Document 2JNOgyjZGm5xKb2M6LzV6pdY6

i croo Oo ro TOXICITY OF INDUSTRIAL METALS SECOND EDITION ETHEL BROWNING, M.D. Formerly 11.M. Medical Inspector of Factories; 1969 NEW YORK. appleton-century-crofts Division or Morediih Corporation LONDON HOTTERWORTHS 40 TOX1C1TV OP INDUSTRIAL METALS reverberatory furnace, with small amounts of iron pyrites or galena. When eooled by passage through a seeks of brick chambers, the oxide condenses as a crude product to be purified by re-sublimation (l)uchanan, 1961). Arsenic can also be prepared from mispickcl by heating in earthenware retorts and distilling off the arsenic condensed on sheet iron in the neck of the retort. It can also be obtained, free from oxide, by reducing pure ASjO* with zirconium. PROPERTIES In its stable form arsenic is a steel-gray, brittle, crystalline metalloid. It exhibits allotropy, the two other forms usually distinguished being yellow and black respectively. It forms three oxide*--the trioxidc, As.O, (the most abundant commercial source or arsenical compounds); the pcnloxidc, As,Ot (the primary material for many arsenical insecticides); and (he telroxide, As,0,. Atomic number, 18; atomic weight, 74-91; specific gravity, 5-73 (yellow allotrope 3-7, black allotrope4-7; fhre&old limit value 0-3 mg. per c.m.). PROPERTIES OF ARSENIC TRIOXIDE (THE PRINCIPAL COMPOUND) The crude arsenic trioxide dust obtained by sublimation during smelting of arsenic-containing ores consists of approximately 97 per cent of AstO,, Its principal impurity being antimony trioxidc. Pinto and McGill (1953) stated that the particle size of over 23 per cent of the dust is over 5-S/i. It is only slightly soluble in water but soluble in alkaline and acid solutions. It was slated by Schwartze (1922) that the toxicity of arsenic Irioxide was inversely proportional to lire particle size, the oral L.D.,, for the rat varying between 75 and 500 mg. of arsenic per kg. according to the size. Other Inorganic compounds of arsenic include arsenic chloride, (" butter of arsenic "}, a colourless oily liquid used chiefly in the manufacture of pharma ceuticals; arsenites, arsenates and sulphur compounds. The arsenite salts in which the acid corresponds to orsenious and arsenic acids, while of the alkali salts, sodium meta-arsenate, which is readily soluble in water, is the most widely used. Of the arsenates, those of lead, calcium and magnesium are mainly used as spray insecticides, and in recent years magnesium arsenate has been found of value in the manufacture of fluorescent lamps. The sulphur compounds, As.S, (orpimenl) and realgar (AsO,) have been largely supplanted as pigments by lead chromes, and as a depilatory rcalgafltns been generally replaced by sodium sulphide. Arsenical pigments--copper arsenile (Schcelc's Green) and copper uccto arsenite (Scliwcinfurtc Green) were formei ly widely used as pigments in wall paper, calico printing and as wood preservatives, but their use for these pur poses is now much diminished, partly on account of the liberation of llie toxic gas dimethyl ursine by the action of moulds. Organic compounds of arsenic,--'The arsphenamtnes--Salvnrsan and Neosatvarsan--derived from diarscnobenzene, arc best known for their therapeutic effects ip protozoal diseases, which were first demonstrated ARSENIC AND ARSING -1) following the discovery that atoxyl (sodium arscnilatc) had this property, but they have now been largely supplanted by antibiotics. ESTIMATION OF ARSENIC In estimating trace amounts of arsenic in biological or industrial material, it must be rendered soluble. Thereafter, there are several very well-known chemical tests--Reinsch, Marsh and Gutzeit--described in detail in standard works on analytical chemistry, and more concisely by Buchanan (1961). Estimation by radioactivation was first described by Smales and Pate (1952) and adapted by Lemlinn and Smith (1958). The sample to be irradiated is placed in an atomic pile, then converted into arsine, which is absorbed in a solution of mercury chloride and examined by a Geiger counter. Estimation by neutron activation analysis is described by ICrishnan, S. S. tt ah (1966). INDUSTRIAL IISES Arsenic is used industrially for the following purposes. (1) In the manufacture of insecticides, weed killers and fungicides (usually in the form of potassium arsenite), and as a wood preservative. (2) In glass manufacture as a bronzing or decolorizing addition, and in the production of opal glass and enamels, particularly in the majolica industry in Italy (Dcchigi, 1936). (3) As an addition to alloys in amounts of 0-3-0-5 per cent to increase hardening and heat resistance. (4) In tlus manufacture of arsenical organic