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f TELEPHONE HUDSON 3-B12G Manufacturing Chemists' AssociationirlndC (POUNDED 1872) 1825 Connecticut Avenue, N. W. ,/V tj We are sending you herewith copy of the Proceedings of the 94th Annual Meeting of the Association, held at The Greenbrier, White Sulphur Springs, West Virginia, on June 9-11, 1966. This contains a record of all business transacted at the meeting, as well as copies of reports and addresses presented. A limited number of additional copies are available upon request. Sincerely yours, Secretary-Treasurer MFCJr/em Enclosure AP00037458 PROCEEDINGS Manufacturing Chemists' Association, Inc. June 9-11, 1966 The Greenbrier White Sulphur Springs, W. Va. AP00037459 Houdry Process and Chemical Co. , Division of Air Products and Chemicals, Inc. Blomquist, R, A. Burtis, T. A. Ferrell, F. M. Sidoroff, E. N- 1. C. I. (Organics) Inc. Cashford, William G, Reed, Firmin P. Richardson, Thomas Whitby, George F. C. Imperial Oil Limited Doherty, T. B. Flanagan, J. W. Moreton, A. G. Wallar, R. E, Interchemical Corporation Ault, Bromwell Hill, James T. , Jr. Kress, Howard McDaniel, N. W. Forth, Victor J. Interlake Steel Corporation Dye, W. A. Hayes, Scott B Hoyt, Elton, III International Minerals Chemical Corporation Barber, Carl H. Batchelder, John E. Button, Bland B. , Jr. Rudd, Thayer Jefferson Chemical Company, Inc. Goerner, J. K. Griswold, D. L. Monaghan, P. R. Strawn, L- R. The Journal of Commerce Wyss, A1 Page 51 Kaiser Chemicals Davis, G. C. Sims, W. N. Kay-Fries Chemicals, Inc. Vanderhoef, H. Kent Koppers Company, Inc. Byrom, F. L. Eynon, D. L. , Jr. Fritch, M. H. Jackson, W. B. Jones, J. D. Losch, E. D. Wheeley, B. O. Eli Lilly and Company, Elanco Products Company Division Morton, Richard M. Orbaugh, William The Lubrizol Corporation Clapp, Roger Eklund, C. W. Irwin, J. B. McGrew, M. M. M&T Chemicals, Inc. Buchanan, H. Carpenter, C. H. Elf, J. Gloskey, C. HirschLand, H. E. Oberg, J. L. Zedler, R. Mallinckrodt Chemical Works Anonsen, S. H. Fistere, J. Frese, D. J. Krause, J. H. Michener, W. F. Thayer, H. E. AP00037460 INTEROFFICE MEMORANDUM To E. J, Breyne From R Domrzalski_______ _ cc: W. J. Kendrick Date 4 June 1981 Subject BUSINESS AND TRADE ASSOCIATION BUDGET 416 ____ __ Corporate Financial Planning (Location. Or^tnUition, or D*Mrimnt] Public Affairs (Location, Organization, or Department) Ed: The following is a listing of the dues for various Business and Trade Associations which are to be budgeted to Ed Donley's organization code under account 416 for FY82. I've listed what I believe will be the anticipated 1981-82 dues payment and the month in which it will be paid so you can plan accordingly. Organiz ation Amount of Dues Date Payable Alliance for Free Enterprise American Council on Education $25r000 10,000 May, :1981 June, 1982 American Industrial Health Council Business Council of Pa. 25,000 8,000 July, 1982 July, 1982 Chamber of Commerce (Penna.) 3,500 November, 1981 Chamber of Commerce (U. S.) Chemical Manufacturers Assoc. 7,000. 9 5,0 00, March , 1982 June, 1982 European Community - U. S. Businessmen's Council 3,100 November, 19B1 Industrial Development Corp. of Lehigh Valley National Minority Supplier Development Corporation 1,200 3,000 July, 1932 January, 1982 TOTAL $180,800 RD:amr 1320) AP00037461 MANUFACTURING CHEMI STS ASSOCIATION DESCRIPTION: Founded in 1872, MCA is the prime trade association representing the U.S. Chemical Industry. It operates through 10 technical and functional committees and their task-oriented subgroups which are staffed by MCA personnel and in which the relevant company experts from many of the 190 MCA members participate. Lobbying is carried out under the direction of MCAls Director of Government Relations, Bill Stover, and its Government Relations Committee. The President of MCA, Bob Roland, was recently brought on board to fulfill the desire of top Chemical Industry executives to beef-up the trade group's image and active involvement in Washington affairs. KEY UN IT(S}: Board of Directors - 32 members serving for 3 year terms with 1/3 turnover each year. Supervision over MCA's activities is primarily exercised by the Board's Executive, Finance, and Program Committees. New Board members are selected each May by the Chairman of the Board and Executive Committee together with MCAJs President. An outgoing Board member cannot succeed himself for at least a year, but another Executive from the same company can be appointed in the interim. AIR PRQDUCT5 PRESENT INVOLVEMENT: Ed Donley is presently serving as Chairman of MCA's Board through 31May 1979. Numerous Air Products employees, especially from the Chemicals Group, actively participate in MCA's committees. Annual Air Products' dues for 1978 were $45,000 and will increase in 1979. VALUE OF SERVICE: MCA is probably the most relevant of the various trade groups to which Air Products belongs since its legislative and regulatory efforts closely parallel Chemical Group interests and concerns. Close coordination and participation in MCA's legal, technical, and government relations activities can immeasurably enhance Air Products individual efforts. Board involvement provides an excellent opportunity to interact with the top Executives of the Chemical Industry, (see list attached). ADDED RESPONSIBILITIES: MCA's Board meets 5 times a year (5 days). Service in a leadership position of course involves additional time. RECOMMENDATION: Although Ed Donley's term as Board Chairman and member would normally expire on 31 May, 1*179, Rob Roland has indicated that he would like Fd t.o sfrav on the Hoard for on additional period as a board member to provide advice on the reorganization initiated during Ed's tenure as Chairman. AP00037462 ^OGQ INDUSTRIAL TOXICOLOGY THIRD EDITION I 1 Alice Hamilton, M.D. | Late Assistant Professor Emerita of Industrial Medicine/ j Harvard School of Public Health, Boston, Massachusetts Harriet L. Hardy, M.D., F.A.C.P. Pinleal Professor of Occupational Medidne, Department of Preventive Medidne, Harvard Medical School, Boston, Massachusetts | Board of Consultation, Massachusetts General Hospital, Boston, Massachusetts I Former Assistant Medical Director in charge of Occupational Medical Service, ' Massachusetts Institute of Technology, Cambridge, Massachusetts AP00037463 AP00037464 PREFACE It was the privilege of HLH to serve as junior in the preparation of Dr. Alice Hamilton's volume, Industrial Toxicology, for its second fr edition in 1949. The intention of this third volume is to help prac? titioners and to attract medical students and physicians in the field of occupational disease by combining Dr. Hamilton's pioneer wis dom with current industrial hygiene practice and the authors' clinical experience as internists especially interested in industrial illness. To include every reported occupational insult and the reac tion to it would make this book unwieldy. This volume does not attempt to include a description of every industrial operation and of each use of a potentially hazardous material. Aside from the i problem of size of such an undertaking, it is a fact that, during the period this book is being printed, technical innovations will be introduced that may result in new hazards to workers. The plan, therefore, has been that this edition serve both a ready reference and a point of view toward job-related disease as etiology, an often I neglected possibility. Attention is drawn to Section One, designed to be of practical value in guiding the clinician to the criteria needed for a correct diagnosis of occupational disease. Practical advice is included on the difficult demands of the United States Workmen's Compensation benefits, a subject many physicians avoid. I The updating of certain sections of the 1949 edition ofIndustrial ? Toxicology has required considerable reworking. Updating and re$ vision with needed additions have been developed by me and my j. colleagues Drs. Asher Finkel, Clarence Maloof, John Stoeckle, and . Lloyd Tepper. This edition has been enlarged by new sections dealing with potential risks from exposure to plastics and pes ticides, occupational causes of pulmonary disease, and biologic 1 hazards to workers of importance to the physician. The section on i radiant energy includes the great advances in knowledge since i 1949 with emphasis on facts of importance to physicians. Edwin D. Flack prepared the chapters on lasers and microwave radiation and updated those on ultraviolet and infrared radiations. The attempt has been made to provide the reader with a practical, workable bibliography. To accomplish this, the decision has been made to refer, with rare exceptions, to only literature published and available in English. Much of importance in the field of occupational medicine has appeared in other languages, espe cially that knowledge that predates World War II. By using refer ence to abstracts, however, and by citing data in earlier editions of L____ AP00037465 this book and current texts, it is hoped that errors of omission are few. In addition, appendixes have been added, which list both sources of detailed discussions and subjects in the field of occupa tional medicine not covered in this book. References to animal toxicity studies have been deliberately restricted to those of un usual interest to students of worker illness. HLH decided to omit most trade names of industrially used materials except for those that are almost a part of daily language, for example, in the United States, nylon and teflon. The final drait has been strengthened by careful reading for errors and omissions by my Massachusetts Institute of Technology colleagues, members of the staff of the Occupational Medicine Service, Richard Chamberlin, George Boylen, Joseph Leahy, Stephen Piccolo, and Samuel Levin. Gratitude is due Dr. Margot Becklake of the Royal Victoria Hospital of Montreal who reviewed the sections dealing with occupational hazards to the lung. I have had unusual counsel and help from colleagues abroad: the late Dr. Andrew Meiklejohn, Dr. Archie Cochrane, Dr. John Gilson, Dr. Katharine Williams, Dr. Richard Schilling, and Dr. Luigi Parmeggiani. Dr. A. O. Seeler and Dr. Thomas Almy, by freeing me from my usual rounds, made this work possible. The original stimulus for this work came from my colleague, the late Dr. J. Howard Means, Chief of Medicine, and my surgical coworker, Dr. J. Gor don Scannell, both of the Mass. General Hospital, Boston, Mass. The preparation of the manuscript was begun by the late Harriet Newcomb. Miss Jeannine Vallee and Frances Guiggio car ried out the difficult preparation of a workable draft. Finally, the book depended for completion on the good will of Miss Elizabeth O'Brien, Mrs. Jean Lawe, the competence and energy of Mrs. Catherinejohnson, Mrs. Abby McLaughlin, and Mrs. Patricia Davis. I must also record my gratitude for the loyal support of Miss Alice Kennedy and the tireless encouragement of my sister, Mrs. J. Hardy Stewart. Lincoln, Massachusetts December 1973 Harriet L. Hardy, M.D. AP00037466 261 SECTION FOUR CHEMICAL COMPOUNDS II AP00037467 ALIPHATIC HYDROCARBONS 1 The aliphatic series of hydrocarbons includes the saturated (paraf fin, methane, or alkane) and the unsaturated (olefin, ethylene, or alkene) compounds, which are derived almost exclusively from petroleum or petroleum processing. The saturated aliphatic series is comprised of gases (methane, saturated ethane, propane, and butanes), liquids from pentanes (Cs) through hydrocarbons Ci6 compounds, and solids. Compounds in the series are used as fuels, solvents, and lubricants, most commonly as mixtures. From the toxicological point of view these compounds are not particu larly active. The first two members of the series, methane and ethane, have no known biological properties and exert an effect only as simple oxygen-replacing asphyxiants. Methane, as the principal constituent of natural gas, is widely used as a domestic fuel. As such, it is biologically inert and stands in. marked con trast . to the toxic carbon monoxide-containing manufactured gases (water gas and producer gas) which were in common use prior to the transcontinental transportation of natural gas from petroleum-producing fields to commercial markets. The concept of toxic domestic fuel gas remains sufficiently prominent in American thinking to cause a number of attempts at suicide each year by persons who "take gas." The normal consequence of this attempt is an explosion rather than intoxication. The lower limit of flammability for methane approximates 5 percent. In the mining industry methane may be known as marsh gas or fire damp, the principal cause of explosions in coal mines. This gas may become a simple asphyxiant in poorly ventilated pockets in coal mines into which the gas may rise because of its low density. From time to time one notes clinical reports in the medical literature referring to a "gas leak syndrome" (Sherman and Harris, 1968). The usual history includes an upper respiratory infection or other mild illness which requires that a patient be confined In a room containing a gas heater. Complaints of headache, weakness, myalgia, ataxia, and light-headedness or fainting appear to be associated with confinement and unrelated to the primary illness. The physical and laboratory examinations are noncontributory. There is no evidence that leaking natural gas has produced these clinical complaints. It is more than likely that whatever symptoms are related to the heating system are in fact related to faulty flues, causing leakage of carbon monoxide. Insufficient supply of air to replace that which is consumed by the heating system may result in negative pressure which causes back drafts from flues. 263 In general the saturated hydrocarbons from propane (Ca) through the octanes (Ca) show increasingly strong narcotic proper* ties. Heavier members of the series become insufficiently volatile to produce narcotizing concentrations in air unless heat is applied or vapor-saturated atmospheres are encountered in tanks or other confined spaces. The margin between narcosis and lethal depres sion of vital centers is too narrow to permit these compounds to be used as surgical anesthetics. Narcotic effects may be accompanied by exhilaration, dizziness, and headache. There may also be a loss of appetite, nausea, a persisting taste of gasoline, confusion, inabil ity to do fine work, and loss of consciousness in extreme cases. Removal from exposure usually results in a rapid clearing of symp toms, although there may be a transient exacerbation upon coming into the open air. risks to exposed workers The vapors of compounds from pentane through octane are increasingly irritating to mucous membranes, although none of these materials are actually strong irritants. The liquids, as fat solvents, extract sebum from the skin leaving a dry irritated surface prone to cracking and bacterial infection. The likelihood of exposure to individual members of this series is very small; most commonly exposures are to mixtures which may be variously termed petroleum ether, benzine (not benzene), petroleum naphtha, gasoline, mineral spirits, so-called Stoddard solvent, and varsol. Higher boiling mixtures appear as kerosine or jet fuels; heavier yet are the lubricating oils. Such mixtures may contain various branched and cyclic compounds such as benzene which have important toxicological properties of much greater signifi cance than those of the quantitatively predominant aliphatics. The composition of these mixtures will invariably reflect the origin of the petroleum, molecular modifications effected at the refineries, seasonal fuel requirements, specifications by users, and the addi tion of highly dissimilar materials such as antioxidants* anti-knock compounds, corrosion inhibitors, combustion improvers, and dyes. From the practical point of view, and in the absence of ben zene, the manifestations of exposure to vapors of these hydrocarbon mixes are those typical of exposure to heptane or octane--viz., gid diness, vertigo, headache, and anesthetic stupor. In massive acute exposures, as may be experienced upon entry into gasoline storage tanks, rapid central nervous system depression may occur with sud den collapse, deep coma, and death. There may be convulsions Indicative of brain irritation or apneic anoxia. Full recovery without sequelae is the rule. However cerebral microhemorrhages or focal AP00037469 ALIPHATIC HYDROCARBONS / 265 post-inflammatory scarring have been suggested as the etiology of epileptiform seizures months after the acute episode. Pathological examination of tissues from fatal cases gives evidence for wide spread microhemorrhagic phenomena. Irritation of the upper and lower respiratory tract and visceral damage has also been de scribed. From time to time cases are reported of sudden death in persons who have inhaled vapors of volatile liquids such as gasoline. Usually this exposure is not in the line of work but reflects an attempt to obtain an exhilarating or similar psychopharmacological experience ("jag")- The best evidence is that these deaths are due to fatal cardiac arrhythmias in which endogenous releases of epinephrine are implicated (Reinhardt et al., 1971), There is no convincing evidence that prolonged expo sures to vapors of aliphatic hydrocarbons, as in the case of gasoline station attendants, can cause harmful effects. These solvent mixes are all primary irritants and defatting agents when applied to the skin. Carcinoma of the skin which has followed prolonged dermal exposure to cutting oils almost cer tainly represents a reaction to specific carcinogenic polycyclic aromatic compounds and not to the aliphatic materials which are the predominant constituents. In industrial situations kerosine and lubricating oils are insuf ficiently volatile to cause respiratory tract damage. These materials can enter the lungs upon aspiration following ingestion and spon taneous or induced vomiting. Gerarde (1963) has shown experi mentally that the ingestion of these mixes is not especially injuri ous in the absence of vomiting. When vomiting occurs, however, hydrocarbon mixtures of low viscosity (e.g., gasoline) are readily aspirated into the lungs. In such cases there may be rapid death from cardiac arrest, asphyxia, or respiratory paralysis. Rapid sys temic absorption may lead to central nervous system manifesta tions such as convulsions. The aspiration of lesser quantities or of somewhat heavier molecular-weight compounds (Cio-Cw) such as kerosine results in a slower progression of events, marked by chemical pneumonitis with prominent endothelial damage and pulmonary hemorrhage and edema. Heavier and more viscous materials such as mineral oil and motor oil are not readily aspi rated. The pulmonary reaction to these high-viscosity hydrocar bons is one of "lipoid-pneumonia," a chronic localized tissue re sponse, as has been observed in persons taking mineral oil-based nose drops over the course of years. Clinical experience with hydrocarbon ingestion, especially of kerosine by children, is consistent with these observations (Bal dachin and Melmed, 1964). The most common clinical and AP00037470 pathological observation is chemical pneumonitis with pulmonary hemorrhage arvd edema and complicating bacterial pneumonia. Central nervous symptoms are related to systemic absorption of particularly the lighter molecules, and depression or coma are common. When hydrocarbons have been accidentally ingested, the prevention of aspiration is of the utmost importance. The advisability of gastric lavage is a debatable point (Press, 1962), but best current practice seems to indicate this step if precautions are taken--namely, intratracheal intubation. LUBRICATING oils Lubricating oils are based upon aliphatic hydrocarbon molecules containing seventeen or more carbon atoms. Such oils are complex mixtures containing, as well, small amounts of aroma tic and polycyclic substances and a broad variety of dissimilar materials known collectively as "additives." The functions of these additives are multiple; they may inhibit corrosion or oxidation, preserve film integrity, alter viscosity, suppress bacterial growth, and act as detergents. Some of these materials have biological properties which may cause lubricating oil to have health signifi cance in excess of that related to simple aliphatic compounds. A number of skin reactions to these additives to petroleum oils are described in texts on occupational dermatology. Problems are not common, however, and affect primarily those individuals who have developed a high degree of hypersensitivity. CUTTING OILS Cutting fluids are for the most part dissimilar in composition to the lubricating oils. Cutting fluids are applied to metal-cutting tools to facilitate and accelerate machining operations, to cool cut ting surfaces, and to carry metal chips away from work surfaces. It is believed that cutting fluids are the most common cause of indus trial dermatitis and, as such, represent a major cause of disability, lost work time, and work restriction. The problem is exacerbated by the fact that large volumes of fluid may be used at each machine, that compressed air used in chip removal may spatter fluids over the operator and his clothing, and that sharp metal chips imbedded in rags and clothing or on the skin cause small lacerations which impair the skin's resistance to irritating com pounds and infection. Cutting fluids can be classified into three categories: (1) insoluble oils, (2) soluble fluids, and (3) synthetic fluids. Insoluble oils are based upon petroleum oils to which are added various animal or vegetable oils, fats, and waxes. These oils are commonly recirculated for long periods, with metal chips re moved by filtration, and are used chiefly in heavy machining ALIPHATIC HYDROCARBONS / 267 operations such as in the cutting of engine blocks. Soluble fluids or oils are based upon an emulsion of oils and water and are milky in appearance. The chemical or synthetic fluids are mostly water with small amounts of wetting agents. To the basic fluid, regardless of type, various materials may be introduced to provide or improve specific desirable properties. These additives include germicides such as formalin, mercurials, phenolic compounds; emulsifiers such as soaps, petroleum sulfonates; corrosion inhibitors such as borates, dichromates, amines; and extreme pressure compounds of sulfur, chlorine, or phosphorus. The oil-water emulsions tend to become rancid, but they are good coolants, economical, and non combustible. The prevalence of cutting fluid dermatitis is related to the toxldty hygienic status of the working place and the worker. Poor machine enclosure, the use of degraded and contaminated fluid, inadequate washing facilities for personnel, and an insufficient supply of dean dothes and protective garments contribute to the problem. Machinists who are prone to acne-seborrhea or who are swarthy and hirsute are relatively susceptible to blockage of hair follicles by insoluble oils and the consequent folliculitis. Individuals with a previously unresolved skin problem or dry or atrophic skin are vulnerable to soluble fluids, especially those which are clearly alkaline or which contain wetting agents. The usual cutaneous response to oil-based materials is an oil folliculitis which arises as a result of chemical irritation and mechanical plugging of the follicular canal. Onset of the problem usually occurs soon after the first exposure and is marked by acute reactions starting on the dorsal surfaces of the hands and fingers, the extensor surfaces of the forearms and thighs, and the abdomen (i.e,, those surfaces which are in contact with oil or oil-soaked dothing). Comedones and perifollicular papules and pustules ("oil boils") are present. Melanosis may develop later. Secondary infec tion may occur, but bacteria in the oil are rarely primary skin pathogens and are rarely the single cause of folliculitis. Clinical manifestations clear rapidly with the termination of exposure and do not resolve if the exposure is continued. Exposure is controlled through proper machine design to prevent spattering, clean doth ing, protective garments, and careful attention to handwashing. Certain petroleum oils have carcinogenic constituents; this is especially the case with shale oils, which are manufactured and used outside the United States. There are no good data to establish the prevalence of skin cancers among machinists in this country, but malignant tumors or precancerous keratoses are not known to occur in significant numbers above those that occur in a control population. The carcinogenic potency of specific oils has nothing to do with their ability or lack of ability to produce dermatitis. Knowl edge of occupational malignancy of the skin has a long and impor tant history dating from 1775 when Pott identified scrotal cancer in English chimney sweeps (Merewether, 1956, pp. 304-361). The skin reaction to emulsion and synthetic fluids is variable and may include maceration, dryness and "chapping," reddening, and vesiculation. These fluids are potent defatting agents. Bacterial growths in the fluid do not appear to be directly injurious to workers, but rancid fluids and products of bacterial action can be the etiology of skin disorders. As is the case with insoluble oils, both treatment and prevention are based on the control of expo sure. Corticosteroid creams may be used as an adjunct in the treatment. The value of "barrier" creams is not unanimously ac cepted, but they do offer modest usefulness in certain situations. Individual additives in cutting fluids can be a cause of either primary irritative or hypersensitive dermatitis. Detergents, soaps, and wetting agents defat the skin, and alkaline materials damage the keratin of protective superficial skin layers. Formalin in ger micides is a sensitizer. Additives containing sulfur and chlorine are direct irritants, although so-called chloracne is not associated with cutting fluids. Nickel or chromates derived from metals being cut can be a source of allergic dermatitis. Harsh abrasive soaps and solvents such as gasoline and kerosine may contribute to chemical and traumatic dermatitis since these cleaning materials are com mon in machine shops. While grime and grease can certainly be removed from the skin with these substances, it is safer to utilize less injurious cleansers commercially available. The evidence indicates that exposures to mist sprays of insol uble oils used in machine operations are not harmful to the res piratory tract. UNSATURATED ALIPHATIC HYDROCARBONS In general the unsaturated aliphatic hydrocarbons lack biolo gical properties which are important to occupational medicine. These hydrocarbons are for the most part products of the pe trochemical industry and are formed in the cracking and dehy drogenation of petroleum fractions. These compounds are essen tial to the synthesis of various plastics and synthetic rubbers. Ethylene and propylene are weak anesthetics at high concentra tions and have been used in surgical procedures. The butylenes, butadiene, and isoprene (Cs) have similar properties. Acetylene is also an anesthetic material with no known injurious effects upon AP00037473 ALIPHATIC HYDROCARBONS man. When acetylene is prepared from the addition of water to calcium carbide, phosphine (PH3) may be generated from phos phides in the impure carbide. Hence phosphine may be a signifi cant contaminant of commercial grades of acetylene. The wide range of flammability of this gas and its tendency to form explosive acetylides with metals warrant special attention. 