본문 바로가기
HOME> 논문 > 논문 검색상세

논문 상세정보

2년 장기 발암성 검색법의 이슈
Issues in 2-year Long-term in vivo Carcinogenicity Assay

손우찬   (Huntingdon Life Sciences, Pathology, UK  ); 김배환   ((주)태평양 기술연구원 전임상연구센타  ); 장동덕   (국립 독성 연구원 독성연구부CC0136133  ); 한범석   (국립 독성 연구원 독성연구부CC0136133  ); 김종춘   (전남대학교 수의과 대학 독성학 교실UU0001112  ); 이제봉   (농업과학 기술원 농산물 안전성부CC0131248  ); 신진섭   (농업과학 기술원 농산물 안전성부CC0131248  ); 김형진   (한국생명공학연구원 질환동물모델평가연구실CC0186997  );
  • 초록

    2년 발암성 독성시험의 실시와 평가에 대해서는 많은 논란이 있었다. 2년 발암성 시험의 유용성에 대한 많은 비판에도 불구하고 설치류를 이용한 발암성 시험은 사람의 발암성을 예측 할 수 있는 유일한 평가 시스템으로 인식되어 있으며, 아직 이를 대체할 만한 평가 방법은 없다고 할 수도 있다. 그간 규제기관과 학계에서는 다양한 발암성 평가모델을 제시해 왔지만 이런 시험 모델들이 과학적 타당성과 검증된 데이터에 근거하는지에 대해서는 논란이 있다. 2년 설치류 발암성 시험에 제기되는 문제들 즉, 종 및 품종의 선택, 용량설정, 시험기간, 군당 동물의 수, 배경병변, 검사항목, 시험 종료시 측정항목, 병리의 피어리뷰, 통계, 대체시험 모델, 종양의 평가, 그리고 위해성 평가 등에 대하여 검토하였다.


    It has been debating about conducting and interpretating of 2-year rodent carcinogenicity bioassay. Although some criticisms arising in usefulness, it has been still known that long-term carcinogenicity studies using rodents would be the only assay system to predict any possible human risks, which would not be replaced. Both regulatory agencies and academies have developed some assay models, however, there have been controversy whether those study designs and interpretations are based on sound scientific rationale and validated data. Such kinds of issues including choice of species/strain, dose level selection, duration of study, number of animals per group, historical control data, monitoring parameters, terminal investigations, peer review, statistics, alternative assay models, interpretation of neoplastic lesions, and risk assessments, were reviewed.


  • 참고문헌 (63)

