The toxicity of the methylimidazolium ionic liquids, with a focus on M8OI and hepatic effects

Ionic liquids are a diverse range of charged chemicals with low volatility and often liquids at ambient temperatures. This characteristic has in part lead to them being considered environmentally-friendly replacements for existing volatile solvents. However, methylimidazolium ionic liquids are slow to break down in the environment and a recent study at Newcastle detected 1 octyl 3 methylimidazolium (M8OI) – an 8 carbon variant methylimidazolium ionic liquid - in soils in close proximity to a landfill site. The current M8OI toxicity database in cultured mammalian cells, in experimental animal studies and in model indicators of environmental impact are reviewed. Selected analytical data from the Newcastle study suggest the soils in close proximity to the landfill site, an urban soil lacking overt contamination, had variable levels of M8OI. The potential for M8OI - or a structurally related ionic liquid – to trigger primary biliary cholangitis (PBC), an autoimmune liver disease thought to be triggered by an unknown agent(s) in the environment, is reviewed

Dansk sammendrag af rapport om ”Forbedret kemikaliesikkerhed for hormonforstyrrende stoffer, alene og i cocktails” – ”FEMINIX”

Risikovurdering af kemikalier i fødevarer og miljø er en stor udfordring, da der mangler viden om mange kemikaliers effekt og virkningsmekanismer, samtidig med at eksponeringsdata for mange stoffer ikke eksisterer. Samtidig er det vigtigt at se på den samlede udsættelse for kemikalier, cocktaileffekten, når risikoen ved kemikalieeksponering skal vurderes. Disse udfordringer er store og samtidig meget ressourcekrævende, da fx testning af hormonforstyrrende stoffers skadelige effekter ofte kræver store toksikologiske dyreforsøg. Sidstnævnte er i sig selv en udfordring, da fremtidig risikovurdering i langt større grad bygger på resultater fra alternative testmetoder fremfor dyreforsøg.For at det skal kunne lade sig gøre at forudsige (prædiktere) skadelige effekter uden at bruge dyreforsøg, er der et stort behov for at forstå de underliggende virkningsmekanismer, så vi kan benytte os af de rigtige testmetoder til risikovurdering. Et af hovedformålene med dette projekt (FEMINIX) var således at karakterisere virkningsmekanismer for hormonforstyrrende effekter, samt undersøge følsomhed for kemikaliepåvirkning under specifikke livsstadier, fx fostertilværelsen og den tidlige postnatale udvikling. For reproduktionsskadelige effekter er både forkortet anogenital afstand og bibeholdte brystvorter i hanligt afkom (dyreforsøg) sensitive biomarkører, der er inkluderet i internationale testmetoder (OECD). Der mangler dog viden om hvilke af biomarkørerne, der er mest følsomme med hensyn til de sensitive perioder og forskellige virkningsmekanismer, der forstyrrer hormonsignaleringen under udviklingen. Et formål var således at forbedre karakteriseringen af disse parametre for til sidst at forbedre prædiktiviteten af alternative testmetoder.Projektet undersøgte kombinationseffekter af kemikalier med anti-androgene mekanismer og anti-androgene effekter. Dette blev gjort med fokus på anvendeligheden af biomarkører for anti- androgene effekter i dyreforsøg, samt med fokus på anvendelighed af human biomonitorerings data i samspil med in vitro aktivitet på den androgene receptor. Desuden fokuseredes på fluorerede kemikalier, da disse udgør en af vor tids mest problematiske kemikalieklasser, da de er persistente stoffer med effekter på bl.a. fødselsvægt og immunforsvaret. Arbejdet med denne stofgruppe blev startet i forbindelse med Fødevareforlig 2 (2011-2015)

Identification of a xenobiotic as a potential environmental trigger in primary biliary cholangitis

Background and Aims: Primary biliary cholangitis (PBC) is an autoimmune-associated chronic liver disease triggered by environmental factors - such as exposure to xenobiotics - leading to a loss of tolerance to the lipoic acid conjugated regions of the mitochondrial branched-chain α-ketoacid dehydrogenase complex, typically to the E2 component (PDC-E2). Methods: Urban landfill and control soil samples from a region with high PBC incidence were screened for xenobiotic activities using analytical, cell-based xenobiotic receptor activation assays and toxicity screens. Results: A variety of potential xenobiotic classes were ubiquitously present, as identified by their interaction with xenobiotic receptors - aryl hydrocarbon (AhR), androgen (AR) and peroxisome proliferator activated receptor alpha (PPARα) receptors - in cell-based screens. In contrast, xenoestrogen – estrogen receptor (ERα) - interacting chemicals were present at higher levels in soil extracts from around an urban landfill. Furthermore, two landfill sampling sites contained a chemical(s) that inhibited mitochondrial oxidative phosphorylation and induced the apoptosis of an hepatic progenitor cell. The mitochondrial effect was also demonstrated in human liver cholangiocytes from 3 separate donors. The chemical was identified as the ionic liquid [3-methyl-1-octyl-1H-imidazol-3-ium]+ (M8OI) and the toxic effects were recapitulated using authentic pure chemical. A carboxylate-containing human hepatocyte metabolite of M8OI - bearing structural similarity to lipoic acid - was also enzymatically incorporated into the E2 component of pyruvate dehydrogenase via the exogenous lipoylation pathway in vitro. Conclusions: These results identify for the first time, a xenobiotic in the environment that may be related to and/or potentially be a component of an environmental trigger for PBC. Lay summary: PBC is a liver disease in which most patients have antibodies to mitochondrial proteins containing lipoic acid binding site(s). This paper identified a man-made chemical present in soils around a waste site and shows that it is metabolised to a product having structural similarity to lipoic acid and is capable of replacing lipoic acid in mitochondrial proteins