'I ' AP00037474 AROMATIC HYDROCARBONS 2 The aromatic series of compounds is based upon benzene and molecules which incorporate one or more benzene rings. Many of the most common members of the series were obtained initially from the distillation of coal in the coking process. The industrial demand for benzene regularly exceeded the supply available from coal carbonization by the early 1950s, and an increasing proportion of the aromatic chemicals is now derived from the reforming or dealkylation of petroleum-derived materials. At the present time the petrochemical industry provides the major source of aromatic compounds. Both coal- and petroleum-derived aromatics are pro duced in ways which lead to complicated mixtures of many com pounds in the series. Accordingly crude distillates and unpurified commercial products may contain substances not indicated on the label, which often reflects only the principal constituents. Minor constituents in industrial or technical grade solvents distributed without adequate warning have been, however, important causes of toxic reactions. Benzene, the parent member of the series, has been the most BENZENE significant from the toxicological point of view. In many instances of intoxication the compound responsible for disease has not been identified as benzene since hazardous amounts of this compound have been present in technical grade "toluene" or other solvent mixes. The European practice of using crude benzene to improve the anti-knock properties of gasolines was utilized in the United States until about 1950 and led to cases of benzene intoxication in persons using this blended motor fuel for solvent purposes. A lack of precision in terminology is a serious problem in recognizing benzene hazards, There has been confusion with the term benzine, which denotes a low-boiling petroleum fraction of predominantly aliphatic compounds and is similar to ordinary gasoline. Benzine, if uncontaminated by benzene, does not have the hematopoietic effect characteristic of chronic benzene poison ing. The term benzol, gradually losing in popularity, has usually been associated with crude aromatic mixtures, predominantly ben zene. In cases of suspected benzene poisoning or when effective health conservation measures are to be applied, it is urgent to learn, by chemical analysis if necessary, whether or not benzene is present and, if so, in what concentration. Since usage in industry varies at different periods as a result of cost and technical needs, it can be necessary to repeat an assay for benzene at intervals. Al- 271 AP00037475 though benzene remains an important solvent, over 90 percent of benzene production goes into the synthesis of other organic com pounds. Benzene is the primary raw material for styrene used in synthetic rubber, for phenol, for nylon intermediates, and for synthetic detergents of the alkylauryl sulfonate type. Solvent ben zene used in rubber cements and in paint strippers has been a frequent cause of injury inasmuch as these materials have often been used under hazardous circumstances by people unaware of the presence or properties of this compound. Benzene used in laboratory extractions and in chromatographic separations is often used under hazardous conditions. toxic effects Like most organic solvents, benzene is a central nervous sys tem depressant at high concentrations and may cause acute narco tic reactions. These are nonspecific and may extend from mild manifestations such as lightheadedness, headache, and excitement to respiratory paralysis and death with or without convulsions. A pattern of apparent drunken behavior due to benzene has been called "benzol jag" by industrial workers and consists of euphoria, unsteady gait, and confusion. Recovery from acute benzene nar cosis is complete unless the levels and duration of exposure cause pathologic changes. Chronic benzene poisoning is of far greater toxicological sig nificance. Its incidence has been gradually decreasing over recent years with the improvement of industrial hygiene measures and a thoughtful and effective search for technically satisfactory and less toxic benzene substitutes. The intoxication is characterized primar ily by a disturbance of the hematopoietic system which can affect every cell line. The clinical picture may vary from person to person. It is often not possible to establish a firm relationship between character of the benzene exposure and the disease. The view that women are more susceptible than men and that the young are more vulnerable than older persons is traditional but not well supported by sound epidemiological data. It is probable that the anemia characteristic of women due to the demands on bone marrow of menses and pregnancy makes them more vulnerable to benzene. In most cases chronic benzene poisoning has followed repeated exposures to unsafe air levels of benzene vapor over the course of months or years. Clinical manifestations of chronic benzene poisoning tend to be insidious in onset, and most recorded cases have been well advanced at the time of diagnosis (Hunter, 1939; Mallory et al., 1939). Classical signs of major hematopoietic injury such as pur pura and overwhelming agranulocytosis are rarely noted in the AP00037476 AROMATIC HYDROCARBONS l 273 more recent literature, however. The more common initial findings tend to be nonspecific and include fatigue and loss of appetite. Hematological evaluation may show anemia, leukopenia, and thrombocytopenia; however, all three cell lines are not always affected or affected to the same degree. Immature cells may be found in the peripheral blood, and there may be an eosinophilia or leukocytosis. The bone marrow may be hypoplastic, hyperplastic, or relatively unchanged. These observations do not correlate well with the clinical picture, the character of the exposure, or the prognosis. In some workers with chronic benzene poisoning there is evidence for shortened red cell survival or extramedullary hematopoiesis. From the clinical point of view, idiopathic aplastic anemia and bone marrow failure due to benzene cannot be distin guished. While there has been no doubt for many years that benzene can produce fatal aplastic anemia, the association between benzene exposure and leukemia has been a matter of more recent con troversy. It is now generally accepted that benzene can produce leukemia of varying forms and that such leukemia can appear with or without an antecedent history of aplastic anemia (Vigliani and Saita, 1964). The conversion of aplastic anemia to leukemia is not uncommon in cases in which the cause of the anemia is unknown. Chronic myelogenous leukemia appears to be the most common type associated with benzene exposures, but acute myelogenous and acute and chronic lymphocytic varieties have been reported as well. Erythroleukemia (Di Gugliclmo's disease) with prominent proliferation of the erythroblastic elements of the marrow has also been associated with benzene exposure (Rozman et al., 1968). Interest in lymphocyte cultures and chromosomal patterns over the past decade has led to their use in epidemiological studies of chromosomal aberrations in benzene-exposed individuals (Tough and Court Brown, 1965; Forni, et al, 1971a, 1971b). It has been possible to demonstrate abnormal chromosomal patterns, in comparison with controls, among former benzene workers with no exposure for over two years. This approach may ultimately shed light upon the nature of the long latent periods which have been described in persons without exposure for many years but who eventually develop aplastic anemia or leukemia. While it is difficult in a single given case to be sure that current anemia or leukemia is the result of benzene exposure twenty or thirty years ago rather than a "spontaneous" event, there are enough such cases to present convincing evidence of a causal association (Medical Grand Rounds, 1950; DeGowin, 1963). It is also worth mentioning that in a number of these cases the initial AP00037477 exposures to benzene were complicated by exposures to other substances (e.g., chlorinated hydrocarbons) which might possibly have had a synergistic effect in producing whatever altered reac tions are necessary for this clinical course (Medical Grand Rounds, 1950). The mechanisms for this interpretation of events are not known. therapy and control Therapy for chronic benzene poisoning, when manifested ejther as aplastic anemia or leukemia, is that which is used when these diseases occur without known cause. The prevention of acute and chronic benzene poisoning is based on control of levels of benzene in air. Convenient survey detector tube and physical instruments are available for measuring benzene in ambient atmospheres. The threshold limit value for benzene has dropped repeatedly in the last several decades, and a concentration of 25 ppm is now considered acceptable for eighthour exposures at the work place. Evidence of hematopoietic in jury at previously higher working levels has led to present criteria (Medical Grand Rounds, 1950). It is also possible to measure metabo lites of benzene in the urine of workers and thereby establish an in dex of exposure. The urinary sulfate ratio has been used for years to express that portion of urinary sulfate which is present in ionic form, normally at least 80 percent (Elkins, 1959). In benzene expo sure, the excretion of phenol sulfate increases so that the proportion of inorganic sulfate drops to less than 80 percent. Inorganic sulfate ratios of less than 80 percent are considered indicative of excessive exposure. Other organic sulfates of nonoccupational origin may be related to the ingestion of bananas, smoked meats or fish, or phenolic drugs. Phenol concentrations in the urine can also be determined, the normal range being 20 to 30 mg/L (Doctor and Zielhuis, 1967). An eight-hour exposure to benzene at an air con centration of 30 ppm will result in a urinary phenol level of about 150 to 200 mg/L. TOLUENE and XYLENE Toluene (also called methyl benzene and toluol) and the xylenes (dimethyl benzenes, xylol) have, relative to benzene, much lower toxicity and volatility. Nevertheless, these compounds, though predominant in certain industrial solvent mixtures, may be associated with benzene to a degree which has been responsible for benzene-induced injury to the hematopoietic system. Those persons responsible for the safety of the work environment must be sure that so-called toluene or xyLene is free of significant amounts of benzene. Various technical solvent mixes such as "sol vent naphtha" or "Hi-flash naphtha" may not be aliphatic naphtha at all but may be blends of toluene, xylenes, and heavier related compounds. References in the literature to bone marrow failure caused by toluene have created confusion with respect to the toxic properties of this compound. An examination of these reports suggests that much of such "toluene" toxicity as had been observed was in fact due to the presence of benzene in a solvent mixture derived from coal tar distillation. In other situations aplastic anemias occurred even though benzene-free toluene was used. Here a careful read ing of the case histories generally discloses prior exposure to ben zene, The action of benzene may not become apparent for years after the cessation of exposure, and subsequent exposure to tol uene need not influence the toxic process, the basis for which had already been established. Animal studies of toluene toxicity have failed to demonstrate a convincing myelotoxic effect. Von Oettingen, Neal, and Donahue (1942) tested the effect of fumes of toluene on three normal per sons, subjecting them to concentrations from 50 ppm up to 800 ppm for daily periods up to eight hours. No definite changes were found in the white blood cell picture, in the circulation, or in the respiration by exposure even to the highest concentration of tol uene. At 200 ppm there was a slight, but definite, impairment of coordination and reaction time, which might bring about a greater liability to accident. With concentrations over 200 ppm these effects become increasingly severe, and at 600 to 800 ppm three hours' exposure resulted in severe fatigue, extreme nausea, confusion, lack of self-control, incoordination, and staggering gait. Since evi dence of neurological impairment occurs at a toluene concentration of 200 ppm, the continuing utilization of this value as the threshold limit value has been questioned, and a reduction to 100 ppm has been proposed. While the preponderant evidence is that chronic exposure to toluene does not produce injury to the bone marrow, isolated cases of this clinical picture and a history of toluene exposure exist. Gattner and May (1963) reported the case of a sixteen-year-old boy who was exposed over the course of nine months to high concen trations of benzene-free toluene used in the cleaning of printing presses. He came under medical care because of fatigue, weakness, and dizziness and was found in the course of his clinical evaluation to have leukocyte counts as low as 1,400 cells/mm3 with a platelet count of 63,000 cells/mm5. Although a clear causal association cannot be established in this situation, the eviHnce associating toluene with myelotoxic changes cannot be ignored. The effects of toluene on the central nervous system, viz., dizziness, weakness, confusion, are not specific for this compound and are typical of the responses to hydrocarbon solvents. The euphoric phase of anesthesia, a manifestation of toluene toxicity, is AP00037479 attractive to certain individuals who have made a practice of "glue sniffing." Sudden death among "sniffers" may be attributed to lethal cardiac arrhythmias following "sensitization" of the myocardium (Reinhardt et al., 1971). In experimental situations benzene has been found to be very potent in this respect, and it is reasonable to anticipate similar effects from toluene. control Toluene does not cause a reduction in the ratio of inorganic sulfates excreted in the urine. Toluene does cause an increased excretion of hippuric acid which can be used to evaluate toluene exposures. The hygienic status of the working place is determined by the direct measurement of toluene in the atmosphere. Toluene is irritating to the skin and conjunctival membranes. The vapors at high concentrations are Irritating to the respiratory tract. The xylenes are very similar to toluene in their toxic effect. DIPHENYL AND Diphenyl and diphenyl oxide are used in industry primarily as DIPHENYL OXIDE heat transfer media. Diphenyl is also used as a fungistatic agent in the preservation of citrus fruits. Leaks from heat transfer systems may obviously be associated with thermal bums. Vapors of these compounds are irritating to the eyes and upper airway. Experience of Finnish observers (Hakkinen et al., 1973) suggests that diphenyl exposure may be associated with nonspecific gastrointestinal symptoms, polyneuritis with pain and numbness, and head ache. Objective changes in electroencephalograms and .electroneuromyograms were reported among workers impregnating fruit wrappers with diphenyl. In addition there were biochemical abnormalities in hepatic function, abnormal hepatic cellular changes in liver biopsy tissue, and evidence that death of one exposed worker was due to acute yellow atrophy of the liver. NAPHTHALENE Naphthalene, familiar as "moth balls" (not paradichlorobenzene), is used primarily as a chemical intermediate in the produc tion of phthalic acid and derivatives for the dye and plastics indus try. The vapors cause eye irritation, headache, and a warm feeling of the skin with profuse sweating. Lenticular opacities have been observed in a number of workers exposed to high concentrations (Ghetti and Mariani, 1956). High levels of exposure, such as may be associated with ingestion, can cause an acute hemolytic anemia especially in individuals with erythrocytic deficiency of glucose-6-phosphate dehydrogenase. CHLORINATED HYDROCARBONS 3 Simple chlorinated hydrocarbons have a widespread and essential NATURE OF role in the chemical industry and in a variety of manufacturing operations. In the chemical industry these compounds provide the CHLORINATED HYDROCARBONS principal routes by which chlorine reaches the chemical market for use in plastics, pesticides, and other chlorinated organic com pounds of great economic significance. As solvents the simple chlorohydrocarbons are widely used because of their excellent solvent properties for oils, waxes, fats, and various organic molecules, their relative cheapness, and the nonflammable charac teristics associated with most of them. Accordingly they are valu able extractants, dry cleaning agents, surface degreasing com pounds, and vehicles for paints, varnishes, and other industrial coatings. Some chlorohydrocarbons are constituents of paint re movers. For many years carbon tetrachloride was used in the so-called Pyrene fire extinguisher, an application which has been almost universally discontinued because of the toxic properties of the extinguishant and its degradation products. Although the number of readily available solvent chlorohy- drocarbon compounds is very large, about a dozen of them are of industrial significance and, as such, are of potential occupational medical importance. It is useful to be familiar with the nomencla ture of these compounds to avoid a possible confusion when the several common or technical names are used. Not all compounds listed in Table 7 are widely used. Table 7 Chtorohydrocaibon Solvents Common Name Methylene Chloride Chloroform Carbon Tetrachloride Ethylene dichloride Ethylidene dichloride Vinyl trichloride Methyl chloroform Acetylene tetrachloride Acetylene dichloride Acetylene trichloride \ Trichloroethylene 1 Perchloroethylene Chemical Name Dichloromethane Trichloromethane Tetrachloromethane 1,2-DichIoroethane 1,1-Dichlocoethane 1,1,2-Trichloroethane 1,1.1-Trichloroethane 1.1.2.2-Tetrachloroe thane 1.2- Dichioroethylene (Cis & Trans) Trichloroethylene Tetrachloroethylene Formula CHa Ch CH Cb ecu CHa Cl CHa Cl CH Cb CHa CHa Cl CH Cb CHa C Cb CH Cb CHCU CHCl - CHQ CHC1 CCia CCla - COa 277 Many of the members of this series of compounds are ex tremely volatile, a property which permits a hazardous exposure to occur more rapidly than might be anticipated by the inexperienced worker. While many such compounds are of relatively low chemi cal toxicity, the rate at which a hazardous atmospheric concentra tion of the solvent may be achieved may be very rapid. Conse quently a relatively high Threshold Limit Value rating may be misinterpreted as a low hazard rating. In view of the rate at which an atmospheric hazard may develop, special caution is necessary in certain industrial situations, especially those in which the appli- cation of heat may further increase the air levels of solvent materi als. As with many categories of industrial solvents, mixtures of compounds are the rule although the material is sold in com merce under a single chemical or common name. While this may be of no particular health significance because of a similarity be tween the effects associated with many specific compounds, there are several molecules of clearly greater toxicity. Inquiry as to purity is therefore an essential element in the investigation of working conditions or possible etiological factors in disease. Chlorohydrocarbons may be thermally decomposed (cracked) at high temperatures to yield, among other things, hydrogen chloride and phosgene gases. The former is a highly irritant toxic gas, which, because of its irritant effects upon the mucous mem branes of the eyes and upper airway, has excellent warning prop erties which tend to limit exposure. Phosgene, on the other hand, is the classical insidious deep lung irritant without significant sen sory effects to warn of its presence. When chlorohydrocarbon vapors are thermally cracked in open flames or arcs associated with furnaces, boilers, or welding apparatus, sufficient phosgene may be generated to create a hazard of far greater magnitude than that associated with the airborne solvent vapors alone. The amount of phosgene production varies with the compound being cracked and the conditions of heating, moisture and hot ferrous surfaces ap parently contributing to phosgene production. While phosgene poisoning from this type of exposure has not been common, it is obviously important to isolate heating and welding operations from atmospheres containing chlorohydrocarbon vapors. Temper atures of the burning cigarette are high enough to decompose these vapors, but there is no evidence that smoking has ever produced phosgene or phosgene poisoning. In situations where exhaust gases from furnaces may contain cracked solvent products containing hydrogen chloride, special attention should be paid to the duct work inasmuch as it is unusually susceptible to corrosion i AP00037482 AP00037483 CHLORINATED HYDROCARBONS with attendant leaks and the release of carbon monoxide into the work space. Compounds of the chlorohydrocarbon group are most com monly absorbed through the lungs, although absorption from the gastrointestinal tract does occur in cases of ingestion. Absorption through the skin occurs, but it is of no known practical industrial significance except possibly in the case of carbon tetrachloride, which may penetrate the skin in toxic quantities. For the most part, chlorinated hydrocarbons which enter the body through pulmonary gas exchange surfaces leave the body unchanged via the same route. Those compounds which are metabolized may appear as degradation products in the urine. Techniques developed by Stewart have permitted the retrieval of solvent vapors from the exhaled air of exposed workers and the analyses of these vapors to characterize various quantitative and qualitative aspects of the exposures. Using the long path-length gas cell of an infrared spectrometer or the gas chromatograph, he has been able to demonstrate the continuing exhalation of tetrachloroethylene vapors more than 350 hours after the conclusion of exposures (Stewart et ah, 1961b). Chlorohydrocarbons which are actively metabolized, of course, disappear from the breath much more rapidly, e.g., trichloroethylene (Stewart etal., 1961a). Incases of suspected exposure to these materials, the breath collection and analysis technique permits the identification of solvents and the construction of breath excretion curves which can be used to esti mate the quantity of material absorbed. As a group, the chlorohydrocarbons share several biological OCCUPATIONAL properties. Other biological properties are associated with only certain members of the series, and these manifestations may vary DISEASE CAUSED BY TOXIC CHLOROHYDRO- over a wide spectrum according to which compound is responsible CARBONS for the poisoning. This intercompound variability has been most dearly examined experimentally in situations in which the liver is the target organ. In the ingenious work of Plaa and his colleagues (1958) hepa lotoxidty in mice was evaluated by judging the impair ment of detoxication of barbiturates after exposure to members of the chlorinated hydrocarbon series. More recently hepatic damage has been evaluated in mice by determination of the serum glutamicpyruvic transaminase (SGPT) levels after exposure (Gehr- ing, 1968). These experimental studies are in general agreement with each other and with clinical evidence which has accumulated over the years from cases of human overexposure. In order of decreasing hepatotoxidty are carbon tetrachloride, chloroform. AP00037484 1,1,2-trichloroethane, tetrachloroethylene, trichloroethylene, methylene chloride, and 1,1,1-trichloroethane. A. characteristic property of all the members of this series is the ability to depress the central nervous system, leading through the several stages of clinical anesthesia ultimately to death from respiratory paralysis. This property is well known, for indeed chloroform and trichloroethylene have been used as surgical anesthetics. While there is undoubtedly a difference between the anesthetic potencies of the chlorohydrocarbons, the generally ob served phenomena in man are typical of the group. These include dizziness,confusion, drowsiness, nausea, vomiting, and occasion ally abdominal pain. There may be visual disturbances. Deep anes thesia may lead to death from respiratory depression or circulatory failure. Actual anesthesia is not commonly encountered in industry unless the worker enters tanks or confined places, or there is spillage, gross misuse of materials, or intentional inhalation of vapors to produce euphoria or a "jag." It is not uncommon, how ever, to receive reports of vague nonspecific psychological or psycho-physiological reactions associated with exposures to chlorohydrocarbons. Headache, fatigue, irritability, impaired memory, anorexia, and nausea are typical symptoms. Whether or not there is an actual pharmacodynamic explanation for these complaints has not been established. There have been several reports over the years of sudden death in apparently healthy individuals who had been exposed to chlorohydrocarbons of relatively low toxicity. Autopsies in such cases have failed to reveal a cause of death. The possibility that death was related to transient ventricular fibrillation cannot be excluded. There is experimental evidence that chlorohydrocarbons sensitize the myocardium to the effects of endogenous epinephrine (Reinhardt et ai., 1971; Aviado and Beiej, 1973). The vapors of the chlorohydrocarbons are not especially irritat ing to the mucous membranes of the eyes and upper airways. Prolonged contact of these solvents with the skin can result in extreme dryness and fissuring with associated infection. This phenomenon is secondary to the "degreasing" effects of these ma terials on the skin. The incidence of sensitization is very low. Immersion of the fingers in methylene chloride leads to severe pain with transient numbness; pain with trichloroethylene and carbon tetrachloride is less severe; with methylchloroform and perchloroethylene it is minimal. METHYL CHLORIDE Methyl chloride, a colorless gas at room temperatures, is han dled in industry under pressure in the liquid state. It is used almost 5 the i the from ieed gical i the obude ion- les- tory shy e is i of >w- or to red or ese en to ch lat be ns ne It 'S. in is a* v. n n exclusively in the chemical industry as a methylating agent in the production of silicones, butyl rubber, and tetramethyl lead. Its use as a domestic refrigerant, the most common source of intoxication in the past, has almost entirely ceased. Methyl chloride is a potent narcotic causing headache, drows iness, giddiness, ataxia and, ultimately, convulsions, coma and respiratory failure. Several cases of long-standing neuropsychiatric alterations have been described; depression, change of personality, irritability, insomnia, disturbances of vision. It is difficult---if not impossible--to unequivocally associate these manifestations with a specific toxic effect of the suspected compound. Methylene chloride is used as a solvent and extracting agent METHYLENE where a high degree of volatility Is desired. It is a common con CHLORIDE stituent of paint strippers. It is the least toxic of the four chlorinated methane derivatives. Because of its high volatility, it is easy to achieve air levels which result in '`'drunkenness" and associated unreliable behavior. The current threshold limit value (TLV) of 500 ppm is probably excessive in view of the fact that exposure to methylene chloride in the range of 500 to 1,000 ppm can result in CNS depression in some persons (Stewart et al., 1972). It is of additional importance that exposures to this compound are fol lowed by increases in the carboxyhemoglobin level, presumably as a result of metabolism of solvent to carbon monoxide. Experimen tal exposure of human subjects to methylene chloride at 1,000 ppm for two hours has resulted in carboxyhemoglobin saturation levels in excess of those permitted in the workplace from exposure to carbon monoxide alone (Stewart et al., 1972). That the CNS effects of carbon monoxide and methylene chloride are at least additive is evidence for reduction in the permissible levels of industrial ex posure. Chloroform, or trichloromethane, is unimportant as an indus- CHLOROFORM trial solvent or intermediate. Its effects are not unlike those as sociated with carbon tetrachloride. One of the authors (HLH) has cared for two hospital laboratory technicians exposed to chloroform who complained of nausea and anorexia. Their liver function tests were abnormal. Carbon tetrachloride has lost its early predominance as a CARBON cheap nonflammable chlorinated solvent for use in degreasing, dry TETRACHLORIDE cleaning, and extracting. Less toxic compounds such as tri- and tetrachloroethylene have served as admirable substitutes. Carbon tetrachloride "Pyrene" fire extinguishers are also now obsolete. AP00037486 The annual production of carbon tetrachloride continues to in crease, however, with most of the output (80 percent) going into the synthesis of chlorofluoromethane refrigerants, solvents, and aerosol propellants. Relatively smaller amounts of carbon tetra chloride continue to be used as solvents (as in chromatography), in the recovery of tin from scrap metal, as an insecticidal grain fumigant, and as an addition to solvent mixes to lower their flam mability. toiddty Accumulating evidence over the years has shown carbon tet rachloride to be one of the most toxic of the common solvents. It is a potent narcotic and, as such, has properties not dissimilar to other compounds in the series. In addition, however, this com pound has specific toxic effects upon the liver and kidneys. When exposure has been of sufficient magnitude to cause visceral injury, the liver and kidney are commonly both affected although not necessarily to the same degree. Renal injury has been considered the prime manifestation of poisoning following inhalation, and hepatic damage has been thought to be predominant when carbon tetrachloride has been ingested. The evidence does not give sup port to this point of view. Nausea, vomiting, and abdominal cramps have been considered the primary presenting symptoms suggesting liver injury. Such symptoms have appeared in the absence of altered liver function tests, however, suggesting that in some situations this pattern of complaints may represent a non specific effect. Nausea and vomiting usually appear within hours after exposure although a delay up to six days has been noted, probably depending on the quantity and rate of absorption. The abdominal pain has been misinterpreted as indicative of acute ap pendicitis. Tests of hepatic function, especially those based upon a de termination of hepatic enzyme levels in the serum, may give evi dence of liver injury well in advance of clinical signs. Serum glutamic oxaloacetic transaminase (SGOT) levels in excess of 25,000 units have been reported following acute nonfatal carbon tetra chloride poisonings. Maximal liver damage most probably occurs within forty-eight hours of an acute exposure- In severe injury the liver is invariably enlarged and tender, jaundice may be pres ent, and hepatic failure with ammonia intoxication may ensue. The mechanism of carbon tetrachloride hepatotoxicity has been examined in great detail by Recknagel (1967). The collected evidence indicates that the two prime pathologic observations, fatty degeneration and necrosis, have distinct pathogeneses. The hepatic accumulation of Upld is related to injury of the endoplasmic o in; into and :etraY)f in jrain lam- . tetIt is ir to omhen ury, not red and bon upinal )ms the tin onurs ed, 'he ip- ieviun WO ralrs he is- as ed is, he tic CHLORINATED HYDROCARBONS / 283 reticulum and disruption of the mechanism for moving lipid out of the liver through the coupling of triglycerides to the lipoprotein carrier. Although the precise mechanism for the necrosis is not dearly established, it is apparently assodated with the intracellular release of destructive hydrolytic lysosomal enzymes, injury to mitochondria with loss of energy sources, and general metabolic chaos subsequent to loss of cytoplasmic enzymes and coenzymes. While the intact carbon tetrachloride molecule may cause damage to the hepatic cell wall, prime damage is caused by metabolites of the solvent, perhaps CCb radicals. Cells which do not actively metabolize carbon tetrachloride have been shown to be relatively resistant to this compound. Conversely, measures which enhance metabolic ability by stimulating endoreticular expansion and enzyme induction also enhance carbon tetrachloride toxicity (Gamer and McLean, 1969). Following this line of reasoning, one may consider that the increased vulnerability of alcoholics to the hepatotoxicity of carbon tetrachloride may be due to the fact that alcohol leads to the induction of metabolising enzymes of the endoreticular system. Renal impairment is common and may exist in the absence of demonstrable hepatotoxicity (Guild et al., 1958). Costovertebral pain is not uncommon, proteinuria is characteristic, and anuria may occur some one to seven days after an acute exposure and persist for one to fifteen days. An examination of urinary sediment reveals evidence of acute tubular necrosis: red and white blood cells, hyaline, granular, and red cell casts, and renal tubular epithelial cells. The development of the uremic syndrome or potas sium intoxication are indications for hemodialysis. The evidence is that the observed nephrotoxicity is due to the direct effects of carbon tetrachloride upon the proximal tubule and loop of Henle, although the distal tubule is affected to a lesser degree. The prog nosis in severe cases of carbon tetrachloride poisoning has im proved markedly since the availability of dialysis has become common. The simultaneous presence of hepatic failure with im paired urea synthesis and ammonia intoxication is obviously un favorable. Recovery may require months but may be eventually complete. There is no universal agreement as to whether or not acute hepatorenal injury or prolonged exposure without acute phenomena may result in chronic impairment of organ systems. There have been enough cases of cirrhosis following long expo sure, however, to suggest very strongly that the association can be causal in specific instances (McDermott and Hardy, 1963). Hepatocellular carcinoma developing seven years after acute car- bon tetrachloride intoxication has also been reported (Tracey and Sherlock, 1968), and this compound is a potent hepatocarcinogen in animals. It is of course possible that regeneration itself in these cases is the precancerous lesion and that carbon tetrachloride is not a specific carcinogenic material. A bleeding tendency has been observed in many cases of actue carbon tetrachloride poisoning. In some cases it may reflect visceral damage. In others bleeding may be a consequence of aplastic anemia. The evidence that carbon tetrachloride is a direct bone marrow poison is not indisputable, but cases have been presented in which the nature of the exposure and the sequence of events are reasonably convincing (Straus, 1954). ETHYL CHLORIDE Ethyl chloride is a gas at room temperature; however, it is easily liquefied and is familiar to physicians as a local anesthetic agent which freezes the skin when the agent is applied as a spray from a glass cylinder. Ethyl chloride is found in industry almost entirely as a chemical intermediate used in the synthesis of tet raethyl lead and other ethyl compounds. The physiological proper ties of ethyl chloride are related to its anesthetic effect and perhaps to its cardiotoxic properties as a sensitizer of the myocardium to endogenous epinephrine. As far as is known, this compound is excreted via the lungs without significant metabolic degradation in the body. ETHYLENE oichloride The ethylene dichloride, or ethylene chloride, of industry is 1,2-dichloroethane. l,i-Dichloroethane is commonly known as ethylidene dichloride or ethylidene chloride. These are saturated compounds, chlorinated ethanes, and the "ene" endings should not lead to confusion of those compounds with dichloroethylene. Much of this terminology is quite unfortunate, but is so well established among the various industrial traditions that change is unlikely. Both chlorinated ethanes are used as solvents and as chemical intermediates. They are irritating to the eyes and the respiratory tract, producing salivation, sneezing, and coughing. In those few cases of intoxication which have been reported, the anticipated anesthetic effects have been observed with associated dizziness, nausea and vomiting. In severe and fatal cases hepatic and renal injury have been observed. methyl Methyl chloroform (1,1,1-trichloroethane) is a chlorohydrocar- CHLOROFORM ^on solvent which, because of its very low toxicity (Stewart, 1971), is being utilized at an accelerated rate. It is widely applied as a CHLORINATED HYDROCARBONS / 285 vapor degreaser, dry cleaning agent, aerosol vehicle, and cold cleaner. Like many chlorohydrocarbons, methyl chloroform is somewhat unstable, and small amounts of stabilizing compounds are added to the solvent material sold in commerce. Such stabiliz ers or inhibitors may be various ketones, alcohols, esters, nitrogen compounds, etc., which do not change the toxicity of the commer cial product sold under trade names such as Chlorothene or Triethane. Methyl chloroform is a narcotic and skin defatting solvent as harmful effects are the chlorohydrocarbons in general. Exposures to high air con centrations of methyl chloroform may lead to narcosis and even fatal respiratory depression under conditions of grossly negligent overexposure. There is no evidence that this solvent causes hepatic or renal injury such as is characteristic of carbon tetrachloride. Experimental work (Reinhardt et al., 1971; Aviado and Belej, 1973) and clinical experience with anti-tussive preparations containing trichloroethane identifies serious cardiotoxic properties of this compound, and deaths have been attributed to cardiac arrhyth mias, probably mediated through epinephrine sensitization. 