• 1.

    Wells ML, Karlson B, Wulff A, et al.. Future HAB science: directions and challenges in a changing climate. Harmful Algae 2020;91:101632.

  • 2.

    Zastepa A, Taranu ZE, Kimpe LE, et al.. Reconstructing a long-term record of microcystins from the analysis of lake sediments. Sci Total Environ 2017;579:893901.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Stewart I, Seawright AA, Shaw GR. Cyanobacterial poisoning in livestock, wild mammals and birds—an overview. Adv Exp Med Biol 2008;619:613637.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Carmichael W. Astatus report on planktonic cyanobacteria (blue-green algae) and their toxins. Available at: cfpub.epa.gov/si/si_public_record_Report.cfm?Lab=ORD&dirEntryID=37448. Accessed May 11, 2021.

    • Search Google Scholar
    • Export Citation
  • 5.

    Codd GA, Azevedo SMFO, Bagchi SN, et al.. CYANONET: a global network for cyanobacterial bloom and toxin risk management. Paris: International Hydrological Programme, 2005.

    • Search Google Scholar
    • Export Citation
  • 6.

    Roegner AF, Brena B, González-Sapienza G, et al.. Microcystins in potable surface waters: toxic effects and removal strategies. J Appl Toxicol 2014;34:441457.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Schwimmer M, Schwimmer D. Medical aspects of phycology. In: Jackson DF, ed. Algae, man, and the environment. Syracuse, NY: Syracuse University Press, 1968;368412.

    • Search Google Scholar
    • Export Citation
  • 8.

    Wood R. Acute animal and human poisonings from cyanotoxin exposure—a review of the literature. Environ Int 2016;91:276282.

  • 9.

    Metcalf JS, Codd GA. Co-occurrence of cyanobacteria and cyanotoxins with other environmental health hazards: impacts and implications. Toxins (Basel) 2020;12:629.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Hilborn ED, Beasley VR. One health and cyanobacteria in freshwater systems: animal illnesses and deaths are sentinel events for human health risks. Toxins (Basel) 2015;7:13741395.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Carmichael WW, Boyer GL. Health impacts from cyanobacteria harmful algae blooms: implications for the North American Great Lakes. Harmful Algae 2016;54:194212.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Spoof L, Catherine A. Appendix 3: tables of microcystins and nodularins. In: Handbook of cyanobacterial monitoring and cyanotoxin analysis. Chichester, England: John Wiley & Sons Ltd, 2017;526537.

    • Search Google Scholar
    • Export Citation
  • 13.

    Bláha L, Babica P, Maršálek B. Toxins produced in cyanobacterial water blooms - toxicity and risks. Interdiscip Toxicol 2009;2:3641.

  • 14.

    Wacklin P, Hoffmann L, Komárek J. Nomenclatural validation of the genetically revised cyanobacterial genus Dolichospermum (RALFS ex BORNET et FLAHAULT) comb. nova. Fottea (Praha) 2009;9:5964.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Li X, Dreher TW, Li R. An overview of diversity, occurrence, genetics and toxin production of bloom-forming Dolichospermum (Anabaena) species. Harmful Algae 2016;54:5468.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    McGregor GB, Sendall BC. Phylogeny and toxicology of Lyngbya wollei (Cyanobacteria, Oscillatoriales) from north-eastern Australia, with a description of Microseira gen. nov. J Phycol 2015;51:109119.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Beasley VR, Dahlem AM, Cook WO, et al.. Diagnostic and clinically important aspects of cyanobacterial (blue-green algae) toxicoses. J Vet Diagn Invest 1989;1:359365.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Greer B, Meneely JP, Elliott CT. Uptake and accumulation of microcystin-LR based on exposure through drinking water: an animal model assessing the human health risk. Sci Rep 2018;8:4913.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    McLellan NL, Manderville RA. Toxic mechanisms of microcystins in mammals. Toxicol Res (Camb) 2017;6:391405.

  • 20.

    Beasley VR, Cook WO, Dahlem AM, et al.. Algae intoxication in livestock and waterfowl. Vet Clin North Am Food Anim Pract 1989;5:345361.

  • 21.

    Cao L, Massey IY, Feng H, et al.. A review of cardiovascular toxicity of microcystins. Toxins (Basel) 2019;11:507.

  • 22.

    Pearson L, Mihali T, Moffitt M, et al.. On the chemistry, toxicology and genetics of the cyanobacterial toxins, microcystin, nodularin, saxitoxin and cylindrospermopsin. Mar Drugs 2010;8:16501680.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Kleppe R, Herfindal L, Doskeland SO. Cell death inducing microbial protein phosphatase inhibitors—mechanisms of action. Mar Drugs 2015;13:65056520.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24.

    Bouaïcha N, Miles CO, Beach DG, et al.. Structural diversity, characterization and toxicology of microcystins. Toxins (Basel) 2019;11:714.

  • 25.

    Butler N, Carlisle J, Linville R. Toxocological summary and suggested action levels to reduce potential adverse health effects of six cyanotoxins. Sacramento, Calif: California Environmental Protection Agency, 2012.

    • Search Google Scholar
    • Export Citation
  • 26.

    World Health Organization. Cyanobacterial toxins: microcystins. background document for development of WHO guidelines for drinking-water quality and guidelines for safe recreational water environments. Geneva: World Health Organization, 2020.

    • Search Google Scholar
    • Export Citation
  • 27.

    CDC. Immediately dangerous to life or health (IDLH) values. Available at: www.cdc.gov/niosh/idlh/intridl4.html. Accessed Feb 18, 2021.

  • 28.

    Chernoff N, Hill D, Lang J, et al.. The comparative toxicity of 10 microcystin congeners administered orally to mice: clinical effects and organ toxicity. Toxins (Basel) 2020;12:403.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29.

    Carmichael W. Blue-green algae: an overlooked health threat. Available at: www.researchgate.net/publication/303155255. Accessed Feb 17, 2021.

    • Search Google Scholar
    • Export Citation
  • 30.

    Devlin JP, Edwards OE, Gorham PR, et al.. Anatoxin-a, a toxic alkaloid from Anabaena flos-aquae NRC-44h. Can J Chem 1977;55:13671371.

  • 31.

    Carmichael WW, Gorham PR, Biggs DF. Two laboratory case studies on the oral toxicity to calves of the freshwater cyanophite (blue-green alga) Anabaena flos-aquae NRC-44–1. Can Vet J 1977;18:7175.

    • Search Google Scholar
    • Export Citation
  • 32.

    Carmichael WW, Biggs DF, Gorham PR. Toxicology and pharmacological action of Anabaena flos-aquae toxin. Science 1975;187:542544.

  • 33.

    Falconer IR, Humpage AR. Health risk assessment of cyanobacterial (blue-green algal) toxins in drinking water. Int J Environ Res Public Heal 2005;2:4350.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34.

    World Health Organization. Cyanobacterial toxins: anatoxin-a and analogues. Background document for development of WHO guidelines for drinking-water quality and guidelines for safe recreational water environments. Geneva: World Health Organization, 2020.

    • Search Google Scholar
    • Export Citation
  • 35.

    Svirčev Z, Lalić D, Bojadžija Savić G, et al.. Global geographical and historical overview of cyanotoxin distribution and cyanobacterial poisonings. Arch Toxicol 2019;93:24292481.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36.

    Carmichael WW. Cyanobacteria secondary metabolites—the cyanotoxins. J Appl Bacteriol 1992;72:445459.

  • 37.

    Fiore MF, de Lima ST, Carmichael WW, et al.. Guanitoxin, re-naming a cyanobacterial organophosphate toxin. Harmful Algae 2020;92:101737.

  • 38.

    Cook WO, Beasley VR, Lovell RA, et al.. Consistent inhibition of peripheral cholinesterases by neurotoxins from the freshwater cyanobacterium Anabaena flos‐aquae: studies of ducks, swine, mice and a steer. Environ Toxicol Chem 1989;8:915922.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 39.

    Cook WO, Dellinger JA, Singh SS, et al.. Regional brain cholinesterase activity in rats injected intraperitoneally with anatoxin-a(s) or paraoxon. Toxicol Lett 1989;49:2934.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 40.

    Fernandes KA, Pinto E, Ferraz HG, et al.. Availability of guanitoxin in water samples containing Sphaerospermopsis torques-reginae cells submitted to dissolution tests. Pharmaceuticals (Basel) 2020;13:402.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41.

    Mahmood NA, Carmichael WW, Pfahler D. Anticholesterase poisonings in dogs from a cyanobacterial (blue-green algae) bloom dominated by Anabaena flos-aquae. Am J Vet Res 1988;49:500503.

    • Search Google Scholar
    • Export Citation
  • 42.

    Miller TR, Beversdorf LJ, Weirich CA, et al.. Cyanobacterial toxins of the Laurentian great lakes, their toxicological effects, and numerical limits in drinking water. Mar Drugs 2017;15:151.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 43.

    World Health Organization. Cyanobacterial toxins: saxitoxins. Background document for development of WHO guidelines for drinking-water quality and guidelines for safe recreational water environments. Geneva: World Health Organization, 2020.

    • Search Google Scholar
    • Export Citation
  • 44.

    Nagai H, Sato S, Iida K, et al.. Oscillatoxin i: a new aplysiatoxin derivative, from a marine cyanobacterium. Toxins (Basel) 2019;11:1521.

  • 45.

    Zhang H-H, Zhang X-K, Si R-R, et al. Chemical and biological study of novel aplysiatoxin derivatives from the marine cyanobacterium Lyngbya sp. Toxins (Basel) 2020;12:112.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 46.

    World Health Organization. Guidelines for safe recreational water environments: coastal and fresh waters. Available at: www.who.int/water_sanitation_health/publications/srwe1/en/. Accessed May 11, 2021.

    • Search Google Scholar
    • Export Citation
  • 47.

    World Health Organization. Cyanobacterial toxins: cylindrospermopsin. Background document for development of WHO guidelines for drinking-water quality and guidelines for safe recreational water environments. Geneva: World Health Organization, 2020.

    • Search Google Scholar
    • Export Citation
  • 48.

    Pichardo S, Cameán AM, Jos A. In vitro toxicological assessment of cylindrospermopsin: a review. Toxins (Basel) 2017;9:402.

  • 49.

    Hinojosa MG, Gutiérrez-Praena D, Prieto AI, et al.. Neurotoxicity induced by microcystins and cylindrospermopsin: a review. Sci Total Environ 2019;668:547565.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 50.

    Mez K, Beattie K, Codd G, et al.. Identification of a microcystin in benthic cyanobacteria linked to cattle deaths on alpine pastures in Switzerland. Eur J Phycol 1997;32:111117.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 51.

    Roy-Lachapelle A, Solliec M, Bouchard MF, et al.. Detection of cyanotoxins in algae dietary supplements. Toxins (Basel) 2017;9:117.

  • 52.

    Mittelman NS, Engiles JB, Murphy L, et al.. Presumptive iatrogenic microcystin-associated liver failure and encephalopathy in a Holsteiner gelding. J Vet Intern Med 2016;30:17471751.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 53.

    McGorum BC, Pirie RS, Glendinning L, et al.. Grazing livestock are exposed to terrestrial cyanobacteria. Vet Res 2015;46:16.

  • 54.

    Chiswell RK, Shaw GR, Eaglesham G, et al.. Stability of cylindrospermopsin, the toxin from the cyanobacterium, Cylindrospermopsis raciborskii: effect of pH, temperature, and sunlight on decomposition. Environ Toxicol 1999;14:155161.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 55.

    Kitchens CM, Johengen TH, Davis TW. Establishing spatial and temporal patterns in Microcystis sediment seed stock viability and their relationship to subsequent bloom development in Western Lake Erie. PLoS One 2018;13:e0206821.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 56.

