Toxicological Research

  • 제34권4호
  • /
  • Pages.281-290
  • /
  • 2018
  • /
  • 1976-8257(pISSN)
  • /
  • 2234-2753(eISSN)
한국독성학회 (Korean Society of Toxicology & Korea Environmental Mutagen Society)
권호 표지
DOI QR코드

DOI QR Code

Thresholds of Genotoxic and Non-Genotoxic Carcinogens

  • Nohmi, Takehiko (Division of Pathology, Biological Safety Research Center, National Institute of Health Sciences)
  • 투고 : 2018.07.03
  • 심사 : 2018.08.30
  • 발행 : 2018.10.15
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Exposure to chemical agents is an inevitable consequence of modern society; some of these agents are hazardous to human health. The effects of chemical carcinogens are of great concern in many countries, and international organizations, such as the World Health Organization, have established guidelines for the regulation of these chemicals. Carcinogens are currently categorized into two classes, genotoxic and non-genotoxic carcinogens, which are subject to different regulatory policies. Genotoxic carcinogens are chemicals that exert carcinogenicity via the induction of mutations. Owing to their DNA interaction properties, there is thought to be no safe exposure threshold or dose. Genotoxic carcinogens are regulated under the assumption that they pose a cancer risk for humans, even at very low doses. In contrast, non-genotoxic carcinogens, which induce cancer through mechanisms other than mutations, such as hormonal effects, cytotoxicity, cell proliferation, or epigenetic changes, are thought to have a safe exposure threshold or dose; thus, their use in society is permitted unless the exposure or intake level would exceed the threshold. Genotoxicity assays are an important method to distinguish the two classes of carcinogens. However, some carcinogens have negative results in in vitro bacterial mutation assays, but yield positive results in the in vivo transgenic rodent gene mutation assay. Non-DNA damage, such as spindle poison or topoisomerase inhibition, often leads to positive results in cytogenetic genotoxicity assays such as the chromosome aberration assay or the micronucleus assay. Therefore, mechanistic considerations of tumor induction, based on the results of the genotoxicity assays, are necessary to distinguish genotoxic and non-genotoxic carcinogens. In this review, the concept of threshold of toxicological concern is introduced and the potential risk from multiple exposures to low doses of genotoxic carcinogens is also discussed.

키워드

참고문헌

  1. The Food and Agricultural Organization of the United Nations and the World Health Organization (FAO/WHO) (2009) Chapter 5: dose-response assessment and derivation of healthbased guidance values in Environmental Health Criteria 240. pp. 2-55.
  2. Kirsch-Volders, M., Aardema, M. and Elhajouji, A. (2000) Concepts of threshold in mutagenesis and carcinogenesis. Mutat. Res., 464, 3-11. https://doi.org/10.1016/S1383-5718(99)00161-8
  3. Nohmi, T., Toyoda-Hokaiwado, N., Yamada, M., Masumura, K., Honma, M. and Fukushima, S. (2008) International symposium on genotoxic and carcinogenic thresholds. Genes Environ., 30, 101-107. https://doi.org/10.3123/jemsge.30.101
  4. Lovell, D.P. (2000) Dose-response and threshold-mediated mechanisms in mutagenesis: statistical models and study design. Mutat. Res., 464, 87-95. https://doi.org/10.1016/S1383-5718(99)00169-2
  5. Boice, J.D., Jr. (2017) The linear nonthreshold (LNT) model as used in radiation protection: an NCRP update. Int. J. Radiat. Biol., 93, 1079-1092. https://doi.org/10.1080/09553002.2017.1328750
  6. Auerbach, C. (1958) Radiomimetic substances. Radiat. Res., 9, 33-47. https://doi.org/10.2307/3570779
  7. The Food and Agricultural Organization of the United Nations and the World Health Organization (FAO/WHO) (2009) Chapter 7: risk characterization in Environmental Health Criteria 240: Principles and Methods for Risk Assessment of Chemicals in Food. pp. 1-18.