1,1,2-Trichloroethane, vinyl trichloride, an isomer of methyl chloroform, is a more potent anesthetic agent, an irritant to mu* cous membranes, and a significant hepato* andnephrotoxin. It does not have major industrial uses. Industrial references to acetylene tetrachloride or tetra- TETRACHLOROchloroethane are invariably to the symmetrical isomer of ETHANE 1,1,2,2-tetrachloroethane. Clinical evidence indicates that this compound is by far the most poisonous of the chlorohydrocarbons used as industrial solvents. Unfortunately from the health point of view, it is an excellent solvent, often the best available for many applications. Early utilization of tetraehloroethane as a vehicle for the so-called dope to cover airplane fabrics led to numerous severe and fatal cases of toxic hepatitis and atrophy of the liver. The compound is the best solvent for cellulose acetate, which for many years was the best available coating material for fabrics to be used in aviation and products requiring a thin, light, impervious sur face. The recognized toxicity of tetraehloroethane has caused it to be eliminated from most industrial uses unless its specific solvent properties are necessary. The use of this compound is rarely jus tified. Toxic manifestations resemble those associated with carbon tetrachloride; however, the hepatotoxicity of tetraehloroethane is much more prominent. APOOO DICHLOROETHYXENE 1,2-Diehloroethylene or acetylene dichloride is handled in commerce as a mixture of the trans and cis isomers. The material is used as a iow-temperature extracting agent for heat-sensitive sub stances such as perfume oils and caffeine in coffee. Aside from the narcotic properties of this solvent, toxic effects have not been prominent in the rather small-scale industrial usage which exists. viNYUDENE CHLORIDE The 1,1-isomer, or vinytidene chloride, is used almost entirely as a monomer in the manufacture of copolymeric plastics. Experi ence from the synthetic plastics industry indicates that 1,1dichloroethylene has toxicological properties which are similar to those of carbon tetrachloride, i.e., there is significant hepatoand nephrotoxicity. TRICHLOROETHYLENE Trichloroethylene is utilized in very large quantities as a metal degreaser and dry cleaning agent, applications requiring over 90 percent of the amount produced. Minor amounts of the solvent are used in the extraction of fats from fish meal and other natural products, in the manufacture of adhesives and industrial paints, and in the dewaxing of lubricating oils. Trichloroethylene is often used as a substitute for carbon tetrachloride, which has signifi cantly greater toxic properties. Because of its relatively low toxicity and nonflammability, trichloroethylene has been used in clinical medicine as a surgical anesthetic agent under the names Trilene, Trimar, or Trethylene. This use has been largely abandoned be cause of the availability of better anesthetic agents and because of several anesthesia accidents related to the generation of dichloroacetylene when trichloroethylene was passed through a dosed-drcuit apparatus in which a soda-lime carbon dixoide ab sorber was used. In some situations trichloroethylene has been used as an obstetrical analgesic inhalant, often self-administered by the woman in labor. Trichloroethylene is readily absorbed and excreted via the lungs. In addition it is metabolized in the liver, and a principal metabolite, trichloracetic add (TCA), appears in the urine. Tri chloracetic add may be detectable in the urine for several weeks after exposure has terminated. Urinary assays for trichloracetic add and trichloroethanol are widely used in Europe in the medical surveil lance of workers exposed to trichloroethylene. It is the more com mon practice in the United States to estimate the atmospheric concentrations of this material in the worker's breathing zone using a properly calibrated halide meter or detector tubes. In situa tions where the ambient air levels or exposures vary widely, it is possible to monitor the trichloroethylene concentrations in the ex- haled breath of persons exposed (Stewart etal., 1970). The material is excreted exponentially via the lungs, most of the absorbed amount being exhaled during the first twenty-four hours following exposure. Samples of exhaled breath are easily collected in Saran bags and analyzed by infrared specfroscopy or gas chromato graphy. By making serial evaluations during the post-exposure period, the physician may obtain sufficient information to establish the excretion rate and an estimate of the previous vapor exposure. Stewart has presented evidence that data thus obtained are more accurate, more useful, and more easily obtained than those derived from determinations of urinary metabolites. The narcosis produced by absorption of trichloroethylene can- toxidty not be distinguished from that related to the absorption of other chlorohydrocaibons. There may be an excitatory or euphoric stage. In some cases this euphorizing tendency has led to "addiction" and the repeated intentional inhalation of the vapor (Harenko, 1967). There may be dizziness, confusion, drowsiness, and eventu ally loss of consciousness. While most manifestations clear promptly with the breathing of uncontaminated air and the excre tion of the solvent via the lungs, there is evidence of neurological disturbances of longer duration. These may affect the peripheral nerves predominantly, although the central nervous system may show similar involvement. Feldman and Mayer (1968) have dem onstrated a slowing in conduction time which is reversible over the course of months. Various psychosomatic complaints and un common toxic psychoses have also been described (Hamilton and Hardy, 1949, p. 381). There is some dispute in the clinical literature as to die extent to which trichloroethylene can produce toxic effects unrelated to nonspecific chlorohydrocarbon narcosis. Enzyme and urinary urobilinogen studies after exposures at 200 ppm have yielded no evidence of hepatotoxidty. On the other hand, the report by Priest and Horn (1965) of acute fatal toxic hepatitis in a man operating a trichloroethylene degreaser is typical of those which report hepatic injury. In many of these cases the environmental investigations leave much to be desired, and the question of contaminants, in hibitors, or other exposures is always raised. While many of these reports may be in fact misleading, a careful reading of the histories suggests the likelihood of hepatotoxidty in some individuals. The concurrent ingestion of alcoholic beverages has been described as contributory. In the usual industrial exposure, however, it would be inaccurate to suggest that trichloroethylene is a potent hepatotoxin. Evidence that trichloroethylene is a nephrotoxin was APOOb37492 presented by Gutch et al. (1965), who described acute renal failure and toxic myocarditis in a man who had used this solvent in cleaning floors with the rag and bucket technique. Other reports of similar cases are not known. Convincing evidence of hematopoie tic damage is absent. Sudden death in young workers exposed to trichloroethylene has been described by a number of observers (Kleinfield and Tabershaw, 1954), In spite of the lack of supporting anatomical information, the inference that these deaths were due to ventricu lar fibrillation is reasonable. Trichloroethylene vapors are mildly irritating to the eyes and upper airway of some individuals. In many cases these subjective complaints are not reported on repeated or continuing exposure. Open flames and heated surfaces may cause the pyrolysis of this compound to the highly toxic gas, phosgene. PERCHLOROETHYLENE Tetrachloroethylene or perchloroethylene is the principal dry cleaning solvent for clothing and is commonly used as well in degreasing operations. Its toxicological properties parallel very closely those associated with trichloroethylene. harmful effect* The narcotic properties of tetrachloroethylene have been most frequently demonstrated in dry cleaning shops with ineffective ventilation or solvent recovery equipment. There have been an unfortunate number of cases of fatal central nervous system and respiratory depression related to the use of sleeping bags or other heavy articles which had not been thoroughly cleared of the solvent prior to use. The typical story describes the cleaning of a sleeping bag in a coin-operated dry cleaning establishment, failure to air the bag in the open for a period sufficient to permit the evaporation of retained solvent, and failure of the owner to awaken following a night's rest in the bag. Vapors are rapidly absorbed through the alveolar epithelium and are excreted via the same route. Absorption may cause tightheadedness, confusion, and the entire spectrum of narcotic phenomena. The vapors may have a direct, mildly irritating effect upon the eyes and upper airway. The evidence for viscerotoxic effects is similar to that for trichloroethylene. Stewart (1969) noted abnormal liver function tests after exposure, finding SGOT and SGPT levels to reach maxima in about three days. Asymptomatic individuals, who had totally recovered, showed elevated urinary urobilinogen and total serum bilirubin levels seven to ten days after exposure. Stewart raises the question of whether or not acute renal failure, rarely observed in these cases, may be due to shock AP00037493 p. <t after peripheral vascular collapse in deep central nervous system depression. Exposure is evaluated either by environmental measurement or by determining the level of the solvent in exhaled breath (Stewart et al., 1961b). Alveolar breath analysis permits the identifi cation of tetrachloroethylene two weeks after exposure, and serial determinations provide an estimate of the magnitude of exposure. Chlorinated biphenyls (polychlorinated biphenyls, PCB's)and CHLORINATED chlorinated naphthalenes are prepared from diphenyl and BIPHENYLS AND CHLORINATED naphthalene which may be reacted to varying degrees with NAPHTHALENES chlorine to produce a number of compounds designated by various trade names such as Arodor and Halowax. The materials found in commerce are invariably mixtures of specific molecules, and the commercial product is often described in terms of the relative proportion of chlorine. High degrees of chlorine substitution are associated in general with higher toxidties. As the toxicological properties of the chlorinated biphenyls and naphthalenes are not noticeably dissimilar, such mixtures are considered to have biolog ical properties which are common to the components. These materials vary in form from oily liquids to waxy or hard solids. Because of their chemical stability and high dielectric con stants, they are widely used in cable insulation and as impregnants for electrical capadtors. Chlorinated biphenyls and naphthalenes are also used for surface coatings--for example, in paints, plastics, and varnishes, and in extreme pressure lubricants which are sub ject to highly oxidizing conditions, high temperatures, or submer sion. Heat-transfer media may also contain materials of this type as may certain cutting fluid additives and components of carbonless copy paper systems. Chlorinated biphenyls and naphthalenes are potent inducers 1 toxic eftecu of chloracne, which may develop after weeks ox months of cutane ous exposure and commonly appears first lateral to the eyebrows, on the chin, cheeks, forehead, chest, abdomen, thighs, or but tocks. A history of acne vulgaris is not necessarily present, but direct local contact with the compound over a period of time will be evident. The lesions are primarily papules and yellowish cysts surrounded by mild erythema. Comedones, a common feature of acne vulgaris and oil folliculitis, are usually absent, as is melanosis. Pruritis is common. Chloracne, also known in various trades as "cable rash," is the clinical manifestation of a specific effect of these materials upon the pilosebaceous unit. The chlorinated biphenyls and naphthalenes alter the differentiation of the sebaceous gland AP00037494 cells so that keratmocytes form to plug the unit and create keratincontaining cysts. therapy and control The therapy of chloracne is based upon termination of exposure to offending materials and application of those measures which are commonly used to control acne. Prevention through the use of protective clothing, showers, and appropriate clean clothes and lockers is necessary. Barrier creams have been of little, if any, utility in the control of chloracne. When compounds of this group are used in poorly ventilated areas and especially when heat is applied, as in welding or cable splicing, there may be significant systemic absorption of toxic va pors. The target organ is primarily the liver, and cases of fatal acute yellow atrophy have been reported. The physiological mechanism related to this clinical course is not understood. Workers who are exposed to this class of materials, especially to the more highly chlorinated compounds and particularly when volatilizing temper atures are encountered, should receive the benefit of periodic liver function tests. Environmental dissemination of the chlorinated biphenyls and the identification of these materials in plant and animal tissues has become a matter of great international concern. While the full significance of this contamination is yet to be established, clinical experience with toxic exposures of nonoccupational origin em phasizes the biological properties of this class of compounds. An epidemic of "Yusho" ("oil disease") in Japan, related to the con tamination of rice oil with polychlorinated biphenyls, was marked by swelling of the eyelids, chloracne, hyperpigmentation of the skin, and nonspecific digestive or neurological symptoms (Katsuki et al., 1972). Recovery from "Yusho" has been slow, and the disorder, which has affected over 1,000 persons, has been a major medical and social problem in several prefectures of western Japan. Compounds of this category have been associated with sys temic disease in cattle and poultry. The extent to which the disease phenomena in man and animals are due to substances Other than polychlorinated biphenyls and naphthalenes but present as indus trial contaminants remains to be established (Kimbrough, 1972). Such contaminants which have come under intense suspicion in clude tetrachlorodibenzofurans and tetrachlorodibenzodioxins, PARADICHIOROBENZENE White or colorless crystals or "nuggets" of paradichlorobeniene aTe commonly available as "moth-proofing" materials used by homeowners to protect woolen garments. Naphthalene, a less effective but strongly aromatic compound, has also been used for this f dons. the e concc hepat phent attribi probai zene. AP00037495 AP00037496 OTHER HALOGENATED HYDROCARBONS 4 The vast majority of industrial halogenated hydrocarbons are those which contain chlorine--usually without, but occasionally with, other halogen constitutents. Fluorinated compounds are found in a relatively small number of specific materials, although the growth of the fluoro-organic chemical industry is impressive. Industrial bromine-containing organics are even less common, and the iodine derivatives are rare. Those fluorine-containing hydrocarbons which have commer cial application include the simple compounds, often containing chlorine as well, which are marketed with familiar names such as Freons or Geons among others. These compounds are used as propellants In aerosol "bombs" or can-dispensers, as refrigerants, and as solvents for special or critical applications where their rela tively high cost Is warranted. As a group these compounds have been thought to lack biological properties or to have mild, reversible depressant effects on the central nervous system. More recent evidence (Reinhardt, et al., 1971; Aviado and Belej, 1973) draws attention to the prominent cardlotoxic effects, manifested in ar rhythmias, that are associated with pulmonary exposure to fluorocarbons, especially fluorocarbon 11 (trichlorofluoromethane), fluorocarbon 21 (dichloromonofluoromethane) and fluorocarbon 113 (trlchlorotrifluoroethane). Sensitization of the heart to epine phrine is implicated in most of the arrhythmias, but the mechanism is not well understood. In experimental animals variable degrees of tachycardia, myocardial depression, and hypotension have been described. Polymerized fluoroethylene and similar fluoro-chloro com pounds are used in plastics of the so-called Teflon and Kel-F type and are described under that classification. Organo-fluorine com pounds which may decompose or be metabolized to monofluoroacetic add have a specific effect upon the tricarboxylic add cycle and may be extremely toxic. Methyl bromide is a heavy colorless gas used in fumigating warehouses, grain stores, the soil, and other enclosed areas or areas which can be sealed off with impervious plastic sheeting. The gas has a density over three times that of air; consequently, methyl bromide tends to collect in low places. It penetrates easily into bales or sacks of material and is, therefore, a highly effective non- METHYL BROMIDE 293 residual insecticidal material. The gas is highly toxic to man and has most commonly caused injury among fumigating operators and others who enter structures when gas is still present prior to post-treatment ventilation. The compound has also been as sociated with occupational injury in the course of its use as a methylating agent in synthetic chemical operations and as a fire extinguishing agent in special or now obsolete appliances. Methyl bromide was also formerly used as a refrigerant gas, but it has been superseded for this purpose by ammonia or the fluorohydrocarbons. The gas has no warning properties, and those who use it are well advised to have suitable monitoring instruments and personal protective equipment. Methyl bromide is readily absorbed through the lungs. Transcutaneous absorption may occur, but it is not considered to be of significance in occupational poisoning. reports of harmful effects Acute exposure to excessive concentrations of methyl bromide produces headache, nausea, and vomiting. Some patients have described a disagreeable taste to food--bitter or "like burned rub ber." The gas is a delayed pulmonary irritant and can produce bronchitis, pneumonia, and pulmonary edema. Neurological ef fects are more common, often severe, and frequently characterized by a prolonged clinical course. Such effects may be delayed in onset by a latent period which follows the termination of exposure by hours or even days, the delay possibly determined by the amount inhaled during the worker's activity. In cases of mild exposure, neurological phenomena may consist of giddiness, ataxia, vertigo, paresthesias, and weakness. Twitching and epilep tic seizures may occur. More severe episodes are associated with status epilepticus, prolonged loss of consciousness, and pyramidal or extra-pyramidal signs (Rathus and Landy, 1961). These manifes tations may be very slow to resolve, and ataxia and seizure pat terns may persist for months or years. In some cases; with or without a prolonged latent period, a fatal outcome or permanent neurological or psychiatric sequelae may result. Neurological reactions occur at levels of exposure which are insufficient to produce acute or delayed pulmonary manifesta tions, The altered physiological functions in methyl bromide poisoning are notunderstood, although there has been speculation that the clinical manifestations represent an unusual form of bromidism in which the distribution of inorganic bromide is related to hydrolysis of the organic compound after it has been distributed. Methyl bromide is also a potent methylating agent and may act by this mechanism. f AP00037498 AP00037499 ALCOHOLS AND GLYCOLS 5 In the industrial setting alcohols and glycols do not present serious hazards. Although specific compounds (e.g., methanol and ethylene glycol) continue to be identified as causal agents in epidemics or isolated instances of intoxication, the observed illness is almost invariably associated with the intentional oral ingestion of these compounds. Industrial exposures to vapors of alcohols and glycols rarely--if ever--produce symptoms of systemic intoxica tion, and whatever toxicity is observed is usually related to irrita tion of the conjunctivae and mucous membranes of the upper airway. In most industrial situations only the low-molecularweight alcohols are sufficiently volatile to yield significant air con centrations. The alcohols and glycols have narcotic properties; however, these are much less prominent than those associated with solvent hydrocarbons or halogenated hydrocarbons. Methanol (methyl alcohol, wood alcohol, wood spirit, car- METHANOL binol) is used extensively as a solvent for lacquers,, plastics, and various industrial coatings. It is easily available outside industry as a component of lacquer thinners, anti-freeze of the "nonperma nent" type, and canned heating preparations of jellied alcohol. Most gasoline additives to prevent winter fuel line and carburetor idng are based on methanol. The designation "wood alcohol" implies that methanol is derived from the distillation of wood; however, the production of synthetic methanol today from carbon monoxide and hydrogen is of much greater importance. The early literature does describe examples of systemic intoxi toxic effect cation by the inhalation of methanol in various varnishing opera tions or similar situations in which large quantities of solvents were being evaporated into an enclosed space. While the possibility of ingestion cannot be definitely excluded in every report, it is proba ble that some of these exposures were, in fact, only by the respira tory route. The levels of such exposures, however, must have been extremely high, for there is ample evidence today from the photo graphic film industry that repeated exposures to air levels of methanol well in excess of the threshold limit value of 200 ppm do not cause illness or significant discomfort. The onset of symptoms may follow ingestion by a period of less than an hour or may be delayed for thirty hours; a latency period of twelve to eighteen hours is common. In the usual case of poisoning by ingestion the initial symptoms may include those 297 suggestive of ethanol intoxication: headache, weakness, vertigo, visual disturbances, and coma (Roe, 1946; Roe, 1955; Bennett et al., 1953). There may be nausea, vomiting, and abdominal or lumbar pain. The symptoms are associated with metabolic acidosis, reflect ing the accumulation of acid metabolites and their effects upon normal metabolic systems. It is believed that the severity of symp toms is proportional to the intensity of the acidosis. Visual disturbances, the most striking and often the most damaging aspect of methanol intoxication, may develop early (Benton and Calhoun, 1952). A blurring of vision, occasionally with changes in color perception or with scotomata, may develop promptly with little warning. The loss of acuity may be accom panied by the perception of spots or a gray mist sensation, and there may be pain or tenderness of the eyes or photophobia. The initial impairment of vision may be transitory, although the im provement in vision may be followed by complete and permanent blindness. Clinical observations suggest that if there is no im provement within six days the prognosis is very poor. Examina tion of the eye in methanol poisoning often shows the pupils to be dilated and unreacdve. Visual loss is associated with hyperemia of the optic disc. Blurring of the disc margins, indicative of retinal edema, is observed and, when severe, warns of at least some degree of permanent loss of vision. Atrophy of the disc is observed in some thirty to sixty days. The physiological explanation for the vulnerability of the eye in methanol intoxication lies in the very high relative oxygen con sumption of the retina and the impairment of retinal oxidation and glycolysis by formaldehyde, the normal metabolite of methanol. therapy Since the metabolic addosis and eye injury of methanol poison ing are related to the metabolites of methanol rather than to the al cohol itself, the treatment of methanol ingestion is based upon attempts to impair the metabolism of this compound so that it may be excreted unchanged in the urine. The evidence is that methanol oxidization to formaldehyde is catalyzed by alcohol dehydro genase, a zinc metalloenzyme which oxidizes other alcohols as well (Li and ValLee, 1969). Ethanol can compete with methanol for active sites of this enzyme, and in fact the enzyme has a greater affinity for the former than the latter. Consequently the therapeutic administration of ethanol permits it to be preferentially oxidized and diminishes the production of methanol metabolites. It is be lieved by Roc (1955) that suffident ethanol must be administered to produce a blood level of at least 0.1 percent. Control of acidosis is essential in methanol poisoning, and the use of intravenous bicar bonate has been frequently lifesaving. More recently the value of AP00037501 ALCOHOLS AND GLYCOLS I 299 hemodialysis or peritoneal dialysis has been emphasized (Cowen, 1964). The relative availability of peritoneal dialysis and rapid de terminations of blood methanol and acid-base balance has im proved dramatically the prognosis of methanol intoxication (Kane et al., 1968). Ethanol (ethyl alcohol, grain alcohol) used in industry is ETHANOL synthesized almost entirely from ethylene. Beverage ethanol is derived from the fermentation of carbohydrates, and the supply for this purpose is not augmented by synthetic ethanol. While the problems of ethanol intoxication associated with beverage ingestion are well known, industrial exposures to ethanol vapors are of no practical importance. Lester and Greenberg (1951) computed the absorption via the respiratory tract that would be necessary to cause any continuous increase in blood ethanol levels. They concluded that a workman exposed to 1,000 ppm would have to breathe at a rate of 65 L/min. Since a ventilatory rate of 30 L/min. is associated with hard work, the hazard of systemic effects from airborne ethanol is unlikely. At air