Quantitative assessment of cumulative carcinogenic risk for multiple genotoxic impurities in a new drug substance

Regulatory Toxicology and Pharmacology

Volumn 51, Issue 3, 2008, Pages 270-277

  Bercu, Joel P ^a   Hoffman, Wherly P ^a   Lee, Cindy ^a   Ness, Daniel K ^b  

^a ELI LILLY AND COMPANY   (United States)

^b ELAN PHARMACEUTICALS   (United States)

Author keywords

Drug substance; Genotoxic; Impurities; Mixtures

Indexed keywords

AFLATOXIN; AROMATIC AMINE; AZOXY DERIVATIVE; DIBENZODIOXIN DERIVATIVE; DIBENZOFURAN DERIVATIVE; NEW DRUG; NITROSO DERIVATIVE; ORGANOPHOSPHATE; STEROID;

ARTICLE; CANCER RISK; CARCINOGENIC ACTIVITY; DATA BASE; DOSE RESPONSE; DRUG IMPURITY; DRUG SAFETY; GENOTOXICITY; HUMAN; NONHUMAN; PRIORITY JOURNAL; QUANTITATIVE ANALYSIS; RISK ASSESSMENT; STATISTICAL ANALYSIS;

ANIMALS; CARCINOGENICITY TESTS; CARCINOGENS; CONSUMER PRODUCT SAFETY; DRUG CONTAMINATION; DRUG EVALUATION, PRECLINICAL; HUMANS; MICE; MUTAGENICITY TESTS; MUTAGENS; PHARMACEUTICAL PREPARATIONS; RATS; RISK ASSESSMENT;

EID: 47749149515     PISSN: 02732300     EISSN: 10960295     Source Type: Journal    
DOI: 10.1016/j.yrtph.2008.04.011     Document Type: Article

References (42)

