Toxins in Botanical Drugs and Plant-derived Food and Feed – from Science to Regulation: A Workshop Review

Abstract

In September 2022, the 3rd International Workshop on pyrrolizidine alkaloids (PAs) and related phytotoxins was held on-line, entitled ʼToxins in botanical drugs and plant-derived food and feed – from science to regulationʼ. The workshop focused on new findings about the occurrence, exposure, toxicity, and risk assessment of PAs. In addition, new scientific results related to the risk assessment of alkenylbenzenes, a distinct class of herbal constituents, were presented. The presence of PAs and alkenylbenzenes in plant-derived food, feed, and herbal medicines has raised health concerns with respect to their acute and chronic toxicity but mainly related to the genotoxic and carcinogenic properties of several congeners. The compounds are natural constituents of a variety of plant families and species widely used in medicinal, food, and feed products. Their individual occurrence, levels, and toxic properties, together with the broad range of congeners present in nature, represent a striking challenge to modern toxicology. This review tries to provide an overview of the current knowledge on these compounds and indicates needs and perspectives for future research.

Key words

Alkenylbenzenes - carcinogenicity - genotoxicity - pyrrolizidine alkaloids - relative toxic potency - risk assessment

Publikationsverlauf

Eingereicht: 17. September 2023

Angenommen nach Revision: 23. November 2023

Artikel online veröffentlicht:
10. Januar 2024

• References

• 1 EFSA (European Food Safety Authority). Scientific Panel on Contaminants in the Food Chain (CONTAM). Risks for human health related to the presence of pyrrolizidine alkaloids in honey, tea, herbal infusions and food supplements. EFSA J 2017; 15: 4908
• 2 Bodi D, Ronczka S, Gottschalk C, Behr N, Skibba A, Wagner M, Lahrssen-Wiederholt M, Preiss-Weigert A, These A. Determination of pyrrolizidine alkaloids in tea, herbal drugs and honey. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2014; 31: 1886-1895
• 3 Schrenk D, Fahrer J, Allemang A, Fu P, Lin G, Mahony C, Mulder PPJ, Peijnenburg A, Pfuhler S, Rietjens IMCM, Sachse B, Steinhoff B, These A, Troutman J, Wiesner J. Novel insights into pyrrolizidine alkaloid toxicity and implications for risk assessment: occurrence, genotoxicity, toxicokinetics, risk assessment-a workshop report. Planta Med 2022; 88: 98-117
• 4 Clayton MJ, Davis TZ, Knoppel EL, Stegelmeier BL. Hepatotoxic plants that poison livestock. Vet Clin North Am Food Anim Pract 2020; 36: 715-723
• 5 Jiao W, Wang L, Zhu L, Shen T, Shi T, Zhang P, Wang C, Chen H, Wu X, Yang T, Li Q, Hua R. Pyrrolizidine-producing weeds in tea gardens as an indicator of alkaloids in tea. Food Addit Contam Part B Surveill 2023; 16: 50-57
• 6 Fu PP. Pyrrolizidine alkaloids: Metabolic activation pathways leading to liver tumor initiation. Chem Res Toxicol 2017; 30: 81-93
• 7 Neuman MG, Cohen L, Opris M, Nanau RM, Hyunjin J. Hepatotoxicity of pyrrolizidine alkaloids. J Pharm Pharm Sci 2015; 18: 825-843
• 8 Datta DV, Khuroo MS, Mattocks AR, Aikat BK, Chhuttani PN. Veno-occlusive disease of liver due to heliotropium plant, used as medicinal herb (report of 6 cases with review of literature). J Assoc Physicians India 1978; 26: 383-393
• 9 Yang M, Ma J, Ruan J, Ye Y, Fu PPC, Lin G. Intestinal and hepatic biotransformation of pyrrolizidine alkaloid N-oxides to toxic pyrrolizidine alkaloids. Arch Toxicol 2019; 93: 2197-2209
