Intoxication of Humans

Although mad honey is the most common cause of grayanotoxin intoxication, it is not the only one. The ingestion of leaves, nectar and flowers of plants containing grayanotoxin can cause intoxication too. These cases (Table 1) are very rare and occur mainly, but not exclusively, in Asia. The intake can arise from false beliefs in medicinal properties of the plant. In Hong Kong, a 57-day-old baby suffered from grayanotoxin intoxication, presenting respiratory distress, bradycardia, hypotension, constricted pupils, salivation and muscle twitching, after the grandmother added a decoction of Rhododendron simsii to the bottle of milk, convinced it would be beneficial to the airways [8]. Kim et al. [41] reported grayanotoxin intoxication in three patients who ingested either blossom leaves or medicinal preparations made from Rhododendron species. A 61-year-old female presented conduction disturbances and junctional escape beats while two males of 70 and 73 years of age respectively showed sinus bradycardia. All responded well to atropine [41]. A 59-year-old man from Korea drank an herbal tea made from Rhododendron brachycarpum and presented signs of grayanotoxin poisoning (bradycardia, hypotension, dizziness, sweating) [42].

Table 1 Overview of grayanotoxin intoxication cases in humans, unrelated to mad honey requiring hospitalization Full size table

Children that eat the plants are also at risk. A 9-year-old boy from Korea consumed about ten Rhododendron schlippenbachii flowers and, besides the common signs of grayanotoxin intoxication, presented with impaired consciousness and delirium 26 h later. All symptoms resolved completely after a further 17 h [43]. In the USA, ingestion of Ericaceae by children has occurred as well. A 21-month-old girl was admitted to the hospital after eating a Pieris japonica garden plant [44]. She presented with bradycardia (40 bpm), pallor and vomiting, and following treatment with atropine her condition improved [44].

In adults, a lack of knowledge or a (mis)calculated risk can be a reason for intoxication. Some Koreans believe that the Azalea (Rhododendron mucronulatum) is non-poisonous, even though the toxicity of Rhododendron species is commonly understood. Blossoms of the Azalea are therefore ingested in different forms, enabling intoxication. A 76-year-old man was hospitalized when presenting grayanotoxin intoxication (hypotension, sinus bradycardia, dizziness, general inertia) after ingesting the blossom of this plant [45]. A patient in Korea consumed 50 blossoms of the R. schlippenbachii to get rid of his thirst, while aware of the poisonous properties [46].

A 28-year-old woman from Saint-Paul-de-la-Reunion, one of the Mascarene Islands close to Madagascar in the Indian Ocean, who mistakenly drank an herbal tea from leaves of the Agauria salicifolia, a plant from the Ericaceae family, presented the typical signs of grayanotoxin intoxication [47]. The same happened in the USA to a 76-year-old man that presented bradycardia, hypotension, vomiting, blurred vision and seizure, after drinking tea made from P. japonica [44].

Finally, misidentification of plant species may cause intoxication. The toxic sheep laurel (Kalmia angustifolia) resembles R. tomemtosum in appearance [48]. R. tomentosum and R. groenlandicum, named Northern and Bog Labrador Tea, are used for preparing herbal teas for their medicinal qualities according to Native Americans. The Labrador Tea itself is said to be mildly toxic and should be drunk in small quantities only.

Intoxication in Cattle and Pets

In humans, there are few cases known of grayanotoxin intoxication unrelated to mad honey. Mainly cattle are susceptible to grayanotoxin intoxication, but it has also been reported in sheep, goats and donkeys. Plants known for animal intoxication are the Rhododendron, the laurel (Kalmia) and the Japanese Pieris. Rhododendron intoxication is most common in winter and early spring, since Rhododendron leaves are perennial [49]. Rhododendron has a toxic dose of 0.2 % body weight in cattle, while Kalmia has a toxic dose of 0.4 % body weight [49]. When an animal presents gastrointestinal tract irritation, cardiac arrhythmias, and neurological symptoms, grayanotoxin intoxication should be considered. The symptoms of grayanotoxin intoxication in cattle most commonly present themselves 3–14 h after ingestion and remain present for 2 days. The animal may recover, but in contrast to most human cases, the intoxication is often lethal [50–53]. Besides cardiovascular instability, aspiration of the vomitus is a common cause of death [49]. Although cattle-keepers may be well aware of the toxic effects of grayanotoxin containing plants, still, poisoning may occur when animals are fed by bystanders. This was observed in a case of goats that ate P. japonica prune debris thrown into their pasture by the neighbor [54]. Nubian goats of the Riverbanks Zoological Park were given a Rhododendron indica branch by a zoo visitor and developed grayanotoxin poising that was subsequently confirmed by urine and feces analysis [55].

Leengoed and Amerongen described an interesting case of intoxication in a herd of 65 sheep that ingested R. ponticum. The intoxication followed an unexpected course. After treatment with laxatives, the condition of the sheep improved but 36 h after intoxication, the condition of almost all sheep deteriorated again. Leengoed and Amerongen hypothesized this could be due to shut down of rumination caused by intoxication. After initial recovery, rumination was reestablished instigating renewed intoxication. A rumenotomy performed 18 h after intoxication on 1 sheep proved curative [56].

Domestic animals, such as cats and dogs, can also be exposed to grayanotoxin, usually in the form of the Azalea. The Animal Poison Control Center (APCC), part of the American Society for the Prevention of Cruelty to Animals (ASPCA), has received 188 cases of Azalea ingestion of dogs and cats throughout America during January 2001 to December 2003. The signs included vomiting, depression, diarrhea and anorexia. The animals usually had access to the plants because they were accessible in the garden or brought into the house as ornamental plants [57].