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According to the International Agency for Research on Cancer, leukemia ranks 14th in incidence and 11th in mortality and has a 5-year prevalence of approximately 1300,000 cases. Acute lymphoblastic leukemia is the most common hematopoietic syndrome in children during the first 5 years of life and represents approximately 75 % of all neoplasms among the pediatric population. The development of leukemia is strongly governed by DNA alterations that accelerate the growth of bone marrow cells. Currently, the most examined factor in pediatric leukemia is exposure to multiple compounds, such as hydrocarbons. Benzene, an aromatic hydrocarbon, can cause health challenges and is categorized as a carcinogen. Benzene toxicity has been widely associated with occupational exposure. Importantly, studies are underway to generate evidence that can provide clues regarding the risk of environmental benzene exposure and hematological problems in children. In this review, we summarize the existing evidence regarding the effects of benzene on pediatric leukemia, the associations between the effect of benzene on carcinogenesis, and the presence of certain molecular signatures in benzene-associated pediatric leukemia. Although there is sufficient evidence regarding the effects of benzene on carcinogenesis and leukemia, epidemiological research has primarily focused on occupational risk. Moreover, most benzene-induced molecular and cytogenetic alterations have been widely described in adults but not in the pediatric population. Thus, epidemiological efforts are crucial in the pediatric population in terms of epidemiological, clinical, and biomedical research., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: 1,3-Butadiene (BD) exposure's link to leukemia is under regulatory scrutiny. The assessment methods for BD exposure risks have evolved from early animal and limited human studies to advanced exposure-response modelling with comprehensive quantitative data. The objec- tive of this study is to explore the nuances of exposure-response modelling, investigating how various statistical methods have influenced the quan- tification of exposure-response relationships., Material and Methods: Although this study was not conducted as a formal systematic review, a search was performed in Medline/Pubmed to identify all human studies on leukemia risk assessment for BD exposure. This search included articles written in English. The electronic search spanned from inception of records until July 23, 2023, using the search term: "butadiene AND (leukaemia OR leukemia OR myeloid OR lymphoid)" and was restricted to human species. Focusing on the synthetic styrene-butadiene rubber (SBR) industry cohort study conducted by the University of Alabama at Birmingham, USA, this review evaluates various statistical models and factors influenc- ing exposure-response modelling., Results: Peak exposures to BD may be more influential in the dose-response relationship than cumulative or long-term exposure. The authors recommend utilizing β-coefficients derived from the latest SBR study update, employing Cox proportional hazard modelling, non-lagged and non-transformed cumulative BD exposure, and adjusting for age and peak BD exposure. The study reveals that statistical model selection has a limited impact on the calculated dose-response effects. The significant variation in estimated cancer mortality values arises from additional assumptions needed for metrics like the excess leukemia risk or the occupational BD effective concentration., Conclusions: In con- clusion, this study provides insights into exposure-response modelling for BD exposure and leukemia mortality, highlighting the importance of peak exposures. The recommended statistical approach offers a reliable basis for regulatory risk assessment and public health population metrics. Int J Occup Med Environ Health. 2024;37(3):300-10., (This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.)

Background: Oil refinery workers are exposed to benzene, which is a well-known cause of leukaemia, but results on leukaemia in oil refinery workers have been mixed, and the data on workers' exposure is limited. Oil refinery workers are also exposed to asbestos and several studies have shown increased risk of mesothelioma., Aim: The objective was to investigate cancer incidence, especially leukaemia, at low to moderate exposure to benzene in an update of a previous study of employees at three Swedish oil refineries., Methods: Cancer incidence was followed up in 2264 men (1548 refinery operators) employed at three oil refineries in Sweden for at least one year. Job types and employment times were collected from complete company files. A retrospective assessment of the benzene exposure was performed by occupational hygienists in collaboration with the refineries using historic measurements as well as detailed information on changes in the industrial hygiene and technological developments. Cases of cancer were retrieved by a linkage with the Swedish Cancer Register through 35-47 years of follow-up and standardized incidence ratios (SIR) with 95% confidence intervals (CI) were calculated., Results: In total, 258 tumors had occurred versus 240 expected (SIR 1.07; 95% CI 0.95-1.21). There were 10 cases of leukaemia, all in refinery operators (SIR 2.4; 95% CI 1.18-4.51). There were three cases of pleural mesothelioma, two of which in refinery operators. The mean estimated cumulative benzene exposure for the cases of leukaemia was 7.9 ppm-years (median 4.9, range 0.1-31.1)., Discussion: The study suggests that low to moderate average cumulative benzene exposure increases the risk of leukaemia. Limitations include the modest number of cases and potential misclassification of exposure., Conclusion: The present study indicated an increased risk of leukaemia in male oil refinery workers with low to moderate exposure to benzene., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: Exposure to air pollution has been proposed as one of the potential risk factors for leukaemia. Work-related formaldehyde exposure is suspected to cause leukaemia., Methods: We conducted a nested register-based case-control study on leukaemia incidence in the Viadana district, an industrial area for particleboard production in Northern Italy. We recruited 115 cases and 496 controls, frequency-matched by age, between 1999 and 2014. We assigned estimated exposures to particulate matter (PM 10 , PM 2.5 ), nitrogen dioxide (NO 2 ), and formaldehyde at residential addresses, averaged over the susceptibility window 3rd to 10th year prior to the index date. We considered potential confounding by sex, age, nationality, socio-economic status, occupational exposures to benzene and formaldehyde, and prior cancer diagnoses., Results: There was no association of exposures to PM 10 , PM 2.5 , and NO 2 with leukaemia incidence. However, an indication of increased risk emerged for formaldehyde, despite wide statistical uncertainty (OR 1.46, 95%CI 0.65-3.25 per IQR-difference of 1.2 μg/m 3 ). Estimated associations for formaldehyde were higher for acute (OR 2.07, 95%CI 0.70-6.12) and myeloid subtypes (OR 1.79, 95%CI 0.64-5.01), and in the 4-km buffer around the industrial facilities (OR 2.78, 95%CI 0.48-16.13), although they remained uncertain., Conclusions: This was the first study investigating the link between ambient formaldehyde exposure and leukaemia incidence in the general population. The evidence presented suggests an association, although it remains inconclusive, and a potential significance of emissions related to industrial activities in the district. Further research is warranted in larger populations incorporating data on other potential risk factors., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alessandro Marcon reports financial support was provided by ATS della Val Padana. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Although a significant body of evidence has attributed certain occupational exposures with leukemia, such as benzene, formaldehyde, 1,3-butadiene and ionizing radiation, more research is needed to identify work environments at increased risk for this disease. Our study aimed to identify occupational and industry groups associated with an elevated incidence of leukemia using a diverse cohort of workers' compensation claimants from Ontario, Canada. A total of 2,363,818 workers in the Occupational Disease Surveillance System (ODSS) cohort, with claims between 1983-2019, were followed for malignant leukemia diagnoses up to 31 December 2019. We used a Cox proportional-hazards model to estimate the relative incidence of leukemia in specific occupation and industry groups. After adjusting for age and birth year, males in protective services (HR = 1.17, 95% CI = 1.02-1.35), metal machining (HR = 1.23, 95% CI = 1.07-1.41), transport (HR = 1.15, 95% CI = 1.06-1.25), and mining occupations (HR = 1.28, 95% CI = 1.02-1.60) had elevated risks of leukemia compared to other workers in the ODSS, with comparable findings by industry. Among female workers, slight risk elevations were observed among product fabricating, assembling, and repairing occupations, with other increased risks seen in furniture and fixture manufacturing, storage, and retail industries. These findings underscore the need for exposure-based studies to better understand occupational hazards in these settings.

Objectives: To assess leukemia risk in occupational populations exposed to low levels of benzene., Methods: Leukemia incidence data from the Chinese Benzene Cohort Study were fitted using the Linearized multistage (LMS) model. Individual benzene exposure levels, urinary S-phenylmercapturic acid (S-PMA) and trans, trans-muconic acid ( t, t -MA) were measured among 98 benzene-exposed workers from factories in China. Subjects were categorized into four groups by rounding the quartiles of cumulative benzene concentrations (< 3, 3-5, 5-12, ≥12 mg/m 3 ·year, respectively). The risk of benzene-induced leukemia was assessed using the LMS model, and the results were validated using the EPA model and the Singapore semi-quantitative risk assessment model., Results: The leukemia risks showed a positive correlation with increasing cumulative concentration in the four exposure groups (excess leukemia risks were 4.34, 4.37, 4.44 and 5.52 × 10 -4 , respectively; P trend  < 0.0001) indicated by the LMS model. We also found that the estimated leukemia risk using urinary t, t -MA in the LMS model was more similar to those estimated by airborne benzene compared to S-PMA. The leukemia risk estimated by the LMS model was consistent with both the Singapore semi-quantitative risk assessment model at all concentrations and the EPA model at high concentrations (5-12, ≥12 mg/m 3 ·year), while exceeding the EPA model at low concentrations (< 3 and 3-5 mg/m 3 ·year). However, in all four benzene-exposed groups, the leukemia risks estimated by these three models exceeded the lowest acceptable limit for carcinogenic risk set by the EPA at 1 × 10 -6 ., Conclusion: This study demonstrates the utility of the LMS model derived from the Chinese benzene cohort in assessing leukemia risk associated with low-level benzene exposure, and suggests that leukemia risk may occur at cumulative concentrations below 3 mg/m 3 ·year., Competing Interests: MinyL and DH were employed by the company Tianjin Bohai Chemical Industry Group Co Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Jin, Zhu, Wu, Li, Wang, Cheng, Li, Huang and Xing.)

