10,224
Views
30
CrossRef citations to date
0
Altmetric
Review Articles

Origin of the TTC values for compounds that are genotoxic and/or carcinogenic and an approach for their re-evaluation

, , , , , , , , , , , & show all
Pages 710-732 | Received 19 Dec 2016, Accepted 10 Apr 2017, Published online: 16 May 2017

References

  • Adler S, Basketter D, Creton S, Pelkonen O, Van Benthem J, Zuang V, Andersen KE, Angers-Loustau A, Aptula A, Bal-Price A. 2011. Alternative (non-animal) methods for cosmetics testing: current status and future prospects-2010. Arch Toxicol. 85:367–485.
  • Altamira LLC. 2013. The ChemoTyper Application [Internet]. Columbus (OH): Molecular Networks GmbH; [cited 2016 15 Dec]. Available from: https://chemotyper.org/
  • Ashby J. 1994. International Commission for Protection Against Environmental Mutagens and Carcinogens. Two million rodent carcinogens? The role of SAR and QSAR in their detection. Mutat Res. 305:3–12.
  • Ashby J, Tennant RW. 1988. Chemical structure, Salmonella mutagenicity and extent of carcinogenicity as indicators of genotoxic carcinogenesis among 222 chemicals tested in rodents by the U.S. NCI/NTP. Mutat Res. 204:17–115.
  • Ashby J, Tennant RW. 1991. Definitive relationships among chemical structure, carcinogenicity and mutagenicity for 301 chemicals tested by the U.S. NTP. Mutat Res. 257:229–306.
  • Aungst J, Arvidson K, Rua D, Arvidson K, Hristozov D, Mugabe B, Matthews EJ, McCarthy A, Yang C, Cheeseman MA. 2012. Revisiting the TTC approach for cancer assessment: Part of a road map of computational methods at FDA CFSAN OFAS. Paper Presented at 51st Annual Meeting and ToxExpo 2012, San Francisco, California [Internet]. Available from: https://www.toxicology.org/pubs/docs/Tox/2012Tox.pdf
  • Boobis AR, Cohen SM, Dellarco V, McGregor D, Meek MEB, Vickers C, Willcocks D, Farland W. 2006. IPCS framework for analyzing the relevance of a cancer mode of action for humans. Crit Rev Toxicol. 36:781–792.
  • Boobis AR, Doe JE, Heinrich-Hirsch B, Meek ME, Munn S, Ruchirawat M, Schlatter J, Seed J, Vickers C. 2008. IPCS framework for analyzing the relevance of a noncancer mode of action for humans. Crit Rev Toxicol. 38:87–96.
  • BAuA Federal Institute for Occupational Safety and Health (BAuA). 2014. Risk-related concept of measures for activities involving carcinogenic hazardous substances (TRGS 910). Available from: http://www.baua.de/en/Topics-from-A-to-Z/Hazardous-Substances/TRGS/TRGS-910.htm
  • Cassano A, Raitano G, Mombelli E, Fernández A, Cester J, Roncaglioni A, Benfenati E. 2014. Evaluation of QSAR models for the prediction of Ames genotoxicity: a retrospective exercise on the chemical substances registered under the EU REACH regulation. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 32:273–298.
  • Cheeseman MA, Machuga EJ, Bailey AB. 1999. A tiered approach to threshold of regulation. Food Chem Toxicol. 37:387–412.
  • Cohen SM, Klaunig J, Meek E, Hill RN, Pastoor T, Lehman-Mckeeman L, Bucher J, Longfellow DG, Seed J, Dellarco V, et al. 2004. Evaluating the human relevance of chemically induced animal tumors. Toxicol Sci. 78:181–186.
