@article{Wang2005, author = {Wang, Y.P. and Yan, J. and Fu, P.P. and Chou, M.W.}, title = {Human liver microsomal reduction of pyrrolizidine alkaloid N-oxides to form the corresponding carcinogenic parent alkaloid}, journal = {Toxicol Lett}, year = 2005, number = {155(3)}, pages = {411-420}, doi = {10.1016/j.toxlet.2004.11.010} } @article{Lin1998, author = {Lin, G. and Cui, Y.Y. and Hawes, E.M.}, title = {Microsomal Formation of a Pyrrolic Alcohol Glutathione Conjugate of Clivorine.  Firm evidence for the formation of a pyrrolic metabolite of an otonecine-type pyrrolizidine alkaloid}, journal = {Drug Metab Dispos}, year = 1998, number = {26(2)}, pages = {181-4} } @article{Ruan2014, author = {Ruan, J. and Yang, M. and Fu, P. and Ye, Y. and Lin, G.}, year = 2014, title = {Metabolic activation of pyrrolizidine alkaloids: Insights into the structural and enzymatic basis}, journal = {Chem. Res. Toxicol.}, number = 27, pages = {1030–1039}, doi = {10.1021/tx500071q} } @incollection{Piegorsch1991, author = {Piegorsch, W.W. and Zeiger, E.}, booktitle = {Statistical Methods in Toxicology, Lecture Notes in Medical Informatics}, editor = {Hotorn, L.}, publisher = {Springer-Verlag}, year = 1991, title = {Measuring intra-assay agreement for the Ames salmonella assay}, pages = {35–41}, } @article{Dunkel1984, author = {Dunkel, Virginia C. and Zeiger, Errol and Brusick, David and McCoy, Elena and McGregor, Douglas and Mortelmans, Kristien and Rosenkranz, Herbert S. and Simmon, Vincent F.}, title = {Reproducibility of microbial mutagenicity assays: I. Tests with Salmonella typhimurium and Escherichia coli using a standardized protocol}, journal = {Environmental Mutagenesis}, volume = {6}, number = {S2}, pages = {1-50}, keywords = {mutagenicity, Salmonella, E. coli, interlaboratory reproducibility, collaborative study, standardized protocol}, doi = {https://doi.org/10.1002/em.2860060702}, url = {https://onlinelibrary.wiley.com/doi/abs/10.1002/em.2860060702}, eprint = {https://onlinelibrary.wiley.com/doi/pdf/10.1002/em.2860060702}, year = {1984} } @article{Kamber2009, author = {Kamber, Markus and Flückiger-Isler, Sini and Engelhardt, Günter and Jaeckh, Rudolf and Zeiger, Errol}, title = "{Comparison of the Ames II and traditional Ames test responses with respect to mutagenicity, strain specificities, need for metabolism and correlation with rodent carcinogenicity}", journal = {Mutagenesis}, volume = {24}, number = {4}, pages = {359-366}, year = {2009}, month = {05}, abstract = "{The Ames II Salmonella mutagenicity assay procedure was used to test 71 chemicals, and the results were compared with those from the traditional Ames Salmonella test using the NTP database as the reference. All Ames II tests were performed using a fluctuation procedure in microplate format, using TAMix for the detection of base pair substitutions and TA98 to detect frameshift mutations. There was 84\\% agreement between the two procedures in identifying mutagens and non-mutagens, which is equivalent to the intra- and interlaboratory reproducibility of 87\\% for the traditional test. The two tests also performed similarly in their predictions of rodent carcinogenicity.}", issn = {0267-8357}, doi = {10.1093/mutage/gep017}, url = {https://doi.org/10.1093/mutage/gep017}, eprint = {https://academic.oup.com/mutage/article-pdf/24/4/359/3787533/gep017.pdf}, } @article{Rutz2020, author = {Rutz, L. and Gao, L. and Küpper, J.H. and others}, title = {Structure-dependent genotoxic potencies of selected pyrrolizidine alkaloids in metabolically competent HepG2 cells}, journal = {Arch. Toxicol.