Lymphohematopoietic cancers induced by chemicals and other agents and their implications for risk evaluation: An overview

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Review

Lymphohematopoietic cancers induced by chemicals and other agents and their implications for risk evaluation: An overview David A. Eastmond a,*, Nagalakshmi Keshava b, Babasaheb Sonawane b a b

Department of Cell Biology & Neuroscience, University of California, Riverside, CA, USA National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC, USA

A R T I C L E I N F O

A B S T R A C T

Article history: Received 5 September 2013 Received in revised form 2 April 2014 Accepted 3 April 2014 Available online xxx

Lymphohematopoietic neoplasia are one of the most common types of cancer induced by therapeutic and environmental agents. Of the more than 100 human carcinogens identified by the International Agency for Research on Cancer, approximately 25% induce leukemias or lymphomas. The objective of this review is to provide an introduction into the origins and mechanisms underlying lymphohematopoietic cancers induced by xenobiotics in humans with an emphasis on acute myeloid leukemia, and discuss the implications of this information for risk assessment. Among the agents causing lymphohematopoietic cancers, a number of patterns were observed. Most physical and chemical leukemia-inducing agents such as the therapeutic alkylating agents, topoisomerase II inhibitors, and ionizing radiation induce mainly acute myeloid leukemia through DNA-damaging mechanisms that result in either gene or chromosomal mutations. In contrast, biological agents and a few immunosuppressive chemicals induce primarily lymphoid neoplasms through mechanisms that involve alterations in immune response. Among the environmental agents examined, benzene was clearly associated with acute myeloid leukemia in humans, with increasing but still limited evidence for an association with lymphoid neoplasms. Ethylene oxide and 1,3-butadiene were linked primarily to lymphoid cancers. Although the association between formaldehyde and leukemia remains controversial, several recent evaluations have indicated a potential link between formaldehyde and acute myeloid leukemia. The four environmental agents examined in detail were all genotoxic, inducing gene mutations, chromosomal alterations, and/or micronuclei in vivo. Although it is clear that rapid progress has been made in recent years in our understanding of leukemogenesis, many questions remain for future research regarding chemically induced leukemias and lymphomas, including the mechanisms by which the environmental agents reviewed here induce these diseases and the risks associated with exposures to such agents. ß 2014 Elsevier B.V. All rights reserved.

Keywords: Leukemia Neoplasia Carcinogens Environmental agents Risk assessment

Contents 1. 2. 3.

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Introduction to lymphohematopoietic cancers. . . . . . . . . . . . Overall incidence and trends. . . . . . . . . . . . . . . . . . . . . . . . . . Hematopoiesis and origins of lymphohematopoietic cancers Hematopoiesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Origins of lymphohematopoietic neoplasia . . . . . . . . . 3.2. Genetic alterations in t-MDS/t-AML. . . . . . . . . . . . . . . 3.3. Epigenetic changes . . . . . . . . . . . . . . . . . . . . 3.3.1. Leukemia- and lymphoma-inducing agents . . . . . . . . . . . . . . 4.1. Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Major classes of leukemia-inducing agents . . . . . . . . . 4.2.

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* Corresponding author at: Department of Cell Biology & Neuroscience, 2109 Biological Sciences Building, University of California, Riverside, CA 92521, USA. Tel.: +1 951 827 4497; fax: +1 951 827 3087. E-mail addresses: [email protected] (D.A. Eastmond), [email protected] (N. Keshava), [email protected] (B. Sonawane). http://dx.doi.org/10.1016/j.mrrev.2014.04.001 1383-5742/ß 2014 Elsevier B.V. All rights reserved.

Please cite this article in press as: D.A. Eastmond, et al., Lymphohematopoietic cancers induced by chemicals and other agents and their implications for risk evaluation: An overview, Mutat. Res.: Rev. Mutat. Res. (2014), http://dx.doi.org/10.1016/j.mrrev.2014.04.001

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4.2.1. Ionizing radiation . . . . . . . . . . . . . . . . . . . . . . . . . . Chemotherapeutic agents . . . . . . . . . . . . . . . . . . . . 4.2.2. Environmental and occupational agents. . . . . . . . . 4.2.3. Selected factors conferring an increased risk of induced leukemia . Myelosuppression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Genetic polymorphisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Implications for hazard and risk assessment . . . . . . . . . . . . . . . . . . Short-term genotoxicity tests and human biomonitoring. . . 6.1. 6.2. Usefulness of animal bioassays . . . . . . . . . . . . . . . . . . . . . . . Combining different types of lymphohematopoietic cancers 6.3. Metabolism and bioactive dose at the target organ . . . . . . . 6.4. 6.5. DNA-adduct type, metabolism, and repair . . . . . . . . . . . . . . Age-related and individual susceptibility . . . . . . . . . . . . . . . 6.6. Future directions and research needs . . . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction to lymphohematopoietic cancers Lymphohematopoietic neoplasia can be described as an uncontrolled proliferation or expansion of hematopoietic and lymphoid cells that are unable to differentiate normally to form mature blood cells [1]. These neoplasms represent clonal expansions of hematopoietic cells that occur almost always within either the myeloid or lymphoid lineage [2,3]. The myeloid clones are designated as chronic or acute leukemias, depending upon the rate of clonal expansion and the stage of differentiation that dominates the leukemic clone. Lymphoid neoplasms typically manifest themselves in the blood as chronic or acute lymphoblastic leukemias (ALLs) or remain confined to lymphoid proliferative sites such as the lymph nodes or spleen and are designated as lymphomas [2]. Acute leukemias tend to have a rapid onset with a predominance of immature cells whereas chronic leukemias have a more insidious onset and progress over a period of months or years to a blast or acute leukemic phase. Using this basic classification, leukemias can be described as one of four major types—ALL, acute myeloid leukemia (AML), chronic lymphoblastic leukemia (CLL), and chronic myeloid leukemia (CML). Similarly, lymphomas are broadly classified as Hodgkin lymphomas or non-Hodgkin Lymphomas (NHL) depending upon the appearance of a specific cancer cell type, the ReedSternberg cell, which is found in Hodgkin lymphomas [4]. Within these larger groupings, there are numerous subtypes involving specific cells that have unique characteristics, origins, and increasingly recognized clinical significance. These subtypes are generally classified according to morphologic, cytogenetic, immunophenotypic, and more recently, molecular characteristics according to the French-American-British (FAB) or World Health Organization (WHO) classification systems [3,5–7]. The more recent WHO classification system is a detailed and comprehensive classification scheme describing over 125 different lymphohematopoietic diseases with a focus on the origin of the neoplastic cell. While valuable for understanding specific disease subtypes, in practice, the WHO system is difficult to use in a overview article such as this and particularly when referring to leukemias and lymphomas in the older literature which were classified using earlier classification schemes. For simplicity, we have used the FAB classification, a less complicated system based on cell morphology that was commonly used in the past and is still widely used. Among the leukemias, the two major diagnostic categories, ALL and AML, can be further classified based upon cellular features. ALL is subdivided by FAB morphology (L1, L2, and L3) and by immunophenotype (B-cell, early pre-B, pre-B, and T-cell) [8]. AML is classified primarily by morphological characteristics into

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eight different FAB subgroups (M0–M7) based upon the myeloid lineage and degree of maturation involved. Similarly, the myelodysplastic syndromes (MDSs), a series of blood disorders characterized by maturation defects resulting in ineffective hematopoiesis, have also been classified by the FAB and WHO systems. These are commonly considered to be preleukemic because significant proportion (up to 33%) of the various disorders progress to frank AML [3,6,9,10]. MDS developing in patients that have previously been treated with antineoplastic drugs or radiation (t-MDS) represents an early stage neoplasm and is now combined with therapy-related AML (t-AML) in the most recent WHO classification scheme [3]. The objective of this article is to provide an overview of the types of lymphohematopoietic neoplasia induced by chemical agents and radiation in humans, and to summarize recent information on the mechanisms of chemical leukemogenesis. Much of the discussion focuses on AML due to the limited and evolving knowledge about chemically induced lymphoid leukemias and lymphomas that is only now being integrated into ongoing epidemiological and clinical studies. An overview of the major classes of leukemia-inducing agents—radiation, the alkylating agents, and topoisomerase II inhibitors as well as some common environmental and occupational chemicals—is presented followed by a short discussion of factors influencing chemical leukemogenesis. Finally, the review concludes with a brief discussion of how mechanistic information on human leukemiainducing agents may be used to inform risk evaluation from exposure to environmental agents. 2. Overall incidence and trends Lymphohematopoietic neoplasms are an uncommon, yet significant, cause of cancer-related deaths. In 2013, it is estimated that leukemia will be diagnosed in 48,610 people in the United States [11]. About 44% of these will be chronic leukemias (21,600) with the remainder being acute leukemias (20,660) and others that are otherwise classified (6350). Because of the limitations of current therapies, leukemia represents the 6th leading cause of cancer deaths among males and females in the United States [11]. Furthermore, it is estimated that 79,030 new cases of lymphoma would be diagnosed in the United States in 2013 [11]. Of these, 89% were projected to be NHL and 11% Hodgkin lymphoma. Of those with lymphoma, approximately 20,000 are expected to die during 2013. Consequently, NHL represents the 7th leading cause of cancer-related deaths in females and the 9th in males. Incidence rates were stable in men and women for both non-Hodgkin and Hodgkin lymphoma from 2004 to 2008, whereas death rates for

Please cite this article in press as: D.A. Eastmond, et al., Lymphohematopoietic cancers induced by chemicals and other agents and their implications for risk evaluation: An overview, Mutat. Res.: Rev. Mutat. Res. (2014), http://dx.doi.org/10.1016/j.mrrev.2014.04.001

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these cancers have declined significantly due principally to improvements in therapy [11]. While leukemia occurs much more commonly in adults than in children, childhood leukemia still accounts for approximately 30% of all childhood cancers in the United States, and is a leading cause of disease-related deaths among children [12–14]. Almost 90% of leukemia cases are diagnosed in adults 20 years of age and older; CLL accounts for 38% and AML for 30% of the adult total [11]. Among adults, roughly 85% of the acute leukemias are myeloid in origin with the remainder being lymphoid [15]. In contrast among children, approximately 80% of the leukemias develop from lymphoid cells. While the overall trend for adult leukemia has generally declined with time, the incidence of childhood leukemias in the United States appeared to increase during the early 1980s with rates increasing from 3.3 cases per 100,000 in 1975 to 4.6 cases per 100,000 in 1985 [16]. In the subsequent years, the rates have shown no consistent upward or downward trend. However, in Europe and in other developed countries, over the past 30 years, significant increases in childhood lymphoid leukemia and lymphoma have occurred [17,18]. The specific reasons for these increases are unclear but changes in socioeconomic status, hygiene and the environment have been proposed to play a role. Fortunately, there has been significant progress in treating childhood leukemias and lymphomas so that the 5-year survival rate for the affected children is now 84–96% [11]. The 5-year survival rate for adult leukemias and lymphomas varies by cancer type, and ranges from 24% for AML to over 80% for CLL and Hodgkin lymphoma [11]. 3. Hematopoiesis and origins of lymphohematopoietic cancers 3.1. Hematopoiesis Hematopoiesis is the process by which the cells of the blood are formed and originates in several mesodermal lineages in the mammalian conceptus with cells migrating from the primitive streak to three blood-forming tissues: the yolk sac, the para-aortic splanchnopleura/aorta-gonadal-mesonephros region, and the chorio-allantoic placenta [19]. Hematopoietic stem cells capable of conferring a complete long-term and multilineage repopulation of hematopoiesis in irradiated adult recipient mice appear in the aorta-gonadal-mesonephros and other tissues during the middle of embryogenesis. These cells proceed to colonize the liver, then the thymus, spleen and bone marrow where hematopoiesis primarily occurs after birth. The formation of blood cells originates with the hematopoietic stem cell. As described by Wilson and Trumpp [20], stem cells are functionally defined as cells that can both self-renew (maintain their numbers at a constant level) and give rise to all mature cells in the tissue in which they reside. The formation of blood cells is supported by a small population of pluripotent stem cells that exhibit the capacity to self-renew and are capable of extensive proliferation. The balance between stem cell self-renewal and differentiation is believed to be controlled by interactions between the stem cells and the adjacent niche-forming stromal cells or soluble factors produced by the stromal cells [20]. The pluripotent stem cells can also reconstitute all hematopoietic lineages and are capable of long-term reconstitution of the hematopoietic system of recipient animals. With the exception of lymphocytes where maturation also continues in the thymus, spleen and peripheral tissues, the formation of blood cells in normal human adults occurs almost exclusively in the bone marrow. In order to maintain steady-state levels and because circulating blood cells have a finite life, the formation of cells in the marrow must equal the rate of cellular senescence and elimination [21]. As a result, the hematopoietic system has a tremendous proliferative capacity

