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Cyanobacteria commonly form large blooms in waterbodies; they can produce cyanotoxins, with toxic effects on humans and animals, and volatile compounds, causing bad tastes and odors (T&O) at naturally occurring low concentrations. Notwithstanding the large amount of literature on either cyanotoxins or T&O, no review has focused on them at the same time. The present review critically evaluates the recent literature on cyanotoxins and T&O compounds (geosmin, 2-methylisoborneol, β-ionone and β-cyclocitral) to identify research gaps on harmful exposure of humans and animals to both metabolite classes. T&O and cyanotoxins production can be due to the same or common to different cyanobacterial species/strains, with the additional possibility of T&O production by non-cyanobacterial species. The few environmental studies on the co-occurrence of these two groups of metabolites are not sufficient to understand if and how they can co-vary, or influence each other, perhaps stimulating cyanotoxin production. Therefore, T&Os cannot reliably serve as early warning surrogates for cyanotoxins. The scarce data on T&O toxicity seem to indicate a low health risk (but the inhalation of β-cyclocitral deserves more study). However, no data are available on the effects of combined exposure to mixtures of cyanotoxins and T&O compounds and to combinations of T&O compounds; therefore, whether the co-occurrence of cyanotoxins and T&O compounds is a health issue remains an open question., Competing Interests: The authors declare no conflicts of interest.

Increasing toxic cyanobacterial blooms in freshwater demand environmentally friendly solutions to control their growth and toxicity, especially in arid countries, where most drinking water is produced from surface reservoirs. We tested the effects of macrophyte allelochemicals on Microcystis aeruginosa and on the fundamental role of bacteria in nutrient recycling. The effects of Ranunculus aquatilis aqueous extract, the most bioactive of four Moroccan macrophyte extracts, were tested in batch systems on M. aeruginosa growth, toxin production and oxidative stress response and on the ectoenzymatic activity associated with the bacterial community. M. aeruginosa density was reduced by 82.18%, and a significant increase in oxidative stress markers was evidenced in cyanobacterial cells. Microcystin concentration significantly decreased, and they were detected only intracellularly, an important aspect in managing toxic blooms. R. aquatilis extract had no negative effects on associated bacteria. These results confirm a promising use of macrophyte extracts, but they cannot be generalized. The use of the extract on other toxic strains, such as Planktothrix rubescens , Raphidiopsis raciborskii and Chrysosporum ovalisporum , caused a reduction in growth rate but not in cyanotoxin content, increasing toxicity. The need to assess species-specific cyanobacteria responses to verify the efficacy and safety of the extracts for human health and the environment is highlighted.

Cyanotoxins, among which >200 variants of Microcystins (MC), constitute an emerging issue in food safety. Microcystins (MC) toxicity is congener-specific; however, the in vitro inhibition of PP1/PP2A (the key molecular event of MC toxicity) by single MC variants is comparable and MC toxicokinetics seems to be the critical point. Here, the variability in GSH conjugation catalysed by human recombinant enzymes and human hepatic cytosol has been compared between hydrophilic (MC-LR and MC-RR) and hydrophobic (MC-LW, MC-YR and MC-LF) variants, according to measured logPow. In vitro detoxication reaction (spontaneous plus enzymatic) is favored by the variant hydrophilicity, with MC-LF very poorly detoxified. With MC-YR and -LW the spontaneous reaction always gave the major contribution, whereas with MC-LR and -RR the enzymatic reaction became by far predominant when GSH was depleted. Consequently, the well-known GST polymorphisms seems not to be the major driver for potential human variability in susceptibility towards the MC-toxicity, except for MC-RR and -LR when GSH is depleted. Looking at these results and literature data, MC-RR (the least cytotoxic and acutely toxic in rodents) is the more hydrophilic, has the lowest OATP-mediated hepatic uptake and the highest detoxication efficiency. The opposite is true for the most lipophilic MC-LF: once entered in the cells with the highest uptake, it is very poorly detoxified, and resulted as the most toxic in various cell types. MC-dependent TK should be considered in order to estimate the variability in toxicity and to support the use of quantitative in vitro-in vivo extrapolation models of single toxins and their mixtures co-occurring in the environment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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.