  • Committee on Mutagency of Chemicals in Food, Consumer Products and the Environment. 2010. Guidance Statement: Thresholds for In Vivo Mutagens. London, UK
  • Corton JC, Cunningham ML, Hummer BT, Lau C, Meek B, Peters JM, Popp JA, Rhomberg L, Seed J, Klaunig JE. 2014. Mode of action framework analysis for receptor-mediated toxicity: the peroxisome proliferator-activated receptor alpha (PPARα) as a case study. Crit Rev Toxicol. 44:1–49.
  • Cramer GM, Ford RA, Hall RL. 1978. Estimation of toxic hazard – a decision tree approach. Food Cosmet Toxicol. 16:255–276.
  • DeKeyser JG, Shou M, DeKeyser JG, Shou M. 2011. Species differences of drug-metabolizing enzymes. Chapter 5. In: Encyclopedia of drug metabolism and interactions. Hoboken: Wiley.
  • Dertinger SD, Heflich RH. 2011. In vivo assessment of Pig-a gene mutation-recent developments and assay validation. Environ Mol Mutagen. 52:681–684.
  • Doak SH, Jenkins GJS, Johnson GE, Quick E, Parry EM, Parry JM. 2007. Mechanistic influences for mutation induction curves after exposure to DNA-reactive carcinogens. Cancer Res. 67:3904–3911.
  • Eastmond DA, Hartwig A, Anderson D, Anwar WA, Cimino MC, Dobrev I, Douglas GR, Nohmi T, Phillips DH, Vickers C. 2009. Mutagenicity testing for chemical risk assessment: update of the WHO/IPCS Harmonized Scheme. Mutagenesis. 24:341–349.
  • Edler L, Hart A, Greaves P, Carthew P, Coulet M, Boobis A, Williams GM, Smith B. 2014. Selection of appropriate tumour data sets for Benchmark Dose Modelling (BMD) and derivation of a Margin of Exposure (MoE) for substances that are genotoxic and carcinogenic: considerations of biological relevance of tumour type, data quality and uncertainty assessment. Food Chem Toxicol. 70:264–289.
  • Elcombe CR, Peffer RC, Wolf DC, Bailey J, Bars R, Bell D, Cattley RC, Ferguson SS, Geter D, Goetz A, et al. 2014. Mode of action and human relevance analysis for nuclear receptor-mediated liver toxicity: a case study with phenobarbital as a model constitutive androstane receptor (CAR) activator. Crit Rev Toxicol. 44:64–82.
  • Ellison CM, Sherhod R, Cronin MTD, Enoch SJ, Madden JC, Judson PN. 2011. Assessment of methods to define the applicability domain of structural alert models. J Chem Inf Model. 51:975–985.
  • Embry MR, Bachman AN, Bell DR, Boobis AR, Cohen SM, Dellarco M, Dewhurst IC, Doerrer NG, Hines RN, Moretto A, et al. 2014. Risk assessment in the 21st century: roadmap and matrix. Crit Rev Toxicol. 44(Suppl 3):6–16.
  • Enoch SJ, Cronin MTD. 2010. A review of the electrophilic reaction chemistry involved in covalent DNA binding. Crit Rev Toxicol. 40:728–748.
  • Enoch SJ, Cronin MTz. 2011. Development of new structural alerts suitable for chemical category formation for assigning covalent and non-covalent mechanisms relevant to DNA binding. Mutat Res. 743:10–19.
  • Enoch SJ, Cronin MTD. 2012. Development of new structural alerts suitable for chemical category formation for assigning covalent and non-covalent mechanisms relevant to DNA binding. Mutat Res Toxicol Environ Mutagen. 743:10–19.
  • European Chemicals Agency (ECHA). 2015. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.7a: Endpoint specific guidance. Helsinki (Finland). Available from: https://echa.europa.eu/documents/10162/13632/information_requirements_r7a_en.pdf
  • European Commission. 2002. Commission Decision of 23 January 2002 amending Commission Decision 1999/217/EC as regards the register of flavouring substances used in or on foodstuffs. Off J Eur Comm. 49:1–160.
