Environmental Chemical Agents and the Risk of Myelodysplastic Syndrome: A Systematic Review of the Literature

Introduction

Environmental Chemical Agents and the Risk of Myelodysplastic Syndrome (Background) In the literature dedicated to environmental determinants of health, it is observed that systemic metabolic changes do not develop in isolation, but result from complex interactions between external exposures, lifestyle, and individual characteristics of the host (VITUS, n.d.; SALAVOURA, 2025). Recognition of the relationship between environmental chemical agents and the risk of myelodysplastic syndrome developed progressively throughout the 20th century, based on clinical and epidemiological observations in populations exposed to toxic substances. Initially, occupational reports identified a higher frequency of hematological changes among workers exposed to organic solvents, aromatic hydrocarbons, and heavy metals, sparking scientific interest in the hematotoxic effects of these substances (CAZARIN, 2005; BONATES et al., 2010).

Subsequently, extreme environmental exposures, such as those observed in survivors of atomic explosions in Japan, provided robust evidence that chemical and physical agents can induce lasting changes in hematopoiesis, culminating in the late development of myelodysplastic syndrome (ANDO; MIYAZAKI, 2024). With the advancement of epidemiological studies in recent decades, population-based and case-control studies have demonstrated consistent associations between chronic exposure to pesticides, benzene, industrial pollutants, and smoking with an increased risk of myelodysplastic syndrome, both in occupational settings and in the general population (ANWAR et al., 2022; ALLAHVERDI; YASSIN; IBRAHIM, 2021). At the same time, advances in molecular biology and genomics have led to the understanding that these chemical agents act through genotoxic, epigenetic, inflammatory, and mitochondrial mechanisms, promoting genomic instability and bone marrow dysfunction (AOYAGI et al., 2022; PIERRO et al., 2025).

Thus, myelodysplastic syndrome has come to be recognized as the result of a complex interaction between environmental exposure, genetic susceptibility, and cellular changes acquired over time (ROTTER et al., 2023; LI et al., 2022). ALLAHVERDI, YASSIN, and IBRAHIM (2021) emphasize that the study of environmental chemical agents has gained progressive relevance in the investigation of hematological neoplasms, especially in light of the finding that chronic exposure to toxic substances plays a significant role in the development of myelodysplastic syndrome. Historically, as described by CAZARIN (2005), the first evidence of the association between the chemical environment and hematologicaldiseasesarosefromoccupationalobservations, in which workers exposed to solvents, heavy metals, and hydrocarbons had a higher incidence of hematopoietic changes.

The impact of extreme environmental exposures was extensively documented by ANDO and MIYAZAKI (2024) when analyzing survivors of the Nagasaki atomic bombings, showing that physical and chemical agents can induce lasting changes in the bone marrow, favoring the onset of myelodysplastic syndrome decades after initial exposure. Population-based studies, such as that by ANWAR et al. (2022), reinforced this association by demonstrating that environmentalandoccupationalexposurestochemicalagents significantly increase the risk of developing myelodysplastic syndrome, especially in contexts of low environmental regulation (ANWAR et al., 2022). Benzene has historically stood out as one of the main chemical agents implicated in the genesis of hematological diseases, being recognized as a hematotoxic carcinogen in classic and contemporary studies (BONATES et al., 2010; SHALLIS; GORE, 2022).

Brazilian literature has contributed significantly to this understanding, with clinical reports and observational studies demonstrating an association between herbicide exposure and the development of myelodysplastic syndrome in agricultural populations (BATISTA et al., 2022; FRANÇA, 2020). Based on the consolidation of these findings, epidemiological studies began to differentiate between subtypes of myeloid neoplasms, as highlighted by MUNDT et al. (2021), emphasizing the need to specifically evaluate myelodysplastic syndrome when investigating environmental carcinogens (MUNDT et al., 2021). From a pathophysiological perspective, AOYAGI et al. (2022) demonstrated that chemical agents can induce mitochondrial fragmentation and hematopoietic dysfunction, mechanisms that help explain the relationship between environmental exposure and bone marrow failure observed in myelodysplastic syndrome (AOYAGI et al., 2022).

Mitochondrial dysfunction associated with oxidative stress was further explored by PIERRO et al. (2025), showing that environmental chemical agents promote an increase in reactive oxygen species, favoring genomic instability in the bone marrow. From a molecular perspective, JING et al. (2024) highlight that persistent oxidative stress induced by xenobiotics compromises DNA repair mechanisms, contributing to the clonal progression characteristic of myelodysplastic syndrome (JING et al., 2024). The relevance of genotoxic damage was reinforced by DUARTE et al. (2022), who identified an association between exposure to genotoxic agents and the development of myelodysplastic syndrome in referral services in Brazil. Studies on DNA methylation have expanded this understanding, demonstrating that environmental chemical agents can induce lasting epigenetic changes in repair genes, as observed in the works of COSTA (2022) and MONTE (2021) (COSTA, 2022; MONTE, 2021).

