121: Plants

Five to ten percent of all human exposures reported to poison centers involve plants. Probably because plants are so accessible and attractive to youngsters, in approximately 80% of these cases the individuals are younger than 6 years of age. As indoor plants have become ever more popular, the incidence of plant exposures has increased. Data compiled by the American Association of Poison Control Centers (AAPCC) give some indication of which plants are more commonly involved (Chap. 136), but these plants typically have relatively limited toxicity. More than 80% of patients reported to the AAPCC as being exposed were asymptomatic, less than 20% had minor to moderate symptomatology, and less than 7% necessitated a health care visit. The benignity of these exposures is represented by a fatality rate of less than 0.001%. This chapter addresses the toxicologic principles associated with the most potentially dangerous plants.

Aconitine, from monkshood, exemplifies the rich history of plant toxicology. It was believed by the Greeks to be the first poison—“lycotonum”—created by the goddess Hecate from foam of the river Cerebrus. Alkaloid constituents are responsible for its toxic (and therapeutic) effects. Alkaloids represent one of several classes of organic molecules found in plants as defined by the science of pharmacognosy, which is the science of medicines derived from natural sources. The pharmacognosy approach is consistent with the literature of plant efficacy and is applied here to their toxicity (Table 121–1). Unfortunately, the science of pharmacognosy is not always straightforward, and systems of classification may vary depending on the pharmacognosist. Hence our approach borrows primarily from two groups of authors to keep the classification as consistent as possible.^48,120 The major groups are as follows:

1. Alkaloids: Molecules that react as bases and contain nitrogen, usually in a heterocyclic structure. Alkaloids typically have strong pharmacologic activity that defines many major toxidromes.

2. Glycosides: Organic compounds that yield a sugar or sugar derivative (the glycone) and a nonsugar moiety (the aglycone) upon hydrolysis. The aglycone is the basis of subclassification into saponin or steroidal glycosides (including steroidal cardiac glycosides, cyanogenic glycosides, anthraquinone glycosides), and others such as atractyloside and salicin.

3. Terpenes and resins: Assemblages of five-carbon units (isoprene unit) with many types of functional groups (eg, alcohols, phenols, ketones, and esters) attached. This is the largest group of secondary metabolites; approximately 20,000 are identified. Most essential oils are mixtures of monoterpenes, and the terpene name depends on the number of isoprene assemblages. Monoterpenes have two units (C10H16), sesquiterpenes have three isoprene units (C15), diterpenes have four isoprene units (C20), and triterpenes have six (C30). These molecules often play an active role in plant defense mechanisms.

4. Proteins, peptides, and lectins: Proteins consist of amino acid units with various side chains, and peptides consist of linkages among amino acids. Lectins are glycoproteins classified according to the number of protein chains linked by disulfide bonds and by binding affinity for specific carbohydrate ligands, particularly galactosamines. The toxalbumins (eg, ricin) are lectins. These components tend to be neurotoxins, hemagglutinins, or cathartics.

5. Phenols and phenylpropanoids: Phenols contain phenyl rings and have one or more hydroxyl groups attached to the ring. Phenylpropanoids consist of a phenyl ring attached to a propane side chain. These compounds are devoid of nitrogen, even though some are derived from phenylalanine and tyrosine. They constitute a major group of secondary metabolites and among plant toxins include coumarins (lactone side chains), flavonoids (built upon a flavan 2,3-dihydro-2-phenylbenzopyran nucleus, such as naringenin and rutin), lignans (two linked phenylpropanoids, such as podophyllin), lignins (complex polymers of lignans that bind cellulose for woody bark and stem), and tannins (polymers that bind to protein and can be further hydrolyzed or ­condensed).

Plant chemistry is complex. The simplified presentation of one xenobiotic per plant per symptom group used in Table 121–1 overlooks the fact that plants contain multiple xenobiotics that work independently or in concert. Additionally, different plant families may contain similar, if not identical, xenobiotics (either from conservation of biochemical pathways inherited from a common ancestor or through convergent evolution). In some cases, xenobiotics remain unidentified and are grouped in the section Unidentified Toxins.

Dissimilar molecules from diverse pharmacognosy classes that share effects are grouped together for pragmatic purposes in the section Effects Shared Among Different Classes of Xenobiotics. They are further categorized into plant–xenobiotic interactions, sodium channel effects, antimitotic alkaloids and resins, and plant-induced dermatitis.

Our focus is on exposures to flowering plants (angiosperms) related to foraging, dietary, or occupational contact, except for some gymnosperms or algae and, rarely, medicinal contact (medicinal use as herbals is discussed in Chap. 45).⁸³ Because our understanding of plant xenobiotics is poor relative to that of pharmaceuticals, animal research is included to provide a more comprehensive foundation for comparison with human experiences that may otherwise go unrecognized without such precedent, or may likewise prove ultimately incorrect. The science of plant toxicology formally began in the United States as a response to significant poisonings of livestock. The overall quality of literature for human exposures is poor and primarily available as case reports. Many of these cases lack clear links between toxin exposure and illness, and qualitative or quantitative analyses are generally unavailable. Uncertainty is compounded by the fact that plants themselves are inherently variable, and potency and type of xenobiotic depend on the season, geography, growing environment, plant part, and methods of processing.

Positive identification of the plant species should be attempted whenever possible, especially when the patient becomes symptomatic. Communication with an expert botanist, medical toxicologist, or poison center is highly recommended and can be facilitated by transmission of digital images or a fax.¹⁴⁸ Provisionally, simple comparison of the species in question with pictures or descriptions from a field guide of flora may help exclude the identity of the plant from among the most life threatening in Table 121–1. A plant identification can also be compared with those searched in the PLANTOX database (http://www.accessdata.fda.gov/scripts/plantox/index.cfm) managed by the Food and Drug Administration (FDA). To date, with some exceptions laboratory analysis is generally not timely enough to be useful except as a tool in an investigatory or forensic analysis. As the state of analytical science advances, however, it may soon be possible to confirm a diagnosis once a preliminary hypothesis based on botanical identification or symptomatology has been made.

In cases where expert identification cannot be immediately achieved, preliminary recognition of taxonomic families of poisonous plants is the simplest first step to identify or exclude poisonous plants, but it is most easily achieved when the plant is in flower or fruit. For instance, if the flower is described or looks like a flower from a tomato or potato, it probably is in the Solanaceae family. Plants of this family typically produce gastroenteric or anticholinergic findings following ingestion. It then would be appropriate to consider management with a specific antidote such as physostigmine. This approach will be less useful for xenobiotics such as pyrrolizidine alkaloids that occur in numerous different families.

Identified plant species most frequently reported to poison centers are indicated in Table 121–1. In most cases, these species provide reassurance because most exposures result in benign outcomes, and only a few among these are regularly life-threatening depending on the circumstances of the exposure. Given the relatively poor understanding of toxins and in the absence of complete information about an exposure, expectant management and supportive care are the rule. Even if a plant is not marked as life threatening or commonly reported, the patient should undergo a period of observation and follow-up, given the relatively immature science of plant toxicology relative to that of pharmaceuticals.

The difficult task in human plant toxicology is the lack of adequate data to determine risk (Chap. 130). Typically, evaluations of risk are based on poison center data and usually cite the numerous calls without clinical consequence as a part of the risk equation (Chap. 136). However, poison center data are predominantly unconfirmed exposures and cases with unsubstantiated clinical manifestations (Chap. 136). These cases often represent small or nonexistent exposures, and their inclusion in the database may mask actual risks by diluting hazardous exposures with trivial or nonexistent exposures.⁶⁴ Furthermore, misidentification of the plant may occur because of either similar appearance or similar nomenclature.

In summary, basic decontamination and supportive care should be instituted as appropriate for the clinical situation and with poison center consultation. The most consequential and dangerous plant xenobiotics for humans are discussed here, and those that can produce life-threatening signs acutely are denoted in Table 121–1.

Potential symptoms listed in Table 121–1 are organized by plant name and the associated major organ system effects for quick reference as to the type of symptoms and their potential for morbidity or mortality. For instance, life-threatening symptoms such as dysrhythmias or seizures can be searched by “cardi-” or “neuro-” in the third column and compared with the plant(s) in question. The plants and xenobiotics that present life-threatening symptoms are so noted. Exposures associated with one of these plants or xenobiotics or major organ system symptoms dictate the need for possible prompt gastric emptying, decontamination, individualized therapy, and hospitalization. Nonspecific symptoms such as nausea and vomiting are listed only when they are a major cause of morbidity or mortality (toxalbumins such as ricin), but nausea and vomiting are exceptionally common in those individuals with consequential acute poisonings.

Alkaloids

The term alkaloid refers to nitrogen-containing basic xenobiotics of natural origin. They figure prominently in the history of human–plant interaction, ranging from epidemics of poisoning caused by ergot-infected rye bread in the Middle Ages to dependency on cocaine, heroin, and nicotine in contemporary time. Numerous examples of toxic constituents of these families are given in the following discussion, which begins with a description of the major toxidromes that involves alkaloids. See also Sodium Channel Effects under Effects Shared Among Different Classes of Xenobiotics later in this chapter for descriptions of additional life-threatening alkaloids.

Anticholinergic: Belladonna Alkaloids.

