Gunnar Nordberg

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.

Hazards

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.

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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.

Coagulation

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

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.

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Leukaemias

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

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.

Non-Hodgkin lymphoma

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

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.

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The lymphohaemopoietic system consists of the blood, the bone marrow, the spleen, the thymus, lymphatic channels and lymph nodes. The blood and bone marrow together are referred to as the haematopoietic system. The bone marrow is the site of cell production, continually replacing the cellular elements of the blood (erythrocytes, neutrophils and platelets). Production is under tight control of a group of growth factors. Neutrophils and platelets are used as they perform their physiological functions, and erythrocytes eventually become senescent and outlive their usefulness. For successful function, the cellular elements of the blood must circulate in proper numbers and retain both their structural and physiological integrity. Erythrocytes contain haemoglobin, which permits uptake and delivery of oxygen to tissues to sustain cellular metabolism. Erythrocytes normally survive in the circulation for 120 days while sustaining this function. Neutrophils are found in blood on their way to tissues to participate in the inflammatory response to microbes or other agents. Circulating platelets play a key role in haemostasis.

The production requirement of the bone marrow is a prodigious one. Daily, the marrow replaces 3 billion erythrocytes per kilogram of body weight. Neutrophils have a circulating half-life of only 6 hours, and 1.6 billion neutrophils per kilogram of body weight must be produced each day. The entire platelet population must be replaced every 9.9 days. Because of the need to produce large numbers of functional cells, the marrow is remarkably sensitive to any infectious, chemical, metabolic or environmental insult that impairs DNA synthesis or disrupts the formation of the vital subcellular machinery of the red blood cells, white blood cells or platelets. Further, since the blood cells are marrow progeny, the peripheral blood serves as a sensitive and accurate mirror of bone marrow activity. Blood is readily available for assay via venipuncture, and examination of the blood can provide an early clue of environmentally induced illness.

The haematological system can be viewed as both serving as a conduit for substances entering the body and as an organ system that may be adversely affected by occupational exposures to potentially harmful agents. Blood samples may serve as a biological monitor of exposure and provide a way to assess the effects of occupational exposure on the lymphohaematopoietic system and other body organs.

Environmental agents can interfere with the haematopoietic system in several ways, including inhibition of haemoglobin synthesis, inhibition of cell production or function, leukaemogenesis and increased red blood cell destruction.

Abnormality of blood cell number or function caused directly by occupational hazards can be divided into those for which the haematological problem is the most important health effect, such as benzene-induced aplastic anaemia, and those for which the effects on the blood are direct but of less significance than the effects on other organ systems, such as lead-induced anaemia. Sometimes haematological disorders are a secondary effect of a workplace hazard. For example, secondary polycythaemia can be the result of an occupational lung disease. Table 1 lists those hazards which are reasonably well accepted as having a direct effect on the haematological system.

Table 1. Selected agents implicated in environmentally and occupationally acquired methaemoglobinaemia

• Nitrate-contaminated well water
• Nitrous gases (in welding and silos)
• Aniline dyes
• Food high in nitrates or nitrites
• Mothballs (containing naphthalene)
• Potassium chlorate
• Nitrobenzenes
• Phenylenediamine
• Toluenediamine

Examples of Workplace Hazards Primarily Affecting the Haematological System

Benzene

Benzene was identified as a workplace poison producing aplastic anaemia in the late 19th century (Goldstein 1988). There is good evidence that it is not benzene itself but rather one or more metabolites of benzene that is responsible for its haematological toxicity, although the exact metabolites and their subcellular targets have yet to be clearly identified (Snyder, Witz and Goldstein 1993).

Implicit in the recognition that benzene metabolism plays a role in its toxicity, as well as recent research on the metabolic processes involved in the metabolism of compounds such as benzene, is the likelihood that there will be differences in human sensitivity to benzene, based upon differences in metabolic rates conditioned by environmental or genetic factors. There is some evidence of a familial tendency towards benzene-induced aplastic anaemia, but this has not been clearly demonstrated. Cytochrome P-450(2E1) appears to play an important role in the formation of haematotoxic metabolites of benzene, and there is some suggestion from recent studies in China that workers with higher activities of this cytochrome are more at risk. Similarly, it has been suggested that Thalassaemia minor, and presumably other disorders in which there is increased bone marrow turnover, may predispose a person to benzene-induced aplastic anaemia (Yin et al. 1996). Although there are indications of some differences in susceptibility to benzene, the overall impression from the literature is that, in contrast to a variety of other agents such as chloramphenicol, for which there is a wide range in sensitivity, even including idiosyncratic reactions producing aplastic anaemia at relatively trivial levels of exposure, there is a virtual universal response to benzene exposure, leading to bone marrow toxicity and eventually aplastic anaemia in a dose-dependent fashion.

The effect of benzene on the bone marrow is thus analogous to the effect produced by chemotherapeutic alkylating agents used in the treatment of Hodgkin’s disease and other cancers (Tucker et al. 1988). With increasing dosage there is a progressive decline in all of the formed elements of the blood, which is sometimes manifested initially as anaemia, leucopenia or thrombocytopenia. It should be noted that it would be most unexpected to observe a person with thrombocytopenia that was not at least accompanied by a low normal level of the other formed blood elements. Further, such an isolated cytopenia would not be expected to be severe. In other words, an isolated white blood count of 2,000 per ml, where the normal range is 5,000 to 10,000, would suggest strongly that the cause of the leucopenia was other than benzene (Goldstein 1988).

The bone marrow has substantial reserve capacity. Following even a significant degree of hypoplasia of the bone marrow as part of a chemotherapeutic regimen, the blood count usually eventually returns to normal. However, individuals who have undergone such treatments cannot respond by producing as high a white blood cell count when exposed to a challenge to their bone marrow, such as endotoxin, as can individuals who have never previously been treated with such chemotherapeutic agents. It is reasonable to infer that there are dose levels of an agent such as benzene which can destroy bone marrow precursor cells and thus affect the reserve capability of the bone marrow without incurring sufficient damage to lead to a blood count that was lower than the laboratory range of normal. Because routine medical surveillance may not reveal abnormalities in a worker who may have indeed suffered from the exposure, the focus on worker protection must be preventive and employ basic principles of occupational hygiene. Although the extent of the development of bone marrow toxicity in relationship to benzene exposure at the workplace remains unclear, it does not appear that a single acute exposure to benzene is likely to cause aplastic anaemia. This observation might reflect the fact that bone marrow precursor cells are at risk only in certain phases of their cell cycle, perhaps when they are dividing, and not all the cells will be in that phase during a single acute exposure. The rapidity with which cytopenia develops depends in part on the circulating lifetime of the cell type. Complete cessation of bone marrow production would lead first to a leucopenia because white blood cells, particularly granulocytic blood cells, persist in circulation for less than a day. Next there would be a decrease in platelets, whose survival time is about ten days. Lastly there would be a decrease in red cells, which survive for a total of 120 days.

