Particulate Matter 2.5 and Hematological Disorders From Dust to Diseases: A Systematic Review of Available Evidence

Particulate matter 2.5 (PM2.5) in the air enters the human body by diffusion into the blood. Therefore, hematological abnormalities might occur because of these toxic particles, but few studies on this issue have been reported. According to Cochrane guidance, we performed a systematic review on the relationship between exposure to PM2.5 and the risk of hematological disorders. Ten articles were included in this review. Anemia was found among children and elderly populations with 2- to 5-year PM2.5 exposure. Young children from mothers exposed to air pollution during pregnancy had a higher incidence of leukemia similar to the elderly. Supporting these data, outdoor workers also showed abnormal epigenetic modifications after exposure to very high PM2.5 levels. Adults living in high PM2.5 areas for 2 years were more likely to develop thrombocytosis. Finally, elderly populations with 7- to 8-year PM2.5 exposure showed increased risks of venous thromboembolism. In conclusion, the associations between PM2.5 and hematological aberrations among high-risk people with long-term exposure were reported.


INTRODUCTION
Air pollution is one of the most important environmental and health problems worldwide (1,2). Thailand and other countries have been encountering excessive amounts of particulate matter (PM) primarily from combustion of fuels, coal, and natural gases. PMs are complex mixtures of airborne particles with differences in chemical compositions, sizes, and origin (3). They can be classified into coarse (PM 10 ; diameter range 2.5-10 µm), fine (PM 2.5 ; size < 2.5 µm), and ultrafine particulate (UFP; size < 100 nm) matter (4)(5)(6). Both PM 10 and PM 2.5 concentrations are widely measured in the environment. After human exposure to PM, PM 10 remains in the nasal cavities and upper respiratory tracts, but PM 2.5 can reach the alveoli and then penetrate into the blood (3,(7)(8)(9)(10). Fine PM can directly cause health problems such as respiratory (reactive airway, lung cancer, and chronic obstructive pulmonary diseases), cardiovascular (heart failure and myocardial infarction), and allergic diseases (rhinitis and eczema) (9,11). In 2013, the International Agency for Research on Cancer (IARC) of the World Health Organization (WHO) reported that outdoor air pollution is toxic to humans (12). The annual mean PM 2.5 level over 10 µg/m 3 or 24-h mean over 25 µg/m 3 was defined as deleterious to the health of the population (13). Children and women are high-risk groups that are prone to develop cardiovascular diseases (18-27%) and pulmonary diseases (8-20%) from PM exposure (14). As PM 2.5 can be absorbed from the respiratory tract into the blood, they may interact with blood cells and plasma components (7,10). PM 2.5 also affects red blood cells, white blood cells, or platelet functions, and therefore, some patients may acquire hematological diseases. Apart from exposure to PM 2.5 , other risk factors also play synergistic roles in causing the diseases. Therefore, high-risk groups for developing hematologic diseases need to be identified. In this review, we aim to study the relationship between PM 2.5 exposure and risks for abnormal hematological parameters.

METHODS
This systematic review followed the Cochrane guidelines. The search used PubMed R , Science Direct, Mendeley, Google Scholar, and EBSCOhost database. The keywords were separated into three categories. Searching group1 used "air pollution" or "particulate matter" or "PM 2.5 " and "anemia." In group2, the terms "air pollution" or "particulate matter" or "PM 2.5 " and "leukemia" were searched. In group3, "air pollution" or "particulate matter" or "PM 2.5 " and "thrombosis" or "coagulation" were used. In group4, "air pollution" or "particulate matter" or "PM 2.5 " and "lymph nodes" were used. In group5, "air pollution" or "particulate matter" or "PM 2.5 " and "spleen" were added. The inclusion criteria were studies on PM 2.5 in relation to hematological diseases, such as anemia, leukemia, and thrombosis in humans, and publications between 2014 and 2021. Duplicated articles, irrelevant titles, the non-English languages, and unavailable full papers were excluded. Afterwards, eligible articles were archived to the EndNote X7.7.1 for Windows (Thomson Reuters, USA). Interesting information from matched articles of the PM 2.5 related to hematologic diseases were extracted to identify the risk factors and assessed by three independent hematologists. The search algorithms are shown in Figure 1. Table 1 shows the characteristics of the 10 available studies included in this systematic review. Of these, there were three studies using the panel design, four case-control studies, two cohort studies, and one cross-sectional study. Sample sizes of the population per study ranged from 4,121 to 139,368 for the panel design and 453.413 for the cross-sectional study. Most studies included subjects over 35 years of age. The studies were located in Peru, Denmark, the United States, Italy, Canada, China, and Taiwan. Air pollutant data were obtained from fixed sites or personal systems or both. Three studies reported the results related to erythrocyte disorders, four studies related to white blood cells, and three studies demonstrated results associated with platelets or thrombotic conditions. Hematologic Disorders (Anemia, Leukemia, and Thrombosis)

