Cervical cancer related to occupational risk factors: review.

Background
Occupational risk factors are associated with many types of neoplasms including cervical cancer.


Objective
To review the specialized literature for evidence on the relationship between cervical cancer and exposure to occupational hazards.


Methods
Literature search in electronic databases using keywords cervical cancer and occupational risk.


Results
Workers occupationally exposed to tobacco, fungi or bacteria, metalworking fluids and tetrachloroethylene used in dry cleaning and for metal degreasing exhibited higher susceptibility to cervical cancer.


Conclusion
Few studies sought to investigate relationships between cervical cancer and occupational hazards, which hinders the attempts at establishing a causal link.


INTRODUCTION
About 20% of cancers are associated with occupational hazards, with 1.3 million deaths worldwide 1 . Reports in the literature allow inferring that exposure to chemicals, such as benzene, silica, pesticides and ionizing radiation, can lead to several types of cancer 2 . Occupational cancer surveillance guidelines describe a relationship between several neoplasmsincluding skin, lung, peritoneal, nasal cavity, pharyngeal and laryngeal cancer, leukemia, myeloma, gastric, esophageal, liver, bladder, pancreatic, brain and breast cancer-and work environments and occupational hazards 3 . However, cervical cancer is seldom mentioned in this regard.
Cervical cancer is the seventh leading neoplasm worldwide, and the second most frequent among women 4 . It exhibits strong association with the human papillomavirus (HPV) which while sexually transmitted 4,5 might also be related to occupational risk factors 5 .
Just as other neoplasms, also mortality by cervical cancer is higher in underdeveloped and developing countries, to a total of 275,000 deaths worldwide in 2008 5 . India, namely, the second most populous country, exhibits one of the highest rates, 27% 5 .
Although HPV is necessary to cause changes in the cell genome, it does not suffice to account for the full development of cervical cancer. Also other intrinsic viral aspects are relevant, such as infection by oncogenic (high-risk) strains, persistent and recurrent infection, and high viral load. Sexual behavior, early onset sexual activity, multiple sexual partners, smoking and immune factors influence the mechanisms that underlie carcinogenesis 5 .
According to data available at TABNET-DATASUS (Informatics Department, Unified Health System-SUS) mortality by cervical cancer was 5.5/100,000 women in Brazil in 2014. The highest rates corresponded among regions to the North (9.34) and among states to Amazonas (16.09) 6 .
Establishing a causal relationship between cancer and work is difficult for reasons such as heterogeneity in the criteria to grant social security benefits and underreporting 7,8 . To this we may add the large number of workers with informal jobs, poor or no information on the occupational history of workers, lack of nationwide surveys, and scarcity of studies on the etiology of some types of cancer in Brazil 2, 8,9 .
As a function of the abovementioned considerations, the aim of the present study was to perform an integrative review of the literature on the association between cervical cancer and occupational risk factors.

METHODS
We reviewed studies included in databases PubMed (United States National Library of Medicine), Scientific Electronic Library Online (SciELO) and Latin American and Caribbean Health Sciences Literature (LILACS) using search terms cervical cancer AND occupational risk. The time frame was set to 10 years (2009 to 2019). Original articles, PhD and master's dissertations, review articles and meta-analyses published in English, Portuguese or Spanish were considered eligible. We excluded abstracts and studies on cervical cancer that did not analyze its relationship with occupational risk factors.

RESULTS
We initially retrieved 168 studies, 71 of them published within the set time frame; only nine addressed the relationship between cervical cancer and exposure to occupational hazards. Three studies analyzed exposure to tetrachloroethylene, to wit, a metal degreasing solvent and dry cleaning agent 10-12 . One study investigated risk of cervical cancer among tobacco industry workers, and another exposure to metalworking fluids among autoworkers 13,14 . One study performed in Finland analyzed the association between cervical cancer and occupational exposure to fungi and bacteria 15 . The other three studies investigated exposure to asbestos, night work, changes in the circadian rhythm and cosmic radiation, but did not find any relationship with cervical cancer [16][17][18] .
A review and a cohort study reported association between exposure to tetrachloroethylene and cervical cancer [10][11] . While also occupational exposure to tobacco dust exhibited a relationship with the outcome, poor working conditions emerged as one of the factors with negative impact on the health and well-being of the analyzed population 12 . Also water-based metalworking fluids were found to possibly have some role in the etiology of cervical cancer, however, the authors observed that further studies with larger cohorts are needed to establish such relationship more clearly 13 . Occupational exposure to fungi and bacteria proved to be little significant for occurrence of cancer in general. Nevertheless, it is associated with higher risk of some type of neoplasms, including cervical cancer 14 (Table 1).