compounds for therapeutic use. MAXIMUM ALLOWABLE CONCENTRATION The MAC recommended by the American Conference of Governmental Industrial Hygienists in 1962 and not since revised is as follows; Arsenic (dust) 0-5 mg. per c.m. Arsine 0 05 p.p.m, (0-2 mg. per c.m.). METABOLISM Although arsenic Is not an essential element of human metabolism, it is, owing to Us wide distribution in nature, constantly taken into the Unman body in very small quantities, and is therefore regarded by most authorities as a normal constituent of the body. Following the publication of a series of papers by Gautier (1899), claiming that amounts varying from 0-113 lo 0-76 mg. per 100 g. were present in the normal mammary glands, thyroid gland, thymus gland, hair, skin and bones, and the denial of this claim by a Committee of the Freneh Academy, wide controversy was aroused, particularly from the medico-legal experts, but as llie result of a large series of examinations by Myers and Cornwall (1925) it appears to be generally agreed that such small amounts as those postulated by Gautier can bo regarded as " normal ". According to Glaislcr (1931) 42 TOXICITY OP INDUSTRIAL METAIS ARSENIC AND ARSINE 41 " traces of arsenic less than one part per S million pails of viscera should bu per L., indicating that much mure insonic can go through (lie Iumcm body ignored", without causing illness Ilian has been previously realized. Orcslnno and DISTRIBUTION AND STORAGE OF ABSORBED ARSENIC Abb.ilc (I9J7) believe licit (he amount of arsenic eliminated in the urine is indeiiendeiit of the dose so long as this is tolerated. About four-liftIis of (lie amount of nrscalc absorbed is stored and widely With regard to lead nrscuale, it appears from the investigations of Fairhafl distributed in the tissues, including the liver, abdominal viscera, bone, skin, el til. (1938, 1941, 1943) that this compound is broken down in the body with and particularly the Imir ami nails, wlicro it may be dclcclcd many months subsequent excretion of most of the arsenic by the kidney, anti according to after it has disappeared from the urine and faeces. Gcrin (1957) the arsenic disappears from the urine more rapidly than the Determination of the rate ot absorption of arsenic has been facilitated by lead. Fairltall's findings indicated furthermore that in the presence of lead, the modern use of radioactive tracers. Ily exposing the Imir to a tlux of arsenic is eliminated more intensively and (hat the arsenate radical either thermal neutrons, the arsenic is rendered radioactive, and its localization, as decreases the absorption or increases the excretion of lead while soluble a fraction of length of the hair determined (Griffon and Barbaud, 1931), arsenates decrease the lead storage. Arsenic was found in the hair in considerable amount in chemical workers manufacturing a solution of sodium arsonlte (Hill and Fantng, 1948)--108,' 83 and 64 p.p.m. in 3 categories of exposed persons as compared with 13 TOXICOLOGY i p.p.m. in controls. Goidblatt and Gotdbtatt (1936) suggested that " a kind In acute poisoning arsenic is a general protoplasmic poison acting upon t, of equilibrium is readied in the hair which Is Independent of the amount of arsenic passing through the body as indicated by the markedly different various ferment processes, especially the phosphatases (Oelkers, 1937), leading to dimintslted oxidation and tissue respiration. It has also urinary excretion ", a paralytic action on smooth muscle and thus acts as a vascular poison, In a case of subacute poisoning of several weeks* duration, Heyndrickx leading to haemorrhage (Nonnenbiuch el al., 1936). In tire cell, the (1933) found the greatest amount of arsenic in the proximal 3 cm, and from toxic effect is exerted on the chromosomes, particularly--according lo one-tenth to one-twentieth less in the more distal parts of the hair, a finding Bucher (1940)--as a blockage of the mitotic metaphase, a property which it which he considered to suggest that the duration of the intake had been sliares with colchicum. It is believed by some authorities that the immediate longer than the case history indicated. effects on tfie gastro-intestinal mucous membrane are due to increased per The blood of normal women, according to Gutlunann and Grass (1933), meability of the capillaries. contains 20--100 pg. of arsenic per 100 g., and since they found a consider* In industry, acute poisoning from solid arsenic is rare ; subacute and able increase during menstruation and lltc early months of pregnancy, they chronic poisoning usually arises from exposure lo itfsciiic-comaining dust and concluded that arsenic seems to have a direct relationship to growing tissue fume. T'hc most dangerous arsenical compound, no! used as such but end cell proliferation. In women with carcinoma there was an average occurring as the result of accident, is arsine, or hydrogen nrscniic, a powerful increase of 41 percent over that of the inlcrmcnstruul normal value. In rats, haemolytic agent. about 80 per cent of the orseuic In tlie blood is concentrated in the red corpuscles. ARSENICAL POISONING IN ANIMALS Cows' milk contains amounts of arsenic varying between 32 and 60fig. per Acule.