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Chemico-Biological Interactions 186 (2010) 248249 Contents lists available at ScienceDirect Chemico-Biological Interactions journal homepage: www.elsevier.com/locate/chembioint Letter to the Editor Comment on: Implications of latency period between benzene exposure and development of leukemia--A synopsis of literature Keywords: Benzene Leukaemia Latency Individual differences It has been argued that the risk of lung cancer decreases with increasing duration of abstinence after smoking cessation [1]. Similarly, a recent paper in this journal has argued that the risk of leukaemia is small or even absent 1015 years after exposure to benzene has stopped, with higher risks only occurring after recent exposure [2]. This was suggested to be due to a short biological halflife of benzene and effective repair pathways including apoptosis. If genuine, the time-dependence of the risk of leukaemia after benzene exposure should impact on claims for compensation for leukaemia as an occupational disease, especially if the disease occurs long after the exposure. However, we are not convinced that repair mechanisms are likely to reverse the relevant benzeneinduced damage in the years after exposure and that the individual risk for benzene related occupational disease really decreases with time. First, the argument that the risk of leukaemia decreases with time after cessation of exposure, as it is proposed in the abovementioned paper [2], is based on small numbers of cases with malignancy and not all of the studies presented in favour of this argument even fully support the case. For example, based on data from a large study from Australia [3] discussed in [2] we think that the risk decrease with increased lag time is only convincing for cumulative exposures below 10 ppm-years. Second, it must be kept in mind that the proposed timedependence does not apply to all haematological malignancies: Hayes et al. [4] also a study discussed in [2] found that, while the risk for acute nonlymphocytic leukaemia and myelodysplastic syndromes appeared increased with recent benzene exposure more so than with distant exposure, the development of non-Hodgkin lymphoma was linked most strongly to distant exposure (occurring at least 10 years before diagnosis). Third, even if the decrease in the incidence of some haematological malignancies with time after exposure to benzene is genuine, this does not necessarily mean a decrease in the individual risk of developing the disease. We would like to offer an alternative explanation. We propose that there are inter-individual differences in the susceptibility to benzene-induced leukaemia. Genetic differences in the susceptibility to benzene poisoning (a risk factor for haematological malignancy) and benzene-induced haematotoxicity are well documented [5,6]. Furthermore, there is good evidence for genetically determined individual differences in the susceptibil- ity to leukaemia in general, implicating a number of genes including the one coding for NAD(P)H:quinone oxidoreductase 1 (NQO1), an enzyme involved in the detoxification of the benzene metabolite benzoquinone [712], though more work is needed to clarify the precise relationships. If there were individuals of different susceptibility to benzenerelated disease in an exposed cohort, with time more and more of the susceptible individuals would become diseased (with leukaemia or perhaps with another benzene-related disease) and may die, so that the remaining members of the exposed cohort (now depleted of `susceptible' individuals) would have apparently less and less of an increased risk of contracting leukaemia when compared with a control group. This would be an apparent lowering of the risk only because if individuals of the same inherent susceptibility to benzene-induced disease in the exposed and control groups were compared, there would likely still be an elevated risk. The findings of Hayes et al. [4] of a decrease in the risk for nonlymphocytic leukaemia and