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  • br There was evidence of synergistic

    2020-07-06


    There was evidence of synergistic effect-measure modification, on the additive and multiplicative scales, by BMI for six air toxics, in-cluding 2,4-toluene diisocynate, benzidene, Herboxidiene dichloride, ethy-lene oxide, hydrazine, and propylene dichloride (Table 5). In the stra-tified analyses, the direction of the modification suggested a stronger association between the air toxics and breast cancer among those who were overweight/obese compared to those who were not. For example, on the multiplicative scale, ≥median vs. < median concentration of propylene dichloride was associated with a HR of 1.11 (95% CI: 1.01–1.22) among those who were overweight/obese, but a HR of 0.89 (95% CI: 0.79–1.01) among those who were not overweight/obese (ratio of HR = 1.25; 95% CI: 1.07–1.45; LRT p = 0.003). Physical ac-tivity did not modify the air toxic-breast cancer associations (Supple-mental Table 2).
    In sensitivity analyses, results were similar to the results for all women when we restricted models to invasive breast cancer alone (Supplemental Table 3) or to non-Hispanic whites, those who enrolled in 2005 or later, or those who had lived at their baseline address for > 10 years, and when additionally adjusted for region (data not shown). Results were slightly attenuated, but interpretation did not change, when restricted to the cases confirmed by medical record (data not shown).
    Results of this study were interpreted with an emphasis on the magnitude of point estimates and precision of confidence intervals 
    rather than statistical significance testing. Further, air toxics were se-lected for this study based on biological plausibility and a review of animal studies. Therefore, our results are focused on those not adjusted for multiple comparisons. However, due to the large number of air toxics and associations examined we explored a multiple comparisons adjustment using the false discovery rate method as a sensitivity ana-lysis (Benjamini and Hochberg, 1995). Associations for overall, ER+, ER− breast cancer, and modification by BMI observed in the primary analyses were not significant when adjusted for multiple comparisons.
    3.3. Results from the multipollutant classification tree
    Classification tree methods were used in exploratory analyses to identify patterns and combinations of the 29 air toxics and other cov-ariates of interest (age, BMI, physical activity). As shown in Fig. 1, in addition to age, BMI, and methylene chloride, ethylidene dichloride, styrene, propylene dichloride, and ethylene dibromide were important in the formation of the groups. The terminal nodes exhibiting the highest risk of breast cancer consisted of those: (1) younger than 58.7, with higher (≥5.89 μg/m3) methylene chloride; (2) older than 58.7, with a BMI < 29.7 kg/m2 and with higher (≥3.84 μg/m3) methylene chloride; or (3) older than 58.7, with a BMI ≥ 29.7 kg/m2 and with both higher (≥0.001 μg/m3) ethylidene dichloride and higher (≥0.389 μg/m3) styrene. The most common subgroup on the tree consisted of those between the ages of 40 and 58.7, with methylene chloride < 5.89 μg/m3 and propylene dichloride < 0.002 μg/m3. It is noteworthy, however, that when the classification tree determined the best splitting point for some air toxics, it was occasionally at a high concentration. As an example, the distribution of methylene chloride concentrations in this population (overall and among those < age 58.7) shown in Supplemental Fig. 2 demonstrates that the cutpoints identified
    Table 4
    HRs (95% CIs) for the associationsa between hazardous air pollutants and ER− invasive breast cancerb, the Sister Study.
    Air toxic Quintile 1 Quintile 2 Quintile 3 Quintile 4 Quintile 5 p-Trend
    a Models adjusted for race, residence type, education, and smoking status.
    c Air toxic categorized with a concentration of 0 (9.9 × 10−9 for benzidine) as the referent and remaining values split based on tertiles.
    4. Discussion
    In this large, US-wide cohort study, methylene chloride was con-sistently associated with breast cancer across different single and multipollutant models. Evidence of increased overall or ER+ breast cancer risk was also observed for multiple other air toxics, including acrylamide, polycyclic organic matter, propylene dichloride, and styrene. Results were inconsistent for ER− breast cancer; two air toxics demonstrated a positive association, while multiple others demon-strated an inverse association. BMI, but not physical activity, modified some air toxic-breast cancer associations in the direction of a stronger association among women who were overweight/obese.
    pathways, CYP2E1 and glutathione S-transferase (GST), that can lead to the formation of reactive intermediates. The importance of the GST pathway was primarily determined from lung and liver cancer models, but GSTT1 (a key enzyme in the pathway) activity has been detected in mammary tissue (Schlosser et al., 2015).