Benzene not only destroys the pluripotential stem cell, which is responsible for the production of red blood cells, platelets and granulocytic white blood cells, but it also has been found to cause a rapid loss in circulating lymphocytes in both laboratory animals and in humans. This suggests the potential for benzene to have an adverse effect on the immune system in exposed workers, an effect that has not been clearly demonstrated as yet (Rothman et al. 1996).

Benzene exposure has been associated with aplastic anaemia, which is frequently a fatal disorder. Death usually is caused by infection because the reduction in white blood cells, leucopenia, so compromises the body’s defence system, or by haemorrhage due to the reduction in platelets necessary for normal clotting. An individual exposed to benzene at a workplace who develops a severe aplastic anaemia must be considered to be a sentinel for similar effects in co-workers. Studies based on the discovery of a sentinel individual often have uncovered groups of workers who exhibit obvious evidence of benzene haematotoxicity. For the most part, those individuals who do not succumb relatively quickly to aplastic anaemia will usually recover following removal from the benzene exposure. In one follow-up study of a group of workers who previously had significant benzene-induced pancytopenia (decrease in all blood cell types) there were only minor residual haematological abnormalities ten years later (Hernberg et al. 1966). However, some workers in these groups, with initially relatively severe pancytopenia, progressed in their illnesses by first developing aplastic anaemia, then a myelodysplastic preleukaemic phase, and finally to the eventual development of acute myelogenous leukaemia (Laskin and Goldstein 1977). Such progression of disease is not unexpected since individuals with aplastic anaemia from any cause appear to have a higher-than-expected likelihood of developing acute myelogenous leukaemia (De Planque et al. 1988).

Other causes of aplastic anaemia

Other agents in the workplace have been associated with aplastic anaemia, the most notable being radiation. The effects of radiation on bone marrow stem cells have been employed in the therapy of leukaemia. Similarly, a variety of chemotherapeutic alkylating agents produce aplasia and pose a risk to workers responsible for producing or administering these compounds. Radiation, benzene and alkylating agents all appear to have a threshold level below which aplastic anaemia will not occur.

Protection of the production worker becomes more problematic when the agent has an idiosyncratic mode of action in which minuscule amounts may produce aplasia, such as chloramphenicol. Trinitrotoluene, which is absorbed readily through the skin, has been associated with aplastic anaemia in munition plants. A variety of other chemicals has been reported to be associated with aplastic anaemia, but it is often difficult to determine causality. An example is the pesticide lindane (gamma-benzene hexachloride). Case reports have appeared, generally following relatively high levels of exposure, in which lindane is associated with aplasia. This finding is far from being universal in humans, and there are no reports of lindane-induced bone marrow toxicity in laboratory animals treated with large doses of this agent. Bone marrow hypoplasia has also been associated with exposure to ethylene glycol ethers, various pesticides and arsenic (Flemming and Timmeny 1993).

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Gunnar Nordberg

Occurrence and Uses

Barium (Ba) is abundant in nature and accounts for approximately 0.04% of the earth’s crust. The chief sources are the minerals barite (barium sulphate, BaSO₄) and witherite (barium carbonate, BaCO₃). Barium metal is produced in only limited quantities, by aluminium reduction of barium oxide in a retort.

Barium is used extensively in the manufacture of alloys for nickel barium parts found in ignition equipment for automobiles and in the manufacture of glass, ceramics and television picture tubes. Barite (BaSO₄), or barium sulphate, is primarily used in the manufacture of lithopone, a white powder containing 20% barium sulphate, 30% zinc sulphide and less than 8% zinc oxide. Lithopone is widely employed as a pigment in white paints. Chemically precipitated barium sulphate—blanc fixe—is used in high-quality paints, in x-ray diagnostic work and in the glass and paper industries. It is also used in the manufacture of photographic papers, artificial ivory and cellophane. Crude barite is used as a thixotropic mud in oil-well drilling.

Barium hydroxide (Ba(OH)₂) is found in lubricants, pesticides, the sugar industry, corrosion inhibitors, drilling fluids and water softeners. It is also used in glass manufacture, synthetic rubber vulcanization, animal and vegetable oil refining, and fresco painting. Barium carbonate (BaCO₃) is obtained as a precipitate of barite and is used in the brick, ceramics, paint, rubber, oil-well drilling and paper industries. It also finds use in enamels, marble substitutes, optical glass and electrodes.

Barium oxide (BaO) is a white alkaline powder which is used to dry gases and solvents. At 450°C it combines with oxygen to produce barium peroxide (BaO₂), an oxidizing agent in organic synthesis and a bleaching material for animal substances and vegetable fibres. Barium peroxide is used in the textile industry for dyeing and printing, in powder aluminium for welding and in pyrotechnics.

Barium chloride (BaCl₂) is obtained by roasting barite with coal and calcium chloride, and is used in the manufacture of pigments, colour lakes and glass, and as a mordant for acid dyes. It is also useful for weighting and dyeing textile fabrics and in aluminium refining. Barium chloride is a pesticide, a compound added to boilers for softening water, and a tanning and finishing agent for leather. Barium nitrate (Ba(NO₃)₂) is used in pyrotechnics and the electronics industries.

Hazards

Barium metal has only limited use and presents an explosion hazard. The soluble compounds of barium (chloride, nitrate, hydroxide) are highly toxic; the inhalation of the insoluble compounds (sulphate) may give rise to pneumoconiosis. Many of the compounds, including the sulphide, oxide and carbonate, may cause local irritation to the eyes, nose, throat and skin. Certain compounds, particularly the peroxide, nitrate and chlorate, present fire hazards in use and storage.

Toxicity

When the soluble compounds enter by the oral route they are highly toxic, with a fatal dose of the chloride thought to be 0.8 to 0.9 g. However, although poisoning due to the ingestion of these compounds does occasionally occur, very few cases of industrial poisoning have been reported. Poisoning may result when workers are exposed to atmospheric concentrations of the dust of soluble compounds such as may occur during grinding. These compounds exert a strong and prolonged stimulant action on all forms of muscle, markedly increasing contractility. In the heart, irregular contractions may be followed by fibrillation, and there is evidence of a coronary constrictor action. Other effects include intestinal peristalsis, vascular constriction, bladder contraction and an increase in voluntary muscle tension. Barium compounds also have irritant effects on mucous membranes and the eye.

Barium carbonate, an insoluble compound, does not appear to have pathological effects from inhalation; however, it can cause severe poisoning from oral intake, and in rats it impairs the function of the male and female gonads; the foetus is sensitive to barium carbonate during the first half of pregnancy.

