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Toxicology of microcystins with reference to cases of human intoxications and epidemiological investigations of exposures to cyanobacteria and cyanotoxins

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Abstract

Blooms of cyanobacteria have been documented throughout history, all over the world. Mass populations of these organisms typically present hazards to human health and are known for the production of a wide range of highly toxic metabolites—cyanotoxins, of which among the most common and most investigated are the microcystins. The toxicity of the family of microcystin congeners to animal and cell models has received much attention; however, less is known about their negative effects on human health, whether via acute or chronic exposure. Useful information may be acquired through epidemiological studies since they can contribute to knowledge of the relationships between cyanotoxins and human health in environmental settings. The aim of this review is to compile and evaluate the available published reports and epidemiological investigations of human health incidents associated with exposure to mass populations of cyanobacteria from throughout the world and to identify the occurrence and likely role of microcystins in these events. After an initial screening of 134 publications, 42 publications (25 on the chronic and 17 on the acute effects of cyanotoxins) describing 33 cases of poisonings by cyanobacterial toxins in 11 countries were reviewed. The countries were Australia, China, Sri Lanka, Namibia, Serbia, Sweden, UK, Portugal, Brazil, USA, and Canada. At least 36 publications link cyanobacteria/cyanotoxins including microcystins to adverse human health effects. The studies were published between 1960 and 2016. Although the scattered epidemiological evidence does not provide a definitive conclusion, it can serve as additional information for the medical assessment of the role of microcystins in cancer development and other human health problems. This paper discusses the major cases of cyanotoxin poisonings as well as the strengths, weaknesses, and importance of the performed epidemiological research. This study also proposes some recommendations for future epidemiological work.

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Notes

  1. All the Latin genus and species names are taken from the original papers as such without changing the nomenclature.

References

  • Affan A, Khomayis HS, Harbi SMA, Haque M, Khan S (2015) Effect of environmental factors on cyanobacterial abundance and cyanotoxins production in natural and drinking water, Bangladesh. Pak J Biol Sci 18:50–58. doi:10.3923/pjbs.2015.50.58

    Article  PubMed  Google Scholar 

  • Alonso-Andicoberry C, García-Villada L, Lopez-Rodas V, Costas E (2002) Catastrophic mortality of flamingos in a Spanish national park caused by cyanobacteria. Vet Rec 151:706–707

    CAS  PubMed  Google Scholar 

  • Alvarca E, Andrade M, Dias E, Sam Bento F, Batoreu MCC, Jordan P, Silva MJ, Pereira P (2009) Morphological and ultrastructural effect of MC-LR from Microcystis aeruginosa extracts on a kidney cell line. Toxicon 30:1–12

    Google Scholar 

  • Anjos FMA, Bittencourt-Oliveira MC, Zajac MP, Hiller S, Christian B, Erler K, Luckas K, Pinto E (2006) Detection of harmful cyanobacteria and their toxins by both PCR amplification and LC-MS during a bloom event. Toxicon 48(3):239–245

    Article  PubMed  CAS  Google Scholar 

  • Annadotter H, Cronberg G, Lawton LA, Hanson H-B (1996) An outbreak of gastro-enteritis associated with consumption of cyanobacteria. In: Kaas H, Moestrup O, Henriksen P (eds) Abstracts of the first international congress on toxic cyanobacteria, 2. University of Copenhagen, Denmark

    Google Scholar 

  • Annadotter H, Cronberg G, Lawton LA, Hansson HB, Göthe U, Skulberg OM (2001) An extensive outbreak of gastroenteritis associated with the toxic cyanobacterium Planktothrix agardhii (Oscillatoriales, Cyanophyceae) in Scania, South Sweden. In: Chorus I (ed) Cyanotoxins—occurrence, causes, consequences. Springer, Berlin, pp 200–208

    Google Scholar 

  • Araujo De Olivera P (1995) Effects of cyanobacteria on drinking water and human health: an epidemiological study in Evora, Portugal. Assessing and managing health risks from drinking water contamination: approaches and applications. In: Proceedings of the Rome symposium, September 1994. IAHS Publ. no. 233, pp 101–110

  • Azevedo SMFO, Evans WR, Carmichael WW, Namikoshi M (1994) First report of microcystins from a Brazilian isolate of the cyanobacterium Microcystis aeruginosa. J Appl Phycol 6(15):261–265

    Article  CAS  Google Scholar 

  • Azevedo SM, Carmichael WW, Jochimsen EM, Rinehart KL, Lau S, Shaw GR, Eaglesham GK (2002) Human intoxication by microcystins during renal dialysis treatment in Caruaru-Brazil. Toxicology 181–182:441–446

    Article  PubMed  Google Scholar 

  • Bagu JR, Sykes B, Craig M, Holmes CFB (1997) A molecular basis for different interactions of marine toxins with protein phosphatase 1. J Biol Chem 272:5087–5097

    Article  CAS  PubMed  Google Scholar 

  • Bell SG, Codd GA (1994) Cyanobacterial toxins and human health. Rev Med Microbiol 5:256–264

    Article  Google Scholar 

  • Bellem F (2014) As cianobactérias na água e a morbilidade e mortalidade na região do Alentejo. Dissertation, Universidade de Évora

  • Bellem F, Nunes S, Morais M (2013) Cyanobacteria toxicity: potential public health impact in south Portugal populations. J Toxicol Environ Health Part A 76(4–5):263–271

    Article  CAS  PubMed  Google Scholar 

  • Belykh OI, Sorokovikova EG, Federova GA, Kaluzhnaya OV, Korneva ES, Sakirko MV, Sherbakova TA (2011) Presence and genetic diversity of microcystin-producing cyanobacteria (Anabaena and Microcystis) in Lake Kotokel (Russia, Lake Baikal Region). Hydrobiologia 671(1):241–252

    Article  CAS  Google Scholar 

  • Bernard C, Ballot A, Thomazeau S, Maloufi S, Furey A, Mankiewicz-Boczek J, Pawlik-Skowronska B, Capelli C, Salmaso N (2017) Cyanobacteria associated with the production of cyanotoxins. In: Meriluoto J, Spoof L, Codd GA (eds) Handbook of cyanobacterial monitoring and cyanotoxin analysis. Wiley, Chichester, pp 501–525

  • Bhopal RS (2002) Concepts of epidemiology: an integrated introduction to the ideas, theories, principles and methods of epidemiology. Oxford University Press, Oxford

    Google Scholar 

  • Billam M (2006) Development and validation of microcystin biomarkers for exposure studies. Dissertation, Texas Tech University

  • Bittencourt-Oliveira MC, Santos DMS, Moura NA (2010) Toxic cyanobacteria in reservoirs in northeastern Brazil: detection using a molecular method. Braz J Biol 70(4):1005–1010

    Article  CAS  PubMed  Google Scholar 

  • Blank CE, Sanchez-Baracaldo P (2010) Timing of morphological and ecological innovation in the cyanobacteria—a key to the understanding of the rise of atmospheric oxygen. Geobiology 9:495–514

    Google Scholar 

  • Botes DP, Wessels PL, Kruger H, Runnegar MTC, Santikarn S, Smith RJ, Barna JJ, Williams DH (1985) Structural studies on cyanoginosins-LR, YR, YA, and YM, peptide toxins from Microcystis aeruginosa. J Chem Soc Perkins Trans I 1:2747–2748

    Article  Google Scholar 

  • Botha N, Van de Venter M, Downing TG, Shepard EG, Gehringer EG (2004) The effect of intraperitoneally administered microcystin-LR on the gastrointestinal tract of Balb/c mice. Toxicon 43:251–254

    Article  CAS  PubMed  Google Scholar 

  • Bourke ATC, Hawes RB, Neilson A, Stallman ND (1983) An outbreak of hepato-enteritis (the Palm Island mystery disease) possibly caused by algal intoxication. Toxicon 3:45–48

