Patterns and Temporal Trends of 7 Major Organic Solvent Induced Occupational Diseases in Guangdong, China 2006-2015 CURRENT

(1)Background: This study aimed to describe the distribution and of (2) Methods: A total of 1320 OSODs cases diagnosed from 2006 to 2015 were involved in this study, including information of case distribution, working age, industrial type, economic type and enterprise scale. 7 major OSODs accounted for the majority cases (1290 cases, 98%), including benzolism, n-hexane poisoning, 1,2-dichloroethane poisoning, trichloromethane poisoning, dimethyl formamide poisoning, benzene-induced leukemia and trichloroethylene-induced medicamentosa-like dermatitis. (3) Results: The incidence of OSODs was relatively higher in Shenzhen, Dongguan and Guangzhou than other districts. Most cases were related to light industry and electronics for industry type and small and medium-sized and private enterprises for enterprise scales and ownership types. Notably, the case number of benzolism and benzene-induced leukemia presented an increasing trend with year. The onset age of benzolism exhibited an increasing trend with year. The working age of onset of 1,2-dichloroethane poisoning, trichloromethane poisoning and dimethyl formamide poisoning were shorter than others. (4) Conclusions: Since the control and prevention of 7 major OSODs has achieved remarkable results, more measurements are needed to control benzolism and benzene-induced leukemia cases in Guangdong Province.


Introduction
Organic solvents are a group of diverse chemical compounds widely used in industry due to properties convenient for extracting, dissolving, or diluting materials. Their inclusion in numerous products such as paints, degreasers, glues, inks, pharmaceuticals, pesticides, and cosmetic and cleaning products results in exposures in diverse occupational settings [1]. Occupational exposure to organic solvents and the resulting health damages that is Organic solvent induced occupational disease (OSOD) have raised concern [2]. In China, There were 58 severe acute occupational poisoning accidents related to organic solvents from 1989 to 2003 with 393workers poisoned and 48 workers died [3]. Guangdong Province of China, covering an area of 179,700 m 2 , has a total population of 108 million and a working-age population of over 80 million. It is a world-renowned manufacturing center for producing bags, suitcases, footwear, electronic components and chemical industry, so that a large number of people could have occupational exposure to organic solvents. .Since the 1990s, about 40% of the workers could have occupational exposure to organic solvents [4]. OSODs had accounted for more than 70% of occupational poisoning cases in Guangdong Province [5,6].
Notably, accumulating evidence has drawn attention to OSOD as stated above. However, to the best of our knowledge, there was no previous study arising from large samples over a long period of time on patterns and temporal trends of OSOD in Guangdong. Therefore, we initially performed this study using National Occupational Disease and Occupational Health Information Monitoring System (NODOHIMS) [7]. to explore the patterns and temporal trends of major OSODs in Guangdong during 2006-2015. Our study not only provided valuable information for the control and prevention of OSODs in Guangdong Province, but also provided reference for the prevention and control of occupational Organic solvents hazards in developing countries in the stage of rapid industrialization. employees are more than 1000 and operating income is greater than 400 million RMB; 2) mediumsized enterprises: numbers of employees are more than 300 but less than 1000, and operating income is greater than 20 but less than 400 million RMB; 3) small enterprises: numbers of employees are more than 20 but less than 300, and operating income is greater than 3 but less than 20 million RMB; 4) micro-enterprises: numbers of employees people are less than 20, or operating income is less than 3 million RMB. According to Provisions on the Classification of Business Registration Types, economic type of enterprises were divided into "Foreign Funded Economy", " Private Economy", "Collective Economy", "State-owned Economy", "Hong Kong/Macao/Taiwan Economy" respectively.

Diagnostic of OSODs
OSODs are collectively diagnosed by more than 3 professional physicians according to the occupational disease diagnostic criteria in China.

2.2.1.Benzolism
According to the Chinese Diagnostic Criteria [8],the occurrence of benzolism was identified based on having a long-term occupational exposure histroy to benzene, with clinical manifestations of hematopoietic system damage; a) the white blood cell count lower than 4 ×10 9 /L or the number of neutrophils less than 2 ×10 9 /L; b) platelet count less than 80 × 10 9 /L.

Benzene-induced leukemia
According to the Chinese Diagnostic Criteria [9],the occurrence of Benzene-induced leukemia was identified based on suffering from chronic occupational benzene poisoning or having the medical history of occupational chronic benzene toxonosis getting the leukemia. Any patient without the medical history of occupational chronic benzolism should be so diagnosed based on satisfaction of all the three following conditions: positive diagnosis of leukemia, positive occupational history containing exposure to benzene, and engagement of any job exposed to benzene for 6 months (included) or more accumulatively, experiencing a prepatent period of 2 years (included) or more.