    US EPA. Cyanobacteria Assessment Network mobile application (CyAN app). Available at: www.epa.gov/water-research/cyanobacteria-assessment-network-mobile-application-cyan-app. Accessed Feb 22, 2021.

    • Search Google Scholar
    • Export Citation
  • 57.

    Francis G. Poisonous Australian lake. Nature 1878;18:1112.

  • 58.

    Fitzgerald SD, Poppenga RH. Toxicosis due to microcystin hepatotoxins in three Holstein heifers. J Vet Diagn Invest 1993;5:651653.

  • 59.

    Galey FD, Beasley VR, Carmichael WW, et al.. Blue-green algae (Microcystis aeruginosa) hepatotoxicosis in dairy cows. Am J Vet Res 1987;48:14151420.

    • Search Google Scholar
    • Export Citation
  • 60.

    Kerr LA, McCoy CP, Eaves D. Blue-green algae toxicosis in five dairy cows. J Am Vet Med Assoc 1987;191:829830.

  • 61.

    Puschner B, Galey FD, Johnson B, et al.. Blue-green algae toxicosis in cattle. J Am Vet Med Assoc 1998;213:16051607.

  • 62.

    Steffen D. Cyanobacterial toxicoses. Newsletter of the American Association of the Bovine Practitioner, 1992.

  • 63.

    Zin LL, Edwards WC. Toxicity of blue-green algae in livestock. Bov Pract 1979;14:151153.

  • 64.

    Chengappa MM, Pace LW, McLaughlin BG. Blue-green algae (Anabaena spiroides) toxicosis in pigs. J Am Vet Med Assoc 1989;194:17241725.

  • 65.

    Cook WO, Beasley VR, Lovell RA. Blue-green algae toxicosis. Newsletter of the American Association of the Bovine Practitioner, 1987.

  • 66.

    Smith ZJ, Conroe DE, Schulz KL, et al.. Limnological differences in a two-basin lake help explain the occurrence of anatoxin-a, paralytic shellfish poisoning toxins, and microcystins. Toxins (Basel) 2020;12:559 10.3390/toxins12090559.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 67.

    US EPA. Cyanobacteria and cyanotoxins: information for drinking water systems. Available at: www.epa.gov/sites/production/files/2014–08/documents/cyanobacteria_factsheet.pdf. Accessed Feb 24, 2021.

    • Search Google Scholar
    • Export Citation
  • 68.

    Van Halderen A, Harding WR, Wessels JC, et al.. Cyanobacterial (blue-green algae) poisoning of livestock in the western Cape Province of South Africa. J S Afr Vet Assoc 1995;66:260264.

    • Search Google Scholar
    • Export Citation
  • 69.

    Short SB, Edwards WC. Blue-green algae toxicoses in Oklahoma. Vet Hum Toxicol 1990;32:558560.

  • 70.

    Carbis CR, Waldron DL, Mitchell GF, et al.. Recovery of hepatic function and latent mortalities in sheep exposed to the blue-green alga Microcystis aeruginosa. Vet Rec 1995;137:1215.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 71.

    Jackson AR, McInnes A, Falconer IR, et al.. Clinical and pathological changes in sheep experimentally poisoned by the blue-green alga Microcystis aeruginosa. Vet Pathol 1984;21:102113.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 72.

    Main DC, Berry PH, Peet RL, et al.. Sheep mortalities associated with the blue green alga Nodularia spumigena. Aust Vet J 1977;53:578581.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 73.

    Beasley VR, Coppock RW, Simon J, et al.. Apparent blue-green algae poisoning in swine subsequent to ingestion of a bloom dominated by Anabaena spiroides. J Am Vet Med Assoc 1983;182:413414.

    • Search Google Scholar
    • Export Citation
  • 74.

    Andrinolo D, Sedan D, Telese L, et al.. Hepatic recovery after damage produced by sub-chronic intoxication with the cyanotoxin microcystin LR. Toxicon 2008;51:457467.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 75.

    Blough E. Cocklebur toxicosis. Available at: www.addl.purdue.edu/newsletters/2007/Summer/CT.html. Accessed Feb 23, 2021.

  • 76.

    Bildfell R. Overview of pyrrolizidine alkaloidosis. Merck Veterinary Manual. Available at: www.merckvetmanual.com/toxicology/pyrrolizidine-alkaloidosis/overview-of-pyrrolizidine-alkaloidosis. Accessed Feb 23, 2021.

    • Search Google Scholar
    • Export Citation
  • 77.

    Cornell University. Plants poisonous to livestock: saponins. Available at: poisonousplants.ansci.cornell.edu/toxicagents/saponin.html. Accessed Feb 23, 2021.

    • Search Google Scholar
    • Export Citation
  • 78.

    Clayton MJ, Davis TZ, Knoppel EL, et al.. Hepatotoxic plants that poison livestock. Vet Clin North Am Food Anim Pract 2020;36:715723.

  • 79.

    Stich RW. Ectoparasiticides used in large animals. Merck Veterinary Manual. Available at: www.merckvetmanual.com/pharmacology/ectoparasiticides/ectoparasiticides-used-in-large-animals?query=carbamate toxicity. Accessed Feb 23, 2021.

    • Search Google Scholar
    • Export Citation
  • 80.

    Roberts VA, Vigar M, Backer L, et al.. Surveillance for harmful algal bloom events and associated human and animal illnesses - One Health Harmful Algal Bloom System, United States, 2006–2018. MMWR Morb Mortal Wkly Rep 2020;69:18891894.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 81.

    Massey IY, Wu P, Wei J, et al.. A mini-review on detection methods of microcystins. Toxins (Basel) 2020;12:132.

  • 82.

    Wharton RE, Cunningham BR, Schaefer AM, et al.. Measurement of microcystin and nodularin activity in human urine by immunocapture-protein phosphatase 2a assay. Toxins (Basel) 2019;11:729.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 83.

    Moore CE, Juan J, Lin Y, et al.. Comparison of protein phosphatase inhibition assay with LC-MS/MS for diagnosis of microcystin toxicosis in veterinary cases. Mar Drugs 2016;14:54.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 84.

    Puschner B, Hoff B, Tor ER. Diagnosis of anatoxin—a poisoning in dogs from North America. J Vet Diagn Invest 2008;20:8992.

  • 85.

    Rankin KA, Alroy KA, Kudela RM, et al.. Treatment of cyanobacterial (microcystin) toxicosis using oral cholestyramine: case report of a dog from Montana. Toxins (Basel) 2013;5:10511063.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 86.

    US EPA. Laboratories that analyze for cyanobacteria and cyanotoxins. Available at: www.epa.gov/cyanohabs/laboratories-analyze-cyanobacteria-and-cyanotoxins. Accessed Jan 26, 2020.

    • Search Google Scholar
    • Export Citation
  • 87.

    American Association of Laboratory Diagnosticians. Accreditation laboratories. Available at: www.aavld.org/accredited-labs. Accessed Jan 26, 2020.

    • Search Google Scholar
    • Export Citation
  • 88.

    CDC. One Health Harmful Algal Bloom System (OHHABS). Available at: www.cdc.gov/habs/ohhabs.html. Accessed May 11, 2021.

  • 89.

    CDC. One Health Harmful Algal Bloom System (OHHABS)—harmful algal bloom (HAB) event and case definitions. Available at: www.cdc.gov/habs/pdf/ohhabs-case-and-event-definitions-table-508.pdf. Accessed Jan 25, 2020.

    • Search Google Scholar
    • Export Citation
  • 90.

    Mereish KA, Solow R. Effect of antihepatotoxic agents against microcystin-LR toxicity in cultured rat hepatocytes. Pharm Res 1990;7:256259.

  • 91.

    Mereish KA, Bunner DL, Ragland DR, et al.. Protection against microcystin-LR-induced hepatotoxicity by silymarin: biochemistry, histopathology, and lethality. Pharm Res 1991;8:273277.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 92.

    Rao PVL, Jayaraj R, Bhaskar ASB. Protective efficacy and the recovery profile of certain chemoprotectants against lethal poisoning by microcystin-LR in mice. Toxicon 2004;44:723730.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 93.

    Debruyn JM, Wilhelm SW, Ludwig A, et al.. Cyanobacteria (glue-green algae) harmful algal blooms. University of Tennessee Extension Document No. W 340. Available at: extension.tennessee.edu/publications/Documents/W340.pdf. Accessed Jan 24, 2020.

    • Search Google Scholar
    • Export Citation
  • 94.

    Clawson B. Preserve your natural backyard pond. Michigan State University Extension. Available at: www.canr.msu.edu/news/preserve_your_natural_backyard_pond. Accessed Jan 25, 2020.

    • Search Google Scholar
    • Export Citation
  • 95.

    Bass T. Avoiding algae issues in stock ponds. Montana State University Extension. Available at: apps.msuextension.org/magazine/articles/5460. Accessed Feb 25, 2021.

    • Search Google Scholar
    • Export Citation
  • 96.

    US EPA. Control Measures for cyanobacterial HABs in surface water. Available at: www.epa.gov/cyanohabs/control-measures-cyanobacterial-habs-surface-water. Accessed Feb 23, 2021.

    • Search Google Scholar
    • Export Citation
  • 97.

    Schultheis RA. Algae control in stock tanks, ponds and lakes. University of Missouri Extension. Available at: extension.missouri.edu/media/wysiwyg/Extensiondata/CountyPages/Webster/Docs/Algae_Control_in_Tanks_and_Ponds.pdf. Accessed May 11, 2021.

    • Search Google Scholar
    • Export Citation
  • 98.

    Lembi C. Barley straw for algae control. Purdue University Extension Report No. APM-1-W. 2002. Available at: mdc.itap.purdue.edu/item.asp?Item_Number=APM-1-Accessed W. May 11, 2021.

    • Search Google Scholar
    • Export Citation
  • 99.

    Delaware Division of Fish & Wildlife. Barley straw for algae control. Delaware Department of Natural Resources and Environment Control Document No. 40–05–02–02/07/012001. Available at: www.dnrec.delaware.gov/fw/Fisheries/Documents/barleystraw.pdf. Accessed Jan 23, 2020.

    • Search Google Scholar
    • Export Citation
  • 100.

    Haberland M. Pond and lake management part VI: using barley straw to control algae. Rutgers University Extension Document No. FS11712011. Available at: njaes.rutgers.edu/fs1171/. Accessed Jan 23, 2020.

    • Search Google Scholar
    • Export Citation
  • 101.

    Swistock B. Barley straw for algae control. PennState Extension. Available at: extension.psu.edu/barley-straw-for-algae-control. Accessed Jan 24, 2020.

    • Search Google Scholar
    • Export Citation
  • 102.

    Sink T, Gwinn J, Gerke H, et al.. Managing and controlling algae in ponds. Texas A&M University Extension Publication No. EWF-015. Available at: cdn-ext.agnet.tamu.edu/wp-content/uploads/2019/03/EWF-015-managing-and-controlling-algae-in-ponds.pdf. Accessed Jan 24, 2020.

    • Search Google Scholar
    • Export Citation
  • 103.

    Helfrich LA, Neves RJ, Libey G, et al.. Control methods for aquatic plants in ponds and lakes. Virginia Cooperative Extension Document No. 420–2512009. Available at: www.pubs.ext.vt.edu/420/420–251/420–251.html. Accessed Jan 24, 2020.

    • Search Google Scholar
    • Export Citation
  • 104.

    USDA Agricultural Research Service. Phosphorus removal structures. Available at: www.ars.usda.gov/midwest-area/west-lafayette-in/national-soil-erosion-research/docs/phosphorus-removal-structures/. Accessed Mar 22, 2021.