• 10 Chan P. NTP technical report on the toxicity studies of riddelliine (CAS No. 23246–96-0) administered by gavage to F344 rats and B6C3F1 mice. Toxic Rep Ser 1993; 27: 1-D9
• 11 Merz KH, Schrenk D. Interim relative potency factors for the toxicological risk assessment of pyrrolizidine alkaloids in food and herbal medicines. Toxicol Lett 2016; 263: 44-57
• 12 EFSA Panel on Contaminants in the Food Chain (CONTAM). Scientific opinion on pyrrolizidine alkaloids in food and feed. EFSA J 2011; 9: 2406
• 13 Mulder PPJ, López P, Castellari M, Bodi D, Ronczka S, Preiss-Weigert A, These A. Occurrence of pyrrolizidine alkaloids in animal- and plant-derived food: Results of a survey across Europe. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2018; 35: 118-133
• 14 Hoogenboom RLAP, Mulder PPJ, Zeilmaker MJ, van den Top HJ, Remmelink GJ, Brandon EFA, Klijnstra M, Meijer GAL, Schothorst R, Van Egmond HP. Carry-over of pyrrolizidine alkaloids from feed to milk in dairy cows. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2011; 28: 359-372
• 15 Mulder PPJ, Klijnstra MD, Goselink RMA, van Vuuren AM, Cone JW, Stoopen G, Hoogenboom RLAP. Transfer of pyrrolizidine alkaloids from ragwort, common groundsel and viperʼs bugloss to milk from dairy cows. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2020; 37: 1906-1921
• 16 Lamp J, Knappstein K, Walte HG, Krause T, Steinberg P, Schwake-Anduschus C. Transfer of tropane alkaloids (atropine and scopolamine) into the milk of subclinically exposed dairy cows. Food Control 2021; 126: 108056
• 17 Engel AM, Klevenhusen F, Moenning JL, Numata J, Fischer-Tenhagen C, Sachse B, Schäfer B, Fry H, Kappenstein O, Pieper R. Investigations on the transfer of quinolizidine alkaloids from Lupinus angustifolius into the milk of dairy cows. J Agric Food Chem 2022; 70: 11749-11758
• 18 Mulder PPJ, de Witte SL, Stoopen GM, van der Meulen J, van Wikselaar PG, Gruys E, Groot MJ, Hoogenboom RLAP. Transfer of pyrrolizidine alkaloids from various herbs to eggs and meat in laying hens. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2016; 33: 1826-1839
• 19 Mulder PPJ, Mueller-Maatsch JTL, Meijer N, Bosch M, Zoet L, van der Fels-Klerx HJ. Effects of dietary exposure to plant toxins on bioaccumulation, survival, and growth of black soldier fly (Hermetia illucens) larvae and lesser mealworm (Alphitobius diaperinus). Heliyon 2023; Jul 19 [Epub ahead of Print]
• 20 Kaltner F, Rychlik M, Gareis M, Gottschalk C. Influence of storage on the stability of toxic pyrrolizidine alkaloids and their N-oxides in peppermint tea, hay, and honey. J Agric Food Chem 2018; 66: 5221-5228
• 21 de Nijs M, Mulder PPJ, Klijnstra MD, Driehuis F, Hoogenboom RLAP. Fate of pyrrolizidine alkaloids during processing of milk of cows treated with ragwort. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2017; 34: 2212-2219
• 22 Fu PP, Xia Q, Lin G, Chou MW. Pyrrolizidine alkaloids–genotoxicity, metabolism enzymes, metabolic activation, and mechanisms. Drug Metab Rev 2004; 36: 1-55
• 23 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
• 24 Ebmeyer J, Braeuning A, Glatt H, These A, Hessel-Pras S, Lampen A. Human CYP3A4-mediated toxification of the pyrrolizidine alkaloid lasiocarpine. Food Chem Toxicol 2019; 130: 79-88
• 25 Rutz L, Gao L, Küpper JH, Schrenk D. Structure-dependent genotoxic potencies of selected pyrrolizidine alkaloids in metabolically competent HepG2 cells. Arch Toxicol 2020; 94: 4159-4172
• 26 Li X, He X, Chen S, Guo X, Bryant MS, Guo L, Manjanatha MG, Zhou T, Witt KL, Mei N. Evaluation of pyrrolizidine alkaloid-induced genotoxicity using metabolically competent TK6 cell lines. Food Chem Toxicol 2020; 145: 111662
