- zene from the blood occurs within a ft:W minutes afteJ zene poisoning may be encountered later. the exposure is terminated. Higher concentrations The acute effects of benzene exposure result from of benzene are obtained in tissues with a greater fat its depressant action on the central nervous system. content, and saturation and elimination are more In addition to its general narcotic action, benzene gradual.a appa.tently has a chata.cteristic neuro-iuitant effect, which accounts for the hypertonicity, excitement, and Most of the bemene absocbed by the body is metabolized to a variety of substances, the principal convulsions which are encountered. Benzene also one of which is phenol. Minor amounts of pyro- sensitizes the heart muscle to the action of epi- catechol, hyd.roquinone, muconic acid, and similar nephrine, so that instant death due to ventricular substances are also produced.' Whether the toxicity fibrillation may occur. Muscular activity increases the of benzene is due to one of these metabolites or to rate and severity of acute benzene poisoning. Per- unaltered benzene is not known. These substances sons dying of acute benzene poisoning generally show are all eliminated in the urine after combination with absence of clotting of the blood and widespread petechial hemorrhages in the brain, pleura, peri- cardium, urinary tract, intestinal tract, mucous membranes, and skin. There are nu ~cific lesions of sulfate and glycuronic acid. Practically all of the chronic effects of exposure are a result of the influence of benzene or its oxidation products on the blood-forming ;:.yst-..::ti. A variety diagnostic import. of .cea.ctions may be encountered, and there is little Skin contact with benzene results in defatting of correlatio~ between the degree and duration of ex~ ( the skin, and leads to the development of etythema, posure and the severity or nat:Ur~ of the fi.ndin.gs in dty scaling and, in some cases, the formation of .the blood on miaoscopic examination. There is no vesicular papules. Prolonged exposure may produce single change in the blood or bloodforming organs lesions resembling first- or second-degree burns. which is universally present in benzene poisoning.' The production of systemic benzene poisoning The bone marrow where blood is formed may be by skin absorption has received scant attention in the hypoplastic, fairly normal in appearance, or hyper- literature, and defro.itive information on this subject plastic. .Abnormal forms or young cells may abound, is not available. Skin absorption is difficult to dis- tin~ as inhalation of benzene vapor would ac company it and confuse the picture, unless a mask was wom. However, reputable authorities have stated verbally ~ skin absorption is extensive, and should be avoided. and reasonab!f well documented instances of the development of leukemia as a result of chronic ben zene exposure have been cited. It is generally be lieved that various individuals differ in their bone marrow response to benzene-some showing no essential change; some showing decre:lSed cellularity; 2. OKoaic Etreeu Chronic benzene poisoning results from repeated or continuous exposure to relatively low concentrations of benzene vapor. The level and degree of exposure necessary to produce poisoning apparently vary widely. There are at least two well authenticated cases of poisoning by repeated exposures of only 75 ppm; 1 yet many chemists repeatedly e:-..-pose them selves to far higher concentrations over ~ods of many years with no apparent ill effects. and others increased cellularity, and even evidences of malignant changes. Cases with s.:ymptoms fairly soon after exposure usually _have fewer cells in the bone marrow.J wh~eas cases developing later are more apt to have an increased number of cells in the marrow. It is believed tfut this represents an early weeding out of those who develop hypoplastic changes, rather than a gradual shift from one type of response to the other.10 11 The .findings on microscopic examination of the Benzene is relatively insoluble in body fluids and blood are as variable as the bonemarroW response. tissues; therefore, only small :unounts are ~sorbed by They may consist of a reduction in red-cell, white the body. Equilibrium between blood and air is ap cel4 or platelet levels-in any two of these, or in all 41 - - - - - - - - - - - - - - - - - - ------~----. .. ._J.,. .......