    Article  Google Scholar 

  • Bouvy M, Molica R, Oliveira S, Marinho M, Beker B (1999) Dynamics of a toxic cyanobacterial bloom (Cylindrospermopsis raciborskii) in a shallow reservoir in the semi-arid region of Northeast Brazil. Aquat Microb Ecol 20(3):285–297

    Article  Google Scholar 

  • Bradford-Hill A (1965) The environment and disease: association or causation? Proc R Soc Med 58(5):295–300

    Google Scholar 

  • Bruno M, Gallo P, Messineo V, Melchiorre S (2012) Health risk associated with microcystin presence in the environment: the case of an Italian lake (Lake Vico, Central Italy). Int J Environ Prot 2:34–41

    Google Scholar 

  • Burger JS, Grabow WOL, Kfir R (1989) Detection of endotoxins in reclaimed and conventionally treated drinking water. Water Res 23(6):733–738

    Article  CAS  Google Scholar 

  • Byth S (1980) Palm Island mystery disease. Med J Aust 2:40–42

    CAS  PubMed  Google Scholar 

  • Campos A, Vasconselos V (2010) Molecular mechanisms of microcystin toxicity in animal cells. Int J Mol Sci 11(1):268–287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carmichael WW (1992) Cyanobacteria secondary metabolites—the cyanotoxins. J Appl Bacteriol 72(6):445–459

    Article  CAS  PubMed  Google Scholar 

  • Carmichael WW, Li R (2006) Cyanobacteria toxins in the Salton Sea. Saline Syst 2:5. doi:10.1186/1746-1448-2-5

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Carmichael WW, Jones CLA, Mahmood NA, Theiss WC, Krogh P (1985) Algal toxins and water-based diseases. CRC Crit Rev Environ Control 15(3):275–313

    Article  CAS  Google Scholar 

  • Carmichael WW, Azevedo SM, An JS, Molica RJ, Jochimsen EM, Lau S, Rinehart KL, Shaw GR, Eaglesham GK (2001) Human fatalities from cyanobacteria: chemical and biological evidence for cyanotoxins. Environ Health Perspect 109(7):663–668

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cates W (1982) Epidemiology: applying principles to clinical practice. Contemp Ob/Gyn 20:147–161

    Google Scholar 

  • Chen G, Yu S, Wei G (1996) Studies on microcystin contents in different drinking water in highly endemic area of liver cancer. Zhonghua Yu Fang Yi Xue Za Zhi 30:6–9

    CAS  PubMed  Google Scholar 

  • Chen Y, Yu S-Z, Yang J-B (2002) Microcystins in drinking water and cancer mortality in a city along Taihu Lake, China. Oncology 12:485–488

    Google Scholar 

  • Chen T, Wang Q, Cui J, Yang W, Shi Q, Hua Z, Ji J, Shen P (2005) Induction of apoptosis in mouse liver by microcystin-LR: a combined transcriptomic, proteomic, and simulation strategy. Mol Cell Proteomics 4:958–974

    Article  CAS  PubMed  Google Scholar 

  • Chen J, Xie P, Li L, Xu J (2009) First identification of the hepatotoxic microcystins in the serum of a chronically exposed human population together with indication of hepatocellular damage. Toxicol Sci 108:81–89

    Article  CAS  PubMed  Google Scholar 

  • Chen L, Chen J, Zhang X, Xie P (2016) A review of reproductive toxicity of microcystins. J Hazard Mater 301:381–399

    Article  CAS  PubMed  Google Scholar 

  • Chorus I (2001) Introduction: cyanotoxins—research for environmental safety and human health. In: Chorus I (ed) Cyanotoxins occurrence, causes, consequences. Springer-Verlag, Berlin, pp 1–4

    Google Scholar 

  • Chorus I, Bartram J (eds) (1999) Toxic cyanobacteria in water. A guide to their public health consequences, monitoring and management. E&FN SPON, London, England

  • Clark SP, Davis MA, Ryan TP, Searfoss GH, Hooser SB (2007) Hepatic gene expression changes in mice associated with prolonged sublethal microcystin exposure. Toxicol Pathol 35(4):594–605

    Article  CAS  PubMed  Google Scholar 

  • Codd GA, Beattie KA (1991) Cyanobacteria (blue-green algae) and their toxins: awareness and action in the United Kingdom. PHLS Microbiol Dig 8(3):82–86

    Google Scholar 

  • Codd GA, Bell SG (1996) The occurrence and fate of blue-green algal toxins in freshwaters. National Rivers Authority R D Report 29. London, Her Majesty’s Stationery Office

  • Codd GA, Steffensen DA, Burch MD, Baker PD (1994) Toxic blooms of cyanobacteria in Lake Alexandrina, South Australia—learning from history. Aust J Mar Freshw Res 45:731–736

    Article  Google Scholar 

  • Codd GA, Bell S, Kaya K, Ward C, Beattie KA, Metcalf JS (1999) Cyanobacterial toxins, exposure routes and human health. Eur J Phycol 34:405–415

    Article  Google Scholar 

  • Codd GA, Lindsay J, Young LF, Morrison LF, Metcalf JS (2005a) Harmful cyanobacteria, Chap. 1. In: Huisman J, Matthijs HCP, Visser PM (eds) Harmful cyanobacteria. Springer, Netherlands, pp 1–23

    Chapter  Google Scholar 

  • Codd GA, Azevedo SMFO, Bagchi SN, Burch MD, Carmichael WW, Harding WR, Kaya K, Utkilen HC (2005b) CYANONET: a global network for cyanobacterial bloom and toxin risk management: initial situation assessment and recommendations. International Hydrological Programme, Technical documents in Hydrology, No. 76. UNESCO, Paris, pp 1–138

  • Codd GA, Plinski M, Surosz W, Hutson J, Fallowfield HJ (2015) Publication in 1672 of animal deaths at the Tuchomskie Lake, northern Poland and a likely role of cyanobacterial blooms. Toxicon 108:285–286

    Article  CAS  PubMed  Google Scholar 

  • Cronberg G (1999) Qualitative and quantitative investigations of phytoplankton in Lake Ringsjon, Scania, Sweden. Hydrobiologia 404:27–40

    Article  Google Scholar 

  • Cronberg G, Gieske A, Martins E, Nengu PJ, Stenstrom I-M (1995) Hydrobiological studies of the Okavango Delta and Kwando/Linyanti/Chobe river, Botswana. Surf Water Qual Anal Botsw Notes Rec 27:151–226

    Google Scholar 

  • Cronberg G, Annadotter H, Lawton LA (1999) The occurrence of toxic blue-green algae in Lake Ringsjon, southern Sweden, despite nutrient reduction and fish biomanipulation. Hydrobiologia 404:123–129

    Article  Google Scholar 

  • Deng X, Ito T, Carr B, Mumby M, May WS Jr (1998) Reversible phosphorylation of Bcl2 following interleukin 3 or bryostatin 1 is mediated by direct interaction with protein phosphatase 2A. J Biol Chem 273(51):34157–34163

    Article  CAS  PubMed  Google Scholar 

  • Dillenberg HO, Dehnel MK (1960) Toxic water bloom in Saskatchewan 1959. Can Med Assoc J 83:1151–1154

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ding WX, Shen HM, Ong CN (2000) Microcystic cyanobacteria extract induces cytoskeletal disruption and intracellular glutathione alteration in hepatocytes. Environ Health Perspect 108(7):605–609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ding XS, Li XY, Duan HY, Chung IK, Lee JA (2006) Toxic effects of Microcystis cell extracts on the reproductive system of male mice. Toxicon 48:973–979