• 27 Li X, Chen S, Guo X, Wu Q, Seo JE, Guo L, Manjanatha MG, Zhou T, Witt KL, Mei N. Development and application of TK6-derived cells expressing human cytochrome P450 s for genotoxicity testing. Toxicol Sci 2020; 175: 251-265
• 28 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
• 29 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
• 30 Louisse J, Mulder PPJ, Gerssen A, Stoopen G, Rijkers D, van de Schans MGM, Peijnenburg AACM. Bioassay-directed analysis-based identification of relevant pyrrolizidine alkaloids. Arch Toxicol 2022; 96: 2299-2317
• 31 Robinson O, Want E, Coen M, Kennedy R, van den Bosch C, Gebrehawaria Y, Kudo H, Sadiq F, Goldin RD, Hauser ML, Fenwick A, Toledano MB, Thursz MR. Hirmi Valley liver disease: A disease associated with exposure to pyrrolizidine alkaloids and DDT. J Hepatol 2014; 60: 96-102
• 32 Yang M, Ruan J, Gao H, Li N, Ma J, Xue J, Ye Y, Fu PP, Wang J, Lin G. First evidence of pyrrolizidine alkaloid N-oxide-induced hepatic sinusoidal obstruction syndrome in humans. Arch Toxicol 2017; 91: 3913-3925
• 33 He X, Xia Q, Woodling K, Lin G, Fu PP. Pyrrolizidine alkaloid-derived DNA adducts are common toxicological biomarkers of pyrrolizidine alkaloid N-oxides. J Food Drug Anal 2017; 25: 984-991
• 34 Yang M, Ma J, Ruan J, Zhang C, Ye Y, Fu PPC, Lin G. Absorption difference between hepatotoxic pyrrolizidine alkaloids and their N-oxides–Mechanism and its potential toxic impact. J Ethnopharmacol 2020; 249: 112421
• 35 Widjaja F, Alhejji Y, Rietjens IM. The role of kinetics as key determinant in toxicity of pyrrolizidine alkaloids and their N-oxides. Planta Med 2022; 88: 130-143
• 36 Widjaja F, Wesseling S, Rietjens IMCM. Physiologically based kinetic modelling predicts the in vivo relative potency of riddelliine N-oxide compared to riddelliine in rat to be dose dependent. Arch Toxicol 2022; 96: 135-151
• 37 Widjaja F, Alhejji Y, Yangchen J, Wesseling S, Rietjens IMCM. Physiologically-based kinetic modeling predicts similar in vivo relative potency of senecionine N-oxide for rat and human at realistic low exposure levels. Mol Nutr Food Res 2023; 67: e2200293
• 38 Widjaja F, Zheng L, Wesseling S, Rietjens IMCM. Physiologically based kinetic modeling of senecionine N-oxide in rats as a new approach methodology to define the effects of dose and endpoint used on relative potency values of pyrrolizidine alkaloid N-oxides. Front Pharmacol 2023; 14: 1125146
• 39 Alhejji Y, Widjaja F, Tian S, Hoekstra T, Wesseling S, Rietjens IM. The influence of dose, fraction bioactivated and endpoint used on the relative potency value of selected PA N-oxides compared to the parent PAs. Curr Res Toxic (submitted).
• 40 Williams L, Chou MW, Yan J, Young JF, Chan PC, Doerge DR. Toxicokinetics of riddelliine, a carcinogenic pyrrolizidine alkaloid, and metabolites in rats and mice. Toxicol Appl Pharmacol 2002; 182: 98-104
• 41 Xia Q, Zhao Y, Von Tungeln LS, Doerge DR, Lin G, Cai L, Fu PP. Pyrrolizidine alkaloid-derived DNA adducts as a common biological biomarker of pyrrolizidine alkaloid-induced tumorigenicity. Chem Res Toxicol 2013; 26: 1384-1396
• 42 Xia Q, Zhao Y, Lin G, Beland FA, Cai L, Fu PP. Pyrrolizidine alkaloid-protein adducts: Potential non-invasive biomarkers of pyrrolizidine alkaloid-induced liver toxicity and exposure. Chem Res Toxicol 2016; 29: 1282-1292
• 43 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
• 44 Martinez MN, Amidon GL. A mechanistic approach to understanding the factors affecting drug absorption: A review of fundamentals. J Clin Pharmacol 2002; 42: 620-643