The belladonna alkaloids are from the family Solanaceae and the plants can be identified as members of this family by their characteristic flowers (most familiar from nightshade, potato, or tomato flowers). The belladonna alkaloids have potent antimuscarinic effects, manifested by tachycardia, hyperthermia, dry skin and mucous membranes, skin flushing, diminished bowel sounds, urinary retention, agitation, disorientation, and hallucinations (Chap. 3). Since the 1970s, the quest for recreational “highs” has surpassed unintentional ingestions as the main source of toxicity.¹⁴³ Hallucinatory effects are sought in seeds and teas, especially in late summer, when jimsonweed (Datura stramonium) seeds (Fig. 121–1) become available. One hundred of these seeds contain up to 6 mg atropine and related alkaloids, and an ingestion of this amount can be fatal.¹⁸

Although several anticholinergic alkaloid-containing species and even individual plants within species contain differing concentrations of several different phytochemicals, the clinical manifestations usually are similar. The onset of symptoms typically occurs 1 to 4 hours postingestion, and more rapidly if the plants are smoked or consumed as a brewed tea. The duration of effect is partly dose dependent and may last from a few hours to days.²³ The course of anticholinergic poisoning is not substantially altered by the use of physostigmine, though this may be life-saving in patients with seizures or an agitated delirium (Antidotes in Depth: A9).^40,127 Although methods for detection of atropine and scopolamine in clinical specimens are improving, anticholinergic toxicity may be observed without detectable atropine, scopolamine, or hyoscyamine concentrations in biological fluids.

Solanine and chaconine are glycoalkaloids contained in many members of the Solanaceae family, but they are structurally and pharmacologically dissimilar to the belladonna alkaloids. The aglycone solanidine, which lacks the sugar moiety, is a steroidal alkaloid. Solanine inhibits cholinesterase in vitro, although cholinergic symptoms are not noted clinically. Nonetheless, reports of solanine-induced central nervous system (CNS) toxicity include hallucinations, delirium, and coma.¹³⁸ However, most symptomatic patients typically develop nausea, vomiting, diarrhea, and abdominal pain that begins 2 to 24 hours after ingestion, which, like CNS toxicity, may persist for several days. Although solanine is present in most of the 1700 species in the genus Solanum, solanine toxicity in humans is rarely encountered. The content of glycoalkaloids in tubers is usually 10 to 100 mg/kg and the maximum concentrations do not exceed 200 mg/kg. Green potatoes and the green potato plant itself are most commonly associated with symptoms, which is not surprising because the alkaloids are most concentrated in those items. The ingestion of 1 to 3 mg of glycoalkaloid per kilogram of body weight is likely to produce clinical symptoms.¹²⁵ Most reports of death come from the older literature,² and consumption of 2 to 5 g of green components of potatoes per kilogram of body weight per day is not predicted to cause acute toxicity.¹¹³

Nicotine and Nicotinelike Alkaloids: Nicotine, Anabasine, Lobeline, Sparteine, N-Methylcytisine, Cytisine, and Coniine.

Nicotine toxicity (other than from inhaled sources) occurs via ingestion of leaves of Nicotiana tabacum, cigarettes and their remains, e-cigarette refill, organic insecticidal products, and transdermally among farm workers harvesting tobacco (green tobacco sickness)¹⁵ (Chap. 85). A topical folk remedy made from the leaf of Nicotiana glauca (tree tobacco) caused anabasine toxicity in an infant.¹⁰⁵ The alkaloidal form of nicotine and anabasine are pale yellow oils at room temperature and readily penetrate the intact dermis. A dose of nicotine as small as 1 mg/kg of body weight can be lethal although it is more likely with doses > 4 mg/kg.⁹³ Overstimulation of the nicotinic receptors by high doses of the alkaloid produces nicotinism, a toxidrome that progresses from gastrointestinal (GI) symptoms to diaphoresis, mydriasis, fasciculations, tachycardia, hypertension, hyperthermia, seizures, respiratory depression, muscle weakness, and death (Chap. 84). Wearing of protective clothing is essential for tobacco farm workers to prevent green tobacco sickness.⁶

These manifestations are also produced by alkaloids other than nicotine. There are no recent reports of nicotinic toxicity from lobeline (found in all parts of Lobelia inflata), although its use in the 18th century resulted in morbidity and mortality.

Sparteine from broom (Cytisus scoparius) and N-methylcytisine from blue cohosh (Caulophyllum thalictroides)¹¹⁶ are examples of alkaloids that produce nicotinelike effects. Laburnum or golden chain (Cytisus laburnum) contains cytisine, which reportedly is responsible for mass poisonings and fatalities in children and adults who eat the plants or parts thereof (even as little as 0.5 mg/kg, or a few peas).¹⁰³ Unfortunately, such reports have resulted in thousands of unnecessary hospital admissions for patients without morbidity and mortality after ingestion of this plant, demonstrating the difficulty in separating hazard from risk and in obtaining accurate dose–response information in the setting of plant exposures and human variability.

The most famous description of the end stages of nicotinic toxicity dates from approximately 2400 years ago by an observer of Socrates’ fatal ingestion of a decoction of poison hemlock (Conium maculatum).¹¹⁷

Birds do not experience coniine toxicity but provide a vector for poisoning. According to the book of Exodus, quail that fed on seeds (presumably from poison hemlock) became toxic and passed the toxicity on to the Israelites who ate the fowl.¹⁶ In the 20th century, this is especially well documented in Italy, where the toxic alkaloid coniine was detected in bird meat, as well as in the blood, urine, and tissue of some individuals.¹³¹

The age of the plant seems to be directly correlated with increasing concentrations of coniine, whereas the toxin γ-coniceine occurs in greater amounts in new growth; hence, the plant remains toxic over the entire growing season. Fatal poisonings are reported on multiple continents frequently resulting from respiratory arrest. Of 17 poisoned Italian patients, all had elevated liver aminotransferases and myoglobin concentrations, and five had acute tubular necrosis.¹¹⁹ Death developed 1 to 16 days following ingestion.

Cholinergic Alkaloids: Arecoline, Physostigmine, and Pilocarpine.

Betel chewing has been a habitual practice in the East since ancient times. The “quid” consists of betel nut (Areca catechu) and other ingredients. The effects of acute exposure to arecoline, the major alkaloid, include sweating, salivation, hyperthermia, and rarely death.⁵⁵ Prolonged use is linked to dental decay and oral cancer. Physostigmine is an alkaloid derived from the Calabar bean (Physostigma venenosum), where it is present in concentrations of 0.15% (Antidotes in Depth: A9). Pilocarpine is derived from Pilocarpus jaborandi from South America. Its stimulatory effects on muscarinic receptors have proven valuable in the treatment of glaucoma. Reversal of toxicity can be achieved by atropine.

Psychotropic Alkaloids: Lysergic Acid and Mescaline.

Hallucinations from the direct serotonin effects of lysergic acid alkaloids and its derivatives, and from the amphetaminelike serotonin effects of the mescaline alkaloids, are reported following ingestion of morning glory seeds (Ipomoea spp) and peyote cactus (Lophophora williamsii), respectively (Chap. 82). Despite their chemical relatedness to LSD, molecules such as lysergic acid amide and lysergic acid ethylamide, found in Hawaiian baby woodrose seeds (Argyreia nervosa), produce findings that may appear anticholinergic.¹⁷

Alkaloidal Central Nervous System Stimulants and Depressants: Ephedrine, Synephrine, Cathinone, and Opioids.

The use of ephedrine-containing Ephedra spp in herbal dietary supplement products was banned by the FDA in 2004 because of the associated cardiovascular toxicity and deaths. Varieties of Sida cordifolia also contain ephedrine. Synephrine, a xenobiotic structurally related to ephedrine, occurs in bitter orange (Citrus aurantium), which is ingested as a plant, in foods such as marmalades, as a dietary supplement, or as a traditional medicine. Deaths and drug interactions can ensue from their use. Although illegal in the United States, another plant ingested for its CNS stimulant activity is khat (Catha edulis). The plant contains cathinone (α-aminopropiophenone) and cathine [(+)-norpseudoephedrine]. In addition, opioids derived from the poppy plant (Papaver spp) are prototypic CNS depressants and analgesics (Chap. 38).

Pyrrolizidine Alkaloids.

Pyrrolizidine alkaloids are widely distributed both botanically and geographically. Approximately half of the 350 different pyrrolizidine alkaloids characterized to date are toxic when ingested. Pyrro­lizidine alkaloids are found in 6000 plants and in 13 plant families, but they are most heavily represented within the Boraginaceae, Compositae, and Fabaceae families. Within these families, the genera Heliotropium, Senecio, and Crotalaria, respectively, are particularly notable for their content of toxic pyrrolizidine alkaloids, including the unsaturated 1-hydroxymethyl pyrrolizidine.⁵⁶ The hepatic cytochrome P450 (CYP) system converts these compounds to highly reactive pyrroles in vivo. Chronic exposures stimulate the proliferation of the intima of hepatic vasculature and result in hepatic venoocclusive disease (HVOD). Poisonings occur as a result of the use of pyrrolizidine-rich plants for medicinal purposes and by contamination of food grain with seeds of pyrrolizidine–alkaloid-containing plants.⁴⁴ Acute hepatocellular toxicity can occur following ingestion of 10 to 20 mg of pyrrolizidine alkaloid and is probably caused by an oxidant effect producing hepatic necrosis. An estimated 20% of patients with acute pyrrolizidine alkaloid poisoning die, 50% recover completely, and the rest develop subacute or chronic manifestations of HVOD. Pyrrolizidine alkaloids are teratogenic and are also transmitted through breast milk. Pyrrolizidine alkaloids may be present in bee pollen and have been reported in honey. Other types of plant-associated hepatic disorders are discussed in Effects Shared Among Different Classes of Xenobiotics.

Isoquinoline Alkaloids: Sanguinarine, Berberine, and Hydrastine.

Adverse effects on human health due to consumption of edible mustard oil adulterated with argemone oil have been reported. Sanguinarine was detected in 26 family members who consumed a mustard oil contaminated with seeds of Mexican prickly poppy (Argemone Mexicana).¹³⁶ All patients suffered GI distress followed by peripheral edema (dropsy), skin darkening, erythema, skin lesions, perianal itching, anemia, and hepatomegaly. Ascites developed in 12%, and myocarditis and congestive heart failure occurred in approximately a third of affected individuals. Alterations in redox potentials and antioxidants in plasma may be responsible for the histopathological changes, including swollen hepatocytes and fluid accumulation in the spaces of Disse and Kupffer cell hyperplasia.¹⁰ Medicinally, sanguinarine is used for dental hygiene.⁹⁹ In North America, sanguinarine is found in blood root (Sanguinaria canadensis), which, like Argemone, is in the Ranunculaceae family.

