American Journal of Industrial Medicine 15495498 (1989)

EDITORIAL

Benzene and Lymphoma

Key words: benzene exposure, leukemogenesis ~~

Because of its abundance and obvious toxicity, benzene deserves a large literature, but the reviewer cannot avoid disappointment at the uncertainties, ambi- guities, and unknowns that continue to surround a chemical linked to human disease for a century. Why do only some workers develop benzene poisoning? Is there a threshold effect? Does benzene act through reactive intermediates or directly? How does benzene cause bone marrow failure or leukemic transformation? It is with some trepidation, therefore, that benzene's relationship with yet another human disease is broached .

The ability of benzene to suppress bone marrow function has long been recognized, and in the early 1900s benzene was even employed as a treatment of leukemia. A substantial proportion (10-30%) of cases of aplastic anemia are asso- ciated with prior exposure to benzene or related compounds [see Young, 1988 for review]. The risk of aplastic anemia in benzene workers is elevated, but as the degree of risk is likely related to the amount of exposure, figures from epidemiologic surveys are variable (24% of Turkish shoe factory workers had some hematologic abnormality [Aksoy et al., 197 11, but the incidence of chronic benzene poisoning ( = leucopenia) in Chinese workers decreased with the number surveyed (10% of 3,917, 1% of 33,312, 0.5% of 528,729) [Yin et al., 1987a1, presumably due to inclusion of less heavily exposed individuals). Quantitating the risk of acute leukemia has been even more difficult because this disease usually occurs years after benzene exposure.

Recently, a number of studies aimed at leukemia have shown, coincidentally, an increase in the relative risk of lymphoid malignancies among benzene workers. In the NIOSH study of a cohort of I , 165 rubber workers, the standardized mortality ratio for multiple myeloma was 409, compared to 337 for acute leukemia [Rinsky et al., 19871. In a study of 7,676 chemical workers, a statistically significant higher mortality from lymphoma and lymphocytic leukemia was observed in exposed workers (4.7-fold for lymphatic and hematopoietic cancer, 8.6-fold for non- Hodgkin's lymphoma) compared to unexposed workers (but not when compared to the general population) [Wong, 19871. A similar relative risk of 3.6 for lymphore- ticular cancer was reported among another cohort of 259 chemical workers [Decoufle et al. , 19831. Rubber chemical workers who were exposed to benzene had a 4-5-fold higher risk of lymphoid malignancy than those unexposed [Arp et al., 19831. Smaller numbers of patients with lymphoid malignancies have been reported in other series

Address reprint requests to Neal Young, MD, Chief, Cell Biology Section, Clinical Hematology Branch, National Heart, Lung, and Blood Institute, 1017C103, NIH, Bethesda, MD 20892. Accepted for publication November 29, 1988.

0 1989 Alan R. Liss, Inc.

496 Young

[Aksoy, 1987; Yin et al., 1987bl. Hematologic surveys have also suggested that a high proportion of patients with lymphoid malignancy may have a history of benzene exposure (l6/50 chronic lymphocytic leukemia patients [Goguel et al., 19671; 9/61 lymphocytic leukemia [Girard and Revol, 19701). Lymphoma has been linked to organic solvents like phenoxy acids and chlorphenols [Hardell et al., 198 I]. Although myelogenous leukemia is more frequently associated with benzene exposure than lymphocytic leukemia [Aksoy et al., 19761, the relative risk of lymphocytic malig- nancy may have been underestimated in thc past because acute lymphocytic leukemia in adults is uncommon, and the suspected diagnosis must be established using special diagnostic tests (enzyme stains, immunophenotyping).

Certainly, animal studies have demonstrated striking effects of benzene on lymphocyte numbers and functions [see Cronkite 1987; Kalf et al., 1987; Young, 1988, for review]. Mice acutely exposed to benzene become depleted of blood and spleen lymphocytes, with B lymphocytes more affected than T cells [Aoyama, 19861. Benzene globally depresses humoral and cellular immune responses [Rozen et al., 1984; Hsieh et al., 1988; Roscnthal and Snyder, 1987; Aoyama, 19861 and specific macrophage functions [Lewis et al., 19881. Decreased peripheral blood T cell numbers have been measured in human benzene workers [Moszczynski and Lisiewicz, 19831, and lymphopenia is a prominent component of benzene-associated aplastic anemia. Altered lymphocyte function has been implicated in bcnzene- associated aplasia (and other forms of chemically induced bone marrow failure), and the effective immunosuppressant antithymocyte globulin was first successfully tested in rabbits made pancytopenic by benzene administration.