• 45 Plaza A, Toner F, Harris J, Ottersbach P, Roper C, Mahony C. Support for regulatory assessment of percutaneous absorption of retronecine-type pyrrolizidine alkaloids through human skin. Planta Med 2022; 88: 144-151
• 46 EFSA (European Food Safety Authority). Guidance on dermal absorption. EFSA J 2017; 15: 4873
• 47 OECD (Organisation for Economic Co-operation and Development). Test No. 428: Skin Absorption: In Vitro Method. OECD Guidelines for the Testing of Chemicals, Section 4. Paris: OECD Publishing; 2004
• 48 OECD (Organisation for Economic Co-operation and Development). Guidance Document for the Conduct of Skin Absorption Studies, OECD Series on Testing and Assessment, No. 28. Paris: OECD Publishing,; 2004
• 49 SCCS (Scientific Committee on Consumer Safety). Basic criteria for the assessment of dermal absorption of cosmetic ingredients, 22 June 2010. Zugriff am 13. Mai 2023 unter: https://ec.europa.eu/health/scientific_committees/consumer_safety/docs/sccs_s_002.pdf
• 50 HMPC (Committee on Herbal Medicinal Products). Public statement on the use of herbal medicinal products containing toxic, unsaturated pyrrolizidine alkaloids (PAs), EMA/HMPC/893108/2011 Rev. 1, 07.07.2021. Zugriff am 04. Mai 2023 unter: https://www.ema.europa.eu/en/documents/public-statement/public-statement-use-herbal-medicinal-products-containing-toxic-unsaturated-pyrrolizidine-alkaloids-pas-including-recommendations-regarding-contamination-herbal-medicinal-products-pyrrolizidine_en.pdf
• 51 BfArM (Bundesinstitut für Arzneimittel und Medizinprodukte). 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. BfArM Bekanntmachung 01.03.2016 (in German). Zugriff am 26. April 2023 unter: https://www.bfarm.de/SharedDocs/Bekanntmachungen/DE/Arzneimittel/besTherap/bm-besTherap-20160301-pa-pdf.html
• 52 BfR (Bundesinstitut für Risikobewertung). Aktualisierte Risikobewertung zu Gehalten an 1, 2-ungesättigten Pyrrolizidinalkaloiden (PA) in Lebensmitteln Juni 2018 (Stellungnahme Nr. 020/2018) 06.2018 (in German). Zugriff am 13. Mai 2023 unter: https://www.bfr.bund.de/cm/343/aktualisierte-risikobewertung-zu-gehalten-an-1-2-ungesaettigten-pyrrolizidinalkaloiden-pa-in-lebensmitteln.pdf
• 53 BfR (Bundesinstitut für Risikobewertung). Bestimmung von Pyrrolizidinalkaloiden (PA) in Pflanzenmaterial mittels SPE-LC-MS/MS (BfR-PA-Tee-2.0/2014) 10.2014 (in German). Zugriff am 27. Mai 2023 unter: https://www.bfr.bund.de/cm/343/bestimmung-von-pyrrolizidinalkaloiden.pdf
• 54 European Pharmacopoeia. Vol. 10.6. Contaminant pyrrolizidine alkaloids, Council of Europe 01/2022: Ph. Eur. 2.8.26. Zugriff am 07. Dezember 2023 unter: https://pheur.edqm.eu/home
• 55 Lin G, Wang JY, Li N, Li M, Gao H, Ji Y, Zhang F, Wang H, Zhou Y, Ye Y, Hong XX, Zheng J. Hepatic sinusoidal obstruction syndrome associated with consumption of Gynura segetum. J Hepatol 2011; 54: 666-673
• 56 Mohabbat O, Younos MS, Merzad AA, Srivastava RN, Sediq GG, Aram GN. An outbreak of hepatic veno-occlusive disease in north-western Afghanistan. The Lancet 1976; 308: 269-271
• 57 He Y, Long Y, Zhang C, Ma J, Ke C, Tang C, Ye Y, Lin G. Dietary alcohol exacerbates the hepatotoxicity induced by pyrrolizidine alkaloids: Hazard from food contamination. J Hazard Mater 2022; 424: 127706
• 58 He Y, Zhu L, Ma J, Lin G. Metabolism-mediated cytotoxicity and genotoxicity of pyrrolizidine alkaloids. Arch Toxicol 2021; 95: 1917-1942
• 59 He Y, Lian W, Ding L, Fan X, Ma J, Zhang QY, Ding X, Lin G. Lung injury induced by pyrrolizidine alkaloids depends on metabolism by hepatic cytochrome P450 s and blood transport of reactive metabolites. Arch Toxicol 2021; 95: 103-116
