Regulatory Perspectives of Pyrrolizidine Alkaloid Contamination in Herbal Medicinal Products

Abstract

The toxicity of plants containing certain pyrrolizidine alkaloids has long been recognized in grazing animals and humans. Genotoxicity and carcinogenicity data from in vitro and in vivo (animal) studies were published over the last few decades for some of the 1,2-unsaturated pyrrolizidine alkaloids, leading to regulatory action on herbal medicinal products with pyrrolizidine alkaloid-containing plants more than 30 years ago. In recent years, it has become evident that in addition to herbal medicinal products containing pyrrolizidine alkaloid-containing plants, these products may also contain pyrrolizidine alkaloids without actually including pyrrolizidine alkaloid-containing plants. This is explained by contamination by accessory herbs (weeds). The national competent authorities of the European member states and the European Medicines Agency, in this case, the Committee on Herbal Medicinal Products, reacted to these findings by setting limits for all herbal medicinal products. This review article will briefly discuss the data leading to the establishment of thresholds and the regulatory developments and consequences, as well as the current discussions and research in this area.

Key words

pyrrolizidine alkaloids - herbal medicinal products - contamination - HMPC

Publication History

Received: 25 February 2021

Accepted after revision: 26 April 2021

Article published online:
24 June 2021

• References

• 1 Molyneux RJ, Gardner DL, Colegate SM, Edgar JA. Pyrrolizidine alkaloid toxicity in livestock: a paradigm for human poisoning?. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2011; 28: 293-307
• 2 Culvenor CC. Estimated intakes of pyrrolizidine alkaloids by humans. A comparison with dose rates causing tumors in rats. J Toxicol Environ Health 1983; 11: 625-635
• 3 Bundesgesundheitsamt. Bekanntmachung über die Zulassung und Registrierung von Arzneimitteln vom 05. Juni 1992 Abwehr von Arzneimitteln-Stufe II, hier: Arzneimittel, die Pyrrolizidin-Alkaloide mit einem 1,2-ungesättigtem Necin-Gerüst enthalten. BAnz 1992; 111: 4805
• 4 EFSA. Scientific opinion on pyrrolizidine alkaloids in food and feed. EFSA Panel on Contaminants in the Food Chain (CONTAM). EFSA J 2011; 9: 2406
• 5 These A, Bodi D, Ronczka S, Lahrssen-Wiederholt M, Preiss-Weigert A. Structural screening by multiple reaction monitoring as a new approach for tandem mass spectrometry: presented for the determination of pyrrolizidine alkaloids in plants. Anal Bioanal Chem 2013; 405: 9375-9383
• 6 Roeder E. Medicinal plants in China containing pyrrolizidine alkaloids. Pharmazie 2000; 55: 711-726
• 7 Teuscher E, Lindequist U. Biogene Gifte. Biologie-Chemie-Pharmakologie. Stuttgart, Jena, New York: Gustav Fischer; 1994
• 8 Ma J, Xia Q, Fu PP, Lin G. Pyrrole-protein adducts–a biomarker of pyrrolizidine alkaloid-induced hepatotoxicity. J Food Drug Anal 2018; 26: 965-972
• 9 Fu PP. Pyrrolizidine alkaloids: metabolic activation pathways leading to liver tumor initiation. Chem Res Toxicol 2017; 30: 81-93
• 10 Edgar JA, Colegate SM, Boppré M, Molyneux RJ. Pyrrolizidine alkaloids in food: a spectrum of potential health consequences. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2011; 28: 308-324
• 11 Food Standards Australia New Zealand (FSANZ). Pyrrolizidine Alkaloids in Food. A toxicological Review and Risk Assessment. Australia New Zealand Technical Report Series No. 2. [Epub 2001 November]. Canberra, Wellington: Australia New Zealand Food Authority; 2001. Accessed June 16, 2021 at: https://www.foodstandards.gov.au/publications/documents/TR2.pdf