  8. Bolt, H.M. (2008) The concept of "practical thresholds" in the derivation of occupational exposure limits for carcinogens by the scientific committee on occupatinal exposure limits (SCOEL) of the European Union. Genes Environ., 30, 114-119. https://doi.org/10.3123/jemsge.30.114
  9. Ashby, J. and Tennant, R.W. (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. https://doi.org/10.1016/0165-1218(88)90114-0
  10. Hayashi, Y. (1992) Overview of genotoxic carcinogens and non-genotoxic carcinogens. Exp. Toxicol. Pathol., 44, 465-471. https://doi.org/10.1016/S0940-2993(11)80159-4
  11. MacGregor, J.T., Frotschl, R., White, P.A., Crump, K.S., Eastmond, D.A., Fukushima, S., Guerard, M., Hayashi, M., Soeteman-Hernandez, L.G., Johnson, G.E., Kasamatsu, T., Levy, D.D., Morita, T., Muller, L., Schoeny, R., Schuler, M.J. and Thybaud, V. (2015) IWGT report on quantitative approaches to genotoxicity risk assessment II. Use of pointof-departure (PoD) metrics in defining acceptable exposure limits and assessing human risk. Mutat. Res., 783, 66-78. https://doi.org/10.1016/j.mrgentox.2014.10.008
  12. Butterworth, B.E. (1990) Consideration of both genotoxic and nongenotoxic mechanisms in predicting carcinogenic potential. Mutat. Res., 239, 117-132. https://doi.org/10.1016/0165-1110(90)90033-8
  13. Roberts, R.A., Goodman, J.I., Shertzer, H.G., Dalton, T.P. and Farland, W.H. (2003) Rodent toxicity and nongenotoxic carcinogenesis: knowledge-based human risk assessment based on molecular mechanisms. Toxicol. Mech. Methods, 13, 21-29. https://doi.org/10.1080/15376510309823
  14. Ramirez, T., Eastmond, D.A. and Herrera, L.A. (2007) Nondisjunction events induced by albendazole in human cells. Mutat. Res., 626, 191-195. https://doi.org/10.1016/j.mrgentox.2006.09.004
  15. Asanami, S. and Shimono, K. (1999) The effect of hyperthermia on micronucleus induction by mutagens in mice. Mutat. Res., 446, 149-154. https://doi.org/10.1016/S1383-5718(99)00156-4
  16. Armstrong, M.J., Gara, J.P., Gealy, R., III, Greenwood, S.K., Hilliard, C.A., Laws, G.M. and Galloway, S.M. (2000) Induction of chromosome aberrations in vitro by phenolphthalein: mechanistic studies. Mutat. Res., 457, 15-30. https://doi.org/10.1016/S0027-5107(00)00119-6
  17. Galloway, S.M., Miller, J.E., Armstrong, M.J., Bean, C.L., Skopek, T.R. and Nichols, W.W. (1998) DNA synthesis inhibition as an indirect mechanism of chromosome aberrations: comparison of DNA-reactive and non-DNA-reactive clastogens. Mutat. Res., 400, 169-186. https://doi.org/10.1016/S0027-5107(98)00044-X
  18. Elhajouji, A., Van, H.P. and Kirsch-Volders, M. (1995) Indications for a threshold of chemically-induced aneuploidy in vitro in human lymphocytes. Environ. Mol. Mutagen., 26, 292-304. https://doi.org/10.1002/em.2850260405
  19. Kirsch-Volders, M., Gonzalez, L., Carmichael, P. and Kirkland, D. (2009) Risk assessment of genotoxic mutagens with thresholds: a brief introduction. Mutat. Res., 678, 72-75. https://doi.org/10.1016/j.mrgentox.2009.05.001
  20. Hayashi, M. (2016) The micronucleus test-most widely used in vivo genotoxicity test. Genes Environ., 38, 18. doi:10.1186/s41021-016-0044-x.
