Medication–Associated Phthalate Exposure and Childhood Cancer Incidence

Abstract

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 1997–2017, 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 2,027 childhood cancer cases diagnosed over 13.1 million person-years of follow-up. Childhood phthalate exposure was strongly associated with incidence of osteosarcoma (HR = 2.78, 95% CI: 1.63, 4.75). We also observed a positive association with incidence of lymphoma (HR = 2.07, 95% CI: 1.36, 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.

Risks of leukemia, intracranial tumours and lymphomas in childhood and early adulthood after pediatric radiation exposure from computed tomography

“…For example, data on some risk factors for cancer — such as smoking, alcohol consumption, obesity (i.e., body mass index) and exposure to pesticides or phthalate-containing medications — were lacking in the NHIRD database. 54 – 56 About 10% of patients with childhood or adult cancers have germline genomic alterations for which we had no data. 57 – 59 We were unable to eliminate the influence of high-radiation procedures completely; however, the effect should be minimal because the misclassification would have been non-differential between cases and controls.…”

Unmasking metabolic dependencies for anti-cancer treatment in cancer

“…However, Muhammad et al found that monounsaturated and diunsaturated fatty acids could improve the sensitivity of obese patients with CC to radiotherapy, and the tumor volume was significantly reduced in a mouse xenograft tumor model treated with oleate and radiotherapy compared with that in the radiotherapy alone group. The supplementation of oleate and linoleate during radiotherapy increases the expression of P53, PPARg, and CD36 to support increased free fatty acid uptake, thereby regulating the cell cycle and inducing apoptosis (177). However, these contradictory results make the effect of dietary olive oil or OA on cancer inconclusive.…”

“…To this end, phthalic acid and NF340 were able to attenuate QPRT-enhanced invasiveness pCMV6-QPRT-transfected MDA-MB-231 TNBC cell lines (105). Given that NAD is essential for metabolic and immune homeostasis, QPRT inhibitors for cancer therapy warrants investigation, although should be met with some caution due to potential off target toxicities (177)(178)(179).…”

The kynurenine pathway presents multi-faceted metabolic vulnerabilities in cancer

“…To this end, phthalic acid and NF340 were able to attenuate QPRT-enhanced invasiveness pCMV6-QPRT-transfected MDA-MB-231 TNBC cell lines ( 105 ). Given that NAD is essential for metabolic and immune homeostasis, QPRT inhibitors for cancer therapy warrants investigation, although should be met with some caution due to potential off target toxicities ( 177 – 179 ).…”