myelodysplastic syndromes after long continuous exposure to benzene vs. shorter exposure would be more consistent with depletion of susceptible individuals in the exposed group rather than with a limitation of benzene's effects because of a short biological half-life and effective repair mechanisms; these could only be expected to exert an effect after cessation of exposure. Fourth, the proposal that the carcinogenic effects of benzene are reversible challenges a central tenet in toxicology: the dosetime relationship for chemical carcinogens. This states, based on work by Druckrey et al. in 1963 [13], that the product of time and dose of a carcinogen is constant. The findings of Druckrey et al. were later confirmed in large animal studies [14] and the dosetime relationship for chemical carcinogens has been generally accepted as dogma, provided that genotoxic mechanisms are involved. Both classical and recent epidemiological evidence supports that this notion is not restricted to experimental animals: Pott showed in 1775 that chimney sweepers did not get scrotal cancer until after puberty [15]. Smokers have an elevated, though apparently decreasing, lung cancer risk even many years after they have stopped smoking [1,16]. The genotoxic effect of benzene was repeatedly shown in vitro [17,18], in experimental animals, and in humans [1922]. It is now commonly believed that carcinogenic effects of genotoxic carcinogens are irreversible. Of course DNA repair does occur by a variety of mechanisms. However, these mechanisms have two major aspects in common: DNA repair occurs very early after exposure and miss-repair leads to irreversible manifestation of DNA damage. In addition, certain damage to genetic material including chromosome deletions and translocations as far as we know cannot be repaired. Such lesions are often found in leukaemia and were even shown to be of key importance in the causation of leukaemia in case of the Philadelphia chromosome. What do the above arguments mean with regard to compensation for leukaemia as an occupational disease, especially if the 0009-2797/$ see front matter 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.cbi.2010.04.008 Letter to the Editor / Chemico-Biological Interactions 186 (2010) 248249 249 disease occurs long after benzene exposure? The irreversibility of certain mutations associated with leukaemia and alternative explanations of the apparent decrease in risk over time lead us to the conclusion that based on current evidence a long latency between exposure and disease should not necessarily rule out compensation. An individual with a low inherent susceptibility for leukaemia may develop the disease as a result of a multi-step process of accumulating relevant mutations over decades, with early benzene-induced mutations being contributory. Only a comparison with non-exposed low susceptibility individuals would be comparing like with like and establish the true individual risk increase, not a comparison with an `unselected' group of controls. Such a selected comparison is impossible at present because we do not know how to reliably identify low susceptibility individuals; this remains a task for future research. References [1] J.O. Ebbert, P. Yang, C.M. Vachon, et al., Lung cancer risk reduction after smoking cessation: observations from a prospective cohort of women, J. Clin. Oncol. 21 (2003) 921926. [2] G. Triebig, Implications of latency period between benzene exposure and development of leukemia--a synopsis of literature, Chem. Biol. Interact. (2010), doi:10.1016/j.cbi.2009.12.014. [3] S Atkinson, J. Coppock, L. Fritschi, et al., Lympho-haematopoietic Cancer and Exposure to Benzene in the Australian Petroleum Industry, Technical Report and Appendices, Final Report, Monash and Deacon University, 2001, June. [4] R.B. Hayes, M. Song-Nian Yin, M. Dosemeci, et al., Benzene and the dose related incidence of hematologic neoplasms in China, J. Natl. Cancer Inst. 89 (1997) 10651071. [5] N. Rothman, M.T. Smith, R.B. Hayes, et al., Benzene poisoning, a risk factor for hematological malignancy, is associated with the NQO1 609CT mutation and rapid fractional excretion of chlorzoxazone, Cancer Res. 57 (1997) 2839 2842. [6] Q Lan, L. Zhang, M. Shen, et al., Polymorphisms in cytokine and cellular adhesion molecule genes and susceptibility to hematotoxicity among workers exposed to benzene, Cancer Res. 65 (2005) 95749581. [7] M.T. Voso, E. Fabiani, F. D'Alo', et al., Increased risk of acute myeloid leukaemia due to polymorphisms in detoxification and DNA repair enzymes, Ann. Oncol. 