concentrations of 5,000 to 10,000 ppm, there may be mild transient coughing or irritation of the eyes and upper airway. Concentrations of 20,000 ppm are intolerable. Industrial workers sometimes drink ethanol on hand for manufac turing or other industrial purposes, thus adding to the total dose absorbed. Ethanol absorption, regardless of the route of administration, may produce very undesirable effects in workers taking disulfiram or exposed occupationally to this compound or thiram. Propyl and isopropyl alcohol have no current toxicological PROPYL, ISOPROPYL, importance in industry. Of the butyl alcohols, n-butyl alcohol has BUTYt ALCOHOL been most intensively studied. At concentrations of 100 to 200 ppm there may be irritation of the eyes and upper airways, and the apparently specific formation of minute vacuoles of the cornea has been observed in workers coating raincoats with material contain ing this solvent (Cogan and Grant, 1945). The other butyl alcohols have similar Irritative properties. The pentyl or amyl alcohols ("fusel oil") are irritating and have PENTYL OR AMYL produced illnesses, some fatal upon ingestion, The toxicological ALCOHOLS significance in industry of these alcohols and their heavier homologues is small. Allyl alcohol (CHa=CH-CH2-OH) is a pungent chemical in- ALLYLALCOHOL termediate with potent irritant properties. Absorption through the AP00037502 I skin leads to deep muscle pain, presumably due to spasm. Lacri- mation, retro-bulbar pain, photophobia, and blurring of vision may be associated with exposure to vapors, and corneal injury has been described. When this material is used in an open system, exhaust ventilation is essential, and clean-up of spills requires that personal protective devices be used. ETHYLENE CHLOROHYDRIN Ethylene chlorohydrin (chemically 2-chloroethyl alcohol) is an extremely toxic compound used for its special solvent properties and as a chemical intermediate. It readily penetrates the skin and most rubber gloves. The mechanism of toxicity is not understood. Several cases have been described in which the fatal outcome was preceded by nausea and vomiting, weakness, and respiratory fail ure (Bush et al,, 1949). ETHYLENEGLYCOL Ethylene glycol is the basic constituent of "permanent" anti freeze and many hydraulic fluids. It has a low vapor pressure, and significant air concentrations are not achieved unless the com pound is heated or sprayed as a mist. Respiratory exposures or application of the material to the skin are not considered to be of toxicological significance. Intoxication does occur when ethylene glycol is taken by mouth, and an estimated fifty fatalities annually in the United States result from the ingestion of this compound by mistake or as a substitute for beverage ethanol. toxicity The mean lethal dose for an adult has been estimated to be about 100 ml. The cause of death in these cases is either central nervous system depression or renal failure related to the formation of oxalic add, the normal metabolite of the glycol. In most cases the initial symptoms are similar to those of ethanol intoxication, but there may be significant nausea and vomiting, abdominal pain, and respiratory failure. Renal disease is marked by albuminuria and oliguria, and oxalate crystals in the urinary sediment are prom inent. Clinical experience suggests that large doses of ethylene glycol lead to death from relatively prompt central nervous system depression, while somewhat smaller or repeated doses, insuffi cient to cause this depression, result in renal insuffidency. treatment The metabolic basis of ethylene glycol poisoning is related to the oxidation of this compound to oxalic acid by alcohol dehy drogenase. Since impairment of this oxidation has therapeuticvalue, ethanol has been used to compete with glycol for active enzyme S sites (Li and Vallee, 1969). Human alcohol dehydrogenase is dem onstrated to have an affinity for ethanol some thirty to forty tir in ON ps Si so ac tri m lat co faj gi; in' fo cnlot so CO in Se ne P1 al: re w ar C in & ht st 19 th th sc AP00037503 ALCOHOLS AND GLYCOLS / 301 times lhat for ethylene glycol. That ethanol administration leads to increased urinary excretion of unchanged glycol and reduction in oxalate production has been shown in monkeys and in at least four patients. Dialysis also has value for the removal of ethylene glycol. Supportive measures often must include vigorous treatment with sodium bicarbonate to control severe and persistent metabolic acidosis. Diethylene glycol is a similar compound but with little indus DIETHYLENE GLYCOL trial hazard. From the toxicological point of view it is significant mainly in that over 100 deaths occurred in the United States in the late 1930a as a result of the ingestion of an elixir of sulfanilamide containing 72 percent glycol. Fatal cases showed progressive renal failure with death in less than eight days after the onset of anuria. Other glycols such as propylene glycol and the polyethylene OTHER GLYCOLS glycols are not considered to be of toxicological importance in industry. Their metabolites do not include oxalates, formic acid, or formaldehyde. The principal alkyl derivatives of ethylene glycol are the ALKYL DERIVATIVES monoethyl ether (Cellosolve), the monomethyl ether (methyl Cel- OF ETHYLENE GLYCOL losolve) and the butyl ether (butyl Cellosolve). They are important solvents for industrial coatings and inks. The three compounds are considered to have similar harmful properties with toxicity increas ing in this order. All can be absorbed via the skin, lungs, or gastrointestinal tract. Acute poisoning usually affects the central nervous system and the kidneys. With less intense and more prolonged exposure, involvement of the hematopoietic system is also observed. Anemia, which resolves on cessation of exposure, is reported. In some situations the anemia is described as macrocytic with a predominance of immature leucocytes. The hemolytic anemia which occurs in experimental animals exposed to butyl Cellosolve has not been reported in man. The CeUosolves are all irritating to the skin and mucous membranes. The effects of these glycol derivatives upon the central nervous system include headache, drowsiness, weakness, slurred speech, recrudescent stuttering, staggering gait, tremor, and blurred vision (Zavon, 1963). Changes of personality are often noted first by the family of the affected individual. These changes are such that the patient, in the absence of an accurate occupational history, may be treated for schizophrenia or narcolepsy. In acute poisoning with the ethylene glycol monoalkyl ethers. there is frequently evidence of renal injury: albuminuria and hematuria. The clinical nature of this renal disorder is not well established, but it is unrelated to oxalates. A similar series of monoalkyl ethers of diethylene glycol form the series of solvents known in industry as Carbitols. Diethylene glycol monoethyl ether (Carbitol), diethylene glycol monomethyl ether (methyl Carbitol), and diethylene glycol monobutyl ether (butyl Carbitol) have not been associated with industrial intoxica tion. dioxane Dioxane, a valuable solvent for industrial coatings and a de hydrating agent in the preparation of histological slides, can be inhaled in amounts sufficient to cause serious systemic intoxica tion. Its warning properties are poor. Consequently injury may become apparent hours after termination of an exposure which had been erroneously considered to be negligible. Acute expo sures, as of technicians in a histology laboratory, may lead to headache, nausea, vomiting, and irritation of the eyes. Five fatalities have been reported in the literature (Barber, 1934). While the quantitative aspects of the dioxane exposure were unclear, post-mortem studies in these cases demonstrated prominent renal and hepatic injury. The cause of death was considered to be hemorrhagic nephritis. Animal experiments confirm the nephroand hepatotoxldty of dioxane. 4 AP00037505 KETONES AND ETHERS 6 The ketones, used widely as solvents, have no currently recog nized general toxicological properties. The principal exceptions are certain halogenated or unsaturated ketones with special limited uses. The ketones can be irritating to the eyes and mucous mem branes. Industrial limits of exposure are based primarily on levels in air which do not produce irritation or an unpleasant sensory response. At very high levels it is possible to produce narcotic effects with simple ketones. Industrial experience with acetone (dimethyl ketone) has been extensive. Careful industrial hygiene and occupational medical studies on literally hundreds of workers exposed to levels of 1,000 to 2,000 ppm for many years have confirmed the relative safety of this compound. Methyl ethyl ketone (MEK) is more irritating to the eyes and upper airway than is acetone; however there has been no industrial evidence of organotoxicity. Nausea, vomiting, headache, and other subjective complaints may occur at high levels of exposure. The experience with methyl isobutyl ketone (MIBK) has been similar. Wagoner (1973) has discussed an industrial epidemic of peripheral neuropathy involving some fifty workers exposed to methyl butyl ketone (MBK) in a print shop. This phenomenon had not been associated with previous exposures of similar magnitude to methyl ethyl ketone and methyl isobutyl ketone. The mechanisms of neurological disease production re main to be identified as do many of the clinical and epidemiological aspects of this intoxication. Cyclohexanone and its analogues are not of toxic importance, although they may cause transient irritation. Certain unsaturated ketones have important biological properties. Ethers, well known for their narcotic properties and ability to act as fat solvents upon the skin, have no general industrial tox icological properties of practical importance. The principal excep tion is that presented by bis-chloromethylether (BCME) and pos sibly by chloromethylether (CME) which, however, is almost always contaminated with the former compound. Bischloromethylether is a biologically active alkylating agent with clearly identified carcinogenic properties for mucosa, skin, and lungs. Epidemiological studies in industry (Figueroa, et ai., 1973; Thiess, et al., 1973; Nelson, 1973) have demonstrated that BCME is a potent occupational carcinogen, identified with the induction of "oat cell" ("small cell") carcinoma of the lung. The investigations of Thiess revealed that, of eighteen persons employed in a technical 303 research center, six died of carcinoma of the lung. In addition two of fifty production workers, protected by a "closed system" and fresh air masks, also died of lung cancer during the same six-year period. The evidence for the extreme carcinogenic potency of BCME and the fact that airborne levels of this compound are measurable when formaldehyde and hydrochloric acid react sug gest that histological technicians who conduct operations in which this reaction may occur should be protected by suitable ventilation. s s t s l T F < t ! k. AP00037507 AROMATIC NITRO AND AMINO COMPOUNDS7 Aromatic nitro and amino compounds comprise a varied group of substances which are fundamental to industries producing explo sives, pharmaceuticals, rubber chemicals, and "aniline" or "coal tar" dyes. Other compounds of the group are intermediates in the synthesis of pesticides, plastics, and paints. While certain mem bers of the nitro (--NOj) and amino (--NHj) aromatic group have relatively specific toxic effects, it is generally true that there are properties which are characteristic of the group. Many of these compounds produce methemoglobin, some are bladder car cinogens, and others uncouple oxidation from phosphorylation. There are unusually potent skin sensitizers in die group. Liquid nitro- and amino-aromatics are readily absorbed through the intact skin. Methemoglobinemia is considered to be the outstanding acute reaction to most nitro and amino aromatic compounds (Bodansky, 1951). In cases of chemical methemoglobinemia, it is not-dear whether or not all manifestations in man reflect hypoxemia exclu sively and that the chemical compound implicated (e.g., aniline) is without specific direct pharmacologic influence on body systems. The presence of severe methemoglobinemia tends to obscure other possible acute manifestations reflecting direct toxicity. It is proba ble that chemically active compounds of this group do have direct organ effects, but it is difficult to provide convincing demonstra tions. In biochemical terms methemoglobin is the chemical analogue of hemoglobin in which the iron of the heme moiety has become oxidized from the normal Fe** (ferrous) state to the abnormal Fe++t (ferric state). Oxygen bound to methemoglobin is so firmly attached that it is'not available to tissues and, in fact, can be separated from the carrier pigment only by rather drastic nonphysiological means. Consequently methemoglobin is not an oxygen-transporting pigment. Tissue hypoxia is the consequence of hemoglobin oxidation, not oxygenation, to Fe**T Methemo globin also interferes with the release of oxygen from normal hemoglobin so that hypoxia is more severe than the methemoglo bin levels might suggest (Darling and Roughton, 1942). Organic and inorganic nitrites, organic nitrates, and quinones form methemoglobin directly; inorganic nitrates on ingestion may toxicity 305 produce methemoglobin through the action of intestinal bacteria ! which yield nitrites. In most cases it is probable that metabolites of the aryl nttTO and amino compounds are the proximate cause of blood pigment oxidation. Phenylhydroxylamines and nitroso compounds are prime possibilities as the methemogoblin- producing metabolites. Clinical observations indicate that nitro compounds are associated with a more insidious onset of methemoglobinemia and a more prolonged course than would be the case with the corresponding amino compounds. These obser vations may reflect a somewhat slower conversion of the nitro compounds into the actual methemoglobin producer. Methemoglobin is normally present in man in a low concentra tion. An equilibrium exists between hemoglobin and methemoglo bin, the latter being continuously reduced by an intracellular methemoglobin reductase known a9 diaphorase (Smith, 1969). Glycolysis is adequate to drive this mechanism at a rate sufficient to handle normal pigment loads. With massive chemical exposure, this mechanism is inadequate to handle the load of abnormal oxidized pigment, and clinical cyanosis becomes evident. An aux I iliary reducing mechanism can participate in the reduction of methemoglobin when methylene blue is administered therapeuti cally. The precise biochemical nature of each step in this reduction is not yet dear, but the evidence is good that methylene blue may be of great value in the clinical treatment of methemoglobinemia (Wuertz et al., 1964). Industrial experience with methylene blue has been limited, a fact which is probably related to existing reports that methylene blue is itself a methemoglobin producer. More recent interpretations support the opinion that methylene blue does not produce methemoglobin in most laboratory animals and probably not in man. Aniline, nitrobenzene, and indeed most of their homologues (e.g., dinitrobenzene, nitxoaniline) generate methemoglobin. Many of these compounds penetrate the skin, and vapors or dusts are absorbed rapidly in the lungs. The onset of cyanosis is usually insidious, and the time required is a function of the absorption rate and the specific compound absorbed. Nitrobenzene and other nitro compounds generate methemoglobin more slowly, but cyanosis is more persistant. The onset of cyanosis is often first noted at the lips ("blue tip") and ears. The color is more violet, lilac, or "huckleberry pie" than the cyanosis associated with unoxygenated normal hemoglobin. Symptoms may be absent, although euphoria, flushed facies, and a headache are common. Cyanosis is usually detectable when the proportion of converted hemoglobin approximates 15 percent. 1 AP00037509 AROMATIC NITRO AND AMINO COMPOUNDS / 307 Methemoglobin levels to 40 percent may exist without symptoms other than a sense of well-being. At higher levels headache may become severe; weakness, ataxia, and lightheadedrvess occur. With increasing concentrations of methemoglobin, dyspnea, tachycar dia, and alarming cyanosis are noted. Even at conversion levels approximating 75 percent, however, recovery without specific therapy has been the rule. In most cases of methemoglobinemia the most useful treatment therapeutic procedure is simply a prompt and thorough cleansing of the patient with soap and warm water with special attention to the hair and nails. Contaminated footwear must be discarded. There are numerous examples of a recurrence of "blue lip" after an apparently cured patient puts on. dean clothing and steps into his old shoes, a source of absorbable aniline or nitrobenzene. Bed rest is indicated. The headache is often relieved promptly by die ad ministration of oxygen, although this procedure has no effect on methemoglobin reduction. That these conservative procedures need to be supplemented with active therapeutic measures is not dear. Better industrial practice suggests, however, that methylene blue is indicated when methemoglobin levels rise in excess of 40 percent. The usual dose of the dye is 1 to 2 mg/kg of body weight as a 1 percent solution in saline. Ascorbic acid, a reducing agent, has also been used, but it appears to be less effective than methylene blue. From time to time the possibility of exchange transfusions has been raised. This step is seldom, if ever, considered necessary. Recovery is usually rapid, and spontaneous disappearance of cyanosis may occur in hours. With high levels of methemoglobin and when the agent involved is a nitro compound, twenty-four or more hours may be required. When recovery is slow, the physician must consider the possibility that compounds are still being ab sorbed from the skin. The management of methemoglobinemia is facilitated by prompt accurate determinations of the oxidized pigment in the blood. SpectTophotometric procedures are readily available. Methemoglobinemia has been associated from time to time with reports of a hemolytic anemia. Heinz bodies, small refractile granules in erythrocytes, have been attributed to exposure to aromatic amines and nitro compounds and to nitrate and nitrate esters (Hanley and Mauer, 1961). Hepatic injury related to aryl amino compounds has been rare. There are reports of acute hepatic disorders in benzidene workers, but effects in this population are presumably due to heavy expo- AP00037510 sures. Nitro compounds of the dinitrobenzene and trinitrotoluene (TNT) type have a history of prominent hepatotoxic effects often associated with an aplastic anemia. The data come to a large degree from the British munitions industry in both World Wars and to a lesser extent from similar American sources. Both chemicals are readily absorbed through the skin, especially when the skin is exposed and wet with sweat Hepatic injury is manifested by jaundice, which often is demonstrable only in the conjunctivae since the skin of workers with this degree of exposure may already be dyed yellow from the compounds in question. Unfortunately this clinical manifestation is a late sign of injury and is not satisfac tory in the prevention of acute yellow atrophy. Earlier symptoms are not sufficiently specific to be very useful in prevention. McConnell and Flinn (1946) reported twenty-two cases of fatal TNT poisoning which occurred in American industry in World War II. Of these, thirteen were due to aplasticanemia, eight were due to acute yellow atrophy of the liver, and one was due to hepatitis followed by fatal aplastic anemia. The number of nonfatal cases during the same period was not reported, but recovery from either toxic hepatitis or toxic aplastic anemia is rare. It is very probable that TNT-related disease was much more common than these figures suggest, especially during World War I. There is reason to believe that a somewhat better health record in the TNT industry during World War II may be due to the fact that tetrartftromethane, a toxic and irritating impurity of crude TNT, was removed during that period (Slevers et al., 1947). D{NITROBENZENE Dinitrobenzene is some twenty times as potent a methemoglobin producer as is TNT; consequently, the appearance of cyanosis provides warning of exposure to this potent hepatotoxin. picric acid and TElkYL Other aromatic nitro explosives, picric add (trinitrophenol) an(j tetryl (methyltetranitroaniline) do not pose major industrial health hazards except during very high exposures as encountered in wartime. Tetryl is highly irritating to the skin and mucous membranes and may cause severe upper respiratory tract irritation with coughing and epistaxis. The compound stains the skin and hair yellow. Picric add produces a similar contact dermatitis and staining. There is evidence that heavy exposures to tetryl may cause liver damage (Hardy and Maloof, 1950). TRIMETHYLENE- trinitramine Trimethylenetrinitramine, called cyclonite or RDX, a related heterocyclic compound, is a military high explosive. It has been found to cause convulsions in men working under poor conditions of hygiene (Barsotti and Crotti, 1949). Typical epileptiform seizures AP00037511 AROMATIC NITRO AND AMINO COMPOUNDS / 309 may be preceded by a few days of irritability, insomnia, or rest lessness. Mo sequelae have been observed following the cessa tion of exposure. Primary and sensitizing dermatitis may also be caused by RDX or, more likely, by impurities or chemical inter mediates associated with its production. RDX does not induce methemoglobinemia or nitrate effects. The dinitrochlorobenzenes are almost universal skin sensitiz DINITROCHLOROers; a minute contact will sensitize approximately three-fourths of BENZENES all persons tested. The reaction may vary from a small area of pruritic vesiculopapular eruption to a generalized exfoliative der matitis. The 2,4-lsomer is used in experimental sensitizations; pre sumably it combines with lysine in cutaneous proteins to form a complete antigen. The dinitrophenols and dinitro-o-cresol, referred to as DNOC, DINITROPHENOLS AND which have uses as pesticides, are distinctive from the toxicological DINITRO-O-CRESOL point of view in that they are compounds with marked effects upon energy-producing metabolic mechanisms. Upon absorption, these compounds uncouple oxidation from phosphorylation. Energy made available by oxidation is not converted into active phosphate but is expended in raising body temperature. Cataracts may occur in cases in which extreme elevations of body tempera ture are achieved, and fatal hyperpyrexia has been reported (Bid- strup and Payne, 1951). The so-called aniline tumor of the bladder, is currently be aniline tumor of lieved to be related to absorption of any one of the following four the bladder, industrial illness aromatic compounds: 2-naphthylamine Q3-naphthylamine), 4-aminodiphenyl (xenylamine), 4-nitrodiphenyl, and 4,4-di- aminodiphenyl (benzidine). The disease was first reported in the German dye industry by the surgeon Rehn, who, in 1895, reported four dye workers with tumors of the bladder. He con cluded that vapors of aniline, used in the production of the dye fuchsin, were responsible. Not until 1934 did the first American report appear in the form of a number of articles prepared by a group of physicians associated with E. I. duPont de Nemours Company. Gehrmann's contribution to the symposium described cystoscopic examination of 587 men and the discovery of twentyseven positive cases (Ferguson et al., 1934). Sixteen other cases were found in which there were hemorrhagic areas of the bladder. The age of men affected ranged from thirty to sixty years, and the duration of exposure from four to eighteen years. Except for two ct-naphthyiamine workers, all the men had been exposed to either AP00037512 /3-naphthylamine or benzidine. No tumors were detected in work ers exposed exclusively to aniline. The evidence is convincing that tumors in the a-naphthylamine workers were actually due to con tamination by the /3-isomer. The fact that many aromatic amines and related compounds are present in those segments of the chemical industry in which occupational bladder tumors have arisen has produced speculation as to relative toxicities of compounds, the proximate carcinogen, and the carcinogenetic mechanism. As far as is known, only those compounds listed in the previous paragraph produce bladder tumors in man. Additional data from studies in dogs indicate the carcinogenic potential of other aromatic amines: 2-acetyl- aminofluorene, NtN-dimethyl-4-aminoazobenzene, and 4amino-3:2'-azotoluene. It must be presumed that these com pounds are carcinogenic in man as well; he has been protected by limited industrial exposure. The accumulating evidence supports the view that these compounds themselves are not carcinogenic, for they fail to produce tumors when Implanted directly in the bladder of experimental animals. Man and dogs appear to be species with the necessary biochemical mechanisms for transform ing these compounds into the proximate carcinogen (Troll and Belman, 1967). Carcinogenic metabolites have been isolated in the urine of dogs. This material can induce tumors in the rat bladder, whereas the parent amine cannot, either by direct implantation or by parenteral administration. Occupational tumors of the bladder follow a long latent period averaging about eighteen years, with reported extremes of one and forty-eight years. Durations of exposure have also varied widely from less than a year to many years. Age is not clearly a factor in the development of disease. Once initiated, the course of occupa tional bladder tumors is not dissimilar to bladder tumors arising in the general population. The tumors may present as a benign papil loma, a simple noninvasive, nonmetastasizing growth on the bladder wall. Other tumors may first be found as invasive car cinomata; there are all patterns of intermediate categories. In all instances there is a tendency to recurrence and complications from, hemorrhage and infection. Whether the tumor is a benign papil loma or a metastasizing carcinoma appears to have no relationship to characteristics of the exposure or the worker. Primary tumors in the renal pelvis and ureters have also been observed, but there is no evidence that these carcinogenic aromatic compounds produce tumors outside the urinary system. Treatment is surgical. In a number of cases the bladder has been excised and the ureters have been connected to an ileal f LA AP00037513 AROMATIC NITRO AND AMINO COMPOUNDS ?k- bladder. Medical surveillance is based upon exfoliative cytological tat examinations of urinary sediment and on periodic cystoscopy. In >n- men who are known to have been exposed to bladder carcinogens there does not appear to be an alternative to these procedures. The ds obvious solution in the case of unexposed workers is the enclosure ch and control of relevant industrial processes. In some jurisdictions jn the production of /S-naphthylamine has been made illegal. n, se From time to time hematuria may be observed in men han TOLUIDINES AND er dling toluidines and chlortoluidines. There may be a hemorrhagic CHLORTOLUIDINES te cystitis with painful and frequent micturition. This acute problem '1- is of no long-term significance and clears promptly on cessation of 4- toxic exposure. If hematuria persists, the question of other pathological urinary tract phenomena must be considered. The y cystitis related to these aniline derivatives has no relationship to ts carcinogenic amine-related processes. -I e Para-phenylenediame and para-aminophenol are dye inter PARA-PHENYLENEDIAME e mediates, which, when applied to furs and properly treated, give AND PARA-AMINOPHENOL a brown or black color. TTiese compounds are potent skin and i respiratory allergens and can produce severe bronchial asthma e among workers in the fur-dyeing industry. Dermatitis from prop erly finished fur is rare, however, since these dyes are well fixed to the hairs and do not cause reactions even in highly sensitized persons. Histories of two cases of poisoning from dimethylnitrosamme were picked up by Hamilton in the course of a survey of a large automobile factory (Hamilton and Hardy, 1949, p. 301). Apparently the action of the poison was on the liver, producing cirrhosis with jaundice and ascites. The first subject was violently ill but pulled through, the second was less affected and was recovering when he developed an infection from the paracentesis and died. The liver was cirrhotic, with areas of regeneration. The hepatotoxic action has been confirmed in animal studies reported by Bames and Magee (1954). Elkins (1959 p. 175) describes dimethylnitrosamme as a useful solvent because it is miscible with water, methylene chloride, and vegetable oils. However, in view of the evidence that this compound is a carcinogen, exposure should be reduced to a minimum. AP000375t4 ESTERS 8 Esters are formed when an organic grouping, simple or complex, replaces an acidic hydrogen atom in an organic or inorganic acid. They are used extensively in the plastics industry, either as resins or as plasticizers, and as solvents for lacquers. Esters of inorganic acids may have prominent corrosive or pharmacological proper ties, and indeed this group may be considered to include the dearly toxic organophosphate insecticides. Although there are notable exceptions to the rule, esters of organic acids are generally of low toxicity. Nonspecific irritative effects are commonly as sociated with the presence of a double bond in these esters which, ifsaturated, wouldbeessentiallyharmless. Conjunctivitis and upper airway symptoms may occur and pulmonary edema is possible in cases of massive over-exposure. These irritating unsaturated esters include the acrylates, methacrylates, and crotonates, and various vinyl and ailyl esters. With the exception of certain phosphate esters used as plas- biological effect ticizers, those esters used as resins and plasticizers are physiologically inert in the industrial environment. This group indudes the succinate, adipate, azelate, sebacate, citrate, and phthalate plas ticizers. Minor degrees of epithelial irritation may follow highly unusual or intentionally created exposure conditions in which vapors of heated material are inhaled or in which skin exposures are prolonged. Even then, observed manifestations maybe due to impurities, decomposition products, or physical aspects of the exposure situation. Reports of sensitizing reactions are rare and do not always suggest unequivocal etiologies. Inhalation of dusts has produced no specific pulmonary reaction. The aliphatic esters used as lacquer solvents, primarily ethyl ALIPHATIC ESTERS acetate and butyl acetate, have narcotic properties which are less prominent than those assodated with the chlorinated hydrocar bons. The ester solvents are also powerful defatting agents when applied to the skin and produce a nonspecific drying, cracking, and increased susceptibility to infection. Sensitization is rarely if ever encountered. Solvent ester vapors are generally irritating tp the conjunctivae and mucous membranes of the upper airway but leave no residual effects. There have been rare reports in the literature of visceral injury, effects upon the bone marrow, and nervous symptoms. Careful consideration of all exposure and diagnostic data in these cases almost always suggest that the 313 AP00037515 esters mentioned were not necessarily responsible for the observa tions reported. As a group the ester lacquer solvents comprise a category of compounds that have relatively insignificant toxic properties. HALOGENATEDACID ESTERS A small number of halogenated add esters are potent lach- rymators and vesicants and have the potential for produdng pulmonary edema. Compounds in this category are important organic intermediates and include ethyl chloroformate, ethyl chloroacetate, and related bromo- and iodo-compounds. 