Pneumoconiosis

Barium sulphate is characterized by its extreme insolubility, a property which makes it non-toxic to humans. For this reason and due to its high radio-opacity, barium sulphate is used as an opaque medium in x-ray examination of the gastrointestinal, respiratory and urinary systems. It is also inert in the human lung, as has been demonstrated by its lack of adverse effects following deliberate introduction into the bronchial tract as a contrast medium in bronchography and by industrial exposure to high concentrations of fine dust.

Inhalation, however, may lead to deposition in the lungs in sufficient quantities to produce baritosis (a benign pneumoconiosis, which principally occurs in the mining, grinding and bagging of barite, but has been reported in the manufacture of lithopone). The first reported case of baritosis was accompanied by symptoms and disability, but these were associated later with other lung disease. Subsequent studies have contrasted the unimpressive nature of the clinical picture and the total absence of symptoms and abnormal physical signs with the well marked x-ray changes, which show disseminated nodular opacities throughout both lungs. The opacities are discrete but sometimes so numerous as to overlap and appear confluent. No massive shadows have been reported. The outstanding feature of the radiographs is the marked radio-opacity of the nodules, which is understandable in view of the substance’s use as a radio-opaque medium. The size of the individual elements may vary between 1 and 5 mm in diameter, although the average is about 3 mm or less, and the shape has been described variously as “rounded” and “dendritic”. In some cases, a number of very dense points have been found to lie in a matrix of lower density.

In one series of cases, dust concentrations of up to 11,000 particles/cm³ were measured at the workplace, and chemical analysis showed that the total silica content lay between 0.07 and 1.96%, quartz not being detectable by x-ray diffraction. Men exposed for up to 20 years and exhibiting x-ray changes were symptomless, had excellent lung function and were capable of carrying out strenuous work. Years after the exposure has ceased, follow-up examinations show a marked clearing of x-ray abnormalities.

Reports of post-mortem findings in pure baritosis are practically non-existent. However, baritosis may be associated with silicosis in mining due to contamination of barite ore by siliceous rock, and, in grinding, if siliceous millstones are used.

Safety and Health Measures

Adequate washing and other sanitary facilities should be provided for workers exposed to toxic soluble barium compounds, and rigorous personal hygiene measures should be encouraged. Smoking and consumption of food and beverages in workshops should be prohibited. Floors in workshops should be made of impermeable materials and frequently washed down. Employees working on such processes as barite leaching with sulphuric acid should be supplied with acid-resistant clothing and suitable hand and face protection. Although baritosis is benign, efforts should still be made to reduce atmospheric concentrations of barite dust to a minimum. In addition, particular attention should be paid to the presence of free silica in the airborne dust.

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Gunnar Nordberg

There are three major groups of arsenic (As) compounds:

1. inorganic arsenic compounds
2. organic arsenic compounds
3. arsine gas and substituted arsines.

Occurrence and Uses

Arsenic is found widely in nature and most abundantly in sulphide ores. Arsenopyrite (FeAsS) is the most abundant one.

Elemental arsenic

Elemental arsenic is utilized in alloys in order to increase their hardness and heat resistance (e.g., alloys with lead in shot-making and battery grids). It is also used in the manufacture of certain types of glass, as a component of electrical devices and as a doping agent in germanium and silicon solid-state products.

Trivalent inorganic compounds

Arsenic trichloride (AsCl₃) is used in the ceramics industry and in the manufacturing of chlorine-containing arsenicals. Arsenic trioxide (As₂O₃), or white arsenic, is useful in the purification of synthesis gas and as a primary material for all arsenic compounds. It is also a preservative for hides and wood, a textile mordant, a reagent in mineral flotation, and a decolourizing and refining agent in glass manufacture. Calcium arsenite (Ca(As₂H₂O₄)) and cupric acetoarsenite (usually considered Cu(COOCH₃)₂ 3Cu(AsO₂)₂) are insecticides. Cupric acetoarsenite is also used for painting ships and submarines. Sodium arsenite (NaAsO₂) is employed as a herbicide, a corrosion inhibitor, and as a drying agent in the textile industry. Arsenic trisulphide is a component of infrared-transmitting glass and a dehairing agent in the tanning industry. It is also used in the manufacturing of pyrotechnics and semiconductors.

Pentavalent inorganic compounds

Arsenic acid (H₃AsO₄·½H₂O) is found in the manufacture of arsenates, glass making and wood-treating processes. Arsenic pentoxide (As₂O₅), an herbicide and a wood preservative, is also used in the manufacture of coloured glass.

Calcium arsenate (Ca₃(AsO₄)₂) is used as an insecticide.

Organic arsenic compounds

Cacodylic acid ((CH₃)₂AsOOH) is used as a herbicide and a defoliant. Arsanilic acid (NH₂C₆H₄AsO(OH)₂) finds use as a grasshopper bait and as an additive in animal feeds. Organic arsenic compounds in marine organisms occur in concentrations corresponding to a concentration of arsenic in the range 1 to 100 mg/kg in marine organisms such as shrimp and fish. Such arsenic is mainly made up of arsenobetaine and arsenocholine, organic arsenic compounds of low toxicity.

Arsine gas and the substituted arsines. Arsine gas is used in organic syntheses and in the processing of solid-state electronic components. Arsine gas may also be generated inadvertently in industrial processes when nascent hydrogen is formed and arsenic is present.

The substituted arsines are trivalent organic arsenical compounds which, depending on the number of alkyl or phenyl groups that they have attached to the arsenic nucleus, are known as mono-, di- or tri-substituted arsines. Dichloroethylarsine (C₂H₅AsCl₂), or ethyldichloroarsine, is a colourless liquid with an irritant odour. This compound, like the following one, was developed as a potential chemical warfare agent.

Dichloro(2-chlorovinyl-)arsine (ClCH:CHAsCl₂), or chlorovinyldichloroarsine (lewisite), is an olive-green liquid with a germanium-like odour. It was developed as a potential warfare agent but never used. The agent dimercaprol or British anti-lewisite (BAL) was developed as an antidote.

Dimethyl-arsine (CH₃)₂AsH, or cacodyl hydride and trimethylarsine (CH₃)₃As), or trimethylarsenic, are both colourless liquids. These two compounds can be produced after metabolic transformation of arsenic compounds by bacteria and fungi.

Hazards

Inorganic arsenic compounds

General aspects of toxicity. Although it is possible that very small amounts of certain arsenic compounds may have beneficial effects, as indicated by some animal studies, arsenic compounds, particularly the inorganic ones, are otherwise regarded as very potent poisons. Acute toxicity varies widely among compounds, depending on their valency state and solubility in biological media. The soluble trivalent compounds are the most toxic. Uptake of inorganic arsenic compounds from the gastrointestinal tract is almost complete, but uptake may be delayed for less soluble forms such as arsenic trioxide in particle form. Uptake after inhalation is also almost complete, since even less soluble material deposited on the respiratory mucosa, will be transferred to the gastrointestinal tract and subsequently taken up.

