Pyrrolizidine alkaloids - an “urgent public health concern”?
Pyrrolizidine alkaloids (PAs) are a little-known but potentially deadly class of plant toxins with the potential to harm users of a wide range of plant-based foods, beverages and dietary supplements. In this article, we provide an introduction to pyrrolizidine alkaloids, their toxic effects, and how PAs can contaminate food supplies. We also examine the risks of pyrrolizidine alkaloid poisoning and the dangers posed by consuming products containing high levels of PAs. Finally, we discuss existing regulation of PAs, non-compliance, and what new testing standards might mean for the multi-billion dollar natural products and botanicals industry.
What are pyrrolizidine alkaloids?
Pyrrolizidine alkaloids (PAs) are a class of bitter tasting chemicals that are produced by about three per cent of all flowering plants as a defence against herbivores, such as grazing animals and insects. More than 660 PAs have to date been identified in over 6,000 plant species, mainly in the Asteraceae- (daisy), Boraginaceae- (borage or forget-me-not), and Apocynaceae (dogbane) families, as well in the genus Crotalaria of the Fabaceae (legume, pea and bean) family. While such plants may gain an evolutionary advantage from the presence of PAs, some PA alkaloids are dangerous to human health because of their strong hepatotoxic, genotoxic, cytotoxic, tumorigenic, and neurotoxic characteristics. It is these toxic pyrrolizidine alkaloids - known as 1,2 unsaturated PAs, 1,2-dehydropyrrolizidine ester alkaloids, or dehydroPAs – that manufacturers of foods, beverages and supplements produced from plants need to beware of.
Toxic effects of pyrrolizidine alkaloids
Once bioactivated in the liver, PAs interrupt the transmission of neuronal signals by affecting neuronal receptors, ion channels and enzymes responsible for the degradation of neurotransmitters and second messengers. They can also intercalate (bind) to DNA, stop protein synthesis, induce apoptosis and inhibit the activity of enzymes involved in carbohydrate metabolism.
Chronic poisoning from PAs is most common: causing liver damage, hepatic and pulmonary vein occlusions and damage to blood vessels, as well as potentially harming the kidneys, the gastrointestinal tract, bone marrow, and pancreas. Acute PA poisoning is deadly in around a fifth of human cases, “while 50% recover and the remaining 30% can develop chronic hepatic veno-occlusive disease years after poisoning.”
The presence of pyrrolizidine alkaloids in food supplements and dried plants is also a concern because of links between PAs and cancer. Many PA-containing plants and PA compounds have been tested in animal models and shown to be carcinogenic in different tissues: mainly the liver, but also the lungs, kidneys, skin, bladder, brain and spinal cord, etc. Studies conducted on fruit flies indicate that PAs are mutagenic and genotoxic, while rats and mice fed riddelliine showed a significant increase in both cancers and tumours.
Routes of contamination
PAs are among the most significant naturally occurring toxins, due to the ease with which they spread throughout the food chain – often through the accidental co-harvesting of PA producing weeds and seeds, and “especially in agricultural and minimally processed foods and food supplements.” The common sources of human exposure to PAs include salad crops and cereals contaminated with PA-containing weeds or seeds - together with herbal products, supplements and teas prepared from, or contaminated by, PA-containing plants. Even plants that do not produce PAs can still absorb them if grown on soil containing decomposing PA-containing varieties – as shown by by a 2016 study that showed peppermint, chamomile and parsley all exhibited marked concentrations of PAs soon after being mulched with dried common ragwort.
Livestock can also be affected by grazing on PA-containing plants - meaning that milk, cheese, meat, offal and eggs can also contain pyrrolizidine alkaloids, although PA levels in animal-derived foods tend to be lower than those in cereal- and plant-based products. Additionally, honey is a potential source of human exposure to PAs, as “Pyrrolizidine alkaloids may be present in the nectar of flowers (and) when honeybees forage nectar containing these alkaloids...honey becomes a source of pyrrolizidine alkaloids for both honeybees and humans who consume it.” In 2020, a study found that 58% of 375 honey samples purchased in mainland China and Taiwan contained PAs - predominantly the suspected carcinogen monocrotaline, echimidine, and lycopsamine - with total PA content ranging from 0.2–281.1 μg/kg. The presence of monocrotaline is a particular concern as, despite being evaluated by IARC as carcinogenic in rats, it is not mentioned either in EU regulations or by the current AOAC International (AOAC) working party on new global PA standards (see below for more).
The risk of pyrrolizidine alkaloid poisoning
As Molyneux et al. point out, “Contamination of grain crops with dehydroPA-producing plants has resulted in large-scale incidents of food poisoning in humans, with high morbidity and mortality, especially in Africa and in central and south Asia.” These “episodic and catastrophic” outbreaks of pyrrolizidine alkaloid poisoning are a fact of life in developing countries, and can involve thousands of people (as in India in 1972, Tajikistan in 1992, and on several occasions in Afghanistan since the 1970s). Afghanistan also saw “a multitude of cases” of pyrrolizidine alkaloid poisoning in 2010 that were attributed to cereal crops contaminated with Heliotropium species capable of forming PAs. According to the German Federal Institute for Risk Assessment (BfR), “poisonings have also been associated with the consumption of certain herbs used as part of traditional Chinese medicine, which either contain 1,2-unsaturated PAs themselves or are confused with or contaminated with PA-rich wild herbs.” PAs characteristic of Heliotropium and Crotalaria species have also been detected in qurut - a goat’s milk cheese common in Central Asia.