Vico Lake, a volcanic meso-eutrophic lake in Central Italy, whose water is used for drinking and recreational activities, experienced the presence of the microcystins (MC) producing cyanobacterium Planktothrix rubescens. In order to assess the human health risks and to provide the local health authorities with a scientific basis for planning tailored monitoring activities, we studied P. rubescens ecology and toxicity for two years. P. rubescens generally dominated the phytoplankton community, alternating with Limnothrix redekei, potentially toxic. P. rubescens was distributed throughout the water column during winter; in summer it produced intense blooms where drinking water is collected (-20 m); here MC were detected all year round (0.5-5 μg/L), with implications for drinking water quality. In surface waters, MC posed no risk for recreational activities in summer, while in winter surface blooms and foams (containing up to 56 μg MC/L) can represent a risk for people and children practicing water sports and for animals consuming raw water. Total phosphorus, phosphate and inorganic nitrogen were not relevant to predict densities nor toxicity; however, a strong correlation between P. rubescens density and aminopeptidase ectoenzymatic activity, an enzyme involved in protein degradation, suggested a role of organic nitrogen for this species. The fraction of potentially toxic population, determined both as mcyB(+)/16SrDNA (10-100%) and as the MC/mcyB(+) cells (0.03-0.79 pg MC/cell), was much more variable than usually observed for P. rubescens. Differently from other Italian and European lakes, the correlation between cell density or the mcyB(+) cells and MC explained only ∼50 and 30% of MC variability, respectively: for Vico Lake, monitoring only cell or the mcyB(+) cell density is not sufficient to predict MC concentrations, and consequently to protect population health. Finally, during a winter bloom one site has been sampled weekly, showing that monthly sampling during such a phase could greatly underestimate the 'hazard'. Our results highlight the need to adopt a stepwise monitoring activity, considering the lake and the cyanobacteria specific features. This activity should be complemented with communication to the public and involvement of stakeholders., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

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.

Cyanotoxins (CTX) are widely produced by several cyanobacteria (CB), increasingly spreading in most water bodies and terrestrial habitats, and represent a risk for human health. CB are prokaryotes, and although mostly autotrophic, several examples of heterotrophy in symbiotic relationship with different organisms have been described. In addition to the known routes of exposure, it has been hypothesized that CB might 'colonize' human intestine with relevant implications for human health. Colonization is a complex process and requires specific features of the possible invaders. Still, a short-term persistence as living and toxin-producing organisms within the intestinal lumen of the host could represent an 'internal' source of exposure to CTX. In this work we ran microcosm experiments (4-18days), looking at Microcystis aeruginosa PCC7806 resistance and cyanotoxin-producing capabilities in darkness, 37°C, pH 2, and subsequent recovery in a rich medium, in darkness, 37°C, in the presence of enteric bacteria, mimicking few important features of the gastrointestinal environment. We measured cyanobacterial populations and growth, microcystin (MC) production and the presence of mcyB gene. M. aeruginosa could grow in the dark at 37°C up to 17days, and survive at pH 2 at a rate between 30% and 70%, depending on the age and toxicity of the starting culture. Cell lysis resulted in a substantial amounts of MC released, not degraded at gastric pH. Following the acidic passage, still in the dark at 37°C, M. aeruginosa restarted to grow within 24h for the next 3-4days, independently on the presence of intestinal bacteria, maintaining the MC cell quota and mcyB gene. Our results show new features of CB: a significant resistance of M. aeruginosa in conditions far from its optimal one, that is an environment mimicking some of the important characteristics of human gastrointestinal tract, suggesting the possibility of an internal source of exposure to CTX, with implications for the risk assessment., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Many cyanobacterial species can produce cyanotoxins, among which mycrocistins (MC) are a group of ≈100 congeners of hepatotoxic cyclic heptapeptides. MC-RR differs from MC-LR, the most studied congener only for one residue (arginine vs leucine), resulting in a ten-fold difference in the acute toxicity in mice. Although humans may be exposed to MC through several routes and kinetics appeared to be the major factor affecting congener-specific toxicity, little is known on MC metabolism. The accepted pathway for MC detoxication is GSH conjugation: here the MC-RR conjugation with GSH catalyzed by 5 recombinant human GSTs and human liver cytosol (HLC) has been characterized and appeared to be more efficient than MC-LR conjugation. The catalytic efficiency score is T1-1>A1-1≈P1-1>M1-1>A3-3 (0.161-0.056pmol GSMC-RR (μgproteinminμM)(-1)). In HLC the spontaneous reaction is favored vs the enzymatic one (ratio 3:1) at physiological GSH content. However, at low MC-RR concentrations, representative of repeated oral exposure, and low GSH content (down to 0.05mM), possibly associated to exposure to drugs or in patients affected by several pathologies, the relevance of the enzymatic reaction progressively increases, providing the predominant contribution to MC-RR detoxication., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