Individual genetic influence has also been considered, with ELBADRY et al. (2025) demonstrating that variants in DNA repair genes modulate susceptibility to the hematotoxic effects of environmental chemical agents (ELBADRY et al., 2025). In the field of immunology, recent studies indicate that environmental pollutants can trigger chronic bone marrow inflammation, creating a microenvironment conducive to the development of myelodysplastic syndrome (VILLAUME; SAVONA, 2024; VERMA et al., 2025). The interaction between inflammation and the bone marrow microenvironment was further explored by YU et al. (2023), who demonstrated that inflammatory pathways activated by environmental agents contribute to immune exhaustion and disease progression. Research involving populations exposed to armed conflict and military chemical agents, as described by TIU et al.

(2024), reinforced the role of complex environmental exposures in the risk of myeloid neoplasms, including myelodysplastic syndrome. The international literature also points to the role of food contaminants,suchasheavymetals,ininducinghematological changes, broadening the spectrum of relevant environmental chemical agents (CHARCHUŁA et al., 2025). Observational studies indicate an association between smoking and myelodysplastic syndrome, suggesting that inhaled chemical agents have a cumulative effect on the bone marrow (DE LAS HERAS RODRÍGUEZ et al., 2025). Occupational exposure in specific industrial sectors was detailed by KHALILI and NASRABADI (2023), who highlighted hematological risks associated with chronic inhalation of chemical compounds (KHALILI; NASRABADI, 2023). In the context of public health, SILVA (2016) demonstrated a higher incidence of hematological neoplasms in populations living near industrial complexes, reinforcing the importance of the chemical environment in the etiology of myelodysplastic syndrome (SILVA, 2016).

Studies on environmental pollution and childhood cancer have also contributed to the understanding of early exposure as a lifelong hematological risk factor (NAVARRETE-MENESES et al., 2024). The evolution of knowledge has led to the distinction between de novo and therapy-related myelodysplastic syndrome, as discussed by RENNEVILLE, BERNARD, and MICOL (2023), recognizing that therapeutic chemical agents also act as relevant risk factors (RENNEVILLE; BERNARD; MICOL, 2023). With advances in genomics, myelodysplastic syndrome has come to be understood as the result of complex interactions between environmental chemical agents, genetic predisposition, and acquired epigenetic changes (ROTTER et al., 2023). Finally, the historical synthesis of the literature demonstrates that exposure to environmental chemical agents is one of the central pillars in understanding the risk of myelodysplastic syndrome, consolidating the need for preventive strategies, environmental surveillance, and policies to protect the health of workers and the general population (LI et al., 2022; ROTTER et al., 2023).

Objectives

General Objective To analyze, through a systematic review of the literature and in light of the available scientific evidence, the association between exposure to environmental chemical agents and the risk of developing myelodysplastic syndrome, considering different types of occupational and environmental exposures described in the literature. Specific Objectives  Describe the main environmental chemical agents associated with the risk of myelodysplastic syndrome in adult populations.  Identify the contexts of environmental and occupational exposure most frequently related to the development of myelodysplastic syndrome.  Compare the risk of myelodysplastic syndrome according to the type, intensity, and duration of exposure to environmental chemical agents described in the included studies.

Methodology

Type of study This study was developed in the form of a systematic review, with the aim of answering the following guiding research question: “What is the relationship between exposure to environmental chemical agents and the risk of developing myelodysplastic syndrome?” Sources of information and search strategy This systematic review was prepared based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta- Analyses) guidelines, which provide guidance on conducting and reporting systematic and integrative reviews. Following this protocol, all stages were carried out: identification, selection, eligibility, and inclusion. All steps were performed in a structured and transparent manner, ensuring the traceability of the search process and the methodological quality of the study selection.

