Occurrence and Uses
In nature, Indium (In) is widely distributed and occurs most frequently together with zinc minerals (sphalerite, marmatite, christophite), its chief commercial source. It is also found in the ores of tin, manganese, tungsten, copper, iron, lead, cobalt and bismuth, but generally in amounts of less than 0.1%.
Indium is generally used in industry for surface protection or in alloys. A thin coat of indium increases the resistance of metals to corrosion and wear. It prolongs the life of moving parts in bearings and finds wide use in the aircraft and automobile industries. It is used in dental alloys, and its “wettability” makes it ideal for plating glass. Because of its resistance to corrosion, indium is utilized extensively in making motion picture screens, cathode ray oscilloscopes and mirrors. When joined with antimony and germanium in an extremely pure combination, it is widely used in the manufacture of transistors and other sensitive electronic components. Radioisotopes of indium in compounds such as indium trichloride and colloidal indium hydroxide are used in organic scanning and in the treatment of tumours.
In addition to the metal, the most common industrial compounds of indium are the trichloride, used in electroplating; the sesquioxide, used in glass manufacture; the sulphate; and the antimonide and the arsenide used as semiconductor material.
No cases have been reported of systemic effects in humans exposed to indium. Probably the greatest current potential hazard comes from the use of indium together with arsenic, antimony and germanium in the electronics industry. This is due primarily to the fumes given off during welding and soldering processes in the manufacture of electronic components. Any hazard arising from the purification of indium is probably attributable to the presence of other metals, such as lead, or chemicals, such as cyanide, used in the electroplating process. Exposure of the skin to indium does not seem to present a serious hazard. The tissue distribution of indium in various chemical forms has been studied by administration to laboratory animals.
The sites of highest concentration were kidney, spleen, liver and salivary glands. After inhalation, widespread lung changes were observed, such as interstitial and desquamative pneumonitis with consequent respiratory insufficiency.
The results of animal studies showed that the more soluble salts of indium were very toxic, with lethality occurring after administration of less than 5 mg/kg by way of parenteral routes of injection. However, after gavage, indium was poorly absorbed and essentially non-toxic. Histophathological studies indicated that death was due primarily to degenerative lesions in the liver and kidney. Minor changes in the blood have also been noted. In chronic poisoning by indium chloride the main change is a chronic interstitial nephritis with proteinuria. The toxicity from the more insoluble form, indium sesquioxide, was only moderate to slight, requiring up to several hundred mg/kg for lethal effect. After administration of indium arsenide to hamsters, the uptake in various organs differed from the distribution of ionic indium or arsenic compounds.
Safety and Health Measures
Preventing the inhalation of indium fumes by the use of correct ventilation appears to be the most practical safety measure. When handling indium arsenide, safety precautions such as those applied for arsenic should be observed. In the field of nuclear medicine, correct radiation safety measures must be followed when handling radioactive indium isotopes. Intoxication in rats from indium-induced hepatic necrosis has been reduced considerably by administration of ferric dextran, the action of which is apparently very specific. The use of ferric dextran as a prophylactic treatment in humans has not been possible owing to a lack of serious cases of industrial exposures to indium.
Occurrence and Uses
Germanium (Ge) is always found in combination with other elements and never in the free state. Among the most common germanium-bearing minerals are argyrodite (Ag8GeS6), containing 5.7% germanium, and germanite (CuS·FeS·GeS2), containing up to 10% Ge. Extensive deposits of germanium minerals are rare, but the element is widely distributed within the structure of other minerals, especially in sulphides (most commonly in zinc sulphide and in silicates). Small quantities are also found in different types of coal.
The largest end use of germanium is the production of infrared sensing and identification systems. Its use in fibre-optical systems has increased, while consumption for semiconductors has continued to decline due to advances in silicon semiconductor technology. Germanium is also used in electroplating and in the production of alloys, one of which, germanium-bronze, is characterized by high corrosion resistance. Germanium tetrachloride (GeCl4) is an intermediate in the preparation of germanium dioxide and organogermanium compounds. Germanium dioxide (GeO2) is used in the manufacture of optical glass and in cathodes.
Occupational health problems may arise from the dispersion of dust during the loading of germanium concentrate, breaking up and loading of the dioxide for reduction to metallic germanium, and loading of powdered germanium for melting into ingots. In the process of producing metal, during chlorination of the concentrate, distillation, rectification and hydrolysis of germanium tetrachloride, the fumes of germanium tetrachloride, chlorine and germanium chloride pyrolysis products may also present a health hazard. Other sources of health hazards are the production of radiant heat from tube furnaces for GeO2 reduction and during melting of germanium powder into ingots, and the formation of carbon monoxide during GeO2 reduction with carbon.
The production of single crystals of germanium for the manufacture of semiconductors brings about high air temperatures (up to 45 ºC), electromagnetic radiation with field strengths of more than 100 V/m and magnetic radiation of more than 25 A/m, and pollution of the workplace air with metal hydrides. When alloying germanium with arsenic, arsine may form in the air (1 to 3 mg/m3), and when alloying it with antimony, stibine or antimonous hydride may be present (1.5 to 3.5 mg/m3). Germanium hydride, which is used for the production of high-purity germanium, may also be a pollutant of the workplace air. The frequently required cleaning of the vertical furnaces causes the formation of dust, which contains, apart from germanium, silicon dioxide, antimony and other substances.
Machining and grinding of germanium crystals also give rise to dust. Concentrations of up to 5 mg/m3 have been measured during dry machining.
Absorbed germanium is rapidly excreted, mainly in urine. There is little information on the toxicity of inorganic germanium compounds to humans. Germanium tetrachloride may produce skin irritation. In clinical trials and other long-term oral exposures to cumulative doses exceeding 16 g of spirogermanium, an organogermanium antitumour agent or other germanium compounds have been shown to be neurotoxic and nephrotoxic. Such doses are not usually absorbed in the occupational setting. Animal experiments on the effects of germanium and its compounds have shown that dust of metallic germanium and germanium dioxide causes general health impairment (inhibition of body weight increase) when inhaled in high concentrations. The lungs of the animals presented morphological changes of the type of proliferative reactions, such as thickening of the alveolar partitions and hyperplasia of the lymphatic vessels around the bronchi and blood vessels. Germanium dioxide does not irritate the skin, but if it comes into contact with the moist conjunctiva it forms germanic acid, which acts as an eye irritant. Prolonged intra-abdominal administration in doses of 10 mg/kg leads to peripheral blood changes.
The effects of germanium concentrate dust are not due to germanium, but to a number of other dust constituents, in particular silica (SiO2). The concentrate dust exerts a pronounced fibrogenic effect resulting in the development of connective tissue and formation of nodules in the lungs similar to those observed in silicosis.
The most harmful germanium compounds are germanium hydride (GeH4) and germanium chloride. The hydride may provoke acute poisoning. Morphological examinations of organs of animals which died during the acute phase revealed circulatory disorders and degenerative cell changes in the parenchymatous organs. Thus the hydride appears to be a multi-system poison that may affect the nervous functions and peripheral blood.
Germanium tetrachloride is a strong irritant of the respiratory system, skin and eyes. Its threshold of irritation is 13 mg/m3. In this concentration it depresses the pulmonary cell reaction in experimental animals. In stronger concentrations it leads to irritation of the upper airways and conjunctivitis, and to changes in respiratory rate and rhythm. Animals which survive acute poisoning develop catarrhal-desquamative bronchitis and interstitial pneumonia a few days later. Germanium chloride also exerts general toxic effects. Morphological changes have been observed in the liver, kidneys and other organs of the animals.
Safety and Health Measures
Basic measures during the manufacture and use of germanium should be aimed at preventing the contamination of the air by dust or fumes. In the production of metal, continuity of the process and enclosure of the apparatus is advisable. Adequate exhaust ventilation should be provided in areas where the dust of metallic germanium, the dioxide or the concentrate is dispersed. Local exhaust ventilation should be provided near the melting furnaces during the manufacture of semiconductors, for example on zone-refining furnaces, and during the cleaning of the furnaces. The process of manufacturing and alloying monocrystals of germanium should be carried out in a vacuum, followed by the evacuation of the formed compounds under reduced pressure. Local exhaust ventilation is essential in operations such as dry cutting and grinding of germanium crystals. Exhaust ventilation is also important in premises for the chlorination, rectification and hydrolysis of germanium tetrachloride. Appliances, connections and fittings in these premises should be made of corrosion-proof material. The workers should wear acid-proof clothing and footwear. Respirators should be worn during the cleaning of appliances.
Workers exposed to dust, concentrated hydrochloric acid, germanium hydride and germanium chloride and its hydrolysis products should undergo regular medical examinations.
Chemically, gallium (Ga) is similar to aluminium. It is not attacked by air and does not react with water. When cold, gallium reacts with chlorine and bromine, and when heated, with iodine, oxygen and sulphur. There are 12 known artificial radioactive isotopes, with atomic weights between 64 and 74 and half-lives between 2.6 minutes and 77.9 hours. When gallium is dissolved in inorganic acids, salts are formed, which change into insoluble hydroxide Ga(OH)3 with amphoteric properties (i.e., both acidic and basic) when the pH is higher than 3. The three oxides of gallium are GaO, Ga2O and Ga2O3.
Occurrence and Uses
The richest source of gallium is the mineral germanite, a copper sulphide ore which may contain 0.5 to 0.7% gallium and is found in southwest Africa. It is also widely distributed in small amounts together with zinc blendes, in aluminium clays, feldspars, coal and in the ores of iron, manganese and chromium. On a relatively small scale, the metal, alloys, oxides and salts are used in industries such as machine construction (coatings, lubricants), instrument making (solders, washers, fillers), electronics and electrical equipment production (diodes, transistors, lasers, conductor coverings), and in vacuum technology.
In the chemical industries gallium and its compounds are used as catalysts. Gallium arsenide has been widely used for semiconductor applications including transistors, solar cells, lasers and microwave generation. Gallium arsenide is used in the production of optoelectronic devices and integrated circuits. Other applications include the use of 72Ga for the study of gallium interactions in the organism and 67Ga as a tumour-scanning agent. Because of the high affinity of macrophages of the lymphoreticular tissues for 67Ga, it can be used in the diagnosis of Hodgkin’s disease, Boeck’s sarcoid and lymphatic tuberculosis. Gallium scintography is a pulmonary imaging technique which can be used in conjunction with an initial chest radiograph to evaluate workers at risk of developing occupational lung disease.
Workers in the electronics industry using gallium arsenide may be exposed to hazardous substances such as arsenic and arsine. Inhalation exposures of dusts are possible during the production of the oxides and powdered salts (Ga2(SO4)3, Ga3Cl) and in the production and processing of monocrystals of semiconductor compounds. The splashing or spilling of the solutions of the metal and its salts may act on the skin or mucous membranes of workers. Grinding of gallium phosphide in water gives rise to considerable quantities of phosphine, requiring preventive measures. Gallium compounds may be ingested via soiled hands and by eating, drinking and smoking in workplaces.
