What are pyrrolizidine alkaloids, are they dangerous and what is being done to reduce the risk of contamination?
Recent news reported herbal products having been found to be contaminated with so-called pyrrolizidine alkaloids. One of these findings even led to a recall of six batches of an herbal product containing St John’s Wort in February this year (MHRA, 2016). What are pyrrolizidine alkaloids, why are they so dangerous and what is being done to reduce the risk of contamination?
What are pyrrolizidine alkaloids?
Alkaloids are biologically active chemical compounds which may have some pharmacological activity, are often toxic, and, in many cases, have medicinal or ecological use. Alkaloids are generally non-toxic to the organisms producing them, making their toxicity selective and dependent on different organisms as well as the chemical structure of alkaloids themselves.
Chemically, pyrrolizidine alkaloids (PAs) are made up of two entities – a basic amino alcohol part, referred to as a necine (or the pyrrolizidine nucleus), and one or more acids (necic acids) that esterify the alcohol groups of the necines (Huxtable, 1980; Ober & Kaltenegger, 2009).
Pyrrolizidine alkaloids in plants
Around 700 PAs and their derivatives are known to be present in over 6,000 flowering plant species. Thirteen plant families have been reported to include PA-producing species, specifically Asteraceae, Fabaceae and Boraginaceae. Common examples are Senecio, Heliotropium, and Symphytum, but also animal products, such as honey and eggs, from animals that forage on these species may end up containing traces of PAs. Pyrrolizidine alkaloids are toxic to foreign organisms, but not all are created equal. Some PAs are hepatotoxic, others are carcinogenic, mutagenic, pneumotoxic, genotoxic, fetotoxic and teratogenic to varying degrees. However, PAs without the 1,2-double bond do not show these toxicities. About 50% of all PAs fall into the toxic, the other half into the harmless category (Brown, 2015; Fu, et al., 2004; Chojkier, 2003; Stewart & Steenkamp, 2001; Huxtable, 1980; Mattocks, 1968).
Contamination of herbal products with PAs is not a new phenomenon, however, nowadays highly sensitive analytical methods will detect even minute amounts of PAs in food and medicines. Many episodes of human and animal intoxication were shown to be caused by PAs. First scientific evidence for ragwort (Senecio jacobaea, Asteraceae) causing chronic liver disease in livestock was provided at the beginning of the 20th century. Seeds and dust from plants producing PAs growing as weeds can contaminate cereal grains. Liver damage in humans caused by cereals contaminated by seeds of Senecio spp. and seeds and dust from heliotrope or turnsole (Heliotropium lasiocarpum, Boraginaceae) has been reported in the 1920s and 30s from South Africa and the former Soviet Union, and from Afghanistan and Tajikistan in the 1970s and 90s, respectively. But there is also potential for PAs to occur in other foods. For instance, honey derived from the flowers of PA-containing plants has been shown to contain PAs, and also milk, meat, teas, salads, as well as eggs may contain PAs as carry-over from contaminated feed (Aniszewski, 2007; Wiedenfeld, et al., 2008; HMPC, 2014). Furthermore, medicinal plants containing PAs have been found to potentially cause significant liver damage, especially in children. Recently, PA contamination has been found in various plant materials of various origins at an increasing rate (Bodi, et al., 2014). It has also been demonstrated that PAs can reside in soil (from decayed plant material or mulch) and taken up and stored by crops which otherwise do not themselves contain PAs (Selmar, 2015).
On the other hand, PA-containing plants play an important role in their ecosystem. For instance, PA-containing species are visited by a range of generalist pollinators like bumblebees and honeybees (Irwin, et al., 2014). However, feeding only on the pollen of one species is not typical of bee behavior or natural honey production. Additionally, nectar and pollen contain considerably lower levels of alkaloids compared to other plant parts. Thus, the accumulation of alkaloids in honey is low in natural environmental conditions (FSANZ, 2016). Danaine (e.g., Monarch) and Ithomiine butterflies gather PAs and utilize them for biosynthesis of their major pheromone components and other purposes. Courtship behavior and successful mating depends on their release of these pheromones (Bropée, 1986; Irwin, et al., 2014; Harborne, 2001). Certain standards and certifications (e.g., organic wild, and FairWild) require maintaining or improving the biodiversity of the harvesting areas. If PA-containing plants are removed from the ecosystem, are we then working against biodiversity conservation and long-term survival of pollinators? In the US, for instance, the eastern, migratory population of monarch has declined by about 80% in the ten years since 2005. It has been estimated that ‘the population has a substantial probability of quasi-extinction, from 11–57% over 20 years’ (Semmens, et al., 2016).
Dangers and risks
So, what is the real danger and what is done to protect the consumer? Regulators around the world have addressed the issue by setting contamination limits for herbal products which adequately ensure consumer safety. European regulations have recently been summarized in a statement of the European Medicines Agency’s Committee on Herbal Medicinal Products (HMPC) (HMPC, 2016). HMPC considers PA contamination a resident phenomenon, however, human intake, while constant, must be fairly low in view of the epidemiological relevance of reported incidences of liver damage caused by PAs. Nevertheless, a transitional limit of PA intake from herbal medicinal products based on a safety factor of 10,000 has been set to 1 µg/day, which is currently adopted throughout the European Community. HMAC furthermore recommends risk management strategies ranging from strict adherence to God Agricultural and Collection Practices (GACPs) to regular tests to be conducted on at-risk crop species (HMPC, 2016).