The anode of a two-chamber methane-producing microbial electrolysis cell (MEC) was poised at +0.200V vs. the standard hydrogen electrode (SHE) and continuously fed (1.08gCOD/Ld) with acetate in anaerobic mineral medium. A gas mixture (carbon dioxide 30vol.% in N(2)) was continuously added to the cathode for both pH control and carbonate supply. At the anode, 94% of the influent acetate was removed, mostly through anaerobic oxidation (91% coulombic efficiency); the resulting electric current was mainly recovered as methane (79% cathode capture efficiency). Low biomass growth was observed at the anode and ammonium was transferred through the cationic membrane and concentrated at the cathode. These findings suggest that the MEC can be used for the treatment of low-strength wastewater, with good energy efficiency and low sludge production., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Blue green algae supplements (BGAS) are generally proposed as health-promoting natural products for their purported beneficial effects. Spirulina spp. and Aphanizomenon flos aquae are mainly used in BGAS production. They are usually collected from the natural environment, where other potentially toxic cyanobacteria can be present, making possible BGAS contamination by cyanotoxins, with potential risk for human health. In this work we apply a combined approach, by using chemical and molecular techniques, on BGAS of 17 brands available in Italy. Samples containing Spirulina-only were free of contamination. The Aphanizomenon flos aquae-based samples were contaminated by highly variable levels of microcystins (MC-LR and MC-LA congeners), up to 5.2 μg MC-LR equivalents per gram product. The highest variability (up to 50 fold) was among batches of the same brand, although intra-batch differences were also evidenced. PCR analyses were positive only for the presence of Microcystis sp., identified as the toxin-producing species responsible for contamination. At the maximum contamination levels found, a risk for consumers can be expected following chronic or sub-chronic exposure to a reasonable daily BGAS consumption of 4 g. The need for a strict monitoring by producers and Health Authority to assure an adequate protection for consumers is underscored., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

This paper describes emerging issue related to cyanobacterial dynamics and toxicity and human health risks. Data show an increasing cyanobacteria expansion and dominance in many environments. However there are still few information on the toxic species fitness, or on the effects of specific drivers on toxin production. Open research fields are related to new exposure scenario (cyanotoxins in water used for haemodialysis and in food supplements); to new patterns of co-exposure between cyanotoxins and algal toxins and/or anthropogenic chemicals; to dynamics affecting toxicity and production of different cyanotoxin variants under environmental stress; to the accumulation of cyanotoxins in the food web. In addition, many data gaps exist in the characterization of the toxicological profiles, especially about long term effects.

Many cyanobacterial species are able to produce cyanotoxins as secondary metabolites. Among them, microcystins (MC) are a group of around 80 congeners of toxic cyclic heptapeptides. MC-LR is the most studied MC congener, in view of its high acute hepatotoxicity and tumor promoting activity. Humans may be exposed to cyanotoxins through several routes, the oral one being the most important. The accepted pathway for MC-LR detoxication and excretion in the urine is GSH conjugation. The GSH adduct (GS-MCLR) formation has been shown to occur spontaneously and enzymatically, catalyzed by glutathione transferases (GSTs). The enzymatic reaction has been reported but not characterized both in vitro and in vivo in animal and plant species. No data are available on humans. In the present work, the MC-LR conjugation with GSH catalyzed by five recombinant human GSTs (A1-1, A3-3, M1-1, P1-1, and T1-1) has been characterized for the first time. All GSTs are able to catalyze the reaction; kinetic parameters K(m), k(cat), and their relative specific activities to form GS-MCLR were derived (T1-1 > A1-1 > M1-1 > A3-3 ≫ P1-1). In the range of MC tested concentrations used (0.25-50 μM) GSTT1-1 and A1-1 showed a typical saturation curve with similar affinity for MC-LR (≈80 μM; k(cat) values 0.18 and 0.10 min(-1), respectively), A3-3 and M1-1 were linear, whereas GSTP1-1 showed a temperature-dependent sigmoidal allosteric curve with a k(cat) = 0.11 min(-1). The enzymes mainly expressed in the liver and gastrointestinal tract, GSTA1-1, T1-1, and M1-1, seemed to be mainly involved in the MC-LR detoxification after oral exposure, whereas P1-1 kinetics and location in the skin suggest a role related to dermal exposure. Considering the high frequency of some GST polymorphism, especially M1 and T1 gene deletion, with complete loss in activity, this information could be the first step to identify groups of individual at higher risk associated with MC exposure.

