Ovarian Malignancies Frequency in the Female Population from the Bryansk Region Living in Conditions of Radioactive, Chemical and Combine Contamination (2000–2020)

Abstract Background: Radioactive contamination and chemical pollution of the environment can affect the processes of carcinogenesis, including the formation of malignant neoplasms of the ovaries in women. We used the data of official state statistics for 2000–2020 to test the hypothesis about the effect of radioactive contamination (following the Chernobyl disaster) and chemical pollutants on the incidence of ovarian malignancies in the female population of the Bryansk region. Methods: A variety of statistical approaches were used to estimate the incidence of ovarian malignancies, including the Shapiro–Wilk test, Mann–Whitney U test, Spearman’s rank correlation test and linear regression. Results: We did not establish statistically significant differences in the frequency of primary morbidity of women with malignant neoplasms of the ovaries, regardless of the environmental conditions of living. Furthermore, no significant correlations were found between the frequency of primary morbidity of ovarian malignancies, both with the level of contamination by Cesium-137 and Strontium-90, and air pollution with volatile organic compounds, carbon monoxide, sulfur dioxide and nitrogen oxides. A statistically significant increase in the long-term trend in the frequency of ovarian malignant neoplasms was revealed in the areas of chemical pollution (p = 0.02), however, in other territories, no statistically significant regularities were established. The forecast of the frequency of newly diagnosed malignant neoplasms of the ovaries on average in the Bryansk region shows an increase of 12.4% in 2020 in comparison with the real data for 2020, while the largest increase in predicted values is recorded in the territories of radioactive contamination (by 79.6%), and the least in the combined territories (by 6.9%). Conclusions: The results obtained indicate the need for further work to understand the trends in the presence/absence of independent and combined effects of pollutants and the growth of oncogynecological pathology from the perspective of assessing the distant and regional metastasis, histological and immunohistochemical profile of a specific malignant ovarian neoplasm with levels of environmental contamination.


Introduction
According to the latest estimates of the International Agency for Research on Cancer (IARC) at the World Health Organization (WHO) GLOBOCAN 2020 [1], the incidence of malignant neoplasms in the world has increased to 19.3 million new cases and 10.0 million deaths from them in 2020. Malignant neoplasms of the ovaries occupy the 7th place in terms of prevalence among malignant neoplasms in the world, at the same time as being one of the most fatal oncogynecological pathologies [2]. According to the Russian National In this regard, the study of the health status of the female population living in ecologically unfavorable conditions is highly relevant. Therefore, we carried out a comparative assessment of the frequency of malignant neoplasms of the ovaries in the female population of the Bryansk region living in conditions of radioactive, chemical and combined contamination during 2000-2020.
The density of radioactive contamination of the territories by 137 Cs and 90 Sr due to the Chernobyl accident was estimated according to the data [28], and chemical pollution was acquired from reports on emissions of chemicals into the atmosphere from stationary sources [35]. We identified main gaseous air pollutants: carbon monoxide, sulfur dioxide, nitrogen oxides and VOCs (including benz (a) pyrene, benzene, styrene, pyridine, vinyl chloride, formaldehyde, acrolein and phenol). Recalculation of the amount of gross emissions of chemicals into the atmosphere (tons/year) per city or district area (km 2 ) was carried out in (grams/m 2 ), according to [35].
According to the information guide [36], we used the average annual effective dose for the population from the Chernobyl component. In addition, the exposure dose rate of gamma radiation (level of natural background radiation) in all uncontaminated areas of the Bryansk region does not exceed 0.20 µSv/h, while in radiation-contaminated areas it often exceeds 0.30 µSv/h and in some settlements the exclusion and resettlement zone values reach 0.8-1.6 µSv/h [36].
The primary morbidity of the female population ovaries malignancies (age 18 and over) in the Bryansk region was analyzed according to the data of the Bryansk regional oncological dispensary [37].
In total, in the Bryansk region during 2000-2020 there were 2647 registered cases of malignant neoplasms of the ovaries in woman, including 439 cases in ecologically safe areas, 1750 cases of chemical pollution and 169 and 289 cases of radioactive and combined contamination, respectively. The recalculation of newly diagnosed malignant neoplasms of the ovaries (absolute values) was carried out per 100,000, taking into account the female population in cities and districts.
Statistical analysis of the data obtained was carried out using the tools of the Stata SE 14.2 package (Stata Corp., College Station, TX, USA). The sample mean (M) and the standard error of the mean (m) were used for estimation of main parameters. The normal distribution of the level of chemical and radioactive contamination was assessed using the Shapiro-Wilk test. We showed that the sample is far from normal distribution both for 137 Cs and 90 Sr, and separately for each pollutant and for the sum of pollutants. Therefore, to assess the relationship between the level of chemical and radioactive contamination with the frequency of ovarian malignant neoplasms, we used the Spearman rank correlation test. To test the statistical significance of differences (paired comparisons), we used the Mann-Whitney U test [38].
We calculated the linear regression of the frequency of malignant neoplasms of the ovaries in ecologically different areas in the Bryansk region for 2000-2019. When testing the hypothesis about the relationship between the frequency of malignant neoplasms of the ovaries and the year, the Spearman rank correlation test was used. Calculations of 95% confidence intervals were completed for the angular coefficient a, showing the direction of the trend.
Based on the available data, we calculated the prognosis of the frequency of ovarian malignant neoplasms. To do this, we found a linear function y = ax + b by the least squares method, which most accurately approximates the available statistical data for each of the indicated categories. We used data for 2000-2019. Using this linear function, we calculated the forecast for 2020 and compared the predicted values with the real ones. The presented forecast will allow us to assess how the real values of the frequency of malignant neoplasms of the ovaries differ from those predicted in the context of the COVID-19 pandemic.

