4.1. General data
In terms of the number of publications, the overall trend increased roughly from 12 in 1992 to 22 in 1996 during the first five years, with the increase likely due to the application of biomonitoring techniques to benzene exposure studies.(WE and RF; SM et al.) From 2005 to 2018, the number of publications was approximately symmetrical centered on 2012 (23 counts); however, the number of publications continued to decline during the three years from 2019 to 2022, with the decline likely due to a new coronary heart disease outbreak in 2019, which affected the source of data acquisition for benzene exposure studies and led to a decrease in the number of papers.
According to the top 15 journals, 13.33% of the journals, including the journal of Environmental health perspectives(IF2021,11.035) and Science of the Total Environment(IF2021, 10.753) had an IF greater than 10.000; 26.67% of of the journals, including the journal of Chemico-biological Interactions(IF2021, 5.168), Environmental Research(IF2021, 8.431), Critical Reviews in Toxicology(IF2021, 6.184), and Archives of Toxicology(IF2021, 6.168), had an IF between 5.000 and 10.000; 40.00% of the journals, including the journal of Toxicology Letters(IF2021,4.271), Mutation Research-genetic Toxicology and Environmental Mutagenesis(IF2021,3.189), Occupational and Environmental Medicine(IF2021,4.948), American Journal of Industrial Medicine(IF2021,3.079), International Health Journal of Environmental Research and Public Health(IF2021,4.614), and Environmental and Molecular Mutagenesis(IF2021,3.579), had an IF between 3.000 and 5.000; In addition, journals with high IF (>3.000) contributed 26.87%, (IF >10.000, 6.91%; 10.000 >IF >5.000, 8.62%; 5.000 >IF >3.000, 11.34%) of the total number of publications. In conclusion, publishing articles on chronic low-level benzene exposure and hematologic toxicity in high-IF journals is challenging.
The top 10 countries/regions (4 European countries, 2 American countries, 3 Asian countries, and 1 Middle Eastern country) engaged in long-term low-level benzene exposure and hematotoxicity studies contributed to 521 publications, accounting for 78.31% of the total number of publications. The United States contributed 142 publications (about a quarter of the total number of publications), which indicates the dominance of research on benzene exposure and blood toxicity in the United States. China and Iran are the only two developing countries, but China contributed 82 publications, about one-sixth of all publications, second only to the United States, indicating that China has made significant progress in the life sciences in the last 20 years.
The top 10 institutions engaging in chronic low-level benzene exposure and blood toxicity studies contributed 85 publications, accounting for 16.31% of the total publications. The top two institutions on this list, both from China, are Fudan University and the Chinese Center for Disease Control and Prevention, and the third is the University of California. This is because benzene is one of China's most widely used industrial chemicals. A wide variety of industries and occupations, particularly the footwear and suitcase industries in China, use benzene or benzene-containing solvents and adhesives(SN, Q, et al.; YX et al.)
4.2. Citation data
In this analysis, each of the top 10 authors contributed six or more publications by the number of publications. But unfortunately, in terms of annual co-citations, only one of these authors makes the top 10 list, which means that these prolific authors are only after the number of publications they publish, ignoring their quality. For co-occurrence analysis of co-cited authors, authors with at least 50 co-citation counts included Snyder R, Smith M, Lan Q, and Aksoy M. These authors have played an essential role in the study of long-term low-level benzene exposure and blood toxicity. Smith M, in particular, is not only on the top ten list analyzed by authors but also ranks second in the co-citation count with 63 citations.(L. Q et al.; MT, L, Y, et al.; MT, L, CM, et al.) For the cited reference clusters, the timeline view graph of the co-citation clusters shows that most of the clusters were concentrated between 2010 and 2019. Based on the results for the top 10 references with co-citation counts, Lan Q (2004), published in science, had the highest number of co-citation counts (16), followed by Popp W (1994, 11 co-citation counts), Arnold S (2013, 10 co-citation counts) and Yardleyjones A (1991, 10 co-citation counts), who published in International Archives of Occupational and Environmental Health, Critical Reviews in Toxicology and British Journal of Industrial Medicine
4.3. More information on chronic low benzene exposure and blood toxicity
As the working environment gradually improves, other adverse effects of exposure to low concentrations of benzene become apparent. U.S. Occupational Safety and Health Administration(OSHA) dropped to 1 ppm in 1987 after using ten ppm as an occupational exposure limit (OEL, 8-hour weighted average) in 1969.(DH et al.) According to Schnatter et al.(R. S. A et al.) , neutrophilia and average platelet volume vary from 7.8 to 8.2 PPM benzene, Ward et al.(Ward et al.) reported that If the concentration is lower than five ppm, it may lead to hematotoxicity. Many recent studies have further investigated the effects of low concentrations (less than one ppm). Qu et al(Q. Q et al.) reported a decrease in the number of red blood cells, white blood cells, and neutrophils at a concentration of 0.25 ppm. Lan et al.[10](L. Q et al.) said that concentrations below one ppm affect the number of white blood cells and red blood cells.