Purpose: Diesel exhaust (DE) is an established lung carcinogen. The association with leukemia is not well established. We conducted a systematic review and meta-analysis of cohort studies to determine the association between occupational DE exposure and risk of leukemia., Methods: A systematic literature review was performed to identify all cohort studies on occupational exposure to DE and associated risk of leukemia. STROBE guidelines and PECOS criteria were followed. Meta-analyses with fixed effects (and random-effects model in cases of high heterogeneity) were performed to calculate summary relative risks (RR) and 95% confidence intervals (CI), including subgroup analyses by outcome (mortality or incidence), sex, geographic region, industry type, and study quality. Study quality was assessed using the the Joanna Briggs Institute (JBI) critical appraisal checklist for cohort studies., Results: Of the 30 studies retained, 20 (8 from North America, 12 from Europe) reported a total of 33 estimates of the risk of leukemia. Overall, the relative risk (RR) of leukemia was 1.01 (95% CI = 0.97-1.05, I 2  = 21.2%, n = 33); corresponding results for leukemia incidence and mortality were RR = 1.02 (95% CI = 0.98-1.06, I 2  = 27.9%, n = 19) and RR = 0.91 (95% CI = 0.81-1.02, I 2  = 0.0%, n = 15), respectively. The main results were confirmed in analyses by sex and geographic area. A statistically significant association was detected for miners (RR = 1.58, 95% CI = 1.15-2.15, I 2  = 77.0%, n = 2) but not for other occupational groups. Publication bias was not detected (p = 0.7)., Conclusion: Our results did not indicate an association between occupational DE exposure and leukemia, with the possible exception of miners. Residual confounding cannot be excluded., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Leukemia and lymphoma are the two most common forms of hematologic malignancy, and their etiology is largely unknown. Pathophysiological mechanisms suggest a possible association with air pollution, but little empirical evidence is available. We aimed to investigate the association between long-term residential exposure to outdoor air pollution and risk of leukemia and lymphoma. We pooled data from four cohorts from three European countries as part of the "Effects of Low-level Air Pollution: a Study in Europe" (ELAPSE) collaboration. We used Europe-wide land use regression models to assess annual mean concentrations of fine particulate matter (PM 2.5 ), nitrogen dioxide (NO 2 ), black carbon (BC) and ozone (O 3 ) at residences. We also estimated concentrations of PM 2.5 elemental components: copper (Cu), iron (Fe), zinc (Zn); sulfur (S); nickel (Ni), vanadium (V), silicon (Si) and potassium (K). We applied Cox proportional hazards models to investigate the associations. Among the study population of 247,436 individuals, 760 leukemia and 1122 lymphoma cases were diagnosed during 4,656,140 person-years of follow-up. The results showed a leukemia hazard ratio (HR) of 1.13 (95% confidence intervals [CI]: 1.01-1.26) per 10 μg/m 3 NO 2 , which was robust in two-pollutant models and consistent across the four cohorts and according to smoking status. Sex-specific analyses suggested that this association was confined to the male population. Further, the results showed increased lymphoma HRs for PM 2.5 (HR = 1.16; 95% CI: 1.02-1.34) and potassium content of PM 2.5 , which were consistent in two-pollutant models and according to sex. Our results suggest that air pollution at the residence may be associated with adult leukemia and lymphoma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The objective of this study was to evaluate the worldwide burden of leukemia owing to occupational exposure to formaldehyde (OEF) from 1990 to 2019. Data on leukemia due to OEF were obtained from the Global Burden of Disease Study (GBD) 2019. By region, age, sex, and disease subtype, the numbers and age-standardized rates (ASRs) associated with deaths, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life years (DALYs) were analyzed. Annual average percentage change (AAPC) was used to estimate disease burden trends from 1990 to 2019. To measure the risk of leukemia due to OEF, the population attributable fraction (PAF) was introduced. From 1990 to 2019, the number of deaths, DALYs, YLLs, and YLDs for leukemia caused by OEF increased by 44%, 34%, 33%, and 124%, respectively. Regarding the change in ASRs, the age-standardized YLDs (ASYLDs) rate of leukemia due to OEF, which was 38.03% (AAPC = 1.17 [95% confidence interval [CI] 1.11, 1.23]), indicated an increased trend. But the age-standardized mortality rate (ASMR), age-standardized DALY (ASDALY) rate, and age-standardized YLL (ASYLL) rate showed decline trends, with - 11.90% (AAPC =  - 0.41 [95% CI - 0.45, - 0.37]), - 14.19% (AAPC =  - 0.5 [95% CI - 0.55, - 0.45]), and - 14.97% (AAPC =  - 0.53 [95% CI - 0.58, - 0.48]), respectively. In terms of PAFs, there were increasing trends in PAFs of age-standardized deaths, ASDALYs, ASYLLs, and ASYLDs for leukemia caused by OEF, with 20.15% (95% uncertainty interval [UI] 11.76%, 30.25%), 36.28% (95% UI 21.46%, 53.42%), 51.91% (95% UI 35.05%, 72.07%), and 36.34% (95% UI 21.58%, 53.63%), respectively. Across the socio-demographic index (SDI) regions, the leukemia burden caused by OEF was concentrated in middle and high-middle SDI regions. Besides, OEF poses a more serious risk for acute leukemia among the leukemia subtype. Globally, leukemia caused by OEF remains a public health burden. Policies must be developed to avoid the burden of leukemia caused by OEF., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Since the 1970s, environmental health researchers have documented environmental pollution's impacts on human health, which includes the bioaccumulation of industrial chemicals and how these toxicants contribute to disease. However, the relationship between disease and pollution is often difficult to discern in the disease information provided by dominant institutions. Previous scholarship has identified that print media, television news, online medical publishers, and medical associations consistently obscure the environmental causation frame. However, less has been said about disease information provided by public health agencies. To address this gap, I analyzed the leukemia information provided by Cancer Australia, the United States' National Institutes of Health, and the United Kingdom's National Health Service. My analysis shows that the disease information offered by these health agencies also obscures the environmental causation frame by failing to identify most toxicants that environmental health researchers have linked to leukemia and by emphasizing a biomedical framing of the medical condition. Beyond documenting the problem, this article also discusses the social consequences and sources of the problem., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Importance: The cancer risks associated with treatment with topical calcineurin inhibitors (TCIs) in patients with atopic dermatitis (AD) remain controversial, and limited evidence exists regarding the cancer risks among patients with AD treated with TCIs in Asian populations., Objectives: This study identified the association between TCI use and the risks of developing all cancers, lymphoma, skin cancers, and other cancers., Design: This study was a nationwide, population-based, retrospective cohort study., Setting: Taiwan's National Health Insurance Research Database., Participants: Patients diagnosed at least twice with ICD-9 code 691 or at least one time with ICD-9 codes 691 or 692.9 within 1 year between 1 January 2003 and 31 December 2010 were included and followed until 31 December 2018. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using the Cox proportional hazard ratio model., Exposures: Patients using tacrolimus or pimecrolimus were identified in the National Health Insurance Research Database and compared with patients using topical corticosteroids (TCSs)., Main Outcomes and Measures: The main outcomes were hazard ratios (HRs) of cancer diagnoses and associated outcomes obtained from the Taiwan Cancer Registry database., Results: After propensity score (PS) matching, the final cohort included 195,925 patients with AD, including 39,185 who were initial TCI users and 156,740 who were TCS users. Propensity score matching was performed according to age, sex, index year, and Charlson Comorbidity Index using a ratio of 1:4. Except for leukemia, HR and 95% CI showed no significant associations between TCI use and the risk of developing all cancer, lymphoma, skin cancers, and other cancers. Sensitivity analysis showed that the lag time HRs for every cancer subtype continued to show no significant association between TCI use and cancer risk, except for leukemia., Conclusions and Relevance: Our study found no evidence to support an association between TCI use and the risks of almost all cancers compared with TCS use in patients with AD, but physicians should be aware of potentially higher risks of leukemia with TCI use. This study represents the first population-based study focused on the cancer risk of TCI use among patients with AD in an Asian population., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: In this study, the annual leukemia mortality rate is estimated by occupational groups potentially exposed to benzene in Brazil and compared to non-exposed workers by sex., Methods: Data were extracted from the Mortality Information System and the National Institute of Geography and Statistics from 2006 to 2011. Occupational groups exposed to benzene were defined by using the Finnish Job-Exposure Matrix, FINJEM., Results: We found 21,049 leukemia deaths in 1917 in occupational groups potentially exposed to benzene, corresponding to an annual average mortality rate of 4.5/100,000, higher than the estimate for non-exposed workers: 2.6/100,000, corresponding to a Mortality rate ratio MRR = 1.7. Each benzene-exposed occupational group had increased leukemia mortality, and printers and occupations in graphics presented the highest MRR (2.7), followed by laboratory assistants (MRR = 2.6), laundry workers, chemists, and upholsterers, each of these occupational groups presenting MRR = 2.3., Conclusions: Benzene shows the need for better enforcement of protective norms against this known carcinogen. Our results support the need for better enforcement of protective norms to reduce benzene exposure.

Leukemia is a blood cancer originating in the blood and bone marrow. Therapy-related leukemia is associated with prior chemotherapy. Although cancer therapy with DNA topoisomerase II inhibitors is one of the most effective cancer treatments, its side effects include development of secondary leukemia characterized by the chromosomal rearrangements affecting AML1 or MLL genes. Recurrent chromosomal translocations in the therapy-related leukemia differ from chromosomal rearrangements associated with other neoplasias. Here, we reviewed the factors that drive chromosomal translocations induced by cancer treatment with DNA topoisomerase II inhibitors, such as mobility of ends of double-strand DNA breaks formed before the translocation and gain of function of fusion proteins generated as a result of translocation.

