Beyond Cholinesterase Inhibition: Developmental Neurotoxicity of Organophosphate Ester Flame Retardants and Plasticizers

Abstract

Background: To date, the toxicity of organophosphate esters has primarily been studied regarding their use as pesticides and their effects on the neurotransmitter acetylcholinesterase (AChE). Currently, flame retardants and plasticizers are the two largest market segments for organophosphate esters and they are found in a wide variety of products, including electronics, building materials, vehicles, furniture, car seats, plastics, and textiles. As a result, organophosphate esters and their metabolites are routinely found in human urine, blood, placental tissue, and breast milk across the globe. It has been asserted that their neurological effects are minimal given that they do not act on AChE in precisely the same way as organophosphate ester pesticides. Objectives: This commentary describes research on the non-AChE neurodevelopmental toxicity of organophosphate esters used as flame retardants and plasticizers (OPEs). Studies in humans, mammalian, nonmammalian, and in vitro models are presented, and relevant neurodevelopmental pathways, including adverse outcome pathways, are described. By highlighting this scientific evidence, we hope to elevate the level of concern for widespread human exposure to these OPEs and to provide recommendations for how to better protect public health. Discussion: Collectively, the findings presented demonstrate that OPEs can alter neurodevelopmental processes by interfering with noncholinergic pathways at environmentally relevant doses. Application of a pathways framework indicates several specific mechanisms of action, including perturbation of glutamate and gamma-aminobutyric acid and disruption of the endocrine system. The effects may have implications for the development of cognitive and social skills in children. Our conclusion is that concern is warranted for the developmental neurotoxicity of OPE exposure. We thus describe important considerations for reducing harm and to provide recommendations for government and industry decision makers. https://doi.org/10.1289/EHP9285

Penetration of Organophosphate Triesters and Diesters across the Blood–Cerebrospinal Fluid Barrier: Efficiencies, Impact Factors, and Mechanisms

“…In addition to carcinogenicity, , developmental and reproductive toxicity, and endocrine disruption, , growing evidence from laboratory animal studies and human epidemiological studies has indicated that tri-OPEs cause significant neurotoxicity . For example, exposure of zebrafish/Chinese Rare Minnows to tri­(2-chloroethyl)­phosphate (TCEP), tri­(1,3-dichloro-2-propyl)­phosphate (TDCIPP), tri-phenyl phosphate (TPHP), tri- n -butyl processes phosphate (TNBP), or tri­(2-butoxyethyl)­phosphate (TBOEP) induced hyperactivity, impaired learning/memory performance, and led to significant changes in locomotor behavior .…”

Flame Retardants: New and Old Environmental Contaminants

“…Epidemiological studies on exposure to organophosphates are also gaining ground, especially when it comes to the early stages of development, when organophosphates may have greater consequences [115].…”

Environmental exposure to organophosphate esters and suspected non-alcoholic fatty liver disease among US adults: A mixture analysis

“…Although various in vitro and in vivo studies have investigated the negative health effects of OPE exposure (7)(8)(9), human data results on adult OPEs and NAFLD are still relatively scarce. Given the prevalence of OPEs in the environment and their potential deleterious consequences, investigating their impact on the incidence and progression of NAFLD is vital.…”

“…OPEs can be found in a variety of products, including electronics, building materials, automobiles, furniture, vehicle seats, plastics, and textiles. As a result, OPEs and their metabolites are now commonly discovered in human urine, blood, placental tissue, and breast milk worldwide ( 8 ). Concerns about OPEs have grown in recent years, and previous research revealed that OPEs can have a variety of negative impacts on creatures and people, including poor reproductive health and birth outcomes, obesity, neurodevelopment, hypertension, and sex steroid hormones ( 9 – 12 ).…”