Occupational diseases from gallium have not been described, except for a case report of a petechial rash followed by a radial neuritis after a short exposure to a small amount of fumes containing gallium fluoride. The biological action of the metal and its compounds has been studied experimentally. The toxicity of gallium and compounds depends upon the mode of entry into the body. When administered orally in rabbits over a long period of time (4 to 5 months), its action was insignificant and included disturbances in protein reactions and reduced enzyme activity. The low toxicity in this case is explained by the relatively inactive absorption of gallium in the digestive tract. In the stomach and intestines, compounds are formed which are either insoluble or difficult to absorb, such as metal gallates and hydroxides. The dust of the oxide, nitride and arsenide of gallium was generally toxic when introduced into the respiratory system (intratracheal injections in white rats), causing dystrophy of the liver and kidneys. In the lungs it caused inflammatory and sclerotic changes. One study concludes that exposing rats to gallium oxide particles at concentrations near the threshold limit value induces progressive lung damage that is similar to that induced by quartz. Gallium nitrate has a powerful caustic effect on the conjunctivae, cornea and skin. The high toxicity of the acetate, citrate and chloride of gallium was demonstrated by intraperitoneal injection, leading to death of animals from paralysis of the respiratory centre.
Safety and Health Measures
In order to avoid contamination of the atmosphere of workplaces by the dusts of gallium dioxide, nitride and semiconductor compounds, precautionary measures should include enclosure of dust-producing equipment and effective local exhaust ventilation (LEV). Personal protective measures during the production of gallium should prevent ingestion and contact of gallium compounds with the skin. Consequently, good personal hygiene and the use of personal protective equipment (PPE) are important. The US National Institute for Occupational Safety and Health (NIOSH) recommends control of worker exposure to gallium-arsenide by observing the recommended exposure limit for inorganic arsenic, and advises that concentration of gallium arsenide in air should be estimated by determining arsenic. Workers should be educated in possible hazards, and proper engineering controls should be installed during production of microelectronic devices where exposure to gallium arsenide is likely. In view of the toxicity of gallium and its compounds, as shown by experiments, all persons involved in work with these substances should undergo periodic medical examinations, during which special attention should be paid to the condition of the liver, kidneys, respiratory organs and skin.
Occurrence and Uses
Iron is second in abundance amongst the metals and is fourth amongst the elements, surpassed only by oxygen, silicon and aluminium. The most common iron ores are: haematite, or red iron ore (Fe2O3), which is 70% iron; limonite, or brown iron ore (FeO(OH)·nH2O), containing 42% iron; magnetite, or magnetic iron ore (Fe3O4), which has a high iron content; siderite, or spathic iron ore (FeCO3); pyrite (FeS2), the most common sulphide mineral; and pyrrhotite, or magnetic pyrite (FeS). Iron is used in the manufacture of iron and steel castings, and it is alloyed with other metals to form steels. Iron is also used to increase the density of oil-well drilling fluids.
Alloys and Compounds
Iron itself is not particularly strong, but its strength is greatly increased when it is alloyed with carbon and rapidly cooled to produce steel. Its presence in steel accounts for its importance as an industrial metal. Certain characteristics of steel—that is, whether it is soft, mild, medium or hard—are largely determined by the carbon content, which may vary from 0.10 to 1.15%. About 20 other elements are used in varied combinations and proportions in the production of steel alloys with many different qualities—hardness, ductility, corrosion resistance and so on. The most important of these are manganese (ferromanganese and spiegeleisen), silicon (ferrosilicon) and chromium, which is discussed below.
The most important industrial iron compounds are the oxides and the carbonate, which constitute the principal ores from which the metal is obtained. Of lesser industrial importance are cyanides, nitrides, nitrates, phosphides, phosphates and iron carbonyl.
Industrial dangers are present during the mining, transportation and preparation of the ores, during the production and use of the metal and alloys in iron and steel works and in foundries, and during the manufacture and use of certain compounds. Inhalation of iron dust or fumes occurs in iron-ore mining; arc welding; metal grinding, polishing and working; and in boiler scaling. If inhaled, iron is a local irritant to the lung and gastrointestinal tract. Reports indicate that long-term exposure to a mixture of iron and other metallic dusts may impair pulmonary function.
Accidents are liable to occur during the mining, transportation and preparation of the ores because of the heavy cutting, conveying, crushing and sieving machinery that is used for this purpose. Injuries may also arise from the handling of explosives used in the mining operations.
Inhaling dust containing silica or iron oxide can lead to pneumoconiosis, but there are no definite conclusions as to the role of iron oxide particles in the development of lung cancer in humans. Based on animal experiments, it is suspected that iron oxide dust may serve as a “co-carcinogenic” substance, thus enhancing the development of cancer when combined simultaneously with exposure to carcinogenic substances.
Mortality studies of haematite miners have shown an increased risk of lung cancer, generally among smokers, in several mining areas such as Cumberland, Lorraine, Kiruna and Krivoi Rog. Epidemiological studies of iron and steel foundry workers have typically noted risks of lung cancer elevated by 1.5- to 2.5-fold. The International Agency for Research on Cancer (IARC) classifies iron and steel founding as a carcinogenic process for humans. The specific chemical agents involved (e.g., polynuclear aromatic hydrocarbons, silica, metal fumes) have not been identified. An increased incidence of lung cancer has also been reported, but less significantly, among metal grinders. The conclusions for lung cancer among welders are controversial.
In experimental studies, ferric oxide has not been found to be carcinogenic; however, the experiments were not carried out with haematite. The presence of radon in the atmosphere of haematite mines has been suggested to be an important carcinogenic factor.
Serious accidents can occur in iron processing. Burns can occur in the course of work with molten metal, as described elsewhere in this Encyclopaedia. Finely divided freshly reduced iron powder is pyrophoric and ignites on exposure to air at normal temperatures. Fires and dust explosions have occurred in ducts and separators of dust-extraction plants, associated with grinding and polishing wheels and finishing belts, when sparks from the grinding operation have ignited the fine steel dust in the extraction plant.
The dangerous properties of the remaining iron compounds are usually due to the radical with which the iron is associated. Thus ferric arsenate (FeAsO4) and ferric arsenite (FeAsO3·Fe2O3) possess the poisonous properties of arsenical compounds. Iron carbonyl (FeCO5) is one of the more dangerous of the metal carbonyls, having both toxic and flammable properties. Carbonyls are discussed in more detail elsewhere in this chapter.
Ferrous sulphide (FeS), in addition to its natural occurrence as pyrite, is occasionally formed unintentionally when materials containing sulphur are treated in iron and steel vessels, such as in petroleum refineries. If the plant is opened and the deposit of ferrous sulphide is exposed to the air, its exothermic oxidation may raise the temperature of the deposit to the ignition temperature of gases and vapours in the vicinity. A fine water spray should be directed on such deposits until flammable vapours have been removed by purging. Similar problems may occur in pyrite mines, where the air temperature is increased by a continuous slow oxidation of the ore.
Safety and health measures
The precautions for the prevention of mechanical accidents include the fencing and remote control of machinery, the design of plant (which, in modern steel-making, includes computerized control) and the safety training of workers.
The danger arising from toxic and flammable gases, vapours and dusts is countered by local exhaust and general ventilation coupled with the various forms of remote control. Protective clothing and eye protection should be provided to safeguard the worker from the effects of hot and corrosive substances, and heat.
It is especially important that the ducting at grinding and polishing machines and at finishing belts be maintained at regular intervals to keep up the efficiency of the exhaust ventilation as well as to reduce the risk of explosion.
A ferroalloy is an alloy of iron with an element other than carbon. These metallic mixtures are used as a vehicle for introducing specific elements into the manufacture of steel in order to produce steels with specific properties. The element may alloy with the steel by solution or it may neutralize harmful impurities.
Alloys have unique properties dependent on the concentration of their elements. These properties vary directly in relation to the concentration of the individual components and depend, in part, on the presence of trace quantities of other elements. Although the biological effect of each element in the alloy may be used as a guide, there is sufficient evidence for the modification of action by the mixture of elements to warrant extreme caution in making critical decisions based on extrapolation of effect from the single element.
The ferroalloys constitute a wide and diverse list of alloys with many different mixtures within each class of alloy. The trade generally limits the number of types of ferroalloy available in any one class but metallurgical developments can result in frequent additions or changes. Some of the more common ferroalloys are as follows:
Although certain ferroalloys do have non-metallurgical uses, the main sources of hazardous exposure are encountered in the manufacture of these alloys and in their use during steel production. Some ferroalloys are produced and used in fine particulate form; airborne dust constitutes a potential toxicity hazard as well as a fire and explosion hazard. In addition, occupational exposure to the fumes of certain alloys has been associated with serious health problems.
Ferroboron. Airborne dust produced during the cleaning of this alloy may cause irritation of the nose and throat, which is due, possibly, to the presence of a boron oxide film on the alloy surface. Some animal studies (dogs exposed to atmospheric ferroboron concentrations of 57 mg/m3 for 23 weeks) found no adverse effects.
Ferrochromium. One study in Norway on the overall mortality and the incidence of cancer in workers producing ferrochromium has shown an increased incidence of lung cancer in causal relationship with the exposure to hexavalent chromium around the furnaces. Perforation of the nasal septum was also found in a few workers. Another study concludes that excess mortality due to lung cancer in steel-manufacturing workers is associated with exposure to polycyclic aromatic hydrocarbons (PAHs) during ferrochromium production. Yet another study investigating the association between occupational exposure to fumes and lung cancer found that ferrochromium workers demonstrated excess cases of both lung and prostate cancer.
Ferromanganese may be produced by reducing manganese ores in an electric furnace with coke and adding dolomite and limestone as flux. Transportation, storage, sorting and crushing of the ores produce managanese dust in concentrations which can be hazardous. The pathological effects resulting from exposure to dust, from both the ore and the alloy, are virtually indistinguishable from those described in the article “Manganese” in this chapter. Both acute and chronic intoxications have been observed. Ferromanganese alloys containing very high proportions of manganese will react with moisture to produce manganese carbide, which, when combined with moisture, releases hydrogen, creating a fire and explosion hazard.
Ferrosilicon production can result in both aerosols and dusts of ferrosilicon. Animal studies indicate that ferrosilicon dust can cause thickening of the alveolar walls with the occasional disappearance of the alveolar structure. The raw materials used in alloy production may also contain free silica, although in relatively low concentrations. There is some disagreement as to whether classical silicosis may be a potential hazard in ferrosilicon production. There is no doubt, however, that chronic pulmonary disease, whatever its classification, can result from excessive exposure to the dust or aerosols encountered in ferrosilicon plants.
Ferrovanadium. Atmospheric contamination with dust and fumes is also a hazard in ferrovanadium production. Under normal conditions, the aerosols will not produce acute intoxication but may cause bronchitis and a pulmonary interstitial proliferative process. The vanadium in the ferrovanadium alloy has been reported to be appreciably more toxic than free vanadium as a result of its greater solubility in biological fluids.
Leaded steel is used for automobile sheet steel in order to increase malleability. It contains approximately 0.35% lead. Whenever the leaded steel is subject to high temperature, as in welding, there is always the danger of generating lead fumes.
Safety and health measures
Control of fumes, dust and aerosols during the manufacture and use of ferroalloys is essential. Good dust control is required in the transport and handling of the ores and alloys. Ore piles should be wetted down to reduce dust formation. In addition to these basic dust-control measures, special precautions are needed in the handling of specific ferroalloys.
Ferrosilicon reacts with moisture to produce phosphine and arsine; consequently this material should not be loaded in damp weather, and special precautions should be taken to ensure that it remains dry during storage and transport. Whenever ferrosilicon is being shipped or handled in quantities of any importance, notices should be posted warning workers of the hazard, and detection and analysis procedures should be implemented at frequent intervals to check for the presence of phosphine and arsine in the air. Good dust and aerosol control is required for respiratory protection. Suitable respiratory protective equipment should be available for emergencies.