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with estimates of cell turnover ranging from 130 to 500 billion cells per day in a 70-kg man [22,23]. In addition, the hematopoietic system in the central bone marrow helps respond to a variety of environmental stresses and infection by increasing the blood cell counts of specific lineages when needed [21,24]. In addition to their ability to self-renew, primitive pluripotent hematopoietic stem cells give rise to a number of multipotent progenitor cells, which, in turn, give rise to oligopotent progenitor cells [23]. Among these, the multilymphoid progenitors give rise to mature B lymphocytes, T lymphocytes, and natural killer (NK) cells whereas the common myeloid progenitors give rise to granulocyte–macrophage progenitors (which differentiate into monocytes/macrophages and granulocytes), and megakaryocyte/ erythrocyte progenitors (which differentiate into megakaryocytes/platelets and erythrocytes). Both the myeloid and lymphoid progenitor cells have also been shown to form monocytes and dendritic cells, which play a role in regulating the immune system [25,26]. In addition to these major types of blood cells, a number of the cell types, for example, the granulocytes can further differentiate into more specialized blood cells such as neutrophils, eosinophils, and basophils. As a result, the number of unique cell types derived from the hematopoietic stem cell is quite large, and, as indicated above, the total number of individual cells formed per day numbers in the hundreds of billions. While hematopoietic stem and progenitor cells normally reside in specialized niches in the bone marrow, they can be mobilized into the peripheral blood either at low levels spontaneously or in large numbers as a result of cytokine or chemical treatment [27,28]. There appears to be a constitutive recirculation of hematopoietic stem and progenitor cells between the bone marrow, extramedullary tissues, and the lymphoid compartments [28]. Consequently, it is theoretically possible for DNA damage or other types of potentially leukemogenic alterations to affect hematopoietic stem cells while they circulate in the blood and extramedullary spaces. Upon exposure to mobilizing agents such as specific chemokines, toxicants, antibodies, or growth factors, or under conditions of stress or myelosuppression, large numbers of these stem and progenitor cells can be released into the peripheral blood [27]. The natural role of mobilization is not fully known, but there is evidence that the circulating hematopoietic stem and progenitor cells may help replenish tissue-residing myeloid cells such as specific monocytes, macrophages, and dendritic cells or help in rapidly responding to tissue injury and infection [24,28]. 3.2. Origins of lymphohematopoietic neoplasia As with other cancers, leukemogenesis and lymphomagenesis are multistep processes involving a series of genetic and epigenetic alterations involved in the transformation of a normal cell into a malignant cell. The various lymphohematopoietic cancers are believed to originate in specific types of pluripotent or lineagerestricted cells at different stages in hematopoiesis (Fig. 1; [15]). Leukemias and lymphomas can originate within many types of hematopoietic or hematopoietic-forming cells. In addition, the bone marrow microenvironment can also significantly influence the neoplastic transformation of hematopoietic cells [29–32]. For example, a recent study has reported that mutations occurring in bone marrow osteoblasts can lead to leukemia (AML) occurring in hematopoietic cells [351]. With a few rare exceptions, most leukemias and lymphomas originate at the hematopoietic stem cell stage or at later progenitor or lineage-restricted stages. For example, most adult leukemias of myeloid origin (AML, MDS, and CML) as well as adult ALL are believed to originate at the pluripotent stem or progenitor cell stage whereas childhood leukemias are believed to originate during a subsequent stage of differentiation at either the lineage-restricted lymphoid or

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Fig. 1. Hierarchical stem cell origins of leukemia and related cancers. The arrows denote the likely level of clonal selection for the majority of the leukemia subtypes listed. Abbreviations: AL = acute leukemia; Cut. T lymphoma = cutaneous T-cell lymphoma; ATL = adult T-cell leukemia; T-PLL = T-cell prolymphocytic leukemia; B-cell nonHodgkin lymphoma; PLL = prolymphocytic leukemia; HCL = hairy cell leukemia. Source: Greaves [15]. ‘‘Reprinted from European Journal of Cancer, Vol. 35, M. Greaves, Molecular Genetics, Natural History and the Demise of Childhood Leukaemia, 1941– 1953, 1999, with permission from Elsevier.’’

myeloid stem cell stage. For most types of adult AML, the key leukemic transformations appear to occur in hematopoietic stem cells [33]. However, for acute promyelocytic leukemia, the key transformative event may occur at the committed myeloid progenitor stage [33,34]. In contrast, many lymphomas (NHL, Hodgkin lymphoma, Burkitt lymphoma) and all myelomas, as well as, several rare leukemias/lymphomas (adult T-cell leukemia, prolymphocytic leukemia, hairy cell leukemia) and one common leukemia (CLL) are believed to originate in mature lymphoid cells [15,35]. Consistent with the multistep nature of leukemogenesis, over 300 different genetic alterations and mutations have been identified [36]. In recent years, researchers have begun to identify patterns among the myriad of translocations, gene arrangements, and point mutations involved in myeloid leukemias and have created a model for leukemogenesis [36,37]. Paraphrasing from the model description of Kelly and Gilliland [36], AML results from a collaboration between mutations occurring in two broad classes genes; Class 1 mutations exemplified by activated tyrosine kinases or their down stream effectors (e.g. activating mutations in NRAS, KRAS and FTL3) confer a proliferative or survival advantage to hematopoietic cells. When expressed alone, the mutated genes confer a CML-like disease characterized by leukocytosis with normal maturation and function of cells. Mutations in Class II genes (e.g. AML1/ETO and PML/RARa fusions and mutations in AML1 and C/EBPa) result in loss of function of transcription factors that are necessary for normal hematopoietic differentiation. The Class II mutations would also be predicted to impair subsequent apoptosis in cells that do not undergo terminal differentiation. When expressed individually, these mutations may confer a phenotype like MDS. Individuals with both Class I and Class II mutations in their hematopoietic cells have a clinical phenotype of AML characterized by a proliferative and/or survival advantage to cells and by impaired hematopoietic differentiation. More recently, additional interrelationships between new and previously identified genetic alterations and leukemogenic agents, and types of

leukemia have been reported [38–44]. The interactions between various genes can become quite complicated, and the outcome of these interactions is not fully understood, although these have been shown, in some cases, to be clinically significant [45,46]. The results of many studies have shown that multiple types of genetic changes can play a role in converting a normal hematopoietic stem or progenitor cell into a fully transformed leukemic cell [45]. However, recent studies indicate that the number of mutations needed to convert a specific stem cell into a leukemic cell is relatively small, particularly when compared to other types of cancer [47–49]. In de novo leukemias, mutations in driver genes, those the confer a selective growth advantage, involve a substantial number of pathways including transcription factor genes and fusion genes, DNA-methylation-related genes, tumor suppressor genes, signaling genes, the nucleophosmin gene (NPM1), and chromatin-modifying genes, among others ([48,50,51]. In nearly all de novo AML or MDS samples where detailed studies have been conducted, a potential or likely driver gene has been identified [50,52]). Following activation of these driver genes, mutations may occur in many other genes (passenger genes) which play less significant or no role in carcinogenesis and disease progression [48,51]. Consistent with this, recent studies have indicated that in the progression from MDS to AML hundreds of mutations occur within the late-stage transformed clone [53]. As described by Walter and associates, the genetic evolution of AML from MDS is a ‘‘dynamic process shaped by multiple cycles of mutation acquisition and clonal selection’’ [53]. 3.3. Genetic alterations in t-MDS/t-AML Many mechanisms are involved in de novo and therapy-related acute myeloid leukemias. For more than 20 years, PedersenBjergaard and colleagues have collected information on patients with t-AML and t-MDS who have been treated at their clinic in Copenhagen, Denmark [54]. Based on the genetic alterations seen in this cohort of 140 patients as well as information in the

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Table 1 Early and late stage genetic alterations involved in the development of t-MDS and t-AML. The pathways associated with classes of chemotherapeutic agents are shown. Pathway

t-MDS Early changes

Alkylating agents I 7q/7 II

5q/5

Topoisomerase II inhibitors III IV

V

t-AML Later changes AML1 mutation, then RAS mutations or Tp53 mutations 7q/7, Tp53 gene mutations, 17p/17, complex karyotypes, MLL or AML1 amplification

MDS not typically seen

MDS not typically seen [7q/7 or t(3,21) (infrequently seen)] MDS not typically seen

VI Postulated de novo Normal karyotype VII

VIII

Early changes

Additional genetic and epigenetic changes; >80% p15 promoter methylation Additional genetic and epigenetic changes; 80% p15 promoter methylation

Translocations involving MLL gene at 11q23 Translocations involving AML1 gene at 21q22 or inv(16) and the CBFB gene 15;17 Translocations involving RARA gene 11p15 involving NUP98

RAS or JAK2 mutations

Other changes

Later changes

Normal karyotype

Other changes

RAS mutations BRAF mutations; 50% p15 promoter methylation cKIT mutations; >80% p15 promoter methylation

FLT3 mutations; >80% p15 promoter methylation

FLT3, RAS or AML1 mutations; internal tandem duplications of MLL gene; 50% p15 promoter methylation 40% p15 promoter methylation

Source: Adapted from Pedersen-Bjergaard et al. [54].

literature, they have identified eight separate pathways that appear to lead either directly to AML or lead to MDS and then to AML (Table 1). The pathways have been classified into groups largely based upon the genetic alterations observed and the therapeutic agent that was likely responsible for the leukemia [54]. For example, one pathway was identified in patients who developed t-MDS prior to t-AML and exhibited either loss of chromosome 7 or part of the long arm of chromosome (7q). These patients also did not exhibit the recurrent balanced translocations that are commonly associated with AML. Most of these patients (35/39) had been treated with alkylating agents, and most (35/39) presented with t-MDS prior to t-AML. Methylation of the p15 promoter (84%), considered a late event in leukemogenesis, was commonly seen in the patients. In addition to the chromosome 7 changes, the leukemias of a significant portion (15/39 or 38%) of these patients had point mutations in the AML1 (also known as RUNX1) gene. A number of these patients also had mutations in either the TP53 tumor suppressor gene or an activating mutation in the RAS oncogene. Another pathway was common in patients who had also previously been treated with chemotherapy. These individuals exhibited either loss of all (5) or part of the long arm of chromosome 5 (5q). In addition, approximately half of the patients in this group also had 7 or 7q alterations. As with pathway one, onset of this disease was closely related to the use of alkylating agent chemotherapy (27/34) and manifested with an initial presentation of t-MDS (26/34). Seventy-seven percent of these patients exhibited mutations in TP53. The patients also often presented with a complex karyotype or loss of part of the short arm of chromosome 17 (17p) or showed an amplification or duplication of chromosome bands 11q23 or 21q22. Methylation of the p15 promoter was reported to occur in 80–90% of the time in this group. The next pathway (pathway 3) was characterized by balanced translocations involving the 11q23 chromosome band and one of many partner chromosomes. These translocations frequently occurred in patients who had been previously treated with the epipodophyllotoxin-type of topoisomerase II inhibitors and exhibited AML of the FAB subtypes M4 or M5. Three of the 11 patients in this group had a RAS mutation, and another 3 had a BRAF

mutation. Methylation of the p15 promoter was seen at a 50% level in these patients. Patients with balanced translocations involving chromosome bands 21q22 or 16q22 leading to chimeric rearrangements involving the core binding factor genes AML1 or CBFB were identified as the fourth pathway. These chromosomal changes were also generally associated with previous treatment with topoisomerase II inhibitors, most commonly of the anthracycline class. While a portion of patients in this group with a t(3;21)(q26;q22) presented as t-MDS, most of the others (e.g. those with t(8;21) and inv(16)) presented directly with t-AML. Chromosome 7 alterations were also seen in five of nine patients with 21q22 translocations. Point mutations in KIT (c-Kit) and PTPN11 were seen in a few patients. Methylation of the p15 promoter was seen at a high (83%) level in these patients. Pathway five occurred in only two patients in this series and is characterized by a translocation between chromosomes 15 and 17 involving the PML and RARA genes. Therapy-related promyelocytic leukemia (M3) that exhibits the characteristic t(15;17) has been reported to occur in patients treated with doxorubicin, mitoxantrone or bimolane. One of the patients in this group also had a mutation due to FLT3 internal tandem duplication. The next pathway, an uncommon pathway in which t-AML patients exhibit balanced translocations involving the NU98 gene at chromosome band 11p15. None of the 140 patients in the Copenhagen series exhibited this pattern. In pathway seven, a normal karyotype was exhibited, and most often presented directly as AML. Approximately 17% of the patients in the Copenhagen series fell within this group and have not been consistently associated with any previous type of chemotherapy. The mutations seen are also commonly seen in de novo leukemias suggesting that these may represent sporadic cases of de novo leukemia occurring in these patients. Methylation of the p15 promoter occurred at a 50% level in these patients. The last pathway is composed of patients that exhibit unique or unusual chromosome alterations and represents 14% of the Copenhagen cohort. These cases do not show an association to any specific type of previous therapy and were also suggested to represent cases of de novo leukemia. Methylation of the p15 promoter was also uncommon, occurring at a 40% incidence in these cases.