• 12 Stegelmeier BL, Colegate SM, Brown AW. Dehydropyrrolizidine alkaloid toxicity, cytotoxicity, and carcinogenicity. Toxins (Basel) 2016; 8: 356
• 13 Moreira R, Pereira DM, Valentão P, Andrade PB. Pyrrolizidine alkaloids: chemistry, pharmacology, toxicology and food safety. Int J Mol Sci 2018; 19: 1668
• 14 Ning J, Chen L, Strikwold M, Louisse J, Wesseling S, Rietjens IMCM. Use of an in vitro-in silico testing strategy to predict inter-species and inter-ethnic human differences in liver toxicity of the pyrrolizidine alkaloids lasiocarpine and riddelliine. Arch Toxicol 2019; 93: 801-818
• 15 Stegelmeier BL, Edgar JA, Colegate SM, Gardner DR, Schoch TK, Coulombe RA, Molyneaux RJ. Pyrrolizidine alkaloid plants, metabolism and toxicity. J Natural Toxins 1999; 8: 95-116
• 16 Petzinger E. Pyrrolizidine alkaloids and seneciosis in farm animals. Part 1: occurrence, chemistry and toxicology. Tierarztl Prax Ausg G Grosstiere Nutztiere 2011; 39: 221-230
• 17 Preliasco M, Gardner D, Moraes J, González AC, Uriarte G, Rivero R. Senecio grisebachii Baker: pyrrolizidine alkaloids and experimental poisoning in calves. Toxicon 2017; 133: 68-73
• 18 WHO. International Programme on Chemical Safety (IPCS). Pyrrolizidine Alkaloids. Environmental Health Criteria 80. Geneva: WHO; 1988
• 19 Fashe MM, Juvonen RO, Petsalo A, Räsänen J, Pasanen M. Species-specific differences in the in vitro metabolism of lasiocarpine. Chem Res Toxicol 2015; 28: 2034-2044
• 20 Kolrep F, Numata J, Kneuer C, Preiss-Weigert A, Lahrssen-Wiederholt M, Schrenk D, These A. In vitro biotransformation of pyrrolizidine alkaloids in different species. Part I: Microsomal degradation. Arch Toxicol 2018; 92: 1089-1097
• 21 Xia Q, He X, Shi Q, Lin G, Fu PP. Quantitation of DNA reactive pyrrolic metabolites of senecionine–A carcinogenic pyrrolizidine alkaloid by LC/MS/MS analysis. J Food Drug Anal 2020; 28: 167-174
• 22 Prakash AS, Pereira TN, Reilly PE, Seawright AA. Pyrrolizidine alkaloids in human diet. Mutat Res 1999; 443: 53-67
• 23 Stickel F, Seitz HK. The efficacy and safety of comfrey. Public Health Nutr 2000; 3: 501-508
• 24 Tandon HD, Tandon BN, Tandon R, Nayak NC. A pathological study of the liver in an epidemic outbreak of veno-occlusive disease. Indian J Med Res 1977; 65: 679-684
• 25 Stuart KL, Bras G. Veno-occlusive disease of the liver. Q J Med 1957; 26: 291-315
• 26 Mattocks AR. Chemistry and Toxicology of Pyrrolizidine Alkaloids. London, New York: Academic Press; 1986
• 27 Yee SB, Kinser S, Hill DA, Barton CC, Hotchkiss JA, Harkema JR, Ganey PE, Roth RA. Synergistic hepatotoxicity from coexposure to bacterial endotoxin and the pyrrolizidine alkaloid monocrotaline. Toxicol Appl Pharmacol 2000; 166: 173-185
• 28 Kraus C, Abel G, Schimmer O. Studies on the chromosome damaging effect of some pyrrolizidine alkaloids in human lymphocytes in vitro . Planta Med 1985; 51: 89-91
• 29 Fu PP, Xia Q, Lin G, Chou MW. Pyrrolizidine alkaloids–genotoxicity, metabolism enzymes, metabolic activation, and mechanisms. Drug Metab Rev 2004; 36: 1-55
• 30 Mei N, Guo L, Fu PP, Fuscoe JC, Luan Y, Chen T. Metabolism, genotoxicity, and carcinogenicity of comfrey. J Toxicol Environ Health B Crit Rev 2010; 13: 509-526
• 31 Martin PA, Thorburn MJ, Hutchinson S, Bras G, Miller CG. Preliminary findings of chromosomal studies on rats and humans with veno-occlusive disease. Br J Exp Pathol 1972; 53: 374-380