DISCUSSION
The literature reflects a concern among the global scientific community with the exposure of workers to carcinogenic chemicals 1 . According to the International Agency for Research on Cancer, 29 agents and 13 occupational exposures are potentially liable to trigger cancer in human beings. However, there is appropriate toxicology information for only 20% of them. Measuring these agents is difficult, while length of exposure is essential to establish their actual carcinogenic potential 1 .
Carcinogenesis is a highly complex process that involves genetic and environmental risk factors, including smoking, diet, exposure to radiation and occupational hazards. It might be triggered by physical, chemical and biological factors 3 .
Biological carcinogenesis involves integration of viral DNA into the DNA of a host cell; then the virus becomes able use cell resources to replicate. Such changes in the host cell DNA favor mutations during the transcription of the involved genes. This phenomenon is illustrated, for instance, by the case of the human papillomavirus (HPV) 3 . While the available evidence indicates that all cervical cancers are associated to HPV 10 , infection is not the single factor involved. Early onset sexual activity, multiple sexual partners and frequency of sexual activity are additional factors that contribute to increase the rate of cervical cancer 19 . This profile matches that of a particular population of workers, scarcely considered in the scientific literature and socially discriminated and marginalized, namely that of sex workers 20 . These individuals have resource to sex as a means to earn their living. As a function of the nature of their job, they are exposed to long working hours, sexual and physical violence and poor working conditions, in addition to difficult access to health care and lack of public occupational health policies which take them into account 20 . Chemical carcinogenesis follows direct or indirect exposure to toxic or nontoxic environmental chemicals. Diet, medications, lifestyle and occupational exposure may contribute to chemical carcinogenesis 3 .
While occupational hazards might cause or increase the risk of cancer among workers, the rates in Brazil-attributable risk of 2.3% for men and 0.3% for women-are lower by comparison to other countries 9 .
Cervical cancer is the least mentioned in the literature on the relationship between work and cancer 1-3 . Lung and mesothelial cancer are the most frequently associated with occupational hazards, with attributable risk of 5.44-15.63% and 100% respectively 21 . In addition to a strong association with tobacco, many other inhaled substances present in the workplace exhibit considerable carcinogenic potential 3 .
The rate of work-related cervical cancer was estimated as 0.68% (95% confidence interval-CI95% 0.03-2.13) in the United Kingdom. Workers at highest risk were electricians, pharmacists, tobacco industry workers, waitresses and cleaners 4 .
Smoking is frequently mentioned in the literature as a risk factor for cancer, particularly lung, respiratory tract and oral cavity neoplasms. Carcinogenesis was also reported among workers exposed to tobacco dust. According to some studies, smoking is associated with higher rate of cervical cancer even when HPV infection has been controlled. Tobacco contains chemicals such as nitrosamines, which hinder the treatment and healing of cervical lesions. Nitrosamines were detected in cervical tissue, where they might induce specific local effects leading e.g. to cervical cancer [12][13] . In addition, the poor working conditions to which tobacco industry workers are exposed and lack of use of personal protective equipment (PPE) contribute to make their situation worse 12 . Autoworkers are exposed to metalworking fluids which contain carcinogenic agents, some of them similar to those found in tobacco, as e.g. nitrosamines.
The results of the included study 13 point to a possible relationship between cervical cancer and exposure to metalworking fluids, although the mechanism of carcinogenesis is still unknown.
Tetrachloroethylene-also known as perchloroethylene and a metal degreasing solvent and dry cleaning agent-was described as a risk factor for cervical cancer. It is considered a carcinogen and might be found within several occupational settings, including industries, machinery manufacture, personal and home services, and metallurgy 4,10 . Exposure is rated low in industry and construction as a function of available PPE. In any case, construction jobs do not contribute much to the rate of cervical cancer given the small number of female employees 4 . A review study found that the rate of cervical cancer among 189,605 women exposed to tetrachloroethylene along 40 years was 0.68% (95%CI 0.03-2.13) with seven deaths (95%CI 0-22) in 2005 and 18 (95%CI 1-56) in 2014 attributable to this chemical 10 .
Several jobs involve handling fungi and bacteria, for instance, fermentation in the food industry-bread and cakes, dairy, wine and beer, among others 14 . The analyzed cohort study with exposed workers failed to demonstrate that fungi and bacteria are significant risk factors for most cancers. Nevertheless, they may increase the risk of lung cancer among males and of cervical cancer among females 15 .
Some hints suggest that circadian rhythms disorders might behave as risk factors for cancer 17,18 . Night shift workers and those subjected to jet lag are susceptible to changes in the melatonin homeostasis, with consequent impact on the hypothalamic-pituitary-gonadal axis 18 . Circadian misalignment-related estrogen and melatonin suppression may increase the risk of breast cancer 18 . However, a similar association was not found for cervical cancer.
Occupational exposure to asbestos is known to cause lung, laryngeal, gastric and ovarian cancer 1,21 . However, risk of cervical or breast cancer was not higher for female workers at Wittenoom mines by comparison to other women in Western Australia 16 .

CONCLUSION
Few studies reported association between occupational risk factors and some neoplasms 2 , cervical cancer in particular. Establishing a causal relationship between cancer and work is a complex process, especially when a large number of occupational hazards are involved.
Occupational exposure to tobacco dust, metalworking fluids in the automotive industry, fungi and bacteria, and tetrachloroethylene in dry cleaning and metallurgy might trigger cervical cancer. However, the mechanism underlying carcinogenesis is still poorly known, especially in the case of metalworking fluids and tetrachloroethylene.
More studies on the relationship between cervical cancer and occupation are needed to develop efficacious protective means for countless female workers.