Introduction to the AOP framework concept and online course

Transcription

1 Intrductin t the AOP framewrk cncept and nline curse Catherine Willett Crdinatr, Human Txiclgy Prject Directr, Science Plicy HSUS/HSI kwillett@humanesciety.rg

2 Outline Why Need fr mre efficient tls fr chemcial risk assessment Need t better use ur existing and future data and knwledge What The Adverse Outcme Pathway framewrk Purpse, definitin Hw Relatinal knwledgebase Guidance Evaluatin Training and free curse

3 Issue #1: t many chemicals, current system inadequate e.g. tens f thusands f chemicals await assessment e.g. 95% clinical failure rate fr new drugs in spite f increased spending Faster, mre relevant appraches needed acrss sectrs

4 Issue #2: The need t better leverage ur existing knwledge T much data! Decades f research and testing data Glbal scientific utput dubles every 9 years Where is the data?! Jurnal articles, reprts, labratry ntebks, agency archives, Institutinal and gvernment databases

5 Better access, better rganizatin leads t better understanding PDFs Fragmented Siled Prprietary (adapted frm D. Villeneuve) Searchable Machine-readable Linked Facilitating cllabratin Aviding duplicatin

6 Adverse Outcme Pathway framewrk: linking mlecular initiatin t adverse utcmes? A practical slutin fr a practical prblem: Hw t use mlecular understanding t make better decisins abut chemical safety Prvides a framewrk fr cllecting, rganizing and evaluating bilgical infrmatin

7 AOPs: Linking mlecular infrmatin t adverse utcmes Chemical prperties Prtein binding DNA binding Receptr/ligand binding Gene activatin Prtein prductin Altered signaling Altered physilgy Altered tissue develpment r functin Impaired develpment Impaired reprductin lethality Impaired reprductin/ survival, Ppulatin crash A sequence f events beginning with initial interactins f a stressr with a bimlecule in a target cell r tissue (the mlecular initiating event), prgressing thrugh a dependent series f intermediate events (key events) culminating with an adverse utcme* *if cmpensatry mechanisms are verwhelmed

8 AOPs: Prvides scaffld fr rganizing, evaluating and understanding data Mlecular data Regulatry Endpints Chemical prperties Prtein binding DNA binding Receptr/ligand binding Gene activatin Prtein prductin Altered signaling Altered physilgy Altered tissue develpment r functin Impaired develpment Impaired reprductin lethality Impaired reprductin/ survival, Ppulatin crash High Thrughput Mechanistic Txiclgy Data ( mics, bimarkers) Guideline Studies Clinical, Epidemilgy Ec Field Studies

9 Essential elements f an AOP Chemical prperties Prtein binding DNA binding Receptr/ligand binding Key Events (KEs) ndes Gene activatin Prtein prductin Altered signaling Altered physilgy Altered tissue develpment r functin Change in bilgical r physilgical state Measurable and essential fr prgressin Impaired develpment Impaired reprductin lethality Mlecular Initiating Event (MIE): specialized KE that represents the initial pint f stressr interactin with the rganism Adverse Outcme (AO): specialized KE f regulatry significance Key Event Relatinships (KERs) Cnnectin between tw key events Critical fr assembling evidence in supprt f the AO Facilitates inference r extraplatin Impaired reprductin/ survival, Ppulatin crash

10 Building an AOP Chemical prperties Prtein binding DNA binding Receptr/ligand binding Gene activatin Prtein prductin Altered signaling Altered physilgy Altered tissue develpment r functin Impaired develpment Impaired reprductin lethality Impaired reprductin/ survival, Ppulatin crash Start anywhere but ne AOP = ne MIE leading t ne AO as a pragmatic unit Gather all existing knwledge Nt every detail, but critical steps r check-pints Cllabratin is encuraged Evaluate and dcument the infrmatin Refer t extensive OECD guidance Translate and capture infrmatin as a pathway in the AOP Wiki

11 Fundamental principles f AOP develpment AOPs are mdular Key events and relatinships can be shared by multiple AOPs AOPs are living dcuments AOP descriptins can be expected t evlve ver time As descriptins are updated and expanded all AOP descriptins they link t update autmatically AOP netwrks will emerge and are the basis fr predictin

12 AOP Knwledgebase: an internatinal partnership

13 AOP Wiki: infrmatin strage, linkage and evaluatin Captures and rganizes all infrmatin and supprting dcumentatin fr AOP elements Supprted by extensive guidance, tutrials and an nline curse Is designed t enable rigrus evaluatin and scientific review Publically accessible since

14 AOP WIKI: Hme page AOP Wiki 2.2 released Jan 28, 2018

15 AOP WIKI: search liver fibrsis

16 AOP 38 Summary

17 AOP WIKI: KER and AOP cnfidence evaluatin Bilgical Plausibility:between KE upstream and KE dwnstream? High (strng): Extensive understanding f KER Mderate:KER is plausible Lw (weak): sme empirical supprt Essentiality: are dwnstream KEsprevented if upstream KE s blcked? High(strng): direct evidence frm experimental studies Mderate: indirect evidence Empirical Evidence: amunt, quality, cnsistent, incnsistent? High (strng): extensive evidence fr tempral, dse-respnse Mderate: multiple reprts f cnsistent evidence, sme incnsistent Lw (weak) Nr cntradictry evidence Lw (weak): limitedr n studies and/r significant incnsistencies

18 List f AOPs

19 OECD AOP Develpment Prgramme Extended Advisry Grup fr Mlecular Screening & Txicgenmics (EAGMST) Guidance, users Handbk Review Training Task frce n Hazard Assessment (TFHA) Guidance fr use f AOPs in regulatry decisin making Integrated Appraches t Testing and Assessment (IATA) Sciety fr the Advancement f AOPS Nt fficially part f the OECD prgramme Any persn active in develping an AOP in the wiki can jin Is anther way t enter the AOP wiki Prvides gardening and ther supprt functins

20 OECD AOP Develpment Prgramme AOP Wiki Access: three levels 1. Read access: anyne can access the wiki, search and read entries 2. Cmmenter access: a self-created accunt is needed t leave cmments Create an accunt n the wiki 3. Authr access: t write and edit AOPs must be requested thrugh the wiki Yu shuld have a familiarity with the wiki and desire t build an AOP

21 Wrk Prcess fr Develpment and Review f AOPs thrugh OECD Enter AOP Wiki thrugh SAAOP Enter AOP Wiki thrugh EAGMST SAAOP gardeners check frmat and cmpliance with OECD guidance Cntent and structural review by EAGMST Technical review by scientific expert grup Prcess review by OECD Natinal Crdinatrs (WNT) Publicatin n website in OECD Series n Adverse Outcme Pathways

22 OECD Guidance fr develping AOPs Guidance Dcument fr Develping and Assessing AOPs (2017) Series n Testing & Assessment N. 233 OECD User s Handbk Supplement t the Guidance Dcument fr Develping and Assessing AOPs (2017) Series n Testing & Assessment N. 233 Series n Adverse Outcme Pathways N. 1 Sectin f AOP Wiki AOP Descriptin Sectin 1 KE descriptins (unique pages) Sectin 2 KER descriptins(unique pages) KER evaluatin Sectin f Handbk Sectin 3 Overall AOP assessment Sectin 4

23 AOP Online Training Curse Three vlume curse: 1. Intrductin and Overview 2. AOP Wiki Training with quizes 3. Self exam Please run, dwnlad and share! Dwnlad: Run:

24 Current state f the AOP Wiki The mre participatin, the better it will be! 23 June 2017 D. Villeneuve