Cyanobacteria were present on the earth 3.5 billion years ago; since then they have colonized almost all terrestrial and aquatic ecosystems. They produce a high number of bioactive molecules, among which some are cyanotoxins. Cyanobacterial growth at high densities, forming blooms, is increasing in extension and frequency, following anthropogenic activities and climate changes, giving rise to some concern for human health and animal life exposed to cyanotoxins. Numerous cases of lethal poisonings have been associated with cyanotoxins ingestion in wild animal and livestock. In humans few episodes of lethal or severe human poisonings have been recorded after acute or short-term exposure, but the repeated/chronic exposure to low cyanotoxin levels remains a critical issue. The properties of the most frequently detected cyanotoxins (namely, microcystins, nodularins, cylindrospermopsin and neurotoxins) are here critically reviewed, describing for each toxin the available information on producing organisms, biosynthesis/genetic and occurrence, with a focus on the toxicological profile (including kinetics, acute systemic toxicity, mechanism and mode of action, local effects, repeated toxicity, genotoxicity, carcinogenicity, reproductive toxicity; human health effects and epidemiological studies; animal poisoning) with the derivation of health-based values and considerations on the risks for human health.

This report presents the extensive literature search conducted on 1) the occurrence of different cyanotoxins in food matrices; 2) the analytical methods for their detection; 3) their toxicological profile; 3) the environmental factors affecting toxicity of cyanobacterial population and 4) the combined effects of mixtures of cyanotoxins and other chemicals. It also includes a review of guidelines values or health-alert levels for cyanotoxins in food (or drinking water) adopted world-wide. The methodological aspects and the queries used in the extensive literature search, the collection and screening of retrieved papers and the inventory are briefly described in the report; all details are available in 3 supplementary appendices to this report. The analysis of collected papers indicated that most of them are focused on a single microcystin (MC) variant (MC-LR) out of the almost 100 MC known. Many studies on occurrence are affected by limited quality, due to analytical drawbacks in the detection methods and were not considered in the exposure assessment. Toxicity studies useful for the derivation of health based reference values are few, being many of them carried out using i.p. injection, which is poorly representative of actual human exposure. In addition, those toxicological studies carried out with poorly characterised cyanobacterial extracts or focused on single parameters, using a single dose, devoted to elucidation of mechanism of action, reporting qualitative description of effects were not used for data extraction. The relevant exposure scenarios are also described, although being the available data on exposure very limited, no definite conclusion on the health risks for the exposed population could be drawn. However, the possibility of risky exposure is evidenced for fish and shell-fish consumers and for blue-green algae supplements (BGAS) as well in relation to MC contamination. Finally, many data gaps were identified. © European Food Safety Authority, 2016Key words: Cyanobacteria, cyanotoxins, occurrence, toxicity, exposure, risk assessment, data gaps. Question number: EFSA-Q-2015-00141Correspondence:sc.secretariat@efsa.europa.eu Cyanotoxins in foodThe present document has been produced and adopted by the bodies identified above as author(s). This task has been carried out exclusively by the author(s) in the context of a contract between the European Food Safety Authority and the author(s), awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors.www.efsa.europa.eu/publications 2 EFSA Supporting publication 2016:EN-998NDisclaimer: The present document has been produced and adopted by the bodies identified above as author(s). This task has b...

