Toxicology: Poisonous Plants & Toxins

Module 1: Toxicology and Contaminants

• The module aims to provide info on identification of poisonous plants and their toxic agents that commonly cause poisoning or have adverse effects on farmed and companion animals. Additionally it aims to provide information on the mode of action of plant toxins and give direct and indirect effects on animals, and also list potential feed contaminants, and describe their mode(s) of action relating to animal ingestion.

Poisonous Plants and Their Associated Toxins

• Plant poisoning costs the grazing livestock industry over $200 million USD annually in the USA.
• Fluoroacetate toxicity alone costs the Australian livestock industry around AUD $45 million annually (increased death rates and productivity impacts).
• Pimelea poisoning costs the Australian livestock industry around AUD $50 million annually.
• Direct losses include deaths, weight loss, abortions, lengthened calving/lambing intervals, decreased efficiency and other effects on the animals.
• Indirect losses include fencing, supplemental feeding and management alterations to prevent or minimise poisoning.
• Many animal (and human) poisonings occur when plant toxins contaminate prepared feeds.
• Livestock poisoning by plants can usually be traced to problems of management, overall pasture/range conditions, or both, rather than the mere presence of poisonous plants.
• Many pastures grazed by cattle, sheep, goats, deer, camelids and horses contain potentially toxic plants, in small amounts these plants are tolerated well. However if grazed to excess or under certain conditions, poisonings can occur.
• Some plants are toxic even when consumed in small amounts.
• Other plant toxins can be cumulative (e.g., pyrrolizidine alkaloids), with damage to internal organs (especially the liver).
• The relative toxicity of plants may vary according to the time of year and the stage of plant growth.
• Stock will often ignore toxic plants until feed becomes scarce or when moved into a new paddock.
• Placing animals into weed-infested stockyards following transport is another common scenario for plant poisonings to occur.
• Newly introduced animals may be naïve to suspect plants and become poisoned while the resident herd or flock have learnt to avoid them.
• There are no common distinguishing characteristics (form, colouring, odour or taste) to identify a poisonous plant.
• Chemical, physical, biological, and environmental elements all play a role in determining whether or not a given plant species is poisonous.
• Whether or not consumption of any particular plant causes poisoning depends on the amount and type of toxin(s) they contain, the animal eating it, the amount eaten in relation to the animal's body weight (BW), the time taken to eat that amount, and the health and physiological status of the animal.
• There are multiple causes of death in livestock and often multiple factors are involved, and thus it can be difficult to determine/diagnose plant poisoning as the cause.

Factors Contributing to the Poisoning of Livestock and Pets

• Palatability varies significantly among known poisonous plants. Many fluoroacetate-containing plants, especially Gastrolobium spp. are highly palatable, making them particularly dangerous to browsing animals.
• Applying herbicides may temporarily increase the palatability of some poisonous plants, including variegated thistle (Silybum marianum) in the release of sugars in the plants.
• Plants containing alkaloids (e.g., Heliotrope spp.) are generally bitter and non-palatable.
• Cardiac glycoside-containing plants (e.g., oleander, Nerium oleander) are usually unpalatable.
• Plants with low palatability are likely to be eaten when other feed is scarce or when they are mixed with more palatable feed, including contamination of hay.
• The stage of plant growth can affect the concentration and distribution of toxins in plants.
• Toxin concentrations may vary in different parts of the plant or at different stages of plant maturity.
• Nitrate concentrates in the stem.
• Cyanogenic glycosides and soluble oxalates concentrate in young leaves.
• Only the seeds and first seedling leaves (cotyledons) of Bathurst burr (Xanthium spinosum) are.
• Seed equivalent to 0.3% BW or ingestion of cotyledons at 0.75-1.5% BW is toxic.
• The seeds of Leiocarpa brevicompta (flat billy buttons) are poisonous.
• In several Sorghum species, only the young leaves are poisonous.

