The cumulative risk assessment of phthalates exposure in preterm neonates

Phthalates are widely used plasticizers in various consumer products and medical devices, with some reporting as having estrogenic and anti-androgenic endocrine-disrupting effects. Premature neonates may be exposed to high levels of specific phthalates during hospitalization in the neonatal intensive care unit (NICU) because of reliance on multiple medical procedures that pose a possible health risk. The present study utilized seven urinary phthalate metabolites of dibutyl phthalate isomers [(di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP)], butylbenzyl phthalate (BBzP), and di(2-ethylhexyl) phthalate (DEHP) that had been previously measured in 33 preterm neonates sampled at hospital admission (N = 23) and daily during their NICU stay (N = 260). We aimed to perform: (1) cumulative risk assessment (CRA) using the volume and creatinine-adjusted models; (2) examine the temporal variability of CRA from repeated measures and (3) estimate the risk of cumulative exposure to phthalates based on their anti-androgenic and/or estrogenic properties. We multiplied the relative activity of individual phthalates exhibiting estrogenic or anti-androgenic effects by daily intake. For each preterm neonate, CRA was assessed based on the hazard index (HI) metric [the sum of hazard quotients] based on three reference doses for anti-androgenicity: the tolerable daily intake (TDI) from the European Food Safety Authority, the reference dose (RfD-AA) published in 2010 and newly revised published in 2020 (NRfD-AA). The metabolites of BBzP and DEHP were 2-23 fold higher in preterm neonates during their NICU stay. Median HIs increased in the order of HI_NRfDAA > HI_RfDAA > HI_TDI. In the creatinine-based model, 87% (92%), 87% (96%), and 100% (100%) of preterm neonates at admission (during NICU stay) showed HI_TDI, HI_RfD-AA, and HI_NRfD-AA exceeding 1, respectively with DEHP the most prevalent. The temporal reproducibility of HI (based on three reference doses) during preterm neonate stay in the NICU was high, with intra-class correlation coefficients ranging between 0.77 and 0.97, suggesting persistent exposure to phthalates. The four phthalates that preterm neonates were exposed to in the NICU exhibited estrogenic binding and anti-androgenic effects with median values (creatinine-based) of 98.7 and 56.9 μg/kg body weight/day, respectively. This was especially true for DEHP. The results indicate that preterm neonates in this NICU setting are probably at high risk of cumulative phthalate exposure with anti-androgenic properties that may have long-term adverse reproductive and developmental effects.