Is PM 2.5 a Risk Factor for Anemia?
A few studies linked PM 2.5 exposure to erythrocyte disorders, especially anemia. According to the WHO criteria, anemia was defined as a hemoglobin (Hb) level lower than 13.0 g/dl in men, 12.0 g/dl in women, and 11.0 g/dl in children (23,24). A study by Morales-Ancajima et al. (17) was performed in 139,368 children (age 6-35 months) to evaluate the association between Hb and air pollution in their residential areas. Hb levels decreased among children who were exposed to PM 2.5 (range 24.97-28.84 µg/m 3 ) during the 4-year study. Mild to moderate anemia in children was related to areas with high 24h PM 2.5 concentrations with the means between 25 (25) and 50 µg/m 3 (26). Moderate to severe anemia in children were associated with very high 24-h mean PM 2.5 of over 50 µg/m 3 [odds ratio (OR) = 2.83, 95% confidence interval (CI) 1.39-5.75] (27). Anemic children were detectable in 30.8% of the population, while moderate to severe anemia was observed in 8.8% of the population (17). Similarly, Honda et al. (18) showed that 4,121 elderly people with anemia (34.9%) lived in areas with high annual mean PM 2.5 levels (>11.1 ± 2.8 µg/m 3 ). Interestingly, elderly subjects with 2-to 5-year exposure to PM 2.5 pollution showed declines in Hb levels of approximately 0.81 ± 0.06 g/dl. Honda et al. (18) explained the relationship between air pollution and anemia in the elderly population with elevated C-reactive protein (CRP) levels that indicated chronic inflammatory responses to PM 2. 5 . In an animal model, the increased harmful effects of PM 2.5 exposure to young rather than adolescent mice were mediated by the impairment of bone marrow microenvironment (27,28). The mechanism of PM 2.5 action is probably a reactive oxygen species formation which increases inflammatory cytokines (TNF-α, IL-1β, and IL-6) in the cells. Inflammation may inhibit differentiation and proliferation of erythroid precursor cells and enhance an erythropoietin (Epo) resistant state (27)(28)(29). Another potential explanation is that inflammatory cytokines can upregulate hepcidin synthesis causing breakdown of ferroportin, thus reducing iron absorption in the gastrointestinal tract (30,31). In another mouse model, an association between particulate matters (PM 2.5 and PM 0.1 ) and the deformation of murine erythrocytes was found (6). The mice exposed to PM 2.5 (100 s for 8 days) increased erythrocyte distortion, which finally led to hemolytic anemia (6). Anemia observed in mice exposed to air pollution showed significant dose and time dependency (27).
How Is PM 2.5 Related to Leukemia?
It has been known since 1997 that gasoline pollution is one of the factors in gene-toxin-environmental interactions promoting leukemogenesis (32,33). Leukemia is a malignant clonal disease that results in abnormal proliferation and impaired cellular differentiation of hematopoietic stem cells. Multiple myelotoxicity substances commonly injure hematopoietic cells (3). Exposure to environment toxins might be one of the  . This study design showed the strongest relationship between fetal exposure to air pollution during pregnancy and leukemia in the first year of age. A study by Hvidtfeldt et al. (16) showed a high OR ratio of 2.05 (IQR = 1.10-3.38) in childhood non-Hodgkin lymphoma with exposure to PM 2.5 . Molecular epidemiology studies suggested that DNA methylation of the leukemic gene was positively correlated with exposure to environmental toxins (37,38). DNA methylation incorporates a methyl group to the position of the fifth carbon of cytosine to produce 5-methylcytosine (5mC). Subsequently, 5mC is oxidized into 5-hydroxymethylcytosine (5hmC) which suppresses gene expression. Both 5mC and 5hmC are markers for DNA methylation in malignancy cells (39,40). A study by Sanchez-Guerra et al. (20) demonstrated the increase in methylated genomic contents (5hmC and 5mC) among subjects who were exposed to PM 10 and PM 2.5 for 4-7 work-days. Blood samples of 60 outdoor workers exposed to PM 10 showed significantly higher 5hmC levels (p = 0.001  at 4 work-days, p = 0.005 at 7 work-days, and p < 0.001 at 14 work-days) and increasing 5mC levels in people exposed to PM 2.5 (p = 