Occupational exposure to inorganic arsenic compounds through inhalation, ingestion or skin contact with subsequent absorption may occur in industry. Acute effects at the point of entry may occur if exposure is excessive. Dermatitis may occur as an acute symptom but is more often the result of toxicity from long-term exposure, sometimes subsequent to sensitization (see the section “Long-term exposure (chronic poisoning)”).

Acute poisoning

Exposure to high doses of inorganic arsenic compounds by a combination of inhalation and ingestion may occur as a result of accidents in industries where large amounts of arsenic (e.g., arsenic trioxide), are handled. Depending on dose, various symptoms may develop, and when doses are excessive, fatal cases may occur. Symptoms of conjunctivitis, bronchitis and dyspnoea, followed by gastrointestinal discomfort with vomiting, and subsequently cardiac involvement with irreversible shock, may occur in a time course of hours. Arsenic in blood was reported to be above 3 mg/l in a case with fatal outcome.

With exposure to sub-lethal doses of irritant arsenic compounds in air (e.g., arsenic trioxide), there may be symptoms related to acute damage to the mucous membranes of the respiratory system and acute symptoms from exposed skin. Severe irritation of the nasal mucosae, larynx and bronchi, as well as conjunctivitis and dermatitis, occur in such cases. Perforation of the nasal septum can be observed in some individuals only after a few weeks following exposure. A certain tolerance against acute poisoning is believed to develop upon repeated exposure. This phenomenon, however, is not well documented in the scientific literature.

Effects due to accidental ingestion of inorganic arsenicals, mainly arsenic trioxide, have been described in the literature. However, such incidents are rare in industry today. Cases of poisoning are characterized by profound gastrointestinal damage, resulting in severe vomiting and diarrhoea, which may result in shock and subsequent oliguria and albuminuria. Other acute symptoms are facial oedema, muscular cramps and cardiac abnormalities. Symptoms may occur within a few minutes following exposure to the poison in solution, but may be delayed for several hours if the arsenic compound is in solid form or if it is taken with a meal. When ingested as a particulate, toxicity is also dependent on solubility and particle size of the ingested compound. The fatal dose of ingested arsenic trioxide has been reported to range from 70 to 180 mg. Death may occur within 24 hours, but the usual course runs from 3 to 7 days. Acute intoxication with arsenic compounds is usually accompanied by anaemia and leucopenia, especially granulocytopenia. In survivors these effects are usually reversible within 2 to 3 weeks. Reversible enlargement of the liver is also seen in acute poisoning, but liver function tests and liver enzymes are usually normal.

In individuals surviving acute poisoning, peripheral nervous disturbances frequently develop a few weeks after ingestion.

Long-term exposure (chronic poisoning)

General aspects. Chronic arsenic poisoning may occur in workers exposed for a long time to excessive concentrations of airborne arsenic compounds. Local effects in the mucous membranes of the respiratory tract and the skin are prominent features. Involvement of the nervous and circulatory system and the liver may also occur, as well as cancer of the respiratory tract.

With long-term exposure to arsenic via ingestion in food, drinking water or medication, symptoms are partly different from those after inhalation exposure. Vague abdominal symptoms—diarrhoea or constipation, flushing of the skin, pigmentation and hyperkeratosis—dominate the clinical picture. In addition, there may be vascular involvement, reported in one area to have given rise to peripheral gangrene.

Anaemia and leucocytopenia often occur in chronic arsenic poisoning. Liver involvement has been more commonly seen in persons exposed for a long time via oral ingestion than in those exposed via inhalation, particularly in vineyard workers considered to have been exposed mainly through drinking contaminated wine. Skin cancer occurs with excess frequency in this type of poisoning.

Vascular disorders. Long-term oral exposure to inorganic arsenic via drinking water may give rise to peripheral vascular disorders with Raynaud’s phenomenon. In one area of Taiwan, China, peripheral gangrene (so-called Blackfoot disease) has occurred. Such severe manifestations of peripheral vascular involvement have not been observed in occupationally exposed persons, but slight changes with Raynaud’s phenomenon and an increased prevalence of low peripheral blood presssure on cooling have been found in workers exposed for a long time to airborne inorganic arsenic (doses of absorbed arsenic are given below.

Dermatological disorders. Arsenical skin lesions differ somewhat, depending on the type of exposure. Eczematoid symptoms of varying degrees of severity do occur. In occupational exposure to mainly airborne arsenic, skin lesions may result from local irritation. Two types of dermatological disorders may occur:

1. an eczematous type with erythema (redness), swelling and papules or vesicles
2. a follicular type with erythema and follicular swelling or follicular pustules.

Dermatitis is primarily localized on the most heavily exposed areas, such as the face, back of the neck, forearms, wrists and hands. However, it may also occur on the scrotum, the inner surfaces of the thighs, the upper chest and back, the lower legs and around the ankles. Hyperpigmentation and keratoses are not prominent features of this type of arsenical lesions. Patch tests have demonstrated that the dermatitis is due to arsenic, not to impurities present in the crude arsenic trioxide. Chronic dermal lesions may follow this type of initial reaction, depending on the concentration and duration of exposure. These chronic lesions may occur after many years of occupational or environmental exposure. Hyperkeratosis, warts and melanosis of the skin are the conspicuous signs.

Melanosis is most commonly seen on the upper and lower eyelids, around the temples, on the neck, on the areolae of the nipples and in the folds of the axillae. In severe cases arsenomelanosis is observed on the abdomen, chest, back and scrotum, along with hyperkeratosis and warts. In chronic arsenic poisoning, depigmentation (i.e., leukoderma), especially on the pigmented areas, commonly called “raindrop” pigmentation, also occurs. These chronic skin lesions, particularly the hyperkeratoses, may develop into pre-cancerous and cancerous lesions. A transverse striation of the nails (so-called Mees lines) also occurs in chronic arsenical poisoning. It should be noted that the chronic skin lesions may develop long after cessation of exposure, when arsenic concentrations in skin have returned to normal.

Mucous membrane lesions in chronic arsenic exposure is most classically reported as perforation of the nasal septum after inhalation exposure. This lesion is a result of irritation of the mucous membranes of the nose. Such irritation also extends to the larynx, trachea and bronchi. Both in inhalation exposure and in poisoning caused by repeated ingestion, dermatitis of the face and eyelids sometimes extends to keratoconjunctivitis.