1. Anderson L.M. Introduction and overview. Perinatal carcinogenesis: growing a node for epidemiology, risk management, and animal studies. Toxicol. Appl. Pharmacol. 199 (2004) 85-90
2. Argentine M.D., Owens P.K., and Olsen B.A. Strategies for the investigation and control of process-related impurities in drug substances. Adv. Drug Deliv. Rev. 59 (2007) 12-28
3. Arni P., and Hertner T. Chromosomal aberrations in vitro induced by aneugens. Mutat. Res. 379 (1997) 83-93
4. Ashby J., and Tennant R.W. Definitive relationships among chemical structure, carcinogenicity and mutagenicity for 301 chemicals tested by the U.S. NTP. Mutat. Res. 257 (1991) 229-306
5. Barlow S., Renwick A.G., Kleiner J., Bridges J.W., Busk L., Dybing E., Edler L., Eisenbrand G., Fink-Gremmels J., Knaap A., Kroes R., Liem D., Muller D.J., Page S., Rolland V., Schlatter J., Tritscher A., Tueting W., and Wurtzen G. Risk assessment of substances that are both genotoxic and carcinogenic report of an International Conference organized by EFSA and WHO with support of ILSI Europe. Food Chem.Toxicol. 44 (2006) 1636-1650
6. Barlow S.M., Kozianowski G., Wurtzen G., and Schlatter J. Threshold of toxicological concern for chemical substances present in the diet. Report of a workshop, 5-6 October 1999, Paris, France. Food Chem. Toxicol. 39 (2001) 893-905
7. Beddowes E.J., Faux S.P., and Chipman J.K. Chloroform, carbon tetrachloride and glutathione depletion induce secondary genotoxicity in liver cells via oxidative stress. Toxicology 187 (2003) 101-115
8. Cheeseman M.A., Machuga E.J., and Bailey A.B. A tiered approach to threshold of regulation. Food Chem. Toxicol. 37 (1999) 387-412
9. Committee for Medicinal Products for Human Use, European Medicines Agency, 2007. Guideline on the limits of genotoxic impurities. EMEA/CHMP/QWP/251344/2006, Available from: .
10. Decordier I., Dillen L., Cundari E., and Kirsch-Volders M. Elimination of micronucleated cells by apoptosis after treatment with inhibitors of microtubules. Mutagenesis 17 (2002) 337-344
11. Delaney E.J. An impact analysis of the application of the threshold of toxicological concern concept to pharmaceuticals. Regul. Toxicol. Pharmacol. 49 (2007) 107-124
12. Doak S.H., Jenkins G.J., Johnson G.E., Quick E., Parry E.M., and Parry J.M. Mechanistic influences for mutation induction curves after exposure to DNA-reactive carcinogens. Cancer Res. 67 (2007) 3904-3911
13. Dobo K.L., Greene N., Cyr M.O., Caron S., and Ku W.W. The application of structure-based assessment to support safety and chemistry diligence to manage genotoxic impurities in active pharmaceutical ingredients during drug development. Regul. Toxicol. Pharmacol. 44 (2006) 282-293
14. Fiori J.M., and Meyerhoff R.D. Extending the threshold of regulation concept: de minimis limits for carcinogens and mutagens. Regul. Toxicol. Pharmacol. 35 (2002) 209-216
15. Galloway S.M., Miller J.E., Armstrong M.J., Bean C.L., Skopek T.R., and Nichols W.W. DNA synthesis inhibition as an indirect mechanism of chromosome aberrations: comparison of DNA-reactive and non-DNA-reactive clastogens. Mutat. Res. 400 (1998) 169-186
16. Gold L.S., Manley N.B., Slone T.H., and Rohrbach L. Supplement to the Carcinogenic Potency Database (CPDB): results of animal bioassays published in the general literature in 1993 to 1994 and by the National Toxicology Program in 1995 to 1996. Environ. Health Perspect. 107 Suppl 4 (1999) 527-600
17. Gold L.S., Slone T.H., Manley N.B., Garfinkel G.B., Hudes E.S., Rohrbach L., and Ames B.N. The Carcinogenic Potency Database: analyses of 4000 chronic animal cancer experiments published in the general literature and by the U.S. National Cancer Institute/National Toxicology Program. Environ. Health Perspect. 96 (1991) 11-15
18. Hayashi M., Kamata E., Hirose A., Takahashi M., Morita T., and Ema M. In silico assessment of chemical mutagenesis in comparison with results of Salmonella microsome assay on 909 chemicals. Mutat. Res. 588 (2005) 129-135
19. Hogg R.V., McKean J.W., and Craig A.T. Introduction to Mathematical Statistics. sixth ed. (2005), Pearson Education, Inc., NJ
20. Humfrey C.D. Recent developments in the risk assessment of potentially genotoxic impurities in pharmaceutical drug substances. Toxicol Sci. 100 (2007) 24-28
21. International Conference on Harmonisation, 1997a. S1B: Testing for carcinogenicity of pharmaceuticals. Available from: .
