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.

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

BACKGROUND & AIMS: Primary biliary cholangitis (PBC) is an autoimmune-associated chronic liver disease triggered by environmental factors, such as exposure to xenobiotics, which leads to a loss of tolerance to the lipoic acid-conjugated regions of the mitochondrial pyruvate dehydrogenase complex, typically to the E2 component. We aimed to identify xenobiotics that might be involved in the environmental triggering of PBC. 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 receptor, androgen receptor and peroxisome proliferator activated receptor alpha - in cell-based screens. In contrast, xenoestrogens 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 a hepatic progenitor cell. The mitochondrial effect was also demonstrated in human liver cholangiocytes from three 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 the pyruvate dehydrogenase complex 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 be a component of an environmental trigger for PBC. Therefore, further study in experimental animal models is warranted, to determine the risk of exposure to these ionic liquids. LAY SUMMARY: Primary biliary cholangitis 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. It was then shown that this chemical was metabolized into a product with structural similarity to lipoic acid, which was capable of replacing lipoic acid in mitochondrial proteins.

Environmental Xenoestrogens Super-Activate a Variant Murine ER Beta in Cholangiocytes.

High systemic levels of oestrogens are cholestatic and primary biliary cholangitis (PBC)-which is characterized by hepatic ductular inflammation-is thought to be triggered by exposure to xenobiotics such as those around landfill sites. Xenoestrogens may be a component of this chemical trigger. We therefore hypothesized that xenoestrogens are present at higher levels in the proximity of landfill sites. To test this hypothesis, soil samples were collected, extracts prepared and biological oestrogenic activity examined using cell-based reporter gene assays. Extracts from several sample sites around a landfill site contained a chemical(s) which activated the human ERα in a dose-dependent manner. Extracts from 3 separate control sampling sites were absent of any detectable activity. The mouse ERα and 2 variant mouse ERß cDNAs were cloned and extracts from sample sites around a landfill site also activated these receptors. One variant murine ERß was constitutively active when expressed in cholangiocytes, was readily inactivated by ICI182780 and activated in a dose-responsive, ICI182780-inhibitable manner by oestrogen. However, when this receptor was activated by extracts from landfill site soils, ICI182780 failed to antagonize activation. ERß was readily detectable in murine cholangiocytes and exposing mice acutely to a pooled ER activating soil extracts also gave rise to a mild cholestatic injury. These data indicate that the environment around landfill sites may contain higher levels of xenoestrogens; that these chemicals have "super-activating" characteristics with a variant ERß and therefore these chemicals could be a component of a xenobiotic insult that triggers PBC.

A comparison of methods used to calculate normal background concentrations of potentially toxic elements for urban soil.

To meet the requirements of regulation and to provide realistic remedial targets there is a need for the background concentration of potentially toxic elements (PTEs) in soils to be considered when assessing contaminated land. In England, normal background concentrations (NBCs) have been published for several priority contaminants for a number of spatial domains however updated regulatory guidance places the responsibility on Local Authorities to set NBCs for their jurisdiction. Due to the unique geochemical nature of urban areas, Local Authorities need to define NBC values specific to their area, which the national data is unable to provide. This study aims to calculate NBC levels for Gateshead, an urban Metropolitan Borough in the North East of England, using freely available data. The 'median + 2MAD', boxplot upper whisker and English NBC (according to the method adopted by the British Geological Survey) methods were compared for test PTEs lead, arsenic and cadmium. Due to the lack of systematically collected data for Gateshead in the national soil chemistry database, the use of site investigation (SI) data collected during the planning process was investigated. 12,087 SI soil chemistry data points were incorporated into a database and 27 comparison samples were taken from undisturbed locations across Gateshead. The SI data gave high resolution coverage of the area and Mann-Whitney tests confirmed statistical similarity for the undisturbed comparison samples and the SI data. SI data was successfully used to calculate NBCs for Gateshead and the median+2MAD method was selected as most appropriate by the Local Authority according to the precautionary principle as it consistently provided the most conservative NBC values. The use of this data set provides a freely available, high resolution source of data that can be used for a range of environmental applications.