Computational Modelling for TTC Assessment Andrew Worth 1 and Chihae Yang 2 1) European Commission - Joint Research Centre Institute for Health & Consumer Protection, Systems Toxicology Unit 2) Altamira LLC, Columbus Ohio, USA and Molecular Networks GmbH, Erlangen, Germany Eurotox 2015 Continuing Education Course on “Thresholds of Toxicological Concern – Basics and Latest Developments” Porto, Portugal, 13 September 2015
Overview • Computational tools for the application of the TTC approach • Chemoinformatics in the development of the TTC approach • Quality-controlled datasets for modelling • Investigation of chemical space • Identification of chemotypes • Route to route extrapolation • COSMOS-ILSI decision tree for oral to dermal extrapolation • Internal TTC approach and biokinetic modelling • Take home messages 2
Computational tools for the application of the TTC approach
1. Is the substance a non-essential metal or metal containing compound, or is it a polyhalogenated- 1. Is the substance a non-essential metal or metal containing compound, or is it a polyhalogenated- dibenzodioxin, -dibenzofuran, or -biphenyl? dibenzodioxin, -dibenzofuran, or -biphenyl? NO NO YES YES 2. Are there structural alerts that raise 2. Are there structural alerts that raise Risk assessment requires Risk assessment requires concern for potential genotoxicity? concern for potential genotoxicity? compound-specific toxicity data compound-specific toxicity data Cancer Kroes NO NO YES YES YES YES 3. Is the chemical an aflatoxin-like-, azoxy-, or 3. Is the chemical an aflatoxin-like-, azoxy-, or endpoints decision tree 5. Does estimated intake exceed TTC 5. Does estimated intake exceed TTC N-nitroso- compound? N-nitroso- compound? of 1.5 g/day? of 1.5 g/day? NO NO NO NO YES YES YES YES Substance would Substance would 4. Does estimated intake exceed TTC of 4. Does estimated intake exceed TTC of Structural alert 0.15 g/day? 0.15 g/day? High potency not be expected to not be expected to be a safety concern be a safety concern for genotoxicity NO NO carcinogen 6. Is the compound an organophosphate? 6. Is the compound an organophosphate? Negligible risk (low probability of a life-time Negligible risk (low probability of a life-time cancer risk greater than 1 in 10 6 – see text) cancer risk greater than 1 in 10 6 – see text) NO NO YES YES Organophosphate Non- 8. Is the compound in 8. Is the compound in 7. Does estimated intake exceed 7. Does estimated intake exceed Cramer structural class Cramer structural class TTC of 18 g/day? TTC of 18 g/day? neurotoxicant YES YES III? III? cancer NO NO NO NO YES YES endpoints 9. Does estimated intake 9. Does estimated intake Risk assessment requires Risk assessment requires exceed 90 g/day? exceed 90 g/day? compound-specific toxicity data compound-specific toxicity data YES YES NO NO 10. Is the compound 10. Is the compound in Cramer structural in Cramer structural Substance would not be expected Substance would not be expected class II? class II? to be a safety concern to be a safety concern NO NO YES YES Kroes et al. (2004). Food Chem Toxicol 42, 65-83. 12. Does estimated intake 12. Does estimated intake 11. Does estimated intake 11. Does estimated intake exceed 1800 g/day? exceed 1800 g/day? exceed 540 g/day? exceed 540 g/day? Risk assessment requires Risk assessment requires NO NO YES YES NO NO YES YES compound-specific toxicity data compound-specific toxicity data Substance would not be Substance would not be expected to be a safety concern expected to be a safety concern
No Does the substance have a known structure and are TTC approach cannot exposure data available? be applied Yes Yes Is the substance a member of an EFSA exclusion category? No decision tree Yes Yes Is there a structural alert for Exposure genotoxicity (including > 0.0025 µg/kg bw/day? metabolites) ? No Substance Low probability of Low probability of No requires non-TTC approach health effect health effect (toxicity data, read-across, etc) No Exposure > 0.3 µg/kg bw/day? Yes Yes Is substance an OP/Carbamate? No No Exposure > 1.5 µg/kg bw/day? Yes Yes Is substance in Cramer Class II or III? No No Yes Exposure > 30 µg/kg bw/day? EFSA website: http://www.efsa.europa.eu/en/efsajournal/doc/2750.pdf
Benigni-Bossa rules for genotoxicity & carcinogenicity Structural Alerts (SAs) • 30 SAs for genotoxic carcinogens • 5 SAs for non-genotoxic carcinogens + Three QSAR models Probability = F Hydrophobic + + Electronic Steric of effect Descriptors : logP HOMO, LUMO MR