Berberine is structurally similar to sanguinarine and reportedly also has cardiac depressant effects. A number of medicinal plants contain berberine, including goldenseal (Hydrastis canadensis), Oregon grape (Mahonia spp), and barberry (Berberis spp). It causes myocardial and respiratory depression and contraction of smooth muscle vasculature and the uterus. Strychninelike movement disorders are described following ingestion of hydrastine, which makes up 4% of goldenseal.

Other Alkaloids: Emetine/Cephaline, Strychnine/Curare, and Swainsonine.

Emetine and cephaline are derived from Cephaelis ipecacuanha, a tropical plant native to the forests of Bolivia and Brazil. They are the principal active constituents in syrup of ipecac, which produces emesis. Chronic use of syrup of ipecac, typically by patients with eating disorders or Munchausen syndrome by proxy, can lead to cardiomyopathy, smooth muscle dysfunction, myopathies, electrolyte and acid–base disturbances related to excessive vomiting, and death (Antidotes in Depth: A1). Poisoning in patients ingesting plant material is not reported.

Curare was used as an arrow poison derived from plants of the genus Strychnos as well as Chondrodendron, but the plants and their ­phytochemicals produce very different clinical effects. The convulsant alkaloids strychnine and brucine are found in various members of the genus Strychnos. Although used to produce arrow poison, the more widespread use of Strychnos spp in Africa was for trial by ordeal.¹¹² The seeds of Strychnos nux-vomica are especially rich in strychnine, which causes muscular spasms and rigidity by antagonizing glycine receptors in the spinal cord and brainstem. The plant is used as an herbal remedy for arthritis pain called “maqianzi,” which if improperly processed produces muscle spasm and weakness, including respiratory muscles (Chap. 112).

Curare is an extract of the bark of Chondrodendron tomentosum and certain members of the genus Strychnos. The physiologically active xenobiotic of curare from Chondrodendron is d-tubocurarine chloride, a competitive antagonist of acetylcholine at nicotinic receptors in the neuromuscular junction. Curare is the molecule from which most nondepolarizing neuromuscular blockers are derived (Chap. 68). Plant poisoning is recorded solely with its traditional use as a hunting poison.

Swainsonine has been isolated from Swainsonia canescens, Astragalus lentiginosis (spotted locoweed), Sida carpinifolia, other species of Swainsonia and Astragalus, as well as several species in the genera Oxytropis and Ipomoea, and several fungi. After subsisting on seeds containing swainsonine for nearly 4 months, a naturalist forager manifested profound muscular weakness and died in the wilderness.⁷⁷ The compound is teratogenic and causes chronic neurologic disease called “locoism,” with weakness and failure to thrive in livestock. Swainsonine inhibits the glycosylation of glycoproteins by α-mannosidase II of the Golgi apparatus, resulting in a lysosomal storage disease. Adverse effects included hepatic, pancreatic, and respiratory manifestations, as well as lethargy and nausea.

Glycosides

Glycosides yield a sugar or sugar derivative (the glycone) and a nonsugar moiety (the aglycone) upon hydrolysis. The nonsugar or aglycone group determines the subtype of glycoside. For instance, the cardiac glycosides have saponin (steroid) aglycone groups and are placed among the saponin glycosides.

Saponin Glycosides: Cardiac Glycosides, Glycyrrhizin, and Ilex ­Saponins.

Poisoning by virtually all cardioactive steroidal glycosides is clinically indistinguishable from poisoning by digoxin (Chap. 64), which itself is a cardioactive steroid derived from Digitalis lanata. However, compared with toxicity from pharmaceutical digoxin, toxicity resulting from the cardioactive steroidal glycosides found in plants has markedly different pharmacokinetic characteristics. For example, digitoxin in Digitalis spp has a plasma half-life as long as 192 hours (average 168 hours).

The pharmacologic properties are true across taxonomic boundaries. Poisonings by Digitalis spp,^115,137 squill (Urginea spp),¹⁵⁰ lily of the valley,³ oleander (Nerium spp),¹⁵⁶ yellow oleander (Thevetia spp),⁴¹ and Cerbera manghas⁴² are clinically similar (Fig. 121–2). The potency of these effects depends on the specific cardioactive glycoside constituents and their dose. For instance, lily of the valley is rarely associated with morbidity or mortality, whereas ingestion of only two seeds of yellow oleander by adults can produce severe symptoms, and expected outcome is grave with several more.⁴¹ Poisonings by oleander and yellow oleander occur predominantly in the Mediterranean and in the Near and Far East. These two plants are popular attractive ornamentals and commonly result in poisoning in the United States and Europe.

Patients experience vomiting within several hours, followed by hyperkalemia, cardiac conduction delays, and increased automaticity (bradycardia and tachydysrhythmias). Interestingly, the cardiac manifestations may be difficult to distinguish from those produced by plants containing sodium channel blockers (section Sodium Channel Effects). Activated charcoal was beneficial in preventing death after suicide attempts with yellow oleander in Sri Lanka, and its use should not be delayed in the face of uncertain plant identity.³⁶ Antibody therapy reduces mortality threefold from yellow oleander poisoning but is too expensive for developing countries where oleander-induced mortality is highest.⁴³ In addition, various cardioactive steroids respond differently to therapeutic use of digoxin-specific antibody fragments. Use of very large doses of digoxin-specific antibody (up to 37 vials reported in one case¹¹⁸) may be necessary to capitalize on the therapeutic cross-reactivity between digoxin-specific antibody and the nondigoxin cardioactive steroids, such as oleander.¹²⁶ The potential for success should lead to use of antibody therapy without delay when available. Similarly, there is variable cross-reactivity among the individual plant cardioactive steroids with regard to the degree to which each elevates diagnostic polyclonal digoxin assay measurements in clinical laboratories.³³ These measurements can be used only as qualitative proof of exposure but not as quantitative indicators of the exposure because the elevations can result in marked underestimation of the “functional digoxin concentrations.” Until additional technologic advances occur, any positive digoxin concentration following exposure to a plant should be assumed to be significant.

Glycyrrhizin.

Glycyrrhizin is a saponin glycoside derived from Glycyrrhiza glabra (licorice) and other Glycyrrhiza spp. Glycyrrhizin inhibits 11-β-hydroxysteroid dehydrogenase, an enzyme that converts cortisol to cortisone. When large amounts of licorice root are consumed chronically, cortisol concentrations rise, resulting in pseudo-hyperaldosteronism because of its affinity for renal mineralocorticoid receptors.⁵⁰ Chronic use eventually leads to hypokalemia with muscle weakness, sodium and water retention, hypertension, and dysrhythmias.¹⁶⁵ Assessment involves evaluation of the patient’s fluid and electrolytes, and electrocardiogram. Potassium replacement is the most common necessary intervention.

Ilex Species.

Holly berries from more than 300 Ilex spp are commonly ingested by children, especially during winter holidays. They contain a ­mixture of alkaloids, polyphenols, saponin glycosides, steroids, and triterpenes. Saponin glycosides appear to be responsible for GI symptoms such as nausea, vomiting, diarrhea, and abdominal cramping that result from ingestion of the berries. CNS depression was reported in a case in which a child consumed a “handful” of berries; however, this child was also treated with syrup of ipecac.¹²² The toxic quantity is undefined, but it is typically suggested that no untoward effects are to be expected for ingestions of fewer than six berries. Symptoms may be expected to be restricted to GI effects, and treatment is supportive.

Cyanogenic Glycosides: (S)-Sambunigrin, Amygdalin, Linamarin, and Cyacasin.

Cyanogenic glycosides yield hydrogen cyanide on complete hydrolysis. These glycosides are represented in a broad range of plant ­species.¹⁵³ The species that are most important to humans are cassava (Manihot esculenta), which contains linamarin, and Prunus spp, which contain amygdalin.¹² Cycad toxins are neurotoxic or pseudocyanogenic. Rare reports of cyanide poisoning associated with (S)-sambunigrin in European elderberry (Sambucus nigra; sambunigrin) are more severe when these ingestions include leaves as well as berries.²²

Many North American species of plants contain cyanogenic compounds, including ornamental Pyracantha, Passiflora, and Hydrangea spp, which either do not release cyanide or are rarely consumed in quantities sufficient to result in toxicity. On the other hand, although the fleshy fruit of Prunus spp in the Rosaceae are nontoxic (apricots, peaches, pears, apples, and plums), the leaves, bark, and seed kernels contain amygdalin, which is metabolized to cyanide. Sufficient cyanide can be absorbed to cause acute poisoning.¹⁴⁵ Amygdalin was the active ingredient of Laetrile, an apricot pit extract promoted in the 1970s for its supposed selective toxicity to tumor cells. Its sale was restricted in the United States because it lacked efficacy and safety.^98,100 However, patients went to other countries for Laetrile therapy, which was marketed as “vitamin B-17” and was available through alternative medicine providers. The manifestations of cyanide poisoning and treatment involving use of the cyanide antidote kit are detailed elsewhere (Chap. 126) (Antidotes in Depth: A39–A41).

Acute and chronic cyanide toxicity (including deaths) associated with consumption of inadequately prepared cassava (M. esculenta) are reported worldwide (Chap. 126).¹ Chronic manifestations include visual disturbances (amblyopia), upper motor neuron disease with spastic paraparesis, and hypothyroidism. These findings are associated with protein-deficient states and the use of tobacco and alcohol. The ataxic neuropathy resembles that produced by lathyrism (section Proteins, Peptides, and Lectins). A unifying hypothesis about the etiology of these two similar diseases from seemingly very different sources is that thiocyanate accumulation may lead to degeneration of the α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA)-containing neurons that are first stimulated and then destroyed in neurolathyrism.¹⁴¹

Similarly, seeds of cycads contain cycasin and neocycasin, which belong to the family of cyanogenic glycosides, as well as neurotoxins. The cyanogenic glycosides of cycads are considered pseudocyanogenic, with little potential to liberate hydrogen cyanide, but most typically produce violent vomiting 30 minutes to 7 hours after ingestion of 1 to 30 seeds.²⁶ On the island of Guam, indigenous peoples develop a devastating amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS-PDC) that appears associated with ingestion of Cycas circinalis seeds or the flying foxes that feed extensively upon the cycads.²⁹ The implicated xenobiotic originally was believed to be an excitatory amino acid, but more recently is identified as a sterol glycoside. Research on the mechanism of this cycad-induced disease is ongoing, with the goal of understanding potential mechanisms of this disease and its links to ALS and Parkinson disease.^19,28

Anthraquinone Glycosides: Sennoside and Others.