Petrol stations emit benzene and other contaminants that have been associated with an increased risk of childhood leukemia. We carried out a population-based case-control study in two provinces in Northern Italy. We enrolled 182 cases of childhood leukemia diagnosed during 1998-2019 and 726 age- and sex-matched population controls. We geocoded the addresses of child residences and 790 petrol stations located in the study area. We estimated leukemia risk according to distance from petrol stations within a 1000 m buffer and amount of supplied fuel within a buffer of 250 m from the child's residence. We used conditional logistic regression models to approximate risk ratios (RRs) and 95% confidence intervals (CIs) for associations of interest, adjusted for potential confounders. We also modeled non-linear associations using restricted cubic splines. In secondary analyses, we restricted to acute lymphoblastic leukemia (ALL) cases and stratifed by age (<5 and ≥5 years). Compared with children who lived≥1000 m from a petrol station, the RR was 2.2 (95% CI 0.5-9.4) for children living<50 m from nearest petrol station. Associations were stronger for the ALL subtype (RR=2.9, 95% CI 0.6-13.4) and among older children (age≥5 years: RR=4.4, 95% CI 0.6-34.1; age<5 years: RR=1.6, 95% CI 0.1-19.4). Risk of leukemia was also greater (RR=1.6, 95% CI 0.7-3.3) among the most exposed participants when assigning exposure categories based on petrol stations located within 250 m of the child's residence and total amount of gasoline delivered by the stations. Overall, residence within close proximity to a petrol station, especially one with more intense refueling activity, was associated with an increased risk of childhood leukemia, though associations were imprecise., (© 2023. The Author(s).)

Benzene is a known hematotoxic and leukemogenic chemical. Exposure to benzene cause inhibition of hematopoietic cells. However, the mechanism of how the hematopoietic cells inhibited by benzene undergo malignant proliferation is unknown. The cells carrying leukemia-associated fusion genes are present in healthy individuals and predispose the carriers to the development of leukemia. To identify the effects of benzene on hematopoietic cells, preleukemic bone marrow (PBM) cells derived from transgenic mice carrying the Mll-Af9 fusion gene were treated with benzene metabolite hydroquinone in serial replating of colony-forming unit (CFU) assay. RNA sequencing was further employed to identify the potential key genes that contributed to benzene-initiated self-renewal and proliferation. We found that hydroquinone induced a significant increase in colony formation in PBM cells. Peroxisome proliferator-activated receptor gamma (Ppar-γ) pathway, which plays a critical role in carcinogenesis in multiple tumors, was significantly activated after hydroquinone treatment. Notably, the increased numbers of the CFUs and total PBM cells induced by hydroquinone were significantly reduced by a specific Ppar-γ inhibitor (GW9662). These findings indicated that hydroquinone can enhance self-renewal and proliferation of preleukemic cells by activating the Ppar-γ pathway. Our results provide insight into the missing link between premalignant status and development of benzene-induced leukemia, which can be intervened and prevented., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Background: occupational exposure to benzene represents a threat for the health of a still relevant number of workers. An increased risk of leukaemias has been demonstrated among exposed workers, while a weaker association has been found for other malignancies., Objectives: to evaluate mortality risk among workers exposed to benzene across economic sectors in Italy., Design: proportionate mortality ratios (PMRs) were calculated linking exposure occupational information to national mortality statistics (2005-2018), assuming a Poisson distribution of the data., Setting and Participants: data from the Italian national registry on occupational exposure to carcinogens (SIREP) in the period 1996-2018 were selected., Main Outcomes Measures: PMRs by cause of death were reported. Specific analyses by cancer site and activity sector, profession, and cumulative exposure were performed., Results: a total of 858 deaths (97% in men) were identified among 38,704 exposed workers (91% men). An excess of deaths from malignant neoplasm of the lung was found among exposed workers, in both genders (PMR 1.27 in men; PMR 3.00 in women). An increased proportion of deaths was also found from leukaemias (leukaemia of unspecified cell type: PMR in men 2.99; 95%CI 1.24-7.19), and multiple myeloma in the chemical industry (PMR in men 2.27; 95%CI 1.08-4.76)., Conclusions: the risk of leukaemia in the petrochemical industry has been confirmed, while an excess risk of lung cancer mortality was highlighted in the retail sale of automotive fuels. Epidemiological surveillance and air and biological monitoring are recommended for workers exposed to benzene to ensure compliance with regulatory requirements and reduce exposure-related deaths.

Previous research reported that prolonged benzene exposure during in utero fetal development causes greater fetal abnormalities than in adult-stage exposure. This phenomenon increases the risk for disease development at the fetal stage, particularly carcinogenesis, which is mainly associated with hematological malignancies. Benzene has been reported to potentially act via multiple modes of action that target the hematopoietic stem cell (HSCs) niche, a complex microenvironment in which HSCs and multilineage hematopoietic stem and progenitor cells (HSPCs) reside. Oxidative stress, chromosomal aberration and epigenetic modification are among the known mechanisms mediating benzene-induced genetic and epigenetic modification in fetal stem cells leading to in utero carcinogenesis. Hence, it is crucial to monitor exposure to carcinogenic benzene via environmental, occupational or lifestyle factors among pregnant women. Benzene is a well-known cause of adult leukemia. However, proof of benzene involvement with childhood leukemia remains scarce despite previously reported research linking incidences of hematological disorders and maternal benzene exposure. Furthermore, accumulating evidence has shown that maternal benzene exposure is able to alter the developmental and functional properties of HSPCs, leading to hematological disorders in fetus and children. Since HSPCs are parental blood cells that regulate hematopoiesis during the fetal and adult stages, benzene exposure that targets HSPCs may induce damage to the population and trigger the development of hematological diseases. Therefore, the mechanism of in utero carcinogenicity by benzene in targeting fetal HSPCs is the primary focus of this review.

The incidence and mortality due to neoplastic diseases have shown an increasing tendency over the years. Based on GLOBOCAN 2020 published by the International Agency for Research on Cancer (IARC), leukemias are the thirteenth most commonly diagnosed cancer in the world, with 78.6% of leukemia cases diagnosed in countries with a very high or high Human Development Index (HDI). Carcinogenesis is a complex process initiated by a mutation in DNA that may be caused by chemical carcinogens present in polluted environments and human diet. The IARC has identified 122 human carcinogens, e.g., benzene, formaldehyde, pentachlorophenol, and 93 probable human carcinogens, e.g., styrene, diazinone. The aim of the following review is to present the chemical carcinogens involved or likely to be involved in the pathogenesis of leukemia and to summarize the latest reports on the possibility of detecting these compounds in the environment or food with the use of electrochemical sensors.

Epigenetics is the science of altering gene expression without changing nucleotide sequences and may be induced by various environmental factors, including pesticides. The aim of this study was to investigate certain epigenetic changes including the methylation of CDKN2B, CDKN2A, and MGMT gene promoters and histone modifications of H3K9ac, H4K16ac, H4K20me3, and H3K4me3, as well as their association with the levels of organochlorine pesticides (OCPs) in children with acute lymphoblastic leukemia (ALL). The evaluation of OCP levels, promoter methylation, gene expression, and expression of histone modifications was performed by gas chromatography (GC), methylation-specific polymerase chain reaction (MS-PCR), reverse transcription PCR (RT-PCR), and western blotting, respectively. The results indicated that 76.2 % of CDKN2B promoters and 85.1 % of MGMT promoters were hypermethylated in children with ALL compared to healthy children. In addition, the relative expression of CDKN2B, MGMT, H4K16ac, and H3K4me3 showed a significant decrease in children with ALL compared to healthy children. Levels of OCPs in children with ALL were significantly higher than in healthy children. Furthermore, the results revealed that the rise in the OCP levels was associated with an increase in methylation at the promoter level of CDKN2B and MGMT as well as a decrease in the relative expression of H4K16ac and H3K4me3. Therefore, it can be concluded that exposure to OCPs is associated with the induction of epigenetic changes at the level of DNA and histones, which may lead to leukemia., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Genome-wide sequencing may extensively identify potential pathogenic variants, which helps to understand mechanisms of tumorigenesis, but such study has not been reported in benzene-induced leukemia (BIL)., Methods: We recruited 10 BIL patients and conducted the whole-exome sequencing on their peripheral blood samples. The obtained sequencing data were screened for potential pathogenic and novel variants, then the variants-located genes were clustered to identify cancer-related pathways. Shared or recurrent variants among the BIL cases were also identified and evaluated for their potential functional impact., Results: We identified 48,802 variants in exons in total, 97.3% of which were single nucleotide variants. After filtering out variants with minor allele frequency ≥ 1%, we obtained 8667 potentially pathogenic variants, of which 174 were shared by all the BIL cases. The identified variants located in genes that could be significantly enriched into certain cancer-related pathways such as PI3K-AKT signaling pathway and Ras signaling pathway. We also identified 1010 novel variants with no record in the Genome Aggregation Database and in dbSNP, and one of them was shared by 90% cases. The recurrent and novel variant caused a missense mutation in SESN3., Conclusions: We examined variations of the whole exome in BIL patients for the first time. The commonly shared variants implied a relation with BIL, and the recurrent and novel variant might be specifically related to BIL. The related variants may help unravel the carcinogenic mechanisms of BIL., (© 2023. The Author(s).)

