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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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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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