• 32 Mei N, Guo L, Liu R, Fuscoe JC, Chen T. Gene expression changes induced by the tumorigenic pyrrolizidine alkaloid riddelliine in liver of Big Blue rats. BMC Bioinformatics 2007; 8: S4
• 33 Hartwig A, Arand M, Epe B, Guth S, Jahnke G, Lampen A, Martus HJ, Monien B, Rietjens IMCM, Schmitz-Spanke S, Schriever-Schwemmer G, Steinberg P, Eisenbrand G. Mode of action-based risk assessment of genotoxic carcinogens. Arch Toxicol 2020; 94: 1787-1877
• 34 Schoental R, Magee PN. Chronic liver changes in rats after a single dose of lasiocarpine, a pyrrolizidine (Senecio) alkaloid. J Pathol Bacteriol 1957; 74: 305-319
• 35 NTP. Bioassay of lasiocarpine for possible carcinogenicity. Technical report series No. 39, 1978. Accessed June 16, 2021 at: http://ntp.niehs.nih.gov/ntp/htdocs/lt_rpts/tr039.pdf
• 36 National Toxicology Program. Final report on carcinogens-background document for riddelliine. Rep Carcinog Backgr Doc 2008; (85977): i-104
• 37 Ernst M, Thiele A, Kroth E. Fast 35 Jahre Stufenplanverfahren in Deutschland. Pharm Ind 2014; 76: 1010-1015
• 38 EMA. Public statement on the use of herbal medicinal products containing toxic, unsaturated pyrrolizidine alkaloids (PAs). EMA/HMPC/893108/2011. 24 November 2014. Accessed June 16, 2021 at: http://www.ema.europa.eu/docs/en_GB/document_library/Public_statement/2014/12/WC500179559.pdf
• 39 BfArM. Verunreinigung pflanzlicher Arzneimittel durch Pyrrolizidinalkaloide: BfArM macht der pharmazeutischen Industrie neue Vorgaben. Pressemitteilung Nr 4/16 from 01. 03. 2016 Accessed June 16, 2021 at: https://www.bfarm.de/SharedDocs/Pressemitteilungen/DE/2016/pm4-2016.html
• 40 BfArM. Bekanntmachung zur Prüfung des Gehalts an Pyrrolizidinalkaloiden zur Sicherstellung der Qualität und Unbedenklichkeit von Arzneimitteln, die pflanzliche Stoffe bzw. pflanzliche Zubereitungen oder homöopathische Zubereitungen aus pflanzlichen Ausgangsstoffen als Wirkstoffe enthalten 01.03.2016. Accessed June 16, 2021 at: https://www.bfarm.de/DE/Arzneimittel/Arzneimittelzulassung/Zulassungsarten/BesondereTherapierichtungen/Allgemeines/_node.html
• 41 EMA. Public statement on contamination of herbal medicinal products/traditional herbal medicinal products with pyrrolizidine alkaloids. EMA/HMPC/328782/2016. 2016. 31 May 2016. Accessed June 16, 2021 at: https://www.ema.europa.eu/documents/public-statement/public-statement-contamination-herbal-medicinal-products/traditional-herbal-medicinal-products-pyrrolizidine-alkaloids_en.pdf
• 42 EMA. HMPC meeting report on European Union herbal monographs, guidelines and other activities. 16 January 2019. Accessed June 16, 2021 at: https://www.ema.europa.eu/en/events/committee-herbal-medicinal-products-hmpc-14-16-january-2019
• 43 BfR. Determination of pyrrolizidine alkaloids (PA) in botanical substances using SPE-LC-MS/MS. Description of the Method. 2014. Accessed June 16, 2021 at: https://www.bfr.bund.de/cm/349/determination-of-pyrrolizidine-alkaloids-pa-in-plant-material.pdf
• 44 Council of Europe. European Pharmacopoeia Commission adopts new general chapter Contaminant pyrrolizidine alkaloids (2.8.26). 05 January 2021. Accessed June 16, 2021 at: https://www.edqm.eu/en/news/european-pharmacopoeia-commission-adopts-new-general-chapter-contaminant-pyrrolizidine
• 45 EFSA. Risks for human health related to the presence of pyrrolizidine alkaloids in honey, tea, herbal infusions and food supplements. EFSA EFSA CONTAM Panel (Panel on Contaminants in the Food Chain). EFSA J 2017; 15: 4908