Animal factors

• Differences exist between animal species in their susceptibility to plant poisoning.
• Metabolism differs between ruminants, monogastric mammals and birds which can cause differences in susceptibility to toxins.
• Rumen microbes may detoxify toxins or potentiate them, for example, soluble oxalates are largely destroyed in rumen; however, the relatively harmless nitrate is converted by rumen microbes into the potentially deadly nitrite.
• Poisoning in pet animals is mainly due to accidental exposure.
• The nature, susceptibility and extent of toxicity to different toxins vary between dogs and cats.
• Several factors (age, breed, pregnancy, lactation, disease status, physicochemical properties of the toxicant, environmental factors, etc.) can influence the toxicity of a specific compound. Acute poisoning is more common than chronic poisoning.
• Susceptibility to plant poisoning may vary between native and introduced animal species.
• Kangaroos are susceptible to poisoning by several introduced species including pasture plants, garden plants and weeds.
• Susceptibility of native animals to plant poisoning may also vary between regions.
• Brush-tail possums, bush rats and western grey kangaroos have evolved an efficient fluoroacetate detoxification process in their livers making them resistant to Gastrolobium poisoning but these plants are rapidly fatal if Australian native animals from the eastern States consume them.
• The age of the animal impacts susceptibility to plant poisoning.
• Young animals are generally more susceptible than adults because they have less effective detoxification mechanisms.
• Young animals may be more curious and more likely to eat unfamiliar plants ( particularly young puppies)
• Many young animals are guided by their dams as to which plants are 'safe' to eat; young animals denied these experiences are likely to eat potentially toxic plants.
• Some plant toxins can efficiently cross the placenta and induce congenital malformations (teratogenic effects.
• Some of the most common teratogenic toxic plants include Veratrum spp., Lupinus spp. and Conium maculatum (hemlock)

Environmental factors

• Hungry animals are more likely to consume poisonous plants and consequently poisoning is more common during periods of feed deficit (drought and after floods and fire) and after transport or yarding.
• Stock yards are very common locations for plant poisonings to occur.
• Healthy animals are better able to cope with the effects of poisonous plants.
• Chronic toxicities take time to emerge.
• Pyrrolizidine alkaloids (contained in Paterson's curse, Echium plantagineum) accumulate in the liver over time and poisoned animals exhibit no clinical signs of poisoning until damage exceeds a certain threshold, which can be months to years.
• Tolerance may develop if the animal is exposed to lesser doses of the toxin over a period of time and detoxification processes (rumen microflora or of the liver) have time to develop.
• Ruminants exposed to small, non-toxic amounts of soluble oxalates over a period of time are often able to withstand larger dose that would kill non-exposed animals.
• Access to water may also be implicated in some plant poisonings.
• The toxins (steroidal glycoalkaloids) in Solanum sturtianum (Thargomindah nightshade) that cause poisoning of ruminants are not released from the eaten plants and absorbed from the digestive tract until the animal has drunk water.
• Exposure to poisonous plants also impacts on the likelihood of plant poisoning occurring.
• Most pastures contain some level of potentially poisonous plants and a few scattered plants in healthy pasture are not generally a risk.
• Some plants are toxic if only small amounts are consumed, and some others are preferentially grazed (e.g., Gastrolobium spp.).
• The season of the year dictates the presence or absence of certain annual plants as well as the stage of growth and the physiological status of plants, and consequently the presence or absence of flowers, fruit, seeds or young leaves, some of which may be poisonous.
• Rainfall influences the likelihood of plant poisonings occurring.
• Drought, flooding and fire can influence plant growth as well as the amount of toxins that plants may contain.
• Dry conditions produce wilting, which may increase the concentrations of some toxins.
• Wilted or dried poisonous plants are often just as toxic as the fresh plants.
• Soil type may also play a role in plant poisoning.
• Selenium-accumulating plants are most toxic when growing on Se-rich soils.
• Soils high in N predispose plants to develop high concentrations of both nitrates and soluble oxalates.
• Stockyard soils heavily fertilised by manure and urine provide large amounts of N producing dangerous concentrations of both nitrate and/or soluble oxalates.
• Fertilisers can cause a flush in the growth of potentially poisonous plants and can even increase the concentration of toxin(s) in some plants.