}, number = 94, pages = {4159–4172}, year = 2020, doi = {https://doi.org/10.1007/s00204-020-02895-z}, } @article{Merz2016, title = {Interim relative potency factors for the toxicological risk assessment of pyrrolizidine alkaloids in food and herbal medicines}, journal = {Toxicology Letters}, volume = {263}, pages = {44-57}, year = {2016}, issn = {0378-4274}, doi = {https://doi.org/10.1016/j.toxlet.2016.05.002}, url = {https://www.sciencedirect.com/science/article/pii/S0378427416300911}, author = {K.H. Merz and D. Schrenk}, keywords = {Pyrrolizidine alkaloids, Relative potency factors, Risk assessment, Toxicity}, abstract = {Pyrrolizidine alkaloids (PAs) are among the most potent natural toxins occurring in a broad spectrum of plant species from various families. Recently, findings of considerable contamination of teas/herbal infusions prepared from non-PA plants have been reported. These are obviously due to cross-contamination with minor amounts of PA plants and can affect both food and herbal medicines. Another source of human exposure is honey collected from PA plants. These findings illustrate the requirement for a comprehensive risk assessment of PAs, hampered by the enormous number of different PA congeners occurring in nature. Up to now, risk assessment is based on the carcinogenicity of certain PAs after chronic application to rats using the sum of detected PAs as dose metric. Because of the well-documented large structure-dependent differences between sub-groups of PA congeners with respect to their genotoxicity and (cyto)toxicity, however, this procedure is inadequate. Here we provide an overview of recent attempts to assess the risk of PA exposure and the available literature on the toxic effects and potencies of different congeners. Based on these considerations, we have derived interim Relative Potency (REP) factors for a number of abundant PAs suggesting a factor of 1.0 for cyclic di-esters and open-chain di-esters with 7S configuration, of 0.3 for mono-esters with 7S configuration, of 0.1 for open-chain di-esters with 7R configuration and of 0.01 for mono-esters with 7R configuration. For N-oxides we suggest to apply the REP factor of the corresponding PA. We are confident that the use of these values can provide a more scientific basis for PA risk assessment until a more detailed experimental analysis of the potencies of all relevant congeners can be carried out.} } @article{Yan2008, author = {J. Yan and Q. Xia and M.W. Chou and P.P. Fu}, year = 2008, title =   {Metabolic activation of retronecine and retronecine {N-oxide} - formation of {DHP}-derived {DNA} adducts}, journal = {Toxicol. Ind. Health}, number = {24(3)}, pages = {181-8}, doi =  {https://doi.org/https://doi.org/10.1177/0748233708093727}, } @misc{HMPC2014, author = {HMPC}, year = 2014, title = {Public statement on the use of herbal medicinal products 5 containing toxic, unsaturated pyrrolizidine alkaloids (PAs), European Medicines Agency, Committee on Herbal Medicinal Products (HMPC) EMA/HMPC/8931082011}, } @misc{EMA2020, author = {EMA}, year = 2020, title = {Public statement on the use of herbal medicinal products containing toxic, unsaturated pyrrolizidine alkaloids (PAs) including recommendations regarding contamination of herbal medicinal products with pyrrolizidine alkaloids. European Medicines Agency, Committee on Herbal Medicinal Products (HMPC), EMA/HMPC/893108/2011 Rev.1}, } @article{Forsch2018, author = {Forsch, K. and V. Schöning and L. Disch and B. Siewert and M. Unger and J. Drewe}, year = 2018, title = {Development of an in vitro screening method of acute cytotoxicity of the pyrrolizidine alkaloid lasiocarpine in human and rodent hepatic cell lines by increasing susceptibility}, journal = {Journal of Ethnopharmacology}, number = 217, pages = {134-139}, doi = {https://doi.org/10.1016/j.jep.2018.02.018}, } @misc{ICH2017, author = {{International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)}}, title = {Assessment and control of {DNA} reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk M7(R1)}, year = 2017, note = {\url{https://database.ich.org/sites/default/files/M7_R1_Guideline.pdf}}, note = {Accessed: 29-03-2021}, } @misc{ECHA2017, author ={{European