- ....,""~""' --. - .-...., BeNZENE three. These changes can develop gradually or suddenly. The blood usually shows a moderate reduc( ion in red cells (below 3.5 million) white cells (below 4,,00), and platelets. Evmination of the blood for evid~ces of benzene poisoning should never be limited to a single determination such as a red or white-cell count, but should consist of a com- plete study of the red, white, and platelet fractions. Progressive changes are of more sipiliign~ than the absolute alteration. Benzene is eliminated from the body in part via the lungs and in part via the kidneys. The ratio of renal to lung excretion is not known. That portion excreted in the urine is in combination with sulfate or with glucuronic acid. The combination of benzene with sulfate alters the organic-inorganic sulfate ratio, so that an estimation of the ratio of organic to inorganic sulfate may provide a useful guide to the degree of absorption of benzene by the body.13 u There is speculation in the literature on the occur- rence of latent bone-marrow injury due to benzene without any immediate alteration in blood findings, followed by the development of obvious blood --: changes years later,_ under the stress of intercurrent ( illnesses or the general wear and tear of everyday life.n Conclusive proof is lacking, but the occurrence of delayed toxic effects :Wpeat. likelv, The wide individual vana.tlon m SJtSCeptibility to benzene has already been mentioned. Certain factors have been noted to in6uence this to a limited degree. Overweight individuals are more commonly affected,1:; but no difference in susceptibility has been noted between young men ~d women.11 11 A low protein high-fat diet is said to promote the disease,1 whereas the presence of lung disease, heart ~ and liver or kidney damage are believed to predispose to the condition.1' Pregnant women may be more prone to benzene poisoning than others.~ 3. S:de Limits The American Stmdards Association n and most states 18 have set an arbitrary limit of 100 ppm as the maximum permissible benzene concentration for workers exposed to this substance during :m 8-hour day. M:LSSa.Chusetts and Oregon have set limits of 75 ppm, whereas New York considers 50 ppm as the highest permissible level. Inasmuch_as the ~Y develops 0t1 tolcr:1nce to benzene. arid. as there is a wide variation in individu:ll susceptibilitY~ it is cenwlly considered that the only absolutely safe concentration for benzene is zero.11 The inadequacy of a limit of 100 ppm is indicated by well authenticated reportS of at !east 2 cases of benzene poisoning following exposure to only 75 ppm.T A limit of 50 ppm or less is strongly recommended, particularlY w~ a posures are .recurrent:. Skin conbct should be avoided. V. Treatment of Benzene Poisoning 1 a Acute poisoning by benzene should be considered as an acute emergency. The victim must be removed from the contaminated atmosphere at once, and kepc at compl~t~ rest subsequently. Care must be taken that the rescuers are not also overcome by the fumes. Frequently, rescuers who exert themselves will sub. sequently die, whereas the in.active victim recovers. Artificial respiration should be administered if natural breathing has been interrupted, and oxygen may be administered, as well, if it is available. The use of adrenin should be avoided because of the danger of _ inducing ventricular fibrillation. There are poorly substantiated reports of benefit from the intravenous injection of lecithin, but such measures should be considered with skepticism at present.:o Inasmuch as benzene is excreted rapidly, no specific measures to promote its removal from the body are necessary. Ouonic benzene poisoning is extrt't'nel,. refractory to treatment. Practically all thenpeutic measures attempted have failed, although transfusions are at least temporarily useful in combatting severe anem.ia.:t The administration of fairly large doses of ascorbic acid (100 mg per day) may be of value and should be curied out.:: It is most important, however, that the condition be diagnosed early and the individual withdrawn from all