  21. Lynch, A., Harvey, J., Aylott, M., Nicholas, E., Burman, M., Siddiqui, A., Walker, S. and Rees, R. (2003) Investigations into the concept of a threshold for topoisomerase inhibitorinduced clastogenicity. Mutagenesis, 18, 345-353. https://doi.org/10.1093/mutage/geg003
  22. Elhajouji, A., Lukamowicz, M., Cammerer, Z. and Kirsch-Volders, M. (2011) Potential thresholds for genotoxic effects by micronucleus scoring. Mutagenesis, 26, 199-204. https://doi.org/10.1093/mutage/geq089
  23. Maron, D.M. and Ames, B.N. (1983) Revised methods for the Salmonella mutagenicity test. Mutat. Res., 113, 173-215. https://doi.org/10.1016/0165-1161(83)90010-9
  24. Ashby, J. and Tennant, R.W. (1991) Definitive relationships among chemical structure, carcinogenicity and mutagenicity for 301 chemicals tested by the U.S. NTP. Mutat. Res., 257, 229-306. https://doi.org/10.1016/0165-1110(91)90003-E
  25. Nohmi, T., Masumura, K. and Toyoda-Hokaiwado, N. (2017) Transgenic rat models for mutagenesis and carcinogenesis. Genes Environ., 39, 11. doi:10.1186/s41021-016-0072-6.
  26. Nohmi, T., Katoh, M., Suzuki, H., Matsui, M., Yamada, M., Watanabe, M., Suzuki, M., Horiya, N., Ueda, O., Shibuya, T., Ikeda, H. and Sofuni, T. (1996) A new transgenic mouse mutagenesis test system using Spi- and 6-thioguanine selections. Environ. Mol. Mutagen., 28, 465-470. https://doi.org/10.1002/(SICI)1098-2280(1996)28:4<465::AID-EM24>3.0.CO;2-C
  27. Nohmi, T., Suzuki, T. and Masumura, K. (2000) Recent advances in the protocols of transgenic mouse mutation assays. Mutat. Res., 455, 191-215. https://doi.org/10.1016/S0027-5107(00)00077-4
  28. Masumura, K., Sakamoto, Y., Kumita, W., Honma, M., Nishikawa, A. and Nohmi, T. (2015) Genomic integration of lambda EG10 transgene in gpt delta transgenic rodents. Genes Environ., 37, 24. doi:10.1186/s41021-015-0024-6.
  29. Nohmi, T. (2015) Past, present and future directions of gpt delta rodent gene mutation assays. Food Safety, 4, 1-13.
  30. Suzuki, Y., Umemura, T., Hibi, D., Inoue, T., Jin, M., Ishii, Y., Sakai, H., Nohmi, T., Yanai, T., Nishikawa, A. and Ogawa, K. (2012) Possible involvement of genotoxic mechanisms in estragole-induced hepatocarcinogenesis in rats. Arch. Toxicol., 86, 1593-1601. https://doi.org/10.1007/s00204-012-0865-8
  31. Ishii, Y., Takasu, S., Kuroda, K., Matsushita, K., Kijima, A., Nohmi, T., Ogawa, K. and Umemura, T. (2014) Combined application of comprehensive analysis for DNA modification and reporter gene mutation assay to evaluate kidneys of gpt delta rats given madder color or its constituents. Anal. Bioanal. Chem., 406, 2467-2475. https://doi.org/10.1007/s00216-014-7621-2