Workers engaged in the production and use of ferroalloys should receive careful medical supervision. Their working environment should be monitored continuously or periodically, depending on the degree of risk. The toxic effects of the various ferroalloys are sufficiently divergent from those of the pure metals to warrant a more intense level of medical supervision until more data have been obtained. Where ferroalloys give rise to dust, fumes and aerosols, workers should receive periodic chest x-ray examinations for early detection of respiratory changes. Lung function testing and monitoring of metal concentrations in the blood and/or urine of exposed workers may also be required.
Copper (Cu) is malleable and ductile, conducts heat and electricity exceedingly well and is very little altered in its functional capacity by exposure to dry air. In a moist atmosphere containing carbon dioxide it becomes coated with a green carbonate. Copper is an essential element in human metabolism.
Occurrence and Uses
Copper occurs principally as mineral compounds in which 63Cu constitutes 69.1% and 65Cu, 30.9% of the element. Copper is widely distributed in all continents and is present in most living organisms. Although some natural deposits of metallic copper have been found, it is generally mined either as sulphide ores, including covellite (CuS), chalcocite (Cu2S), chalcopyrite (CuFeS2) and bornite (Cu3FeS3); or as oxides, including malachite (Cu2CO3(OH)2); chrysocolla
(CuSiO3·2H2O) and chalcanthite (CuSO4·5H2O).
Because of its electrical properties, more than 75% of copper output is used in the electrical industries. Other applications for copper include water piping, roofing material, kitchenware, chemical and pharmaceutical equipment, and the production of copper alloys. Copper metal is also used as a pigment, and as a precipitant of selenium.
Alloys and Compounds
The most widely used non-ferrous copper alloys are those of copper and zinc (brass), tin (bronze), nickel (monel metal), aluminium, gold, lead, cadmium, chromium, beryllium, silicon or phosphorus.
Copper sulphate is used as an algicide and molluscicide in water; with lime, as a plant fungicide; as a mordant; in electroplating; as a froth flotation agent for the separation of zinc sulphide ore; and as an agent for leather tanning and hide preservation. Copper sulphate neutralized with hydrated lime, known as Bordeaux mixture, is used for the prevention of mildew in vineyards.
Cupric oxide has been used as a component of paint for ship bottoms and as a pigment in glass, ceramics, enamels, porcelain glazes and artificial gems. It is also used in the manufacture of rayon and other copper compounds, and as an optical glass polishing agent and a solvent for chromic iron ores. Cupric oxide is a component of flux in copper metallurgy, pyrotechnic compositions, welding fluxes for bronze and agricultural products such as insecticides and fungicides. Black cupric oxide is used for correcting copper-deficient soils and as a feed supplement.
Copper chromates are pigments, catalysts for liquid-phase hydrogenation and potato fungicides. A solution of cupric hydroxide in excess ammonia is a solvent for cellulose used in the manufacture of rayon (viscose). Cupric hydroxide is used in the manufacture of battery electrodes and for treating and staining paper. It is also a pigment, a feed additive, a mordant in dyeing and an ingredient in fungicides and insecticides.
Amine complexes of cupric chlorate, cupric dithionate, cupric azide and cuprous acetylide are explosive but are of no industrial or public health importance. Copper acetylide was found to be the cause of explosions in acetylene plants and has caused the abandonment of the use of copper in the construction of such plants. Fragments of metallic copper or copper alloys that lodge in the eye, a condition known as chalcosis, may lead to uveitis, abscess and loss of the eye. Workers who spray vineyards with Bordeaux mixture may suffer from pulmonary lesions (sometimes called “vineyard sprayer’s lung”) and copper-laden hepatic granulomas.
Accidental ingestion of soluble copper salts is generally innocuous since the vomiting induced rids the patient of much of the copper. The possibility of copper-induced toxicity may occur in the following situations:
Although some chemical reference works contain statements to the effect that soluble salts of copper are poisonous, in practical terms this is true only if such solutions are used with misguided or suicidal intent, or as topical treatment of extensively burned areas. When copper sulphate, known as bluestone or blue vitriol, is ingested in gram quantities, it induces nausea, vomiting, diarrhoea, sweating, intravascular haemolysis and possible kidney failure; rarely, convulsions, coma and death may result. Drinking of carbonated water or citrus fruit juices which have been in contact with copper vessels, pipes, tubing or valves can cause gastrointestinal irritation, which is seldom serious. Such beverages are acidic enough to dissolve irritating levels of copper. There is a report of corneal ulcers and skin irritation, but little other toxicity, in a copper-mine worker who fell into an electrolytic bath, but the acidity, rather than the copper, may have been the cause. In some instances where copper salts have been used in the treatment of burns, high concentrations of serum copper and toxic manifestations have ensued.
The inhalation of dusts, fumes and mists of copper salts can cause congestion of the nasal and mucous membranes and ulceration with perforation of the nasal septum. Fumes from the heating of metallic copper can cause metal fume fever, nausea, gastric pain and diarrhoea.
Chronic toxic effects in human beings attributable to copper appears only to be found in individuals who have inherited a particular pair of abnormal autosomal recessive genes and in whom, as a consequence, hepatolenticular degeneration (Wilson’s disease) develops. This is a rare occurrence. Most daily human diets contain 2 to 5 mg of copper, almost none of which is retained. The adult human body copper content is quite constant at about 100 to 150 mg. In normal individuals (without Wilson’s disease), almost all of the copper is present as an integral and functional moiety of one of perhaps a dozen proteins and enzyme systems including, for example, cytochrome oxidase, dopa-oxidase and serum ceruloplasmin.
Tenfold, or more, increases in the daily intake of copper can occur in individuals who eat large quantities of oysters (and other shellfish), liver, mushrooms, nuts and chocolate—all rich in copper; or in miners who may work and eat meals, for 20 years or more, in an atmosphere laden with 1 to 2% copper ores dusts. Yet evidence of primary chronic copper toxicity (well defined from observations of patients with inherited chronic copper toxicosis—Wilson’s disease—as dysfunction of and structural damage to the liver, central nervous system, kidney, bones and eyes) has never been found in any individuals except those with Wilson’s disease. However, the excessive copper deposits that are found in the livers of patients with primary biliary cirrhosis, cholestasis and Indian childhood cirrhosis may be one contributing factor to the severity of the hepatic disease that is characteristic of these conditions.
Safety and Health Measures
Workers exposed to copper dusts or mists should be provided with adequate protective clothing to prevent repeated or prolonged skin contact. Where dust conditions cannot be sufficiently controlled, appropriate respirators and eye protection are necessary. Housekeeping and the provision of adequate sanitary facilities is essential since eating, drinking and smoking should be prohibited at the worksite. In mines where there are water-soluble ores such as chalcanthite, workers should be particularly careful to wash their hands with water before eating.
The prevention of metal fume fever is a matter of keeping exposure below the level of concentration currently accepted as satisfactory for working with copper in industry. The employment of local exhaust ventilation (LEV) is a necessary measure to collect copper fumes at the source.
People with Wilson’s disease should avoid employment in copper industries. The serum concentration of ceruloplasmin is a screen for this condition, since unaffected individuals have levels which range from 20 to 50 mg/100 cm3 of this copper protein whereas 97% of patients with Wilson’s disease have less than 20 mg/100 cm3. This is a relatively expensive procedure for broad-based screening programmes.
Occurrence and Uses
Elemental chromium (Cr) is not found free in nature, and the only ore of any importance is the spinel ore, chromite or chrome iron stone, which is ferrous chromite (FeOCr2O3), widely distributed over the earth’s surface. In addition to chromic acid, this ore contains variable quantities of other substances. Only ores or concentrates containing more than 40% chromic oxide (Cr2O3) are used commercially, and countries having the most suitable deposits are the Russian Federation, South Africa, Zimbabwe, Turkey, the Philippines and India. The prime consumers of chromites are the United States, the Russian Federation, Germany, Japan, France and the United Kingdom.
Chromite may be obtained from both underground and open cast mines. The ore is crusted and, if necessary, concentrated.
The most significant usage of pure chromium is for electroplating of a wide range of equipment, such as automobile parts and electric equipment. Chromium is used extensively for alloying with iron and nickel to form stainless steel, and with nickel, titanium, niobium, cobalt, copper and other metals to form special-purpose alloys.
Chromium forms a number of compounds in various oxidation states. Those of II (chromous), III (chromic) and VI (chromate) states are most important; the II state is basic, the III state is amphoteric and the VI state is acidic. Commercial applications mainly concern compounds in the VI state, with some interest in III state chromium compounds.
The chromous state (CrII) is unstable and is readily oxidized to the chromic state (CrIII). This instability limits the use of chromous compounds. The chromic compounds are very stable and form many compounds which have commercial use, the principal of which are chromic oxide and basic chromium sulphate.
Chromium in the +6 oxidation state (CrVI) has its greatest industrial application as a consequence of its acidic and oxidant properties, as well as its ability to form strongly coloured and insoluble salts. The most important compounds containing chromium in the CrVI state are sodium dichromate, potassium dichromate and chromium trioxide. Most other chromate compounds are produced industrially using dichromate as the source of CrVI.
Sodium mono- and dichromate are the starting materials from which most of the chromium compounds are manufactured. Sodium chromate and dichromate are prepared directly from chrome ore. Chrome ore is crushed, dried and ground; soda ash is added and lime or leached calcine may also be added. After thorough mixing the mixture is roasted in a rotary furnace at an optimum temperature of about 1,100°C; an oxidizing atmosphere is essential to convert the chromium to the CrVI state. The melt from the furnace is cooled and leached and the sodium chromate or dichromate is isolated by conventional processes from the solution.
Technically, chromium oxide (Cr2O3, or chromic oxide), is made by reducing sodium dichromate either with charcoal or with sulphur. Reduction with sulphur is usually employed when the chromic oxide is to be used as a pigment. For metallurgical purposes carbon reduction is normally employed.
The commercial material is normally basic chromic sulphate [Cr(OH)(H2O)5]SO4, which is prepared from sodium dichromate by reduction with carbohydrate in the presence of sulphuric acid; the reaction is vigorously exothermic. Alternatively, sulphur dioxide reduction of a solution of sodium dichromate will yield basic chromic sulphurate. It is used in the tanning of leather, and the material is sold on the basis of Cr2O3 content, which ranges from 20.5 to 25%.
Sodium dichromate can be converted into the anhydrous salt. It is the starting point for preparation of chromium compounds.
Chromium trioxide or chromium anhydride (sometimes referred to as “chromic acid”, although true chromic acid cannot be isolated from solution) is formed by treating a concentrated solution of a dichromate with strong sulphuric acid excess. It is a violent oxidizing agent, and the solution is the principal constituent of chromium plating.
Chromates of weak bases are of limited solubility and more deeply coloured than the oxides; hence their use as pigments. These are not always distinct compounds and may contain mixtures of other materials to provide the right pigment colour. They are prepared by the addition of sodium or potassium dichromate to a solution of the appropriate salt.