5everal of these materials have been used as chemical warfare agents. There is no evidence that they produce chronic disease, but fatalities have occurred from acute pulmonary edema. The highly hazardous character of these compounds appears to be related to the high reactivity of the halogen atom and not to the fact that they are esters. ALKYL ESTERS OF SULFURIC ACID Alkyl esters of sulfuric add, primarily dimethyl and diethyl sulfate, are important alkylating agents in industrial organic syn thesis. These are intensely irritating substances, producing inflam mation of the eyes and upper airway, vesication of the skin, and pulmonary edema. Dimethyl sulfate was used in World War I as an irritant and vesicant. Dimethyl sufate is extremely hazardous be cause of its deficient warning properties and the delayed deep lung reaction. Two cases reported by Littler and McConnell (1955) are typical of those which occur. In one case a young chemist splashed dimethyl sulfate on his skin and clothing but immediately flooded the contaminated areas with water, diluted sodium hydroxide, and ammonia. There were no immediate symptoms; however, bronchospasm, rales, tachycardia, and marked swelling of the eyes occurred about four hours after the incident. Thirteen hours after exposure, large vesicles appeared upon the skin. There was a severe cough with sputum containing shreds of necrotic tracheal mucosa. Subcutaneous emphysema indicated perforation of the trachea or bronchi. The second man, exposed probably only to vapors of dimethyl sulfate, developed pulmonary edema twelve hours after exposure, and swelling of the face and hands, distur bance of visual fields, and analgesia, which has been commonly reported in others. Both men recovered without residual effects, although some scarring of the skin resulted. Cases of this sort were often fatal prior to the availability of antibiotics for control of Infection in areas of skin necrosis. These cases illustrate the potent toxic properties of dimethyl sulfate vapor, the latent period be- f t\v m< ch th \v< pe Cc foi Wc bv ins cat ins 8as ph. 2-e poi use phi pla to US uri phi ing tri car del der pei inh car prc oxi ne$ idt ph< ant AP00037516 tween exposure and illness, and the serious complications which may ensue. ESTERS / 315 Clinical manifestations due to methylchlorosulfonate, ethyl control chlorosulfonate, and methyl-p-toluene sulfonate are similar to those associated with dimethyl sulfate, and similar precautions are warranted. Contaminated areas should be entered only by trained personnel with impervious clothing and air-supplied respirators. Contact of these compounds with the skin or eyes is an indication for rapid and prolonged irrigation of the area with large volumes of water. Decontamination of floors and equipment may be effected by flushing with dilute alkali or ammonia. Specific phosphate esters comprise a major category of organic phosphate ESTERS insecticides with important associated occupational medical impli cations. Other phosphate and phosphite esters, lacking significant insecticidal properties, are widely used as plastidzers and as gasoline additives. Included in this group are tri-o-cresyl phos phate, triphenyl phosphate, tri-2-ethylhexyl phosphate, and 2-ethylhexyl diphenyl phosphate. As plastidzers, these com pounds offer the additional property of flame retardancy and are used widely in vinyl and cellulosic formulations. Triphenyl phos phite is a color stabilizer in alkyd resins and an additive to epoxy plastics. Many phosphate esters used as plasticizers may be added to gasolines to control pre-ignition. Tricresyl phosphate is often used for this purpose, and advertising stressing "TCP" is not unknown. While some of these plasticizer and fuel additive phos* phorus-containing esters do have weak cholinesterase-inhibit ing properties, clinical effects assodated with disturbances of transsynaptic transmission are not important. Of great signifi cance, however, is the fact that some of these compounds induce delayed neurological effects marked by destruction of axons and demyelination in the peripheral nerves and spinal cord. Ex perimentally one can demonstrate that certain cholinesteraseinhibiting insecticides are also delayed neurotoxins; however this can usually be shown only when the animal is protected from prompt lethal cholinergic effects with prophylactic atropine and oximes. There does not appear to be a correlation, positive or negative, between cholinesterase inhibition and delayed neurotox icity. Tri-o-cresyl phosphate (TOCP) and phosphite and triphenyl phosphate and phosphite are delayed neurotoxins lacking potent anti-chollnesterase properties. There are other phosphorus esters in this category, and more will undoubtedly be developed. Health officers responsible for the surveillance of men handling phos phorus esters should insist upon accurate information describing the presence or absence of associated acute or delayed neurotoxic properties. There is species-to-species difference in susceptibility to delayed neurotoxic effects. Accordingly toxicological data must be evaluated critically, and information derived from rodents ex clusively should be regarded as insufficient. reports of Uiness Although clinical cases of delayed neurotoxicity following industrial exposures to several aryl phosphates have been described, the vast majority of cases has followed the ingestion of food or beverages which had been previously contaminated with tricresyl phosphate esters containing the ortho isomer. The United States epidemic occurred in 1930 during Prohibition and produced as many as 15,000 cases of permanent paralysis, often slight, and a small number of deaths. The epidemic of paralytic disease was due to the ingestion of Jamaica ginger extract ("jake") which had be come contaminated with tri-o-cresyl phosphate. "Jake" was an alcoholic preparation sold as a flavoring but used as a substitute for conventional alcoholic beverages, especially by heavy drinkers and homeless male drifters (Kiely and Rich, 1932). There are various theories, none proved, giving explanations for the contamination in communities across the country. Similar paralytic disease has followed the ingestion of this ester in an abortifacient, in several cooking oil epidemics, and in illegal alcoholic beverages. The most recent epidemic occurred in Morroco in 1959 and involved 10,000 people who used olive oil adulterated with jet engine lubricating oil containing TOCP (Albertini etal., 1959). Of these some 10 to 15 percent remain permanently crippled and unable to resume their previous employment. In each of these situations, the clinical picture has been consis tent. There may be a prompt transient gastrointestinal disturbance with nausea, vomiting, and diarrhea lasting a few hours to a few days. The onset of neurological disease is delayed for three days to a month and is marked by sharp, cramping pains in the legs, numbness and tingling in the feet, and, subsequently, weakness of the legs and foot drop. The upper extremities may become in volved days later. The effects are symmetrical, the cranial nerves are rarely involved, and persistent sensory manifestations are held to be lacking in some, but not all, epidemics. The flaccid paralysis is associated with wasting of the calves and small muscles of the hands. Upper motor neuron effects, which may develop over the course of months and bring spasticity, suggest an unfavorable APOOO il ESTERS / 317 :h prognosis as far as complete recovery is concerned. In milder cases recovery may appear to be complete, but residual effects are often demonstrable by detailed neurological examination. Many cases of apparent full recovery may be to a large extent examples of effec tive adaptation to permanent motor loss. ri'CN The nitrates are esters of alcohols and nitric acid. Their most nitrates common use has been in military and mining explosives. Glyceryl trinitrate (nitroglycerin) is used as the active component of dyna mite and as a coronary vasodilator in clinical medicine. Industrial experience with aliphatic nitrates is associated primarily with the explosives industry, which has produced glyceryl trinitrate (nitroglycerin) and ethylene glycol dinitrate for many years. These compounds are the principal sensitizing ingre dients in dynamite; they are absorbed in a "dope" of oxidizing salts and various inert fillers such as wood fibers or com starch. Small amounts of other nitrogen-containing compounds, such as dinitrotoluene, may be added. Ethylene glycol dinitrate, more volatile than the original glyceryl nitrate of early dynamites, is added to this latter compound to increase the stability of the product and lower Us freezing point for low-temperature mining applications. Both nitrate compounds pass readily through the skin and are sufficiently volatile to produce symptoms in a short period. The effects of absorption are observed in explosives makers, dynamite packagers and fillers, miners, and men handling cordite. The principal biological properties of the nitrates are their ability to oxidize heme iron to the ferric state to produce methemoglobinemia and to cause vasodilatation. Vasodilatation is associated with hypotension, intense throbbing headache, flush ing, palpitation, and, less frequently, nausea, vomiting, or abdom inal distress. The interval between exposure and the onset of symptoms and the duration of "nitrate effect" varies with the individual compounds. Glyceryl trinitrate typically gives a prompt response of brief duration; other agents are slower in producing effects. There is variability in the ability of the various nitrates to produce methemoglobin: ethylene glycol dinitrate is very active, glyceryl nitrate is less so, and ethyl nitrate is weakly active. Most nitrates produce Heinz bodies, small round erythrocyte inclusions commonly associated with methemoglobin and a his tory of exposure to inorganic nitrates, organic nitrates, and aroma tic nitro- and amino-compounds (Hanley and Mauer, 1961). Red cells containing Heinz bodies have relatively short life spans and appear to be preferentially sequestered by the spleen. Their persis- toxic effects AP00037519 tence in the peripheral blood is usually of longer duration, how ever, than that of associated methemoglobinemia, The current view is that Heinz bodies are composed of insoluble degradation products of hemoglobin which precipitate. GLYCERYL TRINITRATE AND ETHYLENE GLYCOL DINTOLATE harmful effects These compounds produce hypotension, tachycardia, palpita tion, nausea, vomiting, and a characteristic headache or "powder head." The headache usually commences as a feeling of warmth or fullness in the head and develops into a throbbing sensation which progresses from the forehead to the occiput or the back of the neck. Although there is wide variability between individuals, most powder workers develop a tolerance to the effects of these nitrates and have no symptoms as long as exposure is main tained. The tolerance may be lost over a weekend or holiday, in which case the return to work is marked by a return of symptoms. There are many reports of workers who carried small pieces of dynamite in their hatbands or who placed pieces around their homes so as to maintain exposure and tolerance. Such reports also describe, however, the violent headaches experienced by persons not in the explosives industry who entered these homes as visitors and thereby became exposed to an acute dose of nitrate. A physiological explanation for the powder headache may be related to dilatation of the cerebral vasculature and drop in cerebrospinal fluid pressure under the influence of these compounds. Tempor ary relief of headache can be obtained with vasopressors or ergotamine tartrate. More intense exposure has been associated with hypotension, confusion, and methemoglobinemia. The concurrent absorption of beverage alcohol has been noted on many occasions to intensify the confusion, and frankly maniacal phenomena have been described. There is evidence that the cardiovascular effects induced by glyceryl trinitrate and ethylene glycol dinitrate may be associated with sudden death in explosives workers--often on Monday morn ing (referred to as Monday morning death), on return from a holiday, or from a weekend (Carmichael and Lieben, 1963). The clinical diagnosis has been acute myocardial infarction, often, but not always, with little evidence of antecedent coronary artery dis ease or of coronary occlusion. Critical review of the literature suggests that some three-fourths of sudden death in these workers occurs after one or two days' absence from exposure. Although the epidemiological evidence for a causal association between expo sure and sudden death is impressive--though circumstantial --there are several theories which might provide an explanation for the observations. It may be that coronary artery vasospasm ] \ \ follov or the dent Thest expla theor ing d arten there tion lishe can pet: nitre cont. tach shoe devt occv part sim: effe Hiy: trar ties nat trie laa mo AP00037520 >w- ESTERS I 319 ent follows the vasodilatation of acute re-exposure without tolerance ion or that vasodilatation and a drop in blood pressure causes insuffi cient return of blood to the right heart and cardiovascular collapse. These views are favored in the literature when no anatomical ta- explanation for death is found at post-mortem. An additional ier theory is based upon the view that chronic exposure to vasodilat or ing drugs may impair nutrient arterioles in the walls of coronary on arteries causing the deposition of hyaline connective tissue. While of there is experimental evidence for this interpretation, the explana Is, tion for the epidemiological observations is not yet clearly estab :se lished. nin Pentaerythritol tetranitrate is used as a detonator or booster or PENTAERYTHRITOL is. can be combined with trinitrotoluene. The nitrate effects from TETRANITRATE of PETN are much less apparent than those associated with the use of eir nitroglycerin or ethylene glycol dinitrate although there may be a so contact dermatitis. ns >rs The alkyl nitrites such as amyl nitrite produce vasodilatation, ALKYL NITRITES A tachycardia, and hypotension which may lead to collapse and ed shock. A throbbing headache is characteristic, and tolerance is lal developed with repeated exposure. Methemoglobinemia may >r- occur, but Heinz bodies are not known to be present. For the most :r- part it is apparent that the effects of alkyl nitrates and nitrites are th similar. nt ns Aliphatic nitro compounds, not esters, do not cause nitrate ve effects but can induce methemoglobinemia. Dyspnea, cough, and dizziness in men handling crude TNT has been attributed to letranitromethane, an impurity, with prominent irritating proper 2d ties. Other aliphatic nitro compounds are also irritants. The chlori n- nated aliphatic nitro compounds can be extremely irritating, and a trichioronitromethane (chloropicrin) has been used as a military ie lacrimator which produces coughing, nausea, vomiting, and pul at monary edema, fi re rs le > al >n m AP00037521 CARBON DISULFIDE 9 Carbon disulfide (CS2) is said to have been first discovered by Lampadius of Freiburg in 1796. It was recommended as a remedy for a great variety of diseases and was actually used in medicine, more or less, during the following half century. It has been used as an insecticide and in the production of viscose rayon. It is a solvent for waxes, resins, gums, and rubber. For many years it played a very important part in the rubber industry in European countries, somewhat less in England and much less in the United States. In rubber manufacture the crude latex must be made into an elastic, heat-resistant solid and this is done by incorporating sulfur, a process known as vulcanizing. It may be accomplished by adding flowers of sulfur to the mass which is then subjected to heat and pressure. This is known as the "heat cure." Or it may be done by exposing rubber to the action of sulfur chloride either in vapor form or by dipping it Into the liquid, or by painting. The carrier or solvent for sulfur chloride usually was carbon disulfide. American manufacturers always have pre ferred the heat cure for rubber, while Europeans preferred the socalled cold or acid cure with carbon disulfide. It is this last com pound that gave to European rubber manufacture a very bad reputation, and the older literature is full of reports of carbon disulfide poisoning in rubber workers. When the process of mak ing an artificial silk called viscose rayon was worked out in Switzer land, France, and England, reports began to come from abroad describing cases of carbon disulfide poisoning in this new indus try. In the production of viscose rayon, the starting point is cel lulose from wood pulp or cotton, lintess, which is treated with an alkali to form flake-like "white crumbs," alkali cellulose. This is changed to an orange-yellow, rubbery mass, known as cellulose xanthate by being treated with carbon disulfide in revolving "churns," or "barattes," or "tumbling barrels." From the chums the xanthate goes to viscose mixing machines. The most severe exposure to fumes of CSi takes place in the chum room, from leaking pipes and churns, from discharging the chums and scrap ing out the xanthate that sticks to the walls, and from conveying the xanthate to the viscose mixers and dumping it. A lesser exposure occurs in the spinning process. The viscose, a thick syrup which is sodium-cellulose-xanthogertate, comes from the mixers and is forced through spinnerets of different degrees of fineness according to the weight of the yam desired, into the spinning bath of sulfuric acid, sulphates, and other chemicals. 321 Here the syrup coagulates and decomposes, releasing pare cel lulose which is drawn out as a thread and wound on bobbins. There is a Lesser production of CS2 fumes caused by the "ripening" of the cellulose xanthate in the spinning bath with the formation and escape of H2S and CSi. Poisoning from the latter is not so frequent nor so severe as in the churn room. Since the recognition of carbon disulfide poisoning as a compensible occupational dis ease, these processes have been elaborately safeguarded by venti lation systems and routine air analyses are made to check on the efficiency of these systems, WORKER ILLNESS A series of reports are quoted by Hamilton and Hardy (1949, pp. 398-408). Carbon disulfide was recognized as an industrial poison by the French almost one hundred years before psychia trists in the United States were trilling to do so. Payen, who first described its action in 1851, was followed by Delpech in 1856, the latter describing twenty-four cases in rubber workers and also experimental poisoning in animals. Constansoux and Heim (1910) gave a detailed picture of CSa poisoning in French rubber workers, with loss of appetite, dyspepsia, disturbance of vision, sensory disturbances, and sexual impotence. Two very important studies came from Germany: Laudenheimer published the medical his tories of no less than fifty patients with carbon disulfide insanity. The early symptoms consisted of headache, dizziness, increasing sense of weariness, loss of strength, transient excitement, and slight delirium, very like alcoholic intoxication. Later came deep depression and loss of memory, increasing indifference, and apathy. This might change suddenly to acute mania or delusions of persecution with hallucinations. Such cases usually developed early, during the victim's first months of work. Some ended in recovery, others in incurable dementia. Koester described a slower form, usually a toxic polyneuritis, with paralysis and atrophy. He believed carbon disulfide poison ing to be as varied in its manifestations as poisoning from lead. Probably because of this and because so many of the victims were young girls, the French, led by Pierre Marie, maintained for some time that CS2 was not primarily a cause of nervous derangement but an "agent provocateur" of hysteria in those predisposed to it. However, the work of Koester disposed of that theory. He found, in experimental animals, degenerative changes in the cerebral cells and in thecells ofspinal ganglia after CSa exposure. An autopsy performed on a worker who had had acute CS2 delirium revealed severe diffuse changes in the cerebral cortex and the ganglion cells. worl give to th whic artic. splic CS2depr lucin cenh whic forei node can ] came appa letti, arisir . and * shov psyc natet psycl dittos some sion, natio sense peroi borec retro with from sanit vent. stud; foun poise epid AP00037523 The first two papers on CS2 poisoning in United States rubber workers were published in 1892 and attracted little attention. These give histories of three rubber vulcanizers, all men, who were sent to the State Hospital for the Insane, suffering from acute mania which subsided after a few weeks. In 1902 a third United States article appeared, describing a case of amblyopia in a woman who spliced inner tubes with CSa (Heath, 1902). By 1914, United States plants in the rubber industry were using CSa. Histories of intoxication from foremen reported irritability, depression, apathy, sudden outbursts of rage, or fear, with hal lucinations, even maniacal seizures. Yet no physician in rubber centers knetf of such occurrences nor that CSa was a poison to which rubber workers were exposed. In spite of the wealth of foreign literature on CSa poisoning in rubber workers, almost no notice was taken of the striking, if rare, cases occurring in Ameri can plants. A few years later reports of CSa poisoning in viscose workers came from Europe, especially from Italy, where exposure was apparently excessive and mechanization little developed. Ranilletti, reviewing the histories of 100 cases of CSa poisoning (77 arising in the artificial silk industry, the rest in the extraction of fats and in the vulcanization of rubber), found that 80 of the patients showed involvement of the nervous system, and 52 of these were psychoses. In 20, gastrointestinal symptoms and anemia predomi nated. The psychoses were mainly of a maniacal type, with psychomotor excitement, delirium, hallucinations, distraught con dition, or so-called dementia. The early stage, appearing after some months or even years of exposure is usually one of depres sion, but there may be a sudden attack of excitement with halluci nations. Ten of these workers had various forms of neuritis, the sensory nerves being less seriously affected than the motor. The peroneal muscles of the legs may be affected, and the gait is la bored and dragging. Amblyopia was noted, and in one case a retrobulbar neuritis. Recovery takes place, according to Ranelletti, with surprising rapidity, as a rule, when the victim is removed from the exposure, even if the intoxication has resulted in "in sanity." During the Second World War, the blackout interfered with ventilation, and workers suffered from malnutrition. Vigliani studied 100 cases of chronic intoxication under wartime stress. He found that 160 to 800 ppm of CS2 in work room air led to signs of poisoning in a few months. Palach (1948) reported 148 cases in two epidemics of CSa poisoning from Poland under the conditions of AP00037524 enemy occupation. Both authors emphasized the prevalence of polyneuritis, affecting especially the legs, never the arms alone. Biopsy showed myopathy, with both hypertrophy and atrophy of fibers. Mild cases usually recover in two to three months, severe cases in six to eight months. If recovery is not noted in that time, it probably will not take place. An earlier belief that carbon disulfide polyneuritis is a temporary affliction with a favorable prognosis is not true in all cases. Jump and Cruice (1904) were the first to call American atten tion to the viscose rayon industry as a source of CS* poisoning. They reported three cases in churn-room men in a report that attracted little attention. Alice Hamilton (1925) saw two cases of CS2 poisoning in the United States. The first man had just returned to work in the viscose plant after a week on sick leave. He was very nervous, excitable, irritated by questions, and unable to bear any opposition. He had no wish to exaggerate his disability; on the contrary, he wanted to get back to his job in the churn room, provided he could sit down, for he had distinct loss of power in his legs. There was a certain degree of ataxia evident. The second man was in the hospital, with symptoms of acute psychosis. He seemed on the point of bursting into tears and suffered keen mortification over his loss of self-control, saying, "I was all right, doctor, till you came and stirred me up again." In spite of the great growth of viscose manufacture in the United States in the 1930s, this danger to the employees was very tardily recognized; indeed as late as 1946 psychiatrists in state institutions for the mentally ill were entering in their records items such as "etiology occupational" or "unknown" or"exogeneous poison" but making no mention of CS2, which apparently was not accepted as a cause of mental disease. Lewey (1941) examined 120 men who were employed at the time as chum-room men and spinners. This is the most thorough study made of early CS2 poisoning in the United States. Mild forms of poisoning were found in 60 percent of spinners, whose exposure is not high, while in churners, whose exposure is much higher, severe poisoning was found in 20 percent in one plant, in 44 percent in the other. Lewey found that chronic carbon disulfide intoxication may involve all parts of the central and peripheral nervous systems, begin ning with psychic symptoms, later peripheral neuropathy and damage to the cranial nerves, decrease of corneal and pupillary reflexes as well as pyramidal and extrapyramidal signs. A variety of clinical pictures very like Parkinson's disease were also ob served. AP0003752S CARBON DISULFIDE / 325 Although the chronic form of poisoning is far more serious, SUMMARY OF we do see the acute cases in which the concentrated vapors cause syndromes irritation to the eyes, nose, and skin. In chronic carbon disulfide poisoning the nervous system bears the brunt of damage. Neuritis affecting peripheral or cranial nerves (optic and auditory) is very common. Usually the trouble begins with a sensation of crawling over the skin, formication, a tendency for the arms and legs to "go to sleep," a sensation of coldness and heaviness, and a curious feeling that the hand and foot belong to someone else. Pain is associated with these symptoms and tenderness along the nerve trunk, and at the same time tests may show touch, pain, and the temperature sense to be heightened, rarely diminished. There is usually constant or paroxysmal pain in the distribution of one or several nerves and, during the night, pain in the legs may reach an intolerable intensity. Any of the nerves may be affected, but those more usually involved are the radial and ulnar, the sciatic and external peroneal. These symptoms are followed soon by signs of motor nerve involvement. The worker complains of fatigue, in i creased loss of strength and weakness in the legs. The reflexes are most often diminished. The course of carbon disulfide neuritis is slow--slower than that of alcoholic, rheumatic, or syphilitic origin. Recovery proceeds with extreme slowness, and the prognosis must be guarded, be cause the atrophy, pain, paresthesia, and other manifestations may persist even if the victim quits his job. The most striking and the most disastrous effects of carbon disulfide poisoning are upon the brain. The mental symptoms run the gamut from simple irritability and depression to manicdepressive insanity. If the basal ganglia are involved, Parkinsonian palsy occurs. In typical cases the attack of active or violent mental disturbance comes on fairly suddenly, but careful questioning of the family and working mates always will bring to light an earlier stage of emotional upset, irritability, depression, and complaint of loss of memory. Even in milder poisoning, changes in personality are evident, especially in the man's relations with his wife and children, and the victims realize this but are powerless to help it. Sleeplessness, dreams, and loss of memory are frequent com plaints. Disturbances of vision, though rarely of a pronounced character, are present often and give valuable aid in the diagnosis. Central scotoma for color, abnormal color vision, loss of visual acuity, and paralysis of accommodation have been described (Gordy and Trumper, 1943). Gastric disturbances are common in some reports with symp- AP00037526 toms that mimic those of a peptic ulcer. Heart, liver, and kidney damage are described by some authors as associated with high and continuous CS2 exposure. Beginning in 1950, chronic poisonings have been reported which presented symptoms very similar to those found in pre-seniie cerebral arteriosclerosis. Workers in the age group from forty-two to fifty-five are usually affected, and they often have associated kidney damage. While some cases present only one aspect of the atherosclerotic process, some present a complete picture of cerebral, renal