Goldstein, Bernard

Goldstein, Bernard

Address: Environmental and Occupational Health Sciences Institute, 681 Frelinghuysen Road, PO Box 1179, Piscataway, New Jersey 08855-1179

Country: United States

Phone: 1 (908) 445-0205

Fax: 1 (908) 445-0131

E-mail: bgold@eohsi.rutgers.edu

Education: MD, 1962, New York University School of Medicine

Areas of interest: Benzene; ozone; risk assessment; air pollution; workplace hazards; leukaemia

 

Thursday, 10 February 2011 21:35

Agents or Work Conditions Affecting the Blood

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 Avariant 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 Avariant (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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Thursday, 10 February 2011 21:23

Haematopoietic and Lymphatic System

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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