N-hexane poisoning
According to the Chinese Diagnostic Criteria [10],the occurrence of N-hexane poisoning was identified based on an long-term occupational exposure history to normal hexane shows the clinical manifestations mainly by multiple peripheral nerve damage and one of following items: a) The distal parts of extremities feel symmetrically distributed pain, hypesthesia or disturbance of tuning fork vibration sensing accompanying with Achilles tendon hyporeflexia; b) the nerve-electromyography shows positive neurogenic damage.

Trichloroethylene-induced medicamentosa-like dermatitis
According to the Chinese Diagnostic Criteria [11],the occurrence of Trichloroethylene-induced medicamentosa-like dermatitis was identified based on an occupational exposure history to trichlorethylene; skin lesion is acute dermatitis, mostly commonly appears as exfoliative dermatitis, some appears as erythema multiforme, Stevens-Johnson syndrome or epidermolysis bullosa; frequently with fever, liver damage and superficial lymph node enlargement.

1,2-dichloroethane poisoning
According to the Chinese Diagnostic Criteria [12],the occurrence of 1,2-dichloroethane poisoning was identified based on an short-term occupational exposure history to dichloroethane of high concentration shows the clinical manifestations mainly by central nervous system damage and such central nervous system symptoms as dizziness, headache and debilitation, who may also feel nausea, emesis or irritation of eyes or the upper respiratory tract.

Trichloromethane poisoning
According to the Chinese Diagnostic Criteria [13], the occurrence of Trichloromethane poisoning was identified based on an occupational history positively related to the poisoning, including the specific type of the occupational toxicant, the exposure mode and the reason for intensive absorption in a short period shows corresponding clinical manifestations of acute liver damage, excluding similar diseases caused by other reasons.

Dimethyl Formamide Poisoning
According to the Chinese Diagnostic Criteria [14],the occurrence of Dimethyl Formamide Poisoning was identified based on A short-term exposure to dimethylamide resulted in dizziness, nausea, vomiting, loss of appetite, abdominal pain and acute toxic liver disease.

Statistical analyses
A descriptive analysis was performed to explore the characteristics of the OSODs reported in Guangdong during 2006-2015, including annual changes of reported occupational disease cases, distribution of disease categories, regional distribution, average working age of onset, and the overall annual changing trend of age of onset. Moreover, a linear trend test was conducted for number of cases, median working age of onset, and median for age of onset with curve fit method, taking the diagnosis year as the independent variable. A trend test was conducted by the chi-square test for distribution of major OSODs in industrial type, ownership type and enterprise scale. All the data cleaning and analysis were conducted using SPSS20.0 software (SPSS lnc., Chicago, IL, USA). There were slightly more males than females in gender(699 cases vs 591cases). but less males than females in n-hexane poisoning(159 cases vs 47cases). In the terms of the enterprise scale a larger proportion of OSODs cases were distributed in smallsized (220 cases, 37.2%) and medium-sized enterprises (172 cases, 29.1%). But Trichloromethane poisoning cases are mainly distributed in large-sized enterprises (30 cases, 57.7%).   (Table 4).