    Article  CAS  PubMed  Google Scholar 

  • Dissanayake DM (2010) The cyanobacterial toxins: a hidden health hazard. Selected invited speaker abstracts from the 9th Asia Pacific Association of Medical Toxicology, Hanoi, Vietnam, 16–19 Nov 2010

  • Drobac D (2015) Putevi izloženosti čoveka cijanotoksinima i njihov uticaj na zdravlje. Dissertation, University of Novi Sad

  • Drobac D, Svirčev Z, Tokodi N, Vidovic M, Baltic V, Bozic-Krstic V, Lazic D, Pavlica T (2011) Microcystins—potential risk factors in carcinogenesis of primary liver cancer in Serbia. Geogr Pannonica 15(3):70–80

    Google Scholar 

  • Drobac D, Tokodi N, Simeunovic J, Baltić V, Stanić D, Svirčev Z (2013) Human exposure to cyanotoxins and their health effects. Arh Hig Rada Toksikol 64(2):305–316

    Article  CAS  Google Scholar 

  • Duan H, Ma R, Xu X, Kong F, Zhang S, Kong W, Hao J, Shang L (2009) Two-decade reconstruction of algal blooms in China’s Lake Taihu. Environ Sci Technol 43(10):3522–3528

    Article  CAS  PubMed  Google Scholar 

  • Edwards C, Beattie KA, Scrimgeour CM, Codd GA (1992) Identification of anatoxin-a in benthic cyanobacteria (blue-green-algae) and in associated dog poisonings at Loch Insh, Scotland. Toxicon 30:1165–1175

    Article  CAS  PubMed  Google Scholar 

  • Edwards C, Annadotter H, Codd GA (1994) Cyanobacterial (blue-green algal) toxins in waterbodies and supply sources: scientific advances and management needs. In: Proceedings of the Stockholm water symposium. Stockholm Vatten. Stockholm, pp 391–400

  • El Saadi OE, Esterman AJ, Cameron S, Roder DM (1995) Murray River water, raised cyanobacterial cell counts, and gastrointestinal and dermatological symptoms. Med J Aust 162(3):122–125

    PubMed  Google Scholar 

  • Elleman TC, Falconer IR, Jackson ARB, Runnegar MTC (1978) Isolation, characterization and pathology of the toxin from a Microcystis aeruginosa (= Anacystis cyanea) bloom. Aust J Biol Sci 31:209–218

  • El-Serag HB, Mason AC (1999) Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 340:745–750

    Article  CAS  PubMed  Google Scholar 

  • EPA United States Environmental Protection Agency (2015) Health effects support document for the cyanobacterial toxin cylindrospermopsin. U.S. Environmental Protection Agency Office of Water (4304t), Health and Ecological Criteria Division Washington, DC, 20460

  • Eriksson JE, Meriluoto J, Lindholm T (1986) Can cyanobacterial toxins accumulate in aquatic food chains? In: Proceedings of the 4th international symposium of microbiol ecology, Ljubljana (Yugoslavia), pp 655–658

  • Falconer IR (1989) Effects on human health of some toxic cyanobacteria (blue green algae) in reservoirs, lakes and rivers. Toxic Assess 4:175–184

    Article  CAS  Google Scholar 

  • Falconer IR (1991) Tumor promotion and liver injury caused by oral consumption of cyanobacteria. Environ Toxicol Water Qual 6(2):177–184

    Article  Google Scholar 

  • Falconer I (1999) An overview of problems caused by toxic blue-green algae (cyanobacteria) in drinking and recreational water. Environ Toxicol 14:5–12

    Article  CAS  Google Scholar 

  • Falconer IR (2001) Toxic cyanobacterial bloom problems in Australian waters: risks and impacts on human health. Phycology 40(2):228–233

    Article  Google Scholar 

  • Falconer IR (2007) Health effects associated with controlled exposures to cyanobacterial toxins. In: Proceedings of the interagency, international symposium on cyanobacterial harmful algal blooms (ISOC-HAB), State of the science and research needs, pp 617–622

  • Falconer IR, Buckley TH (1989) Tumour promotion by Microcystis sp., a blue-green alga occurring in water supplies. Med J Aust 150:351

    CAS  PubMed  Google Scholar 

  • Falconer IR, Yeung SK (1992) Cytoskeletal changes in hepatocytes induced by Microcystis toxins and their relation to hyperphosphorylation of cell proteins. Chem Biol Interact 81:181–196

    Article  CAS  PubMed  Google Scholar 

  • Falconer IR, Beresford AM, Runnegar MT (1983) Evidence of liver damage by toxin from a bloom of the blue-green alga, Microcystis aeruginosa. Med J Aust 1(11):511–514

    CAS  PubMed  Google Scholar 

  • Fischer WJ, Altheimer S, Cattori V, Meier PJ, Dietrich DR, Hagenbuch B (2005) Organic anion transporting polypeptides expressed in liver and brain mediate uptake of microcystin. Toxicol Appl Pharmacol 203(3):257–263

    Article  CAS  PubMed  Google Scholar 

  • Fleming LE, Stephan W (2001) Blue-green algae, their toxins and public health issues. The Florida Harmful Algal Bloom Taskforce, Florida St. Petersburg

    Google Scholar 

  • Fleming LE, Rivero C, Burns J, Williams C, Bean JA, Shea KA, Stinn J (2002) Blue-green algal (cyanobacterial) toxins, surface drinking water, and liver cancer in Florida. Harmful Algae 1(2):157–168

    Article  CAS  Google Scholar 

  • Francis G (1878) Poisonous Australian lake. Nature 18:11–12

    Article  Google Scholar 

  • Fu WY, Xu LH, Yu YN (2005) Proteomic analyses of cellular response to microcystin in human amnion FL cells. J Proteome Res 4:2207–2215

    Article  CAS  PubMed  Google Scholar 

  • Fujiki H, Suganuma M, Yoshizawa S, Kanazawa H, Sugimura T, Manam S, Kahn SM, Jiang W, Hoshina S, Weinstein IB (1989) Codon 61 mutations in the c-Harvey-ras gene in mouse skin tumors induced by 7,12-dimethylbenz(a)anthracene plus okadaic acid class tumor promoters. Mol Carcinog 2(4):184–187

    Article  CAS  PubMed  Google Scholar 

  • Gaudin J, Huet S, Jarry G, Fessard V (2008) In vivo DNA damage induced by the cyanotoxin microcystin-LR: comparison of intra-peritoneal and oral administration by use of the comet assay. Mutat Res 652:65–71

    Article  CAS  PubMed  Google Scholar 

  • Gehringer MM (2004) Microcystin-LR and okadaic acid-induced cellular effects: a dualistic response. FEBS Lett 557:1–8

    Article  CAS  PubMed  Google Scholar 

  • Ghosh S, Khan SA, Wickstrom M, Beasley V (1995) Effects of microcystin-LR on actin and the actin-associated proteins alpha-actinin and talin in hepatocytes. Nat Toxins 3(6):405–414

    Article  CAS  PubMed  Google Scholar 

  • Giannuzzi L, Sedan D, Echenique R, Andrinolo D (2011) An acute case of intoxication with cyanobacteria and cyanotoxins in recreational water in Salto Grande Dam, Argentina. Mar Drugs 9:2164–2175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Graham JL, Loftin K, Ziegler AC, Meyer MT (2008) Guidelines for design and sampling for cyanobacterial toxin and taste-and-odor studies in lakes and reservoirs: U.S. Geological Survey Scientific Investigations Report, 2008–5039, pp 1–39

  • Graham JL, Loftin K, Meyer MT, Ziegler AC (2010) Cyanotoxin mixtures and taste-and-odor compounds in cyanobacterial blooms from the midwestern United States. Environ Sci Technol 44(19):7361–7368

    Article  CAS  PubMed  Google Scholar 

  • Griffiths DJ, Saker ML (2003) The Palm Island mystery disease 20 years on: a review of research on the cyanotoxin cylindrospermopsin. Environ Toxicol 18(2):78–93