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Consistent with the descriptions presented above, patients with t-AML with leukemic cells exhibiting loss of all or part of chromosomes 5 or 7, frequently presented initially with t-MDS and had often been previously treated with alkylating agent chemotherapeutic drugs. In contrast, t-AMLs exhibiting certain specific reciprocal translocations such as t(11q23) and t(21q22) occurred in patients that were previously treated with a topoisomerase II-containing chemotherapeutic regimen and typically developed without a preceding MDS (for further details of these pathways, refer to Pedersen-Bjergaard et al. [54]). Recent studies have provided support for the importance of these genetic changes. For example, in patients with t-MDS and/or t-AML, mutations in the TP53 and TET2 genes were identified as the most common mutations and were detected in 21% and 10.5% of the patients, respectively [55]. 3.3.1. Epigenetic changes In addition to genetic alterations, the study of epigenetics is providing valuable insights into leukemogenesis. Epigenetics, the study of changes in gene function that are mitotically and/or meiotically heritable but do not entail a change in DNA sequence [56], appear to play a significant role in the mechanism of action of numerous diseases including leukemias, through DNA methylation, histone modification and small non-coding RNA regulation. Recent studies have analyzed the potential role of miRNA, one class of non-coding, small RNAs that regulates expression of target genes at the post-transcriptional levels [57–59] in leukemias and other diseases. The discovery of these miRNAs has added a new layer to the complexicity to the understanding of the pathogenesis and cellular function of the diseases. Recent studies demonstrate that these miRNAs may play important roles in hematopoiesis and in the pathogenesis of lymphohematopoietic malignancies [60– 63]. Using miRNA profiling, studies have revealed differential expression profiles between normal and leukemia cells, between lymphohematopoietic cancer subtypes, such as AML and ALL [64], and between cytogenetic subtypes and AML [62]. For example, use of system-level pathway analysis approaches to identify AMLassociated biological pathways has resulted in the identification of 53 AML-associated molecules called ‘‘AML Signalisome’’ that were associated with aryl hydrocarbon receptor pathway, a major regulator of hematopoiesis [65]. Results of recent miRNA studies indicate, specific miRNA expression may be either up or downregulated in lymphohematopoietic cancers. Furthermore, several miRNAs are now thought to act as candidate oncogenes and tumor suppressor genes (miR495 in MLL-rearranged leukemia) and may serve as clinical biomarkers [59,66]. A number of miRNAs with tumor suppressor function are down regulated in leukemias such as miR-29b in CLL, whereas oncogenic miRNAs such as the miR-106-363 cluster in human T-cell leukemias [31] and miR-221 are upregulated suggesting oncogenic functions. Other miRNAs such as miR-145 and mi-146a are thought to play key roles in hematological changes occurring in leukemias developing in patients with the 5qsyndrome [67]. A recent study by Starczynowski and colleagues has provided convincing evidence that loss of miR-145 or miR146a in a long-term repopulating cell results in an inappropriate activation of innate immune signaling and produces a number of the clinical and hematological features of the 5q-syndrome [67]. Since t-AML induced by alkylating agents also show deletions on this chromosome 5q arm, this suggests that miR-145 or miR-146a may play important roles in the pathogenesis of t-AML. Evidence from genetic studies indicate that chromosomal translocations can also mediate epigenetic silencing of gene expression. For example, the most frequent chromosomal rearrangement in AML, the t(8;21) translocation resulting in the AML/ ETO fusion, has many putative and established epigenetic targets

[68] such as inhibiting acetylation of GATA1 and blocking C/EBPa auto-regulation. This translocation has been reported to be induced by various topoisomerase 2 inhibitors such as anthracyclines [69], bimolane [70], and possibly by benzene [71,72]. Evidence from another study [66] indicates that another miRNA, miR-495, likely functions as a tumor suppressor in MLL-rearranged leukemia, the type of t-AML induced by the epipodophyllotoxin class of topoisomerase 2 inhibitors. 4. Leukemia- and lymphoma-inducing agents 4.1. Overview While most leukemias occur in individuals with no obvious exposure to radiation or chemical carcinogens (de novo leukemias), a significant number, known as secondary leukemias develop in individuals who have previously been exposed to radiation, industrial chemicals, or chemotherapeutic agents. Among the 100+ agents that International Agency for Research on Cancer (IARC) has evaluated to be Group 1 (human) carcinogens, approximately 25% have been established as causing a lymphohematopoietic cancer. These include nine therapeutic drugs or mixtures, four industrial chemicals or contaminants, two immunosuppressive drugs, four forms of radiation, two occupational or lifestyle exposures, and six infectious agents. Thus, leukemias and lymphomas represent one of the most common types of cancer induced by a wide variety of cancer-inducing agents. Of the 66 Group 2A agents, there is evidence based either on human studies, animal bioassays, or structural similarities that at least 10 of these chemicals are likely to cause leukemia or lymphoma in humans. Table 2 lists these IARC Group 1 and 2A agents and shows the likely mechanisms involved in the carcinogenesis of the known (Group 1) and probable (Group 2A) human leukemia- and lymphomainducing agents. In examining the information in Table 2, a number of general patterns become apparent. Leukemias are the primary type of cancer induced by the chemical agents, and most of these are acute nonlymphocytic leukemias (ANLLs, synonymous with AML and its variants). These were almost always induced by agents that are either directly DNA-reactive or that can be metabolized (or otherwise converted) into DNA-reactive species. Many of the leukemogens are bifunctional alkylating agents, chemicals that form adducts on DNA bases involved in base-pairing such as the O6 of guanine, or induce chromosomal damage through the inhibition of topoisomerase II. The primary mode of action (MOA) for physical and chemical agents is through the induction of either gene or chromosomal mutations [73–75]. Consistent with their proposed mutagenic mechanisms, most of the leukemia-inducing agents have been reported to induce structural chromosome aberrations (SCA) in the peripheral blood of exposed humans. Myelotoxicity is also commonly seen in humans (and experimental animals) exposed to these leukemogenic agents. Exposure to radiation in various forms was frequently associated with ALL and CML, in addition to ANLL. The induced cancers are also likely due to the effects of ionizing radiation on DNA, either directly or indirectly, and are believed to occur through mutagenic and epigenetic mechanisms [74,75]. In contrast to these DNA-damaging agents, exposure to a variety of infectious agents is causally related to the formation of lymphoid neoplasms. The induced lymphomas appear to be primarily associated with chronic infection with either viruses or Helicobacter bacteria that are immunomodulating and/or specifically target lymphoid cells. These agents are believed to act as either direct carcinogens acting on the cellular DNA, indirect carcinogens acting through chronic inflammation, or through

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Cancer

Class

Initiating property

Postulated key mechanism

Related toxicitya,b

Chromosomal aberrations

Key references

Group 1 agents DNA-reactive alkylating agents Melphalan

ANLL

Therapeutic agent

Positive

[73,319,320]

ANLL

Therapeutic agent

Myelotoxic

Positive

[73,319,321,322]

Chlorambucil

ANLL

Therapeutic agent

Myelotoxic

Positive

[73,319,321,323,324]

Semustine (methyl-CCNU)

ANLL

Therapeutic agent

Gene or chromosomal mutation Gene or chromosomal mutation Gene or chromosomal mutation Gene or chromosomal mutation

Myelotoxic

Busulfan (Myleran)

Myelotoxic

No information

[73,319]

Cyclophosphamide

ANLL

Therapeutic agent

Positive

[73,319]

ANLL

Combination of therapeutic agents

Gene or chromosomal mutation Gene or chromosomal mutation

Myelotoxic

MOPP therapy

Myelotoxic

Positive

[73,320,325]

Treosulfan

ANLL

Therapeutic agent Therapeutic agent

No information, positive in mice Positive

[73,319,320,326]

Leukemia

Gene or chromosomal mutation Gene or chromosomal mutation

Myelotoxic

Thio-TEPA

Ethylene oxide

[NHL, MM, CLL]c

Industrial chemical

Direct-acting bifunctional alkylating agent Direct-acting bifunctional alkylating agent Direct-acting bifunctional alkylating agent Degrades to direct-acting alkylating and carbam-oylating agents Bioactivated to bifunctional alkylating agent and acrolein A direct-acting bifunctional and an indirect monofunctional alkylating agent, a microtubule inhibitor, and a glucocorticoid Converts to a mono- and bifunctional alkylating agent Direct-acting trifunctional alkylating agent. Also, metabolized to monofunctional alkylating agent aziridine Direct-acting alkylating agent

[161,190,196,199]

Lymphohematopoietic cancers

Industrial chemical

Bioactivated to mono- and bifunctional alkylating agents

Mixed immunotoxicity results Negative (some evidence of immunotoxicity in animals)

Positive

1,3-Butadiene

Gene or chromosomal mutation Gene or chromosomal mutation

Negative (positive in animals)

[73,161,199,201,328,329]

ANLL, CML, ALL

Direct and indirect DNA damage

Gene or chromosomal mutation Gene or chromosomal mutation

Myelotoxic

Positive

[74,330]

ANLL (CML and ALL for Th-32)

Therapeutic, and military Therapeutic, and military

Positive

[75,330]

ANLL

Therapeutic agent

Topoisomerase II-poison

Mutation resulting from chromosomal breakage and translocations

Myelotoxic

Positive (micronuclei)

[73,129,319,331,332]

Myeloid leukemias

Industrial and endogenous chemical

Unknown, possibly gene or chromosomal mutation

Mixed myelotoxicity results

Mixed results

[161,199,204]

Benzene

ANLL [NHL, ALL, CLL, MM]

Industrial chemical and environmental agent

Direct-acting, forms DNAprotein crosslinks and DNA adducts Metabolized into multiple reactive protein and DNAbinding species

Myelotoxic

Positive

[161,199]

Tobacco smoking and tobacco smoke Tobacco smoking (parental)

ANLL

Lifestyle use

Direct and indirect DNA damage

Immunotoxic

Positive

[333–335]

[Childhood leukemia, ALL]

Parental smoking

Direct and indirect DNA damage

Unknown, likely mutation resulting from either DNA binding, topoisomerase IIinhibition, and/or oxidative damage Unknown, likely gene or chromosomal mutation Unknown, assumed gene or chromosomal mutation occurring in germ cells or in utero

Immunotoxic

No information

[333–335]

Radiation X- and Gamma-radiation Alpha and beta particle emitters

Topoisomerase II inhibitor Etoposide

Other mechanisms Formaldehyde

energy uses energy uses

Direct and indirect DNA damage

Myelotoxic

Myelotoxic for

32

P

[73,319,327]

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Table 2 Likely mechanisms involved in the carcinogenesis of selected known (Group 1) and probable (Group 2A) human leukemia- and lymphoma-inducing agents.

7

Class

Initiating property

Postulated key mechanism

Related toxicitya,b

Chromosomal aberrations

Key references

Rubber manufacturing occupation

Leukemia, Lymphoma

Occupational exposure

Unknown but DNA-reactive chemicals are used

No information

Positive

[161,293]

Painting occupation

[Childhood leukemia, ALL]

Occupational exposure

Unknown but DNA-reactive chemicals are used

Unknown, assumed to be gene or chromosomal mutations and/or immunosuppression Unknown, assumed gene or chromosomal mutation occurring in germ cells or in utero

No information

No information

[161,293]

Immunosuppressive agents Cyclosporine

NHL

Therapeutic agent

Immuno-suppression

Immunotoxic

Positive

[73,319,336–338]

Azathioprine

NHL

Therapeutic agent

Immuno-suppression

Immunotoxic

Positive

[319,320,339]

2,3,7,8-TCDD

[NHL]

Environ-mental contaminant

Unknown, postulated immuno-suppression

Immunotoxic

Negative

[77,161,199]

Trichloroethylene

[NHL]

Occupational exposure

Inhibition of transcription factors that regulate inducible cytokine expression Metabolized into nucleotide analog Receptor-mediated effects modifying cellular replication and apoptosis Bioactivation to a genotoxic or immunotoxic species

Unknown, postulated immuno-suppression or mutation

Immunotoxic

No information

[205,340]

Burkitt lymphoma, NHL, NK/T-cell lymphoma, Hodgkin lymphoma NHL, Hodgkin lymphoma

Infectious agent

Viral infection and expression of viral proteins leading to lymphocyte transformation

Immunotoxic

No information

[76,341,342]

Infectious agent

Immunotoxic

No information

[76,341,342]

Adult T-cell leukemia and lymphoma NHL

Infectious agent

Viral infection and expression of viral proteins leading to loss of CD 4+ T lymphocytes Viral infection and expression leading to lymphocyte transformation Viral infection and expression of viral proteins leading to chronic immune stimulation Inflammation leading to cellular alterations, chronic immune stimulation

Alteration in normal Blymphocyte function leading to cell proliferation, inhibition of apoptosis, genomic instability, and cell migration Immunosuppression (as an indirect effect) Immortalization and transformation of T cells

Immunotoxic

No information

[341–343]

Chronic immune stimulation

Immunotoxic

No information

[341,342]

Oxidative stress, altered cellular turnover and gene expression, methylation, and mutation

Immunotoxic

No information

[341,342]

Infectious agents Epstein–Barr virus (EBV)

Human immuno-deficiency virus Type 1 Human T-cell lymphotrophic virus Type 1 Hepatitis C virus

Helicobacter pylori

Kaposi’s sarcoma herpes virus

Group 2A agents DNA-reactive alkylating agents Bischloroethyl nitrosourea (BCNU; carmustine) 1-(2-)Chlorethyl-3-cyclohexyl1-nitrosurea (CCNU; lomustine) N-Ethyl-N-nitrosourea

Infectious agent

Low-grade Bcell mucosaassociated lymphoid tissues 18 effusion lymphoma

Infectious agent

Infectious agent

Viral infection and expression of viral proteins

Cell proliferation, inhibition of apoptosis, genomic instability, cell migration

Immunotoxic

No information

[342]

ANLL

Therapeutic agent

Direct-acting bifunctional alkylating agent

Gene or chromosomal mutation

Myelotoxic

[116,320]

ANLL

Therapeutic agent

Direct-acting bifunctional alkylating agent

Gene or chromosomal mutation

Myelotoxic

No information, positive in animals No information

[ANLL]

Therapeutic agent

Direct-acting alkylating agent

Gene or chromosomal mutation

No information

No information, positive in animals

[116,320]

[116,320]

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Cancer

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Agent

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Table 2 (Continued )

Direct-acting bifunctional DNA binding agent

Gene or chromosomal mutation

Myelotoxic

Nitrogen Mustard (Mechlorethamine) Procarbazine

ANLL

Therapeutic agent Therapeutic agent

Gene or chromosomal mutation Gene or chromosomal mutation

Myelotoxic

ANLL

Direct-acting bifunctional alkylating agent Bioactivated to a monofunctional alkylating agent

Chlorozotocin

ANLL

Therapeutic agent

Direct-acting bifunctional alkylating agent

Gene or chromosomal mutation

Myelotoxic

Topoisomerase II inhibitor Adriamycin

ANLL

Therapeutic agent

Topoisomerase II poison and redox-cycling agent

Teniposide

ANLL

Therapeutic agent

Topoisomerase II poison

Mutation resulting from chromosomal breakage and translocations Mutation resulting from chromosomal breakage and translocations

Other mechanisms Azacytidine

Leukemia

Therapeutic agent

Chloramphenicol

ANLL

Therapeutic agent

Petroleum refining

[Leukemia]

Occupational exposure

DNA methyltransferase inhibitor through metabolism and incorporation into DNA Binds to ribosomal subunit blocking protein synthesis in mitochondria. Metabolite may also induce DNA damage Unknown but DNA-damaging chemicals are used

Burkitt lymphoma (endemic)

Infectious agent

Parasitic infection leading to immune system disturbances, particularly in children

Infectious agents Malaria

a b c

Agents that cause myelotoxicity will also often cause immunotoxicity. Immunotoxic refers to immunosuppression, immunomodulation and immunostimulation. Entries with limited evidence are presented in brackets.

