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.3–8
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.
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,58–63 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.
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 |
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 |
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).75–78 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.81–83 Types of samples commonly used for detection of cyanotoxins include urine, gastrointestinal contents (eg, stomach or rumen contents, vomitus, and feces), and serum.83–85 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,17,20,38,58–60,62 calcium,17,20,58–60,62 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.97–101 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.102,106–108 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
CyAN app. Available at: github.com/USGS-R/CyAN. Accessed Apr 9, 2021.
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.
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