Discussion
The recognition that organic Solvent exhibits Occupational Diseases accelerator property has motivated growing interest in the research area of Occupational Health. This study aimed to explore the distribution characteristics and temporal trends of major OSODs in Guangdong during 2006-2015.
In our study, the case numbers of benzolism and leukemia induced by benzene exhibited an exponential growth during 2006-2015 in Guangdong. The reasons of the rapid growth are as follows: Firstly, Guangdong is the one of provinces with huge demands for benzene production and usage, and thus have many occupational exposure groups. Some studies have indicated that the production and usage of pure benzene in China were increasing year by year. The average annual production and consumption capacity of pure benzene in China was increasing at the rates of 9.82% and 7%, respectively [15]. Secondly, compared with the permissible concentration-time weighted average of 1 ppm in major developed countries and regions, occupational exposure limit to benzene(that is 1.7ppm) is still high in our country. A recent study has shown that the exposure concentration to  [16]. Another recent study has shown that exposure to benzene air 1 ppm or even lower may cause hematotoxicity to susceptible populations [17]. Thirdly, nowadays the occupation involved with the use of adhesives and diluent containing benzene impurities is numerous. According to a study of Zhu et al [18], there are 26 benzene-containing solvents in 898 organic solvents, accounting for 2.9% of them. Such exposure to benzene lead to larger difficulties for benzene prevention and control. Ultimately, numerous measures have objectively decreased the rate of missed diagnosis and report of occupational poisoning and leukemia induced by benzene, such as the implementation of the responsibility of enterprises, the promoted supervision by regulatory authorities, the enhancement of laborers' rightprotection awareness, the improvement of occupational physical examination standards, populations and exam rates, the elimination of barriers for accepting occupational disease diagnosis and the improvement of occupational disease report ability.
At same time, compared with occupational diseases induced by other organic solvents, the workers, enterprises, regulatory authorities and society have higher awareness and attention on benzolism and benzene-induced leukemia. More laborers may seek further examination and diagnosis in case of similar health damage and the technical service divisions have a higher ability and level to test the benzene and the occupational health examination. Our study showed that the reported benzolism age was increasing. Yet on the other hand, the prevention and control for benzolism in Guangdong has achieved some effects. In general, the protection for traditional occupational diseases in large enterprises should be better than that in small and medium enterprises. In our research, the reports of benzolism demonstrated an increasing trend with the rising proportion of large enterprises. This also indicated that the increase of reported cases of benzolism in Guangdong was not attributable to the poor prevention and control, but the rights and interests of laborers with benzolism were more extensively maintained.
Chronic N-hexane poisoning is caused by occupational poisoning and some of which are poisoned for long-time addicted to N-hexane. Our study suggested that the average working age for onset of Nhexane poisoning was 8 months and the longest was 56 months. These data are consistent with the conclusions of the preliminary research on chronic N-hexane poisoning made by our hospital, in which the working year range was 3~39 months and the average working year range was (10.6 ± 6.0) months [19]. These data are basically consistent with the conclusions of other domestic research [20].
It is reported in Chinese research that in the working place where the poisoning accidents occurred in the early 1990s, the N-hexane concentration in air was even up to 6000~9000 mg/m 3 . With the introduction of relevant national laws, standards and management systems, as well as the raising safety and health awareness of enterprises and laborers, the N-hexane concentration in air of the working place was gradually declining. However, among the enterprises having poisoning accidents, the over-limit rate of N-hexane concentration was still up to 96.7%.
Hexane poisoning was mainly centralized in small and private enterprises in Shenzhen and Dongguan of Guangdong with statistical significance. Combining with the Research and relevant preliminary researches [21], we speculated that the reasons for occurrence of occupational N-hexane poisoning accidents included: N-hexane poisoning mostly occurred in labor-intensive enterprises (e.g. shoemaking, leather, suitcase & bag enterprises), which had large mobility of worker that were still dominated by handwork and short of necessary occupational health monitoring, as well as had difficulties in conducting occupational health monitoring, so as to cause that the N-hexane damage to health could not be found and treated as earlier as possible. The companies were not well aware of the harm of N-hexane, and used a large amount of N-hexane without taking targeted prevention and control measures as well as sufficient occupational disease protective measures, and proper ventilation and detoxification facilities were not provided, especially in winter business peak season, when the companies would conduct overtime work with doors and windows closed for a long time.
The laborers also lacked protection awareness for occupational diseases, and the protective equipment are not effectively used. cases accounting for 71.3%. As for enterprise scale, poisoning incidents increased in small-sized enterprises, with 43 cases accounting for 45.7%. After the onset, the condition progressed rapidly; the complications were relatively numerous; the treatment was highly difficult and case-fatality rate was high [22]. Indicate that the pathogenesis should belong to allergic reaction, most probably type IV.
However, since the industrial TCE that patients expose is complicated in components and mixed with stabilizer, further study shall be made to determine whether there are other elements in allergen besides TCE. The pathogenesis of occupational trichloroethylene-induced medicamentosa-like dermatitis has not been clarified. Therefore, in order to strengthen the supervision management on relevant enterprises, enterprises shall be encouraged to adopt other new type of chemical reagents to replace trichloroethylene so as to prevent and control the occurrence of occupational trichloroethylene-induced medicamentosa-like dermatitis.

Conclusion
Of reported 1320 cases of OSODs during 2006-2015,1290 cases (98%) were from the 7 major OSODs, including benzolism (592 cases), n-hexane poisoning (206 cases), 1,2-dichloroethane poisoning (65 cases), trichloromethane poisoning (52 cases), dimethyl formamide poisoning (49 cases), benzeneinduced leukemia (232 cases) and trichloroethylene-induced medicamentosa-like dermatitis (94 cases). Three of them are acute poisoning caused by exposure to high concentrations of poisons, including 1,2-dichloroethane poisoning, trichloromethane poisoning and dimethyl formamide poisoning. 1290 cases mainly occurred in Shenzhen, Dongguan and Guangzhou and these cases were mainly observed in light industry and electronics, small and medium-sized enterprises as well as private economy. Except Trichloromethane poisoning, which is more likely to occur in large enterprises. Among them, a higher rate was seen in males than that females. Benzene-induced leukemia and benzolism exhibited an increasing trend, while there was an increasing trend in the onset age of benzolism. In summary, the prevention and control of OSOD in Guangdong has achieved remarkable efforts, while benzolism and benzene-induced leukemia continues to be an important problem. This study may provide reference for the prevention and control of occupational hazards in developing countries in the stage of rapid industrialization.

Ethics approval and consent to participate
This work was agreed by Medical Ethics Committee,Guangdong Province Hospital for Occupational Disease Prevention and Treatment.

Availability of data and materials
Not applicable.

Competing interests:
The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.   1 A, B, C, D, E represent "Foreign Funded Economy", " Private Economy", "Collective Economy", "Stateowned Economy", " Hong Kong/Macao/Taiwan Economy" respectively.