--A wide variation of toxicity has been reported in various animal L. (Hove el <il., 1938). y species ami even in strains of tho same species ; both Ihc particle size and EXCRETION the amount of impurity have been found lo inllucncc Ihc L.D. ,, dose. From the investigations of Harrison et al. (1938) it appears that the strain variation Arsenic is excreted slowly, some appearing in the urine and, to a smaller is less marked in the mouse titan in other animals. They also found that extent, in the faeces within 24 hours, but a large proportion of the amount solutions or arsenic trioxide are many times more toxic than the dry powder, absorbed is stored in the tissues and eliminated at varying intervals of time. and that the high purity compound was less irritant to the gastro-intestinal The normal value of urinary arsenic for persons with no known exposure tract than die crude sample, possibly on account of the presence of impurities has been variously calculated as 0 014 mg. per L. (Webster, 1941); 0-017 mg. such as antimony. Gastro-intestinal damage, as evidenced by severe con of As,0> per 100 ml. (Watrous and McCaughcy, 1945) ; and 0-13 mg. vulsions and retching, and haemorrhage of the stomach and intestines was a per L. (Pinto and McGill, 1953). According to Grollman 0938) there is marked feature of the crude arsenic Irioxide, while tlie pure preparation practically no difference in the urinary arsenic content of adults and children. caused much less discomfort and only slight reddening of the gastric mucosa. . The urinary arsenic of workers exposed to arsenic may show tmicli higher The ultimate L.D. ,,, however, was less for the pure than tlie crude prepara values than non-exposed persons. Pinto and McGill found levels of an tion (39-4 mg. of arsenic per kg. as compared with 42-9). In the liver, fatty average of 0-82 mg. per L. as compared with 0-13 for the controls, but degeneration, cell necrosis and reparative changes following acute injury by Stated that evidence ofsystemic poisoning is rare even with a level of4-5 mg. arsenic have been observed (Bussing, 1941). ucc 0321 46 TOXICITY OF INDUSTRIAL MRTAI.S Arsenic trichloride (AsCl,) a liquid cviiporalinu with emission of dense while fumes, causes n severe conjunctival reaction with chcmosis mul necrotic cojneal lesions{Ulnlo, I94G). (r) /Inine, In n case reported by Dernelil, Stead and Nan (11141), intense initathm of (lie eyes, will' palpebral oedema, occurred in ft inehiiTelineiy t where fume was accidentally generated. Arsine was thouaht lo be lire most, active agent but siibine and sulphur hytlritles were also present. ; (,/) Oiaiwlc ArxcnUals. The extreme toxicity lo tire eyes of some Irivalent organic compounds is due, according to Duke Elder (1954) lo their rapid linkage with the sulphydryl groups lit proteins and enzymes essential for carbohydrate metabolism, a view also held by Dixon and Needham (1946). Hie most virulent is Lewisite (chlorovinyldichloronrsinc), once intended but not used fordtemical warfare. Chronic.--The chronic symptoms observed in workers exposed to arsenic and its compounds arc related chiefly to the skin, mucous membranes, gastro-intcstinal and nervous systems, and in a few cases disorders of the circulatory system and the liver have been recorded. German observers have described many of these manifestations from the use of arsenic as an insecticide, particularly in wine dressers (Dorle and Ziegler, 1930; jjehorndorIT, I93S; von Pein, 1940;'von Pein and Daurhcnn, 1943) though it has been suggested that the arsenic poisoning of wine dressers is not due so much lo inhalation or skin contact, but as the result of ingestion of contaminated wine. The question of a potential carcinogenic action of arsenic on organs other tlian the skin has been much debated. The recorded cases of caremomn of the lung, larynx, viscera, and multiple tumours of the skin or visccra.