  • European Commission. 2003. Guidance document on the assessment of the relevance of metabolites in groundwater of substances regulated under Council Directive 91/414/EEC. Brussels. Available from: https://ec.europa.eu/food/sites/food/files/plant/docs/pesticides_ppp_app-proc_guide_fate_metabolites-groundwtr.pdf
  • European Medicines Agency (EMA). 2008. Guideline on the Assessment of Genotoxicity of Herbal Substances/Preparations Adoption by HMPC for Release for Consultation. London. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003569.pdf
  • European Food Safety Authority (EFSA). 2009. Guidance of the Scientific Committee on Use of the benchmark dose approach in risk assessment. EFSA J. 7:1150.
  • European Food Safety Authority (EFSA). 2012. Scientific Opinion on Exploring options for providing advice about possible human health risks based on the concept of Threshold of Toxicological Concern (TTC). EFSA J. 10:2750.
  • European Food Safety Authority (EFSA). 2016. Review of the Threshold of Toxicological Concern (TTC) approach and development of new TTC decision tree. EFSA Support. Publ. 13. Available from: http://onlinelibrary.wiley.com/doi/10.2903/sp.efsa.2016.EN-1006/pdf
  • European Food Safety Authority (EFSA). 2017. Update: use of the benchmark dose approach in risk assessment. EFSA J. 15:4658.
  • European Union Joint Research Centre (JRC). 2010. Applicability of QSAR analysis to the evaluation of the toxicological relevance of metabolites and degradates of pesticide active substances for dietary risk assessment. EFSA Support Publ. 7:1–311. Available from: http://onlinelibrary.wiley.com/doi/10.2903/sp.efsa.2010.EN-50/pdf;jsessionid=F31C6F1127637AAC94772B95414F7F24.f04t04
  • Federal Register. 1993. Toxicological principles for the safety assessment of direct food additives and color additives used in food. Fed Regist. 58:16536.
  • Federal Register. 1995. Food additives; threshold of regulation for substances used in food-contact articles. Fed Regist. 60:36582–36596. Available from: https://www.gpo.gov/fdsys/pkg/FR-1995-07-17/pdf/95-17435.pdf
  • Frawley JP. 1967. Scientific evidence and common sense as a basis for food-packaging regulations. Food Cosmet Toxicol. 5:293–308.
  • Fung VA, Barrett JC, Huff J. 1995. The carcinogenesis bioassay in perspective: application in identifying human cancer hazards. Environ Health Perspect. 103:680–683.
  • Gocke E, Ballantyne M, Whitwell J, Muller L. 2009a. MNT and MutaMouse studies to define the in vivo dose response relations of the genotoxicity of EMS and ENU. Toxicol Lett. 190:286–297.
  • Gocke E, Bürgin H, Müller L, Pfister T. 2009b. Literature review on the genotoxicity, reproductive toxicity, and carcinogenicity of ethyl methanesulfonate. Toxicol Lett. 190:254–265.
  • Gocke E, Müller L. 2009. In vivo studies in the mouse to define a threshold for the genotoxicity of EMS and ENU. Mutat Res. 678:101–107.
  • Gold LS, Manley NB, Slone TH, Garfinkel GB, Ames BN, Rohrbach L, Stern BR, Chow K. 1995. Sixth plot of the carcinogenic potency database: results of animal bioassays published in the General Literature 1989 to 1990 and by the National Toxicology Program 1990 to 1993. Environ Health Perspect. 103(Suppl):3–122.
  • Gold LS, Sawyer CB, Magaw R, Backman GM, de Veciana M, Levinson R, Hooper NK, Havender WR, Bernstein L, Peto R. 1984. A carcinogenic potency database of the standardized results of animal bioassays. Environ Health Perspect. 58:9–319.
  • Gold LS, Slone TH, Bernstein L. 1989. Summary of carcinogenic potency and positivity for 492 rodent carcinogens in the carcinogenic potency database. Environ Health Perspect. 79:259–272.