Increasing concern for human health related to cyanotoxin exposure imposes the identification of pattern and level of exposure; however, current monitoring programs, based on cyanobacteria cell counts, could be inadequate. An integrated approach has been applied to a small lake in Italy, affected by Planktothrix rubescens blooms, to provide a scientific basis for appropriate monitoring program design. The cyanobacterium dynamic, the lake physicochemical and trophic status, expressed as nutrients concentration and recycling rates due to bacterial activity, the identification/quantification of toxic genotype and cyanotoxin concentration have been studied. Our results indicate that low levels of nutrients are not a marker for low risk of P. rubescens proliferation and confirm that cyanobacterial density solely is not a reliable parameter to assess human exposure. The ratio between toxic/non-toxic cells, and toxin concentrations, which can be better explained by toxic population dynamic, are much more diagnostic, although varying with time and environmental conditions. The toxic fraction within P. rubescens population is generally high (30-100%) and increases with water depth. The ratio toxic/non-toxic cells is lowest during the bloom, suggesting a competitive advantage for non-toxic cells. Therefore, when P. rubescens is the dominant species, it is important to analyze samples below the thermocline, and quantitatively estimate toxic genotype abundance. In addition, the identification of cyanotoxin content and congeners profile, with different toxic potential, are crucial for risk assessment., (Copyright 2009 Elsevier Ltd. All rights reserved.)

The control of groundwater and surface water quality in relation to the presence of pesticides and their metabolites is a rather complicated task. National and local authorities with the responsibility to guarantee an adequate quality of water cannot rely on international guidelines for monitoring activities. In a national project, forty-three pesticides and pesticide metabolites were selected on the basis of sale, monitoring and physical-chemical data, and investigated from some of the main Italian agricultural areas, susceptible to pesticide contamination. Twelve compounds were found in the tested water samples at levels exceeding the 0.1 µg/L European Union (EU) limit for drinking water (European Directive 98/83/EC). Maximum levels up to 0.62 were determined. Several water samples were characterized by the simultaneous occurrence of pesticides and their metabolites (up to ten). In some samples, the total concentration of pesticides and their metabolites was higher than the EU limit of 0.5 µg/L. Total triazine concentrations up to 1.02 µg/L were found. In all the cases the highest concentrations were well below the respective guideline values defined by the World Health Organization (WHO) for drinking water quality.

Background, Aims and Scope: Laboratory studies were conducted with the aim of defining the leaching potential of some phenylureas and their metabolites. A first study was performed for calculating their leaching index (as GUS) on the base of intrinsic properties: persistence (as DT50) and mobility (as Koc) in soil. Another study consisted of aged column leaching experiments whose meaning was to semi-quantify the occurrence of the tested compounds in the leachates, so simulating in field conditions., Methods: The tested compounds were: diuron, linuron and monolinuron (parents); 3,4-dichloroaniline (DCA), 4-chloroaniline (CLA), 1-(3,4-dichlorophenyl)-3-methylurea (DCPMU), 1-(3,4-dichlorophenyl)urea (DCPU), 1-(4-chlorophenyl)urea (CPU) and monuron, this latter considered both as a metabolite and parent compound. The Koc values of the examined substances were determined by the HPLC screening methods, according to the OECD TG 121. DT50 determinations and aged column leaching experiments were carried out according to SETAC procedures., Results and Discussion: The examined compounds showed a rather wide range of persistence in soil, with DT50 values less than 2 days for DCA and CLA, close to 8 days for DCPU and CPU and from 16 (diuron) up to 24.8 (DCPMU) days for the others. Their mobility was generally high, based on their Koc values, which ranged from 33 (CPU) to 406 (linuron). The GUS indices indicated that monuron has a clear potential to contaminate groundwater (> 2.8); DCPMU, monolinuron, CPU and diuron are intermediate contaminants (1.8-2.8). Linuron, DCPU, CLA and DCA exhibited a non-leaching behaviour (< 1.8). The aged leaching column experiments showed that parents were found in the leachates at very high percentages respect to the doses applied. The metabolites reached much less percentages, the highest values were observed for monuron from diuron (5.7), CPU (7.2) and DCPMU (8.2%)., Conclusion: Diuron, Monuron, CPU and DCPMU on the basis of their intrinsic properties, formation from their parents and occurrence in leachates from aged column leaching studies, seem to possess the characteristics of groundwater contaminants. The methodological approach of this study is relatively easy and rapid, hence it can represent a tool for a first screening of compounds such as pesticide metabolites (generally available only in small quantities and for which a field study is not conceivable) or other compounds for which not adequate environmental data are available.