and myocardial sclerosis! (Browning, 1965, p. 705). Von Rechenberg in 1957, and Vigliani and Cazzullo reported that workers exposed to CSi first noted pain in the calf of the leg with difficulty in walking (Browning, 1965, pp. 710-711). In some cases electrocardiograms suggested previous myocardial infarctions (Brieger, 1961). At autopsy atheromatous plaques are found, general arteriosclerosis with retinal vessel changes resembling those in hypertension and glomerulosclerosis. While some of these reports are old and describe European experience in rubber factories--because CSi is used as a raw mate rial in the manufacture of viscose rayon and has excellent solvent properties--exposures continue. According to Kleinfield and Tabershaw (1955) poisoning is rare in the United States. Brieger (1961) reviewed the knowledge of CSa toxicity derived from labora tory animal studies as well as occupational illness. The biological behavior of CSi has the attention of a number of research laboratories, especially in Italy and Czechoslovakia, summarized in a conference held in Prague in 1966 (Brieger and Teisinger, 1967). The details of the biologic effect of absorbed CSi are to be found in Brieger's review (1961) and Browning's text (1965), pp. 702-712). Briefly stated, CSa has been shown to have a toxic action on protein metabolism. In addition, by hepatic damage, CS2 causes nervous system disease and hypercholesteremia which leads to early arteriosclerosis. At present the accepted threshold limit value (TLV) in the United States is 20 ppm (Documentation of the Threshold Limit Values, 1971). Russia in 1967 felt that a 4 ppm limit afforded more safety, and the Czechoslovakian observers in 1969 felt a 10 ppm would be safer than our TLV. Direct measurement Of blood and urine for carbon disulfide levels gives some evidence of intensity of exposure (Patty, 1963). A more specific chemical test is available to evaluate exposure by measuring urine metabolites of CSa using the iodine-azide test developed by Djuric, Surdu6ki, Berkes (1965). AP00037527 AP00037528 i329 i The organic high polymers, regardless of their ultimate applications, are similar to the extent that they are based upon the structural repetition of smaller units (monomers) and often contain additional substances which are not actually part of the polymer itself. Toxic phenomena associated with the high polymers may be related to their unreacted or under-reacted constituents, to various auxiliary substances, or to degradation products. It is uncommon for a fully reacted or "cured" polymer to cause illness, and most ofthese materials show a high degree of biological inertness and insolubility. The term elastomers is applied to those polymers which can be stretched easily and which return to their original dimen sions when the stressing force is removed. Natural and synthetic rubbers are elastomers. Linear tnacromolecules with high longitudinal mechanical strength and lateral flexibility can beutilized toform syntheticfibers for textile applications. AP00037529 PLASTICS 1 The term resin has an imprecise meaning in the pla9tics industry and may be used interchangeably for the term plastic. In some applications resins are short-chain uncured polymers which are subjected to further polymerization and hardening. In other appli cations resins are granular fully-cured thermoplastics which can be heated for extrusion, molding, or calendering. The principal plastics may be divided into two groups: (1) thermosets, which cannot be reformed or melted after the initial "cure;" and (2) thermoplastics, which can be heated and reshaped repeatedly. A simple classification may be outlined in the following manner. Table 6 Principal Plastics Thermoiet* Aminos (urea and melamine) Epoxys (ethoxylin) Phenolics Polyesters (and alkyds) Polyurethanes Silicones Thermoplastics Acetals Acrylics Aaylonitrile-butadiene-styrene Cellulosics (cellulose acetate, propionate, butyrate) Fluoroplastics Polyvinyl alcohol Polyvinyl chloride Nylons Polycarbonates Polyethylene Phenylene oxide Polypropylene Polystyrene Polyvinylindene chloride Polysylenes The amino resins are almost entirely based upon ureaformaldehyde and melamine-formaldehyde and are typically used for electrical switch housings, knobs, molded dinnerware, adhe sives, plywood glues, coatings, and industrial laminates. Creaseresistant garments are produced by pressing to the desired shape textiles impregnated with suitable amino resin formulations. Hexamethylenetetramine, called "hexa," is used as a stabilizer in amino resin systems to prevent premature hardening. aminos The component of primary toxicological interest is formaldehyde, which is present in the production of the resin or in association with incompletely cured products. At concentrations above 3 ppm formaldehyde is irritating to the eyes and upper airway. Higher levels cause severe burning sensations, coughing, and profuse lacrimation. Deep lung irritation in man has not been harmful effects 331 AP00037530 r observed, but it presumably could occur under extreme circum stances. Skin sensitization to formaldehyde in the vapor state is unusual, and pulmonary reaction has not been reported. Persons who are already sensitized, however, may show a skin reaction to this type of exposure. Cross reactions to other aldehydes have been noted in sensitive individuals. Formaldehyde is a potent skin irritant and sensitizer; eczematous reactions are observed in work ers handling improperly cured crease-resistant textiles (Fisher et al., 1962). Hexamethylenetetramine decomposes to form formal dehyde and is a possible source of irritating and sensitizing cutaneous reactions, but it has never been a major problem either in this application or in the explosives industry. Acetic add ac celerators do not present unusual problems. epoxy resins Cured epoxy resins have outstanding resistance to heat and chemicals and find wide application in reinforced plastics, coat ings, adhesives, and in casting, "potting," and encapsulation. The typical resin is prepared from epichlorohydrin and a polyhydroxy compound (e.g., bisphenol A) in the presence of a curing agent. Epoxy resins are cured by cross-linking agents known as "harden ers," such as the polyamines (diethylenetriamine, triethylenetetramine, piperazine) or the add anhydrides and polybasic adds (phthalic anhydride, adipic add). Catalysts perform a similar curing action but do not themselves act as cross-linking agents. Common catalysts include various polyamides, monoethylamine, and ter tiary amines such as triethyiamine and benzyldimethylamine. Diluents--phenyl, allyl, and butyl glyddyl ether, styrene oxide, styrene, and other epoxides--may be utilized to reduce the viscos ity of uncured resin systems. biological ction Epichlorohydrin, bisphenol A, and liquid epoxy resins are skin irritants and sensitizers. Epichlorohydrin is highly irritating and can produce severe bums, but there have been no examples in man of serious pulmonary or systemic injury. Because this com pound can cause renal damage in experimental animals, however, persons handling epichlorohydrin in the manufacture of epoxy resins should be under surveillance (Gage, 1959). The reactive diluent glyddyl ethers and related epoxy compounds are cutane ous irritants and sensitizers. It has been pointed out that the epoxy group may be assodated with radiomimetic effects, presumably reflecting biological alkylation (Kotin and Falk, 1963). There is no evidence, however, that these materials are comparable to the nitrogen mustards in this regard, or that there is an industrial hazard related to this property. sur pri rea prc me cai Bli oc< wi so rei P ur ax sv ar th in re P S' d b d a r- AP00037531 Industrial health problems most frequently arise from expo sure to aliphatic polyamine hardeners, which can cause severe primary irritative and hypersensitivity dermatitis and asthma-like reactions. These amines are strongly basic (pH 13-14) and can produce chemical burns of the skin. Some contain dye bases that may yellow the skin upon oxidation. Cutaneous amine reactions cause erythema, intolerable itching, and severe facial swelling. Blistering with weeping of serous fluid, crusting, and scaling may occur. An apparently permanent hypersensitive state may develop with extreme reactivity to amines. Examples are recorded of per sons with previous amine dermatitis who experience a dramatic return of symptoms upon minute re-exposure. Highly sensitive persons may also react to cured resins containing small amounts of unreacted amine hardeners. Although pulmonary reactions in the modem plastics industry are most commonly attributed to components of polyurethane systems, amine hardeners for epoxies do cause bronchospasm and coughing episodes which may persist for several days after the cessation of exposure. Repeated attacks of acute amineinduced respiratory disease are often associated with increased responsiveness to these compounds, for faint traces of amine va pors in the air have been sufficient to trigger intense return of symptoms in persons with a history of amine asthma. Acid anhy dride and polyamide hardeners and catalysts are contact irritants, but industrial problems related to their use have been uncommon. Diluents such as xylene or the ketones do not sensitize but defat the skin with repeated contact. Glass fibers used in many applications are mechanically irritating and pruritic and may be released when inert laminates or other forms are cut or tooled. Sawing, machining, and other manipulations of solid cured resins which produce heat may give rise to degradation products that contain free amines or unreacted epichlorohydrin. PLASTICS 1 333 Prevention of problems from epoxy exposure is based upon meticulous cleanliness of work areas. Mixing of resin and hardener and the application of the liquid formulation should be done under appropriate ventilation. Material which Is spilled on the skin should be removed promptly with soap and water. Organic sol vents used for this purpose tend to spread contamination and irritate the skin. control The modern plastics industry is based upon Leo Baekeland's PHENOLICS discovery (1909) of phenol-formaldehyde thermo-setting materials. The term phenolic resins now encompasses a variety of similar products made by reacting a phenol-like compound with an al dehyde. Commercial "phenols" include phenol, cresol, xylenol, p-t-butylphenol, and resorcinol. Important aldehydes include formaldehyde, paraformaldehyde, and furfural. Catalysts include hexamethylenetetramine (referred to as "hexa"), ammonia, and various other amines. The applications of the phenolic resins are similar to those indicated for the amino resins, which have similar structures and properties. Large quantities of phenolformaldehyde resins are used in bonded brake linings and dutch facings and as bonding agents for foundry sand molds. worker illness Important industrial effects are those of dermatitis. Phenol is a potent primary irritant, and resordnol, furfural, and formaldehyde are irritants and sensitizers. Furfural is a photosensitizer. In some applications cashew nut shell oil has been used as a phenolic component in the resin formulation. This oil is chemically related to poison ivy resins, but the oil used in industry is said to have been treated to render it safe for handling. Nevertheless persons highly sensitive to Rhus-type oleoresins may be reactive. POLYESTERS AND ALKYDS Materials of the polyesters and alkyds group are fundamental to reinforced plastics technology, which is increasingly important in the boat and automotive body industry and in the market for structural panels, electrical appliances, and home furnishings. The reinforcement is generally provided by glass fiber textiles, and the typical structure is composed of laminations of polyester and a textile. The polyesters themselves are derived from the reaction of a polyfunctional add (e.g., phthalic or maleic add anhydride) with a polyfunctional alcohol (e.g., propylene glycol, ethylene glycols, pentaerythritol). Polyesters are dissolved in styrene and stabilized with an inhibitor such as hydroquinone to form a viscous syrup-like liquid which does not readily solidify. When gelation is desired, a catalyst, usually a peroxide (e.g., benzoyl peroxide or methyl ethyl ketone peroxide), is added. To accelerate this styrene cross-linking solidification, promoters or accelerators (djmethylaruline or cobalt salts) may also be added. While styrene is generally the reactive solvent and cross-linking group between the polyester macromolecules, other equivalent compounds may be used for special purposes. Methylmethacrylate increases resistance to weathering, diallyl phthalate resists polymerization of the un catalyzed syrup, and triallyl cyanurate increases resistance to ele vated temperatures. toxic effects The acid anhydrides, when applied to the damp skin, can cause burns. The dusts are irritating to the eyes and upper airways. T1 be an he no po idt ox kecol me km be* of \ ter me (po use app gan cou ing blot basi into heal fron refei j com j heat 1 that prol with of sc ings usua "incr and the c spasi AP00037533 There is no important systemic toxicity, however. Styrene (vinyl benzene) vapors are irritating and narcotic at high concentrations and can produce a "styrene sickness" consisting of nausea, headache, fatigue, dizziness, and drowsiness. The compound is not a hematopoietic poison. The irritant properties are sufficiently potent to protect workers against serious effects. Organic perox ides are highly irritating to epithelial tissues and are flammable oxidizing agents. There is evidence that benzoyl and methyl ethyl ketone peroxides are skin sensitizers as well. Dimethylaniline and cobalt naphthenate are both sensitizers; the former can produce most of the effects of aniline. Although the allyl group has wellknown toxic properties, serious occupational hazards have not been associated with diallyl phthalate and triallyl cyanurate, both of which are irritating. Industrial health problems from the polyes ter group are infrequent, and most of them may be attributed to the mechanical effects of glass fibers upon the skin. PLASTICS I 335 Urethane polymers are formed by reactions between a polyol (polyhydroxy) compound and a diisocyanate. Polyurethanes are used in coatings, elastomers, and foamed cushioning or flotation applications. Catalysts used to promote the reaction include organotin compounds, cobalt naphthenate, or various amines. In the course of polymerization reactions, carbon dioxide is evolved giv ing rise to bubbles or a foam. To obtain additional gas, a foaming or blowing agent may be included to supplement gases evolved in the basic reaction. Polyurethane foams are typically poured or sprayed into position, where the so-called final cure occurs. POLYURETHANES Although amines are irritating and sensitizing, the main reporta of occupational health problem associated with polyurethane plastics arises disease from the diisocyanates, most commonly toluene diisocyanate referred to as TDI. Vapors of these compounds invariably be come airborne in polymerization reactions, especially since heat and gas are evolved. Clinical experience with TDI shows that it is a potent irritant of the eyes and upper airway. With prolonged exposure there may be significant respiratory distress with dry painful cough, chest pain, and occasional blood-streaking of scant sputum. In some cases fever, cyanosis, and general feel ings of distress are noted. The x-ray in these situations has been usually normal, although diagnoses or descriptions of bronchitis, "increased markings," or "reticulation" have been made (Brugsch and Wilkins, 1963). With continued or repeated exposures to TDI the clinical picture has been dominated by evidence of bronchospasm, sometimes very severe, with chest tightness, wheezing. AP00037534 cyanosis, and cobapse. Some workers become exceedingly sensi tive to TDI vapors and respond dramatically to minute amounts of this material in the air. The nature of the "sensitivity" to TDI has not been clearly established. There is experimental evidence for antigen-antibody mechanisms, while other observations suggest that a direct irritant effect on susceptible tissues is responsible. It is also not clear whether chronic injury occurs, either in response to repeated acute episodes or to low-level long-term exposures with out prominent symptoms. control and therapy There is evidence that the already low threshold level value (TLV) of 0.02 ppm is not sufficiently low to preclude the develop ment of bronchospastic responses in "sensitized" persons. Peters and his associates (1970) have shown that TDI concentrations in the order of one-tenth of the TLV may cause significant depressions in the forced vital capacity and forced expiratory volume in one sec ond. Treatment of these pulmonary responses is based almost en tirely upon control of exposure. For highly sensitive people, work with polyurethane foams must be eliminated. Engineering mea sures are essential to the adequate control of vapors. Bronchospasm responds to bronchodilators; oxygen may be indicated in severe cases. SILICONES Silicones are composed of chains of alternate atoms of oxygen and silicon. Various organic groups can be attached to the silicon atoms, and the amount of cross-linkage between chains by these groups determines whether the polymer will be hard, an elastomer, or a fluid. The fully reacted polymers are remarkably inert and thus find use in heart valves, prostheses, heart-lung machines, and artificial kidneys. Major industrial uses are in lubricants, encapsulations, dielectric laminates, and "non-stick" release compounds. The biological properties of the silicone intermediates have not been studied. Of the silicones, chlorosilanes are corrosive to mu cous membranes; ethoxysilanes, less so. No reports of injury have appeared in the clinical literature. Various metallic soaps, acetic acid, and toluene solvents may be used in final applications. ACETAL RESINS (POLYFORMAL DEHYDE) Of the acetal resins, polyformaldehyde is a material of unusu ally good mechanical properties. It may be thermally degraded, as in an overheated molding machine, to formaldehyde with its wellrecognized irritant and sensitizing properties. AP00037535 mai ls Of has ! for gest It is ;e to 'ith- ilue lopters the sin jec- enork iaho- 5en con ese ler, md ics, US, ase not nuive etic iU- as ell- Acrylic plastics such as Lucite and Plexiglas are based upon methyl and ethyl acrylate and methacrylate; methyl methacrylate is the major constituent, These are respiratory and cutaneous irri tants, the acrylates more so than the methacrylates, but have no known cumulative or chronic toxic properties. Methyl methacry late vapors can produce headache, irritability, and other non specific symptoms. Acrylic paints are based upon a water emulsion of acrylic polymers, which are of no known biological importance. The materials of this mixture can be varied in relative quantity ACRYLONITRILEand treatment to produce a family of plastics suited to home BUTADIENE-STYRENE appliances, automobile instrument panels, boats, recreational ve toridty hicle bodies, and a heterogeneous group of other applications. The monomeric reactants all have biological properties absent in the finished product. Butadiene is a weak irritant and narcotic gas, which is combustible and explosive. It is used primarily in the production of synthetic rubber. Acrylonitrile is a flammable volatile liquid which can be absorbed through the skin, lungs, and intesti nal mucosa. Its biological properties are those of cyanide, and the intensity of intoxication appears to correlate with the blood level of cyanide ion. That the toxidty of acrylonitrile is related to other pharmacological properties has not been established. Medical therapy for acrylonitrile poisoning is the same as that for hydrogen cyanide poisoning and is based upon the formation of cyanmethemoglobin. Since acrylonitrile can pass through the intact skin, special attention to decontamination and the dean-up of spills is especially important. The compound can also penetrate various types of rubber, and gloves may not provide suitable protection. Cellulose acetate, propionate, and butyrate have almost en tirely replaced cellulose nitrate, which is highly flammable and is a source, when burned, of nitrogen dioxide gas. Modem cellulosics are used in nontoxic films and coatings in small parts such as knobs, eyeglass frames, and pencil barrels. Toxicity is not assodated with these polymers. The synthetic process may involve exposure to solvents and organic acid compounds which may result in skin reactions, Fluoroplastics vary somewhat in composition and include polytetrafluoroethylene, fluorinated ethylenepropylene, and polyvinylidene fluoride. These materials are extremely inert biolog ically and can be used for human organ prostheses as well as for AP00037536 highly resistant insulations, chemical piping, containers, gaskets, and coatings. The widely used Teflon is a fluoroplastic. worker illness Harmful worker exposures are not commonly related to the production of the polymers themselves, inasmuch as the reactions are conducted in closed systems. The chemical intermediates indude fluorohydrocarbons of the so-called Freon type, which are relatively inert or have only narcotic properties at high concentra tions. More active reactants may occur in the process and may be highly corrosive or possibly nephrotoxic. Such exposure would be most unlikely. Illness, which has been related to the fluorohyd rocarbons, is described by the teim "polymer-fume fever," a syndrome similar in character to influenza (Lewis and Kerby, 1965). Symptoms appear within some four to five hours of exposure to sublimates or thermal decomposition products of fluoroplastics. In most situations the toxic material is generated when polymer dust contaminates tobacco products. The temperature of burning to bacco or equivalent heat sources is sufficient to cause physical and pyrolytic changes in the otherwise inert polymer. Chest tightness and dyspnea are early and common complaints. General malaise, headache, and cough are noted, and chills with fever to 104F follow the onset of symptoms by some twelve hours. The acute illness may be alarming and uncomfortable when it is severe, but it is short in duration and without known sequelae. The composition of the thermal decomposition products is not well defined, and it is doubtful that there is a single compound responsible for polymer fume fever. Under some arcumstances, transient pulmonary edema has been observed. This is not surpris ing since hydrogen fluoride and other highly irritative materials are contained in fluoroplastic pyrolysis fume. There is no evidence, however, of deaths or chronic illness in man from this cause. Control of whatever problem exists is effected through warn ing to the worker, prohibition of tobacco in the work place, hand washing, and attention to airborne dust and to heat sources. NYLONS, POLYAMIDES Nylons are polyamides used in fibers, filaments, castings, and extrusions and can be classified into two families: the diaminedibasic add type and the condensed amino add type. The finished plastic in either case has no known toxic effects. Diamine-dibasic acid nylons are prepared by reacting a diamine such as hexamethylenediamine with an acid such as adipic or sebacic acid. The diamine has a primary irritant and sensitizing effect on the skin and is irritating to the eyes and upper airway. The dibasic acids are not a source of illness. Amino add nylons are formed from the J i ; ' 1 < 1 ; ' eo bu ha re. D) be P<-' tu Pl to be th is th ni di w ici ra to di P Bi P' ai P1 w d b< P ir ti o ti n o AP00037537 ;askets. to the actions tes to rch are rentranay be olid be -ohyda syn1965). ure to ics.In \t dust ng toal and htness alaise, 104F acute but it is not sound ances, irprisals are ience, warnhand s, and mineushed libasic :h as :acid. e skin ds are m the condensation of materials such as E-caprolactam, which is of little biological interest. Rare skin reactions to virgin nylon products have been described and have been generally attributed to residual reactants or to low-molecular weight polyamides (Morris, 1960). Dyes and finishes applied to nylon for wearing apparel have also been uncommon causes of contact dermatitis. The most prominent air contaminant in many typical polycaprolactam nylon operations is derived from an eutectic mix ture of diphenyl and diphenyl oxide. This material is heated and pumped under pressure as a heat transfer fluid. Small leaks give rise to vapors and mists of which the workers complain, with nausea, but of no described systemic toxicity. In heat transfer applications the material may be heated to temperatures as high as 700F. There is an obvious potential for severe burns. Heat transfer agents of this type have been used in organically cooled and moderated nuclear reactors. High temperature and radiation fields modify diphenyl and diphenyl oxide to a variety of high-boiling residues which must be removed from the coolant streams. Thorough tox icological studies have not been performed upon these thermal and radiation-induced degradation products, but carcinogenic and toxic molecules may be present. PLASTICS / 339 Polycarbonates are polyesters formed by the polymerization of POLYCARBONATES dihydric phenols through carbonate linkages. The plastic is used primarily for small mechanical parts such as gears and cams. Biological properties have not been associated with the finished polymer. However various synthetic approaches to the polycarbon ates utilized potentially harmful compounds such as bisphenol A, phosgene, dioxane, and other solvents. Materials of this group are widely used in packaging, house- POLYETHYLENE, wares, toys, and vapor barriers. The polymerizations take place in POLYPROPYLENE, POLYOLEFINS closed reaction vessels under the influence of catalysts such as benzoyl peroxide, metallic oxides, or active organometallic com pounds such as triethyl aluminum. The finished resin, sold com mercially for thermoplastic molding, extrusion, or other applica tions is essentially without biological properties. Under conditions of thermal stress above 250C these polyolefins undergo degrada tion to compounds which are irritating and injurious. The hazard is not greatly different from that associated with any combustion of organic materials. Polystyrene is prepared from the polymerization of styrene POLYSTYRENE (vinyl benzene) under the influence of organic peroxides such as benzoyl peroxide, lauroyl peroxide, etc. Styrene can polymerize AP00037538 prematurely in storage; this tendency is controlled by the addition of inhibitors, usually phenols such as butylcatechol or hydroquinone, both sensitizers. Polystyrene is used in appliances, toys, furniture, and a variety of packagings. Monomeric styrene is strongly irritating to the eyes, pharynx, and upper respiratory tract and can produce headache, nausea, vomiting, and primary skin irritation. No chronic toxicity has been associated with styrene exposure. VINYL POLYMERS AND COPOLYMERS The vinyl group of plastics includes polyvinyl chloride used in floor tiles, ducting, waterproof clothing and upholstery, insula tions, and pipe; polyvinyl acetate used in adhesives and coatings; polyvinyl alcohol (water-soluble); and polyvinylidene chloride. In all of these applications the finished plastic has been found to be without injurious properties. Untilrecently the monomeric precursors have not been thought to have toxicological importance, although it has beefl known that vinyl chloride and vinyl acetate may produce dizziness and confusion. It has become apparent, however, that vinyl chloride may be a potent carcinogen inasmuch as six cases of hepatic angiosarcoma have been reported among the employee population of a single plant in which vinyl chloride is polymerized. That this striking clinical phenomenon has occurred in other industrial establishmeats or that it is definitely caused by vinyl chloride remains to be established. The incidence of hepatic angiosarcoma in the entire population of the United States approximates 25 cases per annum. There are no reports of occupational illness associated with exposure to vinylidene chloride (1,1-dichloroethylene), although the toxicological properties of the compound are similar to those of carbon tetrachloride. Thermal degradation products include the monomers and hydrochloric add fumes. toxic effect In the last several years a distinctive industrial disease, occu pational aaoosteolysis, has been observed in men working as "polycleaners" in several PVC production fadlities (Wilson et al., 1967). The disease is currently thought to affect only those people who manually dean PVC reaction kettles in which polymerization occurs. The disease does not occur in those who handle the finished thermoplastic resin. The actual toxic agent and the means whereby it causes illness are not presently known. The clinical picture is that of Raynaud's phenomenon with discomfort and blanching of the hands on exposure to cold. Unique roentgenological changes are noted in the distal phalanges of the hands and may -t 4 j i * * I j j i. j i j ; i Mb AP00037539 be present in asymptomatic individuals. The changes consist of loss of cortex of one or more tufts or complete lytic destruction of the tuft and a portion of the adjacent shaft. Healing occurs with a fragmentation of the affected area and union of the fragments. The fingers themselves appear upon inspection to be shortened and "dubbed." Since it is possible to dean reaction vessels by tech niques which do not require hand scraping, new cases of this disease should not occur unless longer experience demonstrates that the toxic agent is present in other operations. Monomeric vinyl chloride is produced by several processes, one of which is based upon the addition of hydrogen chloride to acetylene in the presence of mercuric chloride. This process has been responsible for the introduction of mercury compounds into natural bodies of water, from which mercury is eventually ab sorbed by fish, induding those species used by man as food. PLASTICS ! 