• 60 He Y, Ma J, Fan X, Ding L, Ding X, Zhang QY, Lin G. The key role of gut–liver axis in pyrrolizidine alkaloid-induced hepatotoxicity and enterotoxicity. Acta Pharm Sin B 2021; 11: 3820-3835
• 61 Chen L, Mulder PPJ, Louisse J, Peijnenburg A, Wesseling S, Rietjens I. Risk assessment for pyrrolizidine alkaloids detected in (herbal) teas and plant food supplements. Regul Toxicol Pharmacol 2017; 86: 292-302
• 62 Schrenk D, Gao L, Lin G, Mahony C, Mulder PPJ, Peijnenburg A, Pfuhler S, Rietjens IMCM, Rutz L, Steinhoff B, These A. Pyrrolizidine alkaloids in food and phytomedicine: Occurrence, exposure, toxicity, mechanisms, and risk assessment – A review. Food Chem Toxicol 2020; 136: 111107
• 63 Herzog N, Katzenberger N, Martin F, Schmidtke KU, Küpper JH. Generation of cytochrome P450 3A4-overexpressing HepG2 cell clones for standardization of hepatocellular testosterone 6β-hydroxylation activity. J Cell Biotechnol 2015; 1: 15-26
• 64 Haas M, Wirachowski K, Thibol L, Kupper 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; 97: 1413-1428
• 65 Geburek I, Schrenk D, These A. In vitro biotransformation of pyrrolizidine alkaloids in different species: Part II-identification and quantitative assessment of the metabolite profile of six structurally different pyrrolizidine alkaloids. Arch Toxicol 2020; 94: 3759-3774
• 66 Geburek I, Preiss-Weigert A, Lahrssen-Wiederholt M, Schrenk D, These A. In vitro metabolism of pyrrolizidine alkaloids – Metabolic degradation and GSH conjugate formation of different structure types. Food Chem Toxicol 2020; 135: 110868
• 67 Geburek I, Rutz L, Gao L, Küpper JH, These A, Schrenk D. Metabolic pattern of hepatotoxic pyrrolizidine alkaloids in liver cells. Chem Res Toxicol 2021; 34: 1101-1113
• 68 Shimshoni JA, Barel S, Mulder PPJ. Comparative risk assessment of three native Heliotropium species in Israel. Molecules 2021; 26: 689
• 69 Chen L, Zhang Q, Yi Z, Chen Y, Xiao W, Su D, Shi W. Risk assessment of (herbal) teas containing pyrrolizidine alkaloids (PAs) based on margin of exposure approach and Relative Potency (REP) Factors. Foods 2022; 11: 2946
• 70 Al-Subeihi AAA, Spenkelink B, Punt A, Boersma MG, van Bladeren PJ, Rietjens IMCM. Physiologically based kinetic modeling of bioactivation and detoxification of the alkenylbenzene methyleugenol in human as compared with rat. Toxicol Appl Pharmacol 2012; 260: 271-284
• 71 Martati E, Boersma MG, Spenkelink A, Khadka DB, van Bladeren PJ, Rietjens IMCM, Punt A. Physiologically based biokinetic (PBBK) modeling of safrole bioactivation and detoxification in humans as compared with rats. Toxicol Sci 2012; 128: 301-316
• 72 Punt A, Paini A, Boersma MG, Freidig AP, Delatour T, Scholz G, Schilter B, van Bladeren P, Rietjens IMCM. Use of physiologically based biokinetic (PBBK) modeling to study estragole bioactivation and detoxification in humans as compared with male rats. Toxicol Sci 2009; 110: 255-269
• 73 van den Berg SJPL, Punt A, Soffers AEMF, Vervoort J, Ngeleja S, Spenkelink B, Rietjens IMCM. Physiologically based kinetic models for the alkenylbenzene elemicin in rat and human and possible implications for risk assessment. Chem Res Toxicol 2012; 25: 2352-2367
• 74 Alhusainy W, van den Berg SJPL, Paini A, Campana A, Asselman M, Spenkelink A, Punt A, Scholz G, Schilter B, Adams TB, van Bladeren PJ, Rietjens IMCM. Matrix modulation of the bioactivation of estragole by constituents of different alkenylbenzene-containing herbs and spices and physiologically based biokinetic modeling of possible in vivo effects. Toxicol Sci 2012; 129: 174-187