The mechanism of benzene-associated aplasia and leukemia is not known, but a few general, probably true, statements can be made. Benzene toxicity is probably mediated through a reactive toxic intermediate, possibly a transient epoxide or a quinone metabolite. Marrow toxicity can be directly induced by exposure of animals to benzene catechol, hydroquinone, and benzoquinone derivatives. Marrow damage can be roughly correlated with generation of these metabolites, and benzene damage is decreased in hepatectomized animals, in rats compared to mice, and when toluene is simultaneously administered. The relative preponderance of peroxidases compared to quinone reductase activity in marrow cells may, with the fat solubility of benzene, be an explanation of the selectivity of benzene. Benzene metabolites bind better to RNA and protein than to DNA, and chromosomal abnormalities are not a prominent feature of benzene marrow disease, but the site of action and mode of damage in cells is really unknown. In vitro culture of marrow cells from benzene-exposed animals has shown very broad and often persistent effects on hematopoiesis [Cronkite, 1987 for review]: an early increase in cycling marrow cells (corresponding to marrow hyper- plasia in the animal); markedly decreased numbers of progenitor cells for granulo- cytes (CFU-GM) and erythrocytcs (BFU-E and CFU-E); decreased numbers of pluripotent stem cells (CFU-S), an increased number of which are in cell cycle; and benzene injury to the stromal support cells necessary for hematopoiesis. Damage to the precursor, progenitor, stem cell, or stromal cell would be anticipated to lead to marrow failure; in addition, alterations in immune function, either loss of lymphocyte growth factor production or induction of a cytotoxic immune response to hematopoi- etic cells, are also possible mechanisms of aplasia. The mechanism of leukemogen- esis is even more obscure, although Cronkite observed that benzene exposure led to

Benzene and Lymphoma 497

an extremely high incidence of acute myelogenous leukemia in a mouse strain harboring a radiation sensitive leukemia virus.

How can we relate, even hypothetically, benzene to the pathogenesis of lymphoma and lymphocytic leukemia? Several mechanisms have been identified in the etiology of lymphoma [reviewed in Holt et al., 19871 that may have relevance to chemical exposure. First, in some mice strains, implantation of solid plastic or mineral oil can lead to lymphoma, presumably as a result of chronic antigen exposure. As implied above, benzene or a metabolite may function as a hapten in inducing a lymphocytic response to bone marrow cells. Second, a variety of viruses have been associated with lymphoma, including retroviruses like the human T cell leukemia virus type I (HTLV I) and the murine Abelson virus; the herpesvirus, Epstein-Barr virus; and in mink, the parvovirus, Aleutian disease virus (the latter probably also as a result of chronic antigen exposure). Through its global DNA binding activity, benzene may function to activate latent viruses. Third, chromosomal translocation involving the c-myc locus occurs in some human lymphomas, impli- cating dysregulated oncogene expression in at least one stage of malignant transfor- mation. Benzene reactivity with DNA, RNA, or protein may affect expression of crucial genes that regulate cell proliferation.

Future clinical studies could be addressed at reexamination of the leukemias associated with benzene exposure for lymphoid phenotypic characteristics. Also useful would be a more thorough epidemiologic evaluation of the frequency of chemical exposure among patients with lymphoid malignancies. In the laboratory, for many reasons, lymphoid cells, especially B lymphocytes, have been more readily manipulated than hematopoietic stem cells. Such cell culture systems are amenable to analysis of the role of benzene in latent virus activation, oncogene activation, and generation of specific cytotoxic lymphocytes. The answers to questions of lymphoid malignancy due to chemical exposure will almost certainly bear on the mechanisms of benzene aplastic anemia and leukemia, but if lymphoid malignancy due to chemical exposures occurs as frequently as suggested, these questions deserve examination in their own right.

Neal Young, MD Cell Biology Section,

Clinical Hematology Branch, National Heart, Lung, and Blood Institute,

Bethesda MD 20892

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