Cancer in Women and Its Relation to Work Systematic Review

Nowadays, cancer is one of the main worldwide causes of death and an in-creasing issue in public health. In the European Union, it is the first work-related cause of death. Studies about occupational risk exposure are a useful field of investigation to determine cancerous elements; special attention is paid to the relationship between cancer and work in women, who must con-stantly adapt to the working market and the new working fields, with their diverse degrees of exposure to risks. This revision has reviewed the bibliog-raphy gathered in Medline related to breast cancer, cervix cancer, uterus cancer, and ovarian cancer, along with their relationship with different work-related risks and types of working roles. The results have shown enough scientific evidence to suspect that work related exposition could be a plausible cause of these gynaecological cancers. Therefore, we want to stress the need of enhancing the coordinated investigation between all the medical specialties involved, and to encourage the spread of the necessary knowledge to manage and prevent them. risk Lower risk: women workers in the food industry, wood/paper, footwear/ leather, or meat industries, and in transport or service activities, such as food wholesaling.


Introduction
Nowadays, cancer is one of the main worldwide causes of death and an increas-Occupational Diseases and Environmental Medicine  It is complex to establish relationships between occupational exposures in specific job sectors and cancer in women. Exposure to chemical and physical agents at work appears to be related to gynecological cancer: pesticides, xenobiotics, hydrocarbons, solvents, radiation or alterations of the circadian rhythm form the most studied group of exposures.

Cancer in Women: Risk Factors
Outside Work (n = 6) Epidemiological studies Relate occupational and non-occupational risk factors and cancer in women: ovary, uterus, cervix and breast cancer.
In cancer, genetic factors are relevant, but occupational exposure must be part of the investigation to establish the cause-effect relationship.
In epidemiological studies focused on specific professional groups, a higher incidence or risk of death was observed than the incidence should be related to occupational exposure. However, due to the inconsistency of the results and methodological deficiencies, even today it has not been possible to reach definitive conclusions Women Work-related cancer in Spain (n = 23) Legislative regulation in Spain. Epidemiological studies of prevalence and mortality, notification and registration.
Assess the situation of women's cancer in Spain, its legislative regulation and studies carried out.
Occupational cancer is the lowest reported Occupational Disease in Spain and in neighboring countries, and requires a multidisciplinary and collaborative approach to be able to approximate real figures.
To study occupational cancer in women, a gender perspective is required to prevent it. And facilitate the safe return to work after the illness is over. Occupational Diseases and Environmental Medicine considered as cancerous [5].
Carrying studies on occupational risk exposure allow researchers to keep moving forwards with the identification of cancerous agents; paying special at- Although progress has been made regarding the identification of personal risk factors and the improvement of treatments for breast cancer, incidence rates keep growing. In 1996, it was suggested that, since women were already a considerable fraction of the working masses, it was worth wondering about the existence of work-related risk factors with an impact on breast cancer. The revision showed a low number of high quality occupational studies focused specifically on women and that enabled the unequivocal identification of work-related factors for this kind of neoplasms. This stressed the need of carrying out investigations that took into account risk factors unrelated to work and the exposition of chemical and physical agents that could be posteriorly related to the appearance of breast cancer, hence complementing cohort studies and investigations of specific demographic groups [12].
A series of diverse work-related risk factors have been identified as possible causes of different types of women's cancer. One of the most studied ones has been the exposition of pesticides in industrialised countries, both due to their cancerous effect and the consequences they have on reproduction. In underdeveloped countries, women are increasingly exposed to pesticides, and their M. T. Vicente-Herrero et al. Occupational Diseases and Environmental Medicine toxicity seems to be underestimated. Many of these pesticides' effects will be the same for both men and women, but it is not always the case.
Some organochloride pesticides have been linked with breast cancer in postmenopausal women, but the knowledge about other pesticides is quite limited.
Gender sensitive research is necessary to study the gender-environment interactions that could be related to exposure to these substances and the effects they cause on women [13].