• 75 Alhusainy W, Paini A, van den Berg JHJ, Punt A, Scholz G, Schilter B. In vivo validation and physiologically based biokinetic modeling of the inhibition of SULT-mediated estragole DNA adduct formation in the liver of male Sprague-Dawley rats by the basil flavonoid nevadensin. Mol Nutr Food Res 2013; 57: 1969-1978
• 76 Rietjens IM, Cohen SM, Fukushima S, Gooderham NJ, Hecht S, Marnett LJ, Smith RL, Adams TB, Bastaki M, Harman CG, Taylor SV. Impact of structural and metabolic variations on the toxicity and carcinogenicity of hydroxy- and alkoxy-substituted allyl and propenylbenzenes. Chem Res Toxicol 2014; 27: 1092-1103
• 77 Eisenreich A, Götz ME, Sachse B, Monien BH, Herrmann K, Schäfer B. Alkenylbenzenes in foods: Aspects impeding the evaluation of adverse health effects. Foods 2021; 10: 2139
• 78 Homburger F, Kelley jr. T, Friedler G, Russfield AB. Toxic and possible carcinogenic effects of 4-allyl-1, 2- methylenedioxybenzene (safrole) in rats on deficient diets. Med Exp Int J Exp Med 1961; 4: 1-11
• 79 EC (European Commission). Regulation No 1334/2008 of the European Parliament and of the Council of 16 December 2008 on flavourings and certain food ingredients with flavouring properties for use in and on foods and amending Council Regulation (EEC) No 1601/91, Regulations (EC) No 2232/96 and (EC) No 110/2008 and Directive 2000/13/EC. Off J Europ Union 31.12.2008. Zugriff am 12. Mai 2023 unter: https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2008:354:0034:0050:en:PDF
• 80 SCF (Scientific Committee on Food). Opinion of the Scientific Committee on Food on estragole (1-allyl-4-methoxybenzene). SCF/CS/FLAV/FLAVOUR/6 ADD 2 Final 26 September 2001. Zugriff am 04. April 2023 unter: https://ec.europa.eu/food/system/files/2016-10/fs_food-improvement-agents_flavourings-out104.pdf
• 81 EMA (European Medicines Agency). Committee on Herbal Medicinal Products (HMPC). Public statement on the use of herbal medicinal products containing estragole. EMA/HMPC/137212/2005 Rev 1, 22 September 2021. (Publication March 1st, 2022). Zugriff am 07. Dezember 2023 unter: https://www.ema.europa.eu/en/documents/herbal-comments/overview-comments-received-draft-revised-public-statement-use-herbal-medicinal-products-containing-estragole-emahmpc1372122005-rev-1-2nd-draft_en.pdf
• 82 EMEA (European Medicines Agency). Herbal Medicinal Products Working Party (HMPWP): Position paper on the use of herbal medicinal products containing asarone, 2003. EMEA/HMPWP/41/03 Final. Zugriff am 16. März 2023 unter: https://www.ema.europa.eu/en/documents/press-release/meeting-emea-working-party-herbal-medicinal-products-30-june-and-1-july-2003_en.pdf
• 83 EMEA (European Medicines Agency). Herbal Medicinal Products Committee (HMPC). Public statement on the use of herbal medicinal products containing asarone, 2005. EMEA/HMPC/139215/2005. Zugriff am 29. Mai 2023 unter: https://www.ema.europa.eu/en/documents/scientific-guideline/public-statement-use-herbal-medicinal-products-containing-methyleugenol_en.pdf
• 84 EMEA (European Medicines Agency). Herbal Medicinal Products Committee (HMPC). Public Statement on the use of herbal medicinal products containing methyleugenol, 2005. EMEA/HMPC/138363/2005. Zugriff am 12. Mai 2023 unter: https://www.ema.europa.eu/en/documents/scientific-guideline/public-statement-use-herbal-medicinal-products-containing-methyleugenol_en.pdf
• 85 EMEA (European Medicines Agency). Herbal Medicinal Products Committee (HMPC). Public Statement on the use of herbal medicinal products containing estragole, 2005. EMEA/HMPC/137212/2005. Zugriff am 25. April 2023 unter: https://www.ema.europa.eu/en/documents/scientific-guideline/public-statement-use-herbal-medicinal-products-containing-estragole_en.pdf