Peripheral neuropathy. Peripheral nervous disturbances are frequently encountered in survivors of acute poisoning. They usually start within a few weeks after the acute poisoning, and recovery is slow. The neuropathy is characterized by both motor dysfunction and paresthaesia, but in less severe cases only sensory unilateral neuropathy may occur. Often the lower extremities are more affected than the upper ones. In subjects recovering from arsenical poisoning, Mees lines of the fingernails may develop. Histological examination has revealed Wallerian degeneration, especially in the longer axons. Peripheral neuropathy also may occur in industrial arsenic exposure, in most cases in a subclinical form that can be detected only by neurophysiological methods. In a group of smelter workers with long-term exposure corresponding to a mean cumulative total absorption of approximately 5 g (maximal absorption of 20 g), there was a negative correlation between cumulative absorption of arsenic and nerve conduction velocity. There were also some light clinical manifestations of peripheral vascular involvement in these workers (see above). In children exposed to arsenic, hearing loss has been reported.

Carcinogenic effects. Inorganic arsenic compounds are classified by the International Agency for Research on Cancer (IARC) as lung and skin carcinogens. There is also some evidence to suggest that persons exposed to inorganic arsenic compounds suffer a higher incidence of angiosarcoma of the liver and possibly of stomach cancer. Cancer of the respiratory tract has been reported in excess frequency among workers engaged in the production of insecticides containing lead arsenate and calcium arsenate, in vine-growers spraying insecticides containing inorganic copper and arsenic compounds, and in smelter workers exposed to inorganic compounds of arsenic and a number of other metals. The latency time between onset of exposure and the appearance of cancer is long, usually between 15 and 30 years. A synergistic action of tobacco smoking has been demonstrated for lung cancer.

Long-term exposure to inorganic arsenic via drinking water has been associated with an increased incidence of skin cancer in Taiwan and in Chile. This increase has been shown to be related to concentration in drinking water.

Teratogenic effects. High doses of trivalent inorganic arsenic compounds may cause malformations in hamsters when injected intravenously. With regard to human beings there is no firm evidence that arsenic compounds cause malformations under industrial conditions. Some evidence, however, suggests such an effect in workers in a smelting environment who were exposed simultaneously also to a number of other metals as well as other compounds.

Organic arsenic compounds

Organic arsenicals used as pesticides or as drugs may also give rise to toxicity, although such adverse effects are incompletely documented in humans.

Toxic effects on the nervous system have been reported in experimental animals following feeding with high doses of arsanilic acid, which is commonly used as a feed additive in poultry and swine.

The organic arsenic compounds that occur in foodstuffs of marine origin, such as shrimp, crab and fish, are made up of arsinocholine and arsinobetaine. It is well known that the amounts of organic arsenic that are present in fish and shellfish can be consumed without ill effects. These compounds are quickly excreted, mainly via urine.

Arsine gas and the substituted arsines. Many cases of acute arsine poisoning have been recorded, and there is a high fatality rate. Arsine is one of the most powerful haemolytic agents found in industry. Its haemolytic activity is due to its ability to cause a fall in erythrocyte-reduced glutathion content.

Signs and symptoms of arsine poisoning include haemolysis, which develops after a latent period that is dependent on the intensity of exposure. Inhalation of 250 ppm of arsine gas is instantly lethal. Exposure to 25 to 50 ppm for 30 minutes is lethal, and 10 ppm may be lethal after longer exposures. The signs and symptoms of poisoning are those characteristic of an acute and massive haemolysis. Initially there is a painless haemoglobinuria, gastrointestinal disturbance such as nausea and possibly vomiting. There may also be abdominal cramps and tenderness. Jaundice accompanied by anuria and oliguria subsequently occurs. Evidence of bone marrow depression may be present. After acute and severe exposure, a peripheral neuropathy may develop and can still be present several months after poisoning. Little is known about repeated or chronic exposure to arsine, but since the arsine gas is metabolized to inorganic arsenic in the body, it can be assumed that there is a risk for symptoms similar to those in long-term exposure to inorganic arsenic compounds.

The differential diagnosis should take account of acute haemolytic anaemias that could be caused by other chemical agents such as stibine or drugs, and secondary immunohaemolytic anaemias.

The substituted arsines do not give rise to haemolysis as their main effect, but they act as powerful local and pulmonary irritants and systemic poisons. The local effect on the skin gives rise to sharply circumscribed blisters in the case of dichloro(2-chlorovinyl-)arsine (lewisite). The vapour induces marked spasmodic coughing with frowzy or blood-stained sputum, progressing to acute pulmonary oedema. Dimercaprol (BAL) is an effective antidote if given in the early stages of poisoning.

Safety and Health Measures

The most common type of occupational arsenic exposure is to inorganic arsenic compounds, and these safety and health measures are mainly related to such exposures. When there is a risk of exposure to arsine gas, particular attention needs to be paid to accidental leaks, since peak exposures for short intervals may be of special concern.

The best means of prevention is to keep exposure well below accepted exposure limits. A programme of measurement of air-concentrations of arsenic is thus of importance. In addition to inhalation exposure, oral exposure via contaminated clothes, hands, tobacco and so on should be watched, and biological monitoring of inorganic arsenic in urine may be useful for evaluation of absorbed doses. Workers should be supplied with suitable protective clothing, protective boots and, when there is a risk that the exposure limit for airborne arsenic will be exceeded, respiratory protective equipment. Lockers should be provided with separate compartments for work and personal clothes, and adjacent sanitary facilities of a high standard should be made available. Smoking, eating and drinking at the workplace should not be allowed. Pre-employment medical examinations should be carried out. It is not recommended to employ persons with pre-existing diabetes, cardiovascular diseases, anaemia, allergic or other skin diseases, neurologic, hepatic or renal lesions, in arsenic work. Periodic medical examinations of all arsenic-exposed employees should be performed with special attention to possible arsenic-related symptoms.

Determination of the level of inorganic arsenic and its metabolites in urine allows estimation of the total dose of inorganic arsenic taken up by various exposure routes. Only when inorganic arsenic and its metabolites can be specifically measured is this method useful. Total arsenic in urine may often give erroneous information about industrial exposure, since even a single meal of fish or other marine organisms (containing considerable amounts of non-toxic organic arsenic compound) may cause greatly elevated urinary arsenic concentrations for several days.

Treatment

Arsine gas poisoning. When there is reason to believe that there has been considerable exposure to arsine gas, or upon observation of the first symptoms (e.g., haemoglobinuria and abdominal pain), immediate removal of the individual from the contaminated environment and prompt medical attention are required. The recommended treatment, if there is any evidence of impaired renal function, consists of total-replacement blood transfusion associated with prolonged artificial dialysis. Forced diuresis has proved useful in some cases, whereas, in the opinion of most authors, treatment with BAL or other chelating agents seems to have only limited effect.