In the West, the occurrence of PA poisoning is rare, and the risk of acute events considered low. A New Zealand study of the dietary risks of PAs in honey concluded that “Over a lifetime basis, the average exposure an individual will receive through honey consumption is considered within tolerable levels.” However, it added that “there are uncertainties over high and brand-loyal consumers, and other dietary contributors (and so) risk management approaches to limit or reduce exposures through honey are still of value.”
The European Medicines Agency (EMA) also points out that, “Depending on individual preferences in food selection, great variability of PA exposure in humans is likely” - meaning that consuming certain products containing high levels of PAs can greatly increase the risk of exposure overall. For example, according to the BfR, using herbs “could contribute considerably to both long- and short-term exposure to 1,2-unsaturated PAs”, as “especially high concentrations have been observed in borage, oregano, and lovage in particular, and in mixed spices.”
This risk is further increased by the numbers of products containing high levels of PAs that continue to be - sometimes illegally - exported around the globe. During 2024, there were 65 notifications to the European Union (EU) Rapid Alert System for Food and Feed (RASFF)regarding teas, cocoa products, seeds, herbs, spices, food supplements, and dietetic or novel foods contaminated with PAs - 53 of which were regarded as serious or potentially serious.
“We conclude that (EU) legislation is not being complied with...”
Tabuas et al. meanwhile noted that one sample of organic oregano and one of ground cumin reported to RASFF in 2023 had exceeded the maximum permitted limit for PAs by 60 and 24 times, respectively. “We conclude that (EU) legislation is not being complied with and that strict control is urgently needed to ensure food safety (and) avoid animal and human exposure to PAs,” they wrote. In January this year the EU increased its controls for PAs in dried oregano from Turkey to 30% of shipments, while demanding that all consignments of cumin seeds from that country have an official certificate stating compliance with EU PA limits.
The fast-growing market in dietary supplements also presents risks to both producers and consumers. According to the Drug Induced Liver Injury Network (DILIN), which is funded by the US National Institutes of Health, botanical dietary supplements accounted for 20% of documented liver injury cases in 2017: a substantial increase from 7% in 2004-5. The dietary supplements industry has been plagued by reports of products being mislabelled, adulterated and bulked up, and of manufacturers who “often fail to comply with basic manufacturing standards, such as establishing the identity, purity, or composition of the final product.” In their review of PAs in natural products, Lis-Cieplak et al. concluded that “The market for foods classified as dietary supplements is developing dynamically (but) there is a misconception that these products are always safe and side-effect free.”
Is more regulation coming?
Under Regulation 2023/915, the EU currently sets out maximum permitted levels – ranging from 1.0 to 1,000 ug/kg - for 35 PAs in a range of botanical goods, including herbs, spices, teas, herbal infusions and food supplements. The United States Food and Drug Administration has banned edible products containing, or originating from, the comfrey plant, while Japan has also prohibited the commercialisation of comfrey, including its use in food. In Australia and New Zealand, PAs including Crotalaria, Echium plantagineum, Echium vulgare and Heliotropium may not be added to foods, while both countries employ a system of mixing honeys in order to reduce PA concentrations.
However, scientists with expert knowledge of PAs have criticised the current state of global regulation as wholly inadequate - even where comparatively robust rules apply. “The consumption of PAs and their N-oxides... is an urgent and major public health concern that needs to be addressed,” Tabuas et al. argue. “Contamination levels in various matrices have been exceeded on a large scale (but) harmonized regulations can help ensure food safety for consumers and facilitate international trade.”
Significantly, the influential standards organisation AOAC also believes that better regulation of pyrrolizidine alkaloids is required. In 2022, it announced the formation of a working group to develop “voluntary consensus standard(s) and methods for the 35 PAs in teas, herbal infusions, herbs, seed spices, and botanical dietary supplement ingredients”, arguing that existing quantitative testing approaches were “complex, costly”, and incomplete. AOAC also predicted that the working group would become “a driving force for development of internationally recognized Official Methods of Analysis” – and would “help companies meet the newly adapted regulatory compliance levels, allow consumers to be more confident in trusting product labels, and give suppliers confidence in the integrity of product(s) they sell.”
LGC Standards – supporting pyrrolizidine alkaloid testing in natural products
LGC Standards’ expert scientists are constantly developing our product range to support research and analysis into natural products - enabling laboratories to protect both consumers and the profitability of plant-based foods and dietary supplements.
We provide more than 2,500 reference materials and research standards for phytochemicals, including 300+ alkaloid products and a pyrrolizidine alkaloids mixture that exactly matches the 21 named non co-eluting analytes required by EU regulations. We also supply a range of more than 40 stable isotope labelled alkaloids - including deuterium labelled lycopsamine, as well as labelled and unlabelled monocrotaline.
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