4:30 5:00: Introduction and overview of the OECD AOP framework Catherine Willett, HTPC/Humane Society International

Transcription

1 AOP Hands-n Training: Building the Fundatin fr Predictive Txiclgy Wednesday, March 13, 4:30 PM 6:30 PM Hiltn Baltimre, Paca Rm 401 West Pratt St, Baltimre, MD Agenda: 4:30 5:00: Intrductin and verview f the OECD AOP framewrk Catherine Willett, HTPC/Humane Sciety Internatinal 5:00 5:30: Appraches and tls fr AOP assembly and an example f a Bayesian netwrk apprach t predicting steatsis Natalia Reyer, Envirnmental Labratry, Engineer Research & Develpment Center, US Army Crps f Engineers 5:30 5:40 Applicatin f the AOP framewrk t make regulatry decisins: Early case studies Kristie Sullivan, PCRM 5:40 6:30 AOP Wiki demnstratin and hands-n activity Finding AOPs and AOP inf in the Wiki Entering infrmatin int the Wiki Adding a diagram Kristie Sullivan, PCRM with supprt frm Catherine and Natalia

2 Intrductin t AOPs and the OECD AOP Framewrk Catherine Willett Senir Directr, Science and Regulatry Affairs Humane Sciety Internatinal Crdinatr, Human Txiclgy Prject kwillett@humanesciety.rg

3 Outline Part I: intrductin t AOPs AOPs as the basis fr predictive txiclgy Intrductin t the AOP cncept essential elements f AOPs Brief n building AOPs Part II: the OECD AOP Framewrk The AOP Knwledgebase The OECD AOP develpment and evaluatin prcess Available guidance, tutrials and classes

4 Part I: Intrductin t AOPs

5 Need fr predictive txiclgy Grwing need fr mre infrmatin n tens f thusands f chemicals Need fr imprved drug success rates and lwer cst t market Need fr faster, mre relevant appraches acrss sectrs T increase efficiency and imprve safety decisins: Ø mve frm a system f empirically measured adverse utcmes t a predictive system based n measurement f upstream bilgical events cupled with an explicit bilgical linkage t ptential adverse effects

6 Need fr better use f infrmatin T much data! Decades f research and testing data Glbal scientific utput dubles every 9 years The data is largely inaccessible Jurnal articles, reprts, labratry ntebks, agency archives Institutinal and gvernment databases

7 Issue: t much data in nn-accessible frmats Cllabratin Mdel building Avids duplicatin PDFs Fragmented Siled Prprietary Searchable Machine-readable Linked (adapted frm D. Villeneuve)

8 The Adverse Outcme Pathway framewrk is the basis f predictive txiclgy AOPs: 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

9 Adverse Outcme Pathway framewrk: linking mlecular initiatin t adverse utcmes AOPs: linking mlecular initiatin t adverse utcmes

10 Adverse Outcme Pathway framewrk: linking mlecular initiatin t adverse utcmes AOPs: Linking mlecular infrmatin t adverse utcmes MA 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 beginning with initial interactins f a stressr with a bimlecule in a target cell r tissue (the mlecular initiating event - MIE) prgressing thrugh a dependent series f intermediate events (key events - KE) Linked tgether thrugh Key Event Relatinships (KER) culminating with an adverse utcme (AO)

11 AOPs prvide a framewrk fr rganizing, relating and evaluating bilgical 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 SAR, QSAR High Thrughput Mechanistic Txiclgy Data ( mics, bimarkers) Guideline Studies Clinical, Epidemilgy Ec Field Studies

12 Essential elements f an AOP Chemical prperties Prtein binding DNA binding Receptr/ligand binding Key Events (KEs) 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 Impaired reprductin/ survival, Ppulatin crash 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

13 Fundamental principles f AOP develpment 1. AOPs are nt chemical specific 2. AOPs are mdular Key events and relatinships can be shared by multiple AOPs 3. As a pragmatic cnstruct, an individual AOP is cmpsed f a single sequence f KEs and KERs leading t a single AO 4. AOP netwrks will emerge and are the basis fr predictin 5. AOPs are living dcuments AOP descriptins can be expected t evlve ver time

14 Netwrks emerge as KE and KER are shared Key Events Shared by Multiple AOPs AOP:30 AOP:25 AOP:23 Linkages Shared by Multiple AOPs