Lead chromate is trimorphic; the stable monoclinic form is orange-yellow, “chrome yellow”, and the unstable orthombic form is yellow, isomorphous with lead sulphate and stabilized by it. An orange-red tetragonal form is similar and isomorphous with lead molybdate (VI) PbMoO4 and stabilized by it. On these properties depends the versatility of lead chromate as a pigment in producing a variety of yellow-orange pigments.
Compounds containing CrVI are used in many industrial operations. The manufacture of important inorganic pigments such as lead chromes (which are themselves used to prepare chrome greens), molybdate-oranges, zinc chromate and chromium-oxide green; wood preservation; corrosion inhibition; and coloured glasses and glazes. Basic chromic sulphates are widely used for tanning.
The dyeing of textiles, the preparation of many important catalysts containing chromic oxide and the production of light-sensitive dichromated colloids for use in lithography are also well-known industrial uses of chromium-containing chemicals.
Chromic acid is used not only for “decorative” chromium plating but also for “hard” chromium plating, where it is deposited in much thicker layers to give an extremely hard surface with a low coefficient of friction.
Because of the strong oxidizing action of chromates in acid solution, there are many industrial applications particularly involving organic materials, such as the oxidation of trinitrotoluene (TNT) to give phloroglucinol and the oxidation of picoline to give nicotine acid.
Chromium oxide is also used for the production of pure chromium metal that is suitable for incorporation in creep-resistant, high-temperature alloys, and as a refractory oxide. It may be included in a number of refractory compositions with advantage—for example, in magnetite and magnetite-chromate mixtures.
Compounds with CrIII oxidation states are considerably less hazardous than are CrVI compounds. Compounds of CrIII are poorly absorbed from the digestive system. These CrIII compounds may also combine with proteins in the superficial layers of the skin to form stable complexes. Compounds of CrIII do not cause chrome ulcerations and do not generally initiate allergic dermatitis without prior sensitization by CrVI compounds.
In the CrVI oxidation state, chromium compounds are readily absorbed after ingestion as well as during inhalation. The uptake through intact skin is less well elucidated. The irritant and corrosive effects caused by CrVI occur readily after uptake through mucous membranes, where they are readily absorbed. Work-related exposure to CrVI compounds may induce skin and mucous membrane irritation or corrosion, allergic skin reactions or skin ulcerations.
The untoward effects of chromium compounds generally occur among workers in workplaces where CrVI is encountered, in particular during manufacture or use. The effects frequently involve the skin or respiratory system. Typical industrial hazards are inhalation of the dust or fumes arising during the manufacture of dichromate from chromite ore and the manufacture of lead and zinc chromates, inhalation of chromic acid mists during electroplating or surface treatment of metals, and skin contact with CrVI compounds in manufacture or use. Exposure to CrVI-containing fumes may also occur during welding of stainless steels.
Chrome ulcerations. Such lesions used to be common after work-related exposure to CrVI compounds. The ulcers result from the corrosive action of CrVI, which penetrates the skin through cuts or abrasions. The lesion usually begins as a painless papule, commonly on the hands, forearms or feet, resulting in ulcerations. The ulcer may penetrate deeply into soft tissue and may reach underlying bone. Healing is slow unless the ulcer is treated at an early stage, and atrophic scars remain. There are no reports about skin cancer following such ulcers.
Dermatitis. The CrVI compounds may cause both primary skin irritation and sensitization. In chromate-producing industries, some workers may develop skin irritation, particularly at the neck or wrist, soon after starting work with chromates. In the majority of cases, this clears rapidly and does not recur. However, sometimes it may be necessary to recommend a change of work.
Numerous sources of exposure to CrVI have been listed (e.g., contact with cement, plaster, leather, graphic work, work in match factories, work in tanneries and various sources of metal work). Workers employed in wet sandpapering of car bodies have also been reported with allergy. Affected subjects react positively to patch testing with 0.5% dichromate. Some affected subjects had only erythema or scattered papules, and in others the lesions resembled dyshidriotic pompholyx; nummular eczema may lead to misdiagnosis of genuine cases of occupational dermatitis.
It has been shown that CrVI penetrates the skin through the sweat glands and is reduced to CrIII in the corium. It is shown that the CrIII then reacts with protein to form the antigen-antibody complex. This explains the localization of lesions around sweat glands and why very small amounts of dichromate can cause sensitization. The chronic character of the dermatitis may be due to the fact that the antigen-antibody complex is removed more slowly than would be the case if the reaction occurred in the epidermis.
Acute respiratory effects. Inhalation of dust or mist containing CrVI is irritating to mucous membranes. At high concentrations of such dust, sneezing, rhinorrhoea, lesions of the nasal septum and redness of the throat are documented effects. Sensitization has also been reported, resulting in typical asthmatic attacks, which may recur on subsequent exposure. At exposure for several days to chromic acid mist at concentrations of about 20 to 30 mg/m3, cough, headache, dyspnoea and substernal pain have also been reported after exposure. The occurrence of bronchospasm in a person working with chromates should suggest chemical irritation of the lungs. Treatment is only symptomatic.
Ulcerations of the nasal septum. In previous years, when the exposure levels to CrVI compounds could be high, ulcerations of the nasal septum were frequently seen among exposed workers. This untoward effect results from deposition of CrVI-containing particulates or mist droplets on the nasal septum, resulting in ulceration of the cartilaginous portion followed, in many cases, by perforation at the site of ulceration. Frequent nose-picking may enhance the formation of perforation. The mucosa covering the lower anterior part of the septum, known as the Kiesselbach’s and Little’s area, is relatively avascular and closely adherent to the underlying cartilage. Crusts containing necrotic debris from the cartilage of the septum continue to form, and within a week or two the septum becomes perforated. The periphery of the ulceration remains active for up to several months, during which time the perforation may increase in size. It heals by the formation of vascular scar tissue. Sense of smell is almost never impaired. During the active phase, rhinorrhoea and nose-bleeding may be troublesome symptoms. When soundly healed, symptoms are rare and many persons are unaware that the septum is perforated.
Effects in other organs. Necrosis of the kidneys has been reported, starting with tubular necrosis, leaving the glomeruli undamaged. Diffuse necrosis of the liver and subsequent loss of architecture has also been reported. Soon after the turn of the century there were a number of reports on human ingestion of CrVI compounds resulting in major gastro-intestinal bleeding from ulcerations of the intestinal mucosa. Sometimes such bleedings resulted in cardiovascular shock as a possible complication. If the patient survived, tubular necrosis of the kidneys or liver necrosis could occur.
Carcinogenic effects. Increased incidence of lung cancer among workers in manufacture and use of CrVI compounds has been reported in a great number of studies from France, Germany, Italy, Japan, Norway, the United States and the United Kingdom. Chromates of zinc and calcium appear to be among the most potent carcinogenic chromates, as well as among the most potent human carcinogens. Elevated incidence of lung cancer has also been reported among subjects exposed to lead chromates, and to fumes of chromium trioxides. Heavy exposures to CrVI compounds have resulted in very high incidence of lung cancer in exposed workers 15 or more years after first exposure, as reported in both cohort studies and case reports.
Thus, it is well established that an increase in the incidence of lung cancer of workers employed in the manufacture of zinc chromate and the manufacture of mono- and dichromates from chromite ore is a long-term effect of work-related heavy exposure to CrVI compounds. Some of the cohort studies have reported measurements of exposure levels among the exposed cohorts. Also, a small number of studies have indicated that exposure to fumes generated from welding on Cr-alloyed steel may result in elevated incidence of lung cancer among these welders.
There is no firmly established “safe” level of exposure. However, most of the reports on association between CrVI exposure and cancer of the respiratory organs and exposure levels report on air levels exceeding 50 mg CrVI/m3 air.
The symptoms, signs, course, x-ray appearance, method of diagnosis and prognosis of lung cancers resulting from exposure to chromates differ in no way from those of cancer of the lung due to other causes. It has been found that the tumours often originate in the periphery of the bronchial tree. The tumours may be of all histological types, but a majority of the tumours seem to be anaplastic oat-celled tumours. Water-soluble, acid soluble and water insoluble chromium is found in the lung tissues of chromate workers in varying amounts.
Although it has not been firmly established, some studies have indicated that exposure to chromates may result in increased risk of cancer in the nasal sinuses and the alimentary tract. The studies that indicate excess cancer of the alimentary tract are case reports from the 1930s or cohort studies that reflect exposure at high levels than generally encountered today.
Safety and Health Measures
On the technical side, avoidance of exposure to chromium depends on appropriate design of processes, including adequate exhaust ventilation and the suppression of dust or mist containing chromium in the hexavalent state. Built-in control measures are also necessary, requiring the least possible action by either process operators or maintenance staff.
Wet methods of cleaning should be used where possible; at other sites, the only acceptable alternative is vacuum cleaning. Spill of liquids or solids must be removed to prevent dispersion as airborne dust. The concentration in the work environment of chromium-containing dust and fumes should preferably be measured at regular intervals by individual and area sampling. Where unacceptable concentration levels are found by either method, the sources of dust or fumes should be identified and controlled. Dust masks, preferably with an efficiency of more than 99% in retaining particles of 0.5 µm size, should be worn in situations above non-hazardous levels, and it may be necessary to provide air-supplied respiratory protective equipment for jobs considered to be hazardous. Management should ensure that dust deposits and other surface contaminants should be removed by washing down or suction before work of this type begins. Providing laundering overalls daily may help in avoiding skin contamination. Hand and eye protection is generally recommended, as is repair and replacement of all personal protective equipment (PPE).
The medical surveillance of workers on processes in which CrVI compounds may be encountered should include education in toxic and the carcinogenic properties of both CrVI and CrIII compounds, as well as on the differences between the two groups of compounds. The nature of the exposure hazards and subsequent risks of various diseases (e.g., lung cancer) should be given at job entry as well as at regular intervals during employment. The need to observe a high standard of personal hygiene should be emphasized.
All untoward effects of exposure to chromium can be avoided. Chrome ulcers of the skin can be prevented by eliminating sources of contact and by preventing injury to the skin. Skin cuts and abrasions, however slight, should be cleaned immediately and treated with 10% sodium EDTA ointment. Together with the use of a frequently renewed impervious dressing, this will enhance rapid healing for any ulcer that may develop. Although EDTA does not chelate CrVI compounds at room temperature, it reduces the CrVI to CrIII rapidly, and the excess EDTA chelates CrIII. Both the direct irritant and corrosive action of CrVI compounds and the formation of protein/CrIII complexes are thus prevented. After accidental ingestion of CrVI compounds, immediate swallowing of ascorbic acid may also quickly reduce the CrVI.
Careful washing of the skin after contact and care to avoid friction and sweating are important in the prevention and the control of primary irritation due to chromates. In previous years an ointment containing 10% sodium EDTA was applied regularly to the nasal septum before exposure. This preventive treatment could assist in keeping the septum intact. Soreness of the nose and early ulceration were also treated by regular application of this ointment, and healing could be achieved without perforation.
Results from research indicate that workers exposed to high air concentrations of CrVI could be monitored successfully by monitoring the excretion of chromium in the urine. Such results, however, bear no relation to the hazard of skin allergy. As of today, with the very long latent period of CrVI-related lung cancer, hardly anything can be said regarding the cancer hazard on the basis of urinary levels of Cr.
Occurrence and Uses
Cadmium (Cd) has many chemical and physical similarities to zinc and occurs together with zinc in nature. In minerals and ores, cadmium and zinc generally have a ratio of 1:100 to 1:1,000.
