Academic journal article Environmental Health Perspectives

A Human Mixture Risk Assessment for Neurodevelopmental Toxicity Associated with Polybrominated Diphenyl Ethers Used as Flame Retardants

Academic journal article Environmental Health Perspectives

A Human Mixture Risk Assessment for Neurodevelopmental Toxicity Associated with Polybrominated Diphenyl Ethers Used as Flame Retardants

Article excerpt

Introduction

Owing to a legacy of pollution related to the past use of commercial polybrominated diphenyl ethers (PBDEs) as flame retardants, humans today are exposed to combinations of multiple PBDE congeners. Although other commercial PBDE mixtures are listed as persistent organic pollutants (POPs) under the Stockholm Convention (UNEP 2013), commercial decabromodiphenyl ether (c-decaBDE) is not yet included. There are, however, voluntary agreements to phase out its use. C-deca-BDE is widely used in plastics and textiles and consists mainly of decabromodiphenyl ether (BDE-209) ([greater than or equal to]97%) (ECHA 2012). Lower-brominated, more toxic PBDEs are liberated through the abiotic and biotic debromination of c-decaBDE in the environment and within organisms (see the review by Kortenkamp et al. 2013), and these processes may contribute to the generation of PBDE mixtures.

The potential for combined effects of BDE-209 and lower-brominated BDE congeners led Norway, in 2013, to nominate cdecaBDE for inclusion in the Stockholm convention. The basis of Norway's proposal was a congener-specific human health risk assessment of mixtures of decaBDE and other PBDE congeners that was commissioned by the Norwegian Environmental Protection Agency (Kortenkamp et al. 2013), which we summarize and expand upon in this paper.

The need for conducting mixture risk assessment (MRA) derives from evidence that humans, at all life stages, come into contact with PBDE mixtures. Furthermore, several congeners, including BDE-209, -47, -99, -153, -183, -203, and -206 are capable of inducing neurodevelopmental effects in rodents (Viberg et al. 2006, 2007; Viberg 2009; EFSA 2011). In these studies, alterations in spontaneous behavior, indicating impaired habituation in new environments, and hyperactivity were consistently found in young animals after PBDE exposure. Impaired learning occurred in adult animals exposed prenatally to BDE congeners. Although complex measures of developmental neurotoxicity in rodent models cannot be equated directly with outcomes in humans, experimental findings have raised concerns about the potential for neurodevelopmental effects of PBDE exposures in babies and young children, potentially resulting in IQ loss and other consequences (EFSA 2011). Accordingly, neurodevelopmental toxicity in rodents has been the basis for reference doses used in human risk assessments for BDE-47, -99, -153, and -209 (EFSA 2011). The precise mechanisms by which PBDEs exert neurodevelopmental toxicity have not been fully established. Some PBDEs have been shown to cause pregnane X receptor (PXR)--and constitutive androstane receptor (CAR)-mediated induction of liver enzymes responsible for thyroid hormone clearance, which might compromise brain development by causing thyroid hormone insufficiency (EFSA 2011; Costa and Giordano 2011). Another possible mode of action is via direct toxicity to developing neurons (Costa and Giordano 2011). Given the structural similarity of PBDE congeners, the same potential modes of action might also be expected to operate when PBDEs are present as mixtures. Accordingly, the European Union Scientific Committee SCHER (European Commission 2011) proposed that PBDEs should be subjected to MRA using dose addition as the evaluation concept, with the assumption that all PBDEs exhibit the same mode of action and toxicity.

Meek et al. (2011) performed an MRA for PBDEs to illustrate the tiered mixture assessment framework developed under the auspices of the World Health Organization International Programme on Chemical Safety (WHO/IPCS). In this analysis, they assigned toxicity values to groups of PBDE congeners (e.g., a value for all 42 tetra-brominated PBDEs) instead of using congener-specific data. Their evaluation suggested large margins of exposure (MOEs), such that estimated human exposures were well below minimum exposure levels associated with neurobehavioral effects in mice. …

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