Anthraquinone laxatives are regulated both as nonprescription pharmaceuticals and as dietary supplements. These glycosides, such as sennoside, are metabolized in the bowel to produce derivatives that stimulate colonic motility, probably by inhibiting Na⁺-K⁺-adenosine triphosphatase (ATPase) in the intestine, which also promote accumulation of water and electrolytes in the gut lumen, producing fluid and electrolyte shifts that can be life threatening.¹⁴⁴

Other Glycosides: Salicin, Atractyloside, Carboxyatractyloside, Vicine, and Convicine.

Salicin is an inactive glycoside until it is hydrolyzed to produce salicylic acid (Chap. 39). The glycosidic bond is relatively resistant to stomach acid, and the hydrolysis must be accomplished by gut flora. The ability of individual human flora to produce the necessary enzymes varies significantly, resulting in variable clinical effects for salicin or plant material that contains salicin. However, sufficient hydrolytic capacity for some transformation of the glycoside into salicylic acid occurs in all individuals.

Atractylis gummifera was a favorite agent for homicide during the reign of the Borgias. Atractyloside, the toxic xenobiotic primarily inhibits oxidative phosphorylation in the liver by inhibiting the ADP/ATP antiporter blocking influx of adenosine diphosphate (ADP) into hepatic mitochondria and outflow of ATP to the rest of the cell (Chap. 12). Death or severe illness as a result of liver failure or hepatorenal disease following ingestion is reported.³² Callilepis laureola is a South African medicinal plant that contains atractyloside and carboxyatractyloside and is reported to cause human poisonings. Cocklebur (Xanthium strumarium) is an herbaceous plant with worldwide distribution. The seeds contain the glycoside carboxyatractyloside. The toxic mechanism is similar to that for atractyloside, and seed ingestion has resulted in human fatalities. Nine patients presented with acute onset abdominal pain, nausea and vomiting, drowsiness, palpitations, sweating, and dyspnea after cocklebur ingestion. Several patients developed hepatocellular damage, renal compromise and myocardial injury, and three developed convulsions followed by loss of consciousness and death.¹⁵¹

Favism is a potentially fatal disorder brought about by eating fava beans or vetch seeds (Vicia faba, Vicia sativa, respectively). These seeds contain the pyrimidine glycosides vicine and convicine (divicine is the aglycone of vicine). Consumption of these compounds by individuals with an inborn error of metabolism (glucose-6-phosphate dehydrogenase deficiency) can cause acute hemolytic crisis (Chap. 22).¹³⁵

The effects of the glycosides sinigrin (from Brassica nigra seed and Alliaria officinalis {horseradish} root) and naringen (a polyphenolic glycoside from the grapefruit Citrus paradisi) are discussed in the sections on Plant-Induced Dermatitis and Plant–Xenobiotic Interactions, respectively.

Terpenoids and Resins: Ginkgolides, Kava Lactones, Thujone, Anisatin, Ptaquiloside/Thiaminase, and Gossypol

Ginkgolides in Ginkgo biloba inhibits platelet aggregation. Reports of spontaneous bleeding associated with ingestion of Ginkgo leaf products as an herbal medicine are perhaps explained by this property.¹²³ Another xenobiotic found only in the seed, 4-methoxypyridoxine (pyridine alkaloid), is associated with seizures.⁷⁵ A mechanism similar to isoniazid-induced seizures is plausible, suggesting treatment with pyridoxine phosphate (Chap. 58) (Antidotes in Depth: A14). The dermal effects of Ginkgo are discussed in the section Plant-Induced Dermatitis.

Kava lactones are a family of terpene lactones found in kava (Piper methysticum) that cause central and peripheral nervous system effects. Kava has enjoyed a long, ceremonial history among islanders of the South Pacific, and observers visiting Oceania have recorded its acute and chronic effects (both pleasant and unpleasant) over the centuries. Importation of kava to Australia in 1983 was a measure to assist Aborigines with alcohol abuse problems. However, the kava itself became abused, and its subsequent ban has resulted in the growth of a black market for kava. Proposed mechanisms to explain the effects of kava lactones include effects at γ-aminobutyric acid type A (GABA_A) and GABA_B receptors or local anesthetic effects.¹²⁹ Acute symptoms following ingestion include peripheral numbness, weakness, and sedation. Chronic use leads to kava dermopathy and weight loss. More than 70 cases of hepatotoxicity, several requiring liver transplantation, are associated with both acute and chronic effects of kava extracts on cytochrome oxygenases or other yet-to-be-defined etiologies and prompted regulatory health measures in Europe and North America.¹⁴⁸

Thujone is one of many terpenes associated with seizures. It is found in the wormwood plant (Artemisia absinthium), in absinthe (the liquor flavored with A. absinthium), and in some strains of tansy (Tanacetum vulgare). The α- and β-isomers of thujone are believed to act much like camphor to produce CNS depression and seizures. Invoking the structural similarity of thujone to tetrahydrocannabinol (THC), one of the terpenoids of marijuana, to explain the psychoactive effects is controversial (Chap. 77).⁹⁷

Absinthism is characterized by seizures and hallucinations, permanent cognitive impairment, and personality changes. Acute and chronic absinthism led to a worldwide ban of the alcoholic beverage absinthe, which contained thujone, in the early 1900s.¹¹⁰ Over the past several years, there has been a reexamination of the role of absinthe in the seizure disorders previously attributed to this liquor. Modern analytical procedures have been used to analyze the thujone content of vintage absinthe and modern products made using vintage recipes. Results have largely concluded that thujone content in the liquor was likely to be too low to have produced symptoms.⁷⁸ However, because the essential oil of wormwood is composed almost exclusively of thujone, it, not absinthe, is a potent cause of seizures.¹¹⁰ Wormwood oil for making homemade absinthe is currently available and is responsible for at least two reports of adverse reactions in people seeking its hallucinatory or euphoriant effects.¹⁵⁸

Anisatin is found in Illicium spp. This terpenoid produces seizures as a noncompetitive GABA antagonist. The Chinese star anise (Illicium verum) is sometimes used in teas and occasionally is confused or contaminated with other species of Illicium, particularly Japanese star anise Illicium anisatum.⁷¹ These contaminations have resulted in small epidemics of tonic–clonic seizures, particularly, but not exclusively, in infants after use of the tea to treat their infantile colic. Recently, in the United States, a case series of at least 40 individuals who had consumed teas brewed from “star anise” experienced seizures, motor disturbances, other neurologic effects, and vomiting.⁷¹ These cases include at least 15 infants treated for infantile colic with this home remedy. This trend prompted the FDA to issue an advisory regarding the health risk from remedies sharing the common name “star anise.”

Ptaquilosides are found in the bracken fern (Pteridium aquilinum), a plant that is extending its range and density worldwide. In foraging animals, consumption of ptaquilosides results in acute hemorrhage secondary to profound thrombocytopenia, whereas thiaminases that are also found in the bracken fern result in cerebral disease.⁴⁷ Although no acute human poisonings are reported, these xenobiotics are transmitted through cow’s milk and are associated with increased prevalence of gastric and esophageal cancer in areas where fern is endemic and consumed by cows whose milk is not diluted.¹⁶³ Chronic toxicity through spore inhalation also produces pulmonary adenomas in animals. More recently, research defined links between alimentary cancer in humans who previously consumed bracken fern fiddleheads.

Gossypol is a sesquiterpene that is derived from cottonseed oil. It has been used experimentally as a reversible male contraceptive. The mechanism for its spermicidal effect is unclear, but the effects have been attributed to inhibition of plasminogen activation and plasmin activity in acrosomal tissue. These effects are not currently reported to produce systemic bleeding. Gossypol also inhibits 11-β-hydroxysteroid dehydrogenase, as does glycyrrhizin and may result in hypokalemia.¹⁶⁴

Proteins, Peptides, and Lectins: Ricin and Ricinlike, Pokeweed, Mistletoe, Hypoglycin, Lathyrins, and Microcystins

Lectins are glycoproteins that are classified according to their binding affinity for specific carbohydrate ligands, particularly galactosamines, and by the number of protein chains linked by disulfide bonds. Toxalbumins such as ricin and abrin are lectins that are such potent cytotoxins that they are used as biologic weapons (Chap. 133). Ricin, extracted from the castor bean (Ricinus communis; Fig. 121–3A), exerts its cytotoxicity by two separate mechanisms.⁹ The compound is a large molecule that consists of two polypeptide chains bound by disulfide bonds. It must enter the cell to exert its toxic effect. The B chain binds to the terminal galactose of cell surface glycolipids and glycoproteins. The bound toxin then undergoes endocytosis and is transported via endosomes to the Golgi apparatus and the endoplasmic reticulum. There the A chain is translocated to the cytosol, where it stops protein synthesis by inhibiting the 28S subunit of the 60S ribosome. In addition to the GI manifestations of vomiting, diarrhea, and dehydration, ricin can cause cardiac, hematologic, hepatic, and renal toxicity. All contribute to death in humans and animals.⁹ Despite the obvious toxicity of this compound, death probably can be prevented by early and aggressive fluid and electrolyte replacement after oral ingestion (but not injection or inhalation; Chap. 133). Allergic reactions to some of these lectin-bearing plants and their derivates are noted.