    • Search Google Scholar
    • Export Citation
  • 105.

    Toste A. Combating the “phosphorus paradox.” Available at: www.progressivedairy.com/topics/manure/combating-the-phosphorus-paradox. Accessed Mar 22, 2021.

    • Search Google Scholar
    • Export Citation
  • 106.

    Anderson DM. Approaches to monitoring, control and management of harmful algal blooms (HABs). Ocean Coast Manag 2009;52:342347.

  • 107.

    Anderson DM, Boyer GL, Cammen LM, et al.. Prevention, control and mitigation of harmful algal blooms: a research plan. Available at: www.whoi.edu/cms/files/PCM_HAB_Research_Plan%282%29_18563_23051.pdf. Accessed May 11, 2021.

    • Search Google Scholar
    • Export Citation
  • 108.

    Camberato DM, Lopez RG. Controlling algae in irrigation ponds. Purdue Extension Publication No. HO-247-W. Available at: mdc.itap.purdue.edu/. Accessed Jan 24, 2020.

    • Search Google Scholar
    • Export Citation
  • 109.

    Han W, Clarke W, Pratt S. Composting of waste algae: a review. Waste Manag 2014;34:11481155.

  • 110.

    Arnold M. Frequently asked questions about harmful algal blooms (HABs) in farm ponds used to water livestock. Available at: u.osu.edu/beef/2019/08/28/frequently-asked-questions-about-harmful-algal-blooms-habs-in-farm-ponds-used-to-water-livestock/. Accessed Feb 23, 2021.

    • Search Google Scholar
    • Export Citation
  • 111.

    van der Merwe D, Blocksome C, Hollis L. Identification and management of blue-green algae in farm ponds. K-State Research and Extension Document No. MF-3065. Available at: bookstore.ksre.ksu.edu/pubs/MF3065.pdf. Accessed Feb 24, 2021.

    • Search Google Scholar
    • Export Citation
  • 112.

    Paerl HW, Otten TG, Kudela R. Mitigating the expansion of harmful algal blooms across the freshwater-to-marine continuum. Environ Sci Technol 2018;52:55195529.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 113.

    US EPA. Hypoxia Task Force nutrient reduction strategies. Available at: www.epa.gov/ms-htf/hypoxia-task-force-nutrient-reduction-strategies. Accessed Apr 8, 2021.

    • Search Google Scholar
    • Export Citation
  • 114.

    Matthijs HCP, Jančula D, Visser PM, et al.. Existing and emerging cyanocidal compounds: new perspectives for cyanobacterial bloom mitigation. Aquat Ecol 2016;50:443460.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 115.

    IARC. Ingested nitrate and nitrite, and cyanobacterial peptide toxins. Available at: publications.iarc.fr/112. Accessed Feb 17, 2021.

  • 116.

    Žegura B, Štraser A, Filipič M. Genotoxicity and potential carcinogenicity of cyanobacterial toxins - a review. Mutat Res 2011;727:1641.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 117.

    Lee J, Lee S, Mayta A, et al.. Microcystis toxin–mediated tumor promotion and toxicity lead to shifts in mouse gut microbiome. Ecotoxicol Environ Saf 2020;206:111204.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 118.

    Bernstein JA, Ghosh D, Levin LS, et al.. Cyanobacteria: an unrecognized ubiquitous sensitizing allergen? Allergy Asthma Proc 2011;32:106110.

  • 119.

    Rogers ED, Henry TB, Twiner MJ, et al.. Global gene expression profiling in larval zebrafish exposed to microcystin-LR and microcystis reveals endocrine disrupting effects of cyanobacteria. Environ Sci Technol 2011;45:19621969.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 120.

    Mallia V, Ivanova L, Eriksen GS, et al.. Investigation of in vitro endocrine activities of Microcystis and Planktothrix cyanobacterial strains. Toxins (Basel) 2020;12:228.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 121.

    Backer LC, Miller M. Sentinel animals in a one health approach to harmful cyanobacterial and algal blooms. Vet Sci 2016;3:8.

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Harmful algal bloom resources for livestock veterinarians

Eileen M. WolfeFrom the Harmful Algal Blooms Working Group, AVMA, Schaumburg, IL 60173.

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Abstract

Harmful algal blooms can have deleterious effects on animal and human health as well as the environment and are anticipated to become more frequent and intensified in the future because of climate change. Veterinarians are well positioned to diagnose and treat animals affected by HABs and to educate livestock owners and the public about health risks and environmental issues associated with those toxic events. Pets, livestock, wildlife, and marine life can all be affected by HABs. Information about HABs is becoming increasingly assessable as a result of ongoing research into the structure, properties, toxic mechanisms, and geographic distribution of toxins found in HABs. The AVMA's multi-entity working group on HABs is comprised of members from the Aquatic Veterinary Medicine Committee, Committee on Environmental Issues, and Council on Public Health and is working to make more information and resources regarding HABs available to practicing veterinarians. The present article is the first of those resources and provides a review of HABs, with a focus on livestock. It includes background material about bloom formation, appearance, and persistence as well as descriptions of clinical observations from early field cases and more recent information about the causative organisms and toxins to provide livestock veterinarians a foundation for understanding HABs. Reporting of HABs and prevention and mitigation strategies for livestock owners are also discussed. (J Am Vet Med Assoc 2021;259:151–161)

Abstract

Harmful algal blooms can have deleterious effects on animal and human health as well as the environment and are anticipated to become more frequent and intensified in the future because of climate change. Veterinarians are well positioned to diagnose and treat animals affected by HABs and to educate livestock owners and the public about health risks and environmental issues associated with those toxic events. Pets, livestock, wildlife, and marine life can all be affected by HABs. Information about HABs is becoming increasingly assessable as a result of ongoing research into the structure, properties, toxic mechanisms, and geographic distribution of toxins found in HABs. The AVMA's multi-entity working group on HABs is comprised of members from the Aquatic Veterinary Medicine Committee, Committee on Environmental Issues, and Council on Public Health and is working to make more information and resources regarding HABs available to practicing veterinarians. The present article is the first of those resources and provides a review of HABs, with a focus on livestock. It includes background material about bloom formation, appearance, and persistence as well as descriptions of clinical observations from early field cases and more recent information about the causative organisms and toxins to provide livestock veterinarians a foundation for understanding HABs. Reporting of HABs and prevention and mitigation strategies for livestock owners are also discussed. (J Am Vet Med Assoc 2021;259:151–161)

Introduction

Harmful algal blooms are a one-health issue that is likely to become intensified by climate change.1 Harmful algal blooms can have deleterious effects on animal and human health as well as the environment. As one-health practitioners, veterinarians are well positioned to diagnose and treat animals affected by HABs and to educate livestock owners and the public about human risks and environmental issues associated with those toxic events. Pets, livestock, wildlife, and marine life can all be affected by HABs. Many of the reports in the veterinary literature that describe livestock illness and deaths caused by HABs were published before detailed knowledge of the toxins produced in the blooms was available. That information is becoming increasingly assessable with ongoing research into the structure, properties, toxic mechanisms, and geographic distribution of toxins found in HABs. The AVMA's multi-entity working group on HABs, which is comprised of members from the Aquatic Veterinary Medicine Committee, Committee on Environmental Issues, and Council on Public Health, is working to make more information and resources regarding HABs available to practicing veterinarians. Such resources include educational opportunities as well as clinical information for livestock and companion animal practitioners. This article is the first of those resources and provides a review of HABs, with a focus on livestock. It includes background material about bloom formation, appearance, and persistence as well as descriptions of clinical observations from early field cases and more recent information about the causative organisms and toxins in HABs. Along with data on clinicopathologic and necropsy findings, this information will provide livestock veterinarians an informed basis from which to understand HABs. Reporting of HABs and prevention and mitigation strategies for livestock owners are also discussed.

Description of HABs and the toxins they produce

Harmful algal blooms are defined as the rapid proliferation, or bloom, of toxin-producing phytoplankton. These blooms occur in fresh, saline, or brackish water under favorable growing conditions and can be caused by several types of phytoplankton. The HABs to which livestock are generally exposed occur in freshwater or occasionally brackish water and are caused by cyanobacteria. Although cyanobacteria are true bacteria, they behave like algae in aquatic environments and are often referred to as blue-green algae. There are over 2,000 species of cyanobacteria, not all of which produce toxins. In fact, not all algal blooms are harmful, but the noxious nature of a bloom cannot be determined visually. Currently, at least 95 species of cyanobacteria are known to produce toxins, which are referred to as cyanotoxins. These toxins can adversely affect humans, livestock, companion animals, and wildlife including birds, amphibians, reptiles, and honeybees.

Paleolimnology, a multidisciplinary approach that uses proxy indicators in sediment to reconstruct environmental conditions, indicates that certain cyanotoxins have been present in some bodies of water since the 1800s.2 Therefore, it is unsurprising that centuries-old historical records provide evidence of animal deaths caused by HABs.3 Paleolimnology-based analyses also suggest that, although cyanotoxins were present in lakes prior to land-use changes, their presence in sediments has increased significantly as agricultural use of land has intensified.2 Concomitantly, the number of reports of livestock intoxication caused by algal blooms has increased over the last hundred years or so, and numerous incidents involving HABs and livestock have been summarized in the literature.38

Clinical observations associated with HABs led to the study of cyanotoxins, which has evolved over time from bioassays to the currently used physicochemical analytic methods.9 Historically, cyanotoxins were categorized into groups on the basis of the major system or organ affected (eg, hepatotoxins, neurotoxins, dermatoxins, and cytotoxins); however, more recent research indicates that some cyanotoxins target multiple organ systems.10,11 Several hundred individual cyanotoxins have been chemically defined.11,12 Some of those cyanotoxins have been summarized on the basis of toxin classification, major mode of action, important acute effects on health, and representative genera of cyanobacteria that produce them13 (Table 1). Although most cases of cyanotoxicosis in veterinary species are caused by hepatotoxins and neurotoxins, a more comprehensive discussion of cyanotoxins is warranted owing to the one-health nature of HABs and the rapid pace of new discoveries in the field.

Table 1

Summary of cyanotoxins commonly encountered on the basis of toxin classification, major mode of action, acute effects on health, and representative cyanobacteria that produce those toxins.