~or both, associated with chronic absorption of arsenic are strongly suggestive of such a relationship, but some "adjuvant factor** in the metabolism or hormone balance of the sufferer or in the susceptibility of the affected tissues appears to be also concerned. ~ SYMPTOMS OF CHRONIC INDUSTRIAL POISONING SKIN LESIONS Lesions of Ihc skin in association with industrial exposure to arsenic were described as long ago as 1728 by Mcnckcl (the so-called lliitten-Krillzc). During Ihc nineteenth century many cases of erythematous, pustular, or even ulcerative or gangrenous lesions were described, chiefly from Ihc manufacture or use of Schweinfurtcr Green but also of other arsenical materials. Vignc (1930), describing the cutaneous lesions occurring during the manu facture of insecticides, considered that the most hazardous compounds irt this respect were arsenic trioxide anil Paris Green; sodium arsenite, however, has also been found potent in producing skin lesions of very varied character. Lconcini (1933) described ulceration of Ihe hands and feet, scrotum and perineum from its use ns a vermin killer, and Tamponi (1935) reported erythema, papules and ulceralions from its use as an insecticide. The inorganic arsenical compounds have been regarded by tire majority of observers as primary cutaneous irritants, not sensitizers. Schwartz et at. ARSENIC AND ARSINE 47 (1947) classified arsenic disulphide, sodium arsenate and ;nsenile and potassium arsenate as piim.ny iiiil.mls, but also designated ai -.cmiat com pounds in general as "lire piiueipal sensitizers met with in industry", llofmtpiist (1951), while unable to express an opinion on (he sensitizing capacity of every individual inorganic uiscnical compound, found that the trioxide and pcnioxidc were deiinilcly able lo produce sensitivity; he con sidered that this capacity was shared to a large extent by other compounds of arsenic, tire sensitization being dependent to some degree on Ihc intensity of the exposure. The question as to whether inorganic arsenical compounds can produce sensitivity lo organic compounds has been discussed by Junes (1940). On the basis of two cases--workers in an arsenic mine, who showed skin reactions tl years later following an injection of neonrsphenamine--Jones suggested that previous industrial poisoning may provide the mechanism for later sensitization to organic arscnicals. Nature of (he skill lesions.--Acute and subacute dermatitis is more common than the chronic or subchronic types. In the initial stages, which may arise in less lhan a week or only after years of employment, erythema, associated with burning and itching, is sometimes most intense around the follicles, giving the skin a spotted appearance; when occurring on the face, accom panied by swelling, this may disappear without further development or may be followed by papular and vesicular eruptions. Pustular folliculitis may be accompanied by marked serous discharge, especially in areas exposed to rubbing or chafing, resulting in the formation of crusts. In some cases these lesions heal within a week leaving only slight pigmentation and desquamation; in others Ihc skin becomes lichcuilicd and liable to form new foci of inflammation even after cessation of exposure. In the cases described in great detail by Iloimquisl (1951) where Ihe exposure was related to the metallurgical working of copper ore in smelling works in Sweden, live dermatitis was mainly localized to the areas of greatest exposure--the face, neck, forearms, wrists and hands. It also occurred on Ihc scrotum and thighs, the tipper part of Ihe chest and back and the lower legs. Recurrences in employees removed to departments witli a lesser risk of exposure lo arsenic suggested Hint song: of the lesions were due to sensi tization; this was suptuiricd by the resulls of patch tests, in which eczema tous reactions were produced by arsenical compomuls. A less acute but very prominent feature of skin lesions due to arsenic is hyperkeratosis, often accompanied by hypci hidrosis, especially of the palms nivil soles. Under the name liypetkeratosis, VVatvous and McCaughcy (1945) included cracking skin, thickness and dryness of skin, and warts. A diffuse branny desquamation of the skin of the trunk and extremities with dark, deeply pigmented areas has also been described (llcyman ct ai, 1956) and has been likened to dial of Addison's disease. A case of arsenical ntekmosh in a glass worker who nlso suffered from silicosis wus described by Gilje (1951). In some areas the pigmentation alternated with depigmentation ("rain-drop" pigmentation); in others, especially the hands and feet, it showed a striped appearance. It was assumed that the inhaled silica-containing dust also contained arsenic. The 43 T0XJC1TY OF INDUSTRIAL METALS nature tmd causation of the melanosis Inis been investigated by several observers dating from Wyss (1390) ami Cans (1915) onwards. Osborne (1925), snmmuruing bis own findings and comparing them with those of the earlier observers, wills whom he ugioed on the whole, concluded that the pigment contained no arsenic but lipoids and melanin derived from cell metabolism, not from the " products of brokendown blood ", and lhat it arose chiefly in Ihe cerium and to a lesser cxlcnt in the epidermis, by an indirect action of arsenic on tire mother substance of melanin. Uuchanan (1961) remarks that melanosis is-certainly an indication of systemic absorption of arsenic^ goaemfiy over a lengthy period, and not the result oflocal action. The nails.