Just how lethal are ingestions of the ornamental seeds? The highest concentration of xenobiotic is in the hard, brown-mottled seeds. These seeds are both tempting and available, even to children in the United States, because they are attractive enough to be used to make jewelry, and their parent plants are showy enough to have been exported for horticultural purposes outside of their native India (including to the United States). Although mastication of one seed by a child liberates enough ricin to produce death, this outcome (or even serious toxicity) is uncommon, even if the seeds are chewed, probably because GI absorption of the xenobiotic is poor and supportive care is effective.⁵ Activated charcoal should be administered promptly following ingestion.

Other ricinlike lectins are found in Abrus precatorius (jequirity pea, rosary pea; Fig. 121–3B),³⁸ Jatropha spp,⁸² Trichosanthes spp (eg, T. kirilowii or Chinese cucumber), Robinia pseudoacacia (black locust),⁷⁰ Phoradendron spp (American mistletoe), Viscum album (European mistletoe), and Wisteria spp (wisteria). These all produce at least one double-chain lectin that binds to galactose-containing structures in the gut or inhibits protein synthesis in a manner similar to ricin.

The most commonly ingested toxic plant lectins in the United States are from pokeweed (Phytolacca americana; Fig. 121–3C), which is eaten as a vegetable but rarely causes toxicity or death. The mature, deep purple berries are less toxic. Pokeweed leaves are consumed after boiling without toxic effect if the water is changed between the first and second boiling (parboiling). When this detoxification technique is not followed, as in preparation of poke salad or pokeroot tea, violent GI effects can ensue 0.5 to 6 hours after ingestion. Nausea, vomiting, abdominal cramping, diarrhea, hemorrhagic gastritis, and death may occur. In addition, bradycardia and hypotension, perhaps induced by an increase in vagal tone, may be associated with nausea and vomiting.^65,121 Phytolaccatoxin and pokeweed mitogen are found in all plant parts, but the highest concentrations are found in the plant root. Pokeweed mitogen is a single-chain protein that inhibits ribosomal RNA by removing purine groups.¹⁴ It produces a lymphocytosis 2 to 4 days after ingestion that may last for 10 days, but is without clinical consequence.

Mistletoe berries, both American and European, can produce severe gastroenteritis, especially when delivered as teas or extracts, or particularly as parenteral antineoplastic medicinal agents in Europe. As festive holiday plants they become seasonally available for children. Poison center data suggest that ingestion of three to five berries or one to five leaves of the American species may not cause toxicity, but these suggestions are based on limited evidence (Chap. 136). Despite single reports of seizure, ataxia, hepatotoxicity, and death, most authors performing such retrospective examinations conclude that mistletoe exposures are not a highly consequential risk.¹⁴²

Hypoglycin A (β-methylene cyclopropyl-l-α-aminopropionic acid) and hypoglycin B (dipeptide of hypoglycin A and glutamic acid) are found in the unripe ackee fruit and seeds of Blighia sapida (Euphorbiaceae). The tree is native to Africa but was imported to Jamaica in 1778 and subsequently naturalized in Central America, southern California, and Florida. The scientific name of the plant derives from Captain William Bligh, the British explorer. Epidemics of illness (Jamaican vomiting sickness) associated with consumption of the unripe ackee fruit (raw and cooked) occur in Africa but are more common in Jamaica, where ackee is the national dish.⁷⁴ The most toxic part is the yellow oily aril of the fruit,²⁷ which contains three large, shiny black seeds. Cases may also be associated with canned fruit.⁹⁶ Hypoglycin A is metabolized to methylene cyclopropyl acetic acid, which competitively inhibits the carnitine–acyl coenzyme (CoA) transferase system.¹¹ This prevents importation of long-chain fatty acids into the mitochondria, preventing their β-oxidation to precursors of gluconeogenesis. β-Oxidation and gluconeogenesis are further arrested by inhibition of various enzymes, such as glutaryl CoA dehydrogenase, which blocks the malate shunt (Chap. 13). In addition, increased concentrations of glutaric acid may inhibit glutamic acid decarboxylase, which produces GABA from glutamic acid. This not only depletes GABA but also increases concentrations of excitatory glutamate to produce seizures. Insulin concentrations remain unaffected by hypoglycin and metabolites. Carboxylic and other organic acid substrates build up in the urine and serum as a result of these metabolic disturbances. Detection of these acids can help corroborate the diagnosis.¹¹ Jamaican vomiting sickness is characterized by epigastric discomfort and the onset of vomiting starting 2 to 6 hours after ingestion. Convulsions, coma, and death can ensue, with death occurring approximately 12 hours following consumption. Laboratory findings are notable for profound hepatic aminotransferase and bilirubin abnormalities, and aciduria and acidemia without ketonemia. Cholestatic hepatitis can occur and is reported with chronic use.⁸⁰ Autopsy reveals fatty degeneration of liver, particularly microvesicular steatosis, and other organs with depletion of glycogen stores. Left untreated, patient mortality reaches 80%, with 85% of the fatal cases suffering seizures. Treatment with dextrose and fluid replacement is essential. Benzodiazepines can control seizures, but may fail if the seizures are related to depletion of GABA. l-Carnitine therapy may exert a theoretical therapeutic role similar to that noted with valproic acid toxicity (Chap. 48) (Antidotes in Depth: A8).⁸⁵

The lathyrins β-N-oxalylamino-l-alanine (BOAA) and β-­aminopropionitrile (BAPN) are peptides from the grass pea (Lathyrus sativus) found in the seeds and leaves, respectively. BOAA produces neurolathyrism and BAPN produces osteolathyrism in individuals with a dietary dependence on this plant. Neurolathyrism is nearly indistinguishable from spastic paresis associated with consumption of improperly prepared cassava (section Cyanogenic Glycosides).^13,30 Thiol oxidation with depletion of nicotinamide adenine dinucleotide (NADH) dehydrogenase at the level of neuronal mitochondria (ie, excitatory AMPA receptors) may be the common etiology.¹⁴¹ Epidemics have occurred in Bangladesh, Ethiopia, Israel, and India. Exposure to BOAA results in degeneration of corresponding corticospinal pathways that becomes irreversible if consumption of undetoxified grass peas is not stopped early. BOAA stimulates the AMPA class of glutamate receptors to provide constant neuronal stimulation, eventual degeneration, and hence spasticity.¹⁶² BAPN affects bone matrix and leads to bone pain and skeletal deformities that develop in adulthood. These diseases occur in areas where the plants are endemic, the food is consumed for 2 months or more, and when diets are otherwise poor in protein and possibly in zinc.⁵⁷

Microcystins are found in several cyanobacteria (blue-green algae) belonging to various species of the genera Microcystis, Anabaena, Nodularia, Nostoc, and Oscillatoria. They elaborate a series of peptides called microcystins and nodularins (Nodularia spumigena).³⁹ These compounds produce hepatotoxicity by inhibiting phosphatases and causing deterioration of the microfilament function in hepatocytes, leading to cell shrinkage and bleeding into the hepatic sinusoids. Evidence indicates that these peptides are carcinogenic to humans. Although most cases of untoward effects from blue-green algae occur in animals, the potential for harm was demonstrated by use of microcystin-contaminated water in a dialysis unit in Brazil.⁷³ Unfiltered water was identified as the risk factor for liver disease in 100 patients who attended the dialysis center (Chap. 10). Fifty of these patients died of acute liver failure following early signs of nausea, vomiting, and visual disturbances. Of concern, certain species of cyanobacteria are harvested and consumed as health foods or may be consumed secondarily in fish.⁵⁸

Phenols and Phenylpropanoids: Coumarins, Capsaicin, Karwinskia Toxins, Naringenin and Bergamottin, Asarin, Nordihydroguaiaretic Acid, Podophyllin, Psoralen, and Esculoside

Phenols and phenylpropanoids represent one of the largest groups of plant secondary metabolites. Coumarins and their isomers are phenylpropanoids that are discussed in Chap. 60. Some coumarins are warfarinlike in their activity and are capable of producing a bleeding diathesis when plants containing them are consumed in sufficiently large quantities.⁶⁸ Lignans are formed when phenylpropanoid side chains react to form bisphenylpropanoid derivatives. Lignins are high-molecular-weight polymers of phenylpropanoids that bind to cellulose and provide strength to cell walls of stem and bark. Tannins are polymers that bind to proteins and divide into two groups: hydrolyzable and condensed forms.

Capsaicin is derived from Capsicum annuum or other species of chile or cayenne peppers. Capsaicin is a simple phenylpropanoid that causes release of the neuropeptide substance P from sensory C-type nerve fibers that act upon transient receptor potential (TRP) channels in diverse human tissues.¹⁵⁴ The immediate response to capsaicin is intense local pain and is the rationale for its use as “pepper spray.” Eventual depletion of substance P prevents local transmission of pain impulses from these receptors to the spinal cord, blocking perception of pain by the brain, explaining its use in postherpetic neuralgia.

Painful exposures to capsaicin-containing peppers are among the most common plant-related exposures presented to poison centers. They cause burning or stinging pain to the skin. If ingested in large amounts by adults or small amounts by children, they can produce nausea, vomiting, abdominal pain, and burning diarrhea. Eye exposures produce intense tearing, pain, conjunctivitis, and blepharospasm. Fatality is rare, but has occurred after inhalation and infusion.¹⁴⁰

Skin irrigation, dermal aloe gel, analgesics, and oral antacids are therapeutic agents that may be helpful as appropriate, but patients can be reassured that the effects are transitory and produce no long-term damage. Irritated eyes can be treated with irrigation and local analgesia, but generally resolve without sequelae within 24 hours.