Toxin classification Toxin name Major mode of action Acute effects on health Representative cyanobacteria genera
Hepatotoxin Microcystins Protein phosphatase inhibition, oxidative stress, and tumor promotion Hepatocyte death, intrahepatic hemorrhage, and hypovolemic shock Microcystis, Nostoc, and Dolichospermum*
Nodularins Protein phosphatase inhibition Hepatocyte death, intrahepatic hemorrhage, and hypovolemic shock Nodularia
Neurotoxin Anatoxin-a Nicotinic acetylcholine receptor agonist Respiratory arrest Dolichospermum,* Aphanizomenon, Oscillatoria, and Cylindrospermum
Guanitoxin Irreversible acetylcholinesterase inhibition Respiratory arrest Dolichospermum*
Saxitoxin Sodium channel blockade Respiratory paralysis Dolichospermum,* Aphanizomenon, Cylindrospermum, and Microseira
Dermatoxin Lyngbyatoxin-a Protein kinase C activation and inflammatory agent Dermatitis Lyngbya and Oscillatoria
Aplysiatoxin Protein kinase C activation and inflammatory agent Dermatitis Lyngbya and Oscillatori
Cytotoxin Cylindrospermopsin Protein synthesis inhibition and oxidative stress Cell damage and necrosis across multiple systems Cylindrospermopsis and Dolichospermum*

Adapated from Bláha et al.13

Anabaena has recently been divided into two genera: Dolichospermum, which are pelagic (ie, occur in the water column by virtue of their gas vesicles), and Anabaena, which are benthic (ie, occur attached to surfaces in the bottom environment). Both genera contain toxic and nontoxic members.14,15

Formerly freshwater Lyngbya.16

The term hepatotoxin was derived from the observed hepatocellular destruction caused by such a toxin.17 Microcystins and nodularins are common hepatotoxins produced by some cyanobacteria. Microcystins can be produced in both fresh and salt waters and are the cyanotoxins most frequently confirmed as the cause of cyanotoxicosis in veterinary species and humans.11 At the cellular level, uptake of microcystins is facilitated by OATPs, which are expressed by cells of numerous organs and systems including the liver, kidney, lungs, CNS, and gastrointestinal and reproductive tracts.11,18,19 Hepatocytes have greater expression of OATPs than other cells; therefore, microcystins are more likely to accumulate and cause damage in the liver than in other organs.19 Microcystins inhibit protein phosphatases inside cells, resulting in cytoskeletal collapse and apoptosis.11,19 In the liver, microcystins can lead to hemorrhage, which in turn can result in hypovolemic shock and death.20 Microcystins also cause oxidative stress in multiple organ systems,11,19 and microcystin-induced damage to the cardiovascular system is an area of recent study.21

Nodularins are hepatotoxins produced in salt or brackish water and occur most commonly in algal blooms in coastal waters and estuaries. They have been widely reported in Australia and also detected in New Zealand, Europe, and North America.11,22 Similar to microcystins, nodularins are dependent on OATPs for cellular entry and inhibit protein phosphatases, which leads to apoptosis.23

Microcystins and nodularins are both cyclic peptides with 7 and 5 amino acids, respectively. Over 250 individual microcystins and 10 nodularins have been chemically defined.12,24 The different structural analogs, referred to as congeners, have variations in amino acid content and placement of functional groups such as methyl groups. Microcystin nomenclature is based on the amino acids present at 2 highly variable positions, with a single letter representing the amino acid present (eg, L for leucine and R for arginine).25 Water and tissue samples are generally analyzed for only 12 microcystin congeners, including microcystins-LR, -YR, -RR, and -LA and their metabolic byproducts. Both microcystins and nodularins are heat stable and highly toxic.26 Microcystin-LR, the most common congener, is among the most toxic with an oral LD50 of 5 mg/kg (2.3 mg/lb) in murine species,26 which is similar to the oral LD50 of cyanide and strychnine.27 In a recent study28 of HABs from around the world, the oral toxicity was determined for 10 microcystin congeners, with microcystin-LR and microcystin-LA being the most toxic; results of that study also suggest that the toxic effects of microcystins are dose dependent. The LD50 of nodularin when administered IP is comparable to that of microcystin-LR.29

More than 80 cyanobacterial neurotoxins have been identified, including anatoxin-a and its analogs, guanitoxin, and saxitoxins.11 One of the first neurotoxins identified was anatoxin-a, a toxic alkaloid originally called very fast death factor when it was observed in the field.30 Results of an experimental study indicate that consumption of just over 1 L (1.1 qt) of water from a concentrated toxic bloom containing anatoxin-a can be lethal for a 60-kg (132-lb) calf.31 Initially, the mechanism of action for anatoxin-a was described as a depolarizing neuromuscular blockade that resulted in respiratory arrest.31,32 Subsequent research indicates that anatoxin-a and its congeners are potent nicotinic acetylcholine receptor agonists.17 Anatoxin-a is considered stable in the environment.33 Anatoxins are found primarily in fresh water, and although they can be produced by cyanobacteria with near-global distribution, these toxins have been detected in HABs less frequently than microcystins and cylindrospermopsin.34 A 2019 review35 of human and animal intoxications from HABs around the world found that anatoxin-a was second only to microcystin when both identified and causally inferred cyanotoxins were considered.

Guanitoxin, like anatoxin-a, was originally isolated from Anabaena spp36 and was named anatoxin-a(s) because it causes hypersalivation.11 The name of this neurotoxin was subsequently changed to guanitoxin because it is chemically distinct from anatoxin-a and has a different mode of toxic action. Guanitoxin is an organophosphate compound that acts as an irreversible cholinesterase inhibitor.37 Blood, but not brain, cholinesterase activity is decreased after guanitoxin exposure, which indicates that the toxin has only peripheral anticholinesterase activity.38,39 Guanitoxin is produced by freshwater cyanobacteria, and only 1 guanitoxin congener has been identified to date.40 It is found in water less frequently than microcystins.40 Although guanitoxin is very toxic, with an LD50 comparable to that of microcystin-LR, it is not particularly stable and is inactivated by high temperatures (> 40°C [> 104°F]) and alkaline conditions.11 However, results of an in vitro study suggest that guanitoxin can be bioaccessible in the intestine and stomach, especially in the presence of pancreatic enzymes.40 Morbidity and death caused by guanitoxin have been reported in various animal species, including pigs, ducks, and dogs.17,41 Guanitoxicosis has not been reported in cattle, and results of an in vivo study38 suggest that cattle may not be particularly susceptible to guanitoxin.

Saxitoxins are heat-stable alkaloid neurotoxins, and > 50 saxitoxin congeners have been identified.11,42 Most known saxitoxins are produced by marine shellfish and cause a syndrome called paralytic shellfish poisoning; however, freshwater cyanobacteria also produce saxitoxins.43 The best understood toxic mechanism of highly potent saxitoxins is blockade of sodium channels in both sensory and motor neurons.43 Other potentially harmful effects, such as the blockade of calcium and potassium channels in cardiac cells and direct action on the CNS, have also been considered.43 In the United States, saxitoxins are being detected in northern lake waters with increasing frequency owing to the spread of saxitoxin-producing cyanobacteria from warmer waters.42

Dermatoxins, many of which are grouped as aplysiatoxins, are produced primarily by marine cyanobacteria of the genus Lyngbya and are inflammatory in nature.44,45 The dermal reactions observed in humans after exposure to freshwater cyanobacteria have been attributed to bioactive constituents of cyanobacteria other than dermatoxins,42,46 but it has also been suggested that freshwater Lyngbya spp (currently classified as Microseira wollei) can produce dermatoxins.11

Cylindrospermopsin is an alkaloid cytotoxin produced primarily by freshwater cyanobacteria.11,47 Only a few congeners of cylindrospermopsin have been identified, but they are widely distributed including in the US Midwest.11 Cylindrospermopsins are highly water soluble and are differentiated from other cyanotoxins by the fact that as much as 90% of cylindrospermopsin is found free in water rather than within cyanobacterial cells.47 The cellular uptake and cytotoxic mechanisms of cylindrospermopsin are not fully understood but likely involve inhibition of protein synthesis and oxidative stress.9,48 Other proposed toxic effects of cylindrospermopsin include genotoxicity, immunotoxicity, and possibly carcinogenic activity.9,48 Results of in vitro experiments suggest that cylindrospermopsin may also have neurotoxic effects.49 Organs targeted by cylindrospermopsins include the liver, kidney, gastrointestinal tract, heart, spleen, and thymus.47

Research is ongoing to better characterize cyanotoxins, including their geographic range and the conditions necessary for their production, as well as to elucidate their toxic effects.

Where HABs occur

In the United States, cyanotoxicoses in livestock species have historically been traced to HABs in water, with a wide variety of water sources implicated. Farm ponds or dugouts are common sources of toxic blooms, but HABs can occur in other water sources including lakes, rivers, reservoirs, and water troughs. Factors that contribute to HABs include warm temperatures and water that is stagnant and rich in nutrients, such as phosphorus and nitrogen from fertilizer runoff or excrement contamination. However, microcystins have been identified in colder oligotrophic waters.50 Cyanobacterial blooms are buoyant and often accumulate on the surface of the downwind side of a body of water. Because cyanotoxins affect nearly all species of domestic animals and wildlife, detection of dead muskrats or other pond wildlife is often the first indication of the presence of toxins in an algal bloom.

In humans, cyanobacterial intoxication typically results from ingestion of food such as fish or shellfish owing to bioaccumulation of toxins from water or cyanobacteria within edible tissues. Paralytic shellfish poisoning occurs primarily following ingestion of bioaccumulated saxitoxins in fish or shellfish harvested from marine environments, although bioaccumulation of saxitoxins can also occur in freshwater fish and shellfish.43 Bioaccumulation of microcystins can also occur.26 At the present time, there are no known occurrences of cyanobacterial intoxication of livestock owing to bioaccumulation of cyanotoxins in feed sources.

In recent years, cyanobacteria have become popular as dietary supplements for both humans and companion animals. Those supplements are not currently regulated in the United States despite the fact that microcystins, anatoxins, cylindrospermopsin, and saxitoxin have been detected in commercially available dietary supplements.51 Although it is unlikely that food-animal species will develop cyanotoxicosis from ingestion of dietary supplements, there is a report52 of fatal microcystin intoxication in a horse that was attributed to ingestion of a cyanobacterial supplement.

Toxin-producing cyanobacteria also occur in terrestrial environments.9 The relationship between terrestrial cyanobacteria and the health of grazing livestock has been investigated but remains inconclusive.53

When HABs occur

Harmful algal blooms can occur at any time when conditions are right for cyanobacterial growth. Historically, the incidence of algal blooms peaked during the summer months because warm temperatures favor cyanobacterial growth; however, algal blooms in the fall months are becoming more common. Algal blooms typically last for several days before being dissipated by the wind or other weather conditions but can persist for weeks or months under favorable conditions. Cyanotoxins may be released into water by viable cyanobacterial cells (eg, cylindrospermopsin)47 or found primarily in intact cyanobacterial cells (eg, microcystins and saxitoxins).26,43 Release of anatoxin-a into water is not well understood, and it is thought that most anatoxin-a is retained in intact cyanobacterial cells.34 Cyanobacterial cell death and lysis will increase the cyanotoxin load in water regardless of whether cell death occurs naturally or is induced by treatment of the water.

Cyanotoxins can persist in water after HABs are no longer visible. The duration that toxins persist varies, with microcystins being quite stable owing to their cyclic ring structure.6 Microcystins resist degradation, break down slowly in full sunlight, and can survive boiling.25 Microcystins can last for weeks in the environment6 and for months or even years in cool, dark bodies of water without bacteria to degrade them.25 Saxitoxin can persist in natural waters for up to 2 months.43 Information about the persistence of anatoxin-a in water is limited,34 but results of 1 study25 suggest that anatoxin-a has a half-life of 5 to 14 days in lake and reservoir waters. Anatoxin-a is fairly stable in dark environments but is rapidly degraded by sunlight, especially in alkaline water.25 Cylindrospermopsin is heat stable, including boiling for 15 minutes, and similar to anatoxin-a, it is fairly stable in dark environments.25 Pure cylindrospermopsin is fairly stable in sunlight, but the presence of cyanobacterial cell pigments in the water leads to rapid toxin breakdown.54 Water turbidity and depth, as well as the age of the algal bloom, may affect the persistence of cylindrospermopsin in natural waters because that toxin is released primarily by viable cyanobacterial cells.54 Cyanotoxins are eventually dissipated by a combination of dilution, unfavorable temperatures and pHs, microbial degradation, and removal from the water column by adsorption to soil particles.2 Microcystins can persist for months in soil sediments,2 and the cyanobacteria that produce microcystins are also hardy.55 For example, the genus Microcystis produces microcystins and was found to overwinter in the bottom sediment of Lake Erie.55

Appearance of HABs

Freshwater algal blooms are most often described as looking like spilled paint or pea soup. Generally, the color of algal blooms is initially green and turns to blue as cyanobacteria die, but algal blooms can appear in a wide range of colors including brown, white, and yellow. The blooms often form mats, scum, or foam, and filaments may be observed in the water depending on the cyanobacterial species present. Mats can also form below the surface of the water on rocks and other substrates, which can make the algal blooms more difficult to recognize. Although not all algal blooms contain toxins, there is no way to visually determine whether toxins are present in a bloom, so all blooms should be considered dangerous. The US EPA recently developed a mobile software applicationa that allows users to access satellite data regarding cyanobacterial blooms56 and may be a useful tool for learning to recognize cyanobacterial blooms.