  32. Jin, M., Kijima, A., Hibi, D., Ishii, Y., Takasu, S., Matsushita, K., Kuroda, K., Nohmi, T., Nishikawa, A. and Umemura, T. (2013) In vivo genotoxicity of methyleugenol in gpt delta transgenic rats following medium-term exposure. Toxicol. Sci., 131, 387-394. https://doi.org/10.1093/toxsci/kfs294
  33. Kuroda, K., Ishii, Y., Takasu, S., Kijima, A., Matsushita, K., Watanabe, M., Takahashi, H., Sugita-Konishi, Y., Sakai, H., Yanai, T., Nohmi, T., Ogawa, K. and Umemura, T. (2013) Cell cycle progression, but not genotoxic activity, mainly contributes to citrinin-induced renal carcinogenesis. Toxicology, 311, 216-224. https://doi.org/10.1016/j.tox.2013.07.003
  34. Maeda, J., Kijima, A., Inoue, K., Ishii, Y., Ichimura, R., Takasu, S., Kuroda, K., Matsushita, K., Kodama, Y., Saito, N., Umemura, T. and Yoshida, M. (2014) In vivo genotoxicity of Ginkgo biloba extract in gpt delta mice and constitutive androstane receptor knockout mice. Toxicol. Sci., 140, 298-306. https://doi.org/10.1093/toxsci/kfu090
  35. Onami, S., Cho, Y.M., Toyoda, T., Horibata, K., Ishii, Y., Umemura, T., Honma, M., Nohmi, T., Nishikawa, A. and Ogawa, K. (2014) Absence of in vivo genotoxicity of 3-monochloropropane-1,2-diol and associated fatty acid esters in a 4-week comprehensive toxicity study using F344 gpt delta rats. Mutagenesis, 29, 295-302. https://doi.org/10.1093/mutage/geu018
  36. Kuroiwa, Y., Umemura, T., Nishikawa, A., Kanki, K., Ishii, Y., Kodama, Y., Masumura, K., Nohmi, T. and Hirose, M. (2007) Lack of in vivo mutagenicity and oxidative DNA damage by flumequine in the livers of gpt delta mice. Arch. Toxicol., 81, 63-69. https://doi.org/10.1007/s00204-006-0126-9
  37. Wiseman, R.W., Miller, E.C., Miller, J.A. and Liem, A. (1987) Structure-activity studies of the hepatocarcinogenicities of alkenylbenzene derivatives related to estragole and safrole on administration to preweanling male C57BL/6J x C3H/HeJ F1 mice. Cancer Res., 47, 2275-2283.
  38. Sekizawa, J. and Shibamoto, T. (1982) Genotoxicity of safrole-related chemicals in microbial test systems. Mutat. Res., 101, 127-140. https://doi.org/10.1016/0165-1218(82)90003-9
  39. Zeiger, E., Anderson, B., Haworth, S., Lawlor, T., Mortelmans, K. and Speck, W. (1987) Salmonella mutagenicity tests: III. Results from the testing of 255 chemicals. Environ. Mutagen., 9 Suppl 9, 1-109.
  40. Suzuki, Y., Umemura, T., Ishii, Y., Hibi, D., Inoue, T., Jin, M., Sakai, H., Kodama, Y., Nohmi, T., Yanai, T., Nishikawa, A. and Ogawa, K. (2012) Possible involvement of sulfotransferase 1A1 in estragole-induced DNA modification and carcinogenesis in the livers of female mice. Mutat. Res., 749, 23-28. https://doi.org/10.1016/j.mrgentox.2012.07.002
  41. Phillips, D.H., Miller, J.A., Miller, E.C. and Adams, B. (1981) Structures of the DNA adducts formed in mouse liver after administration of the proximate hepatocarcinogen 1'-hydroxyestragole. Cancer Res., 41, 176-186.
