The present study has evaluated the precise impact of long-term exposure to six criteria ambient air pollutants on MBD in Iranian women for the first time. Actually, many known and unknown factors are involved in breast tissue changes and eventually in breast cancer and it's not possible to control all confounding factors in a single context. By the way, based on the available evidence, we tried to evaluate the effects of six criteria ambient air pollutants on breast density considering the factors that seem to have an impact on MBD (basic and reproductive factors, aspirin, metformin, and supplement intake). To the best of our knowledge, there is no study with this broad level of assessment.
Our results represented that outdoor air NO2 and CO exposure had statistically significant impacts on MBD. We found that an increased level of NO2, as a marker of traffic-related air pollution (27), is associated with a higher MBD. Furthermore, ambient air CO concentration was associated with a lower MBD, while other criteria air pollutants were not related to MBD.
Our present results about ambient air NO2 and PMx (PM2.5 & PM10) concentration were consistent with a recent systematic study and meta-analysis that found an increased risk of breast cancer with an increase in each 10 unit in NO2 exposure (Hazard ratio (HR) = 1.02, 95% CI = 1.01-1.04), while PM2.5 and PM10 revealed no statistically significant associations with breast cancer risk (11). The results of our study on the relationship between air pollutants and MBD seem to be in line with studies that have examined the relationship between these pollutants and breast cancer.
Limited studies have evaluated the association between criteria ambient air pollutants and MBD with inconsistent results (16, 17, 19). Similar to our study, Du Pre and their colleague's results in the Nurses' Health Study couldn't support that recent particulate matter (PM2.5, PM air2.5−10, PM10) or roadway exposure influenced breast density (16). Two other studies had contradictory results with the present study (17, 19). The Danish Diet, Cancer and Health Cohort investigated the association between long-term exposure to traffic-related air pollution (NO2, NOx) and MBD in a prospective cohort of women aged 50 and older. They found a reverse association between air NO2 level and MBD (OR= 0.89, 95% CI: 0.80-0.89 per 10 µg/m3) with no interaction with menopause, smoking, or obesity (17). In Yaghjyan et al. study, women higher than 40 years old with known residential zip codes and estimated PM2.5 and O3 levels for the year preceding the mammogram date were included. They found that women with extreme breast density had higher mean PM2.5 and lower O3 exposure levels (19).
Numerous studies in line with our study have investigated the relationship between endocrine-disrupting chemicals (EDCs) and heavy metals with MBD (13, 14, 18). In a cross-sectional study in 725 women (40-65 years old), a higher urinary level of magnesium was associated with a higher MBD (13). In postmenopausal women (n = 264), women with high serum levels of BPA and mono-ethyl phthalate had an elevated breast density (14). In a large-scale study (n= 222,581), the relation of the MBD of women who underwent a routine screening mammogram in 2011 and residential levels of ambient air polycyclic aromatic hydrocarbons (PAHs) and metals was assessed. Higher residential levels of arsenic, cobalt, lead, manganese, nickel, or PAHs were individually associated with breast density. Comparing the highest to the lowest quartile, higher odds for dense breasts were observed for cobalt (OR = 1.60, 95% CI 1.56–1.64) and lead (OR = 1.56, 95% CI 1.52–1.64). These associations were stronger in premenopausal women (18). An exception is one cross-sectional study of PCBs, which reported some PCB congeners' plasma levels were associated with lower MBD in postmenopausal women (15).
Consistent with the present study, a review study by White and colleagues that summarized eight case-control studies and nine cohort studies suggested little evidence to support an association between particulate matter and breast cancer risk. More consistent findings have reported a relation between NO2 or NOX level and breast cancer (28).
In this study, we found a reverse association between CO level and MBD. Two recent studies that evaluated the effect of ambient air CO on breast cancer had equivocal results. A Korean study reported that CO concentration was positively and significantly associated with breast cancer (OR= 1.08, 95% CI= 1.06-1.10) (29) and another cohort study in Taiwan found that women who had CO poisoning were at a lower risk of developing breast cancer (30). We did not find any studies that examined the association between MBD and carbon monoxide. Since there is a positive correlation between MBD and breast cancer, the results of our study are consistent with the Taiwanese study.
It is very important to note that according to the evidence, environmental pollutants are associated with a higher risk of invasive breast cancer and increased mortality in these patients. Investigation on breast cancer cases has reported that PM2.5 and NO2 were associated with breast cancer (HR = 1.05; 95% CI: 0.99-1.11) and (HR = 1.06; 95%CI: 1.02-1.11), respectively. Invasive breast cancer was associated with PM2.5 only in the Western United States (HR=1.14; 95% CI: 1.02-1.27) and NO2 only in the Southern United States (HR=1.16; 95% CI:1.01-1.33) (31). The meta-analysis showed that each 10 µg/m3 of PM2.5 was associated with a 1.17 (95% CI: 1.05-1.30) fold risk of BC mortality, and each 10 µg/m3 of PM10 was associated with a 1.11 (95% CI: 1.02-1.21) fold risk of BC mortality. However, neither PM10 nor PM2.5 was found to be significantly associated with BC morbidity (32). These findings show the importance of research on the impact of pollutants on women's health, and public health professionals and policymakers should consider these characteristics to develop relevant interventions and prevention strategies that are more cost-effective and efficient.
The advantage of this study is, we considered all the possibly effective factors and known determinants of MBD, all of which are estrogen-related.
As it was demonstrated in Table 1, 91 (11.5%) and 106 (13.4%) women in the present study sample consumed metformin and aspirin, respectively. Numerous studies have evaluated the effects of aspirin and metformin on MBD with inconsistent results (33–36). In addition some researches have shown that higher vitamin D and calcium intake are associated with decreased MBD (37–39).
According to the findings of the mentioned studies and the high percentage of women who had taken metformin (11.5%), aspirin (13.4%), vitamin D (49.7%), and calcium (44.4%) in our study, it seems that without considering the use of these drugs, the results may not be expressed correctly. However, our findings showed that even by considering these factors, the results did not change.
It should be noted that most of the sampling in this study coincided with the worldwide onset of COVID-19 pandemic. Therefore, it is possible that the participants during this period were women at higher risk of breast cancer who had been referred for screening despite the COVID-19 pandemic.