Uterine cancer shows a clear genetic predisposition [14]; however, in 1999 the influence of work-related risk exposure on its development was already evaluated, particularly the influence of pesticides. Studies in Costa Rica showed a higher prevalence of breast cancer, uterine cancer and ovarian cancer in urban areas, whilst cervix cancer was more frequent in rural areas. Thus, hypothesis were established, linking the exposure to pesticides with specific types of cancer that act differently on men and women, and that require individualised studies [15].
The exposition to tobacco smoke on men and women has been evaluated, especially in cases of non-smoker women exposed to the smoke in a passive way, and its effect on breast cancer. A study on Chinese women found positive associations and a dose-answer relationship between post-menopausal women who are passively exposed to tobacco smoke and all subtypes of oestrogen and progesterone receptors of breast cancer. This established a significant relationship between them [16]. Tobacco smoke has also been identified as a risk factor for mucinous ovaric tumours [17] [18] but without a clear effect on its mortality rate [19]; it has also been associated with a higher risk of developing cervical adenocarcinoma [20], although it must be taken into account that the consume of tobacco is linked to other factors (immunologic, psychosocial, nutritional) that difficult the evaluation of their role in the genesis of this cancer [21].
The relationship seems clearer between breast cancer and the exposition to both oestrogenic effect hormones and oestrogen-progesterone combinations, with an increment of the risk of developing it [22]. Organochloride solvents and other substances with oestrogenic properties are considered risk factors for uterine cancer since they act as endocrine disruptors that affect the endometrium. But, despite having shown an association with endometriosis, it has not been possible to demonstrate a clear connection with cancer found in this part of the body [23] [24]. Endocrine aspects, obesity and the lack of physical activity seem to increment the risk of uterine cancer. Endocrine factors admit an increment of the risk due to treatments that use certain contraceptive medication and therapies for menopause that contain oestrogens, in isolation or associated with progesterone [25]. Others studies have estimated the association of breast cancer with the exposition to polycyclic aromatic hydrocarbons, with results that suggest that a prolonged exposition increments the risk in women with antecedents of breast neoplasm in their family history [33]. The same happens in occupational exposure with certain chemical substances that can cause an endocrinal disruption: ethylene oxide, polycyclic aromatic hydrocarbons (PAHs), diverse biocides and solvents [34]. The risk is high in working sectors such as laboratory technicians and assistants, agriculture, plastic manufacturing, tinned food processing, metallurgy, motor industry, painting, foresters and wood workers, health workers, social workers and furniture makers [35] [36] [37].
Regarding ionizing radiation, whilst the exposition to high amounts is associated with a greater risk of developing breast cancer, its association with prolonged exposition to lower rates hasn't been established. A study by the US Radiologic Technologist offers the opportunity of examining the association between low-medium doses of ionizing radiation and the incidence and mortality rates of breast cancer. Work-related radiation was associated with an increase in the risk of developing it, showing that it was higher for women born before 1930; they started working before 1950, when the annual average dose (37 mGy) was considerably higher than in later years (1.3 mGy). However, due to uncertainties and errors in the dose estimations prior to 1960, these findings must be cautiously considered [38]. Further studies suggest that ionizing radiations in the health sector are associated with the risk of developing breast cancer [39] [40].
A significant number of the studies that evaluate cervix cancer influent factors stress the limitations of their obtained results. This is due to the confusing effect that the human papillomavirus (HPV) has on it, which, being key for cancer's development, is not normally taken into consideration for the epidemiological studies that explore its association with the work-related factors [41]. The presence of the sexually transmitted HPV is considered a requirement for the disease to develop, as well as its highest risk factor [42]. In terms of work-related exposure, a higher risk of cervix cancer in female workers has been linked to a high prevalence of the infection [43].
In the last few years, the exposure risk to cosmic radiation and circadian rhythm alterations has been highlighted in some working contexts, such as flight assistants, observing a higher risk towards certain cancers. A US-centred study evaluated the incidence of thyroid cancer, ovary cancer, and uterine cancer in  [44]. Nevertheless, what seems to have been possible with this flight assistant collective is to establish a higher risk of breast cancer; this was showed in a revision carried out between 1995 and 2013, with incidence data, unlike mortality rates, being significantly higher. The explanation seems to lay in the alterations of the circadian rhythm produced by night shifts and the changes of time zones, which, as well as the exposure to cosmic radiation, drives the organism to develop melatonin secretion disorders. In both cases, an increased risk of developing breast cancer is de-