No information, positive in animals Positive

[116,320]

[116,320]

No information, positive in animals No information, positive in animals

[116,320]

Myelotoxic

Positive

[320]

Myelotoxic

No information, positive in animals

[345]

Alters DNA methylation and gene expression. Is also genotoxic Unknown, presumed to be through gene or chromosomal mutation

Myelotoxic

No information, positive in animals No information, positive in animals

[346,347]

Unknown

No information

No information

[348]

Expands the B-cell pool in which endemic Burkitt lymphoma arises, and reactivates latent EBV

Immunotoxic

No information

[349]

Myelotoxic

Myelotoxic

[116,320,344]

[344,346]

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Cisplatin

9

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immune-suppression [76]. The two chemical agents, cyclosporine and azathioprine, which also induce NHL, are also strongly immunosuppressive. In addition, tetrachlorodibenzo-p-dioxin (TCDD), which may induce NHL, has been shown in animal studies to be immunosuppressive [77]. Table 2 also lists the immunosuppressive agents and their autoimmune disorders. Other diseases associated with immune suppression and/or immune stimulation and inflammation are increasingly recognized from large consortia studies as risk factors for lymphoma [78–81]. Similar to the Group 1 agents, the Group 2A leukemogens are primarily associated with the induction of ANLL. For chemicals for which information is available, these agents are also myelotoxic and clastogenic and are believed to most likely induce their leukemogenic effects through a mutagenic mechanism (see Table 2). In summary, based on the IARC evaluations, the vast majority of the human leukemia-inducing agents identified to date are believed to act through mutagenic or genotoxic mechanisms whereas the lymphoma-inducing agents most likely act through immunomodulation and related effects. An overview of the major classes of leukemia-inducing agents is presented below. 4.2. Major classes of leukemia-inducing agents 4.2.1. Ionizing radiation As a result of its widespread medical, military, and energyrelated uses, large numbers of people have been exposed to ionizing radiation, and its adverse effects have been extensively documented. Exposure to ionizing radiation has been shown to result in numerous types of cancer including several types of leukemia as well as adverse effects that are likely to be involved in leukemogenesis including myelotoxicity, immune suppression, and genetic damage leading to chromosomal and gene mutations. The earliest association between radiation and cancer was seen for leukemia, and it has been repeatedly seen in numerous population studies including those exposed through medical, military, and environmental exposures [74,75,82–85]. Assessing the risks associated with radiation exposure is challenging and is influenced by the type of radiation, radioactive materials, the tissue dose, the proportion of the body exposed, the extent of cell killing, and the DNA-repair capacity of the individual or tissue [86]. Host factors such as age, sex, genetic composition, and health of the exposed individuals can also influence the risk of radiation-induced leukemia. All age groups are affected, but children, in particular, have been shown to be at an elevated risk for radiation-induced leukemia as seen in the Life Span Study of the atomic bomb survivors in Hiroshima and Nagasaki [87,88]. Increased risk of leukemia has also been reported following the use of radiation for diagnostic tests, for the treatment of benign diseases, and following radiotherapy for cancer [84,89]. It should be noted that the leukemia risks from medical irradiation appear to have diminished in recent years due to a use of lower and more restricted doses as well as changes in therapeutic strategy in which high doses are applied within limited fields. High radiation doses (above 3–4 Gray) result in extensive killing of marrow-containing progenitor cells and have been associated with a reduced risk of developing leukemia [86,90,91]. 4.2.2. Chemotherapeutic agents The use of chemotherapy with genotoxic agents has been linked to increases in therapy-related leukemias [92–95]. These leukemias, also known as treatment-related or secondary leukemias, consisted primarily of AML, although a small increase in therapyrelated ALL has also been seen [96,97]. Over time, as new agents and therapeutic strategies have been employed; additional agents have been recognized as inducing leukemia in humans. Indeed, as

seen in Table 2, chemotherapeutic drugs comprise the largest group of agents generally recognized as human leukemia-inducing agents. Currently, therapy-related leukemias constitute 10–20% of the leukemia cases seen at major medical institutions [98,99]. The identification of specific agents involved in leukemogenesis and the interpretation of many of the studies can be challenging due to the use of multiple therapeutic agents, varying dosing regimens, concurrent use of radiotherapy, and variable periods of patient follow-up. Over time, two main classes of leukemogenic therapeutic drugs have been identified—alkylating agents and topoisomerase II inhibitors [54,100,101]. An overview of the AMLs (including myelodysplastic syndromes) induced by these two classes of chemotherapeutic drugs is presented in the following sections. 4.2.2.1. Alkylating agent-related leukemias. A large number of studies have demonstrated that patients treated with alkylating agent-based chemotherapy are at an increased risk of MDS and AML [94,101,102]. These risks have been seen for both children and adults and are strongly related to the cumulative dose of the alkylating agent [96,103–106]. The incidence of therapy-related MDS and AML (t-MDS/t-AML) in adults treated with antineoplastic drugs has been reported to range from 1 to >20% [107–109]. The increases in this type of therapy-related leukemia generally appear 1–2 years after treatment and may remain elevated for 8 or more years following the completion of chemotherapy [100,103,110,111]. In adults, leukemias induced by alkylating agents exhibit characteristics that generally allow them to be distinguished from de novo leukemias [101,112]. These leukemias are typically myeloblastic with or without maturation (FAB M1 and M2 subtypes) and are characterized by trilineage dysplasia and clonal unbalanced chromosome aberrations, most commonly involving loss of the entire chromosome or part of the long arms of chromosomes 5 and 7 (7, 7q, 5, 5q). These t-AML have a modal latency period of 4–7 years, and the onset of the actual leukemia is often preceded by myelodysplasia. It should be noted that AML induced by ionizing radiation tends to exhibit similar features (MDS, clonal unbalanced chromosomal aberrations, etc.) although the range of the FAB subtypes induced by radiation tends to be broader [113–115]. Using structure–activity relationships as well as other predictive approaches with in vivo rodent and Drosophila data, Vogel et al. [116] were able to identify three major categories of DNA-reactive chemical and therapeutic agents. As described by the authors, Category 1 consisted of mono-functional alkylating agents such as ethylene oxide and methyl methane sulfonate, which primarily react at the N7 and N3 moieties of purines in DNA. Efficient DNA repair was the major protective mechanism against the relatively weak genotoxic effects of these agents, which might not be detectable in repair-competent cells. High doses were generally needed for the induction of tumors in rodents. Strong target site specificity for the adverse effects was seen, and this appeared to be related to DNA repair capacity. Category 2 agents such as procarbazine and N-nitroso-N-ethylurea (ENU), induce both Oalkyl adducts and N-alkyl adducts in DNA. In general, the induced O-alkyl adducts appeared to be slowly repaired, or not repaired, which made these agents relatively potent carcinogens and germ cell mutagens. The inefficient repair of the O-alkyl-pyrimidines, in particular, was responsible for their potent mutagenic activity. Category 3 agents such as melphalan and busulfan induced structural aberrations through their ability to cross-link DNA, and this was the major factor contributing to their high genotoxic potency, which appeared to be related to the number of DNA crosslinks per target dose unit that were induced. The genotoxic effects for the Category 3 agents occurred at, or near, toxic levels.

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For all three categories of genotoxic agents, strong correlations were observed between their carcinogenic potency, acute toxicity, and germ-cell specificity. 4.2.2.2. Topoisomerase II inhibitor-related leukemias. Epipodophyllotoxins, a class of chemotherapeutic agents, have become widely used, especially for treating childhood cancers, and a large number of studies have been published establishing an association between treatment with these drugs and the subsequent development of leukemia [100,102,109,117–120]. The leukemia risk following epipodophyllotoxin therapy was reported to be very high in early studies, with cumulative incidences approaching 19% in some treatment groups [121]. Interestingly, in some cases, the risk of a treatment-related cancer appeared to be more closely related to the treatment regimen than to total dose [119,122]. Patients receiving epipodophyllotoxins on a weekly or twice-weekly basis had much higher cumulative risks (12.4%) than those receiving the drugs on a biweekly schedule (1.6%). Similar results have been seen in studies by Smith et al. [123] although others have seen a correlation between cumulative dose and epipodophyllotoxin-induced t-AML [124,125]. With implementation of newer treatment protocols, the risk of t-AML has been reduced substantially and is now within the range of that seen with alkylating chemotherapeutic agents [119,126]. There is also evidence that the combined treatment of topoisomerase II inhibitors with alkylating agents (or cisplatin) confers a greater risk of t-AML than seen with either type of chemotherapeutic agent alone [102,127,128]. In most reported cases, the incidence of tAML induced by these drugs is estimated to range from 2 to 12% [107,109]. The epipodophyllotoxins exhibit moderate myelosuppression, identifiable chromosomal damage, and their leukemogenic effects by inhibiting topoisomerase II through a process that involves stabilization of the DNA-enzyme complex [102,129,130]. Topoisomerase II is a nuclear enzyme involved in a wide variety of cellular functions, including DNA replication, transcription, and chromosome segregation [131–133]. Leukemias induced following treatment with epipodophyllotoxin-type topoisomerase inhibitors generally appear from 10 months to 8 years following the initiation of chemotherapy, with a median latency of 2–3 years [102,109]. The induced AMLs are primarily of the monocytic or myelomonocytic subtypes (M4 and M5) and are infrequently preceded by a myelodysplastic phase, a pattern that differs significantly from alkylating agent or radiation-induced leukemias [54,101,102,109]. One of the unique features of t-AML, and to a lesser extent t-ALL, induced by the epipodophyllotoxin-type of topoisomerase II inhibitors, is the presence of clonal-balanced translocations involving the MLL gene (also known as ALL-1, HRX, and HTRX-1) located on the long arm of chromosome 11 (11q23) in the leukemic cells. Cytogenetic studies of patients with leukemias induced by these agents have shown that in over 50% of the cases, the leukemic clone involved a balanced translocation affecting the 11q23 region and another chromosomal partner, usually t(6;11), t(9;11), and t(11;19) [101,102,134]. In children previously treated with topoisomerase inhibitors, up to 90% of the treatment-related leukemias have an 11q23 alteration [134]. Numerous lines of evidence indicate that topoisomerase II as well as DNA-repair enzymes such as those involved in nonhomologous end joining play an important role in the formation of the 11q23 translocations. These have been summarized in a series of reviews [135– 138]. The presence of topoisomerase II recognition sites has been found in proximity to the translocation breakpoints as have recombinase recognition sites, Alu sequences, DNase hypersensitive sites, and scaffold attachment regions, and has been interpreted to suggest that multiple types of damage and repair contributed to the generation of the observed translocations

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[119,137,138]. However, recent evidence indicates that the cleavage site is selected by topoisomerase II based upon the deformability of the DNA sequence rather than though specific DNA sequence information [139]. With regards to the subsequent steps, Cowell et al. [140] have proposed a model in which DNA double strand breaks are introduced by topoisomerase IIb into pairs of genes undergoing transcription at a common transcription factory. These breaks occurring on each partner chromosome become stabilized by topoisomerase II inhibitors and because of their close proximity create the conditions that allow illegitimate end joining and translocation to occur. As an alternative mechanism, the MLL gene has been shown to be prone to breakage during apoptosis, and it has been proposed that the observed translocations occur in hematopoietic cells rescued at an early, reversible stage during the apoptotic process [141–145]. A role for apoptosis has also been proposed in the formation of other leukemia-related translocations [146]. 4.2.2.3. Other likely leukemia-inducing therapeutic agents. In recent years, evidence has accumulated that other inhibitors of topoisomerase II, such as the anthracycline, anthracenedione, and bisdioxopiperazine derivatives, can also induce treatment-related leukemias [69,70,125,128,147–149]. The leukemias induced by these agents are similar to the epipodophyllotoxins in that they have short latency periods and are infrequently preceded by myelodysplasia. However, they typically exhibit different types of clonal-balanced rearrangements (e.g. t(8;21), t(15;17), and inv(16)) and different FAB subtypes (M2 and M3). Although azathioprine, 6-thioguanine, and 6-mercaptopurine are primarily associated with immunosuppression and the induction of NHL, a number of studies have suggested that patients treated with these 6-thioguanosine monophosphate-producing drugs are at an increased risk of developing ANLL [150–152]. It has been suggested that the risks are higher in patients with low thiopurine Smethyltransferase activity and may involve aberrant mismatc repair and microsatellite instability [150,151]. Interestingly, the leukemias of many of these patients also show loss of chromosome 7 or part of chromosomes 5 or 7 (5q or 7q) [152]. 4.2.3. Environmental and occupational agents 4.2.3.1. Benzene. Benzene is an important industrial chemical, a component of gasoline and cigarette smoke, and a widespread environmental contaminant. It has been shown to be a multi-site carcinogen in experimental animals, causing tumors in many tissues including leukemias and/or lymphomas in male and female mice [153–155]. Benzene requires bioactivation to induce its myelotoxic and genotoxic effects [156,157], and a number of benzene-derived reactive species have been identified including benzene epoxide, t,t-muconaldehyde, 1,2- and 1,4-benzoquinone. Benzene binds inefficiently to DNA but more readily to proteins and non-protein sulfhydryls [158–160]. In spite of many years of effort, the specific metabolites and mechanisms involved in benzene’s myelotoxic and carcinogenic effects remain unknown; It is currently believed that multiple metabolites and mechanisms are likely to be involved [161]. Benzene has been extensively studied for its genotoxic and mutagenic effects [162,163]. It is largely inactive in short-term mutagenicity assays conducted in bacteria or in mammalian cells in culture. This inactivity may be due, at least in part, to limitations of common bioactivation systems, the difficulties inherent in testing a lipophilic and volatile chemical using cell culture systems, and the absence of potential targets (e.g. topoisomerase II) in some of these systems [164]. In animal studies in vivo, benzene has been shown to be highly effective at inducing structural chromosomal aberrations, and to a lessor degree numerical aberrations