• 46 EFSA. Update: guidance on the use of the benchmark dose approach in risk assessment. EFSA Scientific Committee. EFSA J 2017; 15: 4658
• 47 Ruan J, Yang M, Fu P, Ye Y, Lin G. Metabolic activation of pyrrolizidine alkaloids: insights into the structural and enzymatic basis. Chem Res Toxicol 2014; 27: 1030-1039
• 48 Merz KH, Schrenk D. Interim relative potency factors for the toxicological risk assessment of pyrrolizidine alkaloids in food and herbal medicine. Toxicol Lett 2016; 263: 44-57
• 49 Chen L, Mulder PPJ, Louisse J, Peijnenburg A, Wesseling S, Rietjens IMCM. Risk assessment for pyrrolizidine alkaloids detected in (herbal) teas and plant food supplements. Regul Toxicol Pharmacol 2017; 86: 292-302
• 50 Allemang A, Mahony C, Lester C, Pfuhler S. Relative potency of fifteen pyrrolizidine alkaloids to induce DNA damage as measured by micronucleus induction in HepaRG human liver cells. Food Chem Toxicol 2018; 121: 72-81
• 51 Louisse J, Rijkers D, Stoopen G, Holleboom WJ, Delagrange M, Molthof E, Mulder PPJ, Hoogenboom RLAP, Audebert M, Peijnenburg AACM. Determination of genotoxic potencies of pyrrolizidine alkaloids in HepaRG cells using the γH2AX assay. Food Chem Toxicol 2019; 131: 110532
• 52 Chen L, Peijnenburg A, de Haan L, Rietjens IMCM. Prediction of in vivo genotoxicity of lasiocarpine and riddelliine in rat liver using a combined in vitro-physiologically based kinetic modeling-facilitated reverse dosimetry approach. Arch Toxicol 2019; 93: 2385-2395
• 53 Lester C, Troutman J, Obringer C, Wehmeyer K, Stoffolano P, Karb M, Xu Y, Roe A, Carr G, Blackburn K, Mahony C. Intrinsic relative potency of a series of pyrrolizidine alkaloids characterized by rate and extent of metabolism. Food Chem Toxicol 2019; 131: 110523
• 54 FAO/WHO (Joint FAO/WHO Expert Committee on Food Additives). Evaluation of certain food additives and contaminants. Eightieth report of the Joint FAO/WHO Expert Committee on Food Additives. (WHO technical report series; no. 995, 2016). Accessed June 16, 2021 at: https://apps.who.int/iris/handle/10665/204410
• 55 Ning J, Chen L, Rietjens IMCM. Role of toxicokinetics and alternative testing strategies in pyrrolizidine alkaloid toxicity and risk assessment; state-of-the-art and future perspectives. Food Chem Toxicol 2019; 131: 110572
• 56 Ferguson LR, Philpott M. Nutrition and mutagenesis. Annu Rev Nutr 2008; 28: 313-329
• 57 EFSA. Opinion of the scientific panel on contaminants in the food chain on a request from the European Commission related to pyrrolizidine alkaloids as undesirable substances in animal feed (Question N° EFSA-Q-2003-065). EFSA J 2007; 447: 1-51
• 58 BAH. Code of Practice to prevent and reduce pyrrolizidine alkaloid contaminations of medicinal products of plant origin. 29 April 2016. Accessed June 16, 2021 at: https://www.journals.elsevier.com/journal-of-applied-research-on-medicinal-and-aromatic-plants/news/code-of-practice-to-prevent-and-reduce-pyrrolizidine-alkaloi
• 59 Dittrich H, Hösel K, Sievers H, Klier B, Waimer F, Heuberger H, Plescher A, Armbrüster N, Steinhoff B. Code of Practice zur Vermeidung und Verringerung von Kontaminationen pflanzlicher Arzneimittel mit Pyrrolizidinalkaloiden. Pharm Ind 2016; 78: 836-845
• 60 Steinhoff B. Pyrrolizidine alkaloid contamination in herbal medicinal products: Limits and occurrence. Food Chem Toxicol 2019; 130: 262-266
• 61 European Commission. Commission Regulation (EU) 2020/2040 of December 2020 amending Regulation (EC) No 1881/2006 as regards maximum levels of pyrrolizidine alkaloids in certain food stuffs. OJEU 2020; 63: L420