  • Hanser T, Barber C, Rosser E, Vessey JD, Webb SJ, Werner S. 2014. Self organising hypothesis networks: a new approach for representing and structuring SAR knowledge. J Cheminf. 6:1–21.
  • Health Canada. 2016. Threshold of Toxicological Concern (TTC)-based approach for certain substances. Available from: https://www.ec.gc.ca/ese-ees/326E3E17-730A-4878-BC25-D07303A4DC13/HC%20TTC%20SciAD%20EN.pdf
  • Hernandez LG, van Steeg H, Luijten M, van Benthem J. 2009. Mechanisms of non-genotoxic carcinogens and importance of a weight of evidence approach. Mutat Res. 682:94–109.
  • International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). 2014. Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk. In: International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH); Geneva.
  • Jacobs MN, Colacci A, Louekari K, Luijten M, Hakkert BC, Paparella M, Vasseur P. 2016. International regulatory needs for development of an IATA for non-genotoxic carcinogenic chemical substances. Altex. 33:359–392.
  • Joint FAO/WHO Expert Committee on Food Additives. 1996. Toxicological evaluation of certain food additives and contaminants in food. Geneva.
  • Kirchmair J, Göller AH, Lang D, Kunze J, Testa B, Wilson ID, Glen RC, Schneider G. 2015. Predicting drug metabolism: experiment and/or computation? Nat Rev Drug Discov. 14:387–404.
  • Kirkland D, Aardema M, Muller L, Makoto H. 2006. Evaluation of the ability of a battery of three in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens II. Further analysis of mammalian cell results, relative predictivity and tumour profiles. Mutat Res. 608:29–42.
  • Kirkland D, Pfuhler S, Tweats D, Aardema M, Corvi R, Darroudi F, Elhajouji A, Glatt H, Hastwell P, Hayashi M, et al. 2007. How to reduce false positive results when undertaking in vitro genotoxicity testing and thus avoid unnecessary follow-up animal tests: report of an ECVAM Workshop. Mutat Res. 628:31–55.
  • Kirkland D, Speit G. 2008. Evaluation of the ability of a battery of three in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens: III. Appropriate follow-up testing in vivo. Mutat Res. 654:114–132.
  • Kirkland D, Zeiger E, Madia F, Corvi R. 2014. Can in vitro mammalian cell genotoxicity test results be used to complement positive results in the Ames test and help predict carcinogenic or in vivo genotoxic activity? II. Construction and analysis of a consolidated database. Mutat Res. 775:69–80.
  • Klaunig JE, Babich MA, Baetcke KP, Cook JC, Corton JC, David RM, Deluca JG, Lai DY, Mckee RH, Peters JM, et al. 2003. PPARα agonist-induced rodent tumors: modes of action and human relevance. Crit Rev Toxicol. 33:655–780.
  • Klimisch HJ, Andreae M, Tillmann U. 1997. A systematic approach for evaluating the quality of experimental toxicological and ecotoxicological data. Regul Toxicol Pharmacol. 25:1–5.
  • Kroes R, Renwick AG, Cheeseman M, Kleiner J, Mangelsdorf I, Piersma A, Schilter B, Schlatter J, Van Schothorst F, Vos JG. 2004. Structure-based Thresholds of Toxicological Concern (TTC): guidance for application to substances present at low levels in the diet. Food Chem Toxicol. 42:65–83.
  • Lehr RE, Kumar S, Levin W, Wood AW, Chang RL, Conney AH, Yagi H, Sayer JM, Jerina DM. 1985. Polycyclic Hydrocarbons and Carcinogenesis. Chapter 4. In: The Bay Region Theory of Polycyclic Aromatic Hydrocarbon Carcinogenesis. Philadelphia (PA): American Chemical Society; p. 63–84. Available from: http://pubs.acs.org/doi/abs/10.1021/bk-1985-0283.ch004
  • Luijten M, Olthof ED, Hakkert BC, Rorije E, van der Laan J-W, Woutersen RA, van Benthem J. 2016. An integrative test strategy for cancer hazard identification. Crit Rev Toxicol. 46:615–639.