Cancer in Women: Risk Factors outside Work
There are other risk factors, such as metabolic risks, are not directly linked with the working environment, but that workspaces can help prevent through health campaigns, especially obesity. The latest is linked to an increment in the preva- cer risk predictor, independently of obesity amongst women [49].
In addition to considering work-related risk factors for the prevention of cancer in women, it is also necessary to take into account that gynaecological cancers, especially breast cancer, are amongst the most frequent ones when it comes to working women. It is highly important to act in a preventive way, facilitating their return to work and investigating the characteristics that have an influence on their reincorporation after treatment. Some authors point out that, in some countries like Japan, when the work doesn't have a regular time schedule, it is more probable that it will affect negatively the return and the adaptation to changes after undergoing treatment for gynaecological cancer [50]. It is a grow-

Women Work-Related Cancer in Spain
In Spain, work-related cancer has generated very few cases of temporary incapacitation (TI)-although these have been of long duration, scarce proposals of permanent incapacitation (PI) and their notification as occupational illness (OI) in the CEPROSS database continues to be low ( Table 2). Notification of cancer as OC has only slightly changed in the past decade ( Figure 2) regarding both cancer types included under the official policies (Real Decreto 1299/2006, de Enfermedades profesionales) [56] (Table 3) and those which aren't. When there is a possible cause-effect association between a work-related exposure risk and the development of a neoplasm, but it cannot be classified as an OP-it will be notified as a work-related accident in the PANOTRASS database. The lack of notification of these cases affects both men and women, but it is especially alarming regarding women specific cancers, uterine, cervix, breast and ovarian  cancers, since none of them, is included in the above-mentioned official regulation document.
Another document to be noted due to its interesting approach is the National Occupational Security and Health Institute (INSST) document about cancerrelated mortality [57] and, more specifically, about gynaecological cancers, occupational risks, and work-related risk exposures (Table 4).
Regarding breast cancer, it is the most frequent type in Spain amongst female workers, as well as their top cause of death. Studies carried out in the working space specify risk factors, the determination of contingency, the criteria for their return-to-work evaluation, the criteria for incapacitation and disability assessments, and the costs of work absence periods [58] [59] [60] [61] [62]. Nevertheless, the absence of positive associations between breast cancer mortality rates and the specific professions clashes against the scientific evidence, since positive associations have already been found between the work-related exposure to different substances and breast cancer in women.
For uterine cancer, the highest mortality rate is found amongst workers in some construction-related activities, and it coincides with previous research results [63], although it is the hospitality waitresses collective the one that shows the highest risk [64] [65]. About cervix cancer, there are differences in the level of risk between countries and even inside each health attention area, both in terms of prevalence and survival. The key seems to be related to socioeconomic inequalities, which opens new opportunities to studies and research that gather information about these cultural, economic, and social aspects [66] [67].
There are very few published studied that connect uterine cancer with the working scene. A higher risk has been found on teachers, retail workers, and se-  [70]. According to the IARC, the evidence that shows an association between that profession and ovarian cancer is limited and it is related to the exposure to  Higher risk: activities of production and distribution of energy and water, maritime and air transport, and the sale of motor vehicles; also with a significantly high risk, but less magnitude in financial intermediation, associative and recreational activities, education, the provision of services to the community and public administration.
Lower risk: operators and assemblers in the manufacturing industry, livestock, domestic employees, housekeeping staff, cooks and other restaurant workers.
Lower risk: livestock and hunting, households with employees, housekeeping staff, agriculture and forestry, hotels and similar, and restaurants.
Cervical cancer Higher risk: service sector female workers, in particular in public sanitation activities, beverage establishments, households with employees and housekeeping staff, and in general construction of buildings Women bricklayers and assimilated women, cooks, waitresses, other restoration workers, domestic workers and housekeeping staff.
Higher risk: hotels and restaurants, with beverage establishments being those with the highest risk. housekeeping staff and households with employees.
Lower risk: secondary and higher education and health activities. Professors, teachers and assimilated, medical and assimilated, other senior professionals and administrative techniques.
Lower risk: teaching, health and services sector.
Higher risk: metallurgy, sale of motor vehicles/components, food retail, agriculture and forestry; a higher risk was also identified in fishing activities and public sanitation.
Lower risk: cooks and teachers and assimilated. Lower risk: primary school workers.
Ovarian cancer Higher risk: industrial occupations (glass/ceramics/processing of non-metallic minerals, other mechanics and plastic workers) and services (police and street vendors) which, together with some industrial activities (chemical, tool making and metal products, furniture manufacturing, business services, motor vehicle maintenance).
By economic activity, no heading was found with a statistically significant risk above the average.
Lower risk: women workers in the food industry, wood/paper, footwear/ leather, or meat industries, and in transport or service activities, such as food wholesaling.
Reference: Spanish National Institute of Safety and Health at Work; 2019. different kinds of dies (amines, aromatics, aminophenol), solvents, propellant substances, and aerosols. Ovarian cancer seems to be connected with dry cleaning activities, printing, and graphic arts, agriculture or the pharmaceutical industry, as well as with other specific occupations such as nursing or teaching. It has also been found a possible relationship with the exposure to combustion-derived fumes, solvents, and silica powders [71]- [78]. The IARC highlights asbestos in its multiple forms as the only work-related exposure agent to which there is enough evidence for establishing an association [79]. From this revision it can be highlighted that the data is not conclusive enough to draw a clear association between these types of cancer that affect women and their relationship with the working field, although the evidence is continuously becoming clearer and lead the way to the future investigation; this is particularly important in our days, at a moment when cancer is still a disease that affects all Occupational Diseases and Environmental Medicine countries and which incidence and prevalence keeps growing, with sanitary, economic and social implications.
Occupational cancer is the least notified OP in Spain and its surrounding countries, and it requires multidisciplinary and collaborative measures in order to be tackled and approximate real data about it.
For studying work-related cancer in women it is crucial to have a gender view that allows the encouragement of preventive activities, anticipating the action to the possible damage, and to facilitate a return to work process without as many risks as possible after surviving the disease.
Good health at work has a very important role in this, and occupational health as a preventive health specialty enables professionals to collaborate from all related competencies: health promotion, risk prevention, specific health screening, formation, training, specialised information, and investigation focused on the working field and, in this case, women.
The present research has not received any funding from agencies related to neither the public, commercial nor non-profit sectors.