--The presence of white striae in Hie fingernails, described by Mecs (1919) Iras come to be regarded as abnost a diagnostic accompaniment of arsenical polyneuritis. Meet observed this broad white band on alt the fingernails or 3 eases of attempted murder or suicide by arsenic and staled lhat its presence in association wills polyneuritis was confirmatory of the diagnosis of arsenical poisoning; it was still distinct long after Ihe dis appearance of arsenic from the urine. In the eases of Heyman el at (1956), all of those wito had had symptoms of arsenical intoxication for 6 weeks or more, showed this phenomenon; it was not present in 4 patients observed for less than that time. These authorities believe that an approximate estimation of the exposure to arsenic could be made from the distance of the lines from Ihe base of the nail; but there was no evidence that the actual growth of Ihe naif was retarded by arsenical neuropathy. In 1 patient the time of migration of the lines to Ihe free edge of live nail was 5 months (the approximate time for the nail to grow from the matrix to the free edge in normal persons). Nevertheless, examination of 2 oilier patients with Mcer' lines showed no arsenic in the hair or urine, indicating that these bands are not pathognomonic of arsenical intoxication. Cancer of the skin.--'The association of arsenic with skin cancer was reported by Hutchinson (1837), in relation to the internal administration of arsenic over loin* periods, and h.is been conlirmed by many authorities since 1 that time, especially from Fowler's solution (Arltclger mid Kremen, 1951) ' and other arsenical medicinal preparations (Sommers and McManus, 1953). Skin cancer from external contact with arsenic-containing stibsliinces in industry has been relatively rarely reported: I.eilch and Kennaway (1922), thougli 11mV had succecdcdln prodnei111; a typic.iIsi|uanuhis-cell cnrcinun a in animals by Ihe external application of potassium arscnilc in akohol, staled that only Iwo instances were on record up lo that lime which could reasonab.y be attributed to employment with arsenic ~GoiTi were workmen dealing with * sheep dip. I the scries of eases of skin cancer recorded by Sommers and McManus * (mf), most were associated with die medicinal use of arsenic; only2were occupational lit origin. One of these had used icail arsenate during hiswo k ns an electroplatcr iiml had shown multiple keratoses ofTlie hands for 5 years before biopsies of a lesion of the thumb showed hyperkeratosis and epithelial r~ hvnemlasi.i. Following amputation an invasive epidermoid carcinoma was found to be present. AItSUN1C AND ARSINE 49 Neubatter (1947) cotlcclcd 143 published cases of arsenical epithelioma following medication with arsenic for diseases of Ilie st m 7psoi iasis was" predominant) and other conditions. _T(te most common form "was again'' Fowler's solution (potassium in senile I per ccnt~c~ilui1alcd~aV~~A sT0 A Arsenic trioxide was also-given ns [nils; Donovan's solution was a com bination of the iodides of arsenic and mercury. Nature of the carcinomatous lesions.--Among the varying types of arsetllcatxaricgr~PfHre~st:Tn. epithelioma'developing on the site of keratoses (Hie ** Hutchinson type") is the commonest. The keratolic lesions may have existed for many years Itefure they begin lo undergo malignant change lo epithelioma, usually of Ihe squamous type. Such lesions have also been recorded as developing in patches of psoriasis, and even in normal skim af arsi basal-cell type and of a low-grade niali gnancy, and with a chronic " precancerous dermatitis " (Bowen's disease i, described by Bowen in 1912, is MUCOUS MEMDUANES Dermatitis of the face and eyelids is sometimes accompanied by con junctivitis, with redness, swelling and pain. Two cases of severe kerato conjunctivitis were described by Paufique and Jlonamonr (1946) following exposure to calcium arsenate as an insecticide. In one ease corneal anaesthesia was accompanied by a corneal ulcer. There may also be irrita tion of llie nose and pharynx, causing acute or chronic rhinitis, and