    1. Cohen, S.M. and L.B. Ellwein (1991) Genetic errors, cell proliferation, and carcinogenesis. Cancer Res. 51: 6495-6505 
    2. EMEA(The European Agency for the Evaluation of medicinal products Evaluation of medicines for human use London) (2002) CPMP/SWP/2877/00, Committee for proprietary medicinal products (CPMP), Note for guidance on carcinogenic potential. (issued 25 July 2002) 
    3. Festing, M.F. (1995) Use of a multistrain assay could improve the NIP carcinogenesis bioassay. Environmental Health Perspectives 103: 44-52 
    4. Haseman, J.K. and G.R. Rao (1992) Effects of com oil, time related changes and inter laboratory variability on tumor occurrence in control Fischer 344 (F344/N) rats. Toxicol. Pathol. 20:52-60 
    5. Hirose, M., A. Hagiwara and K. Inoue (1987) Metabolism of 2 and 3 tert butyl 4 hydroxyanisole (2 and 3 BHA) in the rat (I): Excretion of BHA in urine, feces and expired air and distribution of BHA in the main organs. Toxicology 139-147 
    6. IARC (1992 - 1997): International Classification of Rodent Tumours, Part 1. The Rat (set of 10 fascicles). Mohr U (Ed). IARC Scientific Publications 122, Lyon 
    7. ICH (1997) Guidance for Industry S1B Testing for carcinogenicity of pharmaceuticals. US FDA, CDER/CBER, Rockville, Md 
    8. ICH (1997). Guideline SIC(R). : Addendum to 'dose selection for carcinogenicity studies of phannaceuticals' Addition of a limit dose and related notes. US FDA, CDER/CBER, Rockville, Md 
    9. Kanerva, R.L., G.M. Ridder and F.R Lefever (1987) Comparison of short term renal effects due to oral administration of decali or d limonene in young adult male Fischer 344 rats. Food Chem. Toxicol. 25: 345-353 
    10. Mohr, U. (1999) RITA - Registry of Industrial Toxicology Animal data: Optimization of carcinogenicity bioassays. Exp. Toxic. Pathol. 51:461-475 (editorial) 
    11. Ochoa, R (2002) Pathology issues in the design of toxicology studies. In: Handbook of toxicologic pathology. 2nd ed. Ed Haschek WM, Rousseaux CG, Wallig, MA, pp. 307-326 
    12. Rous, P., J.G. Kidd and W.E. Smith (1952) Experiments on the cause of the rabbit carcinomas derived from virus induced papillomas. II. Loss by the Vx2 carcinoma of the power to immunize hosts against the papilloma virus. J. Exp. Med., 96(2): 159-74 
    13. Son, W.C. (2003b) Factors contributory to early death of young CD 1 mice in carcinogenicity studies. Tox. Letters 145(1): 88-98 
    14. Son, W.C and C. Gopinath (2004) Early occurrence of spontaneous tumors in CD 1 mice and Sprague Dawley rats. Toxicol. Pathol. 32(4): 371-374 
    15. Son, W.C., K. Kamino, Y.S. Lee and K.S. Kang (2003) Strain specific mammary proliferative lesions development following life time oral administration of Ochratoxin A in DA and Lewis rats. International Journal of Cancer 105(3):305-311 
    16. Su, Q and P. Bannasch (2003) Relevance of hepatic preneoplasia for human hepatocarcinogenesis. Toxicol. Pathol. 31(1): 126-133 
    17. The OECD guideline (1999): ENV/JM/MONO(99)35, Series on testing and assessment No. 35, Environment directorate joint meeting of the committee and the working party on chemicals. Environmental health and safety publications 
    18. The OECD guideline, (2002): ENV/JM/MONO(2002)19, Environment directorate joint meeting of the committee and the working party on chemicals, pesticides and biotechnology(issued 4 Sep., 2002) 
    19. Thurman, J.D., T.J. Bucci, R.W. Hart and A. Thrturro (1994) Survival, body weight, and spontaneous neoplas in ad libitum fed and food restricted Fischer 344 rats. Toxicol. Pathol. 22: 1-9 
    20. U.S. Environmental Protection Agency(EPA) (1987): Pesticide Regulation (PR) Notice 87 10, Pathology raw data definitions as it relates to pathology trails and independent pathology peer review system(issued Oct., 9, 1987) 
    21. Weisburger, J.H. and G.M. Williams (1984) Bioassay of carcinogens: In vitro and in vivo tests. In: Chemical Carcinogens, CE Searle (ed). American Chemical Society, Washington, D. C., pp. 1323-1373 
    22. Williams, G.M. and J.H. Weisburger (1991) Chemical carcinogenesis. In: Amdur MO, Douli J, Klaasen CD (eds).: Casarett and Doull's Toxicology, The basic Science of Poisons. Pergamon Press New York pp. 127-200 
    23. Foran, J.A. & The International Life Sciences Institute (ILSI) Risk Sciences Working Group on Dose Selection (1997) Principles for the selection of doses in chronic rodent bioassays. Env. Hlth. Persp. 105: 18 - 20 