Exposure to the substituted arsines should be treated in the same way as inorganic arsenic poisoning (see below).

Poisoning by inorganic arsenic. If there has been exposure to doses that can be estimated to give rise to acute poisoning, or if severe symptoms from the respiratory system, the skin or the gastrointestinal tract occur in the course of long-term exposures, the worker should immediately be removed from exposure and treated with a complexing agent.

The classical agent which has been used most widely in such situations is 2,3-dimercapto-1-propanol or British anti-lewisite (BAL, dimercaprol). Prompt administration in such cases is vital: to obtain maximal benefit such treatment should be given within 4 hours of poisoning. Other pharmaceuticals which may be used are sodium 2,3-dimercaptopropanesulphonate (DMPS or unithiol) or meso-2,3-dimercaptosuccinic acid (DMSA). These drugs are less likely to give side effects and are believed to be more effective than BAL. Intravenous administration of N-acetylcysteine has been reported in one case to be of value; in addition, general treatment, such as prevention of further absorption by removal from exposure and minimizing absorption from the gastrointestinal tract by gastric lavage and administration by gastric tube of chelating agents or charcoal, is mandatory. General supportive therapy, such as maintenance of respiration and circulation, maintenance of water and electrolyte balance, and control of nervous system effects, as well as elimination of absorbed poison through haemodialysis and exchange transfusion, may be used if feasible.

Acute skin lesions such as contact dermatitis and mild manifestations of peripheral vascular involvement, such as Raynaud’s syndrome, usually do not require treatment other than removal from exposure.

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Gunnar Nordberg

Antimony is stable at room temperature but, when heated, burns brilliantly, giving off dense white fumes of antimony oxide (Sb₂O₃) with a garlic-like odour. It is closely related, chemically, to arsenic. It readily forms alloys with arsenic, lead, tin, zinc, iron and bismuth.

Occurrence and Uses

In nature, antimony is found in combination with numerous elements, and the most common ores are stibnite (SbS₃), valentinite (Sb₂O₃), kermesite (Sb₂S₂O) and senarmontite (Sb₂O₃).

High-purity antimony is employed in the manufacture of semiconductors. Normal-purity antimony is used widely in the production of alloys, to which it imparts increased hardness, mechanical strength, corrosion resistance and a low coefficient of friction; alloys combining tin, lead and antimony are used in the electrical industry. Among the more important antimony alloys are babbitt, pewter, white metal, Britannia metal and bearing metal. These are used for bearing shells, storage battery plates, cable sheathing, solder, ornamental castings and ammunition. The resistance of metallic antimony to acids and bases is put to effect in the manufacture of chemical plants.

Hazards

The principal hazard of antimony is that of intoxication by ingestion, inhalation or skin absorption. The respiratory tract is the most important route of entry since antimony is so frequently encountered as a fine airborne dust. Ingestion may occur through swallowing dust or through contamination of beverages, food or tobacco. Skin absorption is less common, but may occur when antimony is in prolonged contact with skin.

The dust encountered in antimony mining may contain free silica, and cases of pneumoconiosis (termed silico-antimoniosis) have been reported among antimony miners. During processing, the antimony ore, which is extremely brittle, is converted into fine dust more rapidly than the accompanying rock, leading to high atmospheric concentrations of fine dust during such operations as reduction and screening. Dust produced during crushing is relatively coarse, and the remaining operations—classification, flotation, filtration and so on—are wet processes and, consequently, dust free. Furnace workers who refine metallic antimony and produce antimony alloy, and workers setting type in the printing industry, are all exposed to antimony metal dust and fumes, and may present diffuse miliar opacities in the lung, with no clinical or functional signs of impairment in the absence of silica dust.

Inhalation of antimony aerosols may produce localized reactions of the mucous membrane, respiratory tract and lungs. Examination of miners and concentrator and smelter workers exposed to antimony dust and fumes has revealed dermatitis, rhinitis, inflammation of upper and lower respiratory tracts, including pneumonitis and even gastritis, conjunctivitis and perforations of the nasal septum.

Pneumoconiosis, sometimes in combination with obstructive lung changes, has been reported following long-term exposure in humans. Although antimony pneumoconiosis is regarded as benign, the chronic respiratory effects associated with heavy antimony exposure are not considered harmless. In addition, effects on the heart, even fatal, have been related to long-term occupational exposure to antimony trioxide.

Pustular skin infections are sometimes seen in persons working with antimony and antimony salts. These eruptions are transient and primarily affect the skin areas in which heat exposure or sweating has occurred.

Toxicology

In its chemical properties and metabolic action, antimony has a close resemblance to arsenic, and, since the two elements are sometimes found in association, the action of antimony may be blamed on arsenic, especially in foundry workers. However, experiments with high-purity metallic antimony have shown that this metal has a completely independent toxicology; different authors have found the average lethal dose to be between 10 and 11.2 mg/100 g.

Antimony may enter the body through the skin, but the principal route is through the lungs. From the lungs, antimony, and especially free antimony, is absorbed and taken up by the blood and tissues. Studies on workers and experiments with radioactive antimony have shown that the major part of the absorbed dose enters the metabolism within 48 hours and is eliminated in the faeces and, to a lesser extent, the urine. The remainder stays in the blood for some considerable time, with the erythrocytes containing several times more antimony than the serum. In workers exposed to pentavalent antimony, the urinary excretion of antimony is related to the intensity of exposure. It has been estimated that after 8 hours exposure to 500 µg Sb/m³, the increase in concentration of antimony excreted in the urine at the end of a shift amounts on average to 35 µg/g creatinine.

Antimony inhibits the activity of certain enzymes, binds sulphydryl groups in the serum, and disturbs protein and carbohydrate metabolism and the production of glycogen by the liver. Prolonged animal experiments with antimony aerosols have led to the development of distinctive endogenous lipoid pneumonia. Cardiac injury and cases of sudden death have also been reported in workers exposed to antimony. Focal fibrosis of the lung and cardiovascular effects have also been observed in animal trials.

The therapeutic use of antimonial drugs has made it possible to detect, in particular, the cumulative myocardial toxicity of the trivalent derivatives of antimony (which are excreted more slowly than pentavalent derivatives). Reduction in amplitude of T wave, increase of QT interval and arrhythmias have been observed in the electrocardiogram.

Symptoms

The symptoms of acute poisoning include violent irritation of the mouth, nose, stomach and intestines; vomiting and bloody stools; slow, shallow respiration; coma sometimes followed by death due to exhaustion and hepatic and renal complications. Those of chronic poisoning are: dryness of throat, nausea, headaches, sleeplessness, loss of appetite, and dizziness. Gender differences in the effects of antimony have been noted by some authors, but the differences are not well established.

