Leukemia risk assessment of exposure to low-levels of benzene based on the linearized multistage model.

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/m3·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; Ptrend < 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/m3·year), while exceeding the EPA model at low concentrations (< 3 and 3-5 mg/m3·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/m3·year.

Benzene metabolite hydroquinone enhances self-renewal and proliferation of preleukemic cells through the Ppar-γ pathway.

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.

Industry Distribution Characteristics of Benzene-Induced Leukemia - 7 PLADs, China, 2005-2019.

What is already known about this topic?: In the 1980s. benzene-induced leukemia (BIL) mainly occurred in shoemaking and painting industries. Now the industry distribution of benzene-induced leukemia may have changed over time. What is added by this report?: BlL cases mainly occurred in the manufacturing industry from 2005-2019, especially in private enterprises and small/medium-sized enterprises. The industry with the largest number of new cases of BIL was the general and special equipment manufacturing. The number of leukemia cases in emerging industries such as computer/electronic product manufacturing was found to be increasing. What are the implications for public health practice?: Strengthening supervision and regulation of manufacturing, especially of small/medium-sized enterprises and emerging manufacturing industry, may be effective in reducing BIL.

Industry Distribution Characteristics of Benzene-Exposed Workers with Cytopenia - Four Provinces, China, 2020.

What is already known about this topic?: Benzene is harmful to the hematopoietic system and can cause leukemia. However, benzene is still being used in various industries including furniture, rubber, plastic products, and metal product manufacturing. What is added by this report?: The white blood cell count of workers in general equipment, special equipment, chemical raw materials, and chemical products manufacturing decreased significantly. The enterprises in which benzene concentration exceeded the occupational exposure limit were small enterprises and private enterprises. What are the implications for public health practice?: Regular health examinations are necessary for benzene-exposed workers. In addition, the monitoring of benzene concentration in small enterprises and private enterprises should be strengthened.

The Distribution and Concentration Monitoring of Benzene Industries - Six PLADs, China, 2020.

WHAT IS ALREADY KNOWN ABOUT THIS TOPIC?: Benzene is classified as a Class I human carcinogen by the International Agency for Research on Cancer. Long-term exposure to benzene increases the risk of chronic benzene poisoning and leukemia. However, benzene is still widely used in the manufacturing industry. WHAT IS ADDED BY THIS REPORT?: The scale of enterprises most exposed to benzene was small enterprises, and joint-equity enterprises had the highest number that exceeded the permissible concentration-time weighted average. WHAT ARE THE IMPLICATIONS FOR PUBLIC HEALTH PRACTICE?: It is still necessary to strengthen the monitoring of benzene concentrations in the manufacturing industry, especially in small enterprises. The occupational exposure limit of benzene should be appropriately reduced.

Characteristics in the Distribution of Chronic Benzene Poisoning Associated Industries - 6 PLADs, China, 2005-2019.

What is already known on this topic? Starting in the early 1950s, the main industries in China associated with chronic benzene poisoning (CBP) included painting, pharmaceuticals, and shoemaking. However, because of rapid socioeconomic development, the distribution of industries associated with CBP likely changed. What is added by this report? From 2005 to 2019, CBP has become an increasingly important type of chronic occupational poisoning (COP) in China. CBP was mainly found to have occurred in manufacturing industries, especially private enterprises and small and medium-sized enterprises. The sub-industry with the highest proportion of CBP cases was general and special equipment manufacturing, followed by chemical raw materials and chemical manufacturing. What are the implications for public health practice? CBP was found to be the main component of COP in China, so the supervision and management in manufacturing, especially in the medium-sized and small enterprises, need to be strengthened. Occupational benzene exposure limits should also be adjusted accordingly.