• 86 Bristol DW. NTP 3-month toxicity studies of estragole (CAS No. 140–67-0) administered by gavage to F344/N rats and B6C3F1 mice. Toxic Rep Ser 2011; 82: 1-111
• 87 EFSA Scientific Cooperation (ESCO) Report. Advice on the guidance document for the safety assessment of botanicals and botanical preparations intended for use as food supplements, based on real case studies. EFSA J 2009; 7: 280
• 88 EMA (European Medicines Agency). Committee on Herbal Medicinal Products (HMPC) Public statement on the use of herbal medicinal products containing estragole. EMA/HMPC/137212/2005 Rev 1 (draft published 2014). Zugriff am 07. Dezember 2023 unter: https://www.ema.europa.eu/en/documents/public-statement/public-statement-use-herbal-medicinal-products-containing-estragole_en.pdf
• 89 EMA (European Medicines Agency). Committee for Human Medicinal Products. ICH guideline M7(R1) on assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk – Step 5 (EMA/CHMP/ICH/83812/2013), 25 August 2015. Zugriff am 07. Dezember 2023 unter: https://www.ema.europa.eu/en/documents/scientific-guideline/ich-guideline-m7r1-assessment-and-control-dna-reactive-mutagenic-impurities-pharmaceuticals-limit-potential-carcinogenic-risk-step-5_en.pdf
• 90 EMA (European Medicines Agency). Co-ordination Group for Mutual Recognition and Decentralised Procedures (CMDh). Report from the CMDh meeting held on 22–23 February 2022 (EMA/CMDh/78976/2022), 2 March 2022. Zugriff am 07. Dezember 2023 unter: https://www.ema.europa.eu/en/documents/agenda/agenda-chmp-meeting-21-24-february-2022_en.pdf
• 91 EMA (European Medicines Agency). Committee on Herbal Medicinal Products (HMPC). European Union herbal monograph on Foeniculum vulgare Miller subsp. vulgare var. vulgare, fructus Draft – Revision July 2022 (EMEA/HMPC/372841/2016). Zugriff am 07. Dezember 2023 unter: https://www.ema.europa.eu/en/medicines/herbal/foeniculi-amari-fructus
• 92 EMA (European Medicines Agency). Committee on Herbal Medicinal Products (HMPC) European Union herbal monograph on Foeniculum vulgare Miller subsp. vulgare var. dulce (Mill.) Batt. & Trab., fructus Draft – Revision July 2022EMEA/HMPC/372839/2016. Zugriff am 07. Dezember 2023 unter: https://www.ema.europa.eu/en/documents/herbal-monograph/european-union-herbal-monograph-foeniculum-vulgare-miller-subsp-vulgare-var-dulce-mill-batt-trab-fructus-revision-1_en.pdf
• 93 EMA (European Medicines Agency). Committee on Herbal Medicinal Products (HMPC) Public statement on Foeniculum vulgare Miller subsp. vulgare var. vulgare, aetheroleum Draft – EMA/HMPC/522456/2021. Zugriff am 07. Dezember 2023 unter: https://www.ema.europa.eu/en/medicines/herbal/foeniculi-amari-fructus-aetheroleum
• 94 Pank F, Schneider E, Krüger H. Possibilities and limitations of estragole content reduction of fennel (Foeniculum vulgare Mill.) and its preparations. Zeitschr Arzn Gewürzpfl 2003; 8: 165-172
• 95 EC (European Commission). Directorate-General for Health and Food Safety, Food and Feed Safety, Innovation E1 – Food information and composition ref. Ares (2022)5233398-19/07/2022. Zugriff am 07. Dezember 2023 unter: https://ec.europa.eu/info/funding-tenders/opportunities/docs/2021-2027/horizon/wp-call/2021-2022/wp-10-european-innovation-ecosystems_horizon-2021-2022_en.pdf
• 96 Smith RL, Adams TB, Doull J, Feron VJ, Goodman JI, Marnett LJ, Portoghese PS, Waddell WJ, Wagner BM, Rogers AE, Caldwell J, Sipes IG. Safety assessment of allylalkoxybenzene derivatives used as flavouring substances – methyl eugenol and estragole. Food Chem Toxicol 2002; 40: 851-870