    Article  CAS  PubMed  Google Scholar 

  • Gunnarsson H, Sanseovic A-M (2001) Possible linkages between algae toxins in drinking water and related illnesses in Windhoek, Namibia. Bachelor’s degree project. University of Kristianstad, Sweden

    Google Scholar 

  • Hagenbuch B, Gao B, Meier PJ (2002) Transport of xenobiotics across the blood–brain barrier. News Physiol Sci 17:231–234

    CAS  PubMed  Google Scholar 

  • Hallegraeff GM (1992) Harmful algal blooms in the Australian region. Mar Pollut Bull 25(5–8):186–190

    Article  Google Scholar 

  • Handeland K, Ostensvik O (2010) Microcystin poisoning in roe deer (Capreolus capreolus). Toxicon 56:1076–1078. doi:10.1016/j.toxicon.2010.06.023

    Article  CAS  PubMed  Google Scholar 

  • Harada K-I, Tsuji K, Watanabe MF, Kondo F (1996) Stability of microcystins from cyanobacteria—III. Effect of pH and temperature. Phycologia 35(6S):83–88

    Article  Google Scholar 

  • Hawkins PR (1986) Some aspects of the limnology of a small tropical impoundment and an assessment of two techniques for managing water quality, with special reference to the growth of cyanobacteria. Dissertation, James Cook University

  • Hawkins PR, Runnegar MTC, Jackson ARB, Falconer IR (1985) Severe hepatotoxicity caused by the tropical cyanobacterium Cylindrospermopsis raciborskii (Woloszynska) Seenaya and Subba Raju isolated from a domestic water supply reservoir. Appl Environ Microbiol 50:1292–1295

    CAS  PubMed  PubMed Central  Google Scholar 

  • Heinze R (1999) Toxicity of the cyanobacterial toxin microcystin-LR to rats after 28 days intake with the drinking water. Environ Toxicol 14:57–60

    Article  CAS  Google Scholar 

  • Henriksen P, Carmichael WW, An J, Moestrup O (1997) Detection of an anatoxin–a(s)–like anticholin-esterase in natural blooms and cultures of cyanobacteria/blue-green algae from Danish lakes and in the stomach contents of poisoned birds. Toxicon 35:901–913

    Article  CAS  PubMed  Google Scholar 

  • Herrero A, Flores E (2008) The cyanobacteria: molecular biology, genomics and evolution. Caister Academic Press, Sevilla, Spain

  • Hindman SH, Favero MS, Carson LA, Petersen NJ, Schonberger LB, Solano JT (1975) Pyrogenic reactions during haemodialysis caused by extramural endotoxin. Lancet 2(7938):732–734

    Article  CAS  PubMed  Google Scholar 

  • http://cyanocost.com/

  • Hiraga A, Tamura S (2000) Protein phosphatase 2A is associated in an inactive state with microtubules through 2A-1- specific interaction with tubuline. Biochem J 346(2):433–439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hu Z, Chen H, Pang C, Lin Q (2008) The expression of p53 and p16 in the course of microcystin-LR inducing of liver tumor. Chin Ger J Clin Oncol 7(12):690–693

    Article  Google Scholar 

  • Hu X, Chen J, Fan H, Xie P, He J (2016) Review of neurotoxicity of microcystins. Environ Sci Pollut Res 23:7211–7219

    Article  CAS  Google Scholar 

  • Humpage AR, Hardy SJ, Moore EJ, Froscio SM, Falconer IR (2000) Microcystins (cyanobacterial toxins) in drinking water enhance the growth of aberrant crypt foci in the mouse colon. J Toxicol Environ Health PartA 61(3):155–165

    Article  CAS  Google Scholar 

  • Hunter PR (1994) An epidemiological critique of reports of human illness associated with cyanobacteria. In: Codd GA, Jefferies TM, Keevil CW, Potter E (eds) Detection methods for cyanobacterial toxins. Royal Society of Chemistry, Cambridge, pp 11–18

    Chapter  Google Scholar 

  • Institute of Public Health Serbia “Dr Milan Jovanović Batut” (2014) Report on the request for access to information of public importance No.8301/1, Belgrade. http://uimenaroda.rs/predmeti/li%C4%8Dni-stav/190-u%C5%BEice-vodosnabdevanje-slika-srbije.html. Accessed 2 Nov 2015

  • International Agency for Research on Cancer (IARC) (2006) Carcinogenicity of nitrate, nitrite, and cyanobacterial peptide toxins. Lancet Oncol 7:628–629. doi:10.1016/S1470-2045(06)70789-6

    Article  Google Scholar 

  • Jackson ARB, Runnegar MTC, Cumming RB, Brunner JF (1986) Experimental acute intoxication of young layer and broiler-chickens with the cyanobacterium (blue-green-alga) Microcystis aeruginosa. Avian Pathol 15:741–748

    Article  CAS  PubMed  Google Scholar 

  • Jackson ARB, McInnes A, Falconer IR, Runnegar MTC (1994) Clinical and pathological changes in sheep experimentally poisoned by the blue-green alga. Vet Pathol 21:102–113

    Article  Google Scholar 

  • Jaroslav Černi Institute for the Development of Water Resources (Institut za vodoprivredu „Jaroslav Černi“) (2014) http://www.graduzice.org/userfiles/files/Izvestaj%20instituta%20J%20Cerni.pdf. Accessed 2 Nov 2015

  • Jayatissa LP, Silva EI, McElhiney J, Lawton LA (2006) Occurrence of toxigenic cyanobacterial blooms in freshwaters of Sri Lanka. Syst Appl Microbiol 29(2):156–164

    Article  CAS  PubMed  Google Scholar 

  • Jochimsen EM, Carmichael WW, An JS, Cardo DM, Cookson ST, Holmes CE, Antunes MB, de Melo Filho DA, Lyra TM, Barreto VS, Azevedo SM, Jarvis WR (1998) Liver failure and death after exposure to microcystins at a hemodialysis center in Brazil. N Engl J Med 338:873–878

    Article  CAS  PubMed  Google Scholar 

  • Kann J, Falter CM (2009) Development of toxic blue-green algal blooms in Black Lake, Kootenai County, Idaho. Lake Reserv Manag 3(1):99–108. doi:10.1080/07438148709354765

    Article  Google Scholar 

  • Keleti G, Sykora JL, Libby EC, Shapiro MA (1979) Composition and biological properties of lipopolysaccharides isolated from Schizothrix calcicola (Ag.) Gomont (cyanobacteria). Appl Environ Microbiol 38:471–477

    CAS  PubMed  PubMed Central  Google Scholar 

  • Komarek J (2016) A polyphasic approach for the taxonomy of cyanobacteria: principles and applications. Eur J Phycol 51:346–353

    Article  CAS  Google Scholar 

  • Komatsu M, Furukawa M, Ikeda R, Takumi S, Nong QQ, Aoyama K, Akiyama S, Keppler D, Takeuchi T (2007) Involvement of mitogen-activated protein kinase signaling pathways in microcystin-LR-induced apoptosis after its selective uptake mediated by OATP1B1 and OATP1B3. Toxicol Sci 97:407–416

    Article  CAS  PubMed  Google Scholar 

  • Krienitz L, Ballot A, Kotut K, Wiegand C, Pütz S, Metcalf JS, Codd GA, Pflugmacher S (2003) Contribution of hot spring cyanobacteria to the mysterious deaths of Lesser Flamingos at Lake Bogoria, Kenya. FEMS Microbiol Ecol 43:141–148. doi:10.1111/j.1574-6941.2003.tb01053.x

    Article  CAS  PubMed  Google Scholar 

  • Kuiper-Goodman T, Falconer IR, Fitzgerald J (1999) Human health aspects. In: Chorus I, Bartram J (eds) Toxic cyanobacteria in water: a guide to their public health consequences, monitoring and management. E&FN SPON, London, pp 113–153