15 Building an AOP Chemical prperties Prtein binding DNA binding Receptr/ligand binding Start anywhere Gene activatin Prtein prductin Altered signaling Altered physilgy Altered tissue develpment r functin Impaired develpment Impaired reprductin lethality 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 When yu are ready, and if yu s desire, yu can then enter the OECD evaluatin prcess Impaired reprductin/ survival, Ppulatin crash

16 Part II: the OECD AOP framewrk

17 OECD AOP Knwledgebase (AOP-KB): an internatinal partnership

18 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 available since

19 AOP Wiki hme page

20 List f AOPs

21 OECD AOP Develpment Prgram AOP Wiki Access: three levels Read access Open t anyne, n accunt required Cmmenting Create accunt, n apprvals required Authr/write access Create accunt Submit brief develper applicatin fr apprval Gardener (experienced AOP develpers/ wiki users) Help ensure cnsistency with published principles and OECD guidelines

22 OECD AOP Develpment Prgramme Extended Advisry Grup fr Mlecular Screening & Txicgenmics (EAGMST) Guidance, users Handbk Review Training Wrking Party n Hazard Assessment (WPHA) 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 prgram 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

23 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 Explained in Wittwehr, C. (2018) Use and acceptance f AOPs fr regulatry applicatins. In Garcia-Reyer & Murphy, A Systems Bilgy Apprach t Advancing Adverse Outcme Pathways fr Risk Assessment (pp ), Springer.

24 List f AOPs

25 The current state f the Wiki June 2017 D. Villeneuve OECD endrsed and published 7 EAGMST apprved 9 Under EAGMST review 14 Participants needed! Mst cmmn endpints addressed: Ectxiclgy Reprductive txicity Neurtxicity carcingenicity endcrine

26 Guidance, tutrials, curses

27 OECD Guidance fr develping and assessing AOPs 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 Guidance Dcument fr Develping and Assessing AOPs (2017) Series n Testing & Assessment N. 233 OECD Guidance Dcument fr the use f adverse utcme pathways in develping integrated appraches t testing and assessment (IATA), Series n Testing and assessment n. 260 (OECD 2016) =ENV/JM/MONO(2016)67/&dclanguage=en OECD website n the AOP prgram: OECD s website n IATA The AOP Wiki:

28 AOP training vides and tutrials SETAC 2015 CE Curse: Develping and Applying Adverse Outcme Pathways What Yu Need t Knw Part 1: Part 2: SOT CE Curse AOP Develpment and Evaluatin : subscriptin required Sciety fr the Advancement f Adverse Outcme Pathways Training vides: Other training resurces:* AOP Learning: Building AOP Structure and Descriptin *This curse des nt mentin Effectpedia: this sftware package will be merged with the AOP Wiki in the next versin f the AOP KB currently under design

29 AOP Online Training Curse Three mdule curse: 1. Intrductin and Overview 2. AOP Wiki Tutrial with quizzes 3. Self exam Dwnlad: Run:

30 Summary

31 The AOP framewrk is: A frmal prcess t cllect, rganize, link, and evaluate bilgical infrmatin A practical slutin t a practical prblem hw t use mechanistic bilgical infrmatin t supprt better regulatry decisins regarding chemical safety A Transparent, highly curated, living dcument representing current knwledge The basis fr predictive txiclgy

32 The AOP framewrk is incredibly time and labr-intensive Its utility is dependent n wide adptin The AOP Framewrk Needs YOU!

33 Thank yu!

34 AOP Hands-n Training: Building the Fundatin fr Predictive Txiclgy Wednesday, March 13, 4:30 PM 6:30 PM Hiltn Baltimre, Paca Rm 401 West Pratt St, Baltimre, MD Agenda: 4:30 5:00: Intrductin and verview f the OECD AOP framewrk Catherine Willett, HTPC/Humane Sciety Internatinal 5:00 5:30: Appraches and tls fr AOP assembly and an example f a Bayesian netwrk apprach t predicting steatsis Natalia Reyer, Envirnmental Labratry, Engineer Research & Develpment Center, US Army Crps f Engineers 5:30 5:40 Applicatin f the AOP framewrk t make regulatry decisins: Early case studies Kristie Sullivan, PCRM 5:40 6:30 AOP Wiki demnstratin and hands-n activity Finding AOPs and AOP inf in the Wiki Entering infrmatin int the Wiki Adding a diagram Kristie Sullivan, PCRM with supprt frm Catherine and Natalia