Chemicals Agency (ECHA)}}, title = {Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7a: Endpoint specific guidance}, year = 2017, note ={\url{https://echa.europa.eu/documents/10162/13632/information_requirements_r6_en.pdf}}, note = {Accessed: 29-03-2021}, isbn = {978-92-9495-970-6}, doi = {10.2823/337352}}, } @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}, doi = {https://doi.org/https://doi.org/10.1016/0165-7992(92)90050-r} } @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}, doi = {https://doi.org/10.1002/jat.1504} } @article{Li2013, title = {Assessment of pyrrolizidine alkaloid-induced toxicity in an in vitro screening model}, journal = {Journal of Ethnopharmacology}, volume = {150}, number = {2}, pages = {560-567}, year = {2013}, issn = {0378-8741}, doi = {https://doi.org/10.1016/j.jep.2013.09.010}, url = {https://www.sciencedirect.com/science/article/pii/S0378874113006430}, author = {Y. H. Li and W. L. T. Kan and N. Li and G. Lin}, keywords = {Pyrrolizidine alkaloids, model, Cytotoxicity, HepG2 cell}, abstract = {Ethnopharmacological relevance Pyrrolizidine alkaloids (PAs) are a group of heterocyclic phytotoxins present in a wide range of plants. The consumption of PA-containing medicinal herbs or PA-contaminated foodstuffs has long been reported to cause human hepatotoxicity. However, the degrees of hepatotoxicity of different PAs are unknown, which makes it difficult to determine a universal threshold of toxic dose of individual PAs for safe regulation of PA-containing natural products. The aim of the present study is to develop a simple and convenient in vitro model to assess the hepatotoxicity of different PAs. Material and methods Six common cytotoxicity assays were used to evaluate the hepatotoxicity of different PAs in human hepatocellular carcinoma HepG2 cells. Results The combination of MTT and bromodeoxyuridine incorporation (BrdU) assays demonstrated to be a suitable method to evaluate the toxic potencies of various PAs in HepG2 cells, and the results indicated that otonecine-type PA (clivorine: IC20=0.013±0.004mM (MTT), 0.066±0.031mM (BrdU)) exhibited significantly higher cytotoxic and anti-proliferative effects than retronecine-type PA (retrorsine: IC20=0.27±0.07mM (MTT), 0.19±0.03mM (BrdU)). While as expected, the known less toxic platyphylline-type PA (platyphylline: IC20=0.85±0.11mM (MTT), 1.01±0.40mM (BrdU)) exhibited significantly less toxicity. The different cytotoxic and anti-proliferative potencies of various PAs in the same retronecine-type could also be discriminated by using the combined MTT and BrdU assays. In addition, the developed assays were further utilized to test alkaloid extract of Gynura segetum, a senecionine and seneciphylline-containing herb, the overall cytotoxicity of two PAs in the extract was comparable to that of these two PAs tested individually. Conclusion Using the developed in vitro model, the cytotoxicity of different PAs and the extract of a PA-containing herb were investigated in parallel in one system, and their different hepatotoxic potencies were determined and directly compared for the first time. The results suggested that the developed model has a great potential to be applied for the quick screening of the toxicity of PAs and PA-containing natural products.} } @article{Xia2013, author = {Q. Xia and Y. Zhao and L.S. Von Tungeln and D.R. Doerge and G. Lin and G. Cai and P.P. Fu}, 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}, doi = {https://doi.org/https://doi.org/10.1021/tx400241c} } @article{Fu2004, author = {P. P. Fu 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}, doi = {https://doi.org/https://doi.org/10.1081/dmr-120028426} } @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 = {J. Louisse and D. Rijkers and G. Stoopen and W. J. Holleboom and M. Delagrange and E. Molthof and P. P.J. Mulder and R. L.A.P. Hoogenboom and M. Audebert and A. 