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+@article{Rubiolo1992,
+  author = {Rubiolo, P. and Pieters, L. and Calomme, M. and Bicchi, C. and Vlietinck, A. and Vanden Berghe, D.},
+  year = 1992,
+  title = {Mutagenicity of pyrrolizidine alkaloids in the Salmonella typhimurium/mammalian microsome system},
+  journal = {Mutation research},
+  number = 281, 
+  pages = {143–147}
+}
+
+@article{Chen2010,
+  author = {Chen, T. and Mei, N. and Fu, P.P.},
+  year = 2010,
+  title = {Genotoxicity of pyrrolizidine alkaloids},
+  journal = {J. Appl. Toxicol.},
+  numbr = 30,
+  pages = {183-96}
+}
+
+@article{Li2013,
+  authors = {Li YH, Kan WL, Li N, Lin G},
+  year = 2013,
+  title = {Assessment of pyrrolizidine alkaloid-induced toxicity in an in vitro screening model},
+  journal = {J. Ethnopharmacol.},
+  number = 150,
+  pages = {560-7}
+}
+
+@article{Xia2013,
+  authors = {Xia, Q. and Zhao, Y. and Von Tungeln, L.S. and Doerge, D.R. and Lin, G. and et al.},
+  year = 2013,
+  title = {Pyrrolizidine alkaloid-derived DNA adducts as a common biological biomarker of pyrrolizidine alkaloid-induced tumorigenicity},
+  journal = {Chem Res. Toxicol.},
+  number = 26,
+  pages = {1384-96}
+}
+
+@article{Fu2004,
+  authors = {Fu, P.P. and Xia, Q. and, Lin, G. and Chou, M.W.},
+  year = 2004,
+  title = {Pyrrolizidine alkaloids--genotoxicity, metabolism enzymes, metabolic activation, and mechanisms},
+  journal = {Drug Metab. Rev.},
+  number = 36,
+  pages = {1-55}
+}
+
+@article{Louisse2019,
+  title = {Determination of genotoxic potencies of pyrrolizidine alkaloids in HepaRG cells using the γH2AX assay},
+  journal = {Food and Chemical Toxicology},
+  volume = {131},
+  pages = {110532},
+  year = {2019},
+  issn = {0278-6915},
+  doi = {https://doi.org/10.1016/j.fct.2019.05.040},
+  url = {https://www.sciencedirect.com/science/article/pii/S0278691519303072},
+  author = {Jochem Louisse and Deborah Rijkers and Geert Stoopen and Wendy Jansen Holleboom and Mona Delagrange and Elise Molthof and Patrick P.J. Mulder and Ron L.A.P. Hoogenboom and Marc Audebert and Ad A.C.M. Peijnenburg},
+  keywords = {Pyrrolizidine alkaloids (PAs), HepaRG, Genotoxicity, γH2AX assay, Relative potency factor (RPF)},
+  abstract = {Pyrrolizidine alkaloids (PAs) are secondary metabolites from plants that have been found in substantial amounts in herbal supplements, infusions and teas. Several PAs cause cancer in animal bioassays, mediated via a genotoxic mode of action, but for the majority of the PAs, carcinogenicity data are lacking. It is assumed in the risk assessment that all PAs have the same potency as riddelliine, which is considered to be one of the most potent carcinogenic PAs in rats. This may overestimate the risks, since many PAs are expected to have lower potencies. In this study we determined the concentration-dependent genotoxicity of 37 PAs representing different chemical classes using the γH2AX in cell western assay in HepaRG human liver cells. Based on these in vitro data, PAs were grouped into different potency classes. The group with the highest potency consists particularly of open diester PAs and cyclic diester PAs (including riddelliine). The group of the least potent or non-active PAs includes the monoester PAs, non-esterified necine bases, PA N-oxides, and the unsaturated PA trachelanthamine. This study reveals differences in in vitro genotoxic potencies of PAs, supporting that the assumption that all PAs have a similar potency as riddelliine is rather conservative.}
+}
+
+@article{Allemang2018,
+  title = {Relative potency of fifteen pyrrolizidine alkaloids to induce DNA damage as measured by micronucleus induction in HepaRG human liver cells},
+  journal = {Food and Chemical Toxicology},
+  volume = {121},
+  pages = {72-81},
+  year = {2018},
+  issn = {0278-6915},
+  doi = {https://doi.org/10.1016/j.fct.2018.08.003},
+  url = {https://www.sciencedirect.com/science/article/pii/S027869151830512X},
+  author = {Ashley Allemang and Catherine Mahony and Cathy Lester and Stefan Pfuhler},
+  keywords = {Pyrrolizidine alkaloids, HepaRG, Genetic toxicology, Micronucleus test, Relative potency factor, Risk assessment},
