In vivocharacterisation of the toxicological properties of DPhP, one of the main degradation products of aryl phosphate esters

Abstract

25Conclusions: 57 Our results suggest that in mice, the effects of chronic exposure to DPhP, even at a low dose, are 58 not negligible. Fatty acid metabolism in the liver in particular is essential for controlling fast and 59 feast periods with adverse consequences on the overall physiology. Therefore, the impact of DPhP 60 on circulating fat, cardiovascular and metabolic disease incidence deserves, in light of our results, 61 further investigations. 62 63 3 1. Introduction 64 Di-phenyl phosphate (DPhP) has been used as a main biomarker for assessing exposure to aryl 65 phosphate esters (APEs), especially tri-phenyl phosphate (TPhP), a molecule suspected of 66 presenting human health hazards. However, this degradation compound can be produced from 67 several APEs including ethylhexyl di-phenyl phosphate (EHDPhP) or the resorcinol 68 bis(diphenyl phosphate) (RDP) 1,2 and tert-butylphenyl diphenyl phosphate (BPDP) 3 . Moreover, 69DPhP itself is largely present in the environment worldwide 4-8 , either owing to its 70 spontaneous/microorganism production from known APEs 5,9 , or to its direct use in industry 10 . 71Most APEs are used as flame retardants. They are added to consumer products and raw 72 materials to delay combustion and meet flammability standards such as the ISO/TC92 Fire 73 Safety, TC89 Fire Hazard existing in Europe. Moreover, unlike other flame retardants, TPhP 74 and EHDPhP are also largely used as plasticizer and lubricants in hydraulic fluids, rubber, 75 paints, textile coatings, food packaging and PVC, drastically increasing their presence in the 76 environment. These compounds are not usually covalently linked to plastic materials and can 77 easily leach into the environment 11 . High vapour pressure of TPhP is also likely to facilitate its 78 release in the air once it is freed from its original material 12 . Not surprisingly, TPhP and 79 EHDPhP are thus ubiquitous components of the human indoor environment where its sources 80 and exposure pathways are quite diverse and heterogeneous with regards to other flame 81 retardants. Indeed, TPhP and EHDPhP quantification in food, house dust, water or air has 82systematically demonstrated their presence in these very different matrices raising awareness 83 on the safety of these compounds [4][5][6][7][8]12,13 . A study characterising the direct biological effects of 84 DPhP and their relationship to TPhP exposure thus appeared to be of particular relevance to 85 better define the effects and mechanisms of action associated with exposure to APEs in a more 86 comprehensive way. 87 105 correlated with TPhP levels present in the same environment 4 , hence raising concerns about 106 these potentially hazardous molecules for human health. 107The complexity of the routes of exposure described above can cast doubts as to the 108 relevance of in vitro and in vivo studies describing the toxicities associated with APEs such as 109 the TPhP. For instance, very high doses of TPhP administered via oral gavage (300 mg/kg/day) 110 in adult mice 21 or through...