Types of livestock affected by HABs

All livestock species can potentially be affected by cyanotoxins. The first report of cyanotoxicosis of livestock in the scientific literature was by George Francis57 in 1878. That report57 described a classic toxic algal bloom in an Australian lake that was associated with the death of an unspecified number of livestock, including cattle, horses, sheep, and pigs, as well as dogs. Since then, multiple literature reviews3,5,6,8,35 have documented instances of livestock being affected by HABs on all inhabited continents. In the United States, most case reports of HABs involve the intoxication of cattle,5863 which likely reflects common husbandry practices (ie, exposure of cattle to farm ponds), the large number of cattle in the country, and the perceived value of individual cattle. Harmful algal blooms have also induced toxicosis in pigs in the United States.64,65 Ingestion of contaminated water is considered the most common route by which livestock are exposed to cyanotoxins. Dermal contact with and inhalation of toxins, which are frequently cited routes of cyanotoxin exposure for humans, could occur simultaneously with ingestion and thus contribute to intoxication of cattle and other livestock.

Clinical signs of cyanotoxicosis

Although it might be assumed that the clinical signs of cyanotoxicosis in affected animals would be consistent with whether the toxin involved is a neurotoxin or hepatotoxin, it is not so straightforward for various reasons. As previously discussed, hepatotoxins can affect tissues other than the liver.11 Clinical signs are also dependent on the level of toxin exposure, including the duration of exposure and concentration of toxins in the bloom. Additionally, it is possible for an algal bloom to contain more than 1 toxin or toxin type.66 Multiple genera of cyanobacteria can be present within a bloom,66 and some cyanobacteria can produce more than 1 type of toxin.67 Nevertheless, certain clinical signs in livestock have been ascribed to hepatotoxins and neurotoxins. Animals clinically affected by hepatotoxins can display weakness, anorexia, vomiting, diarrhea, icterus, and pale mucous membranes.6,17,20,36 Acute death, which may be preceded by recumbency, paddling, convulsions, and coma, can occur within hours because of massive intrahepatic hemorrhage and hypovolemic shock.6,17,20,36 A more protracted death (within weeks) can result from hepatic insufficiency.20,36 Animals that survive can develop secondary photosensitization.17

Animals affected by neurotoxins frequently die peracutely (within minutes to hours) with few or no premonitory signs.3,11,20,31 In North America, the neurotoxins most commonly implicated in livestock intoxications include guanitoxin and anatoxin-a and its congeners. To date, most clinical reports of livestock intoxications from saxitoxin have originated from outside the United States. Clinical signs of neurotoxicosis, when present, include muscle fasciculations, ataxia, collapse, cyanosis, and convulsions regardless of the inciting toxin and whether the intoxication occurred as a result of natural or experimental exposure.3,17,20,31,36 Guanitoxin additionally causes hypersalivation, lacrimation, mucoid nasal discharge, and bruxism.11,20 Guanitoxin also has been reported to cause urination and defecation, particularly in laboratory settings.3,38

Clinical signs reported for cattle (Table 2), sheep (Table 3), and swine (Table 4) with cyanotoxicosis are summarized. Most of these data were acquired from clinical reports of animals that became intoxicated from natural exposure, although some data were acquired from clinical trials. The information presented was obtained from case reports from North America when available; however, the information regarding clinical signs in sheep was obtained from Australia and South Africa.

Table 2

Clinical signs of cyanotoxicosis reported in cattle and the toxin types associated with those signs.

Clinical sign Toxin type Reference No.
Acute or sudden death Hepatotoxin, neurotoxin (anatoxin-a) 20, 58, 61, 62, 65, 68, 69
Weakness or recumbency Hepatotoxin 6, 20, 58, 59, 61, 65
Muscle tremors or fasciculations Hepatotoxin, neurotoxin (anatoxin-a) 20, 31, 60, 62, 63, 65
Depression or unresponsiveness Hepatotoxin 20, 59, 62, 65
Diarrhea, possibly profuse or bloody Hepatotoxin 20, 59, 60, 63
Anorexia Hepatotoxin 20, 58, 59, 61
Convulsions Hepatotoxin, neurotoxin (anatoxin-a) 6, 20, 63
Ataxia or staggering Hepatotoxin, neurotoxin (anatoxin-a) 61, 65
Reluctance to move Hepatotoxin 20, 59
Nervousness Hepatotoxin 6, 61
Nervous signs exacerbated by noise Hepatotoxin 60, 61
Occasional mental derangement Hepatotoxin 20, 59
Dyspnea Hepatotoxin, neurotoxin (anatoxin-a) 63, 65
Pale mucous membranes Hepatotoxin 20, 59
Photosensitization Hepatotoxin 20, 61
Icterus Hepatotoxin 65
Profuse salivation Hepatotoxin 60
Table 3

Clinical signs of cyanotoxicosis reported in sheep and the toxin types associated with those signs.

Clinical sign Toxin type Reference No.
Lethargy or depression Hepatotoxin 70–72
Dyspnea Hepatotoxin 70–72
Recumbency Hepatotoxin 71, 72
Anorexia Hepatotoxin 70, 71
Facial or submandibular edema Hepatotoxin 68, 70
Photosensitization Hepatotoxin 68, 70
Acute or sudden death Hepatotoxin 72
Muscle fasciculations Hepatotoxin 71
Ataxia Hepatotoxin 70
Convulsions Hepatotoxin 72
Opisthotonus Hepatotoxin 72
Diarrhea Hepatotoxin 70
Dermatitis Hepatotoxin 70
Pruritis Hepatotoxin 70
Nasal discharge Hepatotoxin 72
Pyrexia Hepatotoxin 72
Icterus Hepatotoxin 68
Table 4

Clinical signs of cyanotoxicosis reported in swine and the toxin types associated with those signs.

Clinical sign Toxin type Reference No.
Hypersalivation or frothing at mouth Neurotoxin (guanitoxin) 20, 38, 64, 69
Dyspnea Neurotoxin (guanitoxin) 20, 38, 64, 69
Muscle tremors or fasciculations Neurotoxin (guanitoxin) 20, 64, 69, 73
Vomiting Neurotoxin (guanitoxin) 38, 64, 73
Cyanosis (terminal) Neurotoxin (guanitoxin) 20, 38, 73
Ataxia Neurotoxin (guanitoxin) 20, 38
Recumbency Neurotoxin (guanitoxin) 20, 38
Diarrhea, may be bloody Neurotoxin (guanitoxin) 20, 64
Coughing or sneezing Neurotoxin (guanitoxin) 38, 64
Mucoid nasal discharge Neurotoxin (guanitoxin) 20, 38
Bruxism Neurotoxin (guanitoxin) 20, 38
Acute or sudden death Neurotoxin (guanitoxin) 38
Lethargy or dullness Neurotoxin (guanitoxin) 64
Anorexia Neurotoxin (guanitoxin) 64
Chomping fits Neurotoxin (guanitoxin) 69

Clinicopathologic and histologic findings associated with cyanotoxicoses

Animals exposed to hepatotoxins, such as microcystins, will have elevated serum liver enzyme activities and bilirubin concentration.59,60,62,70,71 Hyperkalemia and hypoglycemia may also be observed.6 Although animals with cyanotoxicosis are often recumbent, blood calcium concentration may be within reference limits60 or decreased.59 Leukopenia has also been reported.72 Histologic findings typically include centrilobular hepatocellular degeneration and necrosis.58,62,64,68,71 Microcystin intoxication is associated with characteristic cytoplasmic vacuolation.74 Clinicopathologic and histologic abnormalities are generally not observed in animals exposed to neurotoxins.

Necropsy findings associated with cyanotoxicoses

Gross lesions may or may not be apparent during necropsy of animals with cyanotoxicosis depending on the type of inciting toxin. Lesions caused by hepatotoxins can generally be discerned, with their severity likely dose dependent. Liver abnormalities are frequently observed in animals exposed to cyanobacterial hepatotoxins by both natural and experimental routes.3,58,59,61,62,68,70,71 Hepatomegaly is common, with the liver tissue generally described as dark, hemorrhagic, and friable.3,58,59,61,62,68,70,71 However, in some affected animals, the liver is described as pale or yellow3,71 or, occasionally, having no gross lesions.64 Other lesions sometimes observed during necropsy include cholecystomegaly,70 hemorrhagic foci within the heart,58,61,72 edema or congestion of lung tissue,61,64,71 frank blood or dark-red contents within the intestines,59 excessive gas or watery liquid in the intestines,64 submandibular edema,70 icterus,71 straw-colored peritoneal or pleural fluid,72 and pale skeletal muscle.64 Necropsy findings are generally unremarkable in animals exposed to cyanobacterial neurotoxins.3,31

Diagnosis and reporting of animals with cyanotoxicosis

As with any clinical disease, diagnosis of cyanotoxicosis is dependent on a thorough history, consideration of clinical signs and differential diagnoses, and diagnostic test results. Important differential diagnoses for animals with clinical signs caused by cyanobacterial hepatotoxins include toxicoses caused by alfatoxins and poisonous plants (eg, cocklebur, pyrrolizidine alkaloids, and saponins).7578 Differential diagnoses for animals with clinical signs caused by cyanobacterial neurotoxins include toxicoses associated with organophosphate and carbamate exposure.79

Currently, diagnostic tests for cyanotoxins are not readily available in most clinical settings.80 The available tests are based on various biologic, biochemical, and chemical methods, such as bioassay, ELISA, and liquid chromatography–mass spectrometry.8183 Types of samples commonly used for detection of cyanotoxins include urine, gastrointestinal contents (eg, stomach or rumen contents, vomitus, and feces), and serum.8385 Cyanobacteria can be detected by direct microscopic examination or PCR assay. Water samples and samples obtained from animals with clinical signs of cyanotoxicosis can be tested for cyanotoxins and cyanobacteria. Currently, many laboratories are equipped to test for cyanotoxins or cyanobacteria in water samples; few laboratories are equipped to test for cyanotoxins or cyanobacteria in animal specimens. Detection of cyanotoxins or cyanobacteria in specimens obtained from animals with neurotoxicosis is particularly valuable because affected animals typically do not have any remarkable gross lesions. The US EPA maintains a list of laboratories that can analyze water samples for cyanobacteria and cyanotoxins.86 The list of laboratories accredited by the American Association of Veterinary Laboratory Diagnosticians87 provides information on laboratories that may be able to perform veterinary specimen testing for cyanobacteria and cyanotoxins, perform necropsies, or make further laboratory referrals.

In the United States, animal intoxication resulting from HABs, or cyanotoxicosis, is not a federally reportable disease. Animal diseases reportable at the state level are determined by the respective states, and although few states currently require veterinarians to report cyanotoxicosis in animals, several states are considering adding it to their list of reportable animal diseases. Since 2016, the CDC has maintained the OHHABS, a voluntary reporting system for events associated with HABs in water and disease in humans and animals.88 The OHHABS uses tiered case definitions for illnesses in humans and animals that rely only in part on confirmed detection of cyanotoxin and cyanobacteria.89 For animals, suspect, probable, and confirmed illnesses caused by HABs are defined by various combinations of available data, including exposure to a potential harmful agal bloom, development of clinical signs consistent with cyanotoxicosis following exposure to a potential harmful algal bloom, clinical assessment or diagnosis by a qualified public health or veterinary medical professional, ruling out of other similar illnesses, observational or environmental data from the water source with the suspected harmful algal bloom, laboratory confirmation of cyanotoxin or cyanobacteria in water samples, and laboratory confirmation of cyanotoxin or cyanobacteria in animal samples.