+  abstract = {Plant-based 1,2-unsaturated Pyrrolizidine Alkaloids (PAs) can be found as contaminants in foods like teas, herbs and honey. PAs are responsible for liver genotoxicity/carcinogenicity following metabolic activation, making them a relevant concern for safety assessment. Current regulatory risk assessments take a precautionary approach and assume all PAs are as potent as the known most potent representatives: lasiocarpine and riddelliine. Our study investigated whether genotoxicity potency differed as a consequence of structural differences, assessing micronuclei in vitro in HepaRG cells which express metabolising enzymes at levels similar to primary human hepatocytes. Benchmark Dose (BMD) analysis was used to calculate the critical effect dose for 15 PAs representing 6 structural classes. When BMD confidence intervals were used to rank PAs, lasiocarpine was the most potent PA and plotted distinctly from all other PAs examined. PA-N-oxides were least potent, notably less potent than their corresponding parent PA's. The observed genotoxic potency compared favorably with existing in vitro data when metabolic competency was considered. Although further consideration of biokinetics will be needed to develop a robust understanding of relative potencies for a realistic risk assessment of PA mixtures, these data facilitate understanding of their genotoxic potencies and affirm that not all PAs are created equal.}
+}
+@article{Hadi2021,
+  title = {Genotoxicity of selected pyrrolizidine alkaloids in human hepatoma cell lines HepG2 and Huh6},
+  journal = {Mutation Research/Genetic Toxicology and Environmental Mutagenesis},
+  volume = {861-862},
+  pages = {503305},
+  year = {2021},
+  issn = {1383-5718},
+  doi = {https://doi.org/10.1016/j.mrgentox.2020.503305},
+  url = {https://www.sciencedirect.com/science/article/pii/S1383571820301765},
+  author = {Naji Said Aboud Hadi and Ezgi Eyluel Bankoglu and Lea Schott and Eva Leopoldsberger and Vanessa Ramge and Olaf Kelber and Hartwig Sievers and Helga Stopper},
+  keywords = {Pyrrolizidine alkaloids, Genomic damage, Micronuclei, Crosslink comet assay, HepG2 cells, Huh6 cells},
+  abstract = {Introduction
+Pyrrolizidine alkaloids (PAs) are found in many plant species as secondary metabolites which affect humans via contaminated food sources, herbal medicines and dietary supplements. Hundreds of compounds belonging to PAs have been identified. PAs undergo hepatic metabolism, after which they can induce hepatotoxicity and carcinogenicity. Many aspects of their mechanism of carcinogenicity are still unclear and it is important for human risk assessment to investigate this class of compounds further.
+Material and methods
+Human hepatoma cells HepG2 were used to investigate the genotoxicity of different chemical structural classes of PAs, namely europine, lycopsamine, retrorsine, riddelliine, seneciphylline, echimidine and lasiocarpine, in the cytokinesis-block micronucleus (CBMN) assay. The different ester type PAs europine, seneciphylline, and lasiocarpine were also tested in human hepatoma Huh6 cells. Six different PAs were investigated in a crosslink comet assay in HepG2 cells.
+Results
+The maximal increase of micronucleus formation was for all PAs in the range of 1.64–2.0 fold. The lowest concentrations at which significant induction of micronuclei were found were 3.2 μM for lasiocarpine and riddelliine, 32 μM for retrorsine and echimidine, and 100 μM for seneciphylline, europine and lycopsamine. Significant induction of micronuclei by lasiocarpine, seneciphylline, and europine were achieved in Huh6 cells at similar concentrations. Reduced tail formation after hydrogen peroxide treatment was found in the crosslink comet assay for all diester type PAs, while an equimolar concentration of the monoesters europine and lycopsamine did not significantly reduce DNA migration.
+Conclusion
+The widely available human hepatoma cell lines HepG2 and Huh6 were suitable for the assessment of PA-induced genotoxicity. Selected PAs confirmed previously published potency rankings in the micronucleus assay. In HepG2 cells, the crosslinking activity was related to the ester type, which is a first report of PA mediated effects in the comet assay.}
+}
+
+@InCollection{Hartmann1995,
+  author = {Hartmann, T. and Witte, L.},
+  year = 1995,
+  title = {Chemistry, Biology and Chemoecology of the Pyrrolizidine Alkaloids},
+  booktitle = {Alkaloids: Chemical and Biological Perspectives},
+  editor = {S.W. Pelletier}, 
+  pages = {155-233},
+  publisher = {Pergamon},
+  address = {London, New York}
+}
+
+@article{Langel2011,
+  author = {Langel, D. and Ober, D. and Pelser P.B.},
+  year = 2011,
+  title = {The evolution of pyrrolizidine alkaloid biosynthesis and diversity in the Senecioneae},
+  jounrnal = {Phytochemistry Reviews},
+  number = 10,
+  pages = {3-74}
+}
+
 @article{Weininger1989,
   author = {David Weininger and Arthur Weininger and Joseph L. Weininger},
   title = {SMILES. 2. Algorithm for generation of unique SMILES notation},