  42. Alnouti, Y. and Klaassen, C.D. (2006) Tissue distribution and ontogeny of sulfotransferase enzymes in mice. Toxicol. Sci., 93, 242-255. https://doi.org/10.1093/toxsci/kfl050
  43. Srivastava, S., Sinha, R. and Roy, D. (2004) Toxicological effects of malachite green. Aquat. Toxicol., 66, 319-329. https://doi.org/10.1016/j.aquatox.2003.09.008
  44. Culp, S.J., Mellick, P.W., Trotter, R.W., Greenlees, K.J., Kodell, R.L. and Beland, F.A. (2006) Carcinogenicity of malachite green chloride and leucomalachite green in B6C3F1 mice and F344 rats. Food Chem. Toxicol., 44, 1204-1212. https://doi.org/10.1016/j.fct.2006.01.016
  45. Fessard, V., Godard, T., Huet, S., Mourot, A. and Poul, J.M. (1999) Mutagenicity of malachite green and leucomalachite green in in vitro tests. J. Appl. Toxicol., 19, 421-430. https://doi.org/10.1002/(SICI)1099-1263(199911/12)19:6<421::AID-JAT595>3.0.CO;2-6
  46. Mittelstaedt, R.A., Mei, N., Webb, P.J., Shaddock, J.G., Dobrovolsky, V.N., McGarrity, L.J., Morris, S.M., Chen, T., Beland, F.A., Greenlees, K.J. and Heflich, R.H. (2004) Genotoxicity of malachite green and leucomalachite green in female Big Blue B6C3F1 mice. Mutat. Res., 561, 127-138. https://doi.org/10.1016/j.mrgentox.2004.04.003
  47. Manjanatha, M.G., Shelton, S.D., Bishop, M., Shaddock, J.G., Dobrovolsky, V.N., Heflich, R.H., Webb, P.J., Blankenship, L.R., Beland, F.A., Greenlees, K.J. and Culp, S.J. (2004) Analysis of mutations and bone marrow micronuclei in Big Blue rats fed leucomalachite green. Mutat. Res., 547, 5-18. https://doi.org/10.1016/j.mrfmmm.2003.11.009
  48. Culp, S.J., Blankenship, L.R., Kusewitt, D.F., Doerge, D.R., Mulligan, L.T. and Beland, F.A. (1999) Toxicity and metabolism of malachite green and leucomalachite green during short-term feeding to Fischer 344 rats and B6C3F1 mice. Chem. Biol. Interact., 122, 153-170. https://doi.org/10.1016/S0009-2797(99)00119-2
  49. European Food Safety Authority (EFSA) (2016) Malachite Green in Food. EFSA J., 14, 1-80.
  50. World Health Organization (WHO) (2000) Toxicological evaluation of certain veterinary drug residues in food, fiftyfourth meeting of the Joint FAO/WHO Expert Committee on Food Additives. WHO Food Additive Series, 45, 75-89.
  51. Umemura, T., Kuroiwa, Y., Tasaki, M., Okamura, T., Ishii, Y., Kodama, Y., Nohmi, T., Mitsumori, K., Nishikawa, A. and Hirose, M. (2007) Detection of oxidative DNA damage, cell proliferation and in vivo mutagenicity induced by dicyclanil, a non-genotoxic carcinogen, using gpt delta mice. Mutat. Res., 633, 46-54. https://doi.org/10.1016/j.mrgentox.2007.05.007
  52. Kasper, P., Uno, Y., Mauthe, R., Asano, N., Douglas, G., Matthews, E., Moore, M., Mueller, L., Nakajima, M., Singer, T. and Speit, G. (2007) Follow-up testing of rodent carcinogens not positive in the standard genotoxicity testing battery: IWGT workgroup report. Mutat. Res., 627, 106-116. https://doi.org/10.1016/j.mrgentox.2006.10.007
  53. National Toxicology Program (NTP) (1989) Toxicology and carcinogenesis studies of ochratoxin A (CAS No. 303-47-9) in F344/N rats (gavage studies). Natl. Toxicol. Program. Tech. Rep. Ser., 358, 1-142.
  54. Malir, F., Ostry, V., Pfohl-Leszkowicz, A., Malir, J. and Toman, J. (2016) Ochratoxin A: 50 years of research. Toxins. (Basel), 8, E191. doi:10.3390/toxins8070191.
  55. International Agency for Research on Cancer (IARC) (1993) Ochratoxin A. IARC Monogr. Eval. Carcinog. Risks Hum., 56, 489-521.