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 = {A. Allemang and C. Mahony and C. Lester and S. 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 = {N. S. A. Hadi and E. E. Bankoglu and L. Schott and E. Leopoldsberger and V. Ramge and O. Kelber and H. Sievers and H. 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}, journal = {Phytochemistry Reviews}, number = 10, pages = {3-74} } @article{Weininger1989, author = {D. Weininger and A. Weininger and J. L. Weininger}, title = {SMILES. 2. Algorithm for generation of unique SMILES notation}, journal = {J. Chem. Inf. Comput. Sci.}, year = 1989, number = 29, pages = {97–101}, doi = {https://doi.org/10.1021/ci00062a008}, } @article{Willighagen2017, author = {Willighagen, E.L. and Mayfield, J.W. and Alvarsson, J. et al.}, title = {The Chemistry Development Kit (CDK) v2.0: atom typing, depiction, molecular formulas, and substructure searching}, journal = {J. Cheminform.}, number = {9(33)}, year = 2017, doi = {https://doi.org/10.1186/s13321-017-0220-4} } @article{Schoening2017, author = {V. Schöning and F. Hammann and M. Peinl and J. Drewe}, title = {Editor's Highlight: Identification of Any Structure-Specific Hepatotoxic Potential of Different Pyrrolizidine Alkaloids Using Random Forests and Artificial Neural Networks}, journal = {Toxicol. Sci.}, year = 2017, number = 160, pages = {361-370}, doi = {https://doi.org/https://doi.org/10.1093/toxsci/kfx187}, } @book{Mattocks1986, author = {Mattocks, A.R.}, title = {Chemistry and Toxicology of Pyrrolizidine Alkaloids}, year = 1986, publisher = {Academic Press}, } @article{Maaten2008, author = {van der Maaten, L.J.P. and Hinton, G.E.}, title = {Visualizing Data Using {t-SNE}}, journal = {Journal of Machine Learning Research}, year = 2008, number = 9, pages = "2579–2605" } @article{Helma2018, author = { C. Helma and D. Vorgrimmler and D. Gebele and M. Gütlein and B. Engeli and J. Zarn and B. Schilter and E. Lo Piparo}, title = "Modeling Chronic Toxicity: A comparison of experimental variability with {(Q)SAR}/read-across predictions", year = 2018, journal = {Frontiers in Pharmacology}, number = 9, pages = "413", } @article{Benigni1988, author = { R. Benigni and A. Giuliani }, title = {Computer‐assisted analysis of interlaboratory Ames test variability}, journal = {Journal of Toxicology and Environmental Health}, volume = {25}, number = {1}, pages = {135-148}, year = {1988}, publisher = {Taylor & Francis}, doi = {10.1080/15287398809531194}, note ={PMID: 3418743}, URL = { https://doi.org/10.1080/15287398809531194 }, eprint = { https://doi.org/10.1080/15287398809531194 } } @Article{Kazius2005, author = "Kazius, J. and McGuire, R. and Bursi, R.", year = 2005, title = "Derivation and validation of toxicophores for mutagenicity prediction", journal = "J Med Chem", number = 48, pages = "312-20", } @article{Hansen2009, author = {Hansen, K. and Mika, S. and Schroeter, T. and Sutter, A. and ter Laak, A. and Steger-Hartmann, T. and Heinrich, N. and Müller, K. R.}, title = {Benchmark Data Set for in Silico Prediction of Ames Mutagenicity}, journal = {Journal of Chemical Information and Modeling}, volume = {49}, number = {9}, pages = {2077-2081}, year = {2009}, doi = {10.1021/ci900161g}, note ={PMID: 19702240}, URL = { https://doi.org/10.1021/ci900161g }, eprint = { https://doi.org/10.1021/ci900161g } } @article{Yap2011, author = "Yap, C.W.", year = 2011, title = {{PaDEL-descriptor}: an open source software to calculate molecular descriptors and fingerprints}, journal = "Journal of computational chemistry", number = 32, pages = "1466-74", doi = {https://doi.org/10.1002/jcc.21707} } @Article{Bender2004, author = "A. Bender and H. Y. Mussa and R. C. Glen and S. Reiling", title = "Molecular Similarity Searching Using Atom Environments, Information-Based Feature Selection, and a Naïve Bayesian Classifier", journal = "Journal of Chemical Information and Computer Sciences", volume = "44", number = "1", pages = "170--178", year = "2004", DOI = "10.1021/ci034207y", note = "PMID: 14741025", URL = "http://dx.doi.org/10.1021/ci034207y", eprint = "http://dx.doi.org/10.1021/ci034207y", } @article{OBoyle2011a, abstract = {{BACKGROUND: A frequent problem in computational modeling is the interconversion of chemical structures between different formats. While standard interchange formats exist (for example, Chemical Markup Language) and de facto standards have arisen (for example, SMILES format), the need to interconvert formats is a continuing problem due to the multitude of different application areas for chemistry data, differences in the data stored by different formats (0D versus 3D, for example), and competition between software along with a lack of vendor-neutral formats.RESULTS: We discuss, for the first time, Open Babel, an open-source chemical toolbox that speaks the many languages of chemical data. Open Babel version 2.3 interconverts over 110 formats. The need to represent such a wide variety of chemical and molecular data requires a library that implements a wide range of cheminformatics algorithms, from partial charge assignment and aromaticity detection, to bond order perception and canonicalization. We detail the implementation of Open Babel, describe key advances in the 2.3 release, and outline a variety of uses both in terms of software products and scientific research, including applications far beyond simple format interconversion.CONCLUSIONS: Open Babel presents a solution to the proliferation of multiple chemical file formats. In addition, it provides a variety of useful utilities from conformer searching and 2D depiction, to filtering, batch conversion, and substructure and similarity searching. For developers, it can be used as a programming library to handle chemical data in areas such as organic chemistry, drug design, materials science, and computational chemistry. It is freely available under an open-source license from http://openbabel.org.}}, added-at = {2019-03-11T21:00:05.000+0100}, author = {O'Boyle, N. and Banck, M. and James, C. and Morley, C. and Vandermeersch, T. and Hutchison, G.}, biburl = {https://www.bibsonomy.org/bibtex/27ab2699fef73132efcfa6853c3031bf0/fairybasslet}, booktitle = {Journal of Cheminformatics}, citeulike-article-id = {9866193}, citeulike-linkout-0 = {http://dx.doi.org/doi:10.1186/1758-2946-3-33}, citeulike-linkout-1 = {http://www.jcheminf.com/content/3/1/33}, citeulike-linkout-2 = {http://dx.doi.org/10.1186/1758-2946-3-33}, citeulike-linkout-3 = {http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3198950/}, citeulike-linkout-4 = {http://view.ncbi.nlm.nih.gov/pubmed/21982300}, citeulike-linkout-5 = {http://www.hubmed.org/display.cgi?uids=21982300}, citeulike-linkout-6 = {http://link.springer.com/article/10.1186/1758-2946-3-33}, day = 07, doi = {doi:10.1186/1758-2946-3-33}, interhash = {c20842ab14c8a3bbd2dcf3e8072b82d1}, intrahash = {7ab2699fef73132efcfa6853c3031bf0}, issn = {1758-2946}, journal = {J. Cheminf.}, keywords = {chemical-file-formats computer-program cpsst open-babel open-source software-library toolkit}, month = oct, number = 1, pages = 33, pdf = {file:///H:/publications/OBoyle2011a.pdf}, pmcid = {PMC3198950}, pmid = {21982300}, posted-at = {2011-11-08 10:20:24}, priority = {2}, publisher = {Chemistry Central Ltd}, timestamp = {2019-03-11T21:06:37.000+0100}, title = {{Open Babel: An open chemical toolbox}}, url = {http://www.jcheminf.com/content/3/1/33}, volume = 3, year = 2011 } @article{Rücker2007, author = "Rücker, C and Rücker, G and Meringer, M.", year = 2007, title = "y-Randomization and Its Variants in QSPR/QSAR", journal = "J. Chem. Inf. Model.", number = 47, pages = "2345-57" } @Article{Maunz2013, DOI = "10.3389/fphar.2013.00038", URL = "http://dx.doi.org/10.3389/fphar.2013.00038", year = "2013", publisher = "Frontiers Media {SA}", volume = "4", author = "Andreas Maunz and Martin G{\"{u}}tlein and Micha Rautenberg and David Vorgrimmler and Denis Gebele and Christoph Helma", title = "lazar: a modular predictive toxicology framework", journal = "Frontiers in Pharmacology", } @Article{doi:10.1021/ci00057a005, author = "D. Weininger", title = "SMILES, a chemical language and information system. 