contact with the affecting agent for the rest of his life. VI. Examination5 The pre-employment e!Cmlination should include a detailed history, physical aamin3tion, chest X-ray, and complete blood count. All workers with organic disease of the heart, lungs, liver, or kidneys should be diminated, as should those v.ith any history of previous benzene intoxication or :my evidence of abnormality of the blood or blood-clotting mechanism.tr.. tft API TOXICOLOGICAL REVIEWS BENZENE Periodic re-examinations should be carried out ascorbic acid (vitamin "C') daily to individuals {> ( regularly, their frequency being determined by the unavoidably exposed to benzene vapor might well severity of the exposure. Individuals exposed to con- be of value, although it would be difficult to prove centrations approaching the accepted "safe" limits its effectiveness or to justify its cost. should be examined at monthly intervals at least.u. ~3 The concentration of benzene vapor in the air The examination should include a brief interval his- should be checked regularly in situations where e.<t- tory and physical inspection, together with a com- cessive exposures are apt to be encountered. This plete blood study, including white and differential can be done by a variety of methods, among the best counts and an estimation of the platelet levels. The of which ace the butanone method,.: in which ben- ratio of inorganic to total urinary sulfates should be zene is nitrated to form mdinitrobenzene, which is determined in order to detect the presence of ex- subsequently estimated colorimetrically with the aid cessive absorption and excretion of benzene.u. 14 of butanone; the mdinitrobenzene reduction method.:! Any change in the blood picture or the presence of in which mdinitrobenzene formed from benzene is an inorganic total sulfate ratio of less than 50 per separated from nitrating acids by steam distillation, cent is cause for withdrawal of the worker from any reduced by an excess of standard titanous chloride further exposure. Due to the delayed cha.ract~r of solution, and the excess titanous chloride back-titrated benzene poisoning, it would be well to continue with a standard ferric-alum solution; the use of the periodic blood counts for several months after e."C- benzol indicator, which depends on an indirect mea- posure has ceased. surement of the heat produced by oxidation of benzol; and, finally, the colorimetric determination of ben- VIL Precautionary Measures zene by oxidation with hydrogen peroxide iu Lhe The safety measures necessary for the prevention of benzene poisoning ace primarily those designed to prevent the inhalation of benzene vapor. Ventilation, either by dilution or local exhaust, should be so designed as to prevent toxic concentrationS of the vapors from reaching the breathing zone of the workers. All apparatus and piping should ~ inspected regularly and systematically for the presence of leaks. Workers who must be exposed to benzene vapor should be rotated in order to reduce their e.xposure time to a minimum. When excessive concentrations are unavoidably encountered in operations, such as the cleaning of tank cars, vats, or storage tanks, air masks should be employed.2 ' The concentration of benzene vapor on equipment pre\iously exposed to the liquid should ~ reduced by cleaning with steam, if possible, or by cooling. Apparatus to be cleaned in benzene should be cold, in order to reduce evaporation, and stopcocks or joints should be smeared with giycerin which, being insoluble in benzene, keeps them airtight.:3 Skin contact and possible dermatitis from benzene should be avoided entirely if possible; but, if the hands must contact the solvent, then neoprene gloves presence of a ferrous sulfate solution.2 More re- cently, an absorptiometric method has been introduced in England which is said to be more specific than other methods.:J In this procedure benzene, xylene, and toluene vapors are absorbed in a bead bubbler charged with a nitration mixture, diluted, and neutralized. The nitro derivatives are extracted with butanone, and the yellow color imparted to the butanone by the nitro derivatives of .toluene and xylene is measured. The mixture is then made alka- line, and color development allowed to