    Google Scholar 

  • Kumar V, Abbas AK, Fausto N (2005) Robins and Cortan pathologic basis of disease. Elsevier Saunders, Philadelphia

    Google Scholar 

  • Labine MA (2014) Cyanobacterial toxins and liver cancer. Dissertation, University of Manitoba

  • Labine MA, Green C, Mak G, Xue L, Nowatzki J, Griffith J, Minuk GY (2015) The geographic distribution of liver cancer in Canada does not associate with cyanobacterial toxin exposure. Int J Environ Res Public Health 12:15143–15153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Last JM (ed) (2001) Dictionary of epidemiology, 4th edn. Oxford University Press, New York

    Google Scholar 

  • Lawton LA, Codd GA (1991) Cyanobacterial (blue-green algal) toxins and their significance in UK and European waters. Water Environ J 5(4):460–465

    Article  CAS  Google Scholar 

  • Lawton LA, Edwards C, Beattie KA, Pleasance Dear DJ, Codd GA (1995) Isolation and characterisation of microcystins from laboratory cultures and environmental samples of Microcystis aeruginosa and from an associated animal toxicosis. Nat Toxins 3:50–57

    Article  CAS  PubMed  Google Scholar 

  • Li H, Xie P, Li G, Hao L, Xiong Q (2009) In vivo study on the effects of microcystin extracts on the expression profiles of proto-oncogenes (c-fos, c-jun and c-myc) in liver, kidney and testis of maleWistar rats injected i.v. with toxins. Toxicon 53(1):169–175

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Chen JA, Zhao Q, Pu C, Qiu Z, Zhang R, Shu W (2011) A cross-sectional investigation of chronic exposure to microcystin in relationship to childhood liver damage in the Three Gorges Reservoir Region, China. Environ Health Perspect 119(10):1483–1488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin H, Liu W, Zeng H, Pu C, Zhang R, Qiu Z, Chen JA, Wang L, Tan Y, Zheng C, Yang X, Tian Y, Huang Y, Luo J, Luo Y, Feng X, Xiao G, Feng L, Li H, Wang F, Yuan C, Wang J, Zhou Z, Wei T, Zuo Y, Wu L, He L, Guo Y, Shu W (2016) Determination of environmental exposure to microcystin and aflatoxin as a risk for renal function based on 5493 rural people in southwest China. Environ Sci Technol 50(10):5346–5356

    Article  CAS  PubMed  Google Scholar 

  • Lippy EC, Erb J (1976) Gastrointestinal illness at Sewickley, PA. J Am Water Works Assoc 68:606–610

    Google Scholar 

  • Loftin KA, Clark JM, Journey CA, Kolpin DW, Van Metre PC, Carlisle D, Bradley PM (2016a) Spatial and temporal variation in microcystin occurrence in wadeable streams in the southeastern United States. Environ Toxicol Chem 35(9):2281–2287

    Article  CAS  PubMed  Google Scholar 

  • Loftin KA, Graham JL, Hilborn ED, Lehmann SC, Meyer MT, Dietze JE, Griffith CB (2016b) Cyanotoxins in inland lakes in the United States: occurrence and potential recreational health risks in the EPA National Lakes Assessment 2007. Harmful Algae 56:77–90

    Article  CAS  PubMed  Google Scholar 

  • London WT, McGlynn KA (2006) Liver cancer. In: Schottenfeld D, Fraumeni JF (eds) Cancer epidemiology and prevention, 3rd edn. Oxford University Press Inc, New York, pp 763–786

    Chapter  Google Scholar 

  • Lu H, Choudhuri S, Ogura K, Csanaky IL, Lei X, Cheng X, Song PZ, Klaassen CD (2008) Characterization of organic anion transporting polypeptide 1b2-null mice: essential role in hepatic uptake/toxicity of phalloidin and microcystin-LR. Toxicol Sci 103(1):35–45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • MacKintosh C, Beattie KA, Klumpp S, Cohen P, Codd GA (1990) Cyanobacterial microcystin-LR is a potent and specific inhibitor of protein phosphatases 1 and 2A from both mammals and higher plants. FEBS Lett 264(2):187–192

  • MacKintosh RV, Dalby KN, Campbell DG, Cohen PT, Cohen P, MacKintosh C (1995) The cyanobacterial toxin microcystin binds covalently to cysteine-273 on protein phosphatase-1. FEBS Lett 371(3):236–240

    Article  CAS  PubMed  Google Scholar 

  • Mancini M, Rodriguez C, Bagnis G, Liendo A, Prosperi C, Bonansea M, Tundisi JG (2010) Cyanobacterial bloom and animal mass mortality in a reservoir from Central Argentina. Braz J Biol 70:841–845

    Article  CAS  PubMed  Google Scholar 

  • Marion JW, Lee J, Wilkins JR, Lemeshow S, Lee C, Waletzko EJ, Buckley TJ (2012) In vivo phycocyanin flourometry as a potential rapid screening tool for predicting elevated microcystin concentrations at eutrophic lakes. Environ Sci Technol 46(8):4523–4531

    Article  CAS  PubMed  Google Scholar 

  • Martin P (1998) Hepatocellular carcinoma: risk factors and natural history. Liver Transpl Surg 4(1/5):S87–S91

    CAS  PubMed  Google Scholar 

  • Matsunaga H, Harada KI, Senma M, Ito Y, Yasuda N, Ushida S, Kimura Y (1999) Possible cause of unnatural mass death of wild birds in a pond in Nishinomiya, Japan: sudden appearance of toxic cyanobacteria. Nat Toxins 7:81–84

    Article  CAS  PubMed  Google Scholar 

  • McDermott CM, Nho CW, Howard W, Holton B (1998) The cyanobacterial toxin, microcystin-LR, can induce apoptosis in a variety of cell types. Toxicon 36:1981–1996

    Article  CAS  PubMed  Google Scholar 

  • McGlynn KA, Tsao L, Hsing AW, Devesa SS, Fraumeni JF (2001) International trends and patterns of primary liver cancer. Int J Cancer 94:290–296

    Article  CAS  PubMed  Google Scholar 

  • McQuaid N, Zamyadi A, Prévost M, Bird DF, Dorner S (2011) Use of in vivo phycocyanin fluorescence to monitor potential microcystin-producing cyanobacterial biovolume in a drinking water source. J Environ Monit 13:455–463

    Article  CAS  PubMed  Google Scholar 

  • Metcalf JS, Codd GA (2012) Cyanotoxins. In: Whitton BA (ed) Ecology of cyanobacteia II their diversity in space and time. Springer, Dordrecht, pp 651–675

    Chapter  Google Scholar 

  • Mez K, Beattie KA, Codd GA, Hanselmann K, Hauser B, Naegeli H, Preisig H (1997) Identification of a microcystin in benthic cyanobacteria linked to cattle deaths on alpine pastures in Switzerland. Eur J Phycol 32:111–117

    Article  Google Scholar 

  • Miller MA, Kudela RM, Mekebri A, Crane D, Oates SC, Tinker MT, Staedler M, Miller WA, Toy-Choutka S, Dominik C, Hardin D, Langlois G, Murray M, Ward K, Jessup DA (2010) Evidence for a novel marine harmful algal bloom: cyanotoxin (microcystin) transfer from land to sea otters. PLoS ONE. doi:10.1371/journal.pone.0012576

    Google Scholar 

  • Milutinovic A, Sedmak B, Horvat-Znidarsic I, Suput D (2002) Renal injuries induced by chronic intoxication with microcystins. Cell Mol Biol Lett 7:139–141