18 (2007) 15231528. [8] A.F. Semsei, D.J. Erdlyi, I. Ungvri, et al., Association of some rare haplotypes and genotype combinations in the MDR1 gene with childhood acute lymphoblastic leukaemia, Leuk. Res. 32 (2008) 12141220. [9] M. Aydin-Sayitoglu, O. Hatirnaz, N. Erensoy, et al., Role of CYP2D6, CYP1A1, CYP2E1, GSTT1, and GSTM1 genes in the susceptibility to acute leukemias, Am. J. Hematol. 81 (2006) 162170. [10] R.A. Larson, Y. Wang, M. Banerjee, et al., Prevalence of the inactivating 609CT polymorphism in the NAD(P)H:quinone oxidoreductase (NQO1) gene in patients with primary and therapy-related myeloid leukemia, Blood 94 (1999) 803807. [11] G.G. Yamaguti, G.J. Lourenc o, F.F. Costa, et al., High risk of `de novo' acute myeloid leukaemia in individuals with cytochrome P450 A1 (CYP1A1) and NAD(P)H:quinone oxidoreductase 1 (NQO1) gene defects, Eur. J. Haematol. 83 (2009) 270272. [12] S. Silveira Vda, R. Canalle, C.A. Scrideli, et al., Role of the CYP2D6, EPHX1, MPO, and NQO1 genes in the susceptibility to acute lymphoblastic leukemia in Brazilian children, Environ. Mol. Mutagen. 51 (2010) 4856. [13] V.H. Druckrey, A. Schildbach, D. Schmhl, et al., Quantitative Analyse der karzinogenen Wirkung von Dithylnitrosamin, Arzneim. Forsch. 13 (1963) 841851. [14] R. Peto, R. Gray, P. Brantom, et al., Dose and time relationships for tumor induction in the liver and esophagus of 4080 inbred rats by chronic ingestion of N-nitrosodiethylamine or N-nitrosodimethylamine, Cancer Res. 51 (1997) 64526469. [15] P. Pott. Chirurgical observations relative to the cataract, the polypus of the nose, the cancer of the scrotum, the different kinds of ruptures, and the mortification of the toes and feet (1775). Reprinted in Natl. Cancer Inst. Monogr. 10 (1963) 713. [16] M.T. Halpern, B.W. Gillespie, K.E. Warner, Patterns of absolute risk of lung cancer mortality in former smokers, J. Natl. Cancer Inst. 85 (1993) 457464. [17] L. Zhang, Y. Wang, N. Shang, et al., Benzene metabolites induce the loss and long arm deletion of chromosomes 5 and 7 in human lymphocytes, Leuk. Res. 22 (1998) 105113. [18] G.A. Westphal, J. Bnger, N. Lichey, et al., The benzene metabolite para-benzoqinone is genotoxic in human, phorbol-12-acetate-13-myristate induced, peripheral blood mononuclear cells at low concentrations, Arch. Toxicol. 83 (2009) 721729. [19] D.A. Eastmond, M. Schuler, C. Frantz, et al., Characterization and mechanisms of chromosomal alterations induced by benzene in mice and humans, Res. Rep. Health Eff. Inst. 103 (2001) 168. [20] L. Zhang, N. Rothman, Y. Wang, et al., Increased aneusomy and long arm deletion of chromosomes 5 and 7 in the lymphocytes of Chinese workers exposed to benzene, Carcinogenesis 19 (1998) 19551961. [21] L. Zhang, D.A. Eastmond, M.T. Smith, The nature of chromosomal aberrations detected in humans exposed to benzene, Crit. Rev. Toxicol. 32 (2002) 142. [22] L. Zhang, W. Yang, A.E. Hubbard, et al., Nonrandom aneuploidy of chromosomes 1, 5, 6, 7, 8, 9, 11, 12, and 21 induced by the benzene metabolites hydroquinone and benzenetriol, Environ. Mol. Mutagen. 45 (2005) 388396. Sebastian Straube Gtz A. Westphal Ernst Hallier Department of Occupational and Social Medicine, University of Gttingen, Waldweg 37 B, D-37073 Gttingen, Germany Corresponding author. Tel.: +49 551 39 8044; fax: +49 551 39 6184. E-mail addresses: sebastian.straube@googlemail.com (S. Straube), westphal@ipa-dguv.de (G.A. Westphal), ehallie@gwdg.de (E. Hallier) 9 March 2010 Available online 14 April 2010