Phthalates and bisphenols early-life exposure, and childhood allergic conditions: a pooled analysis of cohort studies

Abstract

Background: Exposure to plastic additives, such as phthalates and bisphenols, has been associated with a higher risk of allergic conditions, but the evidence is inconsistent for children younger than five.

Objective: To examine the association between pre- and postnatal urinary phthalates and bisphenols, and allergic conditions, and potential effect modification by sex, in pre-school children, through a pooled analysis.

Methods: We pooled data from the Barwon Infant Study (Australia), the Canadian Healthy Infant Longitudinal Development Study (Canada), the Health Outcomes and Measures of the Environment (United States) and the Environmental Influences on Child Health Outcomes-wide cohorts (United States). Urinary phthalates and bisphenols were measured during pregnancy and early childhood. We estimated daily intakes from urinary concentrations, except for mono-(3-carboxypropyl) phthalate (MCPP). Outcomes, including asthma, wheeze, eczema, and rhinitis, were assessed up to five years of age through questionnaires and clinical assessments. We used generalised estimating equations for single compounds and quantile G-computation for the chemical mixtures.

Results: 5306 children were included. A two-fold increase in prenatal dibutyl phthalates (DBP; risk ratio [RR] = 1.08; 95% confidence interval [CI]: 1.00-1.16) and benzyl butyl phthalate (BBzP; RR = 1.06; 95%CI: 1.00-1.12) increased the risk of asthma in children under five. Prenatal MCPP levels were associated with rhinitis (RR = 1.05; 95%CI: 1.01-1.09). Postnatal BBzP levels increased the risk of wheezing (RR = 1.05; 95%CI 1.01-1.09), as well as di(2-ethylhexyl) phthalate (DEHP; RR = 1.06; 95%CI: 1.01-1.11) and MCPP (RR = 1.09; 95%CI: 1.04-1.14). These were also inversely associated with eczema. A one-quartile increase in the postnatal chemical mixture increased the risk of wheezing (RR = 1.14; 95%CI: 1.02-1.26). There was limited evidence of effect modification by sex.

Impact: Phthalates and bisphenols are widespread and may contribute to allergic conditions in children. We pooled data from 5000 children across multiple birth cohorts, suggesting that early-life exposure to these chemicals is associated with increased risks of asthma, wheezing, and rhinitis by age five. We further investigated the timing of exposure, non-linear dose-response relationships, and effect measure modification by sex. This study provides a comprehensive assessment of early-life exposure to phthalates and bisphenols and strengthens the evidence for their role in the development of childhood allergic outcomes.

Keywords: Allergies; Asthma; Bisphenols; Children; Phthalates; Pooled-analysis.

Fig. 1. Univariate dose-response relationship between prenatal phthalates and bisphenols and childhood allergic conditions.

Models obtained with generalised estimating equations. Dose-response relationships are displayed with continuous covariates held at their mean values and categorical covariates set to their reference category. P-values for non-linearity obtained with Wald tests on spline terms. Models adjusted for cohort membership, maternal age, ethnicity, parental education, marital status, family history of asthma, sex, prenatal tobacco smoke exposure, and season of birth. All exposures are modelled as estimated daily intakes, except MCPP, which is modelled using biomarker concentrations.

Fig. 2. Univariate dose‒response relationship between postnatal phthalates and bisphenols and childhood allergic conditions.

Models obtained with generalised estimating equations. Dose-response relationships are displayed with continuous covariates held at their mean values and categorical covariates set to their reference category. P-values for non-linearity obtained with Wald tests on spline terms. Models adjusted for cohort membership, maternal age, ethnicity, parental education, marital status, family history of asthma, sex, prenatal tobacco smoke exposure, season of birth, breastfeeding duration, age at outcome assessment, postnatal smoke exposure and gestational age. All exposures are modelled as estimated daily intakes, except MCPP, which is modelled using biomarker concentrations.

Fig. 3. Multivariate dose‒response relationship between the overall chemical mixture and childhood allergic conditions, using quantile G computation.

Dose-response relationships are displayed with continuous covariates held at their mean values and categorical covariates set to their reference category. Prenatal analysis models adjusted for cohort membership, maternal age, ethnicity, parental education, marital status, family history of asthma, sex, prenatal tobacco smoke exposure, and season of birth. Postnatal analysis models were further adjusted for breastfeeding duration, age at outcome assessment, postnatal smoke exposure and gestational age.

Fig. 4. Multivariate dose‒response relationship between the overall chemical mixture and childhood allergic conditions stratified by sex.

Red circles: Females. Blue triangles: Male. Models obtained with quantile G-computation. Prenatal analysis models adjusted for cohort membership, maternal age, ethnicity, parental education, marital status, family history of asthma, prenatal tobacco smoke exposure, and season of birth. Postnatal analysis models were further adjusted for breastfeeding duration, age at outcome assessment, postnatal smoke exposure and gestational age.