    PubMed  Google Scholar 

  • Milutinovic A, Zorc-Pleskovic R, Petrovic D, Zorc M, Suput D (2006) Microcystin-LR induces alterations in heart muscle. Folia Biol (Praha) 52:116–118

    CAS  Google Scholar 

  • Morselli E, Galluzzi L, Kroemer G (2008) Mechanisms of p53-mediated mitochondrial membrane permeabilization. Cell Res 18:708–710

    Article  CAS  PubMed  Google Scholar 

  • Mu L-N, Yu S, Zhao J, Di L, Zhou L (2001) Epidemiological study on microcystin’s effect on pupil health. China Public Health 9:799–801

    Google Scholar 

  • Nasri H, El HS, Bouaïcha N (2008) First reported case of turtle deaths during a toxic Microcystis spp. bloom in Lake Oubeira, Algeria. Ecotoxicol Environ Saf 71(2):535–544. doi:10.1016/j.ecoenv.2007.12.009

    Article  CAS  PubMed  Google Scholar 

  • Ndlela LL, Oberholster PJ, Van Wyk JH, Cheng PH (2016) An overview of cyanobacterial bloom occurrences and research in Africa over the last decade. Harmful Algae 60:11–26

    Article  CAS  PubMed  Google Scholar 

  • Neilan BA, Pearson LA, Moffitt MC, Mihali KT, Kaebernick M, Kellmann R, Pomati F (2007) Chapter 17: the genetics and genomics of cyanobacterial toxicity. In: Hudnell HK (ed) Proceedings of the interagency, international symposium on cyanobacterial harmful algal blooms. Advances in experimental medicine & biology, pp 423–458

  • Nobre ACL, Jorge MCM, Menezes DB, Fonteles MC, Monteiro HSA (1999) Effects of microcystin-LR in isolated perfused rat kidney. Brazil J Med Biol Res 32:985–988

    Article  CAS  Google Scholar 

  • Oberholster PJ, Ashton PJ (2008) State of the nation report: an overview of the current status of water quality and eutrophication in South African rivers and reservoirs. Parliamentary Grant Deliverable, Pretoria, Council for Scientific and Industrial Research (CSIR)

  • Oberholster PJ, Myburgh JG, Govender D, Bengis R, Botha A-M (2009) Identification of toxigenic Microcystis strains after incidents of wild animal mortalities in the Kruger National Park, South Africa. Ecotoxicol Environ Saf 72(4):1177–1182

    Article  CAS  PubMed  Google Scholar 

  • Ohtani I, Moore RE, Runnegar MTC (1992) Cylindrospermopsin: a potent hepatotoxin from the blue-green alga Cylindrospermopsis raciborskii. J Am Chem Soc 114:7941–7942

    Article  CAS  Google Scholar 

  • Oliveira MDR, Montciro MT (1993) Caracterizaçâo biolôgica do sistema de abastecimento de âgua a Évora. Relatório Técnico e Científico do INIP, Lisboa, Agosto 68:43

    Google Scholar 

  • Olson JM (2006) Photosynthesis in the Archean Era. Photosynth Res 88(2):109–117

    Article  CAS  PubMed  Google Scholar 

  • Onodera H, Oshima Y, Henriksen P, Yasumoto T (1997) Confirmation of anatoxin-a(s), in the cyanobacterium Anabaena lemmermannii, as the cause of bird kills in Danish lakes. Toxicon 35(11):1645–1648

    Article  CAS  PubMed  Google Scholar 

  • Park H, Namikoshi M, Brittain SM, Carmichael WW, Murphy T (2001) [d-Leu1] microcystin-LR, a new microcystin isolated from waterbloom in a Canadian prairie lake. Toxicon 39(6):855–862. doi:10.1016/S0041-0101(00)00224-5

    Article  CAS  PubMed  Google Scholar 

  • Pearson MJ, Ferguson AJD, Codd GA, Reynolds CS, Fawell JK, Hamilton RM (1990) Toxic blue-green algae. A report by the UK National Rivers Authority. Water Qual Ser 2:1–128

    Google Scholar 

  • Pilotto LS (2008) Epidemiology of cyanobacteria and their toxins. In: Cyanobacterial harmful algal blooms: state of the science and research needs, vol. 619 of the series advances in experimental medicine and biology, pp 639–649

  • Pilotto LS, Douglas RM, Burch MD, Cameron S, Beers M, Rouch GJ, Robinson P, Kirk M, Cowie CT, Hardiman S, Moore C, Attewell RG (1997) Health effects of exposure to cyanobacteria (blue-green algae) during recreational water-related activities. Aust N Z J Public Health 21(6):562–566

    Article  CAS  PubMed  Google Scholar 

  • Pilotto LS, Kliewer EV, Davies RD, Burch MD, Attewell RG (1999) Cyanobacterial (blue-green algae) contamination in drinking water and perinatal outcomes. Aust N Z J Public Health 23(2):154–158

    Article  CAS  PubMed  Google Scholar 

  • Pouria S, de Andrade A, Barbosa J, Cavalcanti RL, Barreto VT, Ward CJ, Preiser W, Poon GK, Neild GH, Codd GA (1998) Fatal microcystin intoxication in haemodialysis unit in Caruaru, Brazil. Lancet 352(9121):21–26

    Article  CAS  PubMed  Google Scholar 

  • da Teixeira MG, da Costa MC, de Carvalho VL, dos Pereira MS, Hage E (1993) Gastroenteritis epidemic in the area of the Itaparica Dam, Bahia, Brazil. Bull Pan Am Health Organ 27(3):244–253

    Google Scholar 

  • Rankin KA, Alroy KA, Kudela RM, Oates SC, Murray MJ, Miller MA (2013) Treatment of cyanobacterial (microcystin) toxicosis using oral cholestyramine: case report of a dog from Montana. Toxins 5(6):1051–1063

    Article  PubMed  PubMed Central  Google Scholar 

  • Rapala J, Robertson A, Negri IP, Berg KA, Tuomi P, Lyra C, Erkomaa K, Lahti K, Hoppu K, Lepistö L (2005) First report of saxitoxin in Finnish lakes and possible associated effects on human health. Environ Toxicol 20(3):331–340

    Article  CAS  PubMed  Google Scholar 

  • Rodger HD, Turnbull T, Edwards C, Codd GA (1994) Cyanobacterial (blue-green algal) bloom associated pathology in brown trout Salmo trutta L. in Loch Leven, Scotland. J Fish Dis 17:177–181

    Article  Google Scholar 

  • Rudolph-Böhner S, Mierke DF, Moroder L (1994) Molecular structure of cyanobacterial tumour-promoting microcystins. FEBS Lett 349:319–323

    Article  PubMed  Google Scholar 

  • Schirrmeister BE, Antonelli A, Bagheri HC (2011) The origin of multicellularity in cyanobacteria. BMC Evol Biol 11(1):45

    Article  PubMed  PubMed Central  Google Scholar 

  • Schopf JW, Walter MR (1982) Origin and early evolution of cyanobacteria: the geological evidence. In: Carr NG, Whitton BA (eds) The biology of cyanobacteria. Blackwell, Oxford, pp 543–564

    Google Scholar 

  • Sebbag L, Smee N, Van der Merwe D, Schmid D (2013) Liver failure in a dog following suspected ingestion of blue-green algae (Microcystis spp.): a case report and review of the toxin. J Am Anim Hosp Assoc 49(5):342–346

    Article  PubMed  Google Scholar 

  • Secretary of Health of Bahia State (1988) Relatorio final do surto epidemico de gastroenterite ocorrido na regigo de Paulo Afonso, Bahia, no periodo de mar ~ o/abrillmaio de 1988 (3 vol). Salvador: 1988 (Mimeographed document)

  • Shea K, Fleming LE, Wohler Torres B, Mackinnon J, Voti L (2001) Primary liver cancer in Florida. Cancer 91(5):1046–1051