Diagnosis

• Diagnosing field cases of plant poisoning of animals can be challenging, especially where the animal may have had access to several potentially toxic plants.
• There are five main factors to consider when investigating deaths that are suspected to be due to poisonous plants.
  • The poisonous plant must be present in the environment, the animal must have access to it, and evidence must be provided to show that the poisonous plant has been consumed.
  • The toxin must be present in the plant material.
  • Plant material, toxins or toxin metabolites should be present in the ingesta and in biological samples from the intoxicated animal.
  • The clinical signs of the poisoning observed in the poisoned animal are known to be associated with that plant.
  • Other less specific biomarker(s) of poisoning such as haematology, serum biochemistry, or tissue lesions are consistent with the suspected poisonous plant.
• Even if the five factors of plant poisonings have been satisfied, a dead animal is often found in a decomposed state precluding obtaining supporting clinical or post-mortem data.
• If the animal is found alive, non-specific clinical signs (e.g., diarrhoea or weakness) often confound the diagnosis.
• The presence of a sub-clinical concentration of one or more plant toxins does not indicate toxicity.
• Accurate and rapid diagnosis of intoxication is challenging, as no single test detects all possible toxicants,.
• Along with history, more information on age, sex, reproductive status, morbidity and mortality, and progression of clinical signs. Additional questions must be asked to acquire information like recent changes in feed or water, movements of animals, administration of medications or supplements and changes in weather conditions.
• Appropriate samples for toxicology testing from affected live animals include gastrointestinal contents, urine, whole blood, serum and milk.

Cardiac Glycosides

• The two major groups of cardiac glycosides, the cardenolides and bufadienolides, differ mainly on the basis of the size of the unsaturated lactone ring attached.
  • Cardenolides consist of a butyrolactone ring with five carbons.
  • Bufadienolides have a pyrone ring with six carbons.
• Cardiac glycosides occur in plants predominantly as cardenolides.
• Bufadienolides is obtained from animal sources including Buffo (toads), Photinus (fireflies) and Rhabdophis (snakes).
• Historically, cardiac-glycosides were used as arrow poisons by Indigenous peoples of Africa, Asia and South America.
• Cardiac glycosides are composed structurally of three distinct subunits: a steroid backbone consisting of 17 carbons distributed in four rings connected to a lactone ring and either a carbohydrate or sugar moiety in glycosidic linkage.
• The toxicokinetics and toxicodynamics of the cardio-active glycosides are dependent on both the aglycone and the sugar attachments.
• The inherent activity resides in the aglycone, but the sugars render the compounds more soluble and increase the power of fixation of the glycosides to the heart muscle.
• All animal species are susceptible to acute poisoning, specifically cattle and horses. Poisonings involving oleander have also been reported in dogs.
• Toxicosis is rarely reported in avian species.
• Cardiac glycoside-containing plants are usually not palatable and thus are not eaten readily in their normal state, unless other feed is very scarce.
• The palatability of oleander leaves to animals increases after they are trimmed and/or shed from the plant.
• Spraying oleander with herbicide not only increases its palatability but also the concentration of cardiac glycosides in the plant.
• Toxicity is retained; therefore, feeding hay contaminated with cardiac-glycoside containing plants is a risk.
• Biotransformation of cardiac glycosides is primarily hepatic.
• Cardiac glycosides induce direct cardiotoxicity and indirect vagal nerve modulation by inhibiting the Na+/K+ ATPase pump.
• Na⁺ efflux is inhibited, and intracellular Na⁺ is retained. This, in turn, alters the activity of the Na+/Ca2+ exchanger causing a transient rise in intracellular Ca2+ by enhancing Ca2+ influx and/or inhibiting Ca2+ efflux or both
• Increased availability of Ca2+ augments contractility, resulting in sustained contraction which causes cardiac muscle fatigue, heart failure and permanent damage.
• The most obvious clinical sign of poisoning is diarrhea.
• A variety of cardiac arrhythmias and heart block may also be encountered.
  • The rate and rhythm of the heart is affected. It may be faster or slower than normal and there may be dropped beats.
• Pigs may refuse to eat feed contaminated with cardiac glycosides, but if they do, vomiting occurs.
  • Vomiting also occurs in dogs.
• Badly affected animals have difficulty breathing and die rapidly. Affected animals may die suddenly if exercised.
• Ruminal stasis will also be evident.
• Horses often have colic.
• Classic clinical signs of oleander intoxication are primarily heart and digestive disturbances and altered mental status.
• Cattle consuming oleander are frequently found dead, attributed to the profound effects of the toxin on the heart.
• Bradycardia is the first clinical sign noted 30 min after administration of oleander to sheep; tachyarrhythmia is observed in the later stages.
• In sheep following administration of a single oral dose of 250 mg/kg of N. oleander leaves signs of toxicosis were observed 7 h, including uneasiness, anorexia, teeth grinding, salivation, urination, rumen bloat, ataxia and recumbence, with death between 18 and 24 h.
• Males appear to be more susceptible to the effects of oleander poisoning than females.
• The leaves of rubber vine are toxic to cattle, horses, sheep and goats, with horses being particularly susceptible.
• Seed of pheasant's eye fed at 5.6 g/kg of the diet were found to induce virtually total feed refusal within 3 days in growing and finishing pigs causing vomiting, rapid and shallow breathing, and death.
• Cardiac-glycoside poisonings post-mortem examination typically reveals small, scattered groups of dead and dying muscle fibres in the heart of animals that have survived for ≥ 12 h.
• Rapid deaths will have collapsed portions (atelectasis) or fluid-build-up (oedema) being seen in the lungs. -Haemorrhage into the intestines is commonly seen.
• Ulceration of the lining of the omasum may be seen in those ruminants that survive for several days before death.
• Diagnosis involves identification of the plant, evidence of its consumption through a history of access, clinical signs, ECG changes, clinicopathological changes and necropsy findings, A variety of electrocardiograph alterations have been reported.
• Clinicopathological derangements ( acute cardiac glycoside) may include hypoxaemia, acidosis, haemoconcentration, hyperkalaemia, hypochloraemia, hyperglycaemia, elevations in serum urea and creatinine and elevations in creatinine phosphokinase.
• Recombinase polymerase amplification assay (RPA) is a comparatively new, and easy to use method for the rapid detection of R. toxicus in the field.
• Antibody treatments against cardenolides are available, but they are expensive and typically used only for treatment of companion animals.