  • Meek ME, Bucher JR, Cohen SM, Dellarco V, Hill RN, Lehman-McKeeman LD, Longfellow DG, Pastoor T, Seed J, Patton DE. 2003. A framework for human relevance analysis of information on carcinogenic modes of action. Crit Rev Toxicol. 33:591–653.
  • Meek ME, Boobis A, Cote I, Dellarco V, Fotakis G, Munn S, Seed J, Vickers C. 2014. New developments in the evolution and application of the WHO/IPCS framework on mode of action/species concordance analysis. J Appl Toxicol. 34:1–18.
  • Mekenyan O, Dimitrov S, Serafimova R, Thompson ED, Kotov S, Dimitrova N, Walker JD. 2004. Identification of the structural requirements for mutagenicity by incorporating molecular flexibility and metabolic activation of chemicals I: TA100 model. Chem Res Toxicol. 17:753–766.
  • Mekenyan O, Todorov M, Serafimova R, Stoeva S, Aptula A, Finking R, Jacob E. 2007. Identifying the structural requirements for chromosomal aberration by incorporating molecular flexibility and metabolic activation of chemicals. Chem Res Toxicol. 20:1927–1941.
  • Müller L, Singer T. 2009. EMS in Viracept–the course of events in 2007 and 2008 from the non-clinical safety point of view. Toxicol Lett. 190:243–247.
  • Munro IC. 1990. Safety assessment procedures for indirect food additives: an overview. Report of a workshop. Regul Toxicol Pharmacol. 12:2–12.
  • Munro IC, Ford RA, Kennepohl E, Sprenger JG. 1996. Correlation of structural class with no-observed-effect levels: a proposal for establishing a threshold of concern. Food Chem Toxicol. 34:829–867.
  • Munro IC, Kennepohl E, Kroes R. 1999. A procedure for the safety evaluation of flavouring substances. Joint FAO/WHO Expert Committee on Food Additives. Food Chem Toxicol. 37:207–232.
  • Organisation for Economic Cooperation and Development (OECD). 2009a. Test No. 451: Carcinogenicity Studies, OECD Guidelines for the Testing of Chemicals, Section 4. Paris. Available from: http://www.oecd-ilibrary.org/environment/test-no-451-carcinogenicity-studies_9789264071186-en
  • Organisation for Economic Cooperation and Development (OECD). 2009b. Test No. 453: Combined Chronic Toxicity/Carcinogenicity Studies. OECD Publishing (OECD Guidelines for the Testing of Chemicals, Section 4). Paris. Available from: http://www.oecd-ilibrary.org/environment/test-no-453-combined-chronic-toxicity-carcinogenicity-studies_9789264071223-en
  • Organisation for Economic Cooperation and Development (OECD). 2017. OECD Guidelines for the Testing of Chemicals, Section 4: Health Effects. Paris. Available from: http://www.oecd-ilibrary.org/environment/oecd-guidelines-for-the-testing-of-chemicals-section-4-health-effects_20745788
  • Parry JM, Fielder RJ, McDonald A. 1994. Thresholds for aneuploidy-inducing chemicals. Advisory Committee on Mutagenicity of Chemicals in Food, Consumer Products and the Environment of the UK Department of Health. Mutagenesis. 9:503–504.
  • Preston RJ, Williams GM. 2005. DNA-reactive carcinogens: mode of action and human cancer hazard. Crit Rev Toxicol. 35:673–683.
  • Proctor DM, Gatto NM, Hong SJ, Allamneni KP. 2007. Mode-of-action framework for evaluating the relevance of rodent forestomach tumors in cancer risk assessment. Toxicol Sci. 98:313–326.