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[161,165]. Benzene has also been shown to induce gene mutations in mice with stronger responses being seen in the spleen of wildtype mice (hprt mutations) [166,167] than in the lung, spleen and bone marrow of transgenic mice (lacI mutations) [168,169]. Numerous studies have been conducted examining hematotoxic and genotoxic effects in the blood cells of benzene-exposed workers. Chromosome breakage and aneuploidy have been seen in multiple studies of the lymphocytes of exposed workers [170]. The types and patterns of aberrations detected in recent studies have been interpreted by some authors as being consistent with clonal alterations occurring in t-AML induced by alkylating agents [171,172] as well as leukemias caused by topoisomerase II inhibitors [71]. Workers exposed to benzene have also been shown to exhibit an increase in gene-duplicating mutations in the glycophorin A gene rather than gene-inactivating mutations [173]. For over 100 years in humans and nearly as long in experimental animals [174], benzene has been recognized as a hematoxic agent that targets the bone marrow and causes decreases in the numbers of circulating blood cells [175,176]. In humans with elevated and prolonged exposures, all cell lineages can be affected, resulting in pancytopenia and, in severe cases, aplastic anemia [30,175,177]. Benzene has also been shown to have many other effects in exposed humans including immunological effects [178], epigenetic changes within cells, and the altered transcription of genes believed to be involved in leukemogenesis [176]. Benzene was first recognized by IARC as a human leukemiainducing agent in 1982 [161]. Since that time there have been many additional studies which have provided additional evidence for the leukemogenic effects of benzene. While the association between benzene and MDS and AML is widely accepted, benzene’s ability to cause other types of lymphohematopoietic cancers has been the subject of considerable debate. In its most recent evaluation [161], IARC concluded that ‘‘there is sufficient evidence in humans for the carcinogenicity of benzene. Benzene causes acute myeloid leukemia/acute non-lymphocytic leukemia. IARC also noted that ‘‘a positive association has been observed between exposure to benzene and acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, and non-Hodgkin lymphoma’’ [161]. Although there widespread recognition that benzene causes AML/ANLL, there is no consensus about the specific sub-types that are induced. Early studies by Aksoy and colleagues in Turkey and Vigliani and associates in Italy indicated that benzene induced primarily acute myeloblastic leukemia (most likely FAB subtypes M1-2) with notable increases in erythroleukemia (M6) [179]. Studies from the United States and China have suggested a broader distribution of lymphohematopoietic types with fewer cases of ANLL-M6 being formed [180–182]. To some, the onset and descriptions of the leukemias seemed to resemble t-AML induced by alkylating agents [183]. However, more recent studies from Shanghai, China have reported that benzene-induced leukemias seem more to resemble de novo leukemias than t-AML [72]. In the recent Chinese study, the dominant benzene-related subtypes appeared to be ANLL with t(8;21) and t(15;17) which would correspond to those of the ANLL-M2 and ANLL-M3, respectively [72,184]. It should be noted that these are the types of leukemia induced by some types of topoisomerase II inhibitors and mechanistic studies have shown that benzene and its metabolites can inhibit topoisomerase II in vitro and in vivo [165,185,186]. Given that benzene-induced leukemias are rare, some of the observed differences are undoubtedly due to the small numbers of benzene-induced leukemia patients identified in these studies, the imprecise descriptions given in the older reports as well as a failure to detect all benzene-induced cancers, etc. However, another possible explanation could help to explain the discrepant results;

Benzene may act to enhance or promote pre-existing initiated (or preleukemic) cells present in the exposed population. Since the background incidence of leukemia subtypes can vary by geographical location and/or ethnicity [187,188], the sub-types of leukemia induced by benzene (and possibly other agents [189]) may also reflect underlying genetic, cultural or environmental susceptibilities or influences. As a result, the sub-types of leukemia induced by benzene could differ in different regions of the world and among the different exposed populations. 4.2.3.2. Ethylene oxide (this section is largely summarized from [190]). Ethylene oxide is a widely used chemical intermediate, a metabolite of ethylene, and a sterilizing agent. It is a direct-acting alkylating agent that has been shown to bind to DNA, RNA, and protein. The major DNA adduct recovered in vivo is N7-(hydroxyethyl) guanine, an adduct that is not involved in base pairing and is not considered to be promutagenic. The adducted DNA can however depurinate producing an abasic site that can be mutagenic if present during replication [191]. The N7 adduct is also formed endogenously as a result of metabolic processes [191]. Additional adducts such as 3-(2-hydroxyethyl)-adenine and O6-(2hydroxyethyl)guanine, which would be expected to be more mutagenic, are typically either not detected or are detected at very low levels [112,192]. Ethylene oxide is readily metabolized to nonDNA reactive products by glutathione-S-transferases and epoxide hydrolases, and this is likely to reduce the concentrations of ethylene oxide that are able to reach the DNA. In the classification scheme of Vogel and associates [116], ethylene oxide is a Category 1 agent that would be expected to be a relatively weak mutagen and carcinogen in vivo as compared to other, primarily antineoplastic, alkylating agents. Ethylene oxide has been shown to be genotoxic and mutagenic in both somatic and germ cells in a variety of organisms [190,193]. It is highly active in bacteria and cell culture systems, with lesser activity being seen with exposure to whole animals in vivo. Numerous studies have shown that ethylene oxide can induce point mutations in both reporter genes and cancer genes of multiple tissues in mice and rats. Based on these studies, however, ethylene oxide was considered to be a relatively weak point mutagen in vivo. Ethylene oxide was also shown to induce chromosomal damage in rodents, but observable damage occurred only at high concentrations indicating that it is also a relatively weak clastogen in experimental animals. Somewhat surprisingly given its reported weak clastogenicity in animals, increased frequencies of chromosomal aberrations have been seen in the peripheral blood lymphocytes of ethylene oxide-exposed workers in 18 of 24 studies that were evaluated [190]. Previous studies have reported that individuals with elevated frequencies of chromosomal aberrations in their peripheral blood are at an elevated risk of developing cancer in subsequent years [194]. Ethylene oxide induced a variety of tumors in mice and rats in chronic bioassays [190]. Lymphohematopoietic cancers induced include in lymphomas in female mice, and mononuclear cell leukemias in male and female rats. In contrast to most other leukemia-inducing agents, exposure to ethylene oxide has not generally been associated with myelotoxicity in humans. However, one report has indicated that ethylene oxide can cause decreases in circulating white blood cells [195] whereas others have suggested that ethylene oxide may induce lymphocytosis in workers [196– 198]. Of note, a more recent follow-up study did not support a role for ethylene oxide in the observed lymphoctyosis [197]. In its recent evaluation [161,199], the IARC working group indicated that ‘‘there is limited evidence in humans for a causal association of ethylene oxide with lymphatic and haematopoietic cancers (specifically lymphoid tumours, i.e., non-Hodgkin lymphoma, multiple myeloma, and chronic lymphocytic lymphoma). . ..’’

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Interestingly, ANLL was not one of the lymphohematopoietic cancers that was considered by the IARC working group to be associated with ethylene-oxide exposure. As seen in Table 2, the three lymphohematopoietic cancers mentioned by IARC have generally not been associated with other alkylating agents with the exception of butadiene, which has been associated with CLL and NHL (described below). Also of note, the three types of neoplasm listed originate in mature B lymphoid cells (see Fig. 1), which is also somewhat unusual for alkylating agent-related cancers. In making its overall evaluation that ethylene oxide was carcinogenic to humans (Group 1), IARC relied heavily on evidence from experimental animals as well as the compelling data on ethylene oxide’s genotoxicity and mechanism of action [161]. 4.2.3.3. 1,3-Butadiene: (this section is largely summarized from [200,201]). Butadiene is a widely used industrial chemical that has been shown to induce cancer in mice, rats, and humans. Butadiene is metabolized to a number of epoxide metabolites (stereoisomers of epoxybutene, epoxybutanediol, and diepoxybutane) that can react directly with DNA. The most common DNA adduct detected in mice and rats is the N7-guanine adduct (N7trihydroxybutylguanine), which is derived from either epoxybutanediol or diepoxybutane. Other adducts at base-pairing sites that can be formed from the epoxide metabolites of butadiene include adducts at the N3-cytosine, N1-adenine, N6-adenine, N1-guanine, and N2-guanine. Crosslinks between N7-guanines have also been detected in the liver and lungs of butadiene-treated mice. The butadiene epoxide metabolites can be metabolized to non-DNA reactive products by glutathione-S-transferase and epoxide hydrolase enzymes. In the Vogel classification scheme [116], butadiene through its diepoxybutane metabolite was considered a Category 3 agent, which would be expected to be a potent mutagen and carcinogen. However, the authors suggested that because the DNA crosslinks formed by diepoxybutane are primarily intrastrand crosslinks that are more readily repaired, diepoxybutane would be a much weaker mutagen and carcinogen than other Category 3 agents. Metabolic factors are also likely to contribute to butadiene’s reduced potency in rats (and probably humans). However, butadiene is readily bioactivated in mice and is a potent carcinogen in that species. Butadiene and its epoxide metabolites have been shown to be genotoxic and mutagenic in most experimental systems both in vitro (with metabolic activation for butadiene) and in vivo. Butadiene exhibited clastogenic effects in mice inducing chromosomal aberrations, micronuclei, and sister chromatid exchanges. Similar effects were not seen in rats, and this is believed to be due to metabolic differences between the two species. However, relatively few studies have been conducted in rats. Butadiene has also been shown to induce mutations with bioactivation in mammalian cells and in vivo in mice. The epoxide metabolites have also shown positive results in numerous genotoxicity studies. Not surprisingly given its bifunctional nature, the diepoxybutane is the most potent of the three metabolites. For example, when monoepoxybutene, diepoxybutane, and 3,4-epoxy-1,2-butanediol were tested for mutagenicity at HPRT and TK loci in the TK6 human lymphoblastoid cells [202,203], all three epoxides were mutagenic, but the mutagenicity of the diepoxybutane was much greater than that seen for the other two epoxides. However, as noted by IARC [201], while genotoxicity studies have indicated that diepoxybutane is the most genotoxic of the epoxides formed from butadiene, the relative contribution of the various epoxide metabolites to the mutagenicity and carcinogenicity of butadiene is not known as the monoepoxybutene metabolite is likely to be formed in greater quantities. Using either conventional techniques or new molecular cytogenetic techniques such as fluorescence in situ hybridization with DNA probes, increased frequencies of chromosomal aberrations

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have not generally been seen in the peripheral blood lymphocytes of butadiene-exposed workers. Exposure to butadiene has also not been associated with myelotoxicity in exposed humans. In its 2008 evaluation [201], IARC concluded: Overall, the epidemiological studies provide evidence that exposure to butadiene causes cancer in humans. . . . This conclusion is primarily based on the evidence for a significant exposure–response relationship between exposure to butadiene and mortality from leukaemia in the University of Alabama in Birmingham study, which appears to be independent of other potentially confounding exposures. It is also supported by elevated relative risks for non-Hodgkin lymphoma in other studies, particularly in the butadiene monomer production industry. The Working Group was unable to determine the strength of the evidence for particular histological subtypes of lymphatic and haematopoietic neoplasms because of the changes in coding and diagnostic practices for these neoplasms that have occurred during the course of the epidemiological investigations. However, the Working Group considered that there was compelling evidence that exposure to butadiene is associated with an increased risk for leukaemias. The most recent IARC evaluation [161,199] did not provide additional clarification on the histological subtypes, stating that ‘‘there is sufficient evidence in humans for the carcinogenicity of 1,3-butadiene’’ and that ‘‘butadiene causes cancer of the haematolymphatic organs.’’ Assuming that the earlier diagnoses were correct, the types of leukemias in the University of Alabama study that showed significant dose-related associations with butadiene exposure were CLL and CML. Increases in other NHL sub-types such as reticulosarcoma and endothelioma seen in other studies were also provided as supportive evidence. Neither of the two associated types of leukemia has been commonly seen in leukemias induced by most other alkylating agents (see Table 2). However, as noted above, increases in CLL and NHL have been reported in ethylene oxide-exposed workers. 4.2.3.4. Formaldehyde: (this section expands upon the material in [204]). Formaldehyde is a common industrial chemical, an environmental contaminant, and an endogenous metabolite. It has been shown to induce cancer in rats and humans. Formaldehyde is a reactive chemical that primarily binds to sulfhydryl and primary N-terminal amine groups in polypeptides and proteins. It can bind to DNA forming monoadducts and DNA–DNA crosslinks [205] as well as DNA-protein crosslinks, which have been shown to be associated with its cytotoxic and genotoxic effects [206]. Formaldehyde binds readily to reduced glutathione (GSH) nonenzymatically, forming an S-hydroxylmethylglutathione, hemithioacetal adduct, that can be converted to formate in a twostep reaction by formaldehyde dehydrogenase and S-formylglutathione hydrolase releasing free GSH. Formaldehyde has exhibited genotoxic and mutagenic effects in a large number of experimental systems in vitro as well as in vivo [207]. In vitro, it has been shown to induce mutations in bacteria and mammalian cells, form DNA-protein crosslinks and strand breaks, and chromosomal aberrations. In rodent models, DNA adducts, DNA-protein crosslinks, chromosome aberrations, and micronuclei have been observed at the site of exposure, but formaldehyde-derived DNA adducts have not been detected in the bone marrow [191,205,208,209]. The lack of formaldehydederived DNA adducts in the bone marrow of rats and non-human primates have been used by some investigators as evidence that an induction of leukemia by formaldehyde is not biologically plausible [205,351,352]. However, in recent years, there have been a number of studies that have reported significant increases in toxicity, chromosomal and DNA damage as well as oxidative