22. International Conference on Harmonisation, 1997b. S2B: Genotoxicity: A standard battery for genotoxicity testing for pharmaceuticals. Available from: .
23. International Conference on Harmonisation, 2006. Q3A(R2): Impurities in new drug substances. Available from: .
24. Jacobson-Kram D., and Jacobs A. Use of genotoxicity data to support clinical trials or positive genetox findings on a candidate pharmaceutical or impurity .... now what?. Int. J. Toxicol. 24 (2005) 129-134
25. Jenkins G.J., Doak S.H., Johnson G.E., Quick E., Waters E.M., and Parry J.M. Do dose response thresholds exist for genotoxic alkylating agents?. Mutagenesis 20 (2005) 389-398
26. Kaldor J.M., and L'Abbe K.A. Interaction between Human Carcinogens (1990), IARC Sci. Publ. pp. 35-43
27. Kirkland D., Aardema M., Henderson L., and Müller L. Evaluation of the ability of a battery of three in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens I. Sensitivity, specificity and relative predictivity. Mutat. Res. 584 (2005) 1-256
28. Kodell R.L., and Chen J.J. Reducing conservatism in risk estimation for mixtures of carcinogens. Risk Anal. 14 (1994) 327-332
29. Krewski D., Szyszkowicz M., and Rosenkranz H. Quantitative factors in chemical carcinogenesis: variation in carcinogenic potency. Regul. Toxicol. Pharmacol. 12 (1990) 13-29
30. Krewski D., and Thomas R.D. Carcinogenic mixtures. Risk Anal. 12 (1992) 105-113
31. Kroes R., Galli C., Munro I., Schilter B., Tran L., Walker R., and Wurtzen G. Threshold of toxicological concern for chemical substances present in the diet: a practical tool for assessing the need for toxicity testing. Food Chem.Toxicol. 38 (2000) 255-312
32. Kroes R., Renwick A.G., Cheeseman M., Kleiner J., Mangelsdorf I., Piersma A., Schilter B., Schlatter J., van S.F., Vos J.G., and Wurtzen G. Structure-based thresholds of toxicological concern (TTC): guidance for application to substances present at low levels in the diet. Food Chem.Toxicol. 42 (2004) 65-83
33. Lynch A., Harvey J., Aylott M., Nicholas E., Burman M., Siddiqui A., Walker S., and Rees R. Investigations into the concept of a threshold for topoisomerase inhibitor-induced clastogenicity. Mutagenesis 18 (2003) 345-353
34. Matthews E.J., Kruhlak N.L., Cimino M.C., Benz R.D., and Contrera J.F. An analysis of genetic toxicity, reproductive and developmental toxicity, and carcinogenicity data: I. Identification of carcinogens using surrogate endpoints. Regul. Toxicol. Pharmacol. 44 (2006) 83-96
35. Matthews E.J., Kruhlak N.L., Cimino M.C., Benz R.D., and Contrera J.F. An analysis of genetic toxicity, reproductive and developmental toxicity, and carcinogenicity data: II. Identification of genotoxicants, reprotoxicants, and carcinogens using in silico methods. Regul. Toxicol. Pharmacol. 44 (2006) 97-110
36. McGovern T., and Jacobson-Kram D. Regulation of genotoxic and carcinogenic impurities in drug substances and products. TrAC Trends Anal. Chem. 25 (2006) 790-795
37. Müller L., Mauthe R.J., Riley C.M., Andino M.M., Antonis D.D., Beels C., DeGeorge J., De Knaep A.G., Ellison D., Fagerland J.A., Frank R., Fritschel B., Galloway S., Harpur E., Humfrey C.D., Jacks A.S., Jagota N., Mackinnon J., Mohan G., Ness D.K., O'Donovan M.R., Smith M.D., Vudathala G., and Yotti L. A rationale for determining, testing, and controlling specific impurities in pharmaceuticals that possess potential for genotoxicity. Regul. Toxicol. Pharmacol. 44 (2006) 198-211
38. Munro I.C., Kennepohl E., and Kroes R. A procedure for the safety evaluation of flavouring substances. Joint FAO/WHO Expert Committee on Food Additives. Food Chem.Toxicol. 37 (1999) 207-232
39. Peto R., Pike M.C., Bernstein L., Gold L.S., and Ames B.N. The TD50: a proposed general convention for the numerical description of the carcinogenic potency of chemicals in chronic-exposure animal experiments. Environ. Health Perspect. 58 (1984) 1-8
40. United States Environmental Protection Agency, 2000. Supplementary guidance for conducting health risk assessment of chemical mixtures. EPA/630/R-00/002. Available from: .
41. United States Environmental Protection Agency, 2005a. Guidelines for carcinogen risk assessment. EPA/630/P-03/001B. Available from: .
42. United States Environmental Protection Agency, 2005b. Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens. EPA/630/R-03/003F. Available from: .