br Discussion br Using data
Using data from a large epidemiologic case-control study, we ob-served a moderate positive association between occupational exposure to alkylphenolic compounds and breast cancer, and in general, no as-sociations with prostate cancer. In support of the hypothesis of an as-sociation between breast cancer and these chemicals, estimates were stronger among those who ever worked frequently exposed and with high intensity of exposure, compared with those exposed to alkylphe-nolic compounds but never with a frequent and high intensity. Within the different scenarios of exposure, the occupational use of domestic tensioactives was positively associated with breast cancer, while other scenarios showed similar, but not statistically significant associations. The type of JNJ-42153605 most frequently used among exposed women was nonylphenol ethoxylates, which were positively associated with breast cancer. Overall, no associations were observed for prostate cancer and occupational use of alkylphenolic compounds. However, exposures occurred on 1997 or onwards revealed significant associa-tions, as well as occupational use of cosmetic, hair and personal hygiene products, although based on a small sample size.
Despite the growing interest in the potential impact of these che-micals on the environment and on health, data among humans are still scarce, especially for specific EDC (Bergman et al., 2013; Casals-Casas and Desvergne, 2011; Damstra et al., 2002). Alkylphenolic compounds are considered EDC because of their estrogenic and weak anti-andro-genic activities (Bontje et al., 2004). Recent in vitro and in vivo data suggested that low-dose alkylphenol exposure promotes mammary al-terations, and stated that exposure to alkylphenols could be considered as a tumor promoting environment, while the effect as tumor initiators was not evident (Chamard-Jovenin et al., 2017). Although with certain inconsistencies, risks were increased with recent exposures, which
could suggest that the hormone-dependent responses of alkylphenolic compounds might produce the potential effects in a relatively short period of time. However, we observed increased risks among women with triple negative cancer rather than with hormonal receptors posi-tive cancer, which is not in line with our a priori hypothesis of alkyl-phenols promoting mammary cell proliferation by binding to estrogen receptors. Our findings are in accordance with the scarce published literature on the subject (Aschengrau et al., 1998b; Gray et al., 2017; Villeneuve et al., 2010a). Occupational exposure to 4-octylphenol and a higher risk of breast cancer in females has been previously reported in one study performed in Massachusetts using data from the NIOSH Na-tional Occupational Exposure Survey. However, these findings need to be interpreted cautiously as the exposed number of subjects was very small (6 cases and 5 controls) (Aschengrau et al., 1998b). A European case-control study reported an increased risk between occupational exposure to alkylphenolic compounds and breast cancer among males, although with certain inconsistencies, suggesting that alkylphenolic compounds could also play a role in the development of this cancer in men (Villeneuve et al., 2010a).
In accordance with previous literature, breast cancer was associated in our sample with BMI, tobacco, alcohol consumption, age at me-narche, and family history of breast cancer (Sun et al., 2017; Winters et al., 2017). Other exposures related to estrogens trough lifetime (parity, age at menopause, use of hormonal contraceptives or post-menopausal hormonal therapy) are also relevant predictors of breast cancer (Sun et al., 2017; Winters et al., 2017). Although these variables were not statistically significantly associated with breast cancer in our bivariate analyses, they were introduced in the fully adjusted model, similarly to educational level, in order to potentially control for con-founding and selection bias for these factors. Given that participation rates were lower in controls than cases, selection bias could have oc-curred as controls have a higher SES than cases. We therefore controlled all analyses for educational level, and explored other different measures of SES, obtaining similar results, which suggests that our results are not strongly influenced by this potential bias. Sensitivity analyses re-stricting analyses to the unexposed to solvents, as well as reclassifying those with occasional and low intensity as unexposed, yielded similar conclusions. Similarly, associations were not restricted to a particular scenario, such as the occupational use of pesticides. This suggests that our results are not driven by confounding for pesticides or organic solvents, which were previously associated with breast cancer, although with inconsistences (Engel, 2005; Peplonska et al., 2010). None of the previous studies examining associations between alkylphenolic com-pounds and cancer took into account relevant exposure changes over time. Given the short half-live of these chemicals (Müller et al., 1998) and the long latency of diseases such as cancer, it is important to use a method that allows estimating lifetime exposure and that considers the relevant changes in their use over the years. The use of these com-pounds has experienced relevant changes throughout last decades worldwide. For instance, in the United Kingdom, the first use of these compounds was detected in 1944, while in Spain they were introduced in 1959 with the opening to international markets. In the 70s, the first concerns about the toxicity of these compounds and their potential to bioaccumulate in marine organisms and in the environment appeared, and voluntary agreements were undertaken to reduce or eliminate the use and manufacture of these compounds. In 2002–2003 the European Union established regulations to limit the use of NP and NPE (Bontje et al., 2004; European Union, 2003; Martín-Bustamante et al., 2017). This is relevant because 92% of the exposed women and 88% of ex-posed males in our study had an exposure between 1965 and 2002, i.e. before regulations took place to reduce these exposures. We found significant positive associations between breast cancer and both NPE exposure and use of domestic tensioactives. This is probably due to the correlation between these two variables, as NPE is the most frequent compound within the domestic tensioactives scenario (Martín-Bustamante et al., 2017).