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damage in the bone marrow of rodents exposed to formaldehyde [210–214]. Other types of systemic effects including reproductive, neurological and mutagenic effects have also been reported [215– 220]. In humans, formaldehyde-exposed workers have been reported to exhibit increased frequencies of DNA-protein crosslinks in their peripheral blood lymphocytes [217]. Increased frequencies of micronuclei were reported to occur in the nasal and oral mucosa of formaldehyde-exposed workers [217] but were not seen in the oral mucosal cells of volunteers exposed to variable levels of formaldehyde under controlled exposure conditions [221]. Similarly, while negative results were reported in some studies, others have reported that formaldehyde-exposed workers had increased frequencies of structural chromosome aberrations and SCEs in their peripheral blood lymphocytes [204,217,222]. Formaldehyde exposure has not typically been associated with hematotoxicity in humans (or animals), although hematotoxic and immunological effects have been seen in a number of occupational studies from China [223,224]. The mixed results seen in the various studies may be explained, in part, by differences in exposure levels. Recently, a biomonitoring study was conducted on a small group of Chinese workers with particularly high formaldehyde exposures (median 8-h time weighted average exposure level of 1.28 ppm) [225]. The researchers found that the exposed workers had lower blood cell counts and that peripheral stem/progenitor cells obtained from the workers exhibited elevated frequencies of monosomy for chromosome 7 and trisomy for chromosome 8 – cytogenetic alterations commonly seen in human leukemias. However, given its small size, the results of this study should be interpreted cautiously with regard to the potential hematotoxic and aneugenic effects of formaldehyde. In its 2006 evaluation of formaldehyde [204], the IARC working group concluded that ‘‘there is sufficient evidence in humans for the carcinogenicity of formaldehyde’’ based on the occurrence of nasopharyngeal cancer. With regards to leukemia, the working group concluded that ‘‘there is strong but not sufficient evidence for a causal association between leukaemia and occupational exposure to formaldehyde.’’ They felt at that time that it was ‘‘not possible to identify a mechanism for the induction of myeloid leukaemia in humans by formaldehyde.’’ In the more recent 2009 evaluation [161,199], a new IARC working group concluded that ‘‘the epidemiological evidence on leukaemia has become stronger, and new mechanistic studies support a conclusion of sufficient evidence in humans. This highlights the value of mechanistic studies, which in only 5 years, have replaced previous assertions of biological implausibility with new evidence that formaldehyde can cause blood-cell abnormalities that are characteristic of leukaemia development.’’ However, it should be noted that this conclusion was controversial as the working group was almost evenly split on the evaluation, with a slight majority seeing the evidence as sufficient for carcinogenicity, and the minority viewing the evidence as limited. The association between formaldehyde exposure and leukemia continues to be controversial and a number of meta-analyses of epidemiological studies have been conducted to address this issue. An earlier meta-analysis of 18 epidemiology studies [226] showed inconsistent results for formaldehyde exposure and leukemia. However, a more recent compilation and meta-analysis of formaldehyde-associated leukemia studies indicated that formaldehyde exposure was most closely associated with myeloid leukemias, primarily AML, and proposed several possible mechanisms by which formaldehyde might initiate leukemogenesis including some that could occur near the site of exposure [222]. Two subsequent meta-analyses have provided evidence both for [227] and against [228] the reported association between formaldehyde and leukemia. In 2011, the National Toxicology

Program reviewed the evidence for cancer in humans and concluded that there was consistent evidence for an association between formaldehyde exposure and nasopharyngeal, sinonasal and lymphohematopoietic cancer, specifically myeloid leukemia, among individuals with higher measures of exposure (exposure level and duration), which cannot be explained by chance, bias or confounding [229]. More recently, a panel convened by the National Research Council of the National Academies of Science reviewed the EPA’s draft IRIS risk assessment of formaldehyde and raised significant concerns about EPA’s evaluation of the association between formaldehyde exposure and lymphohematopoietic cancers including concerns about the biological plausibility of the association, the combining of all lymphohematopoietic cancers for analysis, and the need for clarification regarding the weightings and evaluations given to different lines of evidence [230]. 5. Selected factors conferring an increased risk of induced leukemia 5.1. Myelosuppression Myelosuppression and immunotoxicity frequently accompany exposure to leukemia-inducing agents, particularly those such as the chemotherapeutic drugs, ionizing radiation, and benzene, for which leukemogenicity has been clearly established (Table 2; [130,231]). The number of individuals affected and the magnitude of toxicity are influenced by the agent and dose-related factors such as total dose, dose per treatment, schedule, and route of administration as well as individual host factors (age, genetic susceptibility, prior therapy, health status, etc.) [232]. A brief overview of the myelosuppressive effects of cancer therapeutic drugs has been written by Gale [232] and is the basis for the following description. The severity of myelotoxicity induced by antineoplastic drugs varies considerably by chemical class. For drugs associated with t-AML, moderate-to-severe effects are generally seen. Epipodophyllotoxins, cisplatin, and procarbazine typically produce more moderate toxicity whereas severe effects are more common for the alkylating agents, the anthracyclines, and the nitrosoureas. The period between dosing and the onset or appearance of the myelosuppression is also related to the class of agent. For some agents such as ionizing radiation, the onset of myelotoxicity occurs within 0–48 h after exposure. For others, longer periods are required. The onset of myelosuppression by the alkylating agents and anthracyclines occurs 1–3 weeks following exposure and is believed to be due to the effect of these agents on immature hematopoietic cells that becomes more evident as the more mature blood cells die and require replacement. Myelosuppression induced by the nitrosoureas and mitomycin C is less frequent and occurs 4–8 weeks after treatment. This delayed effect is believed to be due to a relatively selective effect on immature stem cells. However, the onset of this delayed effect is dose-dependent. A twoto threefold increase in dose reduces the onset of myelotoxicity by these agents to 1 week. For some drugs such as busulfan, the manifestation of the myelotoxic effects is considered to be latent and may only be manifested under stress-related conditions. In most cases, the induced myelotoxicity is transient with the blood cell counts returning to normal following the cessation of treatment or exposure [178,233]. However, in some cases, the induced myelosuppression can be more persistent and progress to pancytopenia or infrequently to aplastic anemia, a condition that confers a much greater risk of developing leukemia (10%) [234– 237]. Increased risks have also been seen for those who have previously exhibited less severe forms of bone marrow toxicity. Studies of benzene-exposed workers have shown that the leukemia mortality rate was much higher for workers who had

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previously been diagnosed with bone marrow poisoning (700 per 106 person-years) as compared to those exposed to, but not poisoned by, benzene (14 per 106 person-years), and particularly as compared to the general population (2 per 106 person-years) [238]. In one report, 36% of the benzene leukemia cases had a history of benzene poisoning with leukopenia or pancytopenia [239]. However, this also indicates that for most cases, clinically detectable myelotoxicity (e.g. leucopenia or pancytopenia) may not be observed. It should also be noted that at lower exposure levels, the decreases in cell counts occurring in exposed groups may fall within what is considered the normal clinical range [240,241]. This highlights one of the challenges in using myelotoxicity as a biomarker, as the normal range varies considerably in adults. For example, the mean white blood cell count in normal adults is 7200  103/mL with a 95% range from 3900 to 10,900  103/mL [22]. 5.2. Genetic polymorphisms Inherited polymorphisms in genes involved in xenobiotic metabolism and other cellular processes have been associated with increased risks of myelotoxicity or leukemia in numerous studies of patients or workers exposed to leukemogenic agents. In some instances, similar associations have been seen in follow-up studies by other investigators. However, in a significant number of cases, the results have either not been repeated or have not been reproducible. This is likely due to the limited nature of the studies that have been conducted to date. Consequently, it is difficult to make firm conclusions about many of the reported polymorphisms. Several relatively recent reviews on polymorphisms and leukemia have been published to which the reader may want to refer for further details [242–246]. The following is a brief overview of some of the genetic polymorphisms involved in DNA metabolism, repair, and xenobiotic metabolism that have been repeatedly associated with altered risks of developing leukemia, particularly induced acute myeloid leukemias. Because most leukemogens are genotoxic and exert their effects by damaging DNA, the DNA repair capacity of the bone marrow is likely to have a significant influence on the risk of t-AML. Indeed, individuals with inherited deficiencies in enzymes that are involved in DNA repair such as ataxia telangiectasia, Bloom syndrome, and Fanconi anemia are at significantly higher risk for developing leukemia and other lymphohematopoietic cancers [247]. The associated risks can to be very high with up to 25% of the affected individuals developing leukemia/lymphoma during their lifetime. Individuals with these and other uncommon genetic syndromes such as neurofibromatosis 1 are also at an increased risk of t-AML following treatment with radiation, alkylating agents, and/or topoisomerase II inhibitors [245,248]. Genetic polymorphisms in DNA repair genes that occur more frequently in the population can also confer an increased risk of tAML. Defective mismatch repair is often manifested by microsatellite instability in cancer cells and is frequently seen in leukemias, particularly in t-AML, where it has been reported to occur in 50% of the cases [245,249]. In contrast, less than 5% of de novo leukemias exhibit microsatellite instability. While the basis for this instability is still unknown, factors that are likely to contribute are deficiencies in DNA-mismatch repair enzymes. In an earlier report, the hMSH2 mismatch repair variant was shown to be significantly overrepresented in t-AML patients that had previously been treated with 06-guanine-forming alkylating agents including cyclophosphamide and procarbazine, as compared with controls [250]. Similarly, polymorphisms in genes involved in DNA repair (e.g. WRN, TP53, hOGG1, XRCC1, ERCC3, and BRCA2) have been reported by a number of investigators to be associated with a decrease in white blood cell counts or an increase in chromosomal damage in benzene-exposed workers [251–255].

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Polymorphisms affecting DNA metabolism have also been reported to confer an increased risk of t-AML. Thiopurine methyltransferase catalyzes the S-methylation of thiopurine medications such as 6-mercaptopurine and 6-thioguanine, which are commonly used as cancer chemotherapeutic agents. As summarized from Cheok and Evans [242], the thiopurine methyltransferase pathway is the primary mechanism for inactivation of thiopurines in hematopoietic tissues. The link between thiopurine methyltransferase polymorphisms and mercaptopurine toxicity has been extensively investigated, and studies have shown a strong relationship between thiopurine methyltransferase deficiency polymorphisms and hematopoietic toxicity. Three variant alleles are responsible for >95% of the cases with low or intermediate thiopurine methyltransferase activity. Patients homozygous or heterozygous for the low activity alleles are inefficient at detoxifying the mercaptopurines and accumulate high concentrations in their hematopoietic tissues. If their administered doses are not modified, they are at high risk for severe hematopoietic toxicity. Inherited thiopurine methyltransferase deficiency has also been associated with a higher risk of tAML, particularly in ALL patients treated with topoisomerase II inhibitors [256,257]. It has been postulated that the increased risk may be due to an interference of 6-thioguanine or methylated 6mercaptopurine with DNA repair after DNA damage has been induced by other chemotherapeutic agents. The influence of polymorphisms in other xenobiotic metabolizing genes on the incidence of leukemia has been the subject of many investigations [14,108,243,245,258,259]. In many cases, there was no difference between the frequencies seen in t-AML patients as compared to de novo leukemia patients or a control cohort. A number of studies have indicated that individuals with genes coding for nonfunctional or less active copies of various glutathione-S-transferases, CYP3A4, and NADPH quinone oxidoreductase 1 (NQO1) have an increased risk for developing t-AML following chemotherapy. However, these results have not consistently been seen. The relationship between NQO1 and leukemia is presented below as an example. However, it should be noted that these genes may have other important cellular functions in addition to their roles in xenobiotic metabolism. For example, NQO1 has recently been reported to also influence cellular signaling within the bone marrow niche [260]. Polymorphisms in NQO1, an enzyme involved with the reduction of quinones and protection against oxidative stress, have been repeatedly associated with the development of leukemia. Studies have reported that an inactivating polymorphism in NQO1 (the C609T, a functionally null variant) was overrepresented in patients with t-AML [261], in those with de novo AML (particularly those with translocations or an inv (16) clonal aberration) [262], in infant leukemias with a 11q23 karyotype, and in infants and children with the t(4;11) form of ALL [263,264]. While these initial studies indicated a consistent association with a number of different leukemia types, more recent studies have been less consistent with many not showing an association [265–268]. Genetic polymorphisms affecting NQO1 have also been associated with increased myelotoxicity and may confer an increased risk of leukemia. For example, benzene-exposed individuals who were rapid CYP2E1 metabolizers and had the C609T null variant for NQO1 had a 7.6-fold increased risk of benzene poisoning as compared to exposed individuals with the slow CYP2E1 metabolizer phenotype who had one or two of the wild type NQO1 alleles [269]. In another study by this research group, different NQO1 polymorphisms, as well as a polymorphism in myeloperoxidase, an enzyme implicated in the bioactivation of benzene’s quinone metabolites in the bone marrow, were associated with lower blood cell counts in benzeneexposed workers [241]. A similar association between NQO1 and