• 97 Anthony A, Caldwell J, Hutt AJ, Smith RL. Metabolism of estragole in rat and mouse and influence of dose size on excretion of the proximate carcinogen 1′-hydroxyestragole. Food Chem Toxicol 1987; 25: 799-806
• 98 Guenthner TM, Luo G. Investigation of the role of the 2′,3′-epoxidation pathway in the bioactivation and genotoxicity of dietary allylbenzene analogs. Toxicology 2001; 160: 47-58
• 99 Jeurissen SM, Punt A, Boersma MG, Bogaards JJP, Yiannis CF, Schilter B, van Bladeren PJ, Cnubben NHP, Rietjens IMCM. Human cytochrome P450 enzyme specificity for the bioactivation of estragole and related alkenylbenzenes. Chem Res Toxicol 2007; 20: 798-806
• 100 Herrmann K, Engst W, Appel KE, Monien BH, Glatt H. Identification of human and murine sulfotransferases able to activate hydroxylated metabolites of methyleugenol to mutagens in Salmonella typhimurium and detection of associated DNA adducts using UPLC-MS/MS methods. Mutagenesis 2012; 27: 453-462
• 101 Suzuki Y, Umemura T, Ishii Y, Hibi D, Inoue T, Jin M, Sakai H, Kodama Y, Nohmi T, Yanai T, Nishikawa A, Ogawa K. Possible involvement of sulfotransferase 1A1 in estragole-induced DNA modification and carcinogenesis in the livers of female mice. Mutat Res 2012; 749: 23-28
• 102 Ishii Y, Suzuki Y, Hibi D, Jin M, Fukuhara K, Umemura T, Nishikawa A. Detection and quantification of specific DNA adducts by liquid chromatography-tandem mass spectrometry in the livers of rats given estragole at the carcinogenic dose. Chem Res Toxicol 2011; 24: 532-541
• 103 Punt A, Delatour T, Scholz G, Schilter B, van Bladeren PJ, Rietjens IMCM. Tandem mass spectrometry analysis of N2-(trans-Isoestragol-3′-yl)-2′-deoxyguanosine as a strategy to study species differences in sulfotransferase conversion of the proximate carcinogen 1′-hydroxyestragole. Chem Res Toxicol 2007; 20: 991-998
• 104 Schulte-Hubbert R, Kupper JH, Thomas AD, Schrenk D. Estragole: DNA adduct formation in primary rat hepatocytes and genotoxic potential in HepG2-CYP1A2 cells. Toxicology 2020; 444: 152566
• 105 Yang X, Feng Y, Zhang Z, Wang H, Li W, Wang DO, Peng Y, Zheng J. In vitro and in vivo evidence for RNA adduction resulting from metabolic activation of methyleugenol. J Agric Food Chem 2020; 68: 15134-15141
• 106 Carlsson MJ, Vollmer AS, Demuth P, Heylmann D, Reich D, Quarz C, Rasenberger B, Nikolova T, Hofmann TG, Christmann M, Fuhlbrueck JA, Stegmüller S, Richling E, Cartus AT, Fahrer J. P53 triggers mitochondrial apoptosis following DNA damage-dependent replication stress by the hepatotoxin methyleugenol. Cell Death Dis 2022; 13: 1009
• 107 Thomas AD, Fahrer J, Johnson GE, Kaina B. Theoretical considerations for thresholds in chemical carcinogenesis. Mutat Res Rev Mutat Res 2015; 765: 56-67
• 108 Doak SH, Jenkins GJ, Johnson GE, Quick E, Parry EM, Parry JM. Mechanistic influences for mutation induction curves after exposure to DNA-reactive carcinogens. Cancer Res 2007; 67: 3904-3911
• 109 Fahrer J, Frisch J, Nagel G, Kraus A, Dörsam B, Thomas AD, Reißig S, Waisman A, Kaina B. DNA repair by MGMT, but not AAG, causes a threshold in alkylation-induced colorectal carcinogenesis. Carcinogenesis 2015; 36: 1235-1244
• 110 Kraus A, McKeague M, Seiwert N, Nagel G, Geisen SM, Ziegler N, Trantakis IA, Kaina B, Thomas AD, Sturla SJ, Fahrer J. Immunological and mass spectrometry-based approaches to determine thresholds of the mutagenic DNA adduct O(6)-methylguanine in vivo. Arch Toxicol 2019; 93: 559-572
• 111 Thomas AD, Jenkins GJ, Kaina B, Bodger OG, Tomaszowski K, Lewis PD, Doak SH. Influence of DNA repair on nonlinear dose-responses for mutation. Toxicol Sci 2013; 132: 87-95