  56. Hibi, D., Suzuki, Y., Ishii, Y., Jin, M., Watanabe, M., Sugita-Konishi, Y., Yanai, T., Nohmi, T., Nishikawa, A. and Umemura, T. (2011) Site-specific in vivo mutagenicity in the kidney of gpt delta rats given a carcinogenic dose of ochratoxin A. Toxicol. Sci., 122, 406-414. https://doi.org/10.1093/toxsci/kfr139
  57. Nohmi, T., Suzuki, M., Masumura, K., Yamada, M., Matsui, K., Ueda, O., Suzuki, H., Katoh, M., Ikeda, H. and Sofuni, T. (1999) Spi- selection: An efficient method to detect gammaray-induced deletions in transgenic mice. Environ. Mol. Mutagen., 34, 9-15. https://doi.org/10.1002/(SICI)1098-2280(1999)34:1<9::AID-EM2>3.0.CO;2-E
  58. Fukushima, S., Gi, M., Kakehashi, A. and Wanibuchi, H. (2016) Qualitative and quantitative assessments on low-dose carcinogenicity of genotoxic hepatocarcinogens: dose-response for key events in rat hapatocarcinogenesis in Thresholds of Genotoxic Carcinogens: from Mechanisms to Regulation (Nohmi, T. and Fukushima, S. Eds.). Elsevier, pp. 1-17.
  59. Fukushima, S., Kinoshita, A., Puatanachokchai, R., Kushida, M., Wanibuchi, H. and Morimura, K. (2005) Hormesis and dose-response-mediated mechanisms in carcinogenesis: evidence for a threshold in carcinogenicity of non-genotoxic carcinogens. Carcinogenesis, 26, 1835-1845. https://doi.org/10.1093/carcin/bgi160
  60. Fukushima, S., Wei, M., Kakehashi, A. and Wanibuchi, H. (2012) Threshold for genotoxic carcinogens: the central concern in carcinogenic risk assessment. Genes Environ., 32, 153-156.
  61. Jenkins, G.J., Zair, Z., Johnson, G.E. and Doak, S.H. (2010) Genotoxic thresholds, DNA repair, and susceptibility in human populations. Toxicology, 278, 305-310. https://doi.org/10.1016/j.tox.2009.11.016
  62. Nohmi, T. and Tsuzuki, T. (2016) Possible mechanisms underlying genotoxic thresholds: DNA repair and translesion DNA synthesis in Thresholds of Genotoxic Carcinogens: from Mechanisms to Regulation (Nohmi, T. and Fukushima, S. Eds.) Elsevier, pp. 49-66.
  63. Suzuki, M., Matsui, K., Yamada, M., Kasai, H., Sofuni, T. and Nohmi, T. (1997) Construction of mutants of Salmonella typhimurium deficient in 8-hydroxyguanine DNA glycosylase and their sensitivities to oxidative mutagens and nitro compounds. Mutat. Res., 393, 233-246. https://doi.org/10.1016/S1383-5718(97)00108-3
  64. Kim, S.R., Kokubo, K., Matsui, K., Yamada, N., Kanke, Y., Fukuoka, M., Yamada, M. and Nohmi, T. (2005) Lightdependent mutagenesis by benzo[a]pyrene is mediated via oxidative DNA damage. Environ. Mol. Mutagen., 46, 141-149. https://doi.org/10.1002/em.20141
  65. Boobis, A., Brown, P., Cronin, M.T.D., Edwards, J., Galli, C.L., Goodman, J., Jacobs, A., Kirkland, D., Luijten, M., Marsaux, C., Martin, M., Yang, C. and Hollnagel, H.M. (2017) Origin of the TTC values for compounds that are genotoxic and/or carcinogenic and an approach for their re-evaluation. Crit Rev. Toxicol., 47, 705-727.
  66. Federal Register (1995) Toxicological principles for the safety assessment of direct food additives and color additives used in food in Fed. Regist. pp. 36582-36596.
  67. 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. (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. https://doi.org/10.1016/j.fct.2003.08.006
  68. Europena 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, 1-50.
  69. Munro, I.C., Ford, R.A., Kennepohl, E. and Sprenger, J.G. (1996) Correlation of structural class with no-observedeffect levels: a proposal for establishing a threshold of concern. Food Chem. Toxicol., 34, 829-867. https://doi.org/10.1016/S0278-6915(96)00049-X
  70. Ohta, T. (2006) Mutagenic activity of a mixture of heterocyclic amines at doses below the biological threshold level of each. Genes Environ., 28, 181-184. https://doi.org/10.3123/jemsge.28.181