Results
As a result of the ecological and hygienic analysis of the condition of the environment in cities and districts of the Bryansk region over a twenty-year study period (2000-2019), we ranked the territories (Table 1) depending on the level of chemical pollution of the atmospheric air by the amount of gross emissions of gaseous pollutants (VOCs, SO 2 , CO and NO x ) on the area of the district, the density of radioactive contamination by 137 Cs and 90 Sr due to the Chernobyl accident and the primary morbidity of ovarian malignancies in women. We also presented the average sample sizes for the female population over 18 years old in cities and districts of the Bryansk region (Table 1).  We identified four groups of territories of the Bryansk region according to the degree of unfavorable ecology of the environment (Table 1): (1) ecologically safe areas; (2) areas of chemical pollution; (3) areas of radioactive contamination; (4) areas of combined radiation and chemical contamination.
As Table 1 indicates, the data on the density of radioactive contamination by 137 Cs and 90 Sr and the level of chemical pollution by leading gaseous pollutants vary within wide limits. For 137 Cs-from 4.4 to 460.6 kBq/m 2 , for 90 Sr-from 0.4 to 16.3 kBq/m 2 . In terms of gross emissions of gaseous pollutants into the air per area (g/m 2 )-from 12 to 32,191, of which: carbon monoxide-from 7 to 5217, nitrogen oxides-from 6 to 10,886, sulfur dioxide-from 0 to 2617 and VOCs-from 0 to 13,470.
Thus, in the group of ecologically safe areas, the density of radioactive contamination is much lower than the established standards for both 137 Cs (up to 37 kBq/m 2 ) and 90 Sr (up to 5.6 kBq/m 2 ). The total level of chemical pollution of atmospheric air by gaseous pollutants is from 12 to 128 g/m 2 , which makes it possible to classify these territories as control (ecologically safe) areas. The frequency of primary morbidity with malignant neoplasms of the ovaries in ecologically safe areas ranges from 15.1 to 26.3; the average over a twenty-year period was 20.6, which is 8.8% less than the all-Russian public values (Table 1).
In the areas of chemical pollution, the gross emissions of gaseous pollutants per area of the district significantly exceed the analogous indicators of ecologically safe territories (sometimes by a factor of thousands), fluctuating within wide limits-from 123 to 32,191 g/m 2 . At the same time, the density of 137 Cs radioactive contamination varies from 4.4 to 38.4 kBq/m 2 , and 90 Sr from 0.4 to 5.9 kBq/m 2 . The data obtained allowed us to classify this group of areas as areas of chemical pollution. The incidence rate of malignant neoplasms of the ovaries varies in this group of districts from 12.7 to 29.3, the average value is 22.7, which exceeds the values in ecologically safe regions by 10.2% and practically coincides with the all-Russian values (22.6).
In the group of areas of radioactive contamination, the 137 Cs contamination density exceeds the established standards by 3.8-12.4 times, and ranges from 139.6 to 460.6 kBq/m 2 . The density of 90 Sr contamination reaches its maximum values in the Zlynkovsky district (16.3 kBq/m 2 ), which exceeds the established standards by 2.9 times, but in two districts (Gordeevsky and Klintsovsky) it does not exceed the established standards, amounting to 5.0 and 4.7 kBq/m 2 . At the same time, the level of atmospheric air pollution by technogenic pollutants is quite low and is comparable to the indicators of ecologically safe areas, ranging from 16.0 to 169 g/m 2 . Such indicators make it possible to classify this group of regions as territories of radioactive contamination. It should be noted that in the areas of radioactive contamination, the incidence of malignant neoplasms of the ovaries ranges from 11.0 to 21.2, the average value is 18.3, which is less than the indicators of the control territories by 11.2% and the all-Russian values by 19.0%.