Exposure to pesticides has been linked to an elevated risk of leukemia. The present research aimed to evaluate the relationship between organochlorine (OC) pesticides and biomarkers of oxidative stress in patients with leukemia. This work was conducted on 109 patients with leukemia and 109 healthy controls. The serum concentrations of seven derivatives of OCs including alpha-hexachlorocyclohexane (HCH), beta-HCH, gamma-HCH, 2,4-dichlorodiphenyltrichloroethane (DDT), 4,4-DDT, 2,4-dichlorodiphenyldichloroethylene (DDE), and 4,4-DDE along with acetylcholinesterase (AChE), glutathione peroxidase (GPx), superoxide dismutase (SOD), paraoxonase-1 (PON1), and catalase (CAT) activities as well as total antioxidant capacity (TAC), nitric oxide (NO), protein carbonyl (PC), and malondialdehyde (MDA) levels were measured in all the subjects. Levels of OCs were remarkably higher in patients with leukemia compared with the controls (p<0.05). In addition, levels of SOD, AChE, GPx, PON1, and TAC were remarkably lower in patients with leukemia compared with controls (p<0.05). In contrast, MDA, NO, and PC concentrations were higher in patients with leukemia than in the controls (p<0.05). Moreover, the serum level of 4,4-DDE was negatively associated with GPx activity (p=0.038). Our findings suggest that OCs may play a role in the development of leukemia by disrupting the oxidant/antioxidant balance., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Exposure to N-nitroso compounds (NOCs) in our environment via pesticides, tobacco, and smoked meat can be potentially carcinogenic. The induction of N-N' ethylnitrosourea (ENU), a genotoxic NOC, leads to leukemogenesis. The study aimed to explore the ameliorating effect of the Ayurvedic herb Eclipta alba on the bone marrow cells of ENU-induced leukemic mice. Eclipta alba is investigated for its anti-cancer effect on various cell lines, but never on haematological malignant models. Theefficacy of the extract was explored on leukemia by changes in body weight, survivability, peripheral blood hemogram, bone marrow cytological, histological, and cell culture studies pre-and post-treatment. The treated group revealed significant immunomodulation of the expressional profile of NF-kB family and IL-1β in marrow cells, by flow-cytometry, and immunofluorescence study. Through our experimental endeavour we depicted the cellular mechanism, signaling modality and tried to establish the anti-cancer potency of Eclipta alba on ENU-induced leukemia.

Background: Close residential proximity to powerlines and high magnetic fields exposure may be associated with elevated childhood leukemia risks as reported by prior studies and pooled analyses. Magnetic fields exposure from high-voltage powerlines is associated with proximity to these powerlines and consequently with any factor varying with distance. Areas underneath powerlines in California may be sites for commercial plant nurseries that can use pesticides, a potential childhood leukemia risk factor., Objectives: Assess if potential pesticide exposure from commercial plant nurseries is a confounder or interacts with proximity or magnetic fields exposure from high-voltage powerlines to increase childhood leukemia risk., Methods: A comprehensive childhood leukemia record-based case-control study with 5788 cases and 5788 controls (born and diagnosed in California, 1986-2008) was conducted. Pesticide, powerline, and magnetic field exposure assessment utilized models that incorporated geographical information systems, aerial satellite images, site visits and other historical information., Results: The relationship for calculated fields with childhood leukemia (odds ratio (OR) 1.51, 95% confidence interval (CI) 0.70-3.23) slightly attenuated when controlling for nursery proximity (OR 1.43, 95% CI 0.65-3.16) or restricting analysis to subjects living far (>300 m) from nurseries (OR 1.43, 95% CI 0.79-2.60). A similar association pattern was observed between distance to high-voltage powerlines and childhood leukemia. The association between nursery proximity and childhood leukemia was unchanged or only slightly attenuated when controlling for calculated fields or powerline distance; ORs remained above 2 when excluding subjects with high calculated fields or close powerline proximity (OR 2.16, 95% CI 0.82-5.67 and OR 2.15, 95% CI 0.82-5.64, respectively). The observed relationships were robust to different time periods, reference categories, and cut points., Discussion: Close residential proximity to nurseries is suggested as an independent childhood leukemia risk factor. Our results do not support plant nurseries as an explanation for observed childhood leukemia risks for powerline proximity and magnetic fields exposure, although small numbers of subjects concurrently exposed to high magnetic fields, close powerline proximity and plant nurseries limited our ability to fully assess potential confounding., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

There are few well-established risk factors for childhood leukemias. While the frequency of childhood leukemias might be partially attributable to some diseases (accounting for a small fraction of cases) or ionizing radiation, the role of heavy metals has not been assessed. The objective of our study was to assess the potential association between levels of cadmium (Cd) and lead (PB) in soil and childhood leukemias incidence. We conducted a population-based case-control study of childhood leukaemia in Spain, covering 2897 incident cases gathered from the Spanish Registry of Childhood Tumours and including 14 Spanish Regions with a total population of 5,307,433 children (period 1996-2015). Cd and Pb bioavailable levels at every children's home address were estimated using data from the Geochemical Atlas of Spain. We used logistic regression to estimate odds ratios (ORs) and their 95% confidence intervals (95%CIs); we included as covariates: sex, rurality, employment rate and socioeconomic status. Metal levels were analysed according to two definitions: as continuous variable assuming linearity and as categorical variables to explore a potentially nonlinear association (quantiles). Increases in both Cd and Pb topsoil levels were associated with increased probability of childhood leukemias incidence. The results for the models with the continuous variables showed that a unit increase on the topsoil level was associated with an OR of 1.11 for Cd (95%CI 1.00-1.24) and an OR of 1.10 for Pb (95%CI 0.99-1.21). Our study may point towards a possible link between residential Cd and Pb topsoil levels and the probability of childhood leukemias incidence. Residing in a location with the highest concentrations of these heavy metals compared to those locations with the lowest could increase the risk around a 20%, for both Cd and Pb., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Evidence-based recommendations for the optimal duration and sequencing of temozolomide-based treatments in advanced neuroendocrine neoplasms are lacking. Here, we conducted a systematic review of the literature for a descriptive analysis of temozolomide-associated myelodysplasias and leukemias to guide treatment planning. A database search of PubMed and Embase was conducted to identify case reports and/or case series reporting secondary myelodysplasias or leukemias in the setting of temozolomide therapy. Key data items extracted from the studies were the temozolomide dose and duration, latency to hematological disorder, type of secondary malignancy and cytogenetics. Reported cases were summarized graphically. A total of 16 studies with 27 patient cases of therapy-related hematologic neoplasms were identified, all of which were case reports or case series. The median treatment duration and cumulative dose were 19 months and 18,000 mg/m 2 , respectively. Most patients (21/27) were diagnosed on, or after, 12 months, while only one patient was diagnosed before 6 months of treatment. Most of the patients were diagnosed, while still on treatment with temozolomide. Graphically, cases clustered around a cumulative dose of 10,000 to 30,000 mg/m 2 and a latency period of 10 to 40 months which translates to an approximate treatment duration of 12.5 to 37.5 months. Taken together, most reported treatment-related hematological neoplasms appear to develop on or beyond the 12-month mark, while patients are still on treatment with temozolomide. For patients with neuroendocrine neoplasms, where sequencing of multiple therapies is important, we suggest an approach to optimizing treatment duration by establishing disease response at 6 months before continuing further treatment and restricting treatment to or establishing closer vigilance beyond 12 months., (© 2022 British Society for Neuroendocrinology.)

Purpose: Benzene is a known carcinogen for adult leukemia. Exposure to benzene through parental occupation and the use of household products has been associated with childhood leukemia (CL). Ambient benzene has also been associated with CL and central nervous system (CNS) tumors. We aimed to investigate whether the higher ambient levels of benzene in proximity of petrol stations are associated with a greater risk of childhood cancers, leukemia, and CNS tumors., Methods: We identified children diagnosed with cancer at age 0-15 years during 1985-2015 from the Swiss Childhood Cancer Registry and selected 10 age and sex-matched controls per case from national censuses. We calculated the distance from children's home to the nearest petrol station using precise geocodes. We estimated odds ratios using conditional logistic regression adjusting for ambient levels of NO 2 , distance to highways, level of urbanization, and presence of a cantonal cancer registry. In addition, we ran a meta-analysis pooling current results for CL with those of previous studies., Results: We identified 6129 cases, of which 1880 were leukemias and 1290 CNS tumors. 24 cases lived within 50 m from a petrol station. The adjusted odds ratio of a cancer diagnosis for children thus exposed compared to unexposed children (> 500 m) was 1.29 (0.84-1.98) for all cancers combined, 1.08 (0.46-2.51) for leukemia, and 1.30 (0.51-3.35) for CNS tumors. During 2000-2015, when exposure assessment was more precise, the adjusted odds ratio for any cancer diagnosis was 1.77 (1.05-2.98). The summary relative risk estimate for CL in the meta-analysis including four studies was 2.01 (1.25-3.22)., Conclusions: Our study provides weak support for an increased risk of childhood cancers among children living close to petrol stations. A meta-analysis including our study suggests an increased risk for CL., (© 2021. The Author(s).)