Cadmium is highly resistant to corrosion and has been widely used for electroplating of other metals, mainly steel and iron. Screws, screw nuts, locks and various parts for aircraft and motor vehicles are frequently treated with cadmium in order to withstand corrosion. Nowadays, however, only 8% of all refined cadmium is used for platings and coatings. Cadmium compounds (30% of the use in developed countries) are used as pigments and stabilizers in plastics, and cadmium is also used in certain alloys (3%). Rechargeable, small portable cadmium-containing batteries, used, for example, in mobile telephones, comprise a rapidly increasing usage of cadmium (55% of all cadmium in industrialized countries in 1994 was used in batteries).
Cadmium occurs in various inorganic salts. The most important is cadmium stearate, which is used as a heat stabilizer in polyvinyl chloride (PVC) plastics. Cadmium sulphide and cadmium sulphoselenide are used as yellow and red pigments in plastics and colours. Cadmium sulphide is also used in photo- and solar cells. Cadmium chloride acts as a fungicide, an ingredient in elecroplating baths, a colourant for pyrotechnics, an additive to tinning solution and a mordant in dyeing and printing textiles. It is also used in the production of certain photographic films and in the manufacture of special mirrors and coatings for electronic vacuum tubes. Cadmium oxide is an elecroplating agent, a starting material for PVC heat stabilizers and a component of silver alloys, phosphors, semiconductors and glass and ceramic glazes.
Cadmium can represent an environmental hazard, and many countries have introduced legislative actions aimed towards decreasing the use and subsequent environmental spread of cadmium.
Metabolism and accumulation
Gastrointestinal absorption of ingested cadmium is about 2 to 6% under normal conditions. Individuals with low body iron stores, reflected by low concentrations of serum ferritin, may have considerably higher absorption of cadmium, up to 20% of a given dose of cadmium. Significant amounts of cadmium may also be absorbed via the lung from the inhalation of tobacco smoke or from occupational exposure to atmospheric cadmium dust. Pulmonary absorption of inhaled respirable cadmium dust is estimated at 20 to 50%. After absorption via the gastrointestinal tract or the lung, cadmium is transported to the liver, where production of a cadmium-binding low-molecular-weight protein, metallothionein, is initiated.
About 80 to 90% of the total amount of cadmium in the body is considered to be bound to metallothionein. This prevents the free cadmium ions from exerting their toxic effects. It is likely that small amounts of metallothionein-bound cadmium are constantly leaving the liver and being transported to the kidney via the blood. The metallothionein with the cadmium bound to it is filtered through the glomeruli into the primary urine. Like other low-molecular-weight proteins and amino acids, the metallothionein-cadmium complex is subsequently reabsorbed from the primary urine into the proximal tubular cells, where digestive enzymes degrade the engulfed proteins into smaller peptides and amino acids. Free cadmium ions in the cells result from degradation of metallothionein and initiate a new synthesis of metallothionein, binding the cadmium, and thus protecting the cell from the highly toxic free cadmium ions. Kidney dysfunction is considered to occur when the metallothionein-producing capacity of the tubular cells is exceeded.
The kidney and liver have the highest concentrations of cadmium, together containing about 50% of the body burden of cadmium. The cadmium concentration in the kidney cortex, before cadmium-induced kidney damage occurs, is generally about 15 times the concentration in liver. Elimination of cadmium is very slow. As a result of this, cadmium accumulates in the body, the concentrations increasing with age and length of exposure. Based on organ concentration at different ages the biological half-life of cadmium in humans has been estimated in the range of 7 to 30 years.
Inhalation of cadmium compounds at concentrations above 1 mg Cd/m3 in air for 8 hours, or at higher concentrations for shorter periods, may lead to chemical pneumonitis, and in severe cases pulmonary oedema. Symptoms generally occur within 1 to 8 hours after exposure. They are influenza-like and similar to those in metal fume fever. The more severe symptoms of chemical pneumonitis and pulmonary oedema may have a latency period up to 24 hours. Death may occur after 4 to 7 days. Exposure to cadmium in the air at concentrations exceeding 5 mg Cd/m3 is most likely to occur where cadmium alloys are smelted, welded or soldered. Ingestion of drinks contaminated with cadmium at concentrations exceeding 15 mg Cd/l gives rise to symptoms of food poisoning. Symptoms are nausea, vomiting, abdominal pains and sometimes diarrhoea. Sources of food contamination may be pots and pans with cadmium-containing glazing and cadmium solderings used in vending machines for hot and cold drinks. In animals parenteral administration of cadmium at doses exceeding 2 mg Cd/kg body weight causes necrosis of the testis. No such effect has been reported in humans.
Chronic cadmium poisoning has been reported after prolonged occupational exposure to cadmium oxide fumes, cadmium oxide dust and cadmium stearates. Changes associated with chronic cadmium poisoning may be local, in which case they involve the respiratory tract, or they may be systemic, resulting from absorption of cadmium. Systemic changes include kidney damage with proteinuria and anaemia. Lung disease in the form of emphysema is the main symptom at heavy exposure to cadmium in air, whereas kidney dysfunction and damage are the most prominent findings after long-term exposure to lower levels of cadmium in workroom air or via cadmium-contaminated food. Mild hypochromic anaemia is frequently found among workers exposed to high levels of cadmium. This may be due to both increased destruction of red blood cells and to iron deficiency. Yellow discolouration of the necks of teeth and loss of sense of smell (anosmia) may also be seen in cases of exposure to very high cadmium concentrations.
Pulmonary emphysema is considered a possible effect of prolonged exposure to cadmium in air at concentrations exceeding 0.1 mg Cd/m3. It has been reported that exposure to concentrations of about 0.02 mg Cd/m3 for more than 20 years can cause certain pulmonary effects. Cadmium-induced pulmonary emphysema can reduce working capacity and may be the cause of invalidity and life shortening. With long-term low-level cadmium exposure the kidney is the critical organ (i.e., the organ first affected). Cadmium accumulates in renal cortex. Concentrations exceeding 200 µg Cd/g wet weight have previously been estimated to cause tubular dysfunction with decreased reabsorption of proteins from the urine. This causes tubular proteinuria with increased excretion of low-molecular-weight proteins such as
α,α-1-microglobulin (protein HC), β-2-microglobulin and retinol binding protein (RTB). Recent research suggests, however, that tubular damage may occur at lower levels of cadmium in kidney cortex. As the kidney dysfunction progresses, amino acids, glucose and minerals, such as calcium and phosphorus, are also lost into the urine. Increased excretion of calcium and phosphorous may disturb bone metabolism, and kidney stones are frequently reported by cadmium workers. After long-term medium-to-high levels of exposure to cadmium, the kidney’s glomeruli may also be affected, leading to a decreased glomerular filtration rate. In severe cases uraemia may develop. Recent studies have shown the glomerular dysfunction to be irreversible and dose dependent. Osteomalacia has been reported in cases of severe chronic cadmium poisoning.
In order to prevent kidney dysfunction, as manifested by β-2-microglobulinuria, particularly if the occupational exposure to cadmium fumes and dust is likely to last for 25 years (at 8 hours workday and 225 workdays/year), it is recommended that the average workroom concentration of respirable cadmium should be kept below 0.01 mg/m3.
Excessive cadmium exposure has occurred in the general population through ingestion of contaminated rice and other foodstuffs, and possibly drinking water. The itai-itai disease, a painful type of osteomalacia, with multiple fractures appearing together with kidney dysfunction, has occurred in Japan in areas with high cadmium exposure. Though the pathogenesis of itai-itai disease is still under dispute, it is generally accepted that cadmium is a necessary aetiological factor. It should be stressed that cadmium-induced kidney damage is irreversible and may grow worse even after exposure has ceased.
Cadmium and cancer
There is strong evidence of dose-response relationships and an increased mortality from lung cancer in several epidemiological studies on cadmium-exposed workers. The interpretation is complicated by concurrent exposures to other metals which are known or suspected carcinogens. Continuing observations of cadmium-exposed workers have, however, failed to yield evidence of increased mortality from prostatic cancer, as initially suspected. The IARC in 1993 assessed the risk of cancer from exposure to cadmium and concluded that it should be regarded as a human carcinogen. Since then additional epidemiological evidence has come forth with somewhat contradictory results, and the possible carcinogenicity of cadmium thus remains unclear. It is nevertheless clear that cadmium possesses strong carcinogenic properties in animal experiments.
Safety and Health Measures
The kidney cortex is the critical organ with long-term cadmium exposure via air or food. The critical concentration is estimated at about 200 µg Cd/g wet weight, but may be lower, as stated above. In order to keep the kidney cortex concentration below this level even after lifelong exposure, the average cadmium concentration in workroom air (8 hours per day) should not exceed 0.01 mg Cd/m3.
Work processes and operations which may release cadmium fumes or dust into the atmosphere should be designed to keep concentration levels to a minimum and, if practicable, be enclosed and fitted with exhaust ventilation. When adequate ventilation is impossible to maintain (e.g., during welding and cutting), respirators should be carried and air should be sampled to determine the cadmium concentration. In areas with hazards of flying particles, chemical splashes, radiant heat and so on (e.g., near electroplating tanks and furnaces), workers should wear appropriate safety equipment, such as eye, face, hand and arm protection and impermeable clothing. Adequate sanitary facilities should be supplied, and workers should be encouraged to wash before meals and to wash thoroughly and change clothes before leaving work. Smoking, eating and drinking in work areas should be prohibited. Tobacco contaminated with cadmium dust from workrooms can be an important exposure route. Cigarettes and pipe tobacco should not be carried in the workroom. Contaminated exhaust air should be filtered, and persons in charge of dust collectors and filters should wear respirators while working on the equipment.
To ensure that excessive accumulation of cadmium in the kidney does not occur, cadmium levels in blood and in urine should be checked regularly. Cadmium levels in blood are mainly an indication of the last few months exposure, but can be used to assess body burden a few years after exposure has ceased. A value of 100 nmol Cd/l whole blood is an approximate critical level if exposure is regular for long periods. Cadmium values in urine can be used to estimate the cadmium body burden, providing kidney damage has not occurred. It has been estimated by the WHO that 10 nmol/mmol creatinine is the concentration below which kidney dysfunction should not occur. Recent research has, however, shown that kidney dysfunction may occur already at around 5 nmol/mmol creatinine.
Since the mentioned blood and urinary levels are levels at which action of cadmium on kidney has been observed, it is recommended that control measures be applied whenever the individual concentrations of cadmium in urine and/or in blood exceed 50 nmol/l whole blood or
3 nmol/mmol creatinine respectively. Pre-employment medical examinations should be given to workers who will be exposed to cadmium dust or fumes. Persons with respiratory or kidney disorders should avoid such work. Medical examination of cadmium-exposed workers should be carried out at least once every year. In workers exposed to cadmium for longer periods, quantitative measurements of ß-2-microglobulin or other relevant low-molecular-weight proteins in urine should be made regularly. Concentrations of ß-2-microglobulin in urine should normally not exceed 34 µg/mmol creatinine.
Treatment of cadmium poisoning
Persons who have ingested cadmium salts should be made to vomit or given gastric lavage; persons exposed to acute inhalation should be removed from exposure and given oxygen therapy if necessary. No specific treatment for chronic cadmium poisoning is available, and symptomatic treatment has to be relied upon. As a rule the administration of chelating agents such as BAL and EDTA is contraindicated since they are nephrotoxic in combination with cadmium.