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chromosomal damage in the peripheral blood lymphocytes of workers exposed to benzene (as well as other potentially confounding chemicals) was also recently reported by another research group [252]. 6. Implications for hazard and risk assessment As indicated above, approximately 25% of the agents established by IARC as human carcinogens induce lymphohematopoietic cancers, and most of these are associated with the induction of leukemia, primarily AML. In addition, certain environmental agents are also associated with lymphohematopoietic cancers. These agents have a wide variety of uses, and given their established carcinogenic effects, they have been the focus of many safety evaluations and risk assessments. The sections below briefly focus on how mechanistic information on these carcinogenic agents can be used to inform risk evaluation. The following discussion is not intended to be comprehensive information on risk assessment implications but rather will focus on some key issues related to contemporary risk assessment discussions. Hazard identification is the process of determining whether exposure to a stressor can cause and/or increase the incidence of specific adverse health effects, and if the adverse health effects are likely to occur in humans. A wide variety of data, including toxicokinetic and toxicodynamic data, are used to support a hazard identification analysis. Furthermore, when human data are not available, information from animal studies are relied upon to make inferences about the potential hazard to humans. Various U.S. federal agencies use different sets of criteria for classification of chemicals as carcinogens or non-carcinogens. When assessing a chemical for its carcinogenic or toxicity potential, the U.S. Environmental Protection Agency (EPA) focuses on MOA and the weight of evidence (WOE) of a chemical’s potential to cause the adverse human health effects [270]. The National Toxicology Program, part of the National Institute for Environmental Health Sciences, uses its own criteria for classifying and developing its Report on Carcinogens (described at http://ntp.niehs.nih.gov/ ?objectid=03C9CE38-E5CD-EE56-D21B94351DBC8FC3). According to the IARC Preamble [204], which describes the IARC groupings and its WOE decision-making process, the Group 1 category ‘‘is used when there is Sufficient Evidence of Carcinogenicity in humans’’. The Group 2A agents represent chemicals that are probable human carcinogens for which there ‘‘is Limited Evidence of Carcinogenicity in humans and Sufficient Evidence of Carcinogenicity in experimental animals’’. For further details on these categories, the reader is referred to IARC [204]. Most of the Group 2A agents listed in Table 2 have mechanisms of action such as mutagenicity that are commonly associated with carcinogenesis. However, they have not been adequately studied in humans, or for many of the chemotherapeutic agents, they were administered in combination therapy often with other carcinogenic agents so that the carcinogenic effects for the agent being investigated cannot be separately identified. For most of the evaluations, studies of cancer in humans and experimental animals have played the primary role in the IARC classification. More recently, however, the role of mechanism of action has increased such that insight into human relevance of observable mechanisms is more frequently used for carcinogenicity hazard characterization. Below are several observations about how mechanistic information has and may be used in hazard identification for leukemia-inducing agents. 6.1. Short-term genotoxicity tests and human biomonitoring As seen in Table 2, most of the agents identified by IARC as human carcinogens are likely to act through a mutagenic or

genotoxic mechanisms. A large proportion of the Group 1 and 2A carcinogens are alkylating agents, but other classes of genotoxic agents such as topoisomerase II inhibitors or nucleotide analogs are also included. Most of these leukemia- and lymphomainducing agents are active in short-term genotoxicity tests both in vitro (with metabolic activation as needed) and in vivo [271]. This is not surprising given their likely mechanisms of action. The exceptions to this tend to be the infectious agents and the immunosuppressive agents that act through nongenotoxic or indirect genotoxic mechanisms of action. Most of the leukemia-inducing agents have been shown to induce chromosomal aberrations (CAs) or micronuclei (MN) in the peripheral blood lymphocytes of exposed humans and experimental animals. There is increasing evidence that elevated frequencies of SCAs and MN in human lymphocytes can serve as predictive indicators (biomarkers) of cancer risk [194,272–277]. The agents listed in Table 2 also frequently cause significant bone marrow toxicity or immunotoxicity with noticeable alterations in the relevant blood cell counts of exposed individuals. There are a few Group 1 agents that are exceptions such as 1,3-butadiene and possibly ethylene oxide which have not been established as manifesting these types of toxicity in humans. In summary, while hematotoxicity can be induced by most of the Group 1 and 2A leukemogens, this is not uniformly the case, and clinically detectable hematotoxicity does not need to occur in order for an agent to be classified as a human leukemogen. 6.2. Usefulness of animal bioassays There is substantial evidence to indicate that chronic animal bioassays are effective in detecting human carcinogens. As described in the IARC Preamble [204] ‘‘all known human carcinogens that have been studied adequately for carcinogenicity in experimental animals have produced positive results in one or more animal species.’’ Even though it cannot be established that all agents that cause cancer in experimental animals also cause cancer in humans, it is biologically plausible that if there is sufficient evidence of carcinogenicity in animals, it would likely present a carcinogenic hazard to humans. Accordingly, the majority of the Group 1 leukemia- and lymphoma-inducing agents shown in Table 2 have been reported previously to be carcinogenic in rodent bioassays [231], particularly in mice and often in rats. Interestingly, there can be fundamental differences between the types of tumors, particularly lymphohematopoietic tumors, induced in humans and rodents. For example, following treatment with alkylating agents, t-AML is the predominant cancer induced in humans whereas T-cell leukemia/lymphoma preferentially occurs in mice. Similarly, the lymphohematopoietic cancers induced by benzene in mice are generally lymphocytic leukemias/lymphomas [153,154,278]. Occasionally increases in benzene-induced granulocytic or myeloid leukemia have been reported in treated mice but other investigators have had difficulties reproducing the results [155,279]. The reason for these differences is unknown but may be related to species differences in hematopoiesis and/or immune surveillance [231]. The general correlation seen for animals and humans mentioned above was based primarily on the results for chemical carcinogens and probably does not hold for many of the infectious agents, which primarily infect only humans and closely related species. In addition, it is not clear, at this point, if this correlation will hold true for the topoisomerase II inhibitors, as most of them have not been adequately tested in experimental animals. While the fusion gene products have clearly been shown to affect hematopoiesis and can cause leukemias in mice [280–285], it is not certain if the critical genes are located in regions in the rodent genomes that will allow the same chimeric genes to be formed.

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Lastly it should also be noted that the Group 2A carcinogens are also positive in rodent bioassays; however, this is to be expected, as this characteristic is one of the primary reasons that the chemicals have been listed. 6.3. Combining different types of lymphohematopoietic cancers for analysis In evaluating epidemiological studies, a decision has to be made about which specific types of disease should be combined for the analysis. Often the reporting of leukemias has been grouped into the four common categories of AML, CML, ALL, and CLL. Similarly, the lymphomas and myelomas have been grouped into NHL (lymphosarcoma, reticulosarcoma, and other malignant neoplasms of lymphoid and histocytic tissue), Hodgkin disease, and multiple myeloma (MM). More recent case–control studies of lymphoma have expanded the NHL grouping to include CLL, or to group lymphomas by cell type or by specific International Classification of Disease – Oncology category (e.g. diffuse lymphatic B-cell lymphoma, follicular lymphoma, etc.). In addition, evaluations of the induction of lymphohematopoietic diseases by an agent over time can be challenging due to changes in diagnosis, names of diseases, and classification schemes, as well as lack of detailed case and exposure information. Other issues such as misclassification errors and insufficient information on death certificates can also influence the outcome of the studies. The decision about how to analyze the data can also have a significant influence on the outcome of the analysis and the conclusions of the study. In performing evaluations, one key question is ‘‘Which categories of lymphohematopoietic cancer should be combined for analysis?’’ In theory, only the relevant disease entities would be combined for analysis. This might include combining specific types of hematopoietic cancer that share an underlying mechanism, that originate from a common cell, or that share key biological (morphologic, genetic, immunologic, etc.) features. However, in practice this becomes challenging, because all myeloid and lymphoid cells originate in the hematopoietic stem cells of the bone marrow, and it is often not clear at what stage in maturation, the critical genetic and epigenetic events occurred. In addition, the delineation between myeloid and lymphoid lineages and the separation between lymphoid leukemias and lymphomas are not as distinct or dichotomous as once thought [3,25,26,190,201,286–288]. The value of combining uncommon lymphohematopoietic cancers has been demonstrated for benzene [289,290]. Benzene exposure is strongly associated with AML. However, its association with lymphoid cancers has been a source of ongoing discussion. Savitz and Andrews [289,290] showed that by analyzing non-AML hematopoietic cancers together, a significant association between benzene exposure and these cancers could also be shown. Other studies or analyses have reported associations between benzene and combined lymphoid neoplasms [278] or specific cancers such as NHL [291,292]. IARC, in its most recent evaluation, has also given credence to an association between benzene and other lymphohematopoietic cancers as it concluded that there was evidence, albeit limited, for an association between benzene and the specific lymphohematopoietic subtypes ALL, CLL, NHL, and multiple myeloma [73,76,161,199,293]. More recently, a similar association between benzene exposure and an increased incidence of lymphoid cancers (MM, ALL and CLL) was seen in a metaanalysis of occupational benzene studies [294]. These results suggest that the critical events induced by benzene that result in the development of leukemias and lymphomas occur either in the bone marrow hematopoietic stem cell and/or progenitor cells that give rise to both the myeloid and lymphoid lineages or that benzene can target both the hematopoietic stem and progenitor cells as well as the more mature lymphoid cells.

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In addition to combining specific types of cancers for analysis during individual studies, it may be informative to see how various authoritative bodies such as the IARC, the National Academies of Sciences, Biological Effects of Ionizing Radiation committee (BEIR), and the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) have combined the lymphohematopoietic cancers in making decisions about risk or for weight of evidence determinations for various leukemogenic agents. As indicated above for benzene, IARC chose to evaluate the major types of cancer separately. However, it is likely that the association between benzene and one type of cancer provided supportive evidence that benzene could be associated with another type of lymphohematopoietic cancer. This type of supporting evidence also appears to have played an important role in the evaluations of 1,3-butadiene where associations with CML, CLL, and to some degree, NHL, were combined in concluding that butadiene exposure caused cancer of the ‘‘haematolymphatic organs’’ [201]. Similarly, information on associations with different types of lymphohematopoietic cancers contributed to the recent IARC evaluation on formaldehyde (AML and CML) and ethylene oxide (NHL, MM, and CLL) [161]. It should be noted that for 1,3-butadiene and probably benzene, supportive evidence came from associations with both myeloid and lymphoid tumors. In the BEIR and UNSCEAR evaluations of ionizing radiation, it has been common to use all leukemias or combine the results for ALL, AML, and CML in modeling the data and assessing cancer risks [82,83,85] and references therein. Increases in CLL have not been seen in radiation-exposed study groups. In contrast, in its recent review of U.S. EPA’s draft Integrated Risk Information System risk assessment for formaldehyde, a National Research Council review committee concluded that the broad grouping of ‘‘all lymphohematopoietic cancers’’ included at least 14 biologically distinct diagnoses in humans and should not be used in determinations of causality [295]. The committee recommended that the EPA focus on the most specific diagnoses available in the epidemiological data. Thus, as illustrated in the evaluation of the various cancerinducing agents by the different authoritative groups, there is a range of opinions and no strict consensus on how specific lymphohematopoietic cancers should be combined for analysis and weight-of-evidence determinations. As discussed above, a variety of combinations including those combining acute and chronic myeloid neoplasms as well as lymphoid and myeloid neoplasms have been used in recent evaluations. With an increased understanding of the biology and mechanisms underlying de novo and induced lymphohematopoietic cancers, a more accurate identification of the appropriate groupings for these cancers could be achievable. 6.4. Metabolism and bioactive dose at the target organ One of the fundamental principles of toxicology is that the toxicological response is related to the dose of the bioactive agent in the target tissue. However, the tissue dose of the bioactive agent may differ significantly from the external exposure dose. For many carcinogens, even if exposure occurs, the chemical may not reach the target organ in a form that enables it to exert a biological response due to pharmacokinetic reasons (absorption, distribution, metabolism and elimination). In fact, this is a fundamental difference between the risk assessment of ionizing radiation and chemical leukemogens. Because of its ability to directly penetrate tissues, radiation risk estimates are almost always based on the dose of radiation that reaches the bone marrow. In contrast, risks for chemical leukemogens such as benzene, or 1,3-butadiene are typically based on the exposure dose and may not accurately reflect the bioactive dose that reaches the bone marrow.