1. Introduction to methodology and encoding rules", journal = "Journal of Chemical Information and Computer Sciences", volume = "28", number = "1", pages = "31--36", year = "1988", DOI = "10.1021/ci00057a005", URL = "http://dx.doi.org/10.1021/ci00057a005", eprint = "http://dx.doi.org/10.1021/ci00057a005", } @Article{OBoyle2011, DOI = "10.1186/1758-2946-3-33", URL = "http://dx.doi.org/10.1186/1758-2946-3-33", year = "2011", publisher = "Springer Science and Business Media", volume = "3", number = "1", pages = "33", author = "Noel M OBoyle and Michael Banck and Craig A James and Chris Morley and Tim Vandermeersch and Geoffrey R Hutchison", title = "Open Babel: An open chemical toolbox", journal = "Journal of Cheminformatics", } @Article{mazzatorta08, author = "Paolo Mazzatorta and Manuel Dominguez Estevez and Myriam Coulet and Benoit Schilter", title = "Modeling Oral Rat Chronic Toxicity", journal = "Journal of Chemical Information and Modeling", volume = "48", number = "10", pages = "1949--1954", year = "2008", DOI = "10.1021/ci8001974", note = "PMID: 18803370", URL = "http://dx.doi.org/10.1021/ci8001974", eprint = "http://dx.doi.org/10.1021/ci8001974", } @Manual{pls, title = "pls: Partial Least Squares and Principal Component Regression", author = "Bjørn-Helge Mevik and Ron Wehrens and Kristian Hovde Liland", year = "2015", note = "R package version 2.5-0", URL = "https://CRAN.R-project.org/package=pls", } @Article{Kuhn08, author = "Max Kuhn", title = "Building predictive models in R using the caret package", journal = "J. of Stat. Soft", year = "2008", } @Article{Jeliazkova15, author = "Nina Jeliazkova and Charalampos Chomenidis and Philip Doganis and Bengt Fadeel and Roland Grafström and Barry Hardy and Janna Hastings and Markus Hegi and Vedrin Jeliazkov and Nikolay Kochev and Pekka Kohonen and Cristian R. Munteanu and Haralambos Sarimveis and Bart Smeets and Pantelis Sopasakis and Georgia Tsiliki and David Vorgrimmler and Egon Willighagen", title = "The eNanoMapper database for nanomaterial safety information", journal = "Beilstein J. Nanotechnol.", pages = "1609–1634", number = "6", year = "2015", DOI = "doi:10.3762/bjnano.6.165", } @TechReport{Fowler2011, author = "B. Fowler and S. Savage and B. Mendez", year = "2011", title = "White paper: Protecting public health in the 21st century: the case for computational toxicology", institution = "ICF International, Inc.icfi.com.", } @Article{Cotterill2008, author = "Cotterill, J.V. and Chaudry, M.Q. and Mattews, W. and R. W. Watkins", year = "2008", title = "In silico assessment of toxicity of heat-generated food contaminants", journal = "Food Chemical Toxicology", number = "46(6)", pages = "1905--1918", } @Article{Grob2006, author = "Grob, K. and Biedermann, M. and Scherbaum, E. and Roth, M. and K. Rieger", year = "2006", title = "Food contamination with organic materials in perspective: packaging materials as the largest and least controlled source? A view focusing on the European situation", journal = "Crit. Rev. Food. Sci. Nutr.", number = "46", pages = "529--35", DOI = "10.1080/10408390500295490", } @Article{LoPiparo2011, author = "Lo Piparo, E. and Worth, A. and Manibusan, A. and Yang, C. and Schilter, B. and Mazzatorta, P. and Jacobs, M.N. and Steinkelner, H. and L. Mohimont", year = "2011", title = "Use of Computational tools in the field of food safety", journal = "Regulatory Toxicology and Pharmacology", number = "60(3)", pages = "354--362", } @Article{LoPiparo2014, author = "Lo Piparo, E. and Maunz, A. and Helma, C. and Vorgrimmler, D. and