Karwinskia toxins are found in plants commonly named buckthorn, coyotillo, tullidora, wild cherry, or capulincillo (Karwinskia humboldtiana). These xenobiotics are identified by their molecular weights (T-514, T-496, T-516, T-544). Toxicity has been known for more than 200 years. In 1920, an epidemic of deaths was reported after 20% of 106 Mexican soldiers died following ingestion of foraged Karwinskia fruits.⁹² The fruits are attractive to children. Epidemic poisonings have been reported in Central America and are possible wherever the shrub is found (in semidesert areas throughout the southwestern United States and in the Caribbean, Mexico, and Central America).⁸ Uncoupling of oxidative phosphorylation or dysfunction of peroxisome assembly and integrity is described as the mechanism of action of T-514 on Schwann cells. Each xenobiotic exhibits similar cytotoxic effects at the cellular level, but with tropism for different organs in animal models.⁹²

Within a few days of ingestion, a symmetric motor neuropathy ascends from the lower extremities to produce a bulbar paralysis that may lead to death. Deep-tendon reflexes are abolished in affected areas, but cranial nerve findings are absent. Distinction of this demyelinating motor neuropathy from Guillain-Barré syndrome, poliomyelitis, solvent, and other polyneuropathies is difficult without a history of the fruit ingestion,¹⁰⁸ but can be assisted by detection of T-514 in the blood of affected patients. The other recognized toxins are not detected in blood. Occasionally, axonal damage is observed, but demyelination is the predominant finding on biopsy. Nerve conduction studies always demonstrate loss or abolition of function in fast-conducting axons. Cerebrospinal fluid demonstrates normal protein, glucose, and cytology. Treatment is supportive, with mechanical ventilation as needed, and recovery typically is slow.

Naringin and naringenin are flavonoid, while bergamottin and 6′,7′-dihydroxybergamottin are furanocoumarin phenylpropanoids derived from grapefruit that inhibit CYP3A4 in gut and liver. Grapefruit juice consumption can increase circulating concentrations of drugs reliant on CYP3A4 for metabolic elimination, including carbamazepine, felodipine, and the statins. The most plausible mechanism is inhibition of enteric CYP3A4 and P-glycoprotein.¹¹¹ These effects are maximally achieved by a single glass of grapefruit juice.⁸⁹

Comedication with St. John’s wort resulted in decreased plasma concentrations of a number of xenobiotics.⁹⁰ Hyperforin is a phenylpropanoid found in St. John’s wort (Hypericum perforatum) and is associated with plant–xenobiotic interactions through strong induction of CYP3A4 mediated drug metabolism as well as induction of P-glycoprotein. These combinedmechanisms can cause subtherapeutic concentrations of xenobiotics meta­bolized via these pathways.

Asarin is a term sometimes used for the naturally occurring mixture of α- and β-asarones found in the root of Asarum europaeum, Asarum arifolium, and Acorus calamus (sweet flag). Essential oils of the plants have anthelmenthic and nematocidal activity, but putative euphoric and hallucinogenic effects that motivate recreational ingestion are in contrast to confirmed reports of unpleasant GI effects.¹⁵²

Nordihydroguaiaretic acid (NDGA) is associated with hepatotoxicity after ingestion of chaparral (Larrea tridentata).⁶⁰ Podophyllin and psoralens are phenylpropanoids discussed in the sections Antimitotic Alkaloids and Resins, and Plant-Induced Dermatitis, respectively.

Esculoside (also called esculin or aesculin) has triterpene saponin side chains and is believed to be the toxic component in horse chestnut (Aesculus hippocastanum). Horse chestnut extracts are used medicinally in patients with venous insufficiency. The therapeutic use of these extracts at high doses (> 340 μg/kg) is associated with renal failure or a lupuslike syndrome.⁶¹ Leaves, twigs, or horse chestnuts ingested by children or consumed as a tea by adults results in a syndrome that resembles nicotine intoxication. The syndrome consists of vomiting, diarrhea, muscle twitching, weakness, lack of coordination, dilated pupils, paralysis, and stupor. The mechanism of toxicity is not defined, but massive ingestion of horse chestnuts is suggested to be poisonous to a child.

Carboxylic Acids: Aristolochic Acids, Oxalic Acid, and Oxalate Raphides

Nitrophenanthrene carboxylic acids, collectively called aristolochic acids, are present in most members of the genus Aristolochia, including those used ornamentally and as traditional medicines. Consumption of these compounds can cause aristolochic acid nephropathy (AAN), a progressive renal interstitial fibrosis frequently associated with urothelial malignancies (Chap. 45).³⁷ Sources of exposure are via consumption of flour made from wheat contaminated with the seeds of Aristolochia clematis or other Aristolochia species (so called Balkan endemic nephropathy),⁶² or through use of certain traditional Asian medicines made from Aristolochia spp (Chinese herb nephropathy).³⁴

Oxalic acid is the strongest acid among the carboxylic acids found in living organisms. It forms poorly soluble chelates with calcium and other divalent cations. Higher plants have varying ability to accumulate these include both soluble and insoluble oxalates, and many contain crystals of calcium oxalate called raphides. Certain plant families, such as the Araceae, Chenopodiaceae, Polygonaceae, Amaranthaceae, and several of the grass families, are rich in oxalates. Human dietary sources include rhubarb, spinach, strawberries, chocolate, tea, and nuts. Human consumption of soluble oxalate-rich foods correlates with kidney stone formation.⁸⁴

The insoluble calcium oxalate raphides that are present in certain plants, usually in the Araceae family, are found in conjunction with a protein toxin that increases the painful irritation to skin or mucous membranes. This special manifestation is discussed in greater detail in the section Plant-Induced Dermatitis.

Alcohols: Cicutoxin

Cicutoxin, a diacetylenic diol, is found in Cicuta maculata (water hemlock), Cicuta douglasii (western water hemlock), and Oenanthe crocata (hemlock water dropwort). O. crocata is native to Europe where intoxications are reported and is now naturalized to the United States. Ingestion of any part of these plants constitutes the most common form of lethal plant ingestion in the United States. Hemlock has dominated plant-related fatalities among the most recent 10-year reviews of the AAPCC data and Centers for Disease Control and Prevention (CDC) plant-poisoning records (Chap. 135). In contrast to most plant exposures in humans, which tend to involve children, these ingestions usually involve adults who incorrectly identify the plant as wild parsnip, turnip, parsley, or ginseng.¹³⁴ All plant parts are poisonous at all times, but the tuber is especially toxic, and more so during the winter and early spring. Absorption of cicutoxin is rapid and occurs through the skin as well as through the gut. Although the mechanism is not fully understood, cicutoxin may noncompetitively inhibit GABA-chloride channels or block potassium channels.¹³⁴

Symptoms of mild or early poisonings consist of GI symptoms (nausea, vomiting, epigastric discomfort) and begin as early as 15 minutes after ingestion. Diaphoresis, flushing, dizziness, excessive salivation, bradycardia, hypotension, bronchial secretions with respiratory distress, and cyanosis occur and rapidly progress to violent seizures. Ingestion of as little as a 2-cm section of the sweet-tasting root of Cicuta can produce status epilepticus.¹³⁴ Other complications include rhabdomyolysis with renal failure and severe acidemia. Immediate gastric evacuation should be performed if practical, and benzodiazepines should be administered for seizures. No specific antidote exists; supportive and symptomatic care should be provided.

Unidentified Toxins

Consistent with the inherent complexity of plants and the relatively early stage of the science, identification of the active ingredient(s) involved in poisoning is not always possible. An epidemic of the irreversible lung disease bronchiolitis obliterans developed in Taiwan in 1994 that involved more than 200 dieters who had been eating Sauropus androgynous as a weight-loss vegetable. The effects were dose related (usually approximately 100 g/d) and manifested by month 7 after approximately 10 weeks of use.⁶⁹ The cases were associated with at least four deaths, in addition to pulmonary disease resulting in lung transplantation.⁸⁸ Torsade de pointes occurred in three patients, consistent with the plant’s high concentration of papaverine, a toxin that produces dysrhythmias in animals. Corticosteroid and bronchodilator therapy consistently failed to improve pulmonary symptoms. A report of a later outbreak in Japan noted that the plant was consumed in an uncooked state.¹⁰⁹

Milk sickness is a historic poisoning described by pioneer farmers. It was caused by transmission of the nontoxic ketone tremetone to humans via milk of animals grazing on white snake-root plants (Ageratina altissima, formerly Eupatorium rugosum). Tremetone is transformed into an unknown, unstable toxin by hepatic microsomal enzymes.⁸¹ Toxicity is cumulative. Milk sickness can be fatal in 1 to 21 days or is associated with a slow recovery marked by weakness for months or years, relapsing sometimes to death. A delay in the development of the lactating animal’s symptoms provided a lag time when xenobiotic-laden milk was taken from asymptomatic animals and thereby transmitted to humans before the problem was detected.

Breynia officinalis, the air potato or bitter yam (Dioscorea bulbifera) are associated with hepatotoxicity.⁸⁷ Black cohosh (Actaea racemosa) hepatoxicity is suggested in case reports, but causality is not established.¹⁴⁷

Consumption of the food star fruit (Averrhoa carambola) and preexisting renal insufficiency are associated with development of intractable hiccups, vomiting, motor disabilities, paresthesias, confusion, seizures, and death unless patients receive supportive care and hemodialysis.¹⁴⁹ The unidentified toxin appears to be neuroexcitatory and may be oxalate.^21,49 Charcoal hemoperfusion is reported to be successful but clearance was not determined and causality not confirmed.²⁴

Plant–Xenobiotic Interactions

By increasing the metabolic rate of CYP enzymes and P-glycoprotein, hyperforin in St. John’s wort (H. perforatum) decreases concentrations of several drugs including amitriptyline, cyclosporine, digoxin, indinavir, irinotecan, warfarin, phenprocoumon, alprazolam, dextrometorphan, simvastatin, theophylline, and oral contraceptives.¹¹⁴ Bergamottins and naringenin from grapefruit reduce activity of the CYP system enzymes and increase drug concentrations. Other Citrus species also appear to increase drug concentrations.⁶⁷

Pharmacodynamic interactions may be responsible for serotonin excess or mild serotonin syndrome when St. John’s wort is used concurrently with tryptophan or serotonin reuptake inhibitors.¹³² Additive effects also appear to be responsible for increased prothrombin time in patients taking G. biloba and various drugs that affect coagulation (eg, warfarin or aspirin) because the ginkgolides have antiplatelet activity.³⁵ Hawthorn (Crataegus spp), used medicinally for cardiac disorders, may produce an additive effect when taken concomitantly with digoxin, producing bradycardia. Excessive intake of broccoli provides enough vitamin K to competitively inhibit the effects of warfarin on vitamin K activation.