Searches were performed in multiple electronic databases (PubMed, Scopus, Web of Science, and Google Scholar). After removing duplicates, the articles were evaluated by title and abstract, followed by full-text reading to verify eligibility according to previously established criteria. Search strategies were developed using controlled descriptors from Medical Subject Headings (MeSH), combined with free terms and Boolean operators (AND, OR), as described below: Search strategy – Environmental Chemical Agents and Myelodysplastic Syndrome (“Myelodysplastic Syndromes”[MeSH Terms] OR “Myelodysplastic Syndrome” OR MDS) AND (“Environmental Exposure”[MeSH Terms] OR “Occupational Exposure” OR “Environmental Chemicals” OR “Chemical Agents”) AND (“Pesticides”[MeSH Terms] OR “Benzene”[MeSH Terms] OR “Organic Solvents” OR “Heavy Metals”) AND (“Risk Factors”[MeSH Terms] OR “Disease Risk” OR “Epidemiology”) Inclusion and exclusion criteria Original articles, observational studies, cross-sectional studies, longitudinal studies, case-control studies, cohorts, and epidemiological trials addressing the association between exposure to environmental chemical agents and the risk of myelodysplastic syndrome in adult populations published in the last twenty years (2005 to 2025) were included in the review.

Studies published in languages other than English and Portuguese were disregarded in order to maintain linguistic consistency and data comparability, and reviews, duplicate publications, isolated case reports, conference abstracts, editorials, and brief communications were excluded. Data selection and analysis process The screening of studies was carried out in three sequential stages: 1. Reading of titles; 2. Reading of abstracts; 3. Reading of potentially eligible texts in full. The selected articles were organized in a standardized spreadsheet containing the following variables: author, year of publication, country, type of study, study population, type of chemical agent, exposure context (environmental or occupational), exposure time, and association with myelodysplastic syndrome. Data analysis was conducted in a descriptive and comparative manner, grouping the findings according to the type of chemical agent and exposure pattern.

The results were presented in narrative and tabular form, allowing the identification of patterns, consistencies, and divergences between the included studies. Ethical aspects As this is a systematic review based exclusively on secondary data in the public domain, this study did not involve direct experimentation with humans or the collection of individual information, and therefore did not require review by a Research Ethics Committee. All included studies were duly cited and referenced, respecting analyses were conducted in an impartial, transparent, and responsible manner.

Results

The initial search aimed to identify studies published between 2005 and 2025 related to exposure to environmental chemical agents and the risk of developing myelodysplastic syndrome, considering epidemiological, occupational, and environmental aspects. FIGURE 1 shows the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flowchart, based on three stages; Stage 1 – Identification A total of 230 records were identified in electronic databases (PubMed, Scopus, Web of Science, and Google Scholar), in addition to 20 additional records from other sources. After removing duplicates, 210 unique articles remained for screening. Stage 2 – Selection The 210 records were evaluated by title and abstract, resulting in the exclusion of 136 studies that did not meet the inclusion criteria because they did not address environmental chemical agents, did not present relevant epidemiological data, or did not specifically address myelodysplastic syndrome.

This left 74 articles to be read in full. Step 3 – Eligibility The 74 articles were evaluated for methodological eligibility, thematic relevance, and scientific quality. This process ensured the inclusion of publications with consistent epidemiological and environmental evidence, comprehensively representing current scientific knowledge on the relationship between environmental chemical agents and the risk of myelodysplastic syndrome. Chart 1. PRISMA Flowchart - Selection of Studies on Environmental Chemical Agents and the Risk of Myelodysplastic Syndrome (adapted from PRISMA 2020). Table 1 systematically summarizes the main evidence available in the literature on the association between exposure to environmental and occupational chemical agents and the risk of developing myelodysplastic syndrome (MDS). Studies with different methodological designs were included, covering epidemiological investigations, observational studies, systematic reviews, case reports, and experimental or mechanistic studies from different geographical and occupational contexts.