Occurrence and Uses
In nature, bismuth (Bi) occurs both as the free metal and in ores such as bismutite (carbonate) and bismuthinite (double bismuth and tellurium sulphide), where it is accompanied by other elements, mainly lead and antimony.
Bismuth is used in metallurgy for the manufacture of numerous alloys, especially alloys with a low melting point. Some of these alloys are used for welding. Bismuth also finds use in safety devices in fire detection and extinguishing systems, and in the production of malleable irons. It acts as a catalyst for making acrylic fibres.
Bismuth telluride is used as a semiconductor. Bismuth oxide, hydroxide, oxychloride, trichloride and nitrate are employed in the cosmetics industry. Other salts (e.g., succinate, orthoxyquinoleate, subnitrate, carbonate, phosphate and so on) are used in medicine.
There have been no reports of occupational exposure during the production of metallic bismuth and the manufacture of pharmaceuticals, cosmetics and industrial chemicals. Because bismuth and its compounds do not appear to have been responsible for poisoning associated with work, they are regarded as the least toxic of the heavy metals currently used in industry.
Bismuth compounds are absorbed through the respiratory and gastrointestinal tracts. The main systemic effects in humans and animals are exerted in the kidney and liver. The organic derivatives cause alterations of the convoluted tubules and may result in serious, and sometimes fatal, nephrosis.
Gum discolouration has been reported with exposure to bismuth dusts. The insoluble mineral salts, taken orally over prolonged periods in doses generally exceeding 1 per day, may provoke brain disease characterized by mental disorders (confused state), muscular disorders (myoclonia), motor coordination disorders (loss of balance, unsteadiness) and dysarthria. These disorders stem from an accumulation of bismuth in the nerve centres which manifests itself when bismuthaemia exceeds a certain level, estimated at around 50 mg/l. In most cases, bismuth-linked encephalopathy gradually disappears without medication within a period of from 10 days to 2 months, during which time the bismuth is eliminated in the urine. Fatal cases of encephalopathy have, however, been recorded.
Such effects have been observed in France and Australia since 1973. They are caused by a factor not yet fully investigated which encourages the absorption of bismuth through the intestinal mucous membrane and leads to an increase in bismuthaemia to a level as high as several hundred mg/l. The danger of encephalopathy caused by inhaling metallic dust or oxide smoke in the workplace is very remote. The poor solubility of bismuth and bismuth oxide in blood plasma and its fairly rapid elimination in the urine (its half-life is about 6 days) argue against the likelihood of a sufficiently acute impregnation of the nerve centres to reach pathological levels.
In animals, inhalation of insoluble compounds such as bismuth telluride provokes the usual lung response of an inert dust. However, long-term exposure to bismuth telluride “doped” with selenium sulphide can produce in various species a mild reversible granulomatous reaction of the lung.
Some bismuth compounds decompose into dangerous chemicals. Bismuth pentafluoride decomposes on heating and emits highly toxic fumes.
Circulating Red Blood Cells
Interference in haemoglobin oxygen deliverythrough alteration of haeme
The major function of the red cell is to deliver oxygen to the tissue and to remove carbon dioxide. The binding of oxygen in the lung and its release as needed at the tissue level depends upon a carefully balanced series of physicochemical reactions. The result is a complex dissociation curve which serves in a healthy individual to maximally saturate the red cell with oxygen under standard atmospheric conditions, and to release this oxygen to the tissues based upon oxygen level, pH and other indicators of metabolic activity. Delivery of oxygen also depends upon the flow rate of oxygenated red cells, a function of viscosity and of vascular integrity. Within the range of the normal haematocrit (the volume of packed red cells), the balance is such that any decrease in blood count is offset by the decrease in viscosity, allowing improved flow. A decrease in oxygen delivery to the extent that someone is symptomatic is usually not observed until the haematocrit is down to 30% or less; conversely, an increase in haematocrit above the normal range, as seen in polycythaemia, may decrease oxygen delivery due to the effects of increased viscosity on blood flow. An exception is iron deficiency, in which symptoms of weakness and lassitude appear, primarily due to the lack of iron rather than to any associated anaemia (Beutler, Larsh and Gurney 1960).
Carbon monoxide is a ubiquitous gas which can have severe, possibly fatal, effects on the ability of haemoglobin to transport oxygen. Carbon monoxide is discussed in detail in the chemicals section of this Encyclopaedia.
Methaemoglobin-producing compounds. Methaemoglobin is another form of haemoglobin that is incapable of delivering oxygen to the tissues. In haemoglobin, the iron atom at the centre of the haeme portion of the molecule must be in its chemically reduced ferrous state in order to participate in the transport of oxygen. A certain amount of the iron in haemoglobin is continuously oxidized to its ferric state. Thus, approximately 0.5% of total haemoglobin in the blood is methaemoglobin, which is the chemically oxidized form of haemoglobin that cannot transport oxygen. An NADH-dependent enzyme, methaemoglobin reductase, reduces ferric iron back to ferrous haemoglobin.
A number of chemicals in the workplace can induce levels of methaemoglobin that are clinically significant, as for example in industries using aniline dyes. Other chemicals that have been found frequently to cause methaemoglobinaemia in the workplace are nitrobenzenes, other organic and inorganic nitrates and nitrites, hydrazines and a variety of quinones (Kiese 1974). Some of these chemicals are listed in Table 1 and are discussed in more detail in the chemicals section of this Encyclopaedia. Cyanosis, confusion and other signs of hypoxia are the usual symptoms of methaemoglobinaemia. Individuals who are chronically exposed to such chemicals may have blueness of the lips when methaemoglobin levels are approximately 10% or greater. They may have no other overt effects. The blood has a characteristic chocolate brown colour with methaemoglobinaemia. Treatment consists of avoiding further exposure. Significant symptoms may be present, usually at methaemoglobin levels greater than 40%. Therapy with methylene blue or ascorbic acid can accelerate reduction of the methaemoglobin level. Individuals with glucose-6-phosphate dehydrogenase deficiency may have accelerated haemolysis when treated with methylene blue (see below for discussion of glucose-6-phosphate dehydrogenase deficiency).
There are inherited disorders leading to persistent methaemoglobinaemia, either due to heterozygosity for an abnormal haemoglobin, or to homozygosity for deficiency of red cell NADH-dependent methaemoglobin reductase. Individuals who are heterozygous for this enzyme deficiency will not be able to decrease elevated methaemoglobin levels caused by chemical exposures as rapidly as will individuals with normal enzyme levels.
In addition to oxidizing the iron component of haemoglobin, many of the chemicals causing methaemoglobinaemia, or their metabolites, are also relatively non-specific oxidizing agents, which at high levels can cause a Heinz-body haemolytic anaemia. This process is characterized by oxidative denaturation of haemoglobin, leading to the formation of punctate membrane-bound red cell inclusions known as Heinz bodies, which can be identified with special stains. Oxidative damage to the red cell membrane also occurs. While this may lead to significant haemolysis, the compounds listed in Table 1 primarily produce their adverse effects through the formation of methaemoglobin, which may be life threatening, rather than through haemolysis, which is usually a limited process.
In essence, two different red cell defence pathways are involved: (1) the NADH-dependent methaemoglobin reductase required to reduce methaemoglobin to normal haemoglobin; and (2) the NADPH-dependent process through the hexose monophosphate (HMP) shunt, leading to the maintenance of reduced glutathione as a means to defend against oxidizing species capable of producing Heinz-body haemolytic anaemia (figure 1). Heinz-body haemolysis can be exacerbated by the treatment of methaemoglobinaemic patients with methylene blue because it requires NADPH for its methaemoglobin-reducing effects. Haemolysis will also be a more prominent part of the clinical picture in individuals with (1)deficiencies in one of the enzymes of the NADPH oxidant defence pathway, or (2) an inherited unstable haemoglobin. Except for the glucose-6-phosphate dehydrogenase (G6PD) deficiency, described later in this chapter, these are relatively rare disorders.
Figure 1. Red blood cell enzymes of oxidant defence and related reactions
GSH + GSH + (O) ←-Glutathione peroxidase-→ GSSG + H2O
GSSG + 2NADPH ←-Glutathione peroxidase-→ 2GSH + 2NADP
Glucose-6-Phosphate + NADP ←-G6PD-→ 6-Phosphogluconate + NADPH
Fe+++·Haemoglobin (Methaemoglobin) + NADH ←-Methaemoglobin reductase-→ Fe++·Haemoglobin
Another form of haemoglobin alteration produced by oxidizing agents is a denatured species known as sulphaemoglobin. This irreversible product can be detected in the blood of individuals with significant methaemoglobinaemia produced by oxidant chemicals. Sulphaemoglobin is the name also given, and more appropriately, to a specific product formed during hydrogen sulphide poisoning.
Haemolytic agents: There are a variety of haemolytic agents in the workplace. For many the toxicity of concern is methaemoglobinaemia. Other haemolytic agents include naphthalene and its derivatives. In addition, certain metals, such as copper, and organometals, such as tributyl tin, will shorten red cell survival, at least in animal models. Mild haemolysis can also occur during traumatic physical exertion (march haemoglobinuria); a more modern observation is elevated white blood counts with prolonged exertion (jogger’s leucocytosis). The most important of the metals that affects red cell formation and survival in workers is lead, described in detail in the chemicals section of this Encyclopaedia.
Arsine: The normal red blood cell survives in the circulation for 120 days. Shortening of this survival can lead to anaemia if not compensated by an increase in red cell production by the bone marrow. There are essentially two types of haemolysis: (1) intravascular haemolysis, in which there is an immediate release of haemoglobin within the circulation; and (2) extravascular haemolysis, in which red cells are destroyed within the spleen or the liver.
One of the most potent intravascular haemolysins is arsine gas (AsH3). Inhalation of a relatively small amount of this agent leads to swelling and eventual bursting of red blood cells within the circulation. It may be difficult to detect the causal relation of workplace arsine exposure to an acute haemolytic episode (Fowler and Wiessberg 1974). This is partly because there is frequently a delay between exposure and onset of symptoms, but primarily because the source of exposure is often not evident. Arsine gas is made and used commercially, often now in the electronics industry. However, most of the published reports of acute haemolytic episodes have been through the unexpected liberation of arsine gas as an unwanted by-product of an industrial process—for example, if acid is added to a container made of arsenic-contaminated metal. Any process that chemically reduces arsenic, such as acidification, can lead to the liberation of arsine gas. As arsenic can be a contaminant of many metals and organic materials, such as coal, arsine exposure can often be unexpected. Stibine, the hydride of antimony, appears to produce a haemolytic effect similar to arsine.
Death can occur directly due to complete loss of red blood cells. (A haematocrit of zero has been reported.) However, a major concern at arsine levels less than those producing complete haemolysis is acute renal failure due to the massive release of haemoglobin within the circulation. At much higher levels, arsine may produce acute pulmonary oedema and possibly direct renal effects. Hypotension may accompany the acute episode. There is usually a delay of at least a few hours between inhalation of arsine and the onset of symptoms. In addition to red urine due to haemoglobinuria, the patient will frequently complain of abdominal pain and nausea, symptoms that occur concomitantly with acute intravascular haemolysis from a number of causes (Neilsen 1969).
