Although the vast majority of epidemiologic studies do not support the association between BC and OCPs [15, 20, 32, 43, 44], the well-known association between BC and prolonged exposure to estrogens suggests that environmental estrogens, may play a critical role in the cellular and molecular changes that occur during breast carcinogenesis . In this sense, most OCPs are considered as xenoestrogens and may modulate steroid sex hormones homeostasis, such as estrogen or testosterone, as agonists or antagonists or as mixed effects . In fact, there are a number of studies that seem to indicate that the association between BC and OCPs could exist [27, 47].
The best known and studied OCP with respect to its role in breast cancer is the main DDT-metabolite, DDE. DDT is converted to DDE, that apparently does not undergo further biotransformation, and it is stored for an indefinite period of time in adipose tissues. Due to this fact, this compound is the highest prevalent DDT-derivative found in human beings . On the other hand, the major detoxification pathway of DDT is via dechlorination to DDD. The population of the Canary Islands presents similar serum levels of DDT and DDE to those found in other European countries . In the present study, serum levels of DDE were higher in BC patients than in healthy women, although, after a multivariate analysis, DDE do not seem to be a risk factor for BC. These results agree with those reported previously . However, there are other highly prevalent OCPs (DDT- and non-DDT-derivatives) in female populations at concentrations highly enough to exert biological effects on breast cells . In this sense, our findings demonstrating that serum levels of DDD were higher among BC patients than in non-affected women and that exposure to DDD could represent, at least, a moderately risk factor for developing BC (OR = 1.008), point to the possibility that other less evaluated OCPs, such as DDD, could play a more relevant role as risk factor for BC.
We reported that background exposure to non-DDT-derivative-OCPs was higher in non-affected women than in BC patients. This result was mainly due to the fact that endrin was not detected in any sample from BC patients, while residues of endrin were present in more than 58% of the samples from healthy women at median concentrations higher than 29 ng/g fat. On the contrary, the presence of residues of aldrin was higher in serum samples from BC patients than in healthy women. Thus, depending on the specific subclass of OCP, the environmental exposure to these contaminants might be related or not with the etiology of BC. Our results showing that DDD could be considered as risk factors for BC must be taken with caution due to the several limitations of our study. Firstly, controls were originally selected for a different purpose (ENCA survey) than analyzed in this study. The use of controls from a nutritional survey may introduce bias if the probability of selection into the study is associated with factors that influence both the prevalence of exposure and the probability of disease status. One such factor is age, which was statistically different among groups of subjects (47.6% of healthy women were older than 45 years old while 86.8% of BC patients were in this age subgroup); together with BMI or menopause status (both variables also considered as BC risk factors and important for the prevalence of exposure to OCPs). Secondly, several established risk factors for breast cancer (mainly family history of breast cancer, reproductive factors (such as number of children or duration of lactation), or alcohol intake) were not available nor in controls nor in BC patients, and, as a consequence, unmeasured or residual confounding factors have not been included in the analyses. Thirdly, because these chemicals are stored in fat, it is believed that adipose tissue loss could result in increased \organ and blood concentrations of these compounds . Thus, if changes in body weight occur as a consequence of the development of cancers, the levels of OCPs measured in this study may not reflect the background exposure to these chemicals for both groups of women. In addition, body fat is an important risk factor for breast cancer . Although we adjusted for BMI in our analyses, BMI as a measure of body fat has certain limitations . To make matters worse, because serum concentrations of OCPs are highly correlated with each other and can be correlated with unmeasured substances, the associations observed here might not always have represented the direct effect of the OCPs measured.
It is assumed that the biological effects exerted by environmental contaminants on human tissues, taken individually, clearly differ from the effects exerted by their combinations. However, most studies about environmental contaminants as risk factors for BC have focused on single-chemicals. Currently, it seems clear the importance of the exposure to chemical mixtures and their contribution to the disease by causing cellular-level dysfunction along key pathways. In this sense, we have recently reported that DDD, DDE, aldrin, and dieldrin, sharply upregulated the expression of a number of protein kinases genes that could be involved in the etiology of BC, such as ACVRL1, ALK-1, KIT, ERBB3, and ALK-1, at concentrations close to those detected in human populations . Additionally, it has to be taken into account that the potential effects exerted on breast cells by environmental contaminants could be due not only to the organochlorine pesticides measured in the present study, even more so other environmental pollutants not measured could be implicated. Complex interactions between chemicals, endogenous or exogenous hormones, and their natural ligands and receptors may alter the internal homeostasis of the estrogenic environment of mammary tissue, leading to malignant transformation and cancer. Our findings agree with those observed in vitro by Aubé (2011) suggesting that aldrin and DDD, together with other OCP compounds, increased the proliferation of MCF-7 cells . However, to our knowledge, population-based studies evaluating the role of OCPs mixtures in relation to breast cancer are scarce . Our findings showing the lack of overlaps between the profiles of mixtures of OCPs among healthy and affected women suggest a relevant role of these chemical mixtures in relation to the disease. Future studies achieving the association between environmental contaminants and BC should analyze the combined effect of these compounds and the interactions with endogenous hormones and other substances that affect endocrine function.