This approach allows for a comprehensive view of the topic, covering multiple types of exposures such as pesticides, herbicides, benzene, persistent organic pollutants, industrial pollution, and other genotoxic agents, as well as different strategies for measuring risk and outcomes related to MDS. Table 1. Studies on environmental/occupational chemical exposure and the risk of MDS Reference Population/sample Exposure (occupational/ environmental) Outcome Main findings on association with MSD ANWAR et al., 2022 Cases of SMD vs. controls Environmental and occupational exposure MSD Positive association between environmental/occupational exposure and increased risk of SMD BATISTA et al., 2022 1 patient Herbicides SMD Plausible temporal relationship between herbicide exposure and SMD BONATES et al., 2010 — Occupational benzene Hematological neoplasms Benzene recognized as a hematological carcinogen BUCKSTEIN, 2020 — Recognized chemical exposures SMD Environmental exposures included as etiological factors of SMD DUARTE et al., 2022 Outpatients Genotoxic agents SMD/AML Clinical association between genotoxic exposure and secondary MDS/AML COSTA, 2022 SMD and farmers Pesticides SMD Epigenetic changes associated with exposure to pesticides FRANCE, 2020 Farmers Pesticides SMD biomarkers Mechanistic plausibility of the exposure–SMD association MONTE, 2020 — Pesticides Hematological neoplasms Increasing risk trend for hematological neoplasms MUNDT et al., 2021 — Environmental carcinogens Myeloid neoplasms Advocates specific analysis of MDS in epidemiological studies YAROSH et al., 2021 Cases of MDS Environmental/iatrogenic exposures MDS Differences between de novo SMD and therapy-related SMD SHALLIS & GORE, 2022 — Agent Orange/dioxin Myeloid neoplasms History of association with myeloid neoplasms TIU et al., 2024 War veterans Military exposures MPN Increased risk in the context of environmental exposure SILVA, 2016 Population near the refinery Industrial pollution Hospitalizations Populationsignalofhematological risk KHALILI & NASRABADI, 2023 Aeronautical workers Inhalation of chemical compounds Occupational exposure Characterizes chemical risk scenarios SALAVOURA, 2025 — Organic pollutants Associated diseases Classification of pollutants and biological mechanisms VERMA et al., 2025 — Environmental pollution SMD Association between pollution, inflammation, and increased risk of SMD ANDO & MIYAZAKI, 2024 Nagasaki survivors Ionizing radiation SMD Environmental exposure associated with SMD Source: Authors In general, the compiled studies indicate a consistent association between chronic exposure to environmental and occupational chemical agents and an increased risk of SMD, although there is heterogeneity in terms of exposure types, assessment methods, and effect magnitude.

More robust evidence is observed for occupational exposures to pesticides, herbicides, and benzene, especially in agricultural and industrial populations, in which both a higher frequency of SMD and plausible biological changes, such as genetic and epigenetic damage, are identified. Methodological studies and reviews reinforce the importance of specifically analyzing SMD, avoiding the dilution of risk when grouped with other hematological neoplasms. Despite the limitations inherent in some designs, such as memory bias, lack of accurate quantification of exposure, and use of intermediate outcomes, the body of evidence supports the relevance of environmental and occupational factors in the etiology of MDS, providing a basis for preventive, clinical, and public health discussions.

FIGURE 1 describes the main environmental and occupational chemical agents associated with the risk of developing myelodysplastic syndrome (MDS) in adult populations, based on the frequency of mentions in the studies included in the qualitative synthesis of this review. The distribution reflects the relative weight of each exposure category in the analyzed literature. Figure 1. Main environmental chemical agents associated with the risk of MDS (frequency of mentions in the selected literature) Source: Authors Of the 74 articles selected for this review, quantitative information on exposures and agents associated with the risk of myelodysplastic syndrome (MDS) was extracted from 37 studies, which explicitly mentioned environmental, occupational, or iatrogenic factors that could be categorized.

In this subset, there was a higher frequency of studies related to chemotherapy or previous therapies (t-MDS/iatrogenic) and environmental carcinogens in general, both representing 16.2% (6/37) of the articles analyzed. Next were environmental/ industrial pollution and generic occupational exposure, each with 10.8% (4/37) of the studies. Less frequently, pesticides/agrochemicals, drugs such as metformin and nonsteroidal anti-inflammatory drugs, and dietary factors were identified in 5.4% (2/37) of the studies. Finally, more specific exposures including herbicides, benzene, heavy metals, dioxins/Agent Orange, smoking, and ionizing radiation were reported individually in 2.7% (1/37) of the studies. These findings indicate that, although the selected literature covers a broad spectrum of research on SMD, only some of the studies allow for the direct and comparable extraction of data on exposures, reinforcing the methodological and thematic heterogeneity present in this field of investigation.

Together, these studies support the construction of the graph by showing that different environmental and occupational chemical agents, including pesticides, herbicides, benzene, industrial pollutants, dioxins, and genotoxic agents, are recurrently associated with the risk of MDS in adult populations, albeit with methodological variations and limitations inherent to different research designs. Table 2 summarizes the main contexts of environmental and occupational exposure described in the scientific literature as most frequently associated with the development of myelodysplastic syndrome (MDS). The data are organized according to different exposure scenarios, including agricultural, industrial, urban, and military environments, allowing the identification of recurring risk patterns in adult populations. This systematization facilitates understanding of the relationship between the type of environment or work activity, the predominant chemical agents, and the most vulnerable population groups, contributing to an integrated analysis of the environmental and occupational determinants of MDS.

Table 2. Environmental and occupational exposure contexts most frequently associated with the development of myelodysplastic syndrome Exposure context Type (environmental/ occupational) Main agents involved Most affected populations Evidence described in the literature Supporting ⤢ view in PDF

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