341 Acrylamide is a vinyl monomer used in the production of ACRYLAMIDE special polymers. These have applications as flocculating aids for worker the predpitation of suspended solids from aqueous systems and as dliease special chemical grouts. Although the polymer is nontoxic, the absorption of acrylamide through the skin or from dusts has been associated with serious neurological consequences (Garland and Patterson, 1967). A variable polyneuropathy with motor and sen sory impairment is marked by numbness, paresthesias, and weak ness. Ataxia, tremor, dysarthria, and other central nervous system signs are consistent with mid-brain lesions. Although recovery over the course of months has been the rule in mild cases, perma nent neurological sequelae are observed in severe Intoxications. Bergmann et al. (1958) introduced the concept of pulmonary polyvinyldamage following exposures to hair sprays and named the disease PYRROltdone thesaurosis. McLaughlin and his colleagues (1963) reviewed the occupational literature to 1963 and reported on a total of 755 chest x-rays of ***** British hairdressers. Cares (1965) presented the United States ex perience. The reported cases present as sarcoid-like disease clini cally, by chest-x-ray, and by histopathologic findings. Alternative diagnoses in the literature are interstitial fibrosis and foreign body granulomas. With the present data thesaurosis appears to be chiefly a problem in differential diagnosis. The cases seen by one of the authors (HLH) have proved to be Boeck's sarcoid with lesions in organs in addition to the lung, or chronic beryllium disease. McLaughlin et al. conclude that it is possible to diagnose thesaurosis by chest x-ray perhaps because of hair spray particles in the lung. They could not correlate quantity of spray inhaled and clinical findings. Their single case in a hairdresser was thought to AP00037540 be an example of unusual hypersensitivity. Gowdy and Wagstoff (1972) describe five cases with pulmonary chest x-ray infiltrates and four with respiratory complaints, all exposed to a variety of aerosols and all cured by freedom from exposure. Four biopsies and lung function tests were nonspecific. Further, these authors surveyed 227 beauty operators and found none ill but 11 with increased bronchovascular markings on chest x-ray. The material used exclusively in the United States is polyvinylpyrrolidone (PVP), rather than shellac which is used in England. PVP, used as a plasma expander, has proved safe. Oils and propellants used in hair sprays may have a detrimental effect. However, the evidence at present, in view of the large amount used by young women, is that hair sprays are harmless. additives The primary polymers previously outlined are modified through the addition of materials which are selected to impart particular, desirable properties to the finished product. These addi tives, not being large and thus inert polymeric macromolecules, may have biological characteristics which far outweigh those of the basic plastic under consideration. plasticizers Plasticizers are mixed into polymers to increase flexibility and workability. Phthalate esters account for some two-thirds of total domestic plasticizer production and include di(2-ethylhexyl) phthalate, diisooctyl phthalate, and dibutyl phthalate. Adipate, sebacate, and azelate esters are also commonly used, especially when low-temperature flexibility is desired. These esters have a very low order of toxicity. Polyester and epoxidized plasticizers are also of little industrial health importance, although the epoxy ma terials can be sensitizers. Phosphate esters, among the first plasticizers to be developed, impart flame resistance to polymers. Tricresyl phosphates have been the most important. It is believed that tricresyl phosphate used as a plasticizer is generally free of ortho isomer, which has prominent neuorotoxic properties. Triphenyl phosphate, cresyl diphenyl phosphate, and octyl diphenyl phosphate are also used. The question of the purity of materials in this group and freedom from neurotoxic components is often difficult to establish in an industrial setting. The low vapor pressure of the aromatic phos phate esters is a source of protection. Other plasticizers include chlorinated paraffins and chlori nated biphenyls. The latter group is associated with chloracne and hepatic injury; the paraffins lack this toxicity. Flame retardant properties can be inherent in certain plastics AP0003754I because of high chlorine content or, as in the case of the polycar bonates, because they evolve carbon dioxide upon thermal decom position. Flame retardant additives of hygienic interest include tricresyl phosphate, chlorinated di- and triphenyls, bromine com pounds, halogenated phosphates, and antimony trioxide. Flame retardant intermediates which actually become incorporated into the polymer generally contain chlorine or bromine. Stablizers retard the natural degradation of plastics due to light and heat. Potentially hazardous stabilizers are lead salts or soaps, barium and cadmium systems, and organotin compounds. Ultraviolet absorbers are added to protect polymers against wavelengths which tend to disrupt bonds in organic material. Typical absorbers are found among the benzophenones, benzotriazoles, aryl esters of salicylic, benzoic, and terephthalic acids, and organonickel compounds. Antioxidants include alkylated phenols and bisphenols, amines, and organic phosphites. PLASTICS / 343 For the most part, the biological properties of these additives biological properties are not well established. The metallic compounds and organometallics do, however, present a known hazard. Exposure to these additives tends to be small because they are introduced primarily in early steps of the formulation, and few workers are exposed. Organic peroxides are used to cure polyester resins, to initiate organic peroxides polymerization of vinyl and diene monomers, and to cross-link polymer chains, as in polyolefins or silicones. More than forty-five organic perioxide compounds are available commercially. Al though not all peroxides are hazardous, they are, in general, strong oxidizing agents capable of causing skin irritation or burns and severe eye damage. Peroxides on the skin or in the eyes should be removed promptly with large amounts of water. The use of face shields and protective clothing is indicated for those who handle organic peroxides. These compounds tend to be unstable and to undergo spontaneous decomposition. Fires or explosions can re sult from the contaiminatioh or the improper storage of organic peroxides. Inert fillers and fibrous reinforcements are added to many formulations to improve their mechanical properties, to act as extenders to reduce costs, or to impart certain special properties. The addition of silica, asbestos, talc, mica, glass flakes and fibers, and other materials is common. Some of these substances have inherent biological properties which may create a hazardous en vironmental situation at the time of polymer formulation ox when inert filler* and fibrous reinforcements AP00037542 the finished plastic is cut or machined. Under these circumstances potentially injurious dusts may be generated. Rapid developments within the plastics industry have created high thermal conductivity polymers (beryllia-filled epoxy), antifriction elastomers (molyb denum disulfide-filled), radiation shields (lead-filled polyolefin), and plastics reinforced with exotic fibers (boron, sapphire). Biolog ical effects may be associated with the use of some of these ma terials. foaming agents Foaming agents may be added to increase the porosity of plastics which normally foam or to create foamed structures from plastics which have no inherent foaming properties. Foaming agents may generategasby eitherphysicalorchemicalmeans. Physi cal foaming agents are generally volatile liquids which become gaseous and create cells under the influence of exothermic reaction or externally applied heat. Aliphatic hydrocarbons of the petro leum ether, ligroin, or light spirits type are flammable but do not have prominent toxic properties. Halogenated aliphatic hydrocar bons such as methyl chloride, methylene chloride, and tri chloroethylene are also used as foaming agents. The aliphatic fluorocarbons are essentially inert. So-called chemical blowing agents which are foaming agents are compounds which decompose under the influence of heat to yield a gas, usually nitrogen. The most common commercial chemical foaming agent is azobisformamide, which is considered nontoxic. Azobisisobutyronitrile, however, is toxic, and releases nitrogen gas and a residue of tetramethyl succinic dinitrile, which persists in the foam. This compound is a convulsant in animals and has been believed to be the cause of headache, nausea, and other ill-defined systemic complaints in workers. The substitution of other blowing agents has corrected the problem. Azobisisobutyroniltrile may be used in small amounts for the catalytic polymerization of vinyl plastics. Dinitrosoterephthalamide, also used, has not been a source of industrial illness. Elastomeric polymers are frequently constructed of many of the same monomers used in plastics. Proportions, minor constituents, catalysts, and reaction conditions are varied to yield a product with elastic properties. From the medical point of view, an important distinction between some synthetic elastomers and other macromolecular polymers is that "cured" rubbers can occasionally be a source of toxic ingredients added in the formulation stage. Cured plastics are rarely associated with this type of problem. Elastomers of the silicone, polyurethane (referred to as spandex), and fluorinated groups do not present those problems of the more rubberlike elastomers. Synthetic Elastomers Acrylonitrile*butadiene copolymers Chlorosulfonated polyethylene Ethylene-propylene polymers Fluorinated copolymers Polychloroprene, referred to as Neoprene Polyisobutylene Polysulfide rubber Polyurethane elastomers Silicone rubbers Styrene-butadiene copolymers Elastomers of this group are highly resistant to solvents and ACRYLONITRILE- oils and are used for hoses, gaskets, and protective clothing. Nitrile BUTADIENE COPOLYMER rubber is frequently plasticized with organic phosphates, phthalic esters, or dibenzyl ether. Dibenzyl ether is not believed to have prominent toxic properties. The biological properties of butadiene and acrylonitrile have been well established over many years of production of nitrile rubber. There have been few problems from industrial experience. Such elastomers are prepared by the reaction of sulfur dioxide CHLOROSULFONATED and chlorine on polyethylene. They are used in white sidewall POLYETHYLENES tires, hoses, tank linings, and elsewhere where resistance to heat and oxidation is required. These polymers are cured with oxides of lead or magnesium. Accelerators include mercaptobenzothiazole, benzothiazolyl disulfide, and dipentamethylenethiuram tetra- sulfide. Compounds of this group are known skin sensitizers and may be present in finished rubbers in toxic amounts. 345 AP00037544 ETHYLENEPROPYLENE COPOLYMERS AND TERPOLYMERS To produce an elastomeric polymer, olefins are reacted under the influence of a coordination catalyst such as vanadium oxy chloride or diethylaluminum chloride. Peroxides may be used in the cure, although the incorporation of a third monomer such as dicydopentadiene will permit the use of conventional sulfur vulcaniza tion. The toxicity of this alicydic hydrocarbon is not established, but at present no biologic activity is known. Elastomers of this group are resistant to atmospheric and chemical attack and are used in hose, belts, gaskets, and footwear. FLUORINATED ELASTOMERS Copolymers of vinylidene fluoride and chlorotrifluoroethylene or perfluoropropylene are highly resistant elastomers used in gas kets, seals, and other specialized applications where high-cost materials can be afforded. The elastomers are biologically inert, although extreme heating can produce a hazardous exposure to harmful substances. Curing agents include diamines, peroxides, or ionizing radiation. NEOPRENE toxidty Neoprene rubber is highly resistant to oil, solvents, oxygen, ozone, and heat. It is of greatest service in mechanical and automo tive applications such as belts, hose, seals, and gaskets. Neoprene is formed from the polymerization of chloroprene, a colorless li quid which can be irritating to the skin and to the respiratory tract. Animal experiments show evidence of liver and kidney damage, thought to be nonspecific. The most unusual effect of chloroprene or perhaps of small polymeric intermediates is the temporary loss of hair which has been observed in neoprene producers. Termina tion of exposure is associated with the return of normal hair growth. Butyl rubber is formed from the polymerization of isobutene (isobutylene) with small amounts of chloroprene or butadiene. The reaction is carried out in a closed system with an aluminum chloride catalyst. Butyl rubber is highly impervious to gases and finds its major use in inner tubes, air chambers; and dielectrics. Isobutene is an anesthetic and asphyxiant gas, but it is only a hazard if concentrations are high enough to produce asphyxia. Under these circumstances a concurrent hazard of explosion exists. Elastomers of this group are highly resistant to oils, solvents, and weathering and are therefore found in caulking compound, coatings, adhesives, and mechanical components. Polysulfide elas tomers are based on the condensation products of sodium polysul fides and dichloro compounds such as ethylene dichloride. More complex chlorinated hydrocarbons yield products with improved AP00037545 properties. This group of elastomers is plasticized with biologically active compounds such as tetramethylthiuram disulfide or ben- zothiazolyl disulfide. Organic peroxides and lead compounds may also be present. In most applications of the polysulfide rubbers, occupational health problems are related to sensitizing contact dermatitis. ELASTOMERS / 347 So-called spandex fibers are polyurethane elastomers polyurethane which are biologically inert. They can be substituted for rubber by persons who have become sensitized to auxiliary compounds in variably present in natural and synthetic rubbers. All spandex formulations are not identical; many are based on polytetramethylene glycol, 2,4-toluene diisocyanate, other diisocyanates, and hydrazine. The solvent for extrusion is dimethylformamide. The toxocological effects of diisocyanates are well known and con stitute the principal health problem in production of these fibers. Industrial problems have not been prominent in the prepara SILICONE tion or use of silicone rubbers. Benzoyl peroxide may be used as a RUBBERS vulcanizer. Rubbers of this group are prepared in large commercial quan tities for tiretreads and other similar applications. The biological properties of styrene and butadiene are significant, but from the industrial health point of view various additives have been a far greater source of difficulty. STYRENE-BUTADIENE COPOLYMER RUBBERS Various substances added to rubber formulations in the course ADDITIVES IN of production may be a cause of skin reaction in persons who use ELASTOMER SYSTEMS the finished products as well as in industrial workers. The addi tives are generally similar in the case of natural rubber, nitrile hazards rubber, polybutadiene, neoprene, butyl rubber, and ethylene- propylene polymers. Vulcanizers are generally based on elemental sulfur, although zinc and magnesium oxides are important in the neoprene cure, and peroxides are used for ethylene-propylene systems. The rate of vulcanization is influenced by accelerators, which are potent sensitizers. Common accelerators include: benzothiazolyl disulfide mercaptobenzothiazole (MBT) tetraethyl thiuramdisulfide (disuifiram) tetramethyl thiuramdisulfide (thiram) thiocarbarvilide dithiocarbamates (zinc dimethyl, zinc diethyl, zinc dibutyl, lead dimethyl compounds) diphenytguanidine phthalate hexamethylene tetramine 1 AP00037546 Besides causing allergic contact dermatitis, the accelerators disulfiram and thiram can produce severe reactions when they are absorbed in conjunction with alcohol or paraldehyde. The response is related to the inhibition of the normal metabolic degradation of aldehydes, which accumulate and produce flushing, palpi tations, dyspnea, nausea, and hypotension. Disulfiram of phar maceutical grade is a drug used to produce intolerance in the therapy of alcoholism. It has been noted that cutaneous exposure to thiram will produce the alcohol effect. These reactions are due to the inhibition of aldehyde dehydrogenase, presumably through the chelation of molybdenum, and do not involve sensitization. Inorganic accelerators such as lead oxide (litharge) may also be used. ANTIOXIDANTS Antioxidants are used to protect rubbers against the destruc tive effects of atmospheric oxygen. Those most commonly used include: monobenzylether of hydroqulnone (agerite alba) s-di-(B-naphthyl)-p-phenylenediamine mono and dioctyl diphenylamines phenyl a and (3 naphthylamine The monobenzyl ether of hydroquinone, in addition to being a sensitizer, is capable of producing pigment loss in many individu als, often in the absence of any previous skin reaction. This is most apparent in Negroes, in whom the response resembles vitiligo. Exposures to this compound have been sharply reduced through modifications in the rubber compounding process. Most of the amines are potent sensitizers. Pigments and tillers include carbon black, whiting (calcium carbonate), clay, silica, and asbestos. The properties of the fibrogenic dusts are well established. There has been speculation that polycyclic aromatic carcinogens are adsorbed to carbon black parti cles handled in commerce, but there has been no evidence that this pigment has toxic properties. I i i t 1 i AP00037547 trueused ng a 'iducnost ligo. )Ugh : the SYNTHETIC FIBERS 3 Polymeric textiles resemble to a great extent many of the high polymers used in plastics and elastomers. Significant chemical and physical modifications in production provide those properties which are necessary for fibers and filaments. Virgin unfinished textiles are remarkably free of biological properties. Synthetic Textiles Acetates Acrylics (polyacrylonitrile) Modacrylics Nylon (polyamides) Olefin, polypropylene Polyester Rayon Cellulose acetate rayons are made from wood pulp or cotton linters treated with acetic acid and acetic anhydride. Both the acid and its anhydride have a pungent odor and are potent lachrimators. The anhydride is a severe skin and eye irritant and it may occasionally be a sensitizer. This response is presumably due to its reaction with amino groups of cutaneous protein. ACETATES In the production of fibers the cellulose acetate is dissolved in potential a solvent for extrusion. In the case of triacetate material the solvent toxidty can be methyl acetate, gladal acetic add, dimethylformamide, or dimethylsulfoxide. Dimethylformamide is a "universal organic solvent" which is irritating to the eyes, mucous membranes, and skin. The solvent can pass through the intact skin or can be ab sorbed through the lungs. Systemic intoxication is not known to have occurred in man, but evidence from animal experimentation indicates that a potential for visceral injury exists. The unpleasant fishy odor serves as a warning and tends to limit exposure. Di methylsulfoxide has also been suggested as a vehicle for transport ing other drugs through the skin. The application of this chemical to the skin generally results in erythema, itching, and burning. Wheal and erythema reactions may occur at distant sites. For cellulose acetate (other than triacetate) the conventional solvent is acetone, a compound of very low toxidty. Acrylonitrile is the chief constituent of acrylic fibers. To improve the dye and working properties of the material, acrylonitrile is frequently copolymerized with small amounts of other mono mers such as acrylates, amides, vinyl esters, and various hydrocar- acrylics (POLYACRYLONITRILE) 349 I' AP00037548 bons (for example, styrene, isobutene). When the comonomer is vinyl chloride or vinylidene chloride and is present in quantities approximately equal to the acrylonitrile, the polymer is said to be a modacrylic. Modacrylics are extruded in acetone solution; acrylics are prepared for extrusion in solvents which may include dimethylformamide, dimethylsulfoxide, strong adds, and concen trated inorganic salt solutions. nylon The polyamides known as nylon are used principally as fibers, to a lesser extent as resins in the plastics industry. In fiber applica tions nylon may be modified by titanium dioxide, a delusterant; manganese and phosphorus salts, as light stabilizers; and copper salts and acridine compounds, as heat stabilizers. These materials are not released from the finished fiber. There are no reports of ill effects among exposed workers. polyester Fibers of this group are formed of polyethylene terephthalate. This polymer is produced from dimethyl terephthalate and ethylene glycol under the influence of catalysts which include oxides, carbonates, or acetates of the metal zinc, antimony, man ganese, cobalt, calcium, or magnesium. The terephthales have few, if any, biological properties. (For Olefins, see Polyolefin Plastics, p. 339.) RAYON Rayon in its finished form is essentially cellulose and is with out intrinsic toxicological properties. The phases of production which have been hazardous are those in which there are oppor tunities for exposure to carbon disulfide. In the production of rayon, wood pulp is treated with sodium hydroxide to produce alkali cellulose. This material is then reacted with carbon disulfide to produce cellulose xanthate. So-called xanthate crumb, when dissolved in dilute sodium hydroxide to form viscose, is extrudable to form rayon fibers. Modem practice is generally such that this process takes place in closed systems. Hazardous exposure is pos sible, however, when safe practice is ignored or if ventilation is defective. Carbon disulfide is not used in the cuprammonium process, which is used on a limited scale. AP00037549 AP00037550 PESTICIDES 1 It is the continuing objective of the chemical and agricultural indus tries to develop materials which control specific categories of pests and have minimal potential for detrimental effects in man and other desirable animal and plant species. Unfortunately this goal has not yet been achieved, and examples of clinical intoxication continue to appear, usually as the result of accidents or incorrect methods of distribution and application. The average annual death rate due to pesticides in the United States has been estimated by the Public Health Service as one per million population, Nonfatal reported poisonings approximate one per 10,000 population, or 20,000, in the country each year. While there are literally hundreds of pesticides, their purpose, chemical structure, and toxicological properties permit agents to be classified in groups (Table 9) (Milby, 1971). Specified materials are usually not pure compounds but may be complex technical-grade mixtures which contain various isomers, by-products, and reac tants. Trade-name products may include in the formulation a com bination of pesticides, synergists, diluents, and other substances, all of which may have biological properties. Moreover, the compo sition of such formulations may change without a corresponding change in the trade name. Table 9 Insecticides a. Organophosphorus Compounds Most Dangerous ____ Tetraethyl pyrophosphate (TEPP) Phorate Disulfoton Paiathion Demeton (systox) Mevinphos Ethyl p-nitrophenyl thionobenzene phosphonate (EPN) ScKradan Methyl parathion Azinphosmethyl Dicrotophos Dangerous Dichlorvos Diazinon Dioxathion Methyl demeton 353 Dimethoate Naled Phostex Trichlorfon Least Dangerous Malathon Ronnel b. Chlorinated Hydrocarbon Compounds Most Dangerous Isobenzan Endrin Aldrin Dieldrin Toxaphene Dangerous Endosulfan Dichlorodiphenyltrichloroethane (DDT) Heptachlor Benzene Hexachloride (BHQ Strobane Chlordane Dimite Bandane Dicofol Least Dangerous Chlorbenside Chlorobenzllate Ll-dichloro-2,2-bis(p-chlorophenyl)ethane (TDE) Chloropropylate Methoxychlor ORGANO- compound! Of the indicated pesticide categories, the group most com- monly associated with toxic effects in man has been that which encompasses the organophosphorus compounds. Materials of this general type were originally developed as chemical warfare agents; their mechanism of action, probably in both insects and verte brates, is based upon their inactivation of acetylcholinesterase. biologic iction Acetylcholine (AcCh), the natural substrate of this enzyme, is a primary neurohumoral transmitter substance of the nervous sys tem and is necessary for impulse transmission between: (1) pre ganglionic and postganglionic fibers of the sympathetic and parasympathetic autonomic systems; (2) postganglionic parasym pathetic (cholinergic) nerves and secretory cells, smooth muscle, and cardiac muscle; (3) motor nerves and motor endplates of striated muscle; and (4) certain components of the central nervous sys lo%% anc cau the ana the to t zyr que fun tior me phc vel tha ma cor me ins cap inb dot oxi not ton bet in ` ph pe: po to ph am I me exj po Pa. th; ific AP00037552 system. The normal transmission of an impulse by AcCh is fol lowed by the rapid hydrolysis of the transmitter by the enzyme and limitation of the duration and intensity of the stimulus. Organophosphorus compounds of suitable configuration, be cause of certain structural similarities to AcCh, become oriented to the surface of AcCh esterase molecules and undergo changes analogous to those undergone by AcCh, the natural substrate. In the case of the organophosphorus compounds, however, the bond to the enzyme is abnormally stable, and the phosphorylated en zyme loses its normal function as an AcCh esterase. AcCh conse quently accumulates and causes sustained stimulation, increased function, and finally decreased function with greater accumula tion. There is, a wide variation in the mammalian toxicity shown by members of this group. Certain sulfur-substituted organophos phorus compounds require metabolic oxidation before toxicity de velops. Since this in vivo reaction occurs more rapidly in insects than in man, this chemical property is useful in increasing mam malian safety while maintaining insecticidal potency. The oxidative conversion occurs in man but is offset to a variable degree by metabolic inactivation of biologically significant portions of the Insecticide molecule. As long as the inactivation processes are capable of keeping up with the activation (oxidation) processes, intoxication does not occur. The body deals effectively with small doses of parathion, an agent of this type which requires metabolic oxidation to become toxic. When the inactivation mechanism can not handle the amount of toxic compound presented to it, symp toms occur. The balance between oxidation and inactiviation varies between individuals; it is, therefore, not surprising that variation in susceptibility to intoxication is noted. For reasons which are not yet clearly understood phenothiazine derivatives, especially when taken over a prolonged period, may potentiate the toxicity of organophosphorus com pounds (Arterberry et al., 1962). This phenomenon may be related to experimental evidence for the inhibition of cholinesterase by pharmaceutical preparations of this type. In addition neurotropic amines such as theophylline and aminophylline may have a detri mental effect. The toxicity of these materials is also influenced by exposure to ultraviolet and visible light, which may produce more potent anticholinesterase agents than the parent compound. Parathion exposed to light on plant surfaces is probably more toxic than the unirradiated insecticide (Milby et al., 1964). Organophosphorus compounds which do not require a mod ification to become active are "direct" inhibitors of AcCh and PESTICIDES I 355 AP00037553 generally show high toxicity and rapid onset of systemic symp toms. They may also cause local reactions (e.g., miosis) in the absense of systemic manifestations because absorption into the body and metabolism, probably hepatic, is not necessary for activ ity. Compounds in this group include tetraethyl pyrophosphate (TEPP) and phosdrin, both highly toxic, and dichlorvos (DDVP), which is readily detoxified in vertebrates and consequently less hazardous. Insecticides of the organophosphorus group can be absorbed via the lungs, skin, or gastrointestinal tract. Oral exposure is rarely of occupational origin, but accidental poisoning of children is not uncommon, especially when pesticides are improperly stored, as in soft drink bottles. Manifestations of absorption tend to occur most rapidly after respiratory exposure or after massive exposure directly to the eye. Organophosphorus insecticides are absorbed by the skin, but the rate tends to be slow except in the presence of dermatitis and high ambient temperatures. Poor hygiene, boots and gloves contaminated on the inside, and materials with severe dermal toxicity contribute to the intensity of the hazard. clinical vyndrome* The pattern of symptoms in man reflects the degree of cholinesterase inhibition and the rate at which the enzyme has become inactivated. The level of AcCh esterase can be reduced to a level as low aso0.2 pH/hr gradually over the course of months by repeated small doses without obvious clinical symptoms. Field experience suggests that the gradual depression of AcCh esterase by repeated low doses does not increase susceptibility to a chal lenge dose of insecticide. There is evidently a physiological adapta tion to low enzyme levels. On the other hand, repeated doses administered prior to physiological adjustment tend to produce cumulative effects. After clinical poisoning, physiological adjust ment may be assumed complete only after the blood enzyme level has returned to normal. Moderate systemic effects of acute absorption may occur within thirty minutes after exposure via the respiratory tract, within forty-five minutes after ingestion, and within two to three hours of cutaneous exposure. Absorption from the gastrointestinal tract and skin may be prolonged. Symptoms normally reach their peak four to eight hours after onset and gradually diminish over a period as long as a week. Complete restoration of blood cholines terase levels may require three months, depending upon degree of depression. With massive exposure or direct application of com pounds to the conjunctival epithelium, the onset of symptoms is almost instantaneous, and death may follow within minutes. If the ai tr e\ T) CT Si hi cs & ai th hi d* re tic th AP00037554 onset of symptoms follows exposure by more than eight hours, the diagnosis of organophosphorus poisoning is open to serious question. Clinical evidence of systemic inhibition of cholinesterase is not specific to individual compounds but is