Considering that the contamination risk originates in the wild or in the field, this is where risk management needs to start. GACPs stipulate cultivation, harvesting/collection, and storage/processing practices, strict adherence to which already minimizes the contamination risk. The Codex Committee on Contaminants in Foods of the Joint FAO/WHO Food standards Programme has developed a detailed Code of Practice (CoP) with focus on enhanced aspects of GACP specific to weed control, including agricultural measures such as selective herbicides, manual weeding/sorting, seed cleaning, inspection of fields before harvesting etc. (HMPC, 2016; EFSA, 2011; Codex Alimentarius Commission, 2014). Organic practices may very well prove superior in weed control compared to conventional methods.
In summary: the risk of contamination of herbal raw materials with PAs is real, and so is their toxicity. Even though the likelihood of serious intoxication is low, adherence to enhanced GACPs is paramount, as is the manufacturer’s obligation to educate and control their supply chain. With official limits in place guaranteeing consumers’ safety, regular tests conducted on raw materials and finished products should eliminate the contamination risk without the need for leading a ‘war’ on PA-containing plants and thus negatively impacting the balance of our ecosystem.
- Aniszewski, T., 2007. Alkaloids – Secrets of Life. Alkaloid Chemistry, Biological Significance, Applications and Ecological Role. Amsterdam & London: Elsevier.
- Bodi, D. et al., 2014. Determination of pyrrolizidine alkaloids in tea, herbal drugs and honey. Food Additives & Contaminants: Part A., Issue 31(11), pp. 1886-95.
- Bropée, M., 1986. Insects pharmacophagously utilizing defensive plant chemicals (pyrrolizidine alkaloids). Naturwissenschaften, Issue 73(1), pp. 17-26.
- Brown, A., 2015. Relative Toxicity of Select Dehydropyrrolizidine Alkaloids and Evaluation of a Heterozygous P53 Knockout Mouse Model for Dehydropyrrolizidine Alkaloid Induced Carcinogenesis. PhD Thesis: Utah State University.
- Chojkier, M., 2003. Hepatic sinusoidal-obstruction syndrome: toxicity of pyrrolizidine alkaloids. Journal of hepatology, Issue 39(3), pp. 437-46.
- Codex Alimentarius Commission, 2014. Code of Practice for Weed Control to Prevent and Reduce Pyrrolizidine Alkaloid Contamination in Food and Feed, Rome: Codex Alimentarius Commission Secretariat.
- EFSA, 2011. EFSA Scientific Opinion on Pyrrolizidine alkaloids in food and feed. EFSA Panel on Contaminants in the Food Chain (CONTAM). EFSA Journal, Issue 9(11), pp. 1-134.
- FSANZ, 2016. Natural contaminants in honey, s.l.: Food Standards Australia and New Zealand (FSANZ).
- Fu, P., Xia, Q., Lin, G. & Chou, M., 2004. Pyrrolizidine alkaloids—genotoxicity, metabolism enzymes, metabolic activation, and mechanisms. Drug metabolism reviews, Issue 36(1), pp. 1-55.
- Harborne, J., 2001. Twenty-five years of chemical ecology. Natural Product Reports, Issue 18, pp. 361-79.
- HMPC, 2014. Public statement on the use of herbal medicinal products containing toxic, unsaturated pyrrolizidine alkaloids (PAs), s.l.: EMA, Committee on Herbal Medicinal Products (HMPC).
- HMPC, 2016. Public statement on contamination of herbal medicinal products/traditional herbal medicinal products with pyrrolizidine alkaloids. Transitional recommendations for risk management and quality control, s.l.: EMA, Committee on Herbal Medicinal Products (HMPC).
- Huxtable, R., 1980. Herbal teas and toxins: novel aspects of pyrrolizidine poisoning in the United States. Perspectives in biology and medicine., Issue 24(1), pp. 1-4.
- Irwin, R. et al., 2014. Secondary compounds in floral rewards of toxic rangeland plants: impacts on pollinators. Journal of Agricultural and Food Chemistry, Issue 62(30), pp. 7335-44.
- Mattocks, A., 1968. Toxicity of pyrrolizidine alkaloids. Nature, Issue 217, pp. 723-8.
- MHRA, 2016. Precautionary recall – six batches of St John’s Wort Tablets. [Online] Available at: https://www.gov.uk/government/news/precautionary-recall-six-batches-of-st-johns-wort-tablets
- Ober, D. & Kaltenegger, E., 2009. Pyrrolizidine alkaloid biosynthesis, evolution of a pathway in plant secondary metabolism. Phytochemistry, Issue 70(15), pp. 1687-95.
- Selmar, D., 2015. Die Aufnahme von Pyrrolizidinalkaloiden aus dem Boden: Ein Beispiel für den horizontalen Transfer von Naturstoffen. s.l., s.n.
- Semmens, B. et al., 2016. Quasi-extinction risk and population targets for the Eastern, migratory population of monarch butterflies (Danaus plexippus). Scientific reports, Issue 6, pp. 1-7.
- Stewart, M. & Steenkamp, V., 2001. Pyrrolizidine poisoning: a neglected area in human toxicology. Therapeutic drug monitoring, Issue 23(6), pp. 698-708.
- Wiedenfeld, H., Roeder, E., Bourauel, T. & Edgar, J., 2008. Pyrrolizidine alkaloids: structure and toxicity. Bonn: V&R Unipress