Toxicity of organic arsenic compounds

Inorganic arsenic is a well-documented human carcinogen and the EFSA Panel on Contaminants in the Food Chain has concluded in their recent Scientific Opinion on Arsenic in Food that risks to human health related to the presence of inorganic arsenic in food cannot be excluded. Furthermore, recent advances in analytical technology have highlighted groups of previously unknown organic arsenicals in seafood and fish samples, namely arsenosugars and arsenolipids, for which to date no toxicological data exist. In contrast to arsenobetaine, which is not metabolized by humans, arsenosugars and arsenolipids are extensively biotransformed to a multitude of arsenic metabolites and some of these are believed to be strongly toxic. In this project we will synthesize these organoarsenicals and study their cellular bioavailability, biotransformation and toxicity. In total 8 arsenosugars, 6 arsenolipids as well as 14 related metabolites will be studied with respect to their cellular cytotoxicity, direct (induction of DNA damage and micronuclei) and indirect genotoxicity (effects on DNA repair processes) as well as their transport across an intestinal barrier model. The combined use of sensitive speciation and toxicological techniques will facilitate a correlation of individual organoarsenicals with their toxicological effects. The study outcome will represent a robust basis for the urgently required risk assessment for organic arsenic in fish and seafood and will be an important step towards further legislation.

This project has shown that some arsenic compounds naturally occurring in food are toxic to human bladder and human liver cells, and to the common fruit fly, a model whole organism. The project was a joint collaboration between the University of Münster (Potsdam) and the University of Graz to investigate the toxicity of various organic arsenic compounds that occur naturally in foods, particularly in marine foods such as fish and algae. Although the high toxicity of inorganic arsenic compounds is well known, little is known about the organic arsenic compounds. These organic arsenicals comprise both water-soluble and fat-soluble compounds. In Graz, we chemically synthesised, purified and characterised a total of 14 arsenic compounds. The toxic potential of these compounds was then tested with human bladder and human liver cells by our German collaborators. The water-soluble compounds were shown to have generally low toxicity. Three of the six fat-soluble arsenicals, however, were highly toxic to the human cells. Their toxicity was comparable to that of arsenite, but the mode of toxic action was different. Fractions from the cell experiments were then returned to Graz and analysed to determine if the cells had biotransformed the arsenic compounds. The results indicate that the toxicity is related to the fat-solubility of the compounds and their ability to cross the cell membrane, and the ease with which the compounds are biotransformed to even less polar products. The work was then extended to a whole model organism, the common fruit fly. Toxicity was again shown by the same three fat-soluble arsenicals, particularly at the developmental stages of the fly. The fat-soluble arsenicals were readily accumulated by the fly, and imaging techniques applied in Münster clearly showed the arsenic compounds in the brain tissue. Thus, these arsenic compounds, in contrast to inorganic arsenic forms, are able to cross the blood-brain barrier. The toxic consequences of this property must be investigated. The results from the project have been communicated at various scientific conferences and at a public meeting in Tokyo organised by the Japanese Food Safety Commission. The results have significant implications for future regulations concerning arsenic in food.