Corynetoxins

• Corynetoxicity occurs most commonly in Australia but has occurred sporadically in other countries.
• Corynetoxins are tunicaminyluracils, which are glycolipids since glycolipids are poor immunogens, there is no natural immunity to corynetoxins in the field.
• Corynetoxins have a cumulative effect despite short plasma half-life.
• Corynetoxins are generated by gram-positive bacteria infected with bacteriophages. _R. toxicus exhibits a complex life cycle, using the nematode as a physical vector to carry it up to the seed head of the host plant.
• The distribution and occurrence of corynetoxicosis is determined by the availability of the bacterium, nematode, and host plants.
• Multiplying bacteria may produce a yellow slime on the seed heads of infected pasture grasses.
• Upon ingestion, the toxins accumulate and toxic doses are 3-5 mg/kg BW.
• The toxins inhibit production of glycoproteins and interfere with the structure of small blood vessels, decreasing oxygen delivery to tissues. The brain is the most affected organ. Corynetoxins inhibit lipid-linked N-glycosylation that includes enzymes, hormones, structural components and extracellular matrices and membrane receptors
• Glycoproteins are widely distributed in tissues and possess many functions thus their inhibition impedes numerous cellular functions and the potential effects of their toxicity in animals is diverse.
• Clinical signs in livestock appear abruptly, usually following some external stimulation.
• Early clinical signs may include an unsteady, high-stepping gait or 'rocking-horse' gait.
• Twitching of muscles and nodding or swaying of the head. Affected animals collapse with rolling of the eyes, severe spasms and paddling motions of limbs.
• Left undisturbed, animals often regain their feet and stagger away exhibitting depression and ataxia.
• Abortion can occur in up to 10% of pregnant surviving ewes. Removal of stock results in cessation of neurological signs and mortality after about a week and Cattle clinical signs are similar to those in sheep
• Liver is yellowish and friable, sometimes icteric in the carcase, haemorrhages can be found in the gallbladder and commonly small intestine , kidney and cervical musculature Suprascapular nodes ( contain petechial haemorrhages) are enlarged Petechial epicardial and endocardial haemorrhages are found. Meninges are congested.