In the areas of combined contamination, the density of radioactive contamination by 137 Cs, as well as in the radiation-contaminated territories, exceeds the established standards (by 1.23-12.3 times), amounting to 45.4-456.5 kBq/m 2 . The highest density of 137 Cs contamination is recorded in the city of Novozybkov (456.5 kBq/m 2 ), and the density of 90 Sr contamination is exceeded only in the city of Novozybkov (9.7 kBq/m 2 ). At the same time, in addition to the increased and high level of radioactive contamination, the level of chemical pollution by gaseous pollutants is 2.6-491 times higher than the values of radiation-contaminated areas, amounting to 392-7422 g/m 2 , which allows them to be classified as combined (Table 1). In conditions of combined contamination, the incidence of malignant neoplasms of the ovaries varies from 17.4 to 24.0; the average value was 20.1, which is 2.4% less than the indicators of the control areas and 11.1% less than the all-Russian values.
The results obtained indicate that there are no statistically significant differences in the incidence of malignant neoplasms of the ovaries in cities and districts of the Bryansk region, regardless of the environmental conditions of residence (p-values according to the Mann-Whitney U test vary from 0.11 to 0.94), see Table 1.
It should be noted that 35 years after the Chernobyl accident, the average annual effective dose from the Chernobyl component in settlements in the group of ecologically safe areas and areas of chemical pollution does not exceed 0.3 mSv per year, while in the group of radioactive and combined contamination the maximum values reach 5.5 mSv per year [35].
The dynamics of newly diagnosed ovarian malignancies (absolute values) in ecologically different territories of the Bryansk region in 2000-2020 are presented in Table 2. The data in Table 2 indicate that the number of malignant neoplasms of the ovaries in areas of chemical pollution ranges from 34 to 111 cases per year, in areas of radioactive contamination from 2 to 17, in areas of combined contamination from 8 to 20 and in ecologically safe areas from 12 to 32.
The dynamics of the frequency of primary morbidity with ovarian malignancies in ecologically different territories of the Bryansk region in 2000-2020 are presented in Table 3. The data in Table 3     Our forecast of the frequency (based on 2000-2019 data) of newly diagnosed malignant ovarian neoplasms on average in all cities and districts of the Bryansk region shows an increase of 12.4% in 2020 in comparison with real data for 2020. The reason for this, in all probability, is a reorientation of the healthcare system in connection with the COVID-19 pandemic- Figure 1.
Furthermore, the increase in predicted values in comparison with real data is uneven. Thus, the greatest increase in newly diagnosed malignant neoplasms of the ovaries was recorded in areas of radioactive contamination by 79.6% (28.2 forecast for 2020, 15.7 real values for 2020), and a less pronounced increase was found in ecologically safe areas by 18 Correlation analysis of the primary incidence of ovarian malignant neoplasms in cities and districts of the Bryansk region with the level of radiation contamination and chemical pollution of the environment (Table 4) did not reveal significant links between the incidence of primary ovarian malignant neoplasms as with the level of 137 Cs contamination (ρ = −0.19, p = 0.31) and 90 Sr (ρ = 0.02, p = 0.92), as well as air pollution by VOCs (ρ = 0.19, p = 0.32), CO (ρ = 0.09, p = 0.61), NO x (ρ = 0.22, p = 0.23) and SO 2 (ρ = 0.27, p = 0.14).    Our forecast of the frequency (based on 2000-2019 data) of newly diagnosed malignant ovarian neoplasms on average in all cities and districts of the Bryansk region shows an increase of 12.4% in 2020 in comparison with real data for 2020. The reason for this, in all probability, is a reorientation of the healthcare system in connection with the COVID-19 pandemic- Figure 1.
Furthermore, the increase in predicted values in comparison with real data is uneven. Thus, the greatest increase in newly diagnosed malignant neoplasms of the ovaries was recorded in areas of radioactive contamination by 79.6% (28.2 forecast for 2020, 15.7 real

