Association of Exposure to Phthalates and Substitutes with Infection Risk Among U.S. Children

Early-life exposure to di(2-ethylhexyl) phthalate (DEHP) has been associated with compromised immune outcomes in childhood, while evidence regarding DEHP substitutes, such as di-isononyl phthalate (DiNP), di-isononyl cyclohexane-1,2-dicarboxylate (DiNCH) and di(2-ethylhexyl) terephthalate (DEHTP), remains limited. This study analyzed urinary concentrations of 18 phthalate metabolites, including legacy phthalates and the newer substitutes, and examined their associations with overall infection risk among 1,989 U.S. children representative of the US population stratified into three vulnerable age groups (3-5, 6-11, and 12-19 years). We applied logistic and mixture models to examine the associations. We found a higher infection risk associated with DiNP metabolite concentrations (MONP: mono-oxo-isononyl phthalate and MCOP: mono-carboxy-isooctyl phthalate) in children aged 3-5 years (3rd vs 1st tertile, MONP OR: 1.94, 95% CI: 1.12, 3.34) and adolescents aged 12-19 years (MONP OR: 5.49, 95% CI: 2.30, 13.06; MCOP OR: 4.91, 95% CI: 2.11, 11.40). Adolescent urinary concentrations of other phthalate metabolites were associated with higher infection odds, including mono-benzyl phthalate (3rd vs 1st tertile OR: 3.39, 95% CI: 1.56, 7.37), mono-(3-carboxypropyl) phthalate (OR: 2.97, 95% CI: 1.47, 5.99), mono-isobutyl phthalate (OR: 1.71, 95% CI: 1.01, 2.87), mono-hydroxy-isobutyl phthalate (OR: 1.95, 95% CI: 1.09, 3.48), and mono-2-ethyl-5-carboxypentyl phthalate (OR: 2.24, 95% CI: 0.97, 5.16). Among adolescents, each quartile increase in mixture concentration was associated with a higher infection risk (OR: 2.45, 95% CI: 1.26, 4.77). Regarding non-phthalate alternatives, only an isolated deleterious association was found for DiNCH in boys but not girls aged 6-11 years. Although these associations should be validated in longitudinal cohorts, our results suggest that children's exposure to specific phthalates and phthalate mixtures may increase susceptibility to infections, and that DiNP does not appear to be a safe substitute for DEHP regarding immune-related outcomes. More observational and toxicological studies are needed, particularly for newer non-phthalate substitutes such as DiNCH and DEHTP.