Cyanogenic Glycosides

• Cyanogenic glucosides (cyanogens) are relatively concentrated in grasses, pulses, root crops, and fruit kernels that contribute to their bitter taste.
• These compounds can become toxic upon hydrolysis in the rumen.
• Factors such as rumen pH and microflora, rapid ingestion, immature cyanogenic plants consumed, concentration of cyanogenic glycoside, presence of glucosidase and free hydrogen cyanide and the use of Nitrogen fertiliser & herbercide,increase increased cyanogenic toxicity in livestock.
• Releases cyanogenic glycosides from the plant cell vacuoles and exposes them to catabolism by β-glucosidase and hydroxynitrile lyase present, the presence also favours conversion of Cyanogenic glycosides to form HCN
• Ruminants on high-energy grain rations are less susceptible because their lower rumen pH decrease formation of HCN
• its affinity for the ferric heme form of cytochrome c oxidase ( the final enzyme in the respiratory chain) is the cause of HCN toxicity
• Cyanide acts as a respiratory poison since the formation of the cytochrome oxidase-CN complex blocks mitochondrial electron transfer for hypoxic cellular termination , Myocardium tissue is the most severely affected Cardiac failure cerebral anoxia

Fluoroacetate

• Fluoroacetate occurs naturally in several plants which found in Qld, NT and parts of WA belonging to families Fabaceae, Rubiaceae, Bignoniaceae, Malpighiaceae and Dichapetalaceae where about 40 species produce Fluoroacetate
• Species gastrolobium and georgina Gidgee has resulted in toxicity, the distribution in plants showing heart leaf containing up to 2600 mg fluoroacetate/kg DM
• 0 has been recorded LD50 in ruminants-0.3 mg/kg BW, pods toxic

Nitrate – Nitrite

• Ruminants convert nitrate to nitrite and then to ammonia,toxicity is a function of the amount and absorption absorption epithelium ruminal into the blood steam passive diffusion the entry facilitates into erythrocytes in exchange of chloride ions
• The nitrite oxidation ions, which leads to haemoglobin from reducing oxygen ,which greatly decrease RBC Clinical signs appear when 40% -60% total haemogloblin is converted to Met Haemo

Oxalate soluble

• Ingestion several syndromes, 2 Oxalate soluble reduces absorption trace minerals ( Ca,Mg,Fe ) form insoluble blood high, High Oxalate , kidney, High Oxalate
• Action
  • Oxalate combine, Ca, Rumen microflora , Ca Insoluble prevent oxalate neutralise to systematic.
• Absorption,oxalate combine serum Mg with Ca,GIT

Thiaminase

• Destroys thiamine,in GIT significant lead of deficiency brain damage , often ,bracken state in and sheep causes Encephlo T- 1, degrase into biological in inactive form.
• phosphates TCA & pentose
• Softening Brain
• Brain necroses by neurons

Pimelea

• is a genus of about 140 plant species, with 35 species which are endemic in New Zealand remainder in Australia.
• Some of these species are well-known for causing animal poisoning due to the presence of a called toxin. and the of the walls of the pulmonary blood vessels an pressure with heart fluid leakage subcutaneous

Mycotoxins

• Structurally metabolites by not to is essential to growth by the by conditions more by and 300 of from 350 fungal encounter toxin may and consumption by been problem has for sheep on stubble by and are in both countries. are aflatoxin and and DON reports

Aflatoxins

• Produced 28 species and to is toxic immunosuppression and B G or of fluorescence B1 to and C increase in feed may resultIn tissue ,277 3 ppb in poultry

Ergot Alkaloids

• Alkaloids are only produced during store The group is linked on 9 or depending ,are

Photosensitisation

• Energy and species cause DNA damage causing dermatitis solely compounds (St Johns into the into

Lectins

• Lectins are plant based and are composed of of of specific into cell to in

Tans

• are and have when on the. and in, and,