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AOP NEWS


October 2018

AOP NEWS – January 2019

AOP Training:

  • Training at SOT 2019: The Human Toxicology Project Consortium and the Physicians Committee for Responsible Medicine are cosponsoring a seminar on AOPS:

AOP Hands-on Training: Building the Foundation for Predictive Toxicology

Wednesday, March 13, 4:30 PM–6:30 PM

Hilton Baltimore
401 West Pratt St, Baltimore, MD 21201

  • Training in Zagreb:  In December 2018, Dr. Martinovic-Weigelt led a two day AOP workshop in Zagreb, Croatia (40 participants from Croatia and Slovenia representing academia, industry and government). The training included introduction to AOPs and active learning exercises that focused on AOP development and weight of evidence evaluation. The workshop was executed as a part of AOP-related research project funded by Unity Through Knowledge Fund (UKF) - Investigators: Drs. Hudina (U of Zagreb, Croatia), Martinovic-Weigelt  (U of St. Thomas, MN, USA). UKF’s mission is to unite scientific and professional potential in Croatia and diaspora in development of the knowledge based society.  (contact: Dalma Martinovic - mart6831@stthomas.edu)
  • Training in China:  A Continuing Education course was held on Oct 9, 2018, before the 4th International Conference on Toxicity Testing Alternatives and Translational Toxicology and 2nd Asian Congress on Alternatives in Guangzhou, China. Roughly 100 scientists mostly from China but also from Japan and South Korea participated. An introduction to AOPs and the OECD AOP framework was provided by Catherine Willett (HSI), followed by a demonstration of the AOP wiki by Clemens Wittwehr (EU-JRC). Four case study AOPs were presented: Strategy for AOP development in Chemical Mixtures, Seokjoo Yoon (Korea Institute of Toxicology); A hR activation leading to early life stage mortality Pu Xia (Nanjing University); Development of AOP154: Inhibition of calcineurin leading to impaired T-cell dependent antibody response, Shigeru Hisada (Japan ASKA Pharmaceutical Co., Ltd); Development of AOP for screening of inhalation toxicity inducing chemicals, Choi Jinhee (Korea University of Seoul) followed by closing remarks by Prof Peng Shuangqing (Institute of Disease Control and Prevention).  Contact: Kate Willett kwillett@humanesociety.org)

 

AOPWiki

  • JRC Support for AOPWiki: The JRC has announced that they are now contributing to the continuing AOPWiki evolutive maintenance effort.  This includes providing financial support for a new development server and programming support for the AOPWiki.  This will not only guarantee the professional continuation of the AOPWiki service, but also allow the implementation of a series of suggestions for improvements in the AOPWiki.
  • The SAAOP has renewed the contract for the production server for 3 years. This was done to ensure adequate time for development and transition to AOP-KB 2.0.

 

OECD EAGMST News:  