Background: Clozapine is the most efficacious treatment for schizophrenia and is associated with lower overall mortality than are other antipsychotic drugs, despite the risk of agranulocytosis. Preliminary reports over the past 10 years suggest a possible risk of haematological malignancies, but the issue has remained unsettled. We aimed to study the risk of haematological malignancies associated with use of clozapine and other antipsychotics., Methods: We did a nationwide case-control (and cohort) study of people with schizophrenia, using prospectively gathered data from Finnish national registers. A nested case-control study was constructed by individually matching cases of lymphoid and haematopoietic tissue malignancy with up to ten controls without cancer by age, sex, and time since first schizophrenia diagnosis. For the case-control study, we restricted inclusion criteria to malignancies diagnosed on a histological basis, and excluded individuals outside of the age range 18-85 years, and any patients that had a previous malignancy. Analyses were done using conditional logistic regression adjusting for comorbid conditions., Findings: For the case-control study 516 patients with a first-time diagnosis of lymphoid and haematopoietic tissue malignancy during years 2000-17 and diagnosed after their first diagnosis of schizophrenia were identified. 102 patients were excluded due to diagnosis that was without a histological basis, five patients were excluded because of their age, and 34 were excluded for a previous malignancy, resulting in 375 patients being matched to controls. We selected up to ten controls without cancer (3734 in total) for each case from the base cohort of people with schizophrenia. For the cohort study, data for 55 949 people were included for analysis. Cumulative incidence of haematological malignancies during the mean follow-up of 12·3 years (SD 6·5) was 102 (0·7%) cases among 13 712 patients who had used clozapine (corresponding to event rate of 61 cases per 100 000 person-years), and during mean follow-up of 12·9 years (SD 7·2) was 235 (0·5%) malignancies among 44 171 patients having used other antipsychotic medication than clozapine (corresponding to 41 cases per 100 000 person-years). Of the 375 individuals with haematological malignancies (305 lymphomas, 42 leukaemia, 22 myelomas, 6 unspecified) observed from 2000-17, 208 (55%) were males and 167 (45%) were female. Ethnicity data were not available. Compared with non-use of clozapine (most had used other antipsychotics and a few had used no antipsychotics), clozapine use was associated with increased odds of haematological malignancies in a dose-response manner (adjusted odds ratio 3·35, [95% CI 2·22-5·05] for ≥5000 defined daily dose cumulative exposure, p<0·0001). Exposure to other antipsychotic drugs was not associated with increased odds. A complementary analysis showed that the clozapine-related risk increase was specific for haematological malignancies, because no such finding was observed for other malignancies. Over 17 years of follow-up of the base cohort, 37 deaths occurred due to haematological malignancy among patients exposed to clozapine (26 with ongoing use at time of haematological malignancy diagnosis, and 11 in patients who did not use clozapine at the exact time of their cancer diagnosis), whereas only three deaths occurred due to agranulocytosis., Interpretation: Unlike other antipsychotics, long-term clozapine use is associated with increased odds of haematological malignancies. Long-term clozapine use has a higher effect on mortality due to lymphoma and leukaemia than due to agranulocytosis. However, acknowledging that the absolute risk is small compared with the previously observed absolute risk reduction in all-cause mortality is important. Our results suggest that patients and caregivers should be informed about warning signs of haematological malignancies, and mental health clinicians should be vigilant for signs and symptoms of haematological malignancy in patients treated with clozapine., Funding: The Finnish Ministry of Social Affairs and Health and Academy of Finland., Competing Interests: Declaration of interests JT, HT, and AT have participated in research projects funded by grants from Janssen-Cilag and Eli Lilly to their employing institution. JT has been a consultant or advisor to or has received honoraria from: Eli Lilly, Evidera, Janssen-Cilag, Lundbeck, Orion, Otsuka, Mediuutiset, Sidera, and Sunovion. JSB is supported by a National Health and Medical Research Council (NHMRC) Boosting Dementia Research Leadership Fellowship and has received grant funding or consulting funds from the NHMRC, Victorian Government Department of Health and Human Services, Dementia Australia Research Foundation, Yulgilbar Foundation, Aged Care Quality and Safety Commission, Dementia Centre for Research Collaboration, Pharmaceutical Society of Australia, GlaxoSmithKline Supported Studies Programme, Amgen, and several aged care provider organisations unrelated to this work. All grants and consulting funds were paid to the employing institution. HT reports personal fees from Janssen-Cilag and Otsuka. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Benzene is an occupational and environmental toxicant, causing hematopoietic damage. Our study is aimed to extract the trend of benzene-induced leukemia (BIL) and qualitatively and quantitatively estimate research on it. Publications on BIL were identified from the Web of Science Core Collection (WoSCC). Microsoft Excel 2019 (Redmond, WA) and The CiteSpace 5.6.R5 software (Drexel University, Philadelphia, PA) were used to analyze the publication outcomes, countries, institutions, authors, keywords, and research frontiers. The overall 1152 publications were collected from 1990 to 2019 until November 6, 2020. Environ Health Persp had the highest number of articles published. The USA were the top country in terms of BIL. The Smith MT, Yin SN, Lan Q, and Hayes RB are both listed in the top 10 of co-cited authors, high contribution authors, and the authors of co-cited references. High IF articles account for a considerable proportion, among all the publications. Chinese institutions engaged in BIL and contributed a large part of articles. Exposure population, exposure dose, and exposure risk are the research hotspots in this field. The risk of benzene exposure on childhood leukemia is at issue, and the studies on attributable risk of benzene-induced leukemia are few. More early, sensitive, and specific epigenetic biomarkers of benzolism may be the leading research fields of benzene-induced leukemia in the next few years., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Metabolomics has been used to explore the molecular mechanism and screen biomarkers. However, the critical metabolic signatures associated with benzene-induced hematotoxicity remain elusive. Here, we performed a plasma metabolomics study in 86 benzene-exposed workers and 76 healthy controls, followed by a validation analysis in mice, to investigate the dynamical change of the metabolic profile. We found that 8 fatty acids were significantly altered in both benzene-exposed worker and benzene-exposed animal models. These metabolites were significantly associated with S-phenylmercapturic acid and WBC, and they mediated the benzene-induced WBC decline. Furthermore, in vivo results confirm that fatty acid levels were dynamically altered, characterized by a decrease at 15 days and then sharp increases at 30 and 45 days. Following these identified fatty acids, the potential metabolic pathways were investigated. Fatty acids, as precursors for fatty acid oxidation, may disturb the balance of fatty acid biosynthesis and degradation. Our results reveal that fatty acid metabolism was strongly reprogrammed after benzene exposure. This abnormal change of fatty acids might be the key metabolic signature associated with benzene-induced hematotoxicity.

Introduction: In this study, the authors conducted a comprehensive systematic review and meta-analysis (including a dose-response meta-analysis) for a possible causal association between residential radon exposure and leukemia. All 3 types of study design, including ecological, case-control, and cohort studies, were included in this study. In particular, different measurement units of radon exposure among studies were dealt with and analyzed thoroughly., Methods: A medical librarian searched MEDLINE (PubMed), EMBASE, and the Cochrane Library (from January 01, 1970 to November 05, 2020). For ecological studies, a conventional meta-analysis and subgroup analyses with meta-ANOVA analyses were conducted. For case-control and cohort studies, a two-stage dose-response meta-analysis was conducted., Results: A total of 8 ecological, 9 case-control, and 15 ecological-cohort studies were analyzed. For ecological studies, the pooled correlation coefficient was 0.48 (95% CI 0.41-0.54). In the meta-analysis of variance (ANOVA) analyses, the age group (childhood vs. adult) showed a statistically significant result (Q = 7.93 and p = 0.019) with the pooled correlation coefficient for childhood, adult, and all age group of 0.67 (95% CI 0.53-0.77), 0.46 (95% CI 0.05-0.74), and 0.44 (95% CI 0.36-0.51), respectively. For case-control studies, the dose-response meta-analysis showed the pooled OR increase of 1.0308 (95% CI 1.0050-1.0573) for each 100 Bq/m 3 increase of radon dose. The pooled OR increase was 1.0361 (95% CI 1.0014-1.0720) for each 100 Bq/m 3 increase of radon dose for lymphoid leukemia subgroup and 1.0309 (95% CI 1.0050-1.0575) for each 100 Bq/m 3 increase of radon dose for childhood leukemia subgroup. Because of the inclusion of ecological studies with larger exposure assessment units, the pooled RR from ecological-cohort studies should be interpreted conservatively (a tendency towards a higher risk estimate). The overall pooled RR increase for each 100 Bq/m 3 increase of radon dose was 1.1221 (95% CI 1.0184-1.2363). The pooled RR increase was 1.2257 (95% CI 1.0034-1.4972) for each 100 Bq/m 3 increase of radon dose for the myeloid leukemia subgroup and 1.2503 (95% CI 1.0233-1.5276) for each 100 Bq/m 3 increase of radon dose for adult leukemia subgroup., Discussion: A number of epidemiologic concepts, including the issue of sample size justification, the possibility of differential participation selection bias for case-control studies, the possibility of random and systematic errors in radon measurement, ecological fallacy for ecological studies, were discussed. The effect of age group, socioeconomic status, and gamma radiation exposure was also discussed. Future more accurate and conclusive large-scale case-control and cohort studies are needed., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Pesticides are a potential risk factor for childhood leukemia. Studies evaluating the role of prenatal and/or early life exposure to pesticides in the development of childhood leukemia have produced a range of results. In addition to indoor use of pesticides, higher risks have been reported for children born near agricultural crops. No studies have looked at pesticide exposure based on proximity of birth residence to commercial plant nurseries, even though nurseries are located much closer to residences than agricultural crops and can potentially result in chronic year-round pesticide exposure., Objectives: To evaluate whether risk of childhood leukemia is associated with pesticide use as determined by distance of residence at birth to commercial, outdoor plant nurseries., Methods: We conducted a large statewide, record-based case-control study of childhood leukemia in California, which included 5788 childhood leukemia cases and an equal number of controls. Pesticide exposure was based on a spatial proximity model, which combined geographic information system data with aerial satellite imagery., Results: Overall, the results supported an increased childhood leukemia risk only for birth residences very close to nurseries. For birth residences less than 75 m from plant nurseries, we found an increased risk of childhood leukemia (odds ratio (OR) 2.40, 95% confidence interval (CI) 0.99-5.82) that was stronger for acute lymphocytic leukemia (OR 3.09, 95% CI 1.14-8.34)., Discussion: The association was robust to choices of reference group, cut points and data quality. Our findings suggest that close proximity to plant nurseries may be a risk factor for childhood leukemia and that this relationship should be further evaluated., (Copyright © 2021. Published by Elsevier Inc.)