    Article  CAS  PubMed  Google Scholar 

  • Shikata T (1987) Primary liver carcinoma and liver cirrhosis, hepatocellular carcinoma. Wiley, New York

    Google Scholar 

  • Simeunović J (2009) Ekofiziološke karakteristike potencijalno toksičnih i toksičnih vodenih sojeva cijanobakterija na području Vojvodine. Dissertation, University of Novi Sad

  • Skulberg OM (1979) Toxic effects of blue-green algae, first case of Microcystis—poisoning reported from Norway. Tema-rapport No. 4, Norwegian Institute for Water Research (NIVA), Oslo

  • Slatkin DN, Stoner RD, Adams WH, Kycia JH, Siegelman HW (1983) Atypical pulmonary thrombosis caused by a toxic cyanobacterial peptide. Science 220:1383–1385

    Article  CAS  PubMed  Google Scholar 

  • Soares RM, Yuan M, Servaites JC, Delgado A, Magalhaes VF, Hilborn ED, Carmichael WW, Azevedo SM (2006) Sublethal exposure from microcystins to renal insufficiency patients in Rio de Janeiro, Brazil. Environ Toxicol 21(2):95–103

    Article  CAS  PubMed  Google Scholar 

  • Soares M, Cagido VR, Ferraro RB, Meyer-Fernandes JR, Rocco PRM, Zin WA, Azevedo SMFO (2007) Effects of microcystin-LR on mouse lungs. Toxicon 50:330–338

    Article  CAS  PubMed  Google Scholar 

  • Soll MD, Williams MC (1985) Mortality of a white rhinoceros (Ceratotherium simum) suspected to be associated with the blue-green alga Microcystis aeruginosa. J S Afr Vet Assoc 56(1):49–51

    CAS  PubMed  Google Scholar 

  • Soward TE (2011) Evaluation of cancer from exposure to cyanotoxins in drinking water at Grand Lake Saint Marys. Master thesis, Wright State University

  • Spoof L, Catherine A (2017) Tables of microcystins and nodularins. In: Meriluoto J, Spoof L, Codd GA (eds) Handbook of cyanobacterial monitoring and cyanotoxin analysis. Wiley, Chichester, pp 526–537

  • Steffen MM, Belisle BS, Watson SB, Boyer GL, Wilhelm SW (2014) Status, causes and controls of cyanobacterial blooms in Lake Erie. J Great Lakes Res 40(2):215–225

    Article  CAS  Google Scholar 

  • Stewart I, Webb PM, Schluter PJ, Fleming LE, Burns JW Jr, Gantar M, Backer LC, Shaw GR (2006) Epidemiology of recreational exposure to freshwater cyanobacteria—an international prospective cohort study. BMC Public Health 6:93

    Article  PubMed  PubMed Central  Google Scholar 

  • Svirčev Z, Krstić S, Miladinov-Mikov M, Baltić V, Vidović M (2009) Freshwater cyanobacterial blooms and primary liver cancer epidemiological studies in Serbia. J Environ Sci Health Part C 27(1):36–55

    Article  CAS  Google Scholar 

  • Svirčev Z, Baltić V, Gantar M, Juković M, Stojanović D, Baltić M (2010) Molecular aspects of microcystin-induced hepatotoxicity and hepatocarcinogenesis. J Environ Sci Health Part C 28:39–59

    Article  CAS  Google Scholar 

  • Svirčev Z, Drobac D, Tokodi N, Vidović M, Simeunović J, Miladinov-Mikov M, Baltić V (2013) Epidemiology of primary liver cancer in Serbia and possible connection with cyanobacterial blooms. J Environ Sci Health Part C 31(3):181–200

    Article  CAS  Google Scholar 

  • Svirčev Z, Krstić S, Važić T (2014a) The philosophy and applicability of ecoremediations for the protection of water ecosystems. Acta Geogr Slov 54–1:179–188

    Google Scholar 

  • Svirčev Z, Tokodi N, Drobac D, Codd GA (2014b) Cyanobacteria in aquatic ecosystems in Serbia: effects on water quality, human health and biodiversity. Syst Biodivers 12(3):261–270

    Article  Google Scholar 

  • Svirčev Z, Drobac D, Tokodi N, Lužanin Z, Munjas AM, Nikolin B, Vuleta D, Meriluoto J (2014c) Epidemiology of cancers in Serbia and possible connection with cyanobacterial blooms. J Environ Sci Health Part C 32(4):319–337

    Article  CAS  Google Scholar 

  • Svirčev Z, Drobac D, Tokodi N, Đenić D, Simeunović J, Hiskia A, Kaloudis T, Mijović B, Šušak S, Protić M, Vidović M, Onjia A, Nybom S, Važić T, Palanački Malešević T, Dulić T, Pantelić D, Vukašinović M, Meriluoto J. (2017) Lessons from the Užice case: how to complement analytical data. In: Meriluoto J, Spoof L, Codd GA (eds) Handbook of cyanobacterial monitoring and cyanotoxin analysis. Wiley, Chichester, pp 298–308

  • Takumi S, Komatsu M, Furukawa T, Ikeda R, Sumizawa T, Akenaga H, Maeda Y, Aoyama K, Arizono K, Ando S, Takeuchi T (2010) p53 plays an important role in cell fate determination after exposure to microcystin-LR. Environ Health Perspect 118:1292–1298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tango PJ, Butler W (2008) Cyanotoxins in tidal waters of Chesapeake Bay. Northeast Nat 15:403–416. doi:10.1656/1092-6194-15.3.403

    Article  Google Scholar 

  • The Agency for Environmental Protection (Agencija za zaštitu životne sredine) (2013a) http://www.sepa.gov.rs/index.php?menu=504000000&id=20013&akcija=showArhiva. Accessed 2 Nov 2015

  • The Agency for Environmental Protection (Agencija za zaštitu životne sredine) (2013b) Ispitivanje kvaliteta vode akumulacije Vrutci, na teritoriji opštine Užice. http://www.sepa.gov.rs/download/akcidenti/vode/Havarija_Vrutci_final.pdf. Accessed 2 Nov 2015

  • Tisdale E (1931) Epidemic of intestinal disorders in Charleston, WVa, occurring simultaneously with unprecented water supply conditions. Am J Public Health 21:198–200

    Article  CAS  Google Scholar 

  • Tokodi N (2016) Toksične cijanobakterije sa teritorije Republike Srbije. Dissertation, University of Novi Sad

  • Trevino-Garrison I, DeMent J, Ahmed FS, Haines-Lieber P, Langer T, Ménager H, Neff J, van der Merwe D, Carney E (2015) Human illnesses and animal deaths associated with freshwater harmful algal blooms—Kansas. Toxins 7(2):353–366. doi:10.3390/toxins7020353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Turner PC, Gammie AJ, Hollinrake K, Codd GA (1990) Pneumonia associated with cyanobacteria. Br Med J 300:1400–1414

    Google Scholar 

  • Ueno Y, Nagatai S, Tsutsumi T, Hasegawa A, Watanabe M, Park H, Chen G, Chen G, Yu S (1996) Detection of microcystins, a blue-green algal hepatotoxin, in drinking water sampled in Haimen and Fusui, endemic areas of primary liver cancer in China, by highly sensitive immunoassay. Carcinogenesis 17(6):1317–1321

    Article  CAS  PubMed  Google Scholar 

  • Van der Merwe D, Sebbag L, Nietfeld JC, Aubel MT, Foss A, Carney E (2012) Investigation of a Microcystis aeruginosa cyanobacterial freshwater harmful algal bloom associated with acute microcystin toxicosis in a dog. J Vet Diagn Invest 24(4):679–687

