Pyrrolizidine alkaloids (PAs) are natural components of many plants, some of which are also used medicinally. A few years ago, high levels of 1,2-unsaturated PAs were detected in teas and herbal teas. The medicinal plants in the tea blends do not actually produce PAs. Thus, the proven contamination was caused by weeds (harvested at the same time). The properties and effects of PA have been the focus of many scientific studies in recent years. The topic is whether and to what extent liver-damaging, mutagenic, embryo-damaging and cancer-promoting or carcinogenic effects arise. Against the background that a complete avoidance of PA contamination is not possible according to the current state of the art and therefore preventive measures are of essential importance, a Code of Practice was developed jointly by the processing industry and growers.
This describes possible risks of PA contamination and corresponding possibilities of influence along the entire process chain. All process participants from the areas of cultivation, post-harvest treatment, drug processing and the production of extracts or finished medicinal products are involved. The occurrence of PA contamination in plant materials, including those used for the production of herbal medicinal products, has triggered a research project “Investigation of the hepato-cytotoxic and genotoxic potency of selected pyrrolizidine alkaloids, relevant in medicinal plants and preparations thereof” of Kooperation Phytopharmaka with the Department of Chemistry – Food Chemistry & Toxicology (Working Group Prof. Dr. Dr. Dieter Schrenk) of the Technical Institute of Technology University of Kaiserslautern. Within the framework of the project, work was carried out to investigate the relative toxic potency of relevant PAs with regard to their hepatocellular toxicity and genotoxicity by using in vitro models (cell cultures) and to develop model ideas for the transfer of the results to humans. A risk assessment on a solid, scientific basis was urgently needed, especially because some PAs were classified as genotoxic carcinogens. The project started in 2019 and ended in 2022.
Project goal achieved in 2021
On 16 August 2021the HMPC published its Public statement on the use of herbal medicinal products1 containing toxic, unsaturated pyrrolizidine alkaloids (PAs) and states: „the HMPC agreed that an acceptable intake equivalent to 1 μg/day for an adult can be used as the limit for oral intake of PAs“.
This permanently raised the limit value to 1.0 μg PA per day.
In an announcement dated 1 March 2023 (Bekanntmachung zur Prüfung des Gehalts an Pyrrolizidinalkaloiden zur Sicherstellung der Qualität und Unbedenklichkeit von Arzneimitteln, die homöopathische Zubereitungen aus pflanzlichen Ausgangsstoffen als Wirkstoffe enthalten) the BfArM recognises this increase and implements the HMPC requirements nationally.
Essential oils and PAs
An exception to the tests for PAs are essential oils with pharmaceutical quality: „essential oils of pharmaceutical quality contained in HMPs (either as active ingredient or as excipient) would not need to provide specifications concerning PA content.”
As Giera et al. show in their article Quantitative Removal of Pyrrolizidine Alkaloids from Essential Oils by the Hydrodistillation Step in Their Manufacturing Process, pharmaceutical grade essential oils do not contain PAs due to their manufacturing process.
Further information
Schrenk D, Fahrer, J Allemang A et al. Toxins in Botanical Drugs and Plant-derived Food and Feed – from Science to Regulation: A Workshop Review. Planta Med 2024 Jan; doi: 10.1055/a-2218-5667.
Haas M, Wirachowski K et al. Potency ranking of pyrrolizidine alkaloids in metabolically competent human liver cancer cells and primary human hepatocytes using a genotoxicity test battery. Genotoxicity and Carcinogenicity 2023 Mar; doi: https://doi.org/10.1007/s00204-023-03482-8
Bundesverband der Arzneimittelhersteller e.V., Bundesverband der Pharmazeutischen Industrie e.V. (Hg) Mögliche Kontaminationen mit Pyrrolizidinalkaloiden: Anforderungen an die produktspezifische Dokumentation der Qualitätskontrolle Aktualisierte Empfehlungen der Verbände BAH und BPI. 2023 November
Haas M, Wirachowski K, Thibol L, Küpper JH, Schrenk D, Fahrer J. Potency ranking of pyrrolizidine alkaloids in metabolically competent human liver cancer cells and primary human hepatocytes using a genotoxicity test battery. Arch Toxicol. 2023 May;97(5):1413-1428. doi: 10.1007/s00204-023-03482-8. Epub 2023 Mar 16. PMID: 36928417
Haas M, Ackermann G, Küpper JH, Glatt H, Schrenk D, Fahrer J. OCT1-dependent uptake of structurally diverse pyrrolizidine alkaloids in human liver cells is crucial for their genotoxic and cytotoxic effects. Arch Toxicol. 2023 Dec;97(12):3259-3271. doi: 10.1007/s00204-023-03591-4. Epub 2023 Sep 7. PMID: 376763
Gao Lan Structure-dependent relative toxic potencies of selected pyrrolizidine alkaloids. Dissertation, 2022.
Schrenk D, Fahrer J et al. Novel Insights into Pyrrolizidine Alkaloid Toxicity and Implications for Risk Assessment: Occurrence, Genotoxicity, Toxicokinetics, Risk Assessment–A Workshop Report. Planta Med. 2022 Feb;88(2):98-117. doi: 10.1055/a-1646-3618. Epub 2021 Oct 29. PMID: 34715696
Giera, D., Preisitsch, M., Brevard, H., Nemetz, J. Quantitative Removal of Pyrrolizidine Alkaloids from Essential Oils by the Hydrodistillation Step in Their Manufacturing Process. Planta Medica 2021.
Rutz L, Gao L, Küpper JH, Schrenk D. Structure-dependent genotoxic potencies of selected pyrrolizidine alkaloids in metabolically competent HepG2 cells. Arch Toxicol. 2020 Dec;94(12):4159-4172. doi: 10.1007/s00204-020-02895-z. Epub 2020 Sep 10. PMID: 32910235
Gao L, Rutz L, Schrenk D. Structure-dependent hepato-cytotoxic potencies of selected pyrrolizidine alkaloids in primary rat hepatocyte culture. Food Chem Toxicol. 2020 Jan;135:110923. doi: 10.1016/j.fct.2019.110923. Epub 2019 Oct 28. PMID: 31672516
Steinhoff B. Pyrrolizidinalkaloid-Kontaminationen in Arzneipflanzen. Umsetzung regulatorischer Anforderungen bei der Produktion pflanzlicher Arzneimittel. Zeitschrift für Phytotherapie 2020; 41: 1–9.
Schrenk, D., Gao, L., Lin, G., Mahony, C., Mulder, P. P. J., Peijnenburg, A., Pfuhler, S., Rietjens, I. M.C. M., Rutz, L., Steinhoff, B., These, A. Pyrrolizidine alkaloids in food and phytomedicine: Occurence, exposure, toxicity, mechanisms, and risk assessment – A review. Food Chem Toxicol 2020; 136: 111107.
Merz KH, Schrenk D. Interim relative potency factors for the toxicological risk assessment of pyrrolizidine alkaloids in food and herbal medicines. Toxicol Lett. 2016 Nov 30;263:44-57. doi: 10.1016/j.toxlet.2016.05.002. Epub 2016 May 6. PMID: 27157086 Review.