Sodium Channel Effects: Aconitine, Veratridine, Zygacine, Taxine, and Grayanotoxins

Several unrelated plants produce xenobiotics that affect the flow of sodium at the sodium channel. For instance, aconitine and veratrum alkaloids tend to open the channels to influx of sodium, whereas others (eg, taxine) tend to block the flow, and grayanotoxins both increase and block sodium flow.¹⁵⁵ The sodium channel opener aconitine from Aconitum spp or Delphinium spp has the most persistent toxicity and the lowest therapeutic index among the many active alkaloid ingredients of these toxic plants called aconite. Some of the related alkaloids are controlled medicinal substances in the People’s Republic of China and Taiwan.²⁵ Aconite has been abused for its psychoactive “out of body” effects and for suicide and homicide. These alkaloids should be suspected in potentially poisoned patients who manifest cardiac toxicity, paresthesias, and seizures.

The mechanism of action depends on the individual alkaloid. Some compounds block and others activate sodium channels. Aconitine itself opens the voltage-dependent sodium channel at binding site 2 of the α-subunit, initially increasing cellular excitability.⁵⁵ By prolonging sodium current influx, neuronal and cardiac repolarization eventually slows. It also has calcium channel–opening effects. Those alkaloids are used in Asian prescription medicines to treat dysrhythmias and pain by reducing the excitability of the cardiac conducting system and sensory neurons, respectively.²⁵

Approximately one teaspoon (2–5 mg) of the root may cause death. The aconitine alkaloids are rapidly absorbed from the GI tract, and the calculated half-life of aconitine is 3 hours.¹⁰² CNS symptoms typically progress from paresthesias to CNS depression, respiratory muscle depression, paralysis, and seizures. Nausea, vomiting, diarrhea, and abdominal cramping occur.⁸⁶ Cardiotoxicity resembles that caused by cardioactive steroidal glycosides, and typically progresses from bradycardia with atrioventricular conduction blockade to increased ventricular automaticity resulting in diverse tachydysrhythmias. Multifocal premature ventricular contractions, bidirectional ventricular tachycardia,¹³⁹ torsade de pointes, and ventricular fibrillation may occur.⁸⁶

A history of paresthesias or muscle weakness may be useful in differentiating aconitine toxicity from that caused by cardioactive steroids. Aconite poisoning can be diagnosed by detection of the alkaloids in urine by liquid chromatography-mass spectrometry.

Management should not be delayed while awaiting testing. Empiric use of digoxin-specific antibody fragments should be administered if cardioactive steroid poisoning is strongly considered, but these antibodies are ineffective for aconitine poisoning. Antidysrhythmic success with lidocaine is limited, and amiodarone is currently the antidysrhythmic of choice.⁸⁶ Orogastric lavage, activated charcoal, and preparation for cardiac pacing, bypass, or balloon pump assist should be used as indicated, given the potential for rapid cardiovascular deterioration.

Ingestion of veratridine and other veratrum alkaloids (from Veratrum viride and other Veratrum spp) generally results from foraging errors where the root appears similar to leeks (Allium porrum) and above-ground parts appear similar to gentian (Gentiana lutea) used for teas and wines in Europe.¹³³ Typical symptoms develop within an hour of ingestion and include headache followed by nausea, vomiting, and less frequently bradycardia and diarrhea. The mechanism of action is similar to that of aconitine (sodium channel opening) but the duration of effects is shorter.¹⁵⁵ Although severe toxicity has been reported, management is supportive with fluids, atropine, and vasopressors. Deaths are rare.

Zygacine from Zigadenus spp (death camus) and other members of the lily family produces the same toxic effects as veratridine alkaloids (vom­iting, hypotension, and bradycardia).¹⁵⁹ Symptoms begin 1 to 2 hours after ingestion and usually result from errors while foraging for onions because of the plant’s look-alike bulb.¹⁰¹ Treatment options are the same as above with veratrum alkaloids.

Taxine, derived from the yew, is another alkaloid mixture of sodium channel effectors that tend to close the channel (Taxus baccata) (Fig. 121–4). The toxicity of Taxus has been known since antiquity. Toxic alkaloids are contained within the bark, leaves, and hard central seed but not in the surrounding fleshy red aril, which partly explains the low rate of toxicity in reported cases of unintentional exposure.¹⁶¹ Taxine-derived alkaloids (eg, taxine A and B, isotaxine B, paclitaxel), taxane-derived substances (eg, taxol A and B), and glycosides (eg, taxicatine) are responsible for the toxic­ity of Taxus spp. Lethal oral doses (LD_min) of yew leaves in humans are ­estimated to be 0.6 to 1.3 g/kg of body weight, or 3.0 to 6.5 mg taxines/kg of body weight.^160,161 Suicide using leaves is reported despite the large number of leaves required.¹⁵⁷ Clinical manifestations of yew poisoning include dizziness, nausea, vomiting, diffuse abdominal pain, tachycardia (initially), and convulsions followed by bradycardia, respiratory paralysis, and death.

Paclitaxel (Taxol) is an alkaloid component of the relatively rare Pacific yew (Taxus brevifolia) that is used as an antitumor chemotherapeutic xenobiotic because of its ability to promote the assembly of microtubules and to inhibit the tubulin disassembly process in mitotic cells. Within one hour after ingestion, toxicity progresses from nausea, abdominal pain, bradycardia, and cardiac conduction delays to wide-complex ventricular dysrhythmias, paresthesias, ataxia, and mental status changes. Four prisoners who drank an extract of yew experienced profound hypokalemia, and two died of cardiac arrest.⁵¹ Animal models indicate that bradycardia is responsive to atropine, but wide-complex tachydysrhythmias are unresponsive to sodium bicarbonate.¹²⁴

Grayanotoxins (formerly termed andromedotoxins) are a series of 18 toxic diterpenoids present in leaves of various species of Rhododendron, Azalea, Kalmia (Fig. 121–5), and Leucothoe (Ericaceae). They exert their toxic effects via sodium channels, which they open or close, depending on the toxin.¹⁵⁵ Grayanotoxin I increases membrane permeability to sodium and affected calcium channels in a manner similar to that of veratridine (and batrachotoxin).⁷² Grayanotoxins can become concentrated in honey made in areas with densely populated grayanotoxin-containing plants, mainly in the Mediterranean. Accounts of poisoning by honey date back to at least 401 bc when Xenophon’s troops were incapacitated after they consumed honey made from nectar of Rhododendron luteum. Occasionally, grayanotoxin-containing plants or plant preparations rather than honey cause human poisonings. Bradycardia, hypotension, GI manifestations, mental status changes (“mad honey”), and seizures are described in patients or animals suffering grayanotoxin toxicity.⁶³

Antimitotic Alkaloids and Resins: Colchicine, Vincristine, and Podophyllum

Consumption of colchicine from plant sources such as autumn crocus (Colchicum autumnale) produces a spectrum of effects, including nausea, vomiting, watery diarrhea, hypotension, bradycardia, electrocardiographic abnormalities, diaphoresis, alopecia, bone marrow depression, renal failure, hepatic necrosis, acute respiratory distress syndrome, convulsions, and death.¹⁴⁶

Confusion of the bulbs or leaves of this plant with those of wild onions or garlic occur as a foraging error. Unintentional consumption by children and ingestion with suicidal intent account for the other cases involving morbidity or mortality. The mechanism of toxicity is the disruption of microtubule formation in mitotic cells.⁵³

Vincristine and vinblastine are two other indole alkaloids that are used as antineoplastics and are both isolated from the Madagascar periwinkle (Catharanthus roseus). No reports of poisoning by these alkaloids following ingestion of the plant could be found (Chap. 37).

Podophyllum resin is the dry, alcoholic extract of the rhizomes and roots of mayapple (Podophyllum peltatum) (Fig. 121–6). The dry resin ­consists of up to 20% podophyllotoxin, α- and β-peltatin, desoxypodophyllotoxin, and dehydropodophyllotoxin. These xenobiotics are originally present in the plant as β-d-glucosides. Podophyllum resin containing podophyllin is available by prescription for topical treatment of venereal warts. Its medicinal derivative, etoposide, is used for a range of neoplastic diseases. Podophyllum is used as a popular traditional Chinese medicine. Podophyllotoxins make up 20% of the resin from the roots of mayapple (P. peltatum). As a group, they disrupt tubulin formation, producing multisystem organ failure. Poisonings are caused by misidentification and adulteration, possibly because the list of common names by which it is known includes mayapple, as well as mandrake, wild mandrake, American mandrake, and European mandrake.⁵⁴ Catharsis is prominent after ingestion, but onset of symptoms may be significantly delayed. Acute, severe sensorimotor neuropathy and bone marrow suppression following transient leukocytosis can occur even after acute exposures and may be directly related to inhibition of microtubule assembly. Lethargy, confusion, encephalopathy, autonomic instability, sensory ataxia, and death are described following large exposures,¹⁰⁷ but poisoning has also occurred after “therapeutic” doses of a popular traditional Chinese medicine.¹¹⁴

Glutamic acid has been used to prevent vincristine-induced peripheral neuropathy and would be a reasonable therapy following podophyllin ingestion.¹⁰¹

Plant-Induced Dermatitis

A large number of plants result in undesirable dermal, mucous membrane, and ocular effects, and they represent the most common adverse effects reported to US poison centers and occupational health centers. Plant-induced dermal disorders can be readily categorized into four mechanistic groups, that is, dermatis that results from (1) mechanical injury, (2) irritant molecules that penetrate the skin, (3) allergy, or (4) photosensitivity (direct and hepatogenous) (Chap. 18).¹³⁰

There is much overlap between these categories (some plants can produce all types). Clinicians may have difficulty distinguishing between plant-induced dermatitis and skin disorders⁹⁴ or between plant-induced dermatitis and pseudophytodermatitides caused by arthropods, pesticides, or wax (used in fruit and vegetable packaging). Agents that cause adverse skin reactions can also cause eye and local gastric mucosal irritation.