The mechanisms of hematotoxicity caused by low levels of benzene exposure have not been fully investigated in the past decades. This is because the metabolism of benzene is intrinsically complex,(R and CC) occurring primarily in the liver(R. S. A et al.) and lungs, (MW and GP; D et al.) with secondary metabolism in the bone marrow.(Ward et al.; RD et al.; P and G; LS, HA and JR)
Studies have identified cytokines that may be sensitive markers of disease.(VV, P and MT) In a survey by Jwa B et al., exposure to low levels of benzene disrupted the body's early inflammatory response and altered the expression of pro- and anti-inflammatory cytokines.(W. J et al.) Gillis et al. detected 15 cytokines secreted by human peripheral blood mononuclear cells (PBMC) exposed to benzene metabolites.(B et al.) They reported that exposure to benzene metabolites increased IL-4, Monocyte Chemotactic Protein-1(MCP-1), and Macrophage Inflammatory Protein 1-α(MIP1-α) production by PBMC and that activated PBMC increased TNF-α secretion. IL-15 was essential for T cell differentiation and proliferation,(ME et al.) mediated JAK-STAT signaling activity, and drives T cell malignancy.(TT et al.) Vascular endothelial growth factor(VEGF) is associated with benzene exposure and hematologic toxicity. Single-nucleotide polymorphisms(SNP) in VEGF are related to white blood cell count(WBC) and granulocyte counts in benzene-exposed workers.(Hosgood HD et al.) VEGF was found to be involved in chemical carcinogen-induced leukemia (A. A et al.), and increased bone marrow vascularity in newly diagnosed acute myeloid leukemia (AML) patients was associated with high VEGF expression.(Z. J et al.)
4.4. Research hotspots
We conducted a keyword co-occurrence analysis of 521 publications. Among the top 20 keywords for chronic low-level benzene exposure and blood toxicity, we inferred three major research hotspots, which are listed below:
Occupational benzene exposure: Benzene is a common occupational solvent that has been used in multiple industries, particularly as a chemical intermediate in the production of plastics and rubber manufacturing, and has been used as a solvent in common consumer products worldwide.(S et al.) In China, benzene is regularly used in manufacturing industries, and historically high levels of occupational benzene exposure have been reported, with several reports describing cases of benzene poisoning in exposed Chinese workers.(H et al.) However, as its toxic effects became more apparent, it was ever more tightly regulated and, where possible, substituted by less hazardous compounds. The following are examples of industries in which occupational benzene exposure occurs primarily: a) Upstream petrochemical industry: the industry can be broadly classified into exploration, drilling, conventional oil/gas, conventional gas, heavy oil processing, tar sands, and pipelines. Benzene is a natural component of the petroleum streams; (Garlanda et al.) b) Downstream petrochemical industry: benzene exposures occur in four main areas: refinery operations, road tanker distribution, marine and rail car distribution, and at service stations; c) Coke oven industry; d) Vehicle mechanics; e) Aviation industry; f) Firefighters; g) Workers in urban environments; h) Other occupationally exposed group.(AC and LS)
Leukemia: The International Agency for Research on Cancer (IARC) officially classified benzene as a Group I carcinogen in 1982; benzene-induced leukemia was identified as one of China's top eight occupational tumors in 1987.(IARC "- Overall Evaluations of Carcinogenicity: An Updating of Iarc Monographs Volumes 1") Epidemiological studies have also provided evidence for an association with childhood leukemia.(N et al.; JM et al.) The mechanism by which benzene produces leukemia has not been fully elucidated, but comprehensive research over many years has revealed that benzene acts through multiple mechanisms. (MT, L, CM, et al.) In order to produce leukemia, reactive metabolites of benzene may mutate key genes or groups of genes associated with proliferation and differentiation in human stem cells (HSC) by causing chromosomal aberrations (aneuploidy, translocations, inversions, and deletions), abnormal mitotic recombination, gene mutations and/or epigenetic alterations.(N et al.) The study of the mechanism of benzene toxicity and leukemogenesis has progressed slowly, with about a half-century intervening between initial descriptive studies of Santesson, Selling, and Weiskotten and the early studies of Parke and Williams directed to understanding the mechanisms involved. Since then, we have extended our appreciation of benzene metabolism. The next steps require that we take advantage of developments in studies of the bone marrow niches, stem cell biology, and the effects of perturbation of cell signaling if we are to delineate the mechanisms by which benzene causes leukemia.(R)
Cancer among benzene exposure workers: Exposure to benzene, classified as a Group 1 carcinogen by the International Agency for Research on Cancer (IARC), has been determined to cause AML, based in part on several case-control and occupational cohort studies in various populations of the middle.(IARC "- Benzene") An epidemiological survey in China (NCI/CAPM study) extended the quantitative assessment of cancer risk to a broader range of benzene exposure, particularly at lower levels.(SN, RB, et al.) The potential lymphomatous benzene exposure has been the subject of much debate. A recent comprehensive evaluation by the International Agency for cancer research concluded that there is evidence of a positive association between benzene and Non-Hodgkin Lymphoma(NHL), and there was a positive correlation with acute lymphocyte leukemia (ALL), CLL, and multiple myeloma.(IARC "- Benzene") Exposure to benzene has been shown to lead to the development of lymphomas in animal studies, including in a study in Trp53-deficient mice, which also observed an increase in benzene-induced AML.(MT, L, Y, et al.; IARC "- Benzene") The latest IARC assessment of benzene also confirms that there is still sufficient evidence to link AML in humans.(IARC "- Benzene") Given that subtype-specific associations have been suggested in some previous case-control studies,(R et al.; P et al.) future studies with access to tumor samples from a high percentage of cases and pathological review are needed to determine whether associations with specific NHL subtypes are likely to drive observations association with overall NHL risk. Finally, given that NHL is a rare tumor in China, another limitation is the relatively small number of NHL cases in the cohort, which contributes to the relatively wide confidence intervals associated with the observed effect estimates.
4.5. Strengths and limitations
For our part, this is the first recent bibliometric analysis of research trends in long-term low-concentration benzene exposure versus hematological toxicity in three decades. The data was retrieved and extracted from SCI-E and SSCI journals in the WoSCC database. Data analysis is relatively objective and comprehensive. However, the number of publications on this subject retrieved in the WoSCC database is relatively small, and it is hoped that more research will be done in future studies on the relationship between long-term low-concentration benzene exposure and hematological toxicity.