of the bronchial passages. Perforation of the nasal septum was described by Davis (1917) and by Dunlap (1921) in workers employed in copper smelting. The actual perfora tion is in most cases preceded by slight epistaxis, some irritation of tire nose, and the formation of crusts owing to the resultant obstruction to nasal breatiling, pharyngitis and possibly low-grade laryngitis. The perforation develops from a white slightly elevated area about 5 mm. in diameter followed by necrosis on both sides of llie septum, when the cartilage dis appears from dystrophy. It was suggested by Dunlap that the arseniccontaining dust breathed into the nose and coming into contact with the moist membrane forms nrsenious acid, which causes necrosis of the septal mucosa, and by Pinto and McGill (1951) who observed similar eases in llvcir workers exposed lo arsenic Irioxide, that the huge particles (over 5-5p) which form a substantial part of the dust, readily impinge on the septum. GASTRO-INTESTINAL DISTURBANCE True gaslro-cnterilis is not a common occurrence in industrial chronic arsenical poisoning. Pinto and McGill (I95J) found only one case among (heir workers with arsenic Irioxide, bul digestive disturbance, as shown by nausea and vomiting, is occasionally reported. A case itcserilicd by Mayers (1954) in which severe gustro-inlestinul symptoms were predominant was unusual in that it apparently remained undiagnosed for more titan 20 years in cpito of numerous admissions lo hospital for disorders suggestive of 2130 i X ! t; '( . ,t- h\ 8'.'i I. O Sr to O O > JO TOXICITY OP INDUSTRIAL METALS arsenical poisoning. The man's exposure to arsenic in the form of I'arh Green powder had been heavy anJ included (fie possibility of inhalation. Ingestion, and skin absorption. The gaslro-lutcslmal dislurhance began soon after he started work, with acute colic and !menutomesis. He was found to have a itenelitiling gastric nicer which healed but returned when lie resumed work and disappeared only when exposure ceased entirely. During his 20 yean of more or less Intermittent exposure he had repealed attacks of exfoliative dermatitis; these ulso disappeared when exposure ceased but left permanent trophic skin changes with discoloration. Other symptoms characteristic of arsenical poisoning were also present--conjntteI ivitis, upper respiratory irritation end polyneuritis--and death was finally due to cardio vascular degeneration. PERIPHERAL NEURITIS The symptoms of peripheral neuritis following exposure to arsenical com pounds in industry, though infrequent, an identical with those recorded as due to ingestion (Kclynack el of., 1900) and others. Unlike the pcripherel neuritis of lead poisoning, in which pain and disturbance of sensibility are usually absent, arsenical polyneuritis is accompanied by pain, with burning and tenderness in the aflccicd limbs, and difficulty in walking. These symptoms were present in the cases described by Heyman et al. (1956), 7 of which were said to be due to direct contact with arsenate sprays or dusts. Some of the cases had an initial stage In which the symptoms were those of acute poisoning--nausea, vomiting and diarrhoea--but in the 7 industrial workers the onset was gradual, with development of sensory disturbances in the extremities--numbness, tingling and " pins and needles "--followed by severe symmetrical weakness in the feet and legs. As in the cases described by Hassin (1930), high levels of arsenic were found in (lie hair and also in the urine--2-5 mg. per 100 g. in the hair, and 0-1-6 mg. in a 21-hour speci men of urine. In Hassin's cases, where the source of the arsenical poisoning was not determined, the diagnosis was confirmed also by (he presence of ** Mces' lines " on the nails. The difficulty in distinguishing between the polyneuritis of lead poisoning and that of arsenic is emphasized by a case recorded by llarbier cl al. (1912). The polyneuritic symptoms were at first diagnosed as due to lead poisoning, since the man had used lead arsenate os an insecticide spray. The out standing feature of this cose was motor weakness of the hands and difficulty in walking; Site diagnosis of arsenical polyneuritis rested chiclly on the evidence of an initial gastro-intcstinnl disturbance and tltc presence of Mces' bands on the nails; there was no hyperkeratosis and no tingling or numb ness of the hands and feet. THE LIVER Involvement of the liver, with jaundice, sometimes ascites, was noted in early observations us a sequela of arsenical medication. Hutchinson < 1887), for example, described liver injury resembling cirrhosis following arsenical treatment of chronic eczema. One of the first records of