Dermatitis from mechanical injury often is combined with primary or allergic contact dermatitis. Stinging nettles (Urtica dioica and other species) have a specialized apparatus in the form of an elongated silicious cell (glandular trichome) that acts like a hypodermic syringe to deliver irritant chemicals into the skin. Contact with these stinging hairs shears off the tip of the hair, producing micromechanical injury and releasing irritant contents: acetylcholine, histamine, and 5-hydroxytryptamine.⁴ Acute motor polyneuropathy associated with cutaneous exposure to Urtica ferox is reported within 48 hours of walking through a patch of the nettles, with recovery occurring over several weeks.⁶⁶ The barbed trichomes (spicules) of Mucuna pruriens (velvet bean, cowhage) evoke a histamine-independent itch that is mediated by a cysteine protease, mucunain.⁷⁹ Workers who handpick pineapples are subject to fissuring and loss of fingerprints after proteolytic enzyme bromelain exposure following dermal abrasion by raphides.

Exposures to commonly available household plants such as dumbcane (Dieffenbachia spp), Philodendron spp, and Narcissus bulbs can lead to mechanical injury and painful microtrauma produced by bundles of tiny needlelike calcium oxalate crystals called raphides.¹⁰⁶ Packages of hundreds of raphides called idioblasts contain proteolytic enzymes. Dieffenbachia (more than 30 species) (Fig. 121–7) exposures are commonly reported household or malicious plant exposures, although such exposures are rarely serious.¹⁰⁴ When the leaves are chewed, immediate oropharyngeal pain and swelling occur.³¹ Severe oral exposures can be excruciating and progress to profuse salivation, dysphagia, and loss of speech. Soothing liquids, ice, parenteral opioids, corticosteroids, and airway protection may be indicated, but antihistamines provide little relief. The edema and pain typically begin to subside after 4 to 8 days. Ocular exposure to the sap may produce chemical conjunctivitis, corneal abrasions, and, rarely, permanent corneal opacifications.

Similar exposures to oxalate raphide-containing household plants in the same family (Philodendron, Brassaia, Epipremnum aureum, Spathiphyllum, and Scheflera spp) are not as painful as those to dumbcane, presumably because the crystals are packaged differently and do not simultaneously deliver proteolytic enzymes.¹⁰⁶ One exception to their lower severity is a report of death in an 11 month-old child following complications arising from esophageal lesions induced by philodendron.⁹⁵

Irritant dermatitis can result from low-molecular-weight xenobiotics such as phorbol esters (from Euphorbiaceae) that directly penetrate the skin without antecedent mechanical injury. Similar penetrance is achieved by products of glycoside hydrolysis. For instance, hydrolysis of ranunculin gives rise to anemonin in Ranunculaceae, the buttercup family, and hydrolysis of sinigrin in plants in the mustard family Brassicaceae yields allyl isothiocyanate. Exposures to primary irritants in Brassicaceae and Ranuculaceae usually are mild. Alternatively, airborne contact dermatitis occurs in typically exposed sites such as the upper eyelids, neck, uncovered extremities, including antecubital fossae, and other skin folds (Chap. 18).⁹⁹

Phorbol esters found in spurges (Euphorbiaceae) are contained in milky sap that is capable of producing erythema, desquamation, and bullae. The saps of some species are more irritating than others. For instance, the manchineel tree (Hippomane mancinella), found in the Caribbean and Florida, once was planted on graves to deter grave robbers, and juice from the tree has been used to brand animals and to blind people. In addition to dermal and ocular injury,⁴⁶ ingestion of some spurges can induce severe GI injury. Poinsettia (Euphorbia pulcherrima), crown of thorns (Euphorbia splendens), candelabra cactus (Euphorbia lacteal), and pencil tree (Euphorbia tirucalli) are spurges found in the home as holiday or other ornamentation that rarely produce serious injury, despite reputations to the contrary. The poinsettia plant, for instance, gained a reputation of significant toxicity based on a single, inadequately documented case report from Hawaii in 1919, involving the death of a 2 year-old child.⁷ In a subsequent case, an 8 month-old child developed oral mucosal burns after chewing poinsettia.⁴⁵ Contact dermatitis, irritation of mucous membranes, and GI complaints such as nausea, vomiting, and abdominal pain are rare findings among the many reported exposures to poinsettia.

Allergic contact dermatitis results from type IV hypersensitivity response and, unlike irritant dermatitis, requires repeat exposures to the agent before symptoms manifest. The most infamous of these xenobiotics are the urushiol oleoresins derived from catechols that are found in G. biloba (Ginkgoaceae) and members of the Proteaceae (eg, Macadamia integrifolia) and the Anacardaceae. The latter family is notable for inclusion of poison ivy (Toxicodendron radicans), poison oak (Toxicodendron toxicarium, Toxicodendron diver-silobum), and poison sumac (Toxicodendron vernix),⁵⁹ as well as mango (Mangifera indica), pistachio (Pistacia vera), cashew (Ana­cardium occidentale), and Indian marking nut “Bhilawanol” (Semecarpus anacardium). Upon first exposure, urushiol resins penetrate the skin and react with proteins to form antigens to which the body forms antibodies. Upon reexposure to urushiol resins, inflammatory mediators are released, leading to urticaria, itching, swelling, and pain. In extreme cases, these reactions can progress to type I hypersensitivity. Cross-reactivity between allergens is possible, and particular vigilance is required in sensitive individuals.⁵² Prevention by removal of exposed objects that act as fomites for the oils and use of protective linaments are appropriate. Therapy includes washing with soap and water and corticosteroid creams and, for those frequently exposed, desensitization (Chap. 18).⁵⁹

Allergic contact dermatitis is the most common plant-induced occupational injury. In the United States, 33% of 462 floral shops surveyed reported that at least one employee had developed contact ­dermatitis.¹²⁸ Reactions are reported following exposure to tulips, Narcissus, Peruvian lily (Alstroemeria spp), and primroses (Primula spp). Exposure to the glycoside tuliposide A results in “tulip fingers,” the dry, painfully fissured hyperkeratosis of fingers observed in horticultural workers who chronically handle tulips.²⁰ Upon hydrolysis, this compound yields α-methylene-butyrolactone, the true allergen. Cross-reactivity is possible among some of these xenobiotics. Alstroemeria spp, a common ornamental called Peruvian lily, contain tuliposide A and thus can cross-react with antigens in those persons already allergic to tulips, producing an allergic contact dermatitis. Primin (2-methoxy-6-n-pentyl-p-benzoquinone) from members of the Primulaceae family was responsible for the most frequently reported allergic plant dermatitis in northern Europe until workers refused to stock primroses. The “wood cutters dermatitis” of loggers occurs with development of sensitivity to compounds in liverwort (Frullania spp), which is cross-reactive to usnic acid in lichens and mosses found on the wood. Cross-reactivity with common weeds such as ragweed (Ambrosia spp) or dandelion (Taraxacum spp) initiate the risk of hypersensitivity from members of the Compositae family.⁷⁶ A myriad of other types of plants are involved in producing occupational dermatitides.^106,128 Sensitivity to Compositae (daisy family) involves more than 600 sesquiterpene lactones in at least 200 of the 25,000 species in the family and is as ubiquitous as the distribution of species. Chrysanthemum allergy is a common occupational hazard in Europe.

Direct photosensitivity dermatitis is produced when compounds such as psoralens or other linear furocoumarins come into direct contact with the skin or are digested and become bloodborne to dermal capillary beds, where they interact with sunlight. These photosensitizing agents are activated by ultraviolet A radiation (320–400 nm), producing singlet oxygen and DNA adducts. In addition to severe sunburnlike symptoms (erythema, epidermal bullae), hyperpigmentation lasting for several months may result from exposure to these compounds. The mechanism by which this reaction is produced is unknown, but depletion of glutathione is postulated to indirectly stimulate melanogenesis by disinhibiting the normally suppressant tyrosinase.⁹¹ More than 200 of these xenobiotics have been identified in at least 15 plant families, including food sources, such as Apiaceae (anise, caraway, carrot, celery, chervil, dill, fennel, parsley, and parsnip), Rutaceae (grapefruit, lemon, lime, bergamot, and orange), Solanaceae (potato), and Moraceae (figs) family.

Hepatogenous photosensitivity is produced when a xenobiotic that normally is harmlessly ingested, absorbed, and hepatically excreted gains access to the peripheral circulation through failure of a liver excretion or detoxification mechanism. An example is the photosensitivity that occurs when phylloerythrin, a product of chlorophyll digestion normally eliminated in the bile, accumulates in the blood as a result of liver dysfunction. The cyanobacterium Microcystis aeruginosa, as well as the plants Lantana camara, Tribulus terrestris, and Agave lecheuilla reportedly cause this type of photosensitization in animals.

• Plant exposures are among the commonest human exposures but also typically have the least morbidity and mortality.

• Plant xenobiotics can be organized by the principles of pharmacognosy.

• Some xenobiotics act directly or are metabolized to toxic principles such as tremetone, whereas others are toxic through secondary contact in animal meat or milk such as coniine, nitrates, pyrollizidine alkaloids, and ptaquiloside.

• Some reassurance can be achieved by excluding exposure to the most life-threatening plants.

Acknowledgments

Mary Emery Palmer, MD, and Joseph M. Betz, PhD, contributed to this chapter in previous editions.

References