Discussion
As a result of our study, we did not reveal an increased frequency of ovarian malignancies in ecologically unfavorable areas in comparison with ecologically safe ones, as well as a relationship between the level of chemical and radioactive contamination with the primary incidence of ovarian malignant neoplasms. This indicates that the effect of endogenous factors on female reproductive processes is of a greater extent than exogenous.
It should be noted that among the circumstances of the risk of malignant neoplasms, there are many exogenous and endogenous factors, which are practically impossible to take into account. According to the literature [39][40][41][42][43][44], IARC and WHO [45,46], among the main risk factors for malignant neoplasms (including malignant neoplasms of the female reproductive system) are the use of tobacco, alcohol, unhealthy diet, physical inactivity, overweight, drug therapy for infertility, hereditary predisposition, chemical (polycyclic aromatic hydrocarbons, dioxins, pesticides, aflatoxins, arsenic, formaldehyde, nickel, asbestos, cadmium and many others), physical (ionizing and ultraviolet radiation) and biological (infections caused by viruses, bacteria or parasites) environmental carcinogens. Some have suggested that the upward trend in the incidence of malignant neoplasms in the world may reflect some general trends in the increase in the genetic load in human populations, due to the growth of chemical pollution and radiation contamination of the biosphere by "eternal" (half-lives of which are more than a hundred years) and "global" (rapidly spreading from the place of pollution throughout the biosphere) pollutants [34].
When conducting further research, it is necessary to utilize: 1.
More exact measurements of radioactive contamination and chemical pollution of the environment; 2.
More exact estimates of accumulated radiation doses in the population (primarily 137 Cs and 90 Sr); 3.
More exact analysis of the distribution of sources of air pollution and the deposition of emissions from chemicals, taking into account meteorological factors; 4.
A more complete analysis of the dynamics of malignant neoplasms of the ovaries in women of different age groups; 5.
An assessment of the economic and social situation in the cities and districts of the Bryansk region (average wages, retail trade turnover, consumer price index, production index, mortality and natural increase, birthrate).

1.
We did not find statistically significant differences in the frequency of primary morbidity with malignant neoplasms of the ovaries in women, regardless of the environmental conditions of residence.

2.
We did not find significant correlations between the frequency of primary morbidity of malignant neoplasms of the ovaries, both with the level of contamination by 137 Cs and 90 Sr, and air pollution with volatile organic compounds, carbon monoxide, sulfur dioxide and nitrogen oxides.

3.
We found a significant increase in the long-term trend in the frequency of malignant neoplasms of the ovaries in areas of chemical pollution (p = 0.02), however, in other areas, no statistically significant regularities were established. 4.
Our forecast for the frequency of newly diagnosed malignant neoplasms of the ovaries on average in the Bryansk region showed an increase of 12.4% in 2020 in comparison with real data for 2020, while the largest increase in predicted values was recorded in the territories of radioactive contamination (by 79.6%), and the least in the combined territories (by 6.9%).

5.
The results obtained indicate the need for further work to understand the trends in the presence/absence of independent and combined effects of pollutants on the growth of oncogynecological pathology from the perspective of assessing distant and regional metastasis, histological and immunohistochemical profile of a specific malignant ovarian neoplasm with levels of environmental contamination.