CAESAR mutagenicity model Statistically-based • Support Vector Machine classification method + some SAs from the Benigni- • Bossa rulebase Training set: 4225 compounds from the Kazius-Bursi database • http://www.caesar-project.eu http://www.vega-qsar.eu/
CAESAR carcinogenicity model Statistically-based • Classification model based on a Counter-Propagation Artificial Neural Network • (CP-ANN) Training set: 805 compounds from the Carcinogenic Potency Database (CPDB ) • http://www.caesar-project.eu http://www.vega-qsar.eu/
Toxtree • Compound properties • Prediction • Compound structure • Reasoning • Downloadable versions from JRC and Sourceforge (http://toxtree.sourceforge.net) • Current version 2.6.6 (Jun3 2014) includes Cramer, Cramer with Extensions, genotoxicity and carcinogenicity (Benigni-Bossa, In Vivo Micronucleus, Ames), Kroes • Toxtree online: http://toxtree.sf.net/predict
Example: 2-aminoacetophenone 2-aminoacetophenone SMILES: O=C(C)c1ccccc1N naturally occurring in beer, sweet corn, corn tortillas, milk • proposed flavouring agent • EFSA opinion • (2008):http://www.efsa.europa.eu/en/efsajournal/pub/797.htm Estimated intake: • Maximised Survey-derived Daily Intake (MSDI) of 0.012 g/p/day Modified Theoretical Added Maximum Daily Intake (mTAMDI) of 1600 g/p/day
Example: 2-aminoacetophenone 2-aminoacetophenone SMILES: O=C(C)c1ccccc1N Cramer Class III • 1N,2N,3N,5N,6N,7N,16N,17N,19N,23Y,27Y,28N,30Y,31N,32N,22N,33N • TTC for CC III is 90 g / person / day • Estimated intake: • MSDI of 0.012 g/p/day < TTC of 90 g/p/ day for CC III BUT mTAMDI of 1600 g/p/day > TTC of 90 g/p/ day for CC III
Evaluation of Toxtree-Cramer • Many of the original Cramer rules are written in a confusing and inter-dependent way, which leads to difficulties in the rationalisation of the predictions they make. • Two rules are not based on chemical features, but simply make reference to look-up lists of chemicals (Q1, normal body constituents; Q22, common food components). • Some rules make ambiguous references to chemical features (e.g. steric hindrance) which need to be clarified and possibly revised/deleted. • Several studies have identified outliers (e.g. Class I compounds that have low NOELs). A revised / alternative classification scheme should be more discriminating in terms of NOEL values. → need to update Cramer classification scheme Lapenna & Worth (2011). JRC report EUR 24898 EN
Cramer classifications: computer-based predictions vs expert judgement
Toxtree QSAR Toolbox Class II Class III
Cramer classifications: computer-based predictions vs expert judgement
Chemoinformatics in the development of the TTC approach
COSMOS Integrated In Silico Models for the Prediction of Human Repeated Dose Toxicity of Cosmetics to Optimise Safety • Collection of toxicological data • Development of the Threshold of Toxicological Concern (TTC) approach • Development of novel in silico methods • Multiscale modelling: mitochondrial (dys)function, virtual cell-based assay, 2D liver, Physiologically Based Biokinetic (PBBK) models • In silico workflows based on open-source and open-access tools 17
COSMOS database v1.0 • Open-access • High-quality toxicity data (quality control, structure curation) • User-friendly query builder (chemical name, structure, toxicity data) • 44,765 unique chemical structures • 12,538 toxicity studies for 1,660 compounds across 27 endpoints http://cosmosdb.cosmostox.eu/ Webinar and tutorial: http://www.cosmostox.eu/what/COSMOSdb/ 18
COSMOS Cosmetics Inventory Chemical classes • Over 5,500 substances • 66 unique use functions 19
Munro dataset (1996)
COSMOS TTC dataset 1. Toxicity database 2. NOAEL database 3. TTC dataset • Study relevance • Study reliability • Substance & Study • • NOAEL decision NOAEL selection criteria inclusion criteria • Expert review Munro 1996 oRepeatTox NOAEL TTC database DB dataset V1.8 current version Filter 1 Filter 2
Description of COSMOS TTC v1.8 Compound classes COSMOS TTC v1.8 Munro (all tentative counts) All ̴ 560 613 Cosmetics inventory 495 190 Cramer Class I: Class II: Class III* 244: 35: 281 119: 28: 448 (> 40% Class I) (<25 % Class I) Nutrients (removed) - Lipid soluble vitamins - Vitamin A,D,E,K removed - retinol - Essential amino acids - removed - phenyl alanine Compound categories - Hair dyes 110 13 - Parabens 10 7 - Phthalates 7 5 * Cramer Classes assigned by Toxtree v2.6.0
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