cirrhosis front live industrial use of arsenic was that ofDoric and Ziegler (1930) in wine dressers, | 1 j t | ' > [ i j j t ' l j I ' ARSENIC AND ARSINE 51 though, us already remaiked, ns In that of many successive observations on wine ilrossois in Germany, the ingestion of arsenic-contaminated wine is now believed to play a mote impurtnnl part than the actual expostno to (ho arsenical insecticides. Ilarren and 11dolein (1913) slated tltal the increase in liver injury among employees In llto wino industry since the introduction of arsenic spraying was to be largely attributed to the elI'ect of arsenic, and that this injury was degenerative in character, reparable in some cases, but leading finally to cirrhosis. On the basis of the Takala-Ara reaction they found that 70 per cunt of the workers examined showed a variable degree of liver injury though only 36 per cent showed a definite cirrhosis, lu a fatal case with ascites a special feature was live presence of discrete parenchymal necrosis with reparative connective tissue formation. Tlicy conceded, however, tliat live influence of ingested alcohol could not be entirely excluded. This reservation applies also to the supplemental toxic action or nicotine, phosphorus and metabolic disturbance in similar observations by German authorities in the early years of this century. DISORDERS OF THE HEART AND CIRCULATION The subjective and clinical evidence for a primary cardiac injury in arsenic workers is not very definite, but the electrocardiograph has revealed abnormalitics similar to those observed in animals fed on subtoxic amounts of arsenic (Butzengeiger, 1910 and 1919; HadjolofT, 1910 and 1957). Among 216 wine dressers using arsenical insecticides. Dutzcngcigcr found 55, who showed other symptoms of chronic arsenical poisoning, to have an abnormal electrocardiogram indicating a toxic myocardial effect. Among these were 36 whose myocardial injury was severe, and some of them were suffering also from peripheral disturbances indicative of endo-augiitis--gan grene of the extremities, atrophic acrodermatitis and other less severe symptoms of peripheral damage. Butzengeiger described the endo-angiitis as indistinguishable from severe arteriosclerosis or endo-angiitis obliterans. THE CARCINOGENIC ACTION OF ARSENIC Examples of cancer of (he skin in patients receiving arsenical medication and in arsenic workers having external contact with arsenical compounds have already been described, and there seems little doubt that carcinomas of the skin do arise especially on the sites of arsenical keratosis. The evidence for arsenical cancer of other organs is not so universally accented, especially willy* regard to occupational exposure^ 'live view formerly held that the high incidence of lung cancer among the miners of Schneeberg and Joachimslal were due to arsenic has been mote or less discarded in favour of radioactivity ns the carcinogenic agent, partly because of the absence of characterislie ursenic.it skin changes. Huepcr (1942) staled that " the possibility of a causal relation between live inhalation of arsenic dust and live development of pulmonary nmlnmancv may be con ceded but the probability of its relationship is small ", In a clinical and experimental study by Perry i-j al. (19-18) among workers J J2 TOXICITY OP INDUSTRIAL MITfAl.S in a factory manufacturing a solution of sodium arsenate, despite the previous Ending by Hill and Failing (1918) in the same factory that on a statistical basis there was a greater tendency for arsenic workers to die of cancer than for other groups, radiographic examination did not reveal anv ease of bronchogenic carcinoma. More recent investigations by Kolb (1956, 1957) and Braun (195B) Jo, however, show a delinilcly higher incidence among wine dressers in Germany. Roth found 10 eases of bronchial carcinoma among 30 workers with arsenical skin lesions. Braun, comparing the incidence of bronchial cancer in those suffering front arsenical dermatoses during the years 1951-1957 with that between 1939 and 1952 found a greatly increased incidence in the later years. Out of 16 of an average age of 52 years, all showing keratosis and some also melanosis, pre-malignant or malignant skm changes, 9 had inoperable bronchial carcinoma. Tumours of other organs, most frequently in association with arsenical .cancers of the skin, have also been described, notably by Sommers and McManus (1953) in their review or 18 cases ofvisceral cancer reported in various countries up to that year. Among these, or which only 5 were Industrial workers, there were 7 cases of pulmonary tumour, J oi the mouth and tongue, 3 of the ureter and bladder, 2 of the breast, 