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Studies have also shown that pharmacokinetic factors can significantly influence the risks from leukemia-inducing agents. For example, the peak plasma concentrations of melphalan have been shown to vary by over 50-fold after oral dosing due to variability in absorption, first pass metabolism, and rapid hydrolysis [296]. Indeed, for a few patients, detectable plasma levels of melphalan were not seen even after the administration of a high dose (1.5 mg/kg) of the drug [297]. The differences in plasma concentration would undoubtedly have an effect on its efficacy as well as its risk of inducing t-AML. Metabolism has also been shown to exert a major effect on the mutagenic and carcinogenic risks of leukemia-inducing agents. For example, metabolic activation by the cytochrome P450 enzymes (CYP450) has been shown to play an important role in the toxic and genotoxic effects of benzene and cyclophosphamide [298,299]. Other xenobiotic metabolizing enzymes such as epoxide hydrolase, myeloperoxidase, glutathione transferases, NQO1, and other detoxification enzymes, as well as efficient repair of the induced adducts, may also influence the toxicity and carcinogenicity of leukemogenic agents. In addition, population variation in metabolism may also have contributed to the mixed results reported in epidemiological studies [300].

leukemia-inducing agents. For example, age has been shown to be a factor in susceptibility to radiation-induced leukemia. Studies of the atomic bomb survivors, who were exposed to both gamma, and to a lesser extent, neutron radiation, indicated that the highest leukemia risks were seen in children [88,302]. On the contrary, similar increased susceptibility was not seen in children treated with alkylating agent-based chemotherapy as their leukemia risks do not appear to be greater than those seen in adults, and in some cases, may be less [94,106,303]. However, direct comparisons are difficult because in most studies, the children and adults have been treated with different therapeutic regimens. For the nontherapeutic classes of leukemia-inducing agents, little is known about the relative susceptibility of children to leukemia, as the critical studies have almost always been conducted on adults. However, a number of studies on related biomarkers have indicated that children or adolescents are also susceptible to the toxic and genotoxic effects of these leukemogenic chemicals [304–307]. Furthermore, from a population risk perspective, the increased susceptibility associated with the various genetic polymorphisms can have a significant impact on cancer risks, particularly among those exposed to lower doses [308,309]. 7. Future directions and research needs

6.5. DNA-adduct type, metabolism, and repair The type of DNA adducts formed and their repair can have a major impact on the toxicity, mutagenicity, and probably the cancer risk of leukemia-inducing agents. As indicated earlier, three major classes of alkylating agents have been identified that have significantly different mutagenic and carcinogenic potencies [116]. Category 1 agents are mono-functional alkylating agents such as ethylene oxide and methyl methane sulfonate, which primarily react at the N7 and N3 moieties of purines in DNA. These adducts are efficiently repaired, and as a result, these agents tend to be relatively weak mutagens. Category 2 agents such as procarbazine and ENU induce O-alkyl adducts and N-alkyl adducts in DNA, which are often involved in base pairing and are slowly repaired. These agents are generally potent mutagens and carcinogens. Category 3 agents, such as melphalan and busulfan induce DNA breaks and structural aberrations through their ability to cross-link DNA [116]. They are highly toxic, mutagenic, and carcinogenic. For example, 1,3-butadiene can be metabolized to diepoxybutane, a cross linking agent, so it has been classified as a Category 3 agent. However, its potency for rats and probably humans has been reported to be much lower than the other Category 3 agents. This might be due to the need for two separate bioactivation steps to form diepoxybutane as indicated above as well as the nature of the adducts formed by butadiene. The butadiene crosslinks tend to be intrastrand and are more efficiently repaired. Consistent with this explanation is the fact that diepoxybutane is believed to be the reactive intermediate formed from treosulfan, a chemotherapeutic agent that appears to be somewhat less potent in inducing t-AML in humans than other Category 3 chemotherapeutic agents when considered on a mg/kg-basis [301]. Interestingly, it should be noted that treosulfan administration to humans has been associated with AML whereas, as described above, occupational exposure to 1,3-butadiene has been associated with CLL and CML. One possible explanation is that the epoxybutene metabolite may play a more important role than diepoxybutane in inducing the 1,3butadiene-related leukemias in humans. It should be noted, however, that there is also considerable overlap in the carcinogenic potency of chemicals in each of the three categories. 6.6. Age-related and individual susceptibility Many factors such as age, sex, genetic make-up, and general health status have been shown to influence susceptibility to

Our understanding of the origins of lymphohematopoietic cancers and the factors influencing their development has progressed rapidly in recent years. In spite of this progress, many questions remain. Below is a brief overview of some of the advances and areas that need to be addressed so that investigators can more thoroughly understand the origins, mechanisms and risks associated with chemical-induced lymphohematopoietic cancers. Indeed, while much progress has been made on some chemical- and radiation-induced AMLs, little is know about other induced lymphohematopoietic cancers or AML induced by other agents. In particular, the origins and mechanisms involved in the lymphoid neoplasms induced by environmental or occupational chemicals such as ethylene oxide or 1,3-butadiene remain largely unknown. The continuing development and application of new analytical, sequencing and ‘‘omics’’ technologies promise to yield valuable and fundamental insights into the origins and progression of these diseases. However, to understand the lymphohematopoietic cancers induced by specific agents, it will be important to identify and thoroughly characterize the cancers developing in exposed individuals, and preferably preserve both normal and abnormal tissues for future studies. It should be noted that most recent studies and the related advances have focused primarily on de novo or familial leukemias and lymphomas. Much less mechanistic information is available for chemically induced lymphohematopoietic cancers. While it is likely that much of the recently obtained information will be relevant to chemically induced cancers, there is evidence that the induced leukemias and lymphomas can differ in fundamental ways from the majority of the de novo cases [54,310]. Indeed the differences in AML were sufficiently pronounced that the WHO, in its most recent classification scheme, created a separate disease code (ICD-O code 9920/3) for therapy-related myeloid neoplasms [3]. As described in Section 3, progress has clearly been made in identifying chromosomal changes in t-MDS/t-AML (Table 1). In spite of these advances, much remains to be learned about the specific genes involved, the interactions between these genes and gene products as well as the role of epigenetic modifications, hematotoxicity and immunological effects in the development and progression of these cancers. Of note, some particularly interesting advances have recently been made in understanding the specific genes and pathways that contribute to leukemic susceptibility and progression in cancer patients [311]. While promising, repetition

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of these studies, further validation of the techniques, and confirmation of the observed results are needed. For many tAML, loss of large chromosomal regions or entire chromosomes frequently occurs which has made the identification of the specific genes involved very difficult [54,312]. Adding to the complexity, recent evidence indicates that multiple genes are likely involved in leukemogenesis [53,313], and that only loss of a single allele or combination of single alleles may be necessary to initiate or accelerate the process [314,315]. The key studies in this instance were done using cells from individuals with a familial predisposition to MDS (5q syndrome), and the minimal deleted region identified differed from that seen in chemically induced MDS [315–317]. It would be interesting to see similar functional studies conducted with cells from patients with t-MDS. As indicated above, information on the genetic and epigenetic changes occurring in the leukemias and lymphomas induced by environmental and occupational agents is critically needed to fully understand the mechanisms underlying these diseases, and to accurately assess the associated risks. Similarly, information is needed on the specific subtypes of cancer associated with chemical exposures and the inter-relationships between the various leukemia-related factors. In addition, an understanding of the unique susceptibilities and the underlying mechanisms affecting different racial/ethnic groups, and specifically affecting various life-stages is also needed. To identify and monitor various stages of the disease, more predictive molecular and diagnostic biomarkers of exposure, early and intermediate effects, and later clinical disease need to be developed. While significant progress has been made in this area for some agents such as benzene [176,318], more research on biomarkers is needed, and much of the work conducted to date needs independent confirmation. Lastly, the development of reliable animal models that can be used to study chemically related leukemias and lymphomas, particularly induced myeloid neoplasms, remains a ongoing and critical need. 8. Summary Lymphohematopoietic neoplasia represents one of the most common cancers induced by chemical, physical, and/or infectious agents. An understanding of the origin of these cancers as well as morphologic, cytochemical and immunophenotypic features of the neoplastic cells provide valuable information for grouping various lymphohematopoietic cancers and for identifying the cell types targeted by carcinogenic agents. To date, the IARC has identified over 100 agents as human carcinogens based on mechanistic information and WOE determinations from the available scientific data. Of these, approximately 25% have been shown to induce either leukemias or lymphomas in humans. Many of these identified human carcinogens are antineoplastic drugs, but a variety of other agents including industrial chemicals, various forms of radiation, immunosuppressive drugs, and infectious agents have also been shown to induce lymphohematopoietic cancers in humans. An assessment of the risks associated with exposure to environmental chemicals can be enhanced by referring to both MOA information and WOE determinations that have previously been conducted for identified human leukemiainducing agents. Information on short-term genotoxicity tests and human biomonitoring; usefulness of animal bioassays; combining different types of lymphohematopoietic cancers for analysis; metabolism and bioactive dose at the target organ; DNAadduct type, metabolism and repair; age-related and individual susceptibility factors can provide valuable insights into the risks associated with leukemia-inducing agents. Based on current information, leukemia-inducing agents act through a variety of different mechanisms to induce their carcinogenic effects. While most of chemicals have been determined by IARC to likely act

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through mutagenic or genotoxic mechanisms, different leukemogens have different potencies and different associated risks, which appear to be significantly influenced by the specific mechanisms involved. Even among the alkylating agents, different chemicals can have differing potencies that are related to the nature of the DNA adducts formed and their repair as well as metabolic and pharmacokinetic factors. In addition, polymorphisms in genes related to xenobiotic metabolism and DNA repair can lead to increased susceptibility among groups in the population. Furthermore, there is a range of opinions on how specific lymphohematopoietic cancers (induced by various cancer-causing agents) should be combined for analysis and WOE determinations by different authoritative groups. Therefore, identifying the specific types of cancer-causing agents with their associated mechanism(s) and using that information to inform key steps in the risk assessment process remain an important and ongoing challenge in toxicology and cancer risk assessment. Conflict of interest The authors declare that there are no conflicts of interest. Acknowledgments This article is an updated and substantially modified version of a report that was prepared by Dr. Eastmond for the US EPA. That report underwent internal and external peer review as well as public and agency review prior to its publication. The analyses, interpretations and conclusions reported in the paper are those of the authors and do not necessarily reflect the views of the US EPA or the University of California. References [1] C.L. Sawyers, C.T. Denny, W.N. Witte, Leukemia and the disruption of normal hematopoiesis, Cell 64 (1991) 337–350. [2] P.C. Nowell, Origins of human leukemia: an overview, in: J. Brugge, T. Curran, E. Harlow, F. McCormick (Eds.), Origins of Human Cancer. A Comprehensive Review, Cold Spring Harbor Laboratory Press, 1991. [3] WHO, WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, IARC Press, Lyon, France, 2008. [4] ACS, Cancer Facts & Figures 2009, American Cancer Society, Atlanta, 2009. [5] D.R. Head, C.-H. Pui, Diagnosis and classification, in: C.-H. Pui (Ed.), Childhood Leukemias, Cambridge University Press, Cambridge, UK, 1999, pp. 19–37. [6] WHO, Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues, IARC Press, Lyon, France, 2001. [7] T. Haferlach, W. Kern, S. Schnittger, C. Schoch, Modern diagnostics in acute leukemias, Crit. Rev. Oncol. Hematol. 56 (2005) 223–234. [8] S. Bhatia, J.A. Ross, M.F. Greaves, L.L. Robison, Epidemiology and etiology, in: C.H. Pui (Ed.), Childhood Leukemias, Cambridge University Press, Cambridge, 1999, pp. 38–49. [9] E.G. Wright, The pathogenesis of leukaemia, in: J.H. Hendry, B.I. Lord (Eds.), Radiation Toxicology: Bone Marrow and Leukemia, Taylor & Francis, London, 1995, pp. 245–274. [10] H. Hasle, C.M. Niemeyer, J.M. Chessells, I. Baumann, J.M. Bennett, G. Kerndrup, D.R. Head, A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases, Leukemia 17 (2003) 277–282. [11] ACS, Cancer Facts & Figures 2013, American Cancer Society, Atlanta, 2013. [12] M.T. Smith, C.M. McHale, J.L. Wiemels, L. Zhang, J.K. Wiencke, S. Zheng, L. Gunn, C.F. Skibola, X. Ma, P.A. Buffler, Molecular biomarkers for the study of childhood leukemia, Toxicol. Appl. Pharmacol. 206 (2005) 237–245. [13] ACS, Cancer Facts & Figures 2006, American Cancer Society, Atlanta, 2006. [14] R.P. Guillerman, S.D. Voss, B.R. Parker, Leukemia and lymphoma, Radiol. Clin. North Am. 49 (2011) 767–797, vii. [15] M. Greaves, Molecular genetics, natural history and the demise of childhood leukaemia, Eur. J. Cancer 35 (1999) 1941–1953. [16] NCI, Childhood cancers – fact sheet, Bethesda, MA, 2008. [17] O. Hrusak, J. Trka, J. Zuna, A. Polouckova, T. Kalina, J. Stary, Acute lymphoblastic leukemia incidence during socioeconomic transition: selective increase in children from 1 to 4 years, Leukemia 16 (2002) 720–725. [18] E. Steliarova-Foucher, C. Stiller, P. Kaatsch, F. Berrino, J.W. Coebergh, B. Lacour, M. Parkin, Geographical patterns and time trends of cancer incidence and survival among children and adolescents in Europe since the 1970s (the ACCISproject): an epidemiological study, Lancet 364 (2004) 2097–2105. [19] E. Dzierzak, N.A. Speck, Of lineage and legacy: the development of mammalian hematopoietic stem cells, Nat. Immunol. 9 (2008) 129–136.

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