Treatment is aimed at maintenance of renal perfusion and transfusion of normal blood. As the circulating red cells affected by arsine appear to some extent to be doomed to intravascular haemolysis, an exchange transfusion in which arsine-exposed red cells are replaced by unexposed cells would appear to be optimal therapy. As in severe life-threatening haemorrhage, it is important that replacement red cells have adequate 2,3-diphosphoglyceric acid (DPG) levels so as to be able to deliver oxygen to the tissue.
Other Haematological Disorders
White blood cells
There are a variety of drugs, such as propylthiourea (PTU), which are known to affect the production or survival of circulating polymorphonuclear leucocytes relatively selectively. In contrast, non-specific bone marrow toxins affect the precursors of red cells and platelets as well. Workers engaged in the preparation or administration of such drugs should be considered at risk. There is one report of complete granulocytopenia in a worker poisoned with dinitrophenol. Alteration in lymphocyte number and function, and particularly of subtype distribution, is receiving more attention as a possible subtle mechanism of effects due to a variety of chemicals in the workplace or general environment, particularly chlorinated hydrocarbons, dioxins and related compounds. Validation of the health implications of such changes is required.
Similar to leucopenia, there are many drugs that selectively decrease the production or survival of circulating platelets, which could be a problem in workers involved in the preparation or administration of such agents. Otherwise, there are only scattered reports of thrombocytopenia in workers. One study implicates toluene diisocyanate (TDI) as a cause of thrombocytopenic purpura. Abnormalities in the various blood factors involved in coagulation are not generally noted as a consequence of work. Individuals with pre-existing coagulation abnormalities, such as haemophilia, often have difficulty entering the workforce. However, although a carefully considered exclusion from a few selected jobs is reasonable, such individuals are usually capable of normal functioning at work.
Haematological Screening and Surveillance in the Workplace
Markers of susceptibility
Due in part to the ease in obtaining samples, more is known about inherited variations in human blood components than for those in any other organ. Extensive studies sparked by recognition of familial anaemias have led to fundamental knowledge concerning the structural and functional implications of genetic alterations. Of pertinence to occupational health are those inherited variations that might lead to an increased susceptibility to workplace hazards. There are a number of such testable variations that have been considered or actually used for the screening of workers. The rapid increase in knowledge concerning human genetics makes it a certainty that we will have a better understanding of the inherited basis of variation in human response, and we will be more capable of predicting the extent of individual susceptibility through laboratory tests.
Before discussing the potential value of currently available susceptibility markers, the major ethical considerations in the use of such tests in workers should be emphasized. It has been questioned whether such tests favour exclusion of workers from a site rather than a focus on improving the worksite for the benefit of the workers. At the very least, before embarking on the use of a susceptibility marker at a workplace, the goals of the testing and consequences of the findings must be clear to all parties.
The two markers of haematological susceptibility for which screening has taken place most frequently are sickle cell trait and G6PD deficiency. The former is at most of marginal value in rare situations, and the latter is of no value whatsoever in most of the situations for which it has been advocated (Goldstein, Amoruso and Witz 1985).
Sickle cell disease, in which there is homozygosity for haemoglobin S (HbS), is a fairly common disorder among individuals of African descent. It is a relatively severe disease that often, but not always, precludes entering the workforce. The HbS gene may be inherited with other genes, such as HbC, which may reduce the severity of its effects. The basic defect in individuals with sickle cell disease is the polymerization of HbS, leading to microinfarction. Microinfarction can occur in episodes, known as sickle cell crises, and can be precipitated by external factors, particularly those leading to hypoxia and, to a lesser extent, dehydration. With a reasonably wide variation in the clinical course and well-being of those with sickle cell disease, employment evaluation should focus on the individual case history. Jobs that have the possibility of hypoxic exposures, such as those requiring frequent air travel, or those with a likelihood of significant dehydration, are not appropriate.
Much more common than sickle cell disease is sickle cell trait, the heterozygous condition in which there is inheritance of one gene for HbS and one for HbA. Individuals with this genetic pattern have been reported to undergo sickle cell crisis under extreme conditions of hypoxia. Some consideration has been given to excluding individuals with sickle cell trait from workplaces where hypoxia is a common risk, probably limited to the jobs on military aircraft or submarines, and perhaps on commercial aircraft. However, it must be emphasized that individuals with sickle cell trait do very well in almost every other situation. For example, athletes with sickle cell trait had no adverse effects from competing at the altitude of Mexico City (2,200m, or 7,200ft) during the 1968 Summer Olympics. Accordingly, with the few exceptions described above, there is no reason to consider exclusion or modification of work schedules for those with sickle cell trait.
Another common genetic variant of a red blood cell component is the A– form of G6PD deficiency. It is inherited on the X chromosome as a sex-linked recessive gene and is present in approximately one in seven Black males and one in 50 Black females in the United States. In Africa, the gene is particularly prevalent in areas of high malaria risk. As with sickle cell trait, G6PD deficiency provides a protective advantage against malaria. Under usual circumstances, individuals with this form of G6PD deficiency have red blood counts and indices within the normal range. However, due to the inability to regenerate reduced glutathione, their red blood cells are susceptible to haemolysis following ingestion of oxidant drugs and in certain disease states. This susceptibility to oxidizing agents has led to workplace screening on the erroneous assumption that individuals with the common A– variant of G6PD deficiency will be at risk from the inhalation of oxidant gases. In fact, it would require exposure to levels many times higher than the levels at which such gases would cause fatal pulmonary oedema before the red cells of G6PD-deficient individuals would receive oxidant stress sufficient to be of concern (Goldstein, Amoruso and Witz 1985). G6PD deficiency will increase the likelihood of overt Heinz-body haemolysis in individuals exposed to aniline dyes and other methaemoglobin-provoking agents (Table 1), but in these cases the primary clinical problem remains the life-threatening methaemoglobinaemia. While knowledge of G6PD status might be useful in such cases, primarily to guide therapy, this knowledge should not be used to exclude workers from the workplace.
There are many other forms of familial G6PD deficiency, all far less common then the A– variant (Beutler 1990). Certain of these variants, particularly in individuals from the Mediterranean basin and Central Asia, have much lower levels of G6PD activity in their red blood cells. Consequently the affected individual can be severely compromised by ongoing haemolytic anaemia. Deficiencies in other enzymes active in defence against oxidants have also been reported as have unstable haemoglobins that render the red cell more susceptible to oxidant stress in the same manner as in G6PD deficiency.
Surveillance differs substantially from clinical testing in both the evaluation of ill patients and the regular screening of presumably healthy individuals. In an appropriately designed surveillance programme, the aim is to prevent overt disease by picking up subtle early changes through the use of laboratory testing. Therefore, a slightly abnormal finding should automatically trigger a response—or at least a thorough review—by physicians.
In the initial review of haematological surveillance data in a workforce potentially exposed to a haematotoxin such as benzene, there are two major approaches that are particularly helpful in distinguishing false positives. The first is the degree of the difference from normal. As the count gets further removed from the normal range, there is a rapid drop-off in the likelihood that it represents just a statistical anomaly. Second, one should take advantage of the totality of data for that individual, including normal values, keeping in mind the wide range of effects produced by benzene. For example, there is a much greater probability of a benzene effect if a slightly low platelet count is accompanied by a low-normal white blood cell count, a low-normal red cell count, and a high-normal red cell mean corpuscular volume (MCV). Conversely, the relevance of this same platelet count to benzene haematotoxicity can be discounted if the other blood counts are at the opposite end of the normal spectrum. These same two considerations can be used in judging whether the individual should be removed from the workforce while awaiting further testing and whether the additional testing should consist only of a repeat complete blood count (CBC).
If there is any doubt as to the cause of the low count, the entire CBC should be repeated. If the low count is due to laboratory variability or some short-term biological variability within the individual, it is less likely that the blood count will again be low. Comparison with preplacement or other available blood counts should help distinguish those individuals who have an inherent tendency to be on the lower end of the distribution. Detection of an individual worker with an effect due to a haematological toxin should be considered a sentinel health event, prompting careful investigation of working conditions and of co-workers (Goldstein 1988).
The wide range in normal laboratory values for blood counts can present an even greater challenge since there can be a substantial effect while counts are still within the normal range. For example, it is possible that a worker exposed to benzene or ionizing radiation may have a fall in haematocrit from 50 to 40%, a fall in the white blood cell count from 10,000 to 5,000 per cubic millimetre and a fall in the platelet count from 350,000 to 150,000 per cubic millimetre—that is, more than a 50% decrease in platelets; yet all these values are within the “normal” range of blood counts. Accordingly, a surveillance programme that looks solely at “abnormal” blood counts may miss significant effects. Therefore, blood counts that decrease over time while staying in the normal range need particular attention.
Another challenging problem in workplace surveillance is the detection of a slight decrease in the mean blood count of an entire exposed population—for example, a decrease in mean white blood cell count from 7,500 to 7,000 per cubic millimetre because of a widespread exposure to benzene or ionizing radiation. Detection and appropriate evaluation of any such observation requires meticulous attention to standardization of laboratory test procedures, the availability of an appropriate control group and careful statistical analysis.
Leukaemias constitute 3% of all cancers worldwide (Linet 1985). They are a group of malignancies of blood precursor cells, classified according to cell type of origin, degree of cellular differentiation, and clinical and epidemiological behaviour. The four common types are acute lymphocytic leukaemia (ALL), chronic lymphocytic leukaemia (CLL), acute myelocytic leukaemia (AML) and chronic myelocytic leukaemia (CML). ALL develops rapidly, is the most common form of leukaemia in childhood and originates in the white blood corpuscles in the lymph nodes. CLL arises in bone marrow lymphocytes, develops very slowly and is more common in aged persons. AML is the common form of acute leukaemia in adults. Rare types of acute leukaemia include monocytic, basophilic, eosinophilic, plasma-, erythro- and hairy-cell leukaemias. These rarer forms of acute leukaemia are sometimes lumped together under the heading acute non-lymphocytic leukaemia (ANLL), due in part to the belief that they arise from a common stem cell. Most cases of CML are characterized by a specific chromosomal abnormality, the Philadelphia chromosome. The eventual outcome of CML often is leukaemic transformation to AML. Transformation to AML also can occur in polycythaemia vera and essential thrombocythaemia, neoplastic disorders with elevated red cell or platelet levels, as well as myelofibrosis and myeloid dysplasia. This has led to characterizing these disorders as related myeloproliferative diseases.
The clinical picture varies according to the type of leukaemia. Most patients suffer from fatigue and malaise. Haematological count anomalies and atypical cells are suggestive of leukaemia and indicate a bone marrow examination. Anaemia, thrombocytopenia, neutropenia, elevated leucocyte count and elevated number of blast cells are typical signs of acute leukaemia.
Incidence: The annual overall age-adjusted incidence of leukaemias varies between 2 and 12 per 100,000 in men and between 1 and 11 per 100,000 in women in different populations. High figures are encountered in North American, western European and Israeli populations, while low ones are reported for Asian and African populations. The incidence varies according to age and to type of leukaemia. There is a marked increase in the incidence of leukaemia with age, and there is also a childhood peak which occurs around two to four years of age. Different leukaemia subgroups display different age patterns. CLL is about twice as frequent in men as in women. Incidence and mortality figures of adult leukaemias have tended to stay relatively stable over the past few decades.
