Background. Phthalates are ubiquitous in consumer goods (e.g., food containers, cosmetics, and pharmaceuticals), from which they readily leach into the environment. Phthalates interfere with hormonal signaling and may affect reproductive, developmental, and cancer endpoints. Preclinical evidence implicates some phthalates in breast cancer progression—particularly dibutyl phthalate (DBP), which potentiates the estrogen receptor (ER). Associations between phthalates and breast cancer incidence have not been thoroughly investigated. Users of phthalate-containing medications have up to 70-fold higher urinary phthalate levels than other individuals, and represent a highly exposed population for efficient study of phthalate health effects.
Methods. We used the Danish Drug Information Database to identify all phthalate-containing oral medications marketed during the study period. We recorded the product code and the type and mass of phthalate per pill. We identified a nationwide cohort of women at risk for a first cancer between 2005—2015, and who had no previous exposure to a phthalate-containing drug. Using the National Prescription Registry we characterized time-varying, medication-borne phthalate exposure. Incident cancers were ascertained by linking to the Danish Cancer Registry. We fit Cox regression models to estimate associations between cumulative phthalate exposures and breast cancer incidence. Exposures were updated annually and lagged by 1 year. We adjusted for established risk factors, comorbidity, co-medications (e.g., HRT), and drug substances exposed to.
Results. We identified 481 products from 24 drug classes containing either DBP, diethyl phthalate (DEP), cellulose acetate phthalate (CAP), hypromellose phthalate (HPMCP), or polyvinyl acetate phthalate (PVAP). Drugs with phthalate-containing products also included phthalate-free products. Phthalate masses ranged from 3 µg to 1.3 g per pill. We followed 1.12 million women over 9.99 million person-years, during which 27,111 women were diagnosed with invasive breast cancer. Fourteen percent of the cohort (n=161,751) was prescribed a phthalate-containing drug. We observed no breast cancer associations with exposure to CAP, DEP, HPMCP, and PVAP. However, the highest level of cumulative DBP exposure (>10,000 mg; range: 10,024 to 71,340 mg; median=15,390 mg) was associated with an 80% increase in breast cancer risk compared with no exposure (HRadj=1.8; 95% CI: 1.0, 3.1). The association was strongest for ER+ disease (HRadj=1.9; 95% CI: 1.1, 3.5) and among premenopausal women (HRadj=2.2; 95% CI: 0.91, 5.3). There was no evidence of a linear trend in the log-hazard across categories of cumulative DBP exposure. No published evidence links exposure to the drug substances represented by the DBP-containing products (bisacodyl, budesonide, mesalazine, multienzymes, diclofenac, and lithium) with breast cancer risk.
Conclusions. High DBP exposure was associated with increased breast cancer incidence, particularly ER+ disease and among premenopausal women. This association merits further investigation. In the meantime, it may be prudent for women taking DBP-containing medications to substitute a phthalate-free version of the same drug, other considerations being equal.
|Conference||2017 Breast Cancer Symposium|
|Period||05/12/2017 → 09/12/2017|