Compounds

Stibine (SbH₃), or antimony hydride (hydrogen antimonide), is produced by dissolving zinc-antimony or magnesium-antimony alloy in dilute hydrochloric acid. However, it occurs frequently as a by-product in the processing of metals containing antimony with reducing acids or in overcharging storage batteries. Stibine has been used as a fumigating agent. High-purity stibine is used as an n-type gas-phase dopant for silicon in semiconductors. Stibine is an extremely hazardous gas. Like arsine it may destroy blood cells and cause haemoglobinuria, jaundice, anuria and death. Symptoms include headache, nausea, epigastric pain and passage of dark red urine following exposure.

Antimony trioxide (Sb₂O₃) is the most important of the antimony oxides. When airborne, it tends to remain suspended for an exceptionally long time. It is obtained from antimony ore by a roasting process or by oxidizing metallic antimony and subsequent sublimation, and is used for the manufacture of tartar emetic, as a paint pigment, in enamels and glazes, and as a flameproofing compound.

Antimony trioxide is both a systemic poison and a skin disease hazard, although its toxicity is three times less than that of the metal. In long-term animal experiments, rats exposed to antimony trioxide via inhalation showed a high frequency of lung tumours. An excess of deaths due to cancer of the lung among workers engaged in antimony smelting for more than 4 years, at an average concentration in air of 8 mg/m³, has been reported from Newcastle. In addition to antimony dust and fumes, the workers were exposed to zircon plant effluents and caustic soda. No other experiences were informative on the carcinogenic potential of antimony trioxide. This has been classified by the American Conference of Governmental Industrial Hygienists (ACGIH) as a chemical substance associated with industrial processes which are suspected of inducing cancer.

Antimony pentoxide (Sb₂O₅) is produced by the oxidation of the trioxide or the pure metal, in nitric acid under heat. It is used in the manufacture of paints and lacquers, glass, pottery and pharmaceuticals. Antimony pentoxide is noted for its low degree of toxic hazard.

Antimony trisulphide (Sb₂S₃) is found as a natural mineral, antimonite, but can also be synthesized. It is used in the pyrotechnics, match and explosives industries, in ruby glass manufacture, and as a pigment and plasticizer in the rubber industry. An apparent increase in heart abnormalities has been found in persons exposed to the trisulphide. Antimony pentasulphide (Sb₂S₅) has much the same uses as the trisulphide and has a low level of toxicity.

Antimony trichloride (SbCl₃), or antimonous chloride (butter of antimony), is produced by the interaction of chlorine and antimony or by dissolving antimony trisulphide in hydrochloric acid. Antimony pentachloride (SbCl₅) is produced by the action of chlorine on molten antimony trichloride. The antimony chlorides are used for blueing steel and colouring aluminium, pewter and zinc, and as catalysts in organic synthesis, especially in the rubber and pharmaceutical industries. In addition, antimony trichloride is used in the match and petroleum industries. They are highly toxic substances, act as irritants and are corrosive to the skin. The trichloride has an LD₅₀ of 2.5 mg/100 g.

Antimony trifluoride (SbF₃) is prepared by dissolving antimony trioxide in hydrofluoric acid, and is used in organic synthesis. It is also employed in dyeing and pottery manufacture. Antimony trifluoride is highly toxic and an irritant to the skin. It has an LD₅₀ of 2.3 mg/100 g.

Safety and Health Measures

The essence of any safety programme for the prevention of antimony poisoning should be the control of dust and fume formation at all stages of processing.

In mining, dust prevention measures are similar to those for metal mining in general. During crushing, the ore should be sprayed or the process completely enclosed and fitted with local exhaust ventilation combined with adequate general ventilation. In antimony smelting the hazards of charge preparation, furnace operation, fettling and electrolytic cell operation should be eliminated, where possible, by isolation and process automation. Furnace workers should be provided with water sprays and effective ventilation.

Where complete elimination of exposure is not possible, the hands, arms and faces of workers should be protected by gloves, dustproof clothing and goggles, and, where atmospheric exposure is high, respirators should be provided. Barrier creams should also be applied, especially when handling soluble antimony compounds, in which case they should be combined with the use of waterproof clothing and rubber gloves. Personal hygiene measures should be strictly observed; no food or beverages should be consumed in the workshops, and suitable sanitary facilities should be provided so that workers can wash before meals and before leaving work.

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Gunner Nordberg

Occurrence and uses

Aluminium is the most abundant metal in the earth’s crust, where it is found in combination with oxygen, fluorine, silica, etc., but never in the metallic state. Bauxite is the principal source of aluminium. It consists of a mixture of minerals formed by the weathering of aluminium-bearing rocks. Bauxites are the richest form of these weathered ores, containing up to 55% alumina. Some lateritic ores (containing higher percentages of iron) contain up to 35% Al₂O₃· Commercial deposits of bauxite are mainly gibbsite (Al₂O₃·3H₂O) and boehmite (Al₂O₃·H₂O) and are found in Australia, Guyana, France, Brazil, Ghana, Guinea, Hungary, Jamaica and Suriname. World production of bauxite in 1995 was 111,064 million tonnes. Gibbsite is more readily soluble in sodium hydroxide solutions than boehmite and is therefore preferred for aluminium oxide production.

Aluminium is used widely throughout industry and in larger quantities than any other non-ferrous metal; worldwide primary metal production in 1995 was estimated at 20,402 million tonnes. It is alloyed with a variety of other material including copper, zinc, silicon, magnesium, manganese and nickel and may contain small amounts of chromium, lead, bismuth, titanium, zirconium and vanadium for special purposes. Aluminium and aluminium alloy ingots can be extruded or processed in rolling mills, wire-works, forges or foundries. The finished products are used in shipbuilding for internal fittings and superstructures; the electrical industry for wires and cables; the building industry for house and window frames, roofs and cladding; aircraft industry for airframes and aircraft skin and other components; automobile industry for bodywork, engine blocks and pistons; light engineering for domestic appliances and office equipment and in the jewellery industry. A major application of sheet is in beverage or food containers, while aluminium foil is used for packaging; a fine particulate form of aluminium is employed as a pigment in paints and in the pyrotechnics industry. Articles manufactured from aluminium are frequently given a protective and decorative surface finish by anodization.

Aluminium chloride is used in petroleum cracking and in the rubber industry. It fumes in air to form hydrochloric acid and combines explosively with water; consequently, containers should be kept tightly closed and protected from moisture.

Alkyl aluminium compounds. These are growing in importance as catalysts for the production of low-pressure polyethylene. They present a toxic, burn and fire hazard. They are extremely reactive with air, moisture and compounds containing active hydrogen and therefore must be kept under a blanket of inert gas.