Risk factors: Familial factors in the development of leukaemia have been suggested, but the evidence for this is inconclusive. Certain immunological conditions, some of which are hereditary, appear to predispose to leukaemia. Down’s syndrome is predictive of acute leukaemia. Two oncogenic retroviruses (human T-cell leukaemia virus-I, human T-lymphotropic virus-II) have been identified as being related to the development of leukaemias. These viruses are thought to be early-stage carcinogens and as such are insufficient causes of leukaemia (Keating, Estey and Kantarjian 1993).
Ionizing radiation and benzene exposure are established environmental and occupational causes of leukaemias. The incidence of CLL, however, has not been associated with exposure to radiation. Radiation and benzene-induced leukaemias are recognized as occupational diseases in a number of countries.
Much less consistently, leukaemia excesses have been reported for the following groups of workers: drivers; electricians; telephone linepersons and electronic engineers; farmers; flour millers; gardeners; mechanics, welders and metal workers; textile workers; paper-mill workers; and workers in the petroleum industry and distribution of petroleum products. Some particular agents in the occupational environment have been consistently associated with increased risk of leukaemia. These agents include butadiene, electromagnetic fields, engine exhaust, ethylene oxide, insecticides and herbicides, machining fluids, organic solvents, petroleum products (including gasoline), styrene and unidentified viruses. Paternal and maternal exposures to these agents prior to conception have been suggested to increase the leukaemia risk in the offspring, but the evidence at this time is insufficient to establish such exposure as causative.
Treatment and prevention: Up to 75% of male cases of leukaemia may be preventable (International Agency for Research on Cancer 1990). Avoidance of exposure to radiation and benzene will reduce the risk of leukaemias, but the potential reduction worldwide has not been estimated. Treatments of leukaemias include chemotherapy (single agents or combinations), bone marrow transplant and interferons. Bone marrow transplant in both ALL and AML is associated with a disease-free survival between 25 and 60%. The prognosis is poor for patients who do not achieve remission or who relapse. Of those who relapse, about 30% achieve a second remission. The major cause of failure to achieve remission is death from infection and haemorrhage. The survival of untreated acute leukaemia is 10% within 1 year of diagnosis. The median survival of patients with CLL before the initiation of treatment is 6 years. The length of survival depends on the stage of the disease when the diagnosis is initially made.
Leukaemias may occur following medical treatment with radiation and certain chemotherapeutic agents of another malignancy, such as Hodgkin’s disease, lymphomas, myelomas, and ovarian and breast carcinomas. Most of these secondary cases of leukaemia are acute non-lymphocytic leukaemias or myelodysplastic syndrome, which is a preleukaemic condition. Chromosomal abnormalities appear to be more readily observed in both treatment-related leukaemias and in leukaemias associated with radiation and benzene exposure. These acute leukaemias also share a tendency to resist therapy. Activation of the ras oncogene has been reported to occur more frequently in patients with AML who worked in professions deemed to be at high risk of exposure to leukaemogens (Taylor et al. 1992).
Malignant Lymphomas and Multiple Myeloma
Malignant lymphomas constitute a heterogeneous group of neoplasms primarily affecting lymphoid tissues and organs. Malignant lymphomas are divided into two major cellular types: Hodgkin’s disease (HD) (International Classification of Disease, ICD-9 201) and non-Hodgkin lymphomas (NHL) (ICD-9 200, 202). Multiple myeloma (MM) (ICD-9 203) represents a malignancy of plasma cells within the bone marrow and accounts usually for less than 1% of all malignancies (International Agency for Research on Cancer 1993). In 1985, malignant lymphomas and multiple myelomas ranked seventh among all cancers worldwide. They represented 4.2% of all estimated new cancer cases and amounted to 316,000 new cases (Parkin, Pisani and Ferlay 1993).
Mortality and incidence of malignant lymphomas do not reveal a consistent pattern across socio-economic categories worldwide. Children’s HD has a tendency to be more common in less developed nations, while relatively high rates have been observed in young adults in countries in more developed regions. In some countries, NHL seems to be in excess among people in higher socio-economic groups, while in other countries no such clear gradient has been observed.
Occupational exposures may increase the risk of malignant lymphomas, but the epidemiological evidence is still inconclusive. Asbestos, benzene, ionizing radiation, chlorinated hydrocarbon solvents, wood dust and chemicals in leather and rubber-tire manufacturing are examples of agents that have been associated with the risk of unspecified malignant lymphomas. NHL is more common among farmers. Further suspect occupational agents for HD, NHL and MM are mentioned below.
Hodgkin’s disease is a malignant lymphoma characterized by the presence of multinucleated giant (Reed-Sternberg) cells. Lymph nodes in the mediastinum and neck are involved in about 90% of the cases, but the disease may occur in other sites as well. Histological subtypes of HD differ in their clinical and epidemiological behaviour. The Rye classification system includes four subtypes of HD: lymphocytic predominance, nodular sclerosis, mixed cellularity and lymphocytic depletion. The diagnosis of HD is made by biopsy and treatment is radiation therapy alone or in combination with chemotherapy.
The prognosis of HD patients depends on the stage of the disease at diagnosis. About 85 to 100% of patients without massive mediastinal involvement survive for about 8 years from the start of the treatment without further relapse. When there is massive mediastinal involvement, about 50% of the cases suffer a relapse. Radiation therapy and chemotherapy may involve various side effects, such as secondary acute myelocytic leukaemia discussed earlier.
The incidence of HD has not undergone major changes over time but for a few exceptions, such as the populations of the Nordic countries, in which the rates have declined (International Agency for Research on Cancer 1993).
Available data show that in the 1980s the populations of Costa Rica, Denmark and Finland had median annual incidence rates of HD of 2.5 per 100,000 in men and 1.5 per 100,000 in women (standardized to world population); these figures yielded a sex ratio of 1.7. The highest rates in males were recorded for populations in Italy, the United States, Switzerland and Ireland, while the highest female rates were in the United States and Cuba. Low incidence rates have been reported for Japan and China (International Agency for Research on Cancer 1992).
Viral infection has been suspected as involved in the aetiology of HD. Infectious mononucleosis, which is induced by the Epstein-Barr virus, a herpes virus, has been shown to be associated with increased risk of HD. Hodgkin’s disease may also cluster in families, and other time-space constellations of cases have been observed, but the evidence that there are common aetiological factors behind such clusters is weak.
The extent to which occupational factors can lead to increased risk for HD has not been established. There are three predominant suspect agents—organic solvents, phenoxy herbicides and wood dust—but the epidemiological evidence is limited and controversial.
About 98% of the NHLs are lymphocytic lymphomas. At least four different classifications of lymphocytic lymphomas have been commonly used (Longo et al. 1993). In addition, an endemic malignancy, Burkitt’s lymphoma, is endemic in certain areas of tropical Africa and New Guinea.
Thirty to fifty per cent of NHLs are curable with chemotherapy and/or radiotherapy. Bone marrow transplants may be necessary.
Incidence: High annual incidences of NHL (over 12 per 100,000, standardized to world standard population) have been reported during the 1980s for the White population in the United States, particularly San Francisco and New York City, as well as in some Swiss cantons, in Canada, in Trieste (Italy) and Porto Alegre (Brazil, in men). The incidence of NHL is usually higher in men than in women, with the typical excess in men being 50 to 100% greater than in women. In Cuba, and in the White population of Bermuda, however, the incidence is slightly higher in women (International Agency for Research on Cancer 1992).
NHL incidence and mortality rates have been rising in a number of countries worldwide (International Agency for Research on Cancer 1993). By 1988, the average annual incidence in US White men increased by 152%. Some of the increase is due to changes in diagnostic practices of physicians and part due to an increase in immunosuppressive conditions which are induced by the human immunodeficiency virus (HIV, associated with AIDS), other viruses and immunosuppressive chemotherapy. These factors do not explain the entire increase, and a considerable proportion of residual increase may be explained by dietary habits, environmental exposures such as hair dyes, and possibly familial tendencies, as well as some rare factors (Hartge and Devesa 1992).
Occupational determinants have been suspected to play a role in the development of NHL. It is currently estimated that 10% of NHLs are thought to be related to occupational exposures in the United States (Hartge and Devesa 1992), but this percentage varies by time period and location. The occupational causes are not well established. Excess risk of NHL has been associated with electric power plant jobs, farming, grain handling, metal working, petroleum refining and woodworking, and has been found among chemists. Occupational exposures that have been associated with an increased NHL risk include ethylene oxide, chlorophenols, fertilizers, herbicides, insecticides, hair dyes, organic solvents and ionizing radiation. A number of positive findings for phenoxyacetic acid herbicide exposure have been reported (Morrison et al. 1992). Some of the herbicides involved were contaminated with 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD). The epidemiological evidence for occupational aetiologies of NHL is still limited, however.
Multiple myeloma (MM) involves predominantly bone (especially the skull), bone marrow and kidney. It represents malignant proliferation of B-lymphocyte-derived cells that synthesize and secrete immunoglobulins. The diagnosis is made using radiology, a test for the MM-specific Bence-Jones proteinuria, determination of abnormal plasma cells in the bone marrow, and immunoelectrophoresis. MM is treated with bone marrow transplantation, radiation therapy, conventional chemotherapy or polychemotherapy, and immunological therapy. Treated MM patients survive 28 to 43 months on the average (Ludwig and Kuhrer 1994).
The incidence of MM increases sharply with increasing age. High age-standardized annual incidence rates (5 to 10 per 100,000 in men and 4 to 6 per 100,000 in women) have been encountered in the United States Black populations, in Martinique and among the Maoris in New Zealand. Many Chinese, Indian, Japanese and Filipino populations have low rates (less than 10 per 100,000 person-years in men and less than 0.3 per 100,000 person-years in women) (International Agency for Research on Cancer 1992). The rate of multiple myeloma has been on the increase in Europe, Asia, Oceania and in both the Black and White United States populations since the 1960s, but the increase has tended to level off in a number of European populations (International Agency for Research on Cancer 1993).
Throughout the world there is an almost consistent excess among males in the incidence of MM. This excess is typically of the order of 30 to 80%.
Familial and other case clusterings of MM have been reported, but the evidence is inconclusive as to the causes of such clusterings. The excess incidence among the United States Black population as contrasted with the White population points towards the possibility of differential host susceptibility among population groups, which may be genetic. Chronic immunological disorders have on occasion been associated with the risk of MM. The data on social class distribution of MM are limited and unreliable for conclusions on any gradients.
Occupational factors: Epidemiological evidence of an elevated risk of MM in gasoline-exposed workers and refinery workers suggests a benzene aetiology (Infante 1993). An excess of multiple myeloma has repeatedly been observed in farmers and farm workers. Pesticides represent a suspect group of agents. The evidence for carcinogenicity is, however, insufficient for phenoxyacetic acid herbicides (Morrison et al. 1992). Dioxins are sometimes impurities in some phenoxyacetic acid herbicides. There is a reported significant excess of MM in women residing in a zone contaminated with 2,3,7,8-tetrachlorodibenzo-para-dioxin after an accident in a plant near Seveso, Italy (Bertazzi et al. 1993). The Seveso results were based on two cases which occurred during ten years of follow-up, and further observation is needed to confirm the association. Another possible explanation for the increased risk in farmers and farm workers is exposure to some viruses (Priester and Mason 1974).
Further suspect occupations and occupational agents that have been associated with increased risk of MM include painters, truck drivers, asbestos, engine exhaust, hair-colouring products, radiation, styrene, vinyl chloride and wood dust. The evidence for these occupations and agents remains inconclusive.