  • New AOPs endorsed by OECD:  Three new AOPs were published in October 2018 on the OECD Series on Adverse Outcome Pathways, following Joint Meeting declassification.  
    • Adverse Outcome Pathway on Inhibition of the mitochondrial complex I of nigro-striatal neurons leading to parkinsonian motor deficits (DOI:https://doi.org/10.1787/b46c3c00-en)
    • Adverse Outcome Pathway on chronic binding of antagonist to N-methyl-D-aspartate receptors during brain development leading to neurodegeneration with impairment in learning and memory in aging (DOI:https://doi.org/10.1787/95f569ad-en)
    • Adverse Outcome Pathway on Androgen receptor agonism leading to reproductive dysfunction (in repeat-spawning fish) (DOI:https://doi.org/10.1787/b0c6838a-en)
    • All published OECD AOPs can be found at:
    • https://www.oecd-ilibrary.org/environment/oecd-series-on-adverse-outcome-pathways_2415170x
  • Results from the latest OECD EAGMST conference call (18 December 2018):
    • The following AOP was approved by EAGMST and is ready for WNT and WPHA submission for endorsement pending minor revisions:
      • AOP 202: “Inhibitor binding to topoisomerase II leading to infant leukaemia” was.  
    • The following seven AOPs will undergo WNT and WPHA reviews in the end of January 2019:
      • AOP 6: Antagonist binding to PPARalpha leading to starvation-like body-weight loss
      • AOP 10: Binding to the picrotoxin site of ionotropic GABA receptors leading to epileptic seizures
      • AOP 131: AhR activation leading to uroporphyria
      • AOP 150: Aryl hydrocarbon receptor activation leading to embryo lethality via cardiotoxicity
      • AOP 21: AhR activation leading to embryo toxicity
      • AOP 54: Inhibition of Na+/I- symporter (NIS) decreases TH synthesis leading to learning and memory deficits in children
      • AOP 42: Inhibition of Thyroperoxidase and Subsequent Adverse Neurodevelopmental Outcomes in Mammals
    • The following six AOPs were cleared following internal EAGMST review earlier in 2018 and are or will soon be ready for the external review, pending engagement of WNT or the WPHA in the organisation of AOP reviews. .
      • AOP 107 (BIAC): Constitutive androstane receptor activation leading to hepatocellular adenomas and carcinomas in the mouse and the rat
      • AOP 17 (Switzerland): Binding of electrophilic chemicals to SH(thiol)-group of proteins and /or to seleno-proteins during brain development leads to impairment of learning and memory
      • AOP 173 (Canada): Secretion of inflammatory cytokines leading to lung fibrosis
      • AOP 154 (Japan): Inhibition of Calcineurin Activity Leading to Impaired T-Cell Dependent Antibody Response
      • AOP 220 (Canada): Chronic Cyp2E1 Activation Leading to Liver Cancer
      • AOP 212 (Japan): Histone deacetylase inhibition leading to testicular toxicity
    • AOP Workplan: The following AOPs have been added to the AOP Workplan.
      • Wnt ligand stimulation and Wnt signalling activation lead to cancer malignancy
      • Decreased Trypsin activity leading to pancreatic acinar cell tumor formation in rodents 
      • Vitamin D3 receptor activation leading to adrenal pheochromocytoma formation in rats
      • Increased low-digestible carbohydrates in the colon leading to adrenal pheochromocytoma formation in rats 
      • Sodium glucose cotransporter (SGLT1) inhibition leading to adrenal pheochromocytoma formation in rats
      • Inhibition of vesicular monoamine transporter (VMAT) leading to adrenal pheochromocytoma formation in rats
      • D2 receptor antagonism leading to pituitary tumor in mice
      • H/K-ATPase (proton pump) inhibition leading to gastric carcinoid tumor formation in rodents
      • Histamine receptor 2 blockade leading to gastric carcinoid tumor formation in rodents
      • GLP-1 receptor activation leading to thyroid C-cell tumors in rodents
      • Alpha-glucosidase inhibition leading to renal tubular tumors in rats
      • Anti-dopaminergic activity leading to pancreatic islet cell tumor in rats
      • Increased low-digestible carbohydrates in the colon leading to Leydig cell tumor in rats
      • Dopamine agonism/ enhancement leading to Leydig cell tumor in rats
      • TPO inhibition leading to impaired fertility in fish
      • Activation of estrogen receptors in immune cells exacerbates allergic responses
      • Inhibition of JAK3 leading to impairment of TDAR
      • Activation of TLR 7 leading to psoriatic skin disease

 

AOP Handbook Team:

  • The AOP Handbook team is finalising a discussion document on the benefits and risks of using the KERs as the “pragmatic” unit of development and reviewing. They were also tasked to identify best practices for sharing KEs and KERs and prepare a discussion paper on domain of applicability of AOPs in relation to human relevance. Due to the departure of some members and the increase in the delegated tasks, the AOP Handbook group plans to launch soon a call for members of EAGMST to contribute with their expertise to the group.. Contact:  Magda Sachana Magdalini.SACHANA@oecd.org 

