The knowledge of the effects of organophosphate flame retardants on children's neurodevelopment is limited. The purpose of the present research is to evaluate the association between exposure to organophosphate flame retardants and children's neurodevelopment in two European cohorts involved in the Human Biomonitoring Initiative Aligned Studies. The participants were school-aged children belonging to the Odense Child Cohort (Denmark) and the PCB cohort (Slovakia). In each cohort, the children's neurodevelopment was assessed through the Full-Scale Intelligence Quotient score of the Wechsler Intelligence Scale for Children, using two different editions. The children's urine samples, collected at one point in time, were analyzed for several metabolites of organophosphate flame retardants. The association between neurodevelopment and each organophosphate flame retardant metabolite was explored by applying separate multiple linear regressions based on the approach of MM-estimation in each cohort. In the Danish cohort, the mean ± standard deviation for the neurodevelopment score was 98 ± 12; the geometric mean (95% confidence interval (95% CI)) of bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) standardized by creatinine (crt) was 0.52 µg/g crt (95% CI = 0.49; 0.60), while that of diphenyl phosphate (DPHP) standardized by crt was 1.44 µg/g crt (95% CI = 1.31; 1.58). The neurodevelopment score showed a small, negative, statistically imprecise trend with BDCIPP standardized by crt (β = -1.30; 95%CI = -2.72; 0.11; p-value = 0.07) and no clear association with DPHP standardized by crt (β = -0.98; 95%CI = -2.96; 0.99; p-value = 0.33). The neurodevelopment score showed a negative trend with BDCIPP (β = -1.42; 95% CI = -2.70; -0.06; p-value = 0.04) and no clear association with DPHP (β = -1.09; 95% CI = -2.87; 0.68; p-value = 0.23). In the Slovakian cohort, the mean ± standard deviation for the neurodevelopment score was 81 ± 15; the geometric mean of BDCIPP standardized by crt was 0.18 µg/g crt (95% CI = 0.16; 0.20), while that of DPHP standardized by crt was 2.24 µg/g crt (95% CI = 2.00; 3.52). The association of the neurodevelopment score with BDCIPP standardized by crt was -0.49 (95%CI = -1.85; 0.87; p-value = 0.48), and with DPHP standardized by crt it was -0.35 (95%CI = -1.90; 1.20; p-value = 0.66). No clear associations were observed between the neurodevelopment score and BDCIPP/DPHP concentrations that were not standardized by crt. No clear associations were observed with bis(1-chloro-2-propyl) phosphate (BCIPP) in either cohort, due to the low detection frequency of this compound. In conclusion, this study provides only limited evidence of an inverse association between neurodevelopment and exposure to BDCIPP and DPHP. The timing of exposure and effect modification of other organophosphate flame retardant metabolites and other substances should be the subject of further investigations that address this scientific hypothesis.

BrabantAdvies Brabantlaan 3 5216 TV 's Hertogenbosch The Netherlands

Center for Biomedical Research University of Granada 18012 Granada Spain

Central Directorate for Health Social Policies and Disability Friuli Venezia Giulia Region Via Cassa Di Risparmio 10 34121 Trieste Italy

Consortium for Biomedical Research in Epidemiology and Public Health 28029 Madrid Spain

Department of Biomedical Sciences and Toxicological Centre University of Antwerp Campus Drie Eiken Universiteitsplein 1 Wilrijk 2610 Antwerp Belgium

Department of Clinical Pharmacology Pharmacy and Environmental Medicine Institute of Public Health University of Southern Denmark 5000 Odense Denmark

Department of Environmental Medicine Faculty of Public Health Slovak Medical University 83303 Bratislava Slovakia

Department of Medicine Surgery and Health Sciences University of Trieste Strada di Fiume 447 34149 Trieste Italy

Department of Medicine University of Udine Via Colugna 50 33100 Udine Italy

Instituto de Investigación Biosanitaria de Granada 18012 Granada Spain

National Centre for Environmental Health Instituto de Salud Carlos 3 28220 Majadahonda Spain

RECETOX Faculty of Science Masaryk University Kotlářská 2 611 37 Brno Czech Republic

Toxicological Centre University of Antwerp Wilrijk 2610 Antwerp Belgium

Toxicology Department Science Group UK Health Security Agency Harwell Science and Innovation Campus Didcot OX11 0RQ UK

VITO Health Flemish Institute for Technological Research 2400 Mol Belgium

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