The CEFIC LRI. of the CPDB. of Departure Analysis. Project B18: Update. Database and Point. Sylvia Escher Fraunhofer ITEM

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1 The CEFIC LRI Project B18: Update of the CPDB Database and Point of Departure Analysis Sylvia Escher Fraunhofer ITEM Fraunhofer Institute for Toxicology and Experimental Medicine, Germany

2 Mark Cronin (Coordinator) SJ Belfield JW Firman Chihae Yang, Jim Rathman, J Liu, A Mostrag, KR Przybylak, A Tarkhov Sylvia Escher R Kellner Cyril Marsaux Liverpool John Moores University, Liverpool, England/Fraunhofer ITEM, Hanover, Germany/Altamira LLC, Columbus OH, USA/4ILSI Europe a.i.s.b.l., Brussels, Belgium/ Molecular Networks GmbH, Nuremberg, Germany/The Ohio State University, Columbus OH, USA

3 TTC threshold for toxicological concern TTC values are used for prioritization and screening in absence of toxicological data Thresholds are mainly assigned based on structural properties of the compound No risk assumend at exposure level below TTC value Today - TTC for genotoxic compounds LRI B18: Update of the CPDB Database and Point of Departure Analysis Sylvia Escher Fraunhofer ITEM

4 TTC decision tree* Genotoxic carcinogens - first threshold in the TTC decision tree EFSA 2016* Sylvia Escher Fraunhofer ITEM

5 Short history of the TTC values for genotoxic carcinogens

6 The Starting Point* *Rulis et al *Cheeseman et al. 1999

7 US FDA Threshold of Regulation (TOR) Based on an evaluation of the distribution of TD 50 values of 477 substances included in the Carcinogenic Potency Database (CPDB) compiled by Gold et al.* Assumes that a risk of 1/10 6 is acceptable *Cheesemann et al. 1999

8 Reanalysis and exclusion of cohort of concern Some compound groups are not well covered by TOR Cohort of concern excluded e.g. aflatoxins/dioxins/nitroso cmpds, heavy metals etc. Proposed TTC value for genotoxic compounds: 0.15 µg/person/d * LRI B18: Update of the CPDB Database and Point of Departure Analysis *Kroes et al. 2004

9 Need to revisit and revise TTC for genotoxic - carcinogens Boobis A et al. (2017) Critical Reviews in Toxicology 47: LRI B18: Update of the CPDB Database and Point of Departure Analysis

10 Objectives of LRI B18 - Project 1) Construct an updated, curated, freely available Cancer Potency TTC dataset 2) Evaluate mode of action of carcinogens to clearly identify genotoxic and non-genotoxic carcinogens 3) Quantitative analysis of the database comparing TDx and BMDL methods for the Point of Departure 4) Re-evaluation of TTC thresholds LRI B18: Update of the CPDB Database and Point of Departure Analysis

11 1) Updated, curated, freely available CPDB TTC dataset LRI PRESENTATION TITLE

12 updated CPDB 1. Update CPDB

13 Included Criteria for Inclusion of Data Excluded GLP studies or equivalent protocols Appropriate sample size ( 40) Exposures shorter than life time included only if results are statistically positive The lowest TD50 (BMDL) values from oral studies with significant tumorigenic effects (p 0.01) Single dose studies Mixed tumors TBA (all tumor bearing animals), MIX (tumours from more than one site) etc. Negative studies with no significant tumor findings

14 Original CPDB database (status 2012) Added data 34 carcinogens NTP studies 36 chemicals 652 chemicals 572 carcinogens 428 carcinogens + AMES data Fraunhofer RepDose database EFSA draft assessment report (DAR) LRI B18: Update of the CPDB Database and Point of Departure Analysis

15 2) Mode of action genotoxic and non-genotoxic carcinogens LRI PRESENTATION TITLE

16 Compile relevant genotoxicity data Gather in vitro and in vivo genotoxicity data Not available for all compounds Add predicted values based on different QSAR and structural alerts e.g. using CHEMTUNES Classify compounds as genotoxic and non-genotoxic carcinogens using a weight of evidence approach LRI B18: Update of the CPDB Database and Point of Departure Analysis

17 Establish the prioritization strategy to classify compounds Definitive Chemical Structure Adequate Experimental Data? In Vivo > In Vitro > In Silico Classify on Experimental Data In vivo e.g. MN In vitro e.g. AMES/CA Classify on In Silico Predictions e.g. QSAR Structural alerts

18 Next step - WoE approach to group compounds Establish a prioritization and classification strategy for genetic toxicity A more rigorous weight of evidence approach is being developed to assess genotoxicity by applying Dempster Shafer Theory (DST). Enables analysis of genotoxic and non-genotoxic compounds and their TTC values LRI B18: Update of the CPDB Database and Point of Departure Analysis

19 3) Compare different PoD (point of departures) LRI PRESENTATION TITLE

20 Points of Departure (POD) A POD is required to derive the TTC value TD 50 values available from original CPDB database (dose level at which 50% of the tested animals develop a tumor). Relevance of TD 50 vs TD 25 / TD 10 Benchmark Dose Levels (BMR 10%) may be more appropriate LRI B18: Update of the CPDB Database and Point of Departure Analysis

21 Requirements for the calculation of PoD Ideally - dose-dependent increase of tumours over time Many data with High spontaneous tumour rates in control groups No or no dose dependent increase over time LRI B18: Update of the CPDB Database and Point of Departure Analysis

22 TD10 TD25 TD50 Calculating Points of Departure: TDx TD 10, TD 25 and TD 50 calculated from curated existing and new doseresponse data 624 compounds Example: a doseresponse curve for CMS-475 experimental logistic-logit model fit

23 BMDL at BMR 10% by model averaging Calculable for 571 compounds, BMR=10% Proast software used, 7 models used for averaging Minimum of BMDL 10 per compound EFSA approach adopted Weighting of models based on AIC values Include latent variables Proast models 1 two.stage 2 log.logist 3 Weibull 4 log.prob 5 gamma 6 probit 7 logistic LRI B18: Update of the CPDB Database and Point of Departure Analysis

24 Calculating Points of Departure: (Preliminary Results) values were shown within the presentation, but as analyses are ongoing these preliminary results are not included

25 Summary Existing CPDB updated, extended and curated MoA - Genotoxicity strategy utilising experimental and predicted data under development POD calculations using TD 25/10 and BMDL 10 Full data set to be made available to support TTC analyses Access File: end of 2017 Integration into COSMOS DB: March 2018 Strengths and weaknesses of all aspects of the analysis identified TTC values to be analysed LRI B18: Update of the CPDB Database and Point of Departure Analysis

26 Acknowledgement The funding of the CEFIC LRI B18 Project Wout Slob, RIVM THANK YOU! LRI B18: Update of the CPDB Database and Point of Departure Analysis