Human SETD2 is the unique histone methyltransferase that generates H3K36 trimethylation (H3K36me3), an epigenetic mark that plays a key role in normal hematopoiesis. Interestingly, recurrent inactivating mutations of SETD2 and aberrant H3K36me3 are increasingly reported to be involved in hematopoietic malignancies. Benzene (BZ) is a ubiquitous environmental pollutant and carcinogen that causes leukemia. The leukemogenic properties of BZ depend on its biotransformation in the bone marrow into oxidative metabolites, in particular 1,4-benzoquinone (BQ). This hematotoxic metabolite can form DNA and protein adducts that result in the damage and the alteration of cellular processes. Recent studies suggest that BZ-dependent leukemogenesis could depend on epigenetic perturbations, notably aberrant histone methylation. We investigated whether H3K36 trimethylation by SETD2 could be impacted by BZ and its hematotoxic metabolites. Herein, we show that BQ, the major leukemogenic metabolite of BZ, inhibits irreversibly the human histone methyltransferase SETD2, resulting in decreased H3K36me3. Our mechanistic studies further indicate that the BQ-dependent inactivation of SETD2 is due to covalent binding of BQ to reactive Zn-finger cysteines within the catalytic domain of the enzyme. The formation of these quinoprotein adducts results in loss of enzyme activity and protein crosslinks/oligomers. Experiments conducted in hematopoietic cells confirm that exposure to BQ results in the formation of SETD2 crosslinks/oligomers and concomitant loss of H3K36me3 in cells. Taken together, our data indicate that BQ, a major hematotoxic metabolite of BZ, could contribute to BZ-dependent leukemogenesis by perturbing the functions of SETD2, a histone lysine methyltransferase of hematopoietic relevance. SIGNIFICANCE STATEMENT: Benzoquinone is a major leukemogenic metabolite of benzene. Dysregulation of histone methyltransferase is involved in hematopoietic malignancies. This study found that benzoquinone irreversibly impairs SET domain containing 2, a histone H3K36 methyltransferase that plays a key role in hematopoiesis. Benzoquinone forms covalent adducts on Zn-finger cysteines within the catalytic site, leading to loss of activity, protein crosslinks/oligomers, and concomitant decrease of H3K36me3 histone mark. These data provide evidence that a leukemogenic metabolite of benzene can impair a key epigenetic enzyme., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

The causes of leukemia remain largely unknown; our aims were to examine the association between the exposure to outdoor air pollution and leukemia risk and to explore the effect of this exposure during different periods of pregnancy and early life. We searched for all case-control and cohort studies published before February 20, 2021, which measured the risk of leukemia in relation to exposure to the air pollutants: particulate matter, benzene, nitrogen dioxide (NO 2 ), and nitrogen oxides (NO x ). We then carried out a meta-analysis and calculated the summary relative risks (RRs) of leukemia by using a random-effects model. The potential dose-response relationship was further explored. The results showed that the highest exposure to benzene (RR: 1.20, 95%CI: 1.06-1.35) and NO 2 (RR: 1.04, 95%CI; 1.02-1.08) were positively correlated with leukemia risk when compared to the lowest exposure categories for each air pollutant. During pregnancy, exposure to benzene in the third trimester, as well as exposure to NO 2 in the second trimester and entire pregnancy, could also increase the risk of leukemia. In the dose-response analysis, benzene exposure and NO 2 exposure were linearly associated with the risk of leukemia. Other air pollutants did not have a statistical correlation with leukemia risk. There was a certain degree of publication bias in studies on benzene. Overall, our results support a link between outdoor air pollution and leukemia risk, particularly due to benzene and NO 2 . Prospero Registration Number: PROSPERO CRD42020207025., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Leukemia is a malignant tissue-forming disease, which induces the overproduction of large numbers of immature blood cells entering the peripheral blood. It is well documented that inflammation plays a crucial role in the expansion of leukemia. Daphnetin has confirmed anti-inflammatory effects against various diseases. In this experimental study, we evaluated the anti-leukemia and anti-inflammatory effect of daphnetin against benzene-induced leukemia in rats and explored the underlying mechanism. Benzene was used for inducing leukemia in experimental rats. The rats were divided into different groups and the body weight, hematological parameters, bone marrow cells, cytokines, and inflammatory mediators were estimated. Reverse transcription polymerase chain reaction (RT-PCR) was used for estimating the messenger RNA (mRNA) expression of sphingosine-1-phosphate receptor-1. Daphnetin-treated rats showed upregulation of body weight compared to other groups. Moreover, Daphnetin reduced blasts in leukemic rats. It also altered hematological parameters such as red blood cells, white blood cells, lymphocytes, neutrophils, monocytes, eosinophils, monocytes, and basophils, respectively. Daphnetin-treated rats showed a reduction of pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-1β (IL-1β), IL-2, IL-6, and inflammatory mediators including nuclear factor-κB. RT-PCR showed upregulated mRNA expression of sphingosine-1-phosphate receptor-1 of daphnetin-treated group rats compared to other groups. The current study showed that the anti-inflammatory effect of daphnetin against the benzene-induced leukemia via alteration of cytokines., (© 2021 Wiley Periodicals LLC.)

Background: Leukemia is one of the most common forms of hematologic malignancy, which can affect people of all ages. We previously showed an association between exposure to ambient particulate matter 2.5 μg (PM 2.5 ) and risk for leukemia in adults. The aim of this study was to investigate which PM 2.5 constituents were responsible for our previous observation., Methods: This is a nationwide register-based case-control study. We identified 14,983 persons diagnosed with leukemia at age 20 or above, 1989-2014, in the Danish Cancer Registry. We selected up to four sex and age-matched controls per case at random from the entire Danish population (n = 51,613). We modelled concentrations of ambient PM 2.5 and its constituents at the addresses of cases and controls for the 10-year period before index date with a state-of-the-art multiscale air pollution modeling system. We used conditional logistic regression to estimate odds ratios (ORs) adjusted for individual and neighborhood level socio-demographic variables., Result: The results showed higher risk for overall leukemia in association with interquartile range exposure to PM 2.5 (OR = 1.09; 95% CI: 1.02, 1.17), black carbon (BC) (OR = 1.02; 95% CI: 1.00, 1.03), secondary inorganic aerosols (SIA) (OR = 1.15; 95% CI: 1.03, 1.29) and its components ammonium (NH 4 ) (OR = 1.08; 95% CI: 1.00, 1.17) and nitrate (NO 3 ) (OR = 1.08; 95% CI: 1.02, 1.14). In leukemia subtype analysis, statistically significant associations were found for AML with PM 2.5 (OR = 1.14; 95% CI: 1.00, 1.29), BC (OR = 1.03; 95% CI: 1.00, 1.07), SIA (OR = 1.23; 95% CI: 1.01, 1.51), NH 4 (OR = 1.16; 95% CI: 1.01, 1.34) and NO 3 (OR = 1.12; 95% CI: 1.01, 1.24). The association between PM 2.5 and leukemia persisted in two pollutants models including sum of primary emitted black and organic carbon (BC + OC), secondary organic aerosols (SOA), or sea-salt. The association between black carbon (BC) and leukemia persisted in two pollutants models including organic carbon (OC). The three pollutant model with sulfate (SO 4 ), NH 4 and NO 3 showed an association with NO 3 but not with SO 4 or NH 4 ., Conclusion: Ambient concentrations of the PM 2.5 components BC, NH 4 and NO 3 at the residence showed associations with risk of incident leukemia in adults., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Formaldehyde (FA), an economically important and ubiquitous chemical, has been classified as a human carcinogen and myeloid leukemogen. However, the underlying mechanisms of leukemogenesis remain unclear. Unlike many classical leukemogens that damage hematopoietic stem/progenitor cells (HSC/HPC) directly in the bone marrow, FA-as the smallest, most reactive aldehyde-is thought to be incapable of reaching the bone marrow through inhalation exposure. A recent breakthrough study discovered that mouse lung contains functional HSC/HPC that can produce blood cells and travel bi-directionally between the lung and bone marrow, while another early study reported the presence of HSC/HPC in rat nose. Based on these findings, we hypothesized that FA inhalation could induce toxicity in HSC/HPC present in mouse lung and/or nose rather than in the bone marrow. To test this hypothesis, we adapted a commercially available protocol for culturing burst-forming unit-erythroid (BFU-E) and colony-forming unit-granulocyte, macrophage (CFU-GM) colonies from bone marrow and spleen to also enable culture of these colonies from mouse lung and nose, a novel application of this assay. We reported that in vivo exposure to FA at 3 mg/m 3 or ex vivo exposure up to 400 µM FA decreased the formation of both colony types from mouse lung and nose as well as from bone marrow and spleen. These findings, to the best of our knowledge, are the first empirically to show that FA exposure can damage mouse pulmonary and olfactory HSC/HPC and provide potential biological plausibility for the induction of leukemia at the sites of entry rather than the bone marrow.