Schilter, B.", year = "2014", title = "Automated and reproducible read-across like models for predicting carcinogenic potency", journal = "Regulatory Toxicology and Pharmacology", number = "70", pages = "370--378", } @Article{Schilter2014, author = "Schilter, B. and Benigni, R. and Boobis, A. and Chiodini, A. and Cockburn, A. and Cronin, M.T. and Lo Piparo, E. and Modi, S. and Thiel A. and A. Worth", title = "Establishing the level of safety concern for chemicals in food without the need for toxicity testing", year = "2014", journal = "Regulatory Toxicology and Pharmacology", number = "68", pages = "275--298", } @Article{Stanton2016, author = "Stanton, K. and F.H. Krusezewski", year = "2016", title = "Quantifying the benefits of using read-across and in silico techniques to fullfill hazard data requirements for chemical categories", journal = "Regulatory Toxicology and Pharmacology", number = "81", pages = "250--259", DOI = "10.1016/j-yrtph.2016.09.004.", } @Article{Zarn2011, author = "Zarn, J.A. and B.E. Engeli and J.R. Schlatter", year = "2011", title = "Study parameters influencing {NOAEL} and {LOAEL} in toxicity feeding studies for pesticides: exposure duration versus dose decrement, dose spacing, group size and chemical class", journal = "Regul. Toxicol. Pharmacol.", number = "61", pages = "243--250", } @Article{Zarn2013, author = "J.A. Zarn and B.E. Engeli and J.R. Schlatter", year = "2013", title = "Characterization of the dose decrement in regulatory rat pesticide toxicity feeding studies", journal = "Regul. Toxicol. Pharmacol.", number = "67", pages = "215--220", } @article{EFSA2011, author = {EFSA}, title = {Scientific Opinion on Pyrrolizidine alkaloids in food and feed}, journal = {EFSA Journal}, year = 2011, number = 9, pages = {1-134}, doi = {https://doi.org/10.2903/j.efsa.2011.2406}, } @article{EFSA2016, author = {{EFSA}}, title = {Guidance on the establishment of the residue definition for dietary assessment: {EFSA} panel on Plant Protect Products and their Residues ({PPR})}, journal = {EFSA Journal}, year = 2016, number = 14, pages = {1-12}, doi = {https://doi.org/10.2903/j.efsa.2016.4549}, } @TechReport{ECHA2008, author = "{ECHA}", year = "2008", title = "Guidance on information requirements and chemical safety assessment, Chapter R.6: {QSARs} and grouping of chemicals", institution = "ECHA", } @Misc{EFSA2014, author = "{EFSA}", year = "2014", title = "Rapporteur Member State assessment reports submitted for the {EU} peer review of active substances used in plant protection products", URL = "http://dar.efsa.europa.eu/dar-web/provision", note = "accessed 8.1.2015", } @Misc{HealthCanada2016, author = "{Health Canada}", year = "2016", URL = "https://www.canada.ca/en/health-canada/services/chemical-substances/chemicals-management-plan.html", } @InCollection{OECD2015, author = "{OECD}", year = "2015", title = "Fundamental and guiding principles for {(Q)SAR} analysis of chemicals carcinogens with mechanistic considerations Monograph 229 {ENV/JM/MONO(2015)46}", chapter = "229", booktitle = "Series on Testing and Assessment No 229", } @InCollection{Schilter2013, author = "Schilter, B. and Constable, A. and Perrin, I.", title = "Naturally occurring toxicants of plant origin: risk assessment and management considerations", year = "2013", booktitle = "Food Safety Management: a practical guide for industry", chapter = "3", editor = "Y. Motarjemi", publisher = "Elsevier", pages = "45--57", } @Misc{EPA2011, title = "Fact Sheets on New Active Ingredients", author = "{US EPA}", year = "2011", note = "this database was not further maintained by US EPA. Only data used until 27.11.2014, accessed 27.4.11 A.D.", } @TechReport{WHO2011, author = "WHO", year = "2011", title = "Joint {FAO/WHO} Meeting on Pesticide Residues ({JMPR}) publications", URL = "http://www.who.int/foodsafety/publications/jmpr-monographs/en/", note = "accessed 20.3.15 A.D.", }