  • Rhomberg LR, Baetcke K, Blancato J, Bus J, Cohen S, Conolly R, Dixit R, Doe J, Ekelman K, Fenner-Crisp P, et al. 2007. Issues in the design and interpretation of chronic toxicity and carcinogenicity studies in rodents: approaches to dose selection. Crit Rev Toxicol. 37:729–837.
  • Rulis AM. 1987. De minimis and the threshold of regulation. In: Food protection technology. Chelsea: Lewis Publishing; p. 29–37.
  • Scientific Committee on Consumer Safety, Scientific Committee on Health and Environmental Risks (SCCS & SCHER). 2012. Joint opinion on the use of the Threshold of Toxicological Concern (TTC) approach for human safety assessment of chemical substances with focus on cosmetics and consumer products. Brussels. Available from: http://ec.europa.eu/health/scientific_committees/consumer_safety/docs/sccs_o_092.pdf
  • Scientific Committee on Consumer Safety Notes for Guidance (SCCS). 2016. The SCCS notes of guidance for the testing of cosmetic ingredients and their safety evaluation. Paper presented at 11th Plenary Meeting of 29 September 2015; Brussels, Belgium.
  • Serafimova R, Todorov M, Pavlov T, Kotov S, Jacob E, Aptula A, Mekenyan O. 2007. Identification of the structural requirements for mutagencitiy, by incorporating molecular flexibility and metabolic activation of chemicals. II. General Ames mutagenicity model. Chem Res Toxicol. 20:662–676.
  • Slob W. 2014. Benchmark dose and the three Rs. Part I. Getting more information from the same number of animals. Crit Rev Toxicol. 44:557–567.
  • SMARTS. 2016. Daylight Theory SMARTS: A Language for Describing Molecular Patterns. Available from: http://www.daylight.com/dayhtml/doc/theory/theory.smarts.html
  • Tropsha A, Tropsha A. 2010. Recent advances in development, validation, and exploitation of QSAR models. In: Burger’s medicinal chemistry and drug discovery. Hoboken (NJ): Wiley. Available from: http://doi.wiley.com/10.1002/0471266949.bmc002.pub2
  • United States Environmental Protection Agency (EPA). 2005. Guidelines for Carcinogen Risk Assessment [cited 2017 Feb 2]. Available from: https://www.epa.gov/sites/production/files/2013-09/documents/cancer_guidelines_final_3-25-05.pdf
  • United States Environmental Protection Agency (EPA). 2011. Exposure Factors Handbook 2011 Edition (Final). U.S. Environmental Protection Agency, Washington, DC, EPA/600/R-09/052F [cited 2017 Feb 2]. Available from: https://cfpub.epa.gov/ncea/risk/recordisplay.cfm?deid =236252.
  • Votano JR, Parham M, Hall LH, Kier LB, Oloff S, Tropsha A, Xie Q, Tong W. 2004. Three new consensus QSAR models for the prediction of Ames genotoxicity. Mutagenesis. 19:365–377.
  • Weisburger JH, Williams GM. 1981. Carcinogen testing: current problems and new approaches. Science. 214:401–407.
  • Williams RV, Amberg A, Brigo A, Coquin L, Giddings A, Glowienke S, Greene N, Jolly R, Kemper R, O'Leary-Steele C, et al. 2016. It's difficult, but important, to make negative predictions. Regul Toxicol Pharmacol. 6:79–86.
  • World Health Organization (WHO). 1999. Safety evaluation of certain food additives. WHO Food Additives Series, No. 42. Geneva.
  • Yang C, Tarkhov A, Marusczyk J, Bienfait B, Gasteiger J, Kleinoeder T, Magdziarz T, Sacher O, Schwab CH, Schwoebel J, et al. 2015. New publicly available chemical query language, CSRML, to support chemotype representations for application to data mining and modeling. J Chem Inf Model. 55:510–528.