Purpose: As the prognosis of cancer patients deteriorates, secondary carcinogenesis after chemotherapy, especially secondary hematological malignancies, becomes a serious problem. However, information on the frequency and time of onset of secondary hematological malignancies and the risk of hematological malignancy with different drugs is scarce. This study aimed to evaluate the incidence of leukemia and myelodysplastic syndrome in patients with solid tumors, including breast, colon, gastric, pancreatic, small cell lung, non-small cell lung, esophageal, ovarian, cervical, and endometrial cancers., Methods: Using the United States Food and Drug Administration Adverse Event Reporting System, we analyzed the reporting rates, reporting odds ratios, and the reporting onset times of secondary leukemia and myelodysplastic syndrome for each drug used., Results: The leukemia reporting rates were higher in breast, small cell lung, ovarian, and endometrial cancers than in other cancers, and the myelodysplastic syndrome reporting rates were higher in ovarian and endometrial cancers than in other cancers. For each cancer type, the reporting odds ratios of cytocidal anticancer agents, such as taxanes, anthracyclines, alkylating agents, platinum, and topoisomerase inhibitors, were higher than those of other drugs. Alternatively, the reporting odds ratios of molecular targeted drugs and immune checkpoint inhibitors were not higher than those of other drugs. Approximately half of the cases of leukemia and myelodysplastic syndrome were reported within 1 to 4 years after chemotherapy., Conclusions: Our study clarified the risks of leukemia and myelodysplastic syndrome for several anticancer drugs in patients with solid tumors. Our data may aid in the assessment of the risks of secondary leukemia and myelodysplastic syndrome when medical oncologists, clinical pharmacists, and patients select chemotherapy regimens.

Perfluorooctanesulfonate (PFOS) is a persistent pollutant that can induce toxic effects, including leukemia, on blood cells. Vitamin C (VC), a functional nutrient, has been found to possess potent cytoprotective effects. However, there are currently no reports on its ability to treat PFOS-associated leukemia. This study used a molecular networking analysis to reveal the functional action and pharmacological mechanism of VC against PFOS-associated leukemia. The biological informatics findings revealed a total of 17 intersection targets against PFOS-associated leukemia. In addition, seven core-functional targets, including tumor protein p53 (TP53), mitogen-activated protein kinase 1 (MAPK1), estrogen receptor 1 (ESR1), sirtuin 1 (SIRT1), nitric oxide synthase 3 (NOS3), myeloid cell leukemia-1 (MCL1), and telomerase reverse transcriptase (TERT), were screened and identified. Notably, the molecular docking findings indicated that TP53, MAPK1, and ESR1 were potent pharmacological targets of VC against PFOS-associated leukemia. Moreover, the pharmacological functions including biological processes, cell components, and molecular pathways of VC against PFOS-associated leukemia were determined. According to the computational findings, we conclude that VC protects against PFOS-associated leukemia action by suppressing leukemia-associated cell proliferation and tumor growth. The validated genes of TP53, MAPK1, ESR1 may become potential biomarkers for monitoring and treating PFOS-associated leukemia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Formaldehyde is one of the most comprehensively studied chemicals, with over 30 years of research focused on understanding the development of cancer following inhalation. The causal conclusions regarding the potential for leukemia are largely based on the epidemiological literature, with little consideration of cancer bioassays, dosimetry studies, and mechanistic research, which challenge the biological plausibility of the disease. Recent reanalyzes of the epidemiological literature have also raised significant questions related to the purported associations between formaldehyde and leukemia. Because of this, considerable scientific debate and uncertainty remain on whether there is a causal association between formaldehyde inhalation exposure and leukemia. Further complexity in evaluating this association is related to the endogenous production of formaldehyde. Multiple modes of action (MOA) have been postulated for the development of leukemia following formaldehyde inhalation that includes unsupported hypotheses of direct or indirect toxicity to the target cell population. Herein, the available evidence relevant to evaluating the postulated MOAs for leukemia following formaldehyde inhalation exposure is organized in the IPCS MOA Framework. The integration of all the available evidence clearly highlights the limited amount of data that support any of the postulated MOAs and demonstrates a significant amount of research supporting the null hypothesis that there is no causal association between formaldehyde inhalation exposure and leukemia. These analyses result in a lack of confidence in any of the postulated MOAs, increasing confidence in the conclusion that there is a lack of biological plausibility for a causal association between formaldehyde inhalation exposure and leukemia.

Acute leukemia is the most common childhood cancer and has been associated with exposure to environmental carcinogens. This study aimed to identify clusters of acute childhood leukemia (ACL) cases and analyze their relationship with proximity to industrial sources of air pollution in three capital cities in Colombia during 2000-2015. Incident ACL cases were obtained from the population cancer registries for the cities of Bucaramanga, Cali, and Medellín. The inventory of industrial sources of emissions to the air was obtained from the regional environmental authorities and industrial conglomerates were identified. The Kulldorf's circular scan test was used to detect city clusters and to identify clusters around industrial conglomerates. Multivariable spatial modeling assessed the effect of distance and direction from the industrial conglomerates controlling for socioeconomic status. We identified industrials sectors within a buffer of 1 km around industrial conglomerates related to the ACL clusters. Incidence rates showed geographical heterogeneity with low spatial autocorrelation within cities. The spatio-temporal tests identified one cluster in each city. The industries located within 1 km around the ACL clusters identified in the three cities represent different sectors. Exposure to air pollution from industrial sources might be contributing to the incidence of ACL cases in urban settings in Colombia.

Background: The effect of metformin on leukemia risk remains unknown., Methods: The Taiwan's National Health Insurance database was used to enroll 610,089 newly diagnosed type 2 diabetes patients on at least 2 anti-diabetic prescriptions during 1999-2009. We followed-up these patients until 31 December 2011, in order to determine the incidence of leukemia. We used Cox regression model (incorporated with the inverse probability of treatment-weighting using propensity scores) to estimate hazard ratios in both intention-to-treat and per-protocol analyses., Results: We enrolled 414,783 metformin initiators and 195,306 non-metformin initiators. Among them, 598 and 372 patients developed new-onset leukemia after a median follow-up period of 5.08 years and 6.79 years, respectively. The respective incidence rates were 26.52 and 28.40 per 100,000 person-years. The hazard ratio for metformin initiators versus non-metformin initiators was 0.943 (95% confidence interval 0.828-1.074) in the intention-to-treat analysis and 0.852 (95% confidence interval 0.705-1.031) in the per-protocol analysis. Sensitivity analyses after excluding patients using the exclusion criteria (a follow-up duration < 24 and < 36 months, respectively, patients with incretin-based therapies during follow-up, and patients enrolled during 2 different periods of 1999-2003 and 2004-2009) consistently showed a neutral effect. However, metformin initiators had a significantly higher risk of leukemia in the per-protocol analyses when censoring patients at a time without regular follow-up., Conclusion: Metformin use has an overall neutral effect on leukemia but we cannot exclude a significantly higher risk in patients who persistently use the drug., (Copyright © 2020 Tseng.)

Background: Living in an agricultural area or on farms has been associated with increased risk of childhood cancer but few studies have evaluated specific agricultural exposures. We prospectively examined residential proximity to crops and animals during pregnancy and risk of childhood leukemia and central nervous system (CNS) tumors in Denmark., Methods: The Danish National Birth Cohort (DNBC) consists of 91,769 pregnant women (96,841 live-born children) enrolled in 1996-2003. For 61 childhood leukemias and 59 CNS tumors <15 years of age that were diagnosed through 2014 and a ~10% random sample of the live births (N = 9394) with geocoded addresses, we linked pregnancy addresses to crop fields and animal farm locations and estimated the crop area (hectares [ha]) and number of animals (standardized by their nitrogen emissions) by type within 250 meters (m), 500 m, 1000 m, and 2000 m of the home. We also estimated pesticide applications (grams, active ingredient) based on annual sales data for nine herbicides and one fungicide that were estimated to have been applied to >30% of the area of one or more crop. We used Cox proportional hazard models (weighted to the full cohort) to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of childhood leukemia and CNS tumors with crop area, animals, and pesticide applications adjusted for gender and maternal age., Results: Sixty-three percent of mothers had crops within 500 m of their homes during pregnancy; winter and spring cereals were the major crop types. Compared to mothers with no crops <500 m, we found increasing risk of childhood leukemia among offspring of mothers with increasing crop area near their home (highest tertile >24 ha HR: 2.0, CI:1.02-3.8), which was stronger after adjustment for animals (within 1000 m) (HR: 2.6, CI:1.02-6.8). We also observed increased risk for grass/clover (highest tertile >1.1 ha HR: 3.1, CI:1.2-7.7), peas (>0 HR: 2.4, CI: 1.02-5.4), and maize (>0 HR: 2.8, CI: 1.1-6.9) in animal-adjusted models. We found no association between number of animals near homes and leukemia risk. Crops, total number of animals, and hogs within 500 m of the home were not associated with CNS tumors but we observed an increased risk with >median cattle compared with no animals in crop-adjusted models (HR = 2.2, CI: 1.02-4.9). In models adjusted for total animals, the highest tertiles of use of three herbicides and one fungicide were associated with elevated risk of leukemia but no associations were statistically significant; there were no associations with CNS tumors., Conclusions: Risk of childhood leukemia was associated with higher crop area near mothers' homes during pregnancy; CNS tumors were associated with higher cattle density. Quantitative estimates of crop pesticides and other agricultural exposures are needed to clarify possible reasons for these increased risks., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Pesticide exposure is a suspected risk factor for childhood cancer. We investigated the risk of developing childhood cancer in relation to parental occupational exposure to pesticides in Switzerland for the period 1990-2015., Methods: From a nationwide census-based cohort study in Switzerland, we included children aged < 16 years at national censuses of 1990 and 2000 and followed them until 2015. We extracted parental occupations reported at the census closest to the birth year of the child and estimated exposure to pesticides using a job exposure matrix. Cox proportional hazards models, adjusted for potential confounders, were fitted for the following outcomes: any cancer, leukaemia, central nervous system tumours (CNST), lymphoma, non-CNS solid tumours., Results: Analyses of maternal (paternal) exposure were based on approximately 15.9 (15.1) million-person years at risk and included 1891 (1808) cases of cancer, of which 532 (503) were leukaemia, 348 (337) lymphomas, 423 (399) CNST, and 588 (569) non-CNS solid tumours. The prevalence of high likelihood of exposure was 2.9% for mothers and 6.7% for fathers. No evidence of an association was found with maternal or paternal exposure for any of the outcomes, except for "non-CNS solid tumours" (High versus None; Father: adjusted HR [95%CI] =1.84 [1.31-2.58]; Mother: 1.79 [1.13-2.84]). No evidence of an association was found for main subtypes of leukaemia and lymphoma. A post-hoc analysis on frequent subtypes of "non-CNS solid tumours" showed positive associations with wide CIs for some cancers., Conclusion: Our study suggests an increased risk for solid tumours other than in the CNS among children whose parents were occupationally exposed to pesticides; however, the small numbers of cases limited a closer investigation of cancer subtypes. Better exposure assessment and pooled studies are needed to further explore a possible link between specific childhood cancers types and parental occupational exposure to pesticides.