    Article  PubMed  Google Scholar 

  • Van Halderen A, Harding WR, Wessels JC, Schneider DJ, Heine EWP, Van der Merwe J, Fourie JM (1995) Cyanobacterial (blue-green algae) poisoning of livestock in the Western Cape Province of South Africa. J S Afr Vet Assoc 66(4):260–264

    PubMed  Google Scholar 

  • Vasconcelos VM (1994) Cyanobacterias toxicas e suas toxinasem âguas doces portuguesas. Riscos para a Saiide Piiblica. 41 Conferëncia Nacional sobre Qualidade do Ambiente, Lisboa

  • Volterra L (1993) Sanitary implications associated with the use of eutrophic freshwater. Ann Inst Super Sanita 29:327–333

    CAS  Google Scholar 

  • Wannemacher RW (1989) Chemical stability and laboratory safety of naturally occurring toxins. US Army Medical Research, Institute of infectious disease, Fort Detrick, pp 9–11

    Google Scholar 

  • Whitton BA (ed) (2012) Ecology of cyanobacteria II their diversity in space and time. Springer, Dordrecht

    Google Scholar 

  • Willen E, Ahlgren G, Tilahun G, Spoof L, Neffling M-R, Meriluoto J (2011) Cyanotoxin production in seven Ethiopian Rift Valley Lakes. Inland Waters 1(2):81–91

    Article  CAS  Google Scholar 

  • Williams CD, Burns J, Chapman A, Flewelling L, Pawlowicz M, Carmichael W (2001) Assessment of cyanotoxins. In: Florida’s Lakes, Reservoirs, and Rivers. Cyanobacteria Survey Project, Harmful Algal Bloom Task Force, SJRWMD, Palatka, FL

  • Wirsing B, Hoffmann L, Heinze R, Klein D, Daloze D, Braekman JC, Weckesser J (1998) First report on the identification of microcystin in a water bloom collected in Belgium. Syst Appl Microbiol 21(1):23–27. doi:10.1016/S0723-2020(98)80004-0

    Article  CAS  PubMed  Google Scholar 

  • World Health Organization (WHO) (1998) Guidelines for drinking water quality, 2nd edn, Addendum to vol 2. WHO Press, Geneva, Switzerland

  • World Health Organization (WHO) (1999) Toxic cyanobacteria in water: a guide to their public health consequences, monitoring and management. E&FN SPON, London, England

  • Xu M, Yang J, Lin Y, Hu L, Chen Y, Shen Z, Yu S (2003) China microcystins in drinking water and mortality of major cancer in a city along Taihu Lake. Chin J Prev Control Chronic Non Commun Dis 3:112–113

    Google Scholar 

  • Xu L, Qin W, Zhang H, Wang Y, Dou H, Yu D, Ding Y, Yang L, Wang Y (2012) Alterations in microRNA expression linked to microcystin-LR-induced tumorigenicity in human WRL-68 Cells. Mutat Res 743(1–2):75–82

    Article  CAS  PubMed  Google Scholar 

  • Young FM, Thomson C, Metcalf JS, Lucocq JM, Codd GA (2005) Immunogold localization of microcystins in cryosectioned cells of Microcystis. J Struct Biol 151:208–214

    Article  CAS  PubMed  Google Scholar 

  • Yu S-Z (1989) Drinking water and primary liver cancer. In: Tang Z-Y, Wu M-C, Xia S-S (eds) Primary liver cancer. Spring, Berlin, pp 30–37

    Google Scholar 

  • Yu SZ (1995) Primary prevention of hepatocellular carcinoma. J Gastroenterol Hepatol 10:674–682. doi:10.1111/j.1440-1746.1995.tb01370.x

    Article  CAS  PubMed  Google Scholar 

  • Yu SZ, Chen G (1994) Blue-green algae toxins and liver cancer. Chin J Cancer Res 6:6–17

    Google Scholar 

  • Yu SZ, Chen Z-Q, Liu Y-K, Huang Z-Y, Zhao Y-F (1989) The aflatoxins and contaminated water in the etiological study of primary liver cancer. In: Natori S, Hashimoto K, Ueno Y (eds) Mycotoxins & phycotoxins. Elsevier, Amsterdam, pp 37–44

    Google Scholar 

  • Yu SZ, Chen W, Li J (1995) The prospective research of risk factors of primary liver cancer in Nanhui County, Shanghai. Zhonghua Liu Xing Bing Xue Za Zhi 16:22–24

    CAS  PubMed  Google Scholar 

  • Yu S, Zhao N, Zi X (2001) The relationship between cyanotoxin (microcystin, MC) in pond-ditch water and primary liver cancer in China. Zhonghua Zhong Liu Za Zhi 23(2):96–99

    CAS  PubMed  Google Scholar 

  • Yuan M, Carmichael WW, Hilborn ED (2006) Microcystin analysis in human sera and liver from human fatalities in Caruaru, Brazil 1996. Toxicon 48(6):627–640

    Article  CAS  PubMed  Google Scholar 

  • Zegura B (2016) An overview of the mechanism of microcystin-LR genotoxicity and potential carcinogenicity. Mini Rev Med Chem 16:1042–1062

    Article  CAS  PubMed  Google Scholar 

  • Zegura B, Straser A, Filipic M (2011) Genotoxicity and potential carcinogenicity of cyanobacterial toxins—a review. Mutat Res 727:16–41

    Article  CAS  PubMed  Google Scholar 

  • Zhang MD (1993) A population-based case–control study of primary liver cancer in Fusui. Zhonghua Liu Xing Bing Xue Za Zhi 14:14–18

    CAS  PubMed  Google Scholar 

  • Zhang Z, Zhang XX, Qin W, Xu L, Wang T, Cheng S, Yang L (2012) Effects of microcystin-LR exposure on matrix metalloproteinase-2/-9 expression and cancer cell migration. Ecotoxicol Environ Saf 77:88–93

    Article  CAS  PubMed  Google Scholar 

  • Zhang F, Lee J, Liang S, Shum CK (2015) Cyanobacteria blooms and non-alcoholic liver disease: evidence from a county level ecological study in the United States. Environ Health 14:41

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhao N, Yu SZ, Sun WM (1994) Modeling the general relative risk models in case–control studies of primary hepatocellular carcinoma. Zhonghua Zhong Liu Za Zhi 16:331–336

    CAS  PubMed  Google Scholar 

  • Zhou TL, Yu SZ (1990) Laboratory study on the relationship between drinking water and hepatoma-quantitative evaluation using hepatic gamma-GT method. Zhonghua Yu Fang Yi Xue Za Zhi 24(4):203–205

    CAS  PubMed  Google Scholar 

  • Zhou L, Yu H, Chen K (2002) Relationship between microcystin in drinking water and colorectal cancer. Biomed Environ Sci 15(2):166–171

    PubMed  Google Scholar 

  • Zilberg B (1966) Gastroenteritis in Salisbury European children—a five-year study. Cent Afr J Med 12:164–168

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors would like to acknowledge the funding of the Ministry of Education, Science, and Technological Development of the Serbian Government (Project Number: 176020) and also COST Action ES1105 “CYANOCOST—Cyanobacterial Blooms and Toxins in Water Resources: Occurrence, Impacts and Management” of the European Union, for adding value to this study through networking and knowledge sharing with European experts in the field. Parts of this publication were prepared within the framework of an exchange programme between the University of Novi Sad Faculty of Sciences and Åbo Akademi University. The mobility was supported from the Erasmus+ Programme, Project Code 2015-2-FI01-KA107-022151.

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Correspondence to Zorica Svirčev.

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Svirčev, Z., Drobac, D., Tokodi, N. et al. Toxicology of microcystins with reference to cases of human intoxications and epidemiological investigations of exposures to cyanobacteria and cyanotoxins. Arch Toxicol 91, 621–650 (2017). https://doi.org/10.1007/s00204-016-1921-6

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  • DOI: https://doi.org/10.1007/s00204-016-1921-6

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