As of 2019, 18 states had reported events associated with HABs to the OHHABS.80 The easiest way for a veterinarian to report a harmful algal bloom event to the OHHABS is through their state health department.88

Treatment

Although there are no antitoxins or antidotes for specific cyanotoxins, animals with cyanotoxicosis can benefit from supportive treatment. Knowledge of whether the inciting toxin is a hepatotoxin or neurotoxin can help direct that treatment. Treatments mentioned in published case reports of animals with cyanotoxicosis include activated charcoal,17,20,38,5860,62 calcium,17,20,5860,62 IV fluids,59 glucose,20,59,60 cholestyramine,17,20 atropine (for guanitoxicosis),17,38,62 and artificial respiration.17 Results of both in vitro90 and in vivo91,92 laboratory studies suggest that silymarin, an extract of milk thistle, might be beneficial for the treatment of hepatotoxicosis. Many of the described treatments, including silymarin, have not been approved by the FDA for use in food animals. Therefore, veterinarians treating animals with suspected or confirmed cyanotoxicosis need to be cognizant of the rules governing extralabel drug administration, particularly if those animals are food-animal species, and ensure that the treatments are administered within the confines of a valid veterinarian-client-patient relationship.

Prevention and mitigation strategies for HABs in water sources

A number of best practices have been recommended to help prevent or limit HABs in farm water sources. The aim of those practices is to either decrease the nutrient load reaching the water or reduce that load by recycling or removing nutrients that do reach the water. Basic best practices for preventing HABs include not administering fertilizer within 3 m (10 feet) of a pond, maintaining a 6-m (20-foot) buffer zone around a pond where thick growth of native grasses and other vegetation is allowed, and maintaining grass-lined ditches between fields and water sources to redirect runoff.93,94 Further important preventive practices include barring livestock from congregating or loafing near stock ponds by use of limited access points and providing mineral supplements and shade and windbreaks away from ponds.95 An aerator can be placed in a pond to help reduce nitrogen in the water, and winter drawdown or drainage of pond water can allow for nutrient cycling as well as desiccation of cyanobacteria in sediment or on rocks.93,96 Another method for preventing HABs is the application of barley straw to the water surface because the release of unknown chemicals from the straw as it decomposes inhibits cyanobacterial growth.97101 Biologic methods for preventing and controlling cyanobacterial growth include the use of goldfish in stock tanks97 and grass carp in ponds.102,103

Producers with large operations, particularly those with tiled fields, drainage ditches, or substantial field runoff, could benefit from using a software applicationb recently developed by the USDA Agricultural Research Service.104 This application can help users design a system to reduce bioavailable phosphorus reaching surface water by intercepting water carrying dissolved phosphorus and filtering that water through reactive media before discharge to ponds or streams. Types of reactive media include calcium-based compounds or metal oxides such as aluminum oxide or iron oxide. The application uses site data input by the user, such as expected water-flow rates, annual water volume, and dissolved phosphorus concentration in the water as well as the desired phosphorus removal rate and anticipated lifetime performance of the system, to develop a customized design for each user. Producers can also work with their local USDA Natural Resources Conservation Service office in designing systems for removing phosphorus and other organic nutrients from runoff water and, in so doing, may be able to take advantage of various cost-share programs.105

Mitigation of existing HABs can be achieved by mechanical, chemical, or biologic methods.102,106108 It is important to note that any form of mitigation has the potential to expose operators to cyanotoxins through inhalation or dermal contact; therefore, the use of proper personal protective equipment is essential. Mechanical mitigation methods include physical removal of the algal mass by raking it from the water surface and the use of clay aggregates in fish hatcheries.106,107 The removed biomass can be composted at a distance > 15 m (50 feet) from the water.94 Although information regarding the fate of cyanotoxins after composting is limited, evidence suggests that 90% to 95% of microcystins are degraded after approximately 7 weeks of composting.109 Personnel responsible for managing the compost piles should wear personal protective equipment throughout the process. Chemical mitigation methods include algaecides such as copper sulfate.96,97 The application of algaecides to HABs causes lysis of cyanobacterial cells, which release intracellular toxins into the water; therefore, animals must be prevented from accessing the water for some time. It is recommended that animals be prevented from accessing water for a minimum of 1 week following application of copper sulfate to HABs.110 Biologic mitigation methods for existing HABs are the focus of ongoing research and include algaecidal viruses and bacteria.106 The method used to mitigate existing HABs is dependent on many factors including the type (eg, stock tank, dugout, or pond) of water source to be treated and various environmental and economic factors. For example, when chemical methods are used, it is critical that only private water sources are treated and that all state and federal regulations are followed. Another alternative for mitigating HABs is to provide livestock with clean water by digging a well or hauling water from a source free of HABs, although those options are generally expensive and logistically difficult.111 The Cooperative Extension Service can provide further details on prevention and mitigation methods for HABs. More in-depth discussions of both short- and long-term management strategies for preventing HABs in watersheds are also available.106,112 The EPA Hypoxia Task Force has helped states within the priority watersheds of the Mississippi River and Gulf of Mexico develop and implement nutrient-reduction strategies to protect those bodies of water from HABs.113 Research is ongoing to identify the most specific cyanocidal compounds with the fewest undesirable consequences.114

Further areas of research

Most published information about the effects of HABs on animal health is related to acute toxicoses, but the effect of chronic exposure to cyanotoxins in humans is an important topic of research. Microcystins have been classified as possible carcinogens by the International Agency for Research on Cancer,115 and genotoxicity and tumor promotion of various cyanotoxins continue to be investigated.33,116 Results of an experimental study117 involving mice suggest a relationship between chronic microcystin exposure and gut microbiome changes that may favor the development of hepatocellular carcinoma. In addition to toxins, cyanobacteria can produce other bioactive compounds with deleterious health effects, such as allergenicity118 and endocrine disruptions.119,120

Summary

Harmful algal blooms are anticipated to become more frequent and severe in the future owing to changing climatic and hydrologic factors that could favor the survival of cyanobacteria and other toxin-producing phytoplankton over nontoxic species, as well as increased toxin production by toxic species involved in HABs.1 Veterinarians are important one-health professionals whose role in HABs involving livestock goes beyond clinical diagnosis and potential treatment of affected animals. Veterinarians must also be ready to help producers affected by HABs connect with other resources, such as extension agents, agricultural engineers, and university researchers. Animal cyanotoxicoses can be sentinel events for human health,10,121 and veterinarians can play an important role in the collaborative and communicative aspect of one health by reporting suspected or confirmed cases of cyanotoxicosis in livestock species.

Abbreviations

EPA

Environmental Protection Agency

HABs

Harmful algal blooms

OATP

Organic anion transporting polypeptide

OHHABS

One Health Harmful Algal Bloom System

Footnotes

a.

CyAN app. Available at: github.com/USGS-R/CyAN. Accessed Apr 9, 2021.

b.

Penn C, Frankenberger J. P-TRAP phosphorus transport reduction app. Available at: data.nal.usda.gov/dataset/p-trap-phosphorus-transport-reduction-app. Accessed Apr 8, 2021.

References

  • 1.

    Wells ML, Karlson B, Wulff A, et al.. Future HAB science: directions and challenges in a changing climate. Harmful Algae 2020;91:101632.

  • 2.

    Zastepa A, Taranu ZE, Kimpe LE, et al.. Reconstructing a long-term record of microcystins from the analysis of lake sediments. Sci Total Environ 2017;579:893901.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Stewart I, Seawright AA, Shaw GR. Cyanobacterial poisoning in livestock, wild mammals and birds—an overview. Adv Exp Med Biol 2008;619:613637.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Carmichael W. Astatus report on planktonic cyanobacteria (blue-green algae) and their toxins. Available at: cfpub.epa.gov/si/si_public_record_Report.cfm?Lab=ORD&dirEntryID=37448. Accessed May 11, 2021.

    • Search Google Scholar
    • Export Citation
  • 5.

    Codd GA, Azevedo SMFO, Bagchi SN, et al.. CYANONET: a global network for cyanobacterial bloom and toxin risk management. Paris: International Hydrological Programme, 2005.

    • Search Google Scholar
    • Export Citation
  • 6.

    Roegner AF, Brena B, González-Sapienza G, et al.. Microcystins in potable surface waters: toxic effects and removal strategies. J Appl Toxicol 2014;34:441457.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Schwimmer M, Schwimmer D. Medical aspects of phycology. In: Jackson DF, ed. Algae, man, and the environment. Syracuse, NY: Syracuse University Press, 1968;368412.

    • Search Google Scholar
    • Export Citation
  • 8.

    Wood R. Acute animal and human poisonings from cyanotoxin exposure—a review of the literature. Environ Int 2016;91:276282.

  • 9.

    Metcalf JS, Codd GA. Co-occurrence of cyanobacteria and cyanotoxins with other environmental health hazards: impacts and implications. Toxins (Basel) 2020;12:629.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Hilborn ED, Beasley VR. One health and cyanobacteria in freshwater systems: animal illnesses and deaths are sentinel events for human health risks. Toxins (Basel) 2015;7:13741395.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Carmichael WW, Boyer GL. Health impacts from cyanobacteria harmful algae blooms: implications for the North American Great Lakes. Harmful Algae 2016;54:194212.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Spoof L, Catherine A. Appendix 3: tables of microcystins and nodularins. In: Handbook of cyanobacterial monitoring and cyanotoxin analysis. Chichester, England: John Wiley & Sons Ltd, 2017;526537.

    • Search Google Scholar
    • Export Citation
  • 13.

    Bláha L, Babica P, Maršálek B. Toxins produced in cyanobacterial water blooms - toxicity and risks. Interdiscip Toxicol 2009;2:3641.

  • 14.

    Wacklin P, Hoffmann L, Komárek J. Nomenclatural validation of the genetically revised cyanobacterial genus Dolichospermum (RALFS ex BORNET et FLAHAULT) comb. nova. Fottea (Praha) 2009;9:5964.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Li X, Dreher TW, Li R. An overview of diversity, occurrence, genetics and toxin production of bloom-forming Dolichospermum (Anabaena) species. Harmful Algae 2016;54:5468.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    McGregor GB, Sendall BC. Phylogeny and toxicology of Lyngbya wollei (Cyanobacteria, Oscillatoriales) from north-eastern Australia, with a description of Microseira gen. nov. J Phycol 2015;51:109119.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Beasley VR, Dahlem AM, Cook WO, et al.. Diagnostic and clinically important aspects of cyanobacterial (blue-green algae) toxicoses. J Vet Diagn Invest 1989;1:359365.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Greer B, Meneely JP, Elliott CT. Uptake and accumulation of microcystin-LR based on exposure through drinking water: an animal model assessing the human health risk. Sci Rep 2018;8:4913.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    McLellan NL, Manderville RA. Toxic mechanisms of microcystins in mammals. Toxicol Res (Camb) 2017;6:391405.

  • 20.

    Beasley VR, Cook WO, Dahlem AM, et al.. Algae intoxication in livestock and waterfowl. Vet Clin North Am Food Anim Pract 1989;5:345361.

  • 21.

    Cao L, Massey IY, Feng H, et al.. A review of cardiovascular toxicity of microcystins. Toxins (Basel) 2019;11:507.