Hazards

For the production of aluminium alloys, refined aluminium is melted in oil or gas-fired furnaces. A regulated amount of hardener containing aluminium blocks with a percentage of manganese, silicon, zinc, magnesium, etc. is added. The melt is then mixed and is passed into a holding furnace for degassing by passing either argon-chlorine or nitrogen-chlorine through the metal. The resultant gas emission (hydrochloric acid, hydrogen and chlorine) has been associated with occupational illnesses and great care should be taken to see that appropriate engineering controls capture the emissions and also prevent it from reaching the external environment, where it can also cause damage. Dross is skimmed off the surface of the melt and placed in containers to minimize exposure to air during cooling. A flux containing fluoride and/or chloride salts is added to the furnace to assist in separation of pure aluminium from the dross. Aluminium oxide and fluoride fumes may be given off so that this aspect of production must also be carefully controlled. Personal protective equipment (PPE) may be required. The aluminium smelting process is described in the chapter Metal processing and metal working industry. In the casting shops, exposure to sulphur dioxide may also occur.

A wide range of different crystalline forms of aluminium oxide is used as smelter feed stock, abrasives, refractories and catalysts. A series of reports published in 1947 to 1949 described a progressive, non-nodular interstitial fibrosis in the aluminium abrasives industry in which aluminium oxide and silicon were processed. This condition, known as Shaver’s disease, was rapidly progressive and often fatal. The exposure of the victims (workers producing alundum) was to a dense fume comprising aluminium oxide, crystalline free-silica and iron. The particulates were of a size range that made them highly respirable. It is likely that the preponderence of disease is attributable to the highly damaging lung effects of the finely divided crystalline free-silica, rather than to the inhaled aluminium oxide, although the exact aetiology of the disease is not understood. Shaver’s disease is primarily of historical interest now, since no reports have been made in the second half of the 20th century.

Recent studies of the health effects of high level exposures (100 mg/m³) to the oxides of aluminium amongst workers engaged in the Bayer process (described in the chapter Metal processing and metal working industry) have demonstrated that workers with more than twenty years of exposure can develop pulmonary alterations. These changes are clinically characterized by minor, predominantly asymptomatic degrees of restrictive pulmonary function changes. The chest x-ray examinations revealed small, scanty, irregular opacities, particularly at the lung bases. These clinical responses have been attributed to deposition of dust in the lung paraenchyma, which was the result of very high occupational exposures. These signs and symptoms cannot be compared to the extreme response of Shaver’s disease. It should be noted that other epidemiological studies in the United Kingdom regarding widespread alumina exposures in the pottery industry have produced no evidence that the inhalation of alumina dust produces chemical or radiographic signs of pulmonary disease or dysfunction.

The toxicological effects of aluminium oxides remain of interest because of its commerical importance. The results of animal experiments are controversial. An especially fine (0.02 μm to 0.04 μm), catalytically active aluminium oxide, uncommonly used commercially, can cause lung changes in animals dosed by injection directly into the lung airways. Lower dose effects have not been observed.

It should also be noted that so-called “potroom asthma” which has frequently been observed among workers in aluminium processing operations, is probably attributable to the exposures to fluoride fluxes, rather than to the aluminium dust itself.

The production of aluminium has been classified as a Group 1, known human carcinogenic exposure situation, by the International Agency for Research on Cancer (IARC). As with the other diseases described above, the carcinogenicity is most likely attributable to the other substances present (e.g., polycyclic aromatic hydrocarbons (PAHs) and silica dust), although the exact role of the alumina dusts are simply not understood.

Some data on the absorption of high levels of aluminium and nervous tissue damage are found among individuals requiring kidney dialysis. These high levels of aluminium have resulted in severe, even fatal brain damage. This response, however, has also been observed in other patients undergoing dialysis but who did not have similar elevated brain aluminium level. Animal experiments have been unsuccessful in replicating this brain response, or Alzheimer’s disease, which has also been postulated in the literature. Epidemiological and clinical follow-up studies on these issues have not been definitive and no evidence of such effects has been observed in the several large-scale epidemiological studies of aluminium workers.

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The material presented here is based on an exhaustive review, revision and expansion of the data on metals found in the 3rd edition of the Encyclopaedia of Occupational Health and Safety. Members of the Scientific Committee on the Toxicology of Metals of the International Commission on Occupational Health carried out much of the review. They are listed below, along with other reviewers and authors.

The reviewers are:

L. Alessio

Antero Aitio

P. Aspostoli

M. Berlin

Tom W. Clarkson

C-G. Elinder

Lars Friberg

Byung-Kook Lee

N. Karle Mottet

D.J. Nager

Kogi Nogawa

Tor Norseth

C.N. Ong

Kensaborv Tsuchiva

Nies Tsukuab.

The 4th edition contributors are:

Gunnar Nordberg

Sverre Langård.

F. William Sunderman, Jr.

Jeanne Mager Stellman

Debra Osinsky

Pia Markkanen

Bertram D. Dinman

Agency for Toxic Substances and Disease Registry (ATSDR).

Revisions are based on the contributions of the following 3rd edition authors:
A. Berlin, M. Berlin, P.L. Bidstrup, H.L. Boiteau, A.G. Cumpston, B.D. Dinman, A.T. Doig,
J.L. Egorov, C-G. Elinder, H.B. Elkins, I.D. Gadaskina, J. Glrmme, J.R. Glover,
G.A. Gudzovskij, S. Horiguchi, D. Hunter, Lars Järup, T. Karimuddin, R. Kehoe, R.K. Kye,
Robert R. Lauwerys, S. Lee, C. Marti-Feced, Ernest Mastromatteo, O. Ja Mogilevskaja,
L. Parmeggiani, N. Perales y Herrero, L. Pilat, T.A. Roscina, M. Saric, Herbert E. Stokinger,
H.I. Scheinberg, P. Schuler, H.J. Symanski, R.G. Thomas, D.C. Trainor, Floyd A. van Atta,
R. Wagg, Mitchell R. Zavon and R.L. Zielhuis.

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This chapter presents a series of short discussions of many metals. It contains a tabulation of major health effects, physical properties and physical and chemical hazards associated with these metals and many of their compounds (see table 1 and table 2). Not every metal is covered in this chapter. Cobalt and beryllium, for example, appear in the chapter Respiratory sytem. Other metals are discussed in more detail in articles that present information on the industries in which they predominate. The radioactive elements are discussed in the chapter Radiation, ionizing.

Table 1. Physical and chemical hazards

Table 2. Health hazards

The reader is referred to the Guide to chemicals in Volume IV of this Encyclopaedia for additional information on the toxicity of related chemical substances and compounds. Calcium compounds and boron compounds, in particular, are to be found there. Specific information on biological monitoring is given in the chapter Biological monitoring.

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