Benzene is an environmental toxicant found in many consumer products. It is an established human carcinogen and is known to cause acute myeloid leukemia in adults. Epidemiological evidence has since shown that benzene can cross the placenta and affect the fetal liver. Animal studies have shown that in utero exposure to benzene can increase tumor incidence in offspring. Although there have been risk factors established for acute myeloid leukemia, they still do not account for many of the cases. Clearly then, current efforts to elucidate the mechanism by which benzene exerts its carcinogenic properties have been superficial. Owing to the critical role of cell signaling pathways in the development of an organism and its various organ systems, it seems plausible to suspect that these pathways may have a role in leukemogenesis. This review article assesses current evidence of the effects of benzene on critical hematopoietic signaling pathways. Pathways discussed included Hedgehog, Notch/Delta, Wingless/Integrated, nuclear factor-kappaB and others. Following a review of the literature, it seems that current evidence about the effects of benzene on these critical signaling pathways remains limited. Given the important role of these pathways in hematopoiesis, more attention should be given to them., (© 2020 John Wiley & Sons, Ltd.)

Introduction: An in-patient clinical service has been set up in March 2016 in the Occupational Diseases Center of Brest University Hospital, France, to seek for work-relatedness of diseases in patients hospitalized into the oncology and hematology departments. We present here data after two years of existence., Methods: All cases of cancers or malignant hematological diseases (ICD-10 codes C00 to C97 and D37 to D48) seen between March 1, 2016, and March 1, 2018, have been identified. We present sociodemographic data, occupational exposures, occupation, business sector, and tobacco consumption. The causation level between the disease and each of the occupational exposures has been rated as strong, intermediate, weak or null by the occupational medicine specialist of the Occupational Diseases Center., Results: Among the 196 patients encountered, there are 127 work-related diseases and 82 of these had one occupational exposure rated as strong or intermediate. The most frequent occupational hazards were asbestos (48 cases) and ionizing radiation (23 cases). The most frequent business sectors were metallurgy, mechanical engineering, and agriculture. Lung cancer was the most frequently reported disease (49 cases)., Discussion: . We identified well-known couples with occupational exposures and diseases, such as asbestos and lung cancer. We also identified a link between pesticides and leukemias. This in-patient clinical service is helpful to identify work-related exposures and in helping patients to get compensated., (Copyright © 2020 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Murine splenic macrophage plays a decisive role in host immunity through phagocytosis against pathogens. It was reported that, macrophages also involves in phagocytosis of some tumour cells upon its activation initiated by certain cytokines produced by other immune cell or by indigenously treated. In this study, we have investigated the killing of leukemic blast cells by macrophages upon stimulated with IL-15 and GM-CSF alone or in combination in ENU challenged leukemic murine model. Along with, the release of TNF-α, IL-12 and IFN-γ by macrophages were assayed by ELISA. NO production by macrophages was also investigated. The molecular expressions like GM-CSF and TLRs were investigated for better understand of macrophage-leukemic cell interaction. Result shows that in disease condition macrophages have poor phagocytic activities which may be due to less release of TNF-α, IL-12 and IFN-γ by macrophages. This impaired phagocytic activity in leukemic mice was increase upon stimulation with IL-15 and GM-CSF., Competing Interests: Declaration of Competing Interest Authors declare that there is no conflict of interest., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Exposure to chemicals produced by petrochemical industrial complexes (PICs), such as benzene, ionizing radiation, and particulate matters, may contribute to the development of leukemia. However, epidemiological studies showed controversial results. This systematic review and meta-analysis aimed to summarize the association between residential exposure to PICs and the risk of leukemia incidence, focusing on exposure-response effects. We searched PubMed, Embase, Web of Science, and Cochrane Library databases for studies published before September 1st, 2019. Observational studies investigating residential exposure to PICs and the risk of leukemia were included. The outcome of interest was the incidence of leukemia comparing to reference groups. Relative risk (RR) was used as the summary effect measure, synthesized by characteristics of populations, distance to PICs, and calendar time in meta-regression. We identified 7 observational studies, including 2322 leukemia cases and substantial reference groups, in this meta-analysis. Residential exposure to PICs within a maximal 8-km distance had a 36% increased risk of leukemia (pooled RR = 1.36, 95% CI = 1.14-1.62) compared to controls, regardless of sex and age. In terms of leukemia subtypes, residential exposure to PICs was associated with the risks of acute myeloid leukemia (AML, pooled RR = 1.61, 95% CI = 1.12-2.31) and chronic lymphocytic leukemia (CLL, pooled RR = 1.85, 95% CI = 1.11-6.42). In meta-regression, the positive association occurred after 10 years of follow-up with a pooled RRs of 1.21 (95% CI = 1.02-1.44) and then slightly increased to 1.77 (95% CI = 1.35-2.33) at 30 years after follow-up. No effect modification was found by sex, age, and geographic locations., Competing Interests: Declaration of competing interest The authors have declared that no competing interests exist., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

We recently published a next generation framework for assessing the risk of genomic damage via exposure to chemical substances. The framework entails a systematic approach with the aim to quantify risk levels for substances that induce genomic damage contributing to human adverse health outcomes. Here, we evaluated the utility of the framework for assessing the risk for industrial chemicals, using the case of benzene. Benzene is a well-studied substance that is generally considered a genotoxic carcinogen and is known to cause leukemia. The case study limits its focus on occupational and general population health as it relates to benzene exposure. Using the framework as guidance, available data on benzene considered relevant for assessment of genetic damage were collected. Based on these data, we were able to conduct quantitative analyses for relevant data sets to estimate acceptable exposure levels and to characterize the risk of genetic damage. Key observations include the need for robust exposure assessments, the importance of information on toxicokinetic properties, and the benefits of cheminformatics. The framework points to the need for further improvement on understanding of the mechanism(s) of action involved, which would also provide support for the use of targeted tests rather than a prescribed set of assays. Overall, this case study demonstrates the utility of the next generation framework to quantitatively model human risk on the basis of genetic damage, thereby enabling a new, innovative risk assessment concept. Environ. Mol. Mutagen. 61:94-113, 2020. © 2019 The Authors. Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society., (© 2019 The Authors. Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.)

Butyl 2,3-epoxypropyl ether (CAS No. 2426-08-6, synonym: n-butylglycidyl ether, BGE) was exposed by whole body inhalation to F344 rats and BDF1 mice of both sexes (50 animals per group) 6 hours per day, 5 days per week for 104 weeks at targeted concentrations of 0, 10, 30 or 90 ppm (v/v) for rats and 0, 5, 15 or 45 ppm for mice. In rats, 90 ppm of BGE increased the incidences of nasal squamous cell carcinomas in both sexes. Nasal adenomas and splenic mononuclear cell leukemia were increased in male rats exposed to 30 ppm. Splenic mononuclear cell leukemia was increased in female rats by trend test. Non-neoplastic nasal lesions, such as squamous cell hyperplasia with atypia, squamous cell metaplasia and the inflammation of the respiratory region and atrophy of the olfactory epithelium were increased in both sexes in a dose-dependent manner. In mice, the incidences of histiocytic sarcomas of the uterus in female mice were increased in a dose-dependent manner and the incidences of nasal hemangiomas in both sexes were increased in a dose-dependent manner. Nasal squamous cell carcinoma, a rare tumor, was observed, although not statistically significant, in both sexes. Non-neoplastic lesions such as nodular hyperplasia of the transitional epithelium and cuboidal changes of the respiratory epithelium in the nasal cavity, were increased both in males and females in a dose-dependent manner. The present study demonstrated clear evidence of carcinogenicity of BGE in both rats and mice by the 2-year whole body inhalation exposure.