proceed. The solution is then acidified, with disappearance of the blue-green color due to xylene and toluene but persistence of the color due to benzene. This color is then measured. The individual method chosen must depend on circumstances. The mdinitrobenzene reduction method and the absorptiometric method are accurate but rather cumbersome. The butanone and oxidation in presence of hydrogen-peroxide and iron-salts methods are simpler ~d more rapid, but are less accurate. The use of the benzol indicator is probably the simplest, but the presence of other hydrocarbons will interfere seriously, as they are also oxidized. or protective creams should be used. VIII. Bibliogrophy The prophylactic administration of 100 mg of 1. E. Browning. "Toxicity of Industrial Org:1nic Sol- API TOXICOLOGICAL llVJEWS BNZZm / vents,'' Ind11strial H~allh Resur~h Board R~porl No. ( BO (London) {1937). 2. M. G. Jacobs, Th~ Anal]tkal ChnniJtry of Imimtri.J Poisom, H~~Z~Wds, 41fll Solt~mJS, Interscience Publish- ers. ~ New York, 399 (1944). 3. C. D. Hodgman and H. N. Holm~ Htmtlbook of Chemistry 41Ui Ph]sia, 2'th edn.., Olemictl Rubber Publishing Co., Oevehnd (1941). 4. Letter from Humble Oil and Renning Co., Houston. dated June 21 (1946). ' Y. ~etsOCl and H. W. Haggard. NoxiottS G.tus 41fll 1h1 Principles Df R#spiution Injfamcing Th~ir Action, Chemical Catalog Co., Nt:W Yod: 164 (1943). 6. J. L Svitbely, R. C. Dunn, and W. F. von Oettingen. ...The Acute Toxicity of Vapors of Certain Solvents Containing Appceciable Amounts of Benzene and Toluene," J. Ind. Hyg. Toxi~ol. 25, 366 (1943); and "Th.e Ottonic Toxicity of Moderate Concentra- tions of Benzene and .Mixtures of Benzene and Its Homologues for Rats and Dogs," J. Ind. Hyg. Toxkol. 26, 37 (1944). 7. M. Bowditch and H. B. Elkins, "Chronic Exposure to Benzene-!: The Industrial Aspects." J. Ind. Hyg. Toxi~ol. 21,321 {1939). s. H. H. Schrenk, W. P. Yant. S. J. Peuce, F. A. Patty, ( and R. R. Sayen, "Absorption, DistributiOn, and Elimination of Benzene by Body TtsSUCS and Fluids of Dogs Exposed to Benzene Vapor," J. Ind. Hyg. Toxi- ~ol. 23, 20 (1941). 9. L A. Etf and C. P. Rhoa.ds, "The Hemato!.ot;>L....U Ef fects of Benzene Poisoning," J. Ind. HJt Toxkol. 21, 421 (1939). 10. T. B. Millocy, E. A. ~ and W. J. Briddey, "Chronic Exposure to Benzene-ill: The Pathologi- cal Results." J. Itul. H]g. Toxi~ol. 21, 3S6 (194S). 11. F. T. Hunter, "Chronic ExpQsure to Beo%ene-ll: The Oinical Effects,'' J. brd. Hyt. Toxi~ol. 2lt 331 (1939). 12. L Greenburg. M. R. Ma.yen, L Goldwater, and .\. Smith. '.'Benzene Poisoning in the Rotognvure Ptin.ting Indumy in New York Gty,'' J. Ind. Hu. Toxi~ol. 21, 39~ (1939). 13. C. M. Jephcott and F. M. R. Balmer, "The Urinuy Sultate Test in the Supervision of Wodcets Exposed to Benzene," J. Ind. Hyg. Toxkol. 21, 132 (1939). 14. H. H. Sdueol; W. P. Yant, and R. R. Sayen, "A New Procedure for the Coatrol of Benzene Exposure." J .Am. M~d. Au. 107, 849 (1936). 1,. A. F~ "I.e bemolisme pcofc:ssi~.. Pr~su m;J. 41. 6, 129 {1933). 16. C. E. A. W"mslow, ..Summary of the Natiooal Safety Cowcl Study of Benzol Poisoning," J. Ind. Hyg. 9, . 61 {1927). 17. MA Z37.4: ,.Amm~m Stamlard Allowabu Con- antrillion of Bmzen~," .American Standards .c\.ss~ Nt:W York: (1941). 18. W. A. Cook, "Maximum Allowable Concentntioas of Industrial Atmospheric Cont:Jmioants," Inti. M~d. 14, 936 (194') 19. F. J. Wampler, Prindplu am/ Pradiu of Indtutrial M~didn~,. Williams and Willdns Co., Baltimore, 2'9 (1943). 20. H. Nidc. "Cure of Acute Benzol Poisoning under a. lecithin Emal.sion," Klin. Wo~hs~hr. (Vienna) 1. 68 (1942). 21. L J. Goldw.ater and J...t P. Tewksbury, ''Rccovety Following Exposure to Benzene," J. Ind. Hyg. Toxi~ol. 23, 217 (1941). 22. 0. Libowitzlcy and H. Seyfried, "Significance of Va- min 'C for Worlcers Exposd to Benzene," Xlin. w~hs~hr. (Vienna) 53, ,43 {1940). 23. A. _IC2mmer, N. Isenberg, and M. E. Borg, "Medial Supetvision of Benzene-Plant Workex:s," J .Am u~a. Amx. 111, 14'2 (1938). 24. Omtpation ttnd H~ahh EnrJdop~Jia of Hygim~, Pdlholoo. 111U! Sod.tl J1TelfHe, Intetnational Ubor Office, Geneva. 1, 228 (1930). 2~. R. Milton. "A.bsorptiometric Method for Estimation of Atmospheric Benzene (in Presence of Xylene ana Toluene) British J. Ind. JC~J. 2, 36 (194,). : .