  • 22.

    Pearson L, Mihali T, Moffitt M, et al.. On the chemistry, toxicology and genetics of the cyanobacterial toxins, microcystin, nodularin, saxitoxin and cylindrospermopsin. Mar Drugs 2010;8:16501680.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Kleppe R, Herfindal L, Doskeland SO. Cell death inducing microbial protein phosphatase inhibitors—mechanisms of action. Mar Drugs 2015;13:65056520.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24.

    Bouaïcha N, Miles CO, Beach DG, et al.. Structural diversity, characterization and toxicology of microcystins. Toxins (Basel) 2019;11:714.

  • 25.

    Butler N, Carlisle J, Linville R. Toxocological summary and suggested action levels to reduce potential adverse health effects of six cyanotoxins. Sacramento, Calif: California Environmental Protection Agency, 2012.

    • Search Google Scholar
    • Export Citation
  • 26.

    World Health Organization. Cyanobacterial toxins: microcystins. background document for development of WHO guidelines for drinking-water quality and guidelines for safe recreational water environments. Geneva: World Health Organization, 2020.

    • Search Google Scholar
    • Export Citation
  • 27.

    CDC. Immediately dangerous to life or health (IDLH) values. Available at: www.cdc.gov/niosh/idlh/intridl4.html. Accessed Feb 18, 2021.

  • 28.

    Chernoff N, Hill D, Lang J, et al.. The comparative toxicity of 10 microcystin congeners administered orally to mice: clinical effects and organ toxicity. Toxins (Basel) 2020;12:403.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29.

    Carmichael W. Blue-green algae: an overlooked health threat. Available at: www.researchgate.net/publication/303155255. Accessed Feb 17, 2021.

    • Search Google Scholar
    • Export Citation
  • 30.

    Devlin JP, Edwards OE, Gorham PR, et al.. Anatoxin-a, a toxic alkaloid from Anabaena flos-aquae NRC-44h. Can J Chem 1977;55:13671371.

  • 31.

    Carmichael WW, Gorham PR, Biggs DF. Two laboratory case studies on the oral toxicity to calves of the freshwater cyanophite (blue-green alga) Anabaena flos-aquae NRC-44–1. Can Vet J 1977;18:7175.

    • Search Google Scholar
    • Export Citation
  • 32.

    Carmichael WW, Biggs DF, Gorham PR. Toxicology and pharmacological action of Anabaena flos-aquae toxin. Science 1975;187:542544.

  • 33.

    Falconer IR, Humpage AR. Health risk assessment of cyanobacterial (blue-green algal) toxins in drinking water. Int J Environ Res Public Heal 2005;2:4350.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34.

    World Health Organization. Cyanobacterial toxins: anatoxin-a and analogues. Background document for development of WHO guidelines for drinking-water quality and guidelines for safe recreational water environments. Geneva: World Health Organization, 2020.

    • Search Google Scholar
    • Export Citation
  • 35.

    Svirčev Z, Lalić D, Bojadžija Savić G, et al.. Global geographical and historical overview of cyanotoxin distribution and cyanobacterial poisonings. Arch Toxicol 2019;93:24292481.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36.

    Carmichael WW. Cyanobacteria secondary metabolites—the cyanotoxins. J Appl Bacteriol 1992;72:445459.

  • 37.

    Fiore MF, de Lima ST, Carmichael WW, et al.. Guanitoxin, re-naming a cyanobacterial organophosphate toxin. Harmful Algae 2020;92:101737.

  • 38.

    Cook WO, Beasley VR, Lovell RA, et al.. Consistent inhibition of peripheral cholinesterases by neurotoxins from the freshwater cyanobacterium Anabaena flos‐aquae: studies of ducks, swine, mice and a steer. Environ Toxicol Chem 1989;8:915922.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 39.

    Cook WO, Dellinger JA, Singh SS, et al.. Regional brain cholinesterase activity in rats injected intraperitoneally with anatoxin-a(s) or paraoxon. Toxicol Lett 1989;49:2934.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 40.

    Fernandes KA, Pinto E, Ferraz HG, et al.. Availability of guanitoxin in water samples containing Sphaerospermopsis torques-reginae cells submitted to dissolution tests. Pharmaceuticals (Basel) 2020;13:402.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41.

    Mahmood NA, Carmichael WW, Pfahler D. Anticholesterase poisonings in dogs from a cyanobacterial (blue-green algae) bloom dominated by Anabaena flos-aquae. Am J Vet Res 1988;49:500503.

    • Search Google Scholar
    • Export Citation
  • 42.

    Miller TR, Beversdorf LJ, Weirich CA, et al.. Cyanobacterial toxins of the Laurentian great lakes, their toxicological effects, and numerical limits in drinking water. Mar Drugs 2017;15:151.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 43.

    World Health Organization. Cyanobacterial toxins: saxitoxins. Background document for development of WHO guidelines for drinking-water quality and guidelines for safe recreational water environments. Geneva: World Health Organization, 2020.

    • Search Google Scholar
    • Export Citation
  • 44.

    Nagai H, Sato S, Iida K, et al.. Oscillatoxin i: a new aplysiatoxin derivative, from a marine cyanobacterium. Toxins (Basel) 2019;11:1521.

  • 45.

    Zhang H-H, Zhang X-K, Si R-R, et al. Chemical and biological study of novel aplysiatoxin derivatives from the marine cyanobacterium Lyngbya sp. Toxins (Basel) 2020;12:112.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 46.

    World Health Organization. Guidelines for safe recreational water environments: coastal and fresh waters. Available at: www.who.int/water_sanitation_health/publications/srwe1/en/. Accessed May 11, 2021.

    • Search Google Scholar
    • Export Citation
  • 47.

    World Health Organization. Cyanobacterial toxins: cylindrospermopsin. Background document for development of WHO guidelines for drinking-water quality and guidelines for safe recreational water environments. Geneva: World Health Organization, 2020.

    • Search Google Scholar
    • Export Citation
  • 48.

    Pichardo S, Cameán AM, Jos A. In vitro toxicological assessment of cylindrospermopsin: a review. Toxins (Basel) 2017;9:402.

  • 49.

    Hinojosa MG, Gutiérrez-Praena D, Prieto AI, et al.. Neurotoxicity induced by microcystins and cylindrospermopsin: a review. Sci Total Environ 2019;668:547565.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 50.

    Mez K, Beattie K, Codd G, et al.. Identification of a microcystin in benthic cyanobacteria linked to cattle deaths on alpine pastures in Switzerland. Eur J Phycol 1997;32:111117.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 51.

    Roy-Lachapelle A, Solliec M, Bouchard MF, et al.. Detection of cyanotoxins in algae dietary supplements. Toxins (Basel) 2017;9:117.

  • 52.

    Mittelman NS, Engiles JB, Murphy L, et al.. Presumptive iatrogenic microcystin-associated liver failure and encephalopathy in a Holsteiner gelding. J Vet Intern Med 2016;30:17471751.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 53.

    McGorum BC, Pirie RS, Glendinning L, et al.. Grazing livestock are exposed to terrestrial cyanobacteria. Vet Res 2015;46:16.

  • 54.

    Chiswell RK, Shaw GR, Eaglesham G, et al.. Stability of cylindrospermopsin, the toxin from the cyanobacterium, Cylindrospermopsis raciborskii: effect of pH, temperature, and sunlight on decomposition. Environ Toxicol 1999;14:155161.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 55.

    Kitchens CM, Johengen TH, Davis TW. Establishing spatial and temporal patterns in Microcystis sediment seed stock viability and their relationship to subsequent bloom development in Western Lake Erie. PLoS One 2018;13:e0206821.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 56.

    US EPA. Cyanobacteria Assessment Network mobile application (CyAN app). Available at: www.epa.gov/water-research/cyanobacteria-assessment-network-mobile-application-cyan-app. Accessed Feb 22, 2021.

    • Search Google Scholar
    • Export Citation
  • 57.

    Francis G. Poisonous Australian lake. Nature 1878;18:1112.

  • 58.

    Fitzgerald SD, Poppenga RH. Toxicosis due to microcystin hepatotoxins in three Holstein heifers. J Vet Diagn Invest 1993;5:651653.

  • 59.

    Galey FD, Beasley VR, Carmichael WW, et al.. Blue-green algae (Microcystis aeruginosa) hepatotoxicosis in dairy cows. Am J Vet Res 1987;48:14151420.

    • Search Google Scholar
    • Export Citation
  • 60.

    Kerr LA, McCoy CP, Eaves D. Blue-green algae toxicosis in five dairy cows. J Am Vet Med Assoc 1987;191:829830.

  • 61.

    Puschner B, Galey FD, Johnson B, et al.. Blue-green algae toxicosis in cattle. J Am Vet Med Assoc 1998;213:16051607.

  • 62.

    Steffen D. Cyanobacterial toxicoses. Newsletter of the American Association of the Bovine Practitioner, 1992.

  • 63.

    Zin LL, Edwards WC. Toxicity of blue-green algae in livestock. Bov Pract 1979;14:151153.

  • 64.

    Chengappa MM, Pace LW, McLaughlin BG. Blue-green algae (Anabaena spiroides) toxicosis in pigs. J Am Vet Med Assoc 1989;194:17241725.

  • 65.

    Cook WO, Beasley VR, Lovell RA. Blue-green algae toxicosis. Newsletter of the American Association of the Bovine Practitioner, 1987.

  • 66.

    Smith ZJ, Conroe DE, Schulz KL, et al.. Limnological differences in a two-basin lake help explain the occurrence of anatoxin-a, paralytic shellfish poisoning toxins, and microcystins. Toxins (Basel) 2020;12:559 10.3390/toxins12090559.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 67.

    US EPA. Cyanobacteria and cyanotoxins: information for drinking water systems. Available at: www.epa.gov/sites/production/files/2014–08/documents/cyanobacteria_factsheet.pdf. Accessed Feb 24, 2021.

    • Search Google Scholar
    • Export Citation
  • 68.

    Van Halderen A, Harding WR, Wessels JC, et al.. Cyanobacterial (blue-green algae) poisoning of livestock in the western Cape Province of South Africa. J S Afr Vet Assoc 1995;66:260264.

    • Search Google Scholar
    • Export Citation
  • 69.

    Short SB, Edwards WC. Blue-green algae toxicoses in Oklahoma. Vet Hum Toxicol 1990;32:558560.

  • 70.

    Carbis CR, Waldron DL, Mitchell GF, et al.. Recovery of hepatic function and latent mortalities in sheep exposed to the blue-green alga Microcystis aeruginosa. Vet Rec 1995;137:1215.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 71.

    Jackson AR, McInnes A, Falconer IR, et al.. Clinical and pathological changes in sheep experimentally poisoned by the blue-green alga Microcystis aeruginosa. Vet Pathol 1984;21:102113.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 72.

    Main DC, Berry PH, Peet RL, et al.. Sheep mortalities associated with the blue green alga Nodularia spumigena. Aust Vet J 1977;53:578581.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 73.

    Beasley VR, Coppock RW, Simon J, et al.. Apparent blue-green algae poisoning in swine subsequent to ingestion of a bloom dominated by Anabaena spiroides. J Am Vet Med Assoc 1983;182:413414.

    • Search Google Scholar
    • Export Citation
  • 74.

    Andrinolo D, Sedan D, Telese L, et al.. Hepatic recovery after damage produced by sub-chronic intoxication with the cyanotoxin microcystin LR. Toxicon 2008;51:457467.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 75.

    Blough E. Cocklebur toxicosis. Available at: www.addl.purdue.edu/newsletters/2007/Summer/CT.html. Accessed Feb 23, 2021.