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ABSTRACT:Among organophosphorothioate (OPT) pesticides, malathion is considered relatively safe for use in mammals. Its rapid degradation by carboxylesterases competes with the cytochrome P450 (P450)-catalyzed formation of malaoxon, the toxic metabolite. However, impurities in commercial formulations are potent inhibitors of carboxylesterase, allowing a dramatic increase in malaoxon formation. Malathion desulfuration has been characterized in human liver microsomes (HLMs) with a method based on acetylcholinesterase inhibition that is able to detect nanomolar levels of oxon. The active P450 isoforms have been identified by means of a multifaceted strategy, including the use of cDNA-expressed human P450s and correlation, immunoinhibition, and chemical inhibition studies in a panel of phenotyped HLMs. HLMs catalyzed malaoxon formation with a high level of variability (>200-fold). One or two components (K mapp1 ‫؍‬ 53-67 M; K mapp2 ‫؍‬ 427-1721 M) were evidenced, depending on the relative specific P450 content. Results from different approaches indicated that, at low malathion concentration, malaoxon formation is catalyzed by CYP1A2 and, to a lesser extent, 2B6, whereas the role of 3A4 is relevant only at high malathion levels. These results are in line with those found with chlorpyrifos, diazinon, azynphos-methyl, and parathion, characterized by the presence of an aromatic ring in the molecule. Since malathion has linear chains as substituents at the thioether sulfur, it can be hypothesized that, independently from the chemical structure, OPTs are bioactivated by the same P450s. These results also suggest that CYP1A2 and 2B6 can be considered as possible metabolic biomarkers of susceptibility to OPT-induced toxic effects at actual human exposure levels.

Cyanobacteria are ubiquitous photosynthetic micro-organisms forming blooms and scums in surface water; among them some species can produce cyanotoxins giving rise to some concern for human health and animal life. To date, more than 65 cyanobacterial neurotoxins have been described, of which the most studied are the groups of anatoxins and saxitoxins (STXs), comprising many different variants. In freshwaters, the hepatotoxic microcystins represent the most frequently detected cyanotoxin: on this basis, it could appear that neurotoxins are less relevant, but the low frequency of detection may partially reflect an a priori choice of target analytes, the low method sensitivity and the lack of certified standards. Cyanobacterial neurotoxins target cholinergic synapses or voltage-gated ion channels, blocking skeletal and respiratory muscles, thus leading to death by respiratory failure. This review reports and analyzes the available literature data on environmental occurrence of cyanobacterial neurotoxic alkaloids, namely anatoxins and STXs, their biosynthesis, toxicology and epidemiology, derivation of guidance values and action limits. These data are used as the basis to assess the risk posed to human health, identify critical exposure scenarios and highlight the major data gaps and research needs.

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List of abbreviations: AChE = acetylcholinesterase; ADRs = adverse drug reactions; AZIN = azinphos-methyl; CE = carboxylesterases; Cli = intrinsic clearance; CPF = chlorpyrifos; CYP = cytochrome P450; DIA = diazinon; DIM = dimethoate; FEN = fenthion; FMO = fl avin-containing mono-oxigenase; IMI = imipramine; Iso-MAL = isomalathion; MAL = malathion; OP = organophosphorus compounds; OPT = organophosphorothionates; PAR = parathion; PON1 = oxonases.Abstract: Organophosphorothionates (OPT) are one of the most widely used insecticides in the world, both in agriculture and in indoor environment. Therefore, a large part of the population may be exposed to this class of pesticides, either professionally or due to their presence in food and water as residues. OPTs acute toxic effects, mediated by acetylcholinesterase (AChE) inhibition, are relatively selective to insects. However, most of the thousands of deaths annually reported to be associated to pesticide exposure are due to OPT severe poisoning, resulting in hyperexcitability of the nervous system. In addition, long-term neurological and neurobehavioral effects have been described, associated to chronic exposure to OPT low levels. Metabolism is one of the main factors determining OPT adverse effects. OPTs need to be bioactivated by a cytochrome P450 (CYP)-mediated desulfuration to phosphate triesters or oxons, which are the actual powerful inhibitors of brain and serum AChE. The main detoxifi cation pathways are oxon hydrolysis catalyzed by plasma oxonases (PON1), 'sequestration' or hydrolysis by carboxylesterases, CYP-catalyzed dearylation/dealkylation. Variation activity of the enzymes involved in OPT metabolism could be expected to contribute to differences in susceptibility to OPT toxic effects, either due to genetic polymorphism or environmental infl uence, altering the bioactivation/detoxication ratio. The reactions involved in OPT metabolism in humans are described in the paper, with consequences for OPT-induced toxicity. In addition, identifi cation of biomarkers of susceptibility and interactions among different OPTs and with other xenobiotics are briefl y discussed, as factors infl uencing risk assessment of cumulative effects due to OPT exposure.