2 of the oesophagus, 1 of the stomach and 1 of the cervix uteri. Only 6 of these had associated cancer of the skin. In their own scries of 27 eases, of which only 2 were occupational, many had not only multiple skin cancers, but also, among 6 who were submitted to autopsy, 4 had separate internal cancers of the bladder, prbstatc, oesophagus, colon, kidney and chest wall; in 3 eases the growths were multiple. Roth (1956) also noted 5 cases of malignant liver tumour and one of oesophageal cancer associated with liver cirrhosis, ami in Braun's senes there was 1 case of carcinoma of the bile ducts also associated with cirrhosis of the liver, and 1 of a suspected sarcoma of the cervical lymph glands. Rosset (1958) has recorded a case of multiple internal carcinomas in a man who more than 20 years previously had used lead arsenate to spray potatoes, and had at that time developed keratotic lesions on the palms of his hands. The latent period of development of malignant tumours of possible arsenical origin is long--13-50 years according to Sommers and McManus (1953). 13-22 years in (he experience of Roth (1956) and llraun (1958). The most disputed point in the problem of the potential carcinogenicity of arsenic appears to be whether il is a direct agent, or whether it is dependent on other factors such as tissue susceptibility, skin sensitivity, photosensitivity, or other external or internal metabolic cfTccIs. On this point it docs not seem possible at present to arrive at a direct conclusion. Even Goldblatl and Goldblatl (1956) in their admirable review of industrial carcinogenesis, and witIt their extremely wide experience of the subject, can only say that '* the arsenical compound which produces no tumour in a workman is not a carcinogen for him until he, in a given tissue, brings about u meeting between a cell in the appropriate slate and the compound in u sullicicnt concentration ... one!,.. from the very few eases of occupational arsenical cancer hitherto reported it may be considered that a combination of appro priate slate and sufficient concentration is rare ", ARSENIC AND ARSINE S3 Arsine Arsine (arscniurcttcd hydrogen; hydrogen arsenide; AsH,) is not an industrial product in the economic sense, but an accidental evolution when ever nascent hydrogen is liberated in the proximity or trivalcnt arsenic. PROPERTIES Arsine is a colourless inflammable gas with a slight garlic-like odour, depositing arsenic on exposure to light and moisture (threshold limit value for an 8-hour working day, 0 05 p.p.m.). Concentrations of 3-10 p.p.m. will produce slight symptoms after several hours' exposure and 16-30 p.p.m. are dangerous according to Doig (1938). OCCURRENCE Since arsenic is present as a contaminant of many ores--zinc, lead, copper, antimony, gold, silver and tin--the formation of arsine occurs most fre quently In the mctallurgic industry, particularly front the action of acid on . arsenic-bearing metal. It may also occur where the hydrogen ion is formed by hydrolysis. as~in the reaction of moisture with calcium arsenide present as an impurity in fcrrosilicon (Hake, 1910); in the process of wetting of aluminium and phosphate dross (Nau, 19-18; Spolyar and Harger, 1950) ; in lead refining (Wills, 1948; Banik, 19S6); and in the purification of tin (Macaulay and Stanley, 1956). In this last process reports from those of Legge (1924) onwards had previously recorded 30 cases of arsine poisoning with 12 deaths. Its occurrence has also been described during cyanide extraction of gold (Buhner et a!.. 1940); in the process of leaching of zinc (McKinslry and Hickes, 1957); very frequently in the cleaning out of furnaces and tanks (Wills, 1943; Hamilton and Hardy, 1949; Troisi, 1950); and even from mishandling of arsenical insecticides (Moliacck and Stajduhar, 1951). TOXICOLOGY The fatal cflccls of arsine were first reported in 1815, when Gchlcn, a chemist, died from inhaling it in his laboratory. It is a powerful haemolytic poison with both acute and also chronic exposure. In the acute form ibe moi lality rate is high. Muchlbcrger et a!. (1928) slated that 20 percent of 215 eases of poisoning occurring sinco 1815 had been futul; Spolyar and Harger (1950) estimated a mortality of 12 among 30eases recorded between 1923 and 1911, while during (lie years 1945-1946, 13 eases, 4 of them fatal--a mortality of 31 per cent--were recorded in the Annual Reports of the Chief Inspector of Factories. ACUTE l'OISONING The outstanding initial features of acute arsine poisoning arc malaise, abdominal cramps, nausea and vomiting, and a red staining of the conjunc tiva ; this pigmentation, according to Macaulay and Stanley (1956), is not