 

AOP Framework Analysis:

  • The JRC has launched an AOP Framework study, which will analyse the framework's suitability to address regulatory priorities and support regulatory processes and decision-making. The focus of the study will be the AOP knowledge users, i.e. regulatory toxicologists, risk assessors and risk managers. An online survey will help identifying ca. 75 suitable telephone interviewees, from which 10-15 stakeholders will be selected to form a focus group, which will then be examined in-depth (on-site, with advanced ethnological methods) to arrive at observations and suggestions to adapt the framework to best meet stakeholder needs. The results of the study will be available by February 2020

 

AOP  Links 

 

Recent Papers:

  • Pollesch NL, Villeneuve DL, and O’Brien JM. Extracting and Benchmarking Emerging Adverse Outcome Pathway Knowledge. Tox Sci. 2019. (In press)

  • Jeong J, Song T, Chatterjee N, Choi I, Cha YK, Choi J.  Developing adverse outcome pathways on silver nanoparticle-induced reproductive toxicity via oxidative stress in the nematode Caenorhabditis elegans using a Bayesian network model.   Nanotoxicology. 2019 Jan 21:1-16. doi: 10.1080/17435390.2018.1529835. [Epub ahead of print]

  • Foran CM, Rycroft T, Keisler J, Perkins EJ, Linkov I, Garcia-Reyero N.  A modular approach for assembly of quantitative adverse outcome pathways.  ALTEX. 2019 Jan 20. doi: 10.14573/altex.1810181.

  • Perkins EJ, Gayen K, Shoemaker JE, Antczak P, Burgoon L, Falciani F, Gutsell S, Hodges G, Kienzler A, Knapen D, McBride M, Willett C, Doyle FJ, Garcia-Reyero N.   Chemical hazard prediction and hypothesis testing using quantitative adverse outcome pathways. ALTEX. 2019 ALTEX. 2019;36(1):91-102. doi: 10.14573/altex.1808241.

  • Goodchild CG, Simpson AM, Minghetti M, DuRant SE.  Bioenergetics-Adverse Outcome Pathway (AOP): linking organismal and suborganismal energetic endpoints to adverse outcomes.  Environ Toxicol Chem. 2019   Jan;38(1):27-45. doi: 10.1002/etc.4280.

  • Oki NO, Farcal L, Abdelaziz A, Florean O, Doktorova TY, Exner T, Kohonen P, Grafström R, Hardy B.  Integrated analysis of in vitro data and the adverse outcome pathway framework for prioritization and regulatory applications: An exploratory case study using publicly available data on piperonyl butoxide and liver models.  Toxicol In Vitro. 2019 Feb;54:23-32. doi: 10.1016/j.tiv.2018.09.002.

  • Willett, C. 2019. The Use of Adverse Outcome Pathways (AOPs) to Support Chemical Safety Decisions Within the Context. In: Kojima H., Seidle T., Spielmann H. (eds) Alternatives to Animal Testing. Springer, Singapore.

  • Martens M, Verbruggen T, Nymark P, Grafström R, Burgoon LD, Aladjov H, Torres Andón F, Evelo CT, Willighagen EL.   Introducing WikiPathways as a Data-Source to Support Adverse Outcome Pathways for Regulatory Risk Assessment of Chemicals and Nanomaterials.  Front Genet. 2018 Dec 21;9:661. doi: 10.3389/fgene.2018.00661.

  • Chauhan V, Said Z, Daka J, Sadi B, Bijlani D, Marchetti F, Beaton D, Gaw A, Li C, Burtt J, Leblanc J, Desrosiers M, Stuart M, Brossard M, Vuong NQ, Wilkins R, Qutob S, McNamee J, Wang Y, Yauk C.  Is there a role for the adverse outcome pathway framework to support radiation protection?   Int J Radiat Biol. 2018 Oct 29:1-8. doi: 10.1080/09553002.2019.1532617.