characteristic of the entire group. Systemic responses are usually heralded by the onset of effects as a result of parasympathetic stimulation which include anorexia, nausea, sweating, substemal and epigastric tightness, heartburn, and belching. A greater degree of absorption produces vomiting, hyperperistalsis with cramps and diarrhea, increased salivation and lacrimation, profuse sweating, pallor, dyspnea, and wheezing. Miosis may be observed, but it is not a constant feature, and mydriasis has been occasionally noted. Severe symptoms in clude involuntary defecation and urination, excessive bronchial secretions, and pulmonary edema. Evidence of inhibited cholines terase activity at the motor endplate usually occurs after the mus carinic effects have become relatively prominent. These nicotinic phenomena include muscular twitching, fasdculation, cramps of skeletal muscle, and general weakness, especially on exertion. The muscles of respiration may be impaired. PESTICIDES I 357 Central nervous system (CNS) manifestations may include effect* on central anxiety, emotional aberration, insomnia or somnolence, headache, netvousayitam tremor, and intellectual deterioration. Electroencephalographic evidence of CNS impairment may persist for prolonged periods. The significance of these manifestations may be increased by the critical demands of certain jobs (e.g., pilot of crop-dusting aircraft). Studies of workers with chronic exposures to organophosphates have revealed neurological deficits in the absence of obvious clini cal signs of intoxication (Metcalf and Holmes, 1969). Slowness of thinking, memory defects, irritability, and delayed reaction times are apparent. The chronidty and cholinesterase relationship of these clinical phenomena is not established. Death in cases of heavy exposure is usually related to respiratory collapse reflecting depression of the respiratory center, weakness of the muscles of respiration, bronchoconstriction, and excessive pulmonary secre tions. Ventricular fibrillation may ensue when atropine is given in the presence of hypoxia. Slight exposure to an aerosol of a direct inhibitor of cholinesterase may produce local physiological responses without sys temic absorption, Indirect inhibitors cause poisoning only after they have been metabolized and consequently produce no local effects. Local effects upon the eye may include miosis, a sensation of retrobulbar pressure, headache, and conjunctival hyperemia. local effects APOOC These reactions may persist for as long as a day, and miosis has been noted to remain for five days or even longer. Localized skin responses include muscular fasciculation and circumscribed areas of sweating, developing within minutes and lasting for several hours. Respiratory exposure to an aerosol or vapor may lead to increased bronchial secretions, a sensation of chest tightness, and occasionally wheezing, with or without subsequent systemic poisoning. delayed effects Although the evidence is incomplete, some cholinesteraseinhibiting organophosphorus compounds can produce permanent paralysis due to a demyelinating process of the spinal cord, (Bidstrup et al., 1953). This process may not become apparent for as long as a month after exposure and is similar to the chronic neurological phenomena associated with tri-o-cresyLphosphate. Animal data suggest that most organophosphorus insecticides do not have this property, and demyelination in man has been attri buted only to Mipafox, an agent not used in the United States. Evidence is accumulating that renal tubular dysfunctions may be associated with absorption of organophosphorus pesticides (Davies et al., 1969). The mechanisms responsible for observed glycosuria, alterations in phosphate resorption, diminished concen trating ability, and amino add resorption defects have not been identified. It is possible that these manifestations of toxicity are due to oiganophosphate metabolites such as p-nitrophenol, a known irritant which can cause dysuria. treatment Treatment in cases of cholinesterase inhibition, is based upon the prompt administration of atropine in sufficient doses. Atropine does not influence the inactivation of cholinesterase but rather limits the exaggerated muscarinic effects of accumulated acetyl choline. Atropine has no effect upon the nicotinic manifestations of acetylcholine at the motor endplate and consequently does not influence weakness of the respiratory musculature. There is a clear danger of ventricular fibrillation in persons who receive atropine in the presence of hypoxia. While agreement on the point is not unanimous, it is the general view that the cyanotic patient should receive oxygen and artificial ventilation to correct hypoxia before atropine is administered. It is desirable to achieve a mild degree of atropine toxidty such as tachycardia, dry flushed skin, or cessation of salivary secretion, which may require unusually large doses. In severely poisoned persons, as much as 40 mg of atropine can be given in a day without producing overatropinization. A single AP00037556 mic jon intravenous dose of 10 mg atropine sulfate has been inadvertently administered to normal adults with consequent obvious signs of serious overdosage but without causing a critical threat to life. The effects of intravenous atropine begin in one to four minutes and are maximal in eight minutes. The use of atropine as a prophylactic measure prior to anticipated exposure should be avoided. Although atropine does not influence the integrity of the inac tive phosphorylated enzyme complex, specific agents of the oxime type have been developed to accelerate cholinesterase reactivation. The oxime currently available in the United States is 2-pyridine aldoxime known as 2-PAM, pralidoxime chloride.* Other agents have been developed, especially in Europe. The evidence is very good that treatment with both atropine and 2-PAM is more effec tive than treatment with atropine alone. 2-PAM is rapidly excreted, and repeated doses may be necessary, particularly in the case of parathion and other organophosphorus compounds which must undergo bioactivation before becoming toxic. Since 2-PAM is itself a weak anticholinesterase compound, facilities for assisted ventila tion should be available. In severe cases of poisoning (coma, cyanosis) the recom mended treatment should be a$ follows: 1. Correction of hypoxia with oxygen and assisted ventilation; removal of secretions; maintenance of patent airway. 2. Administrationofatropinesulfate, 2 to4mg, intravenously. This should be repeated at 5- to 10-minute intervals until signs of atropine toxicity appear (dry, flushed skin; tachycardia as high as 140/znin, dry mouth). 3. Administration of2-PAM, 1 gm intravenously, slowly. The dose may be given in an infusion of 250 ml of saline over a 30minute period. The dose can be repeated in an hour. In over whelming exposures, the doses may be doubled. 4. Decontamination of skin and hair with soap and water, decon tamination of eyes with saline. Alcohol can be used to remove final traces of material from the skin. 5. Symptomatic treatment. In less severe cases, the following treatment is appropriate: 1. Atropine sulfate, 1 to 2 mg, if symptoms appear, repeated every 15 to 30 minutes until muscarinic symptoms are relieved or until evidence of mild atropine toxicity occurs. 2. Decontamination. 3. Administration of 2-PAM, 1 gm intravenously, slowly, if re sponse to atropine is not satisfactory. 4. Symptomatic treatment. 'Marketed under the nameProtopam chloride, AyerstLaboratories, 3rdAvenue. New York City, N.Y. PESTICIDES ! 359 AP00037557 1 Opiates, theophylline, aminophyUine, phenothiazine, and succinylcholine are contraindicated. Seizures are generally best prevented or controlled by adequate oxygenation and the outlined regimen. Intravenous sodium thiopental can be used if necessary with extreme caution. Persons who are sufficiently ill to require atropine should remain under medical supervision for at least twenty-four hours, since absorption and bioactivation may occur for a prolonged period after the initial exposure. prevention Prevention of occupational exposure can be accomplished through education, care, and the use of protective clothing, res pirators, and air-conditioned cabs. Careful maintenance of equipment is necessary inasmuch as boots, gloves, and overalls become readily contaminated and sources of cutaneous exposure. Spray-soaked clothing should obviously be removed promptly. Contamination of tobacco products and foods must be avoided, and the hands and face should be washed with soap and water prior to eating or smoking. Blood analyses for cholinesterase activity are valuable in diag nosis and in medical surveillance of potentially exposed workers (Witter, 1963). Plasma cholinesterase levels drop to lower levels and recover more rapidly than do red ceil cholinesterase levels which represent the true levels. Red cell cholinesterase recovers only as fast as new erythrocytes are formed, unless there has been treatment with oximes. The normal level for an individual is his pre-exposure level, and it is against this value that subsequent comparisons should be made. In the absence of pre-exposure in formation, group "normals" can be used, but are less satisfactory. Colorimetric field procedures are available which permit iden tification of those persons whose whole blood cholinesterase activ ity has fallen to below 50 percent of control levels, persons who should be removed from further exposure and whose previous exposure should be examined. This method is based upon the rate of pH shift in the sample as acetylcholine is hydrolyzed with the release of acetate. A testing paper yielding relatively crude approx imations of plasma cholinesterase levels is available for diagnostic field and emergency room use. Instructions for use of all field methods must be followed exactly if errors are to be avoided. Various standard laboratory methods are available for more precise enzyme determinations. Micromodifications of the Michael glass electrode pH measurement technique are most common. Normal enzyme levels have been determined by Rider et al. (1957) (in a pH/hr) and are in current use (1974); eithc praci activ carbs sever zynie shoul tom at organ tume storag scribe methc trophc trades In popula malian To that as: an inter by the i through . is not e i with thi i forming i phenom tivating i ticides, . i AP00037558 Table 10 Normal Enzyme Levels Red Cells Range Meanirs.d. Men Women 0.39-1.02 0.34-1.10 0.766*0.081 0.750*0.082 Plasma Range Meanss.d. 0.44-1.63 0.24-1.54 0.953*0.187 0.817*0.187 PESTICIDES / 361 For practical purposes, a cholinesterase level of 0.5 a ph/Hr for either cells or plasma represents depressed activity. Also from the practical point of view, a significant reduction of cholinesterase activity can be caused only by exposure to organophosphorus or carbamate insecticides. When intoxication of at least moderate severity is suspected on clinical and epidemiological grounds, en zyme assays should be regarded as confirmatory, and treatment should not be delayed until a laboratory report Is received. Symp tomatic persons should not be permitted to return to work with organophosphorus compounds until cholinesterase levels have re turned to 75 percent of normal. Procedures for the collection, storage, and shipment of biological materials have been fully de scribed (Morrison and Durham, 1971). An additional surveillance method is based upon the urinary excretion levels of paranitrophenol, a metabolite of parathion and several related insec ticides (Davies et al., 1966). Insecticides of the carbamate group are becoming increasingly carbamate popular because of their efficacy and relatively low order of mam INSECTICIDES malian toxicity. To a large degree carbamates function in a manner similar to torfdty that associated with organophosphorus compounds--viz., there is an interference with the normal hydrolysis of acetylcholine (AcCh) by the enzyme cholinesterase. That the enzyme becomes inactive through carbamylation, the process analagous to phosphorylation, is not established. It may be that carbamates act by competition with the substrate (AcCh) for the enzyme surface rather than by forming a stable bond with the enzyme. In either case, the clinical phenomena reflecting esterase inhibition are the same. The inac tivating reaction is readily reversible in the case of carbamate insec ticides, and the normal enzyme can be easily regenerated. The reversal is so rapid that measurements of blood cholinesterase in cases of poisoning are likely to be inaccurate, appearing as false negatives, unless special precautions are taken. Most carbamates are readily hydrolyzed in mammalian systems, Most carbamates are absorbed via the lungs, 6kin, and gas trointestinal tract. In cases of heavy exposure, manifestations of cholinesterase inhibition may appear and resemble those of organophosphorus poisoning. treatment Atropine sulfate is the treatment of choice. There is disagree ment as to the value of the oximes in carbamate poisoning. The best current practice would appear to avoid the use of 2-PAM in carbaryl intoxication and to regard this oxime as contraindicated. control In carbamate manufacturing operations and in certain com mercial applications, the intensity of exposure may be evaluated by means of determinations of urinary metabolites such as 1-naphthol. CHLORINATED HYDROCARBON INSECTICIDES biologic action The mechanism of action of chlorinated hydrocarbon insec ticides in mammals and insects has never been clearly understood although it is apparent that these materials are neurological poisons. They are soluble in body fat, and numerous.studies have been undertaken to measure the levels of chlorinated hydrocarbon insecticides in normal human tissues. Measurable concentrations of DDT and other agents have been found in normal human fat and even in neonatal tissues; however, the biological significance of these observations i9 unclear. The data do provide evidence that these insecticides are persistent and are absorbed by man from his foods, particularly those of animal origin. Material stored in fat is probably largely inactive, and the total amount stored in the fat of an experimental animal may be greater than the amount necessary for a single fatal dose. These agents or their metabolites may often be identified in urine or milk. Compounds in this category may be absorbed through inges tion and via the respiratory tract. Most of them can be absorbed through the skin, and at least one, dieldrin, can be absorbed in this manner from a dry state without being in solution. Dusts contain ing 5 percent DDT have been applied to the skin in louse control programs for extended periods without untoward effects. clinical slgna and Manifestations of central nervous system stimulation from lymplom--dUgnetlt slight exposures include headache, anorexia, nausea, and irritabil ity. With increasing intensity of exposure weakness, paresthesias. AP00037560 tremOTS, and muscle fibrillation may be observed. Paresthesias of the tongue, face, and lips have been noted early in the course of DDT poisoning, and in severe cases paresthesias may occur in the extremities as well. Relatively high levels of absorption accelerate the onset of these symptoms, and seizures or coma may occur. In most over-exposure situations, symptoms appear within several hours, and a delay of over eight hours would be decidedly un usual. Long-continued low-level exposures are not known to pro duce clinical phenomena which differ from those of the acute response to intense single exposures. Diagnosis is based almost entirely upon the history and clini cal picture. Laboratory techniques, especially gas-liquid chromatography, can identify insecticides or their metabolites in blood, urine, gastric contents, or body fat (Morrison and Durham, 1971). The correlation of these assays with the character of the illness is not very good, and it is apparent that these relatively sophisticated procedures have limited applicability in emergency situations. PESTICIDES I 363 Treatment is symptomatic and supportive, and no specific treatment antidotes are available. Contaminated clothing must be removed, and material on the skin, in the hair, and under the nails must be washed away with water and soap. Emesis or gastric lavage is indicated if toxic material has been ingested. Petroleum-based sol vent vehicles present the additional hazard of aspiration pneumonia; however, this is of less significance than the fact that large amounts of highly toxic material have been ingested. With severe symptoms pentobarbital sodium 0.2 to 0.5 gin maybe given intravenously to control convulsions. Repeated doses may be necessary. With control of seizures, the use of phenobarbttal sodium will provide more prolonged control. In severe intoxica tion, artificial ventilation and supplemental oxygen may be re quired. Mild intoxication may be treated with oral phenobarbetal alone. Symptoms of chlorinated hydrocarbon poisoning may per sist as long as a week, and control of symptoms may be necessary for the entire period. Whether or not delayed effects or chronic sequelae are related to the absorption of chlorinated hydrocarbon insecticides is not clear. Gaims of a causal association with leukemia have not been supported. Aplastic anemias following exposure to lindane, the gamma isomer of benzene hexachloride (BHC) have been reported. The diagnoses are more certain than the direct cause. AP00037561 OTHER INSECTICIDES pyrethrum, rotenone, and nicotine Pyrethrum extract is utilized in many insect sprays and pow ders when a rapid "knock-down" is required. Most aerosol "bombs" for home use contain pyrethrum. This material is a mod erately potent skin sensitizer and cross reacts with chrysan themum, shasta daisy, and ragweed. Systemic intoxication is not a problem. Rotenone is a similar plant derivative with properties similar to pyrethrum, Nicotine sulfate is a potent neurological poison which can be absorbed from the skin, lungs, or gastrointes tinal tract. pipeconyl butoxide Pipeionyl butoxide is not an insecticide but a synergist, which permits the reduction of concentrations of pyrethrum to 10 percent of levels which would otherwise be required. This synergist is comparatively nontoxic when tested alone by conventional tech niques. This and other piperonyl derivatives appear to synergize the action of a number of pesticides by inhibiting enzyme systems or preventing enzyme induction concerned with the metabolism of the primary agent. In the case of certain sulfur-containing organophosphorua insecticides, which require metabolic activation, the enzyme-inhibiting synergists are in fact antagonistic to the development of normal insecticidal potency. At the present time the applicability of these observations to the health of man is not entirely clear (Conney et al., 1972), but there is little reason to doubt that insecticidal synergists influence the metabolic detoxifi cation of agricultural chemicals, hormones, and pharmaceuticals. Arsenicals (e.g., Paris green lead arsenate and other Inorganic compounds of arsenic are used with decreasing frequency. Hy drogen cyanide and methyl bromide are used in homes, ware houses, and ships as fumigants. mitiddes Mites, such as the red spider mite, are not insects and are not controlled by the usual insecticidal agents. Such agents, in fact, tend to kill the insect predators of mites. Nevertheless miticides (acariddes) are included in this section because they are applied in the same manner as are the insecticides and because their probable effects on man resemble those of certain insecticidal groups. The chemicals used, such as chlorbenzilate and chlorbenside, resemble the chlorinated hydrocazbon insecticides and have similar effects in animals. The mammalian toxicity of these agents is not great. Dinitrophenol and its derivatives are miticides of distinctly greater mammalian toxicity, which is outlined relative to their application as herbicides. soil fumigants Nematodes are not insects but inhabit the soil as do various insects, all of which are controlled by nematocidal soil fumigants. The 1,2-c irrita nem bam. per, Thes an u whic AP00037562 hich cent st is echgize :ems m of ; ortion, the time ; not n to >xifi:als. ;anic Hyare- ? not fact, rides :d in >able The nble ts in reat. >ater ition ious ints. The best known of these agents is referred to as DD, a mixture of 1,2-dichloropropane and 1,3-dichloropropene, which is an intense irritant to the eyes, skin, and mucosa of the respiratory tract. Other nematocides include methyl bromide, ethyl dibromide, and car bamates. PESTICIDES I 365 The classical agricultural fungicides, sulfur and inorganic cop- FUNGICIDES per, have never been of great toxicological significance to man. These agents are presently being supplemented or superseded to an increasing extent by synthetic organic compounds some of which are clearly hazardous. Among the most useful organomercurial fungicides are those organomercury based upon alkyl, alkoxyalkyl, and aryl mercury: phenyl mercury comPattnd* acetate, ethyl mercury phosphate, methoxyethyl mercury silicate, and a series of more complex compounds. Alkyl mercurials, which have been used as fungicidal seed dressings, are highly toxic neurological poisons capable of causing constricted visual fields, ataxia, and other widespread manifestations of central and peripheral involvement. Aryl mercury compounds are used to control fungus disease of turf, fruits, vegetables, and grain crops but not under conditions which will leave measurable residue in' foods or animal feeds. The aryl, usually phenyl, derivatives are clearly less toxic; however, they can cause similar neurological disease and an active dermatitis. These materials can also be used as fungicides in paints and some leathers. Compounds of nickel, chromium, and tin may also be found in metal-based fungicides. Dithiocarbamate foliage 9prays include a zinc compound, an dithiocvbunate* iron compound, and a manganese compound. These materials are not considered to have important systemic toxicity, although they may irritate the eyes and upper airway. The material named Thiram is tetramethylthiuram disulfide, a seed protectant, also found in the rubber industry as an accelerator. So-called captan and folpet, which are found in many agri phthilimidc* cultural and home garden fungicides, have not presented significant hazards to man. Both agents do have the phthalimide moiety of thalidomide and are teratogenic in the chick embryo. Present opinion, however, is that an extrapolation of this observation to man cannot be made on the basis of available evidence. Because of unfortunate accidents associated with human con sumption of seed grains that have been treated with organomercuiials, hexachlorobenzene has been used as a fungicidal seed dressing. The consumption of grain prepared in this way has led to 1 AP00037563 epidemics of acquired prophyria cutanea tarda with bullous skin lesions, ulcerations, permanent pigmented scarring, and hyper trichosis (Bleibert et al,, 1964; Cam and Nigogosyan, 1963). Hexachlorobenzene (CCU) is not benzene hexachloride (CsHsCle, BHQ. It is an insecticide which is correctly designated as hexachlorocyclohexane. psntachlorophenol Pentachlorophenol is an insecticide, herbicide, and fungicide used to control weeds and the deterioration of timber. It is not applied to food crops. The action of pentachlorophenol in man is similar to that of the dinitrophenols and is based upon an uncou pling of oxidation and phosphorylation with a resultant marked increase in body temperature. Pentachlorophenol is also a potent skin and upper respiratory tract irritant. Kanthine So-called Karathane is a member of the 4,6-dinitro-o-cresol (DNOQ dinitrophenol group and has potent fungicidal and miticidal properties. It is irritating to the eyes and upper airway but is much less toxic systemically than DNOC. other fungicides Other fungicidal agents used in industrial applications in clude creosote used as a wood preservative. Creosote can produce painful skin bums and is highly toxic on ingestion. Paranitrophenol, a methemoglobin producer, is used on leather. HERBICIDES Inorganic arsenicals and sodium chlorate have been used to kill weeds for many years and to sterilize soils for areas such as parking lots in which no vegetation is desired. Current usage emphasizes organic compounds, many of which are selective her bicides (i.e., agents which affect only certain types of vegetation). chloxphenoxy group This group includes 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic add (2,4,5-T), a related compound, silvex, and 2-methyl-4-chlorphenoxyacetic add. In most applica tions amine salts or esters are used so as to permit control of volatility and drift. Compounds of this group act as growthregulating hormones in plants; however, no hormonal effects are noted in animals. Skin absorption is slight, and toxidty by oral or inhalabonal routes has not been an agricultural health problem. Experimental and suicidal dosing has resulted in weakness, musde twitching, myotonia, convulsions, and coma, the mechanisms for which are unknown. The group can produce a contact dermatitis and chloracne (Kimmig and Schutz, 1957), and a syndrome con forming to the description of porphyria cutanea tarda has occured in chemical operators manufacturing 2,4-D (Bleiberg et al., 1964; AP00037564 PESTICIDES / 367 Poland et al., 1971). There was associated exposure to other chemi cal intermediates in this situation. In each instance treatment is symptomatic. A series of substituted dinitrophenols has been prepared for dinitrophenols use as eradicant herbicides along roadways and rights of way, as JJdceffects selective weed killers in fields, and as blossom thinners for fruit trees. In different formulations these compounds can be used as fungicides, mitiddes, and insectiddes, especially a9 dormant sprays for the control of over-wintering insect eggs in fruit trees. Principal compounds include 4,6-dinitro-o-cresoI (DNOC), 4,6-dinitro-o-sec-butylphenol, and 2,4-dinitrocyclohexylphenol. Each of these compounds, as well as others in the group, are readily absorbed by inhalation or ingestion. Most of them can be absorbed through the skin, although the cyclohexyl derivative is not absorbed in this manner to a significant degree. Compounds in this group share a common toxic mechanism whereby oxidation at the mitochondrial level is uncoupled from phosphorylation. Oxi dation continues and in fact increases in response to the defitit of adenosine triphosphate. Symptoms in man include restlessness, anxiety, flushed skin, sweating, deep and rapid respiration, tachycardia, hyperthermia, cyanosis, weakness, and coma. The increase in metabolic rate is proportional to the absorbed dose, and very high basal metabolic rates may be attained. Under such circumstances the production of heat exceeds the capacity to dissipate heat by a very great margin, and fatal hyperthermia may ensue. High ambient temperatures contribute to the disturbance of heat loss. Chronic intoxication may be marked by fatigue, unusual thirst, and weight loss as well as by symptoms of acute intoxication. There may be yellow staining of the skin from the compounds in question, although staining is not indicative of poisoning. Cataract formation may be observed and was typical of those cases arising in the 1930s from the use of dinitrophenols in weight-reducing drugs. Laboratory findings are not usually helpful with the exception that the basal metabolic rate is elevated. Tests are available for determining blood and urine levels of dinitrophenols. Treatment is symptomatic and based upon controlling the hyperthermia with cold baths. Oxygen and careful attention to fluid and electrolyte balance are indicated. Material on the skin should be removed with soap and water, but there is no reason to attempt to remove the fixed yellow stains of skin and hair. Atropine is absolutely contraindicated, and it is essential not to confuse the evidence for this poisoning with manifestations of cholinesterase inhibition. f AP00037565 Acute poisoning by the dinitrophenols usually runs a rapid course with essentially complete recovery or death within twentyfour to forty-eight hours. The excretion of these compounds is very slow, however, and persons who have shown symptoms of poisoning should be separated from risks of absorption for at least six weeks. Those who regularly apply dinitrophenols should be checked periodically for blood levels of the compounds. Assays give a reasonably good index of the degree of absorption and the hazard to health. cubunatM, trfizln^^Vtives Carbamate herbicides include compounds marketed under a variety of designations. The phenylurea group includes monuron, diuron, and linuron. Simazine and atrazine are of the triazine group. None of these materials has been shown to have a high level of acute mammalian toxicity, but there is evidence that the carbamates and phenylureas affect mitosis. bipyridlaium ndTmddtv *n Diqual and paraquat of the bipyridinium or quaternary am- mon*um group 816 remarkable from the toxicological point of view in that they are capable, under the proper circumstances, of caus ing a proliferative reaction of alveolar macrophages, alveolar cells, pulmonary fibroblasts, and terminal bronchiolar cells. This process leads to thickening and fibrosis of the alveolar walls, respiratory insufficiency, and death. In man this response has been observed only after the ingestion of a large amount of paraquat and is delayed for several days after the acute exposure (Bullivant, 1966). Renal disorders with nitrogen retention and hepatic necrosis have also been observed before the development of pulmonary fibrosis. These compounds appear to affect epithelial tissues primarily, and specific agents may attack those of the kidney or lens of the eye preferentially. In normal field use there is no evidence that compounds of this group are injurious, but it is regarded as prudent to avoid the inhalation of mists generated in spraying. other organic herbiadei One compound named Dalapon is based upon 2,2-dichloropropionic add and is of no great hazard to applicators. Aminotriazole, used mainly for the destruction of poison oak and poison ivy, and the so-called Dacthal, a pre-emergent herbidde, have no prominent clinical toxicological properties. RODENTICIDES Inorganic rodentiddes include compounds of arsenic, phos phorus, and thallium. Warfarin is a coumarin derivative and has anticoagulant properties which are familiar to physicians who use AP00037566 AP00037567 AP00037568