Medication-Associated Phthalate Exposure and Childhood Cancer Incidence

Background: Human phthalate exposure is widespread through contact with myriad consumer products. Exposure is particularly high through medications formulated with phthalates. Phthalates disrupt normal endocrine signaling and are associated with reproductive outcomes and incidence of some cancers. We measured associations between gestational and childhood medication-Associated phthalate exposures and the incidence of childhood cancers. Methods: We identified all live births in Denmark between 1997 and 2017, including both children and birth mothers. Using drug ingredient data merged with the Danish National Prescription Registry, we measured phthalate exposure through filled prescriptions for mothers during pregnancy (gestational exposure) and for children from birth until age 19 years (childhood exposure). Incident childhood cancers were ascertained from the Danish Cancer Registry, and associations were estimated with Cox regression models. Results: Among 1-278-685 children, there were 2027 childhood cancer cases diagnosed over 13.1 million person-years of follow-up. Childhood phthalate exposure was strongly associated with incidence of osteosarcoma (hazard ratio [HR] = 2.78, 95% confidence interval [CI] = 1.63 to 4.75). We also observed a positive association with incidence of lymphoma (HR = 2.07, 95% CI = 1.36 to 3.14), driven by associations with Hodgkin and non-Hodgkin lymphoma but not Burkitt lymphoma. Associations were apparent only for exposure to low-molecular phthalates, which have purportedly greater biological activity. Conclusions: Childhood phthalate exposure was associated with incidence of osteosarcoma and lymphoma before age 19 years. Lingering questions include which specific phthalate(s) are responsible for these associations, by what mechanisms they occur, and to what extent childhood cancer cases could be avoided by reducing or eliminating the phthalate content of medications and other consumer products.