0.005). This study is limited by the exposure times to PM 2.5 . In addition, high 5hmC and 5mC levels, which indicated epigenetic modification, were detectable among people in Beijing (20). The mechanism of PM 2.5 in AML development could be explained by specific proteins. Proteinforming nanoparticles, termed corona proteins, that cover PM 2.5 particles can alter epigenetics and tumor suppressor gene expression (3,15,41,42). DNA methylation is highly sensitive to environmental PM 2.5 exposures (16,20). Therefore, this modification can inhibit gene expression, impeding cellular differentiation as one of the steps of leukemic development.
Long-term exposure to PM 2.5 might alter both gene-coding and non-coding DNA methylation (20). An in vitro study by Jin et al. (43) found that the progression of leukemic cells was induced by prolonged exposure to PM 2.5 . The proposed mechanism is the reactive oxygen species-mediated pathway (43). Moreover, the PM 2.5 component had been classified as a carcinogenic class I agent since 2013 (3). Apart from PM 2.5 particles, its components, i.e., aluminum, black carbon, sulfur, lead, titanium, and silicon, may be involved in the pathogenesis of leukemia (20). In conclusion, a positive relationship between PM 2.5 and leukemic cells is suggested by epidemiological evidence, and the molecular mechanisms are used to explain the pathophysiology of diseases.
Can Thrombosis and Coagulation Be Promoted by PM 2.5 ?
Evidence from related studies links particulate matters to platelet function (2,4,22,(44)(45)(46). The American Heart Association-AHA (2004) proposed that thrombotic mechanisms may be explained by daily exposure to PM 2.5 among patients with atherosclerotic cardiovascular disorders (22). Thrombosis is the most common pathology in patients with acute cardiac ischemia and stroke on top of atherosclerosis (4,47,48 (21). The mechanism of thrombosis by PM 2.5 may be from increased inflammatory cytokine (IL-6) levels, oxidative stress, platelet activation, stimulated coagulation pathway, and reduced fibrinolysis (3,46,49,50). These conditions are known to promote thrombotic phenomena in humans (51). In animal models, there is a study on the effects of PM 2.5 that can cause disseminated intravascular coagulation (DIC) through coagulation activation in rats (46). Liang et al. (46) found that rat exposure to PM 2.5 increasingly expressed inflammatory cytokines, IL-6, IL-1β, and CRP in plasma. Moreover, tissue factor-dependent extrinsic pathways coagulation systems, as well as expression of adhesion molecules, such as VCAM-1 and ICAM-1, were upregulated after moderate to high doses of PM 2.5 (average 35 µg/m 3 for 30 exposure days). Finally, a shift of hemostatic balance to a pro-thrombotic/pro-coagulation state is induced by exposure to PM 2.5 (4).

CONCLUSIONS
High PM 2.5 exposure is one of the most important avoidable hazards to human health. The effects on hematological systems have been less well-studied. There were fewer than 20 available entries in the web search according to the Cochrane recommendation as the damages are not easily analyzed and are mostly unnoticed. All available studies found harmful effects of long-term exposure to PM 2.5 to the hematopoietic system. Hematological parameter changes in people exposed to medium to high PM 2.5 concentrations for more than a year are summarized in Table 2. The pathophysiology of PM 2.5 pollution may be from increased inflammatory responses affecting each hematological component. For the public, avoidance of exposure and reduction in PM 2.5 pollution should be encouraged. Interventions should be focused on the high-risk groups including the elderly with cardiovascular diseases, young children, and pregnant women. Personal facemasks can minimize inhaled small particles and reduce pollution exposure time. Air purifiers also lessen indoor pollution concentrations. Improving air quality has to be addressed for the general population. Decreasing PM 2.5 pollution is essential to prevent hematological adverse events. Further studies are needed to determine whether reducing PM 2.5 exposure can decrease these disorders.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.