  • 76.

    Bildfell R. Overview of pyrrolizidine alkaloidosis. Merck Veterinary Manual. Available at: www.merckvetmanual.com/toxicology/pyrrolizidine-alkaloidosis/overview-of-pyrrolizidine-alkaloidosis. Accessed Feb 23, 2021.

    • Search Google Scholar
    • Export Citation
  • 77.

    Cornell University. Plants poisonous to livestock: saponins. Available at: poisonousplants.ansci.cornell.edu/toxicagents/saponin.html. Accessed Feb 23, 2021.

    • Search Google Scholar
    • Export Citation
  • 78.

    Clayton MJ, Davis TZ, Knoppel EL, et al.. Hepatotoxic plants that poison livestock. Vet Clin North Am Food Anim Pract 2020;36:715723.

  • 79.

    Stich RW. Ectoparasiticides used in large animals. Merck Veterinary Manual. Available at: www.merckvetmanual.com/pharmacology/ectoparasiticides/ectoparasiticides-used-in-large-animals?query=carbamate toxicity. Accessed Feb 23, 2021.

    • Search Google Scholar
    • Export Citation
  • 80.

    Roberts VA, Vigar M, Backer L, et al.. Surveillance for harmful algal bloom events and associated human and animal illnesses - One Health Harmful Algal Bloom System, United States, 2006–2018. MMWR Morb Mortal Wkly Rep 2020;69:18891894.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 81.

    Massey IY, Wu P, Wei J, et al.. A mini-review on detection methods of microcystins. Toxins (Basel) 2020;12:132.

  • 82.

    Wharton RE, Cunningham BR, Schaefer AM, et al.. Measurement of microcystin and nodularin activity in human urine by immunocapture-protein phosphatase 2a assay. Toxins (Basel) 2019;11:729.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 83.

    Moore CE, Juan J, Lin Y, et al.. Comparison of protein phosphatase inhibition assay with LC-MS/MS for diagnosis of microcystin toxicosis in veterinary cases. Mar Drugs 2016;14:54.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 84.

    Puschner B, Hoff B, Tor ER. Diagnosis of anatoxin—a poisoning in dogs from North America. J Vet Diagn Invest 2008;20:8992.

  • 85.

    Rankin KA, Alroy KA, Kudela RM, et al.. Treatment of cyanobacterial (microcystin) toxicosis using oral cholestyramine: case report of a dog from Montana. Toxins (Basel) 2013;5:10511063.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 86.

    US EPA. Laboratories that analyze for cyanobacteria and cyanotoxins. Available at: www.epa.gov/cyanohabs/laboratories-analyze-cyanobacteria-and-cyanotoxins. Accessed Jan 26, 2020.

    • Search Google Scholar
    • Export Citation
  • 87.

    American Association of Laboratory Diagnosticians. Accreditation laboratories. Available at: www.aavld.org/accredited-labs. Accessed Jan 26, 2020.

    • Search Google Scholar
    • Export Citation
  • 88.

    CDC. One Health Harmful Algal Bloom System (OHHABS). Available at: www.cdc.gov/habs/ohhabs.html. Accessed May 11, 2021.

  • 89.

    CDC. One Health Harmful Algal Bloom System (OHHABS)—harmful algal bloom (HAB) event and case definitions. Available at: www.cdc.gov/habs/pdf/ohhabs-case-and-event-definitions-table-508.pdf. Accessed Jan 25, 2020.

    • Search Google Scholar
    • Export Citation
  • 90.

    Mereish KA, Solow R. Effect of antihepatotoxic agents against microcystin-LR toxicity in cultured rat hepatocytes. Pharm Res 1990;7:256259.

  • 91.

    Mereish KA, Bunner DL, Ragland DR, et al.. Protection against microcystin-LR-induced hepatotoxicity by silymarin: biochemistry, histopathology, and lethality. Pharm Res 1991;8:273277.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 92.

    Rao PVL, Jayaraj R, Bhaskar ASB. Protective efficacy and the recovery profile of certain chemoprotectants against lethal poisoning by microcystin-LR in mice. Toxicon 2004;44:723730.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 93.

    Debruyn JM, Wilhelm SW, Ludwig A, et al.. Cyanobacteria (glue-green algae) harmful algal blooms. University of Tennessee Extension Document No. W 340. Available at: extension.tennessee.edu/publications/Documents/W340.pdf. Accessed Jan 24, 2020.

    • Search Google Scholar
    • Export Citation
  • 94.

    Clawson B. Preserve your natural backyard pond. Michigan State University Extension. Available at: www.canr.msu.edu/news/preserve_your_natural_backyard_pond. Accessed Jan 25, 2020.

    • Search Google Scholar
    • Export Citation
  • 95.

    Bass T. Avoiding algae issues in stock ponds. Montana State University Extension. Available at: apps.msuextension.org/magazine/articles/5460. Accessed Feb 25, 2021.

    • Search Google Scholar
    • Export Citation
  • 96.

    US EPA. Control Measures for cyanobacterial HABs in surface water. Available at: www.epa.gov/cyanohabs/control-measures-cyanobacterial-habs-surface-water. Accessed Feb 23, 2021.

    • Search Google Scholar
    • Export Citation
  • 97.

    Schultheis RA. Algae control in stock tanks, ponds and lakes. University of Missouri Extension. Available at: extension.missouri.edu/media/wysiwyg/Extensiondata/CountyPages/Webster/Docs/Algae_Control_in_Tanks_and_Ponds.pdf. Accessed May 11, 2021.

    • Search Google Scholar
    • Export Citation
  • 98.

    Lembi C. Barley straw for algae control. Purdue University Extension Report No. APM-1-W. 2002. Available at: mdc.itap.purdue.edu/item.asp?Item_Number=APM-1-Accessed W. May 11, 2021.

    • Search Google Scholar
    • Export Citation
  • 99.

    Delaware Division of Fish & Wildlife. Barley straw for algae control. Delaware Department of Natural Resources and Environment Control Document No. 40–05–02–02/07/012001. Available at: www.dnrec.delaware.gov/fw/Fisheries/Documents/barleystraw.pdf. Accessed Jan 23, 2020.

    • Search Google Scholar
    • Export Citation
  • 100.

    Haberland M. Pond and lake management part VI: using barley straw to control algae. Rutgers University Extension Document No. FS11712011. Available at: njaes.rutgers.edu/fs1171/. Accessed Jan 23, 2020.

    • Search Google Scholar
    • Export Citation
  • 101.

    Swistock B. Barley straw for algae control. PennState Extension. Available at: extension.psu.edu/barley-straw-for-algae-control. Accessed Jan 24, 2020.

    • Search Google Scholar
    • Export Citation
  • 102.

    Sink T, Gwinn J, Gerke H, et al.. Managing and controlling algae in ponds. Texas A&M University Extension Publication No. EWF-015. Available at: cdn-ext.agnet.tamu.edu/wp-content/uploads/2019/03/EWF-015-managing-and-controlling-algae-in-ponds.pdf. Accessed Jan 24, 2020.

    • Search Google Scholar
    • Export Citation
  • 103.

    Helfrich LA, Neves RJ, Libey G, et al.. Control methods for aquatic plants in ponds and lakes. Virginia Cooperative Extension Document No. 420–2512009. Available at: www.pubs.ext.vt.edu/420/420–251/420–251.html. Accessed Jan 24, 2020.

    • Search Google Scholar
    • Export Citation
  • 104.

    USDA Agricultural Research Service. Phosphorus removal structures. Available at: www.ars.usda.gov/midwest-area/west-lafayette-in/national-soil-erosion-research/docs/phosphorus-removal-structures/. Accessed Mar 22, 2021.

    • Search Google Scholar
    • Export Citation
  • 105.

    Toste A. Combating the “phosphorus paradox.” Available at: www.progressivedairy.com/topics/manure/combating-the-phosphorus-paradox. Accessed Mar 22, 2021.

    • Search Google Scholar
    • Export Citation
  • 106.

    Anderson DM. Approaches to monitoring, control and management of harmful algal blooms (HABs). Ocean Coast Manag 2009;52:342347.

  • 107.

    Anderson DM, Boyer GL, Cammen LM, et al.. Prevention, control and mitigation of harmful algal blooms: a research plan. Available at: www.whoi.edu/cms/files/PCM_HAB_Research_Plan%282%29_18563_23051.pdf. Accessed May 11, 2021.

    • Search Google Scholar
    • Export Citation
  • 108.

    Camberato DM, Lopez RG. Controlling algae in irrigation ponds. Purdue Extension Publication No. HO-247-W. Available at: mdc.itap.purdue.edu/. Accessed Jan 24, 2020.

    • Search Google Scholar
    • Export Citation
  • 109.

    Han W, Clarke W, Pratt S. Composting of waste algae: a review. Waste Manag 2014;34:11481155.

  • 110.

    Arnold M. Frequently asked questions about harmful algal blooms (HABs) in farm ponds used to water livestock. Available at: u.osu.edu/beef/2019/08/28/frequently-asked-questions-about-harmful-algal-blooms-habs-in-farm-ponds-used-to-water-livestock/. Accessed Feb 23, 2021.

    • Search Google Scholar
    • Export Citation
  • 111.

    van der Merwe D, Blocksome C, Hollis L. Identification and management of blue-green algae in farm ponds. K-State Research and Extension Document No. MF-3065. Available at: bookstore.ksre.ksu.edu/pubs/MF3065.pdf. Accessed Feb 24, 2021.

    • Search Google Scholar
    • Export Citation
  • 112.

    Paerl HW, Otten TG, Kudela R. Mitigating the expansion of harmful algal blooms across the freshwater-to-marine continuum. Environ Sci Technol 2018;52:55195529.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 113.

    US EPA. Hypoxia Task Force nutrient reduction strategies. Available at: www.epa.gov/ms-htf/hypoxia-task-force-nutrient-reduction-strategies. Accessed Apr 8, 2021.

    • Search Google Scholar
    • Export Citation
  • 114.

    Matthijs HCP, Jančula D, Visser PM, et al.. Existing and emerging cyanocidal compounds: new perspectives for cyanobacterial bloom mitigation. Aquat Ecol 2016;50:443460.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 115.

    IARC. Ingested nitrate and nitrite, and cyanobacterial peptide toxins. Available at: publications.iarc.fr/112. Accessed Feb 17, 2021.

  • 116.

    Žegura B, Štraser A, Filipič M. Genotoxicity and potential carcinogenicity of cyanobacterial toxins - a review. Mutat Res 2011;727:1641.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 117.

    Lee J, Lee S, Mayta A, et al.. Microcystis toxin–mediated tumor promotion and toxicity lead to shifts in mouse gut microbiome. Ecotoxicol Environ Saf 2020;206:111204.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 118.

    Bernstein JA, Ghosh D, Levin LS, et al.. Cyanobacteria: an unrecognized ubiquitous sensitizing allergen? Allergy Asthma Proc 2011;32:106110.

  • 119.

    Rogers ED, Henry TB, Twiner MJ, et al.. Global gene expression profiling in larval zebrafish exposed to microcystin-LR and microcystis reveals endocrine disrupting effects of cyanobacteria. Environ Sci Technol 2011;45:19621969.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 120.

    Mallia V, Ivanova L, Eriksen GS, et al.. Investigation of in vitro endocrine activities of Microcystis and Planktothrix cyanobacterial strains. Toxins (Basel) 2020;12:228.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 121.

    Backer LC, Miller M. Sentinel animals in a one health approach to harmful cyanobacterial and algal blooms. Vet Sci 2016;3:8.

Contributor Notes

Address correspondence to Dr. Wolfe (emw75@post.harvard.edu).