    24. Page, N, (ed) (1977) Concepts of a bioassay program in environmental carcinogenesis. In: Advances in Medical Toxicology, HF Kraybill and HA Mehlman (ed). Wiley and Sons, New York, pp. 87-171 
    25. Derelanko, M.J. (2000) Toxicologist's Pocket Handbook. CRC Press, Boca Raton, Fla 
    26. Wolley, A. (2003) A guide to practical toxicology, evaluation, prediction and risk. Taylor and Francis, London and New York 
    27. Taylor, J.M., M.A. Weisburger and L. Friedman (1980) Chronic toxicity and carcinogenicity to the urinary bladder of sodium saccharin in the in utero exposed rat. Toxicol. Appl. Phannacol. 54: 57-75 
    28. Maeda, H., C.A. Gleiser, E.J. Masoro, I. Murata, C.A. McMahan, and B.P. Yu (1985) Nutritional influences on aging of Fischer 344 rats: II. Pathology. J. Gerontal. 40(6):671-688 
    29. Mcconnell, E.E. and S. Eustis (1994) Peer review in carcinogenicity bioassays: uses/ abuses. Toxicol. Pathol. 22:141-144 
    30. Mohr, U. and G. Morawietz (1995) Recent progress in the field of toxicologic pathology in Europe and the need for standardisation. J. Toxicol. Pathol. 8: 219-226 
    31. Morawietz, G., S. Rittinghausen and U. Mohr (1992) RITA - Registry of Industrial Toxicology Animal data - Progress of the working group. Exp. Toxic. Pathol. 44: 301 - 309 
    32. IARC (eds) (1987): IARC monographs on the evaluation of carcinogenic risks to humans. The overall evaluation of carcinogenicity: an updating of IARC monographs. vol. 1 to 42. Supplement 7. IARC Lyon, 40-42 
    33. Son, W.C. (2003a) Analysis of fighting associated wounds causing death of young male CD 1 mice in carcinogenicity studies. Scand. J. Lab. Anim. Sci. 30(3): 101-111 
    34. Gopinath, C. (1994) Spontaneous tumour rates: their use to support rodent bioassays. Toxicol. Pathol. 22: 160-164 
    35. Alison, R.H., C.C. Capen and D.E. Prentice (1994) Neoplastic lesions of questionable significance to humans. Toxicol. Pathol. 22: 179-186 
    36. Festing, M.F. (1979) Properties of inbred strain and outbred stocks with special reference to toxicity testing. J. Toxicol. and Environm. Health 5: 53-68 
    37. Hard, G.C. and J. Whysner (1994) Risk assessment of d Limonene: an example of male rat specific renal tumorigens. Crit. Rev. Toxicol. 24: 231-254 
    38. ICH (1994). Guideline S3B: Guidance on Repeat Dose Tissue Distribution Studies. US FDA, CDER/CBER, Rockville, Md 
    39. Doll, R., L.G. Morgan and F.E. Speizer (1970) Cancers of the lung and nasal sinuses in nickel workers. Br. J. Cancer 24: 623-632 
    40. NIEHS (National Institute of Environmental Health Sciences) (1996) (Volume 61, Number 188) Federal Register: The National Toxicology Program (NIP) Revises criteria and process for listing substances in the biennial report on carcinogens (issued 26 September, 1996) 
    41. U.S. Environmental Protection Agency(EPA) (1991): Alpha 2u globulin: Association with chemically induced renal toxicity and neoplasia in the male rat. US Environmental Protection Agency, EPA/625/391/019F, September 1991 
    42. ICH (1995): Guideline S3A: Notes for Guidance on Toxicokinetics. The Assessment of Systemic Exposure in Toxicity Studies. US FDA, CDER/CBER, Rockville, Md 
    43. Rao, G.N., J.K. Haseman, S. Grurnbein, D.D. Crawford and S.L Eustis (1990) Growth, body weight, survival and tumor trends in F344/N rats during an eleven year period. Toxicol. Pathol. 18: 61-70 
    44. Webb, D.R, G.M. Rider and C.L. Alden (1989) Acute and subchronic nephropathy of d limonene in Fischer 344 rats. Food Chem. Toxicol. 27: 639-649 
    45. CD(SD)IGS study group (1998) Biological reference data on CD(SD)IGS rats. 1998. (Matsuzawa T, Hiroyuki Inoue, ed). Yamanouchi Pharmaceutical Co. Ltd., Japan 
    46. The OECD guidelines, (2001): ENV/JM/MONO(2001)6, Series on the testing and assessment, Number 33, Harmonised integrated classification system for human health and environmental hazards of chemical substances and mixtures.(issued 2001) 
    47. Weisburger, J.H. (1996) The 37 year history of the Delaney clause. Exp. Toxic. Pathol., 48: 183-188 
    48. Ward, J.M., J.E Hardisty, J.R. Hailey and C.S. Streett (1995) Peer review in toxicologic pathology. Toxicol. Pathol. 23: 226-234 
    49. Son, W.C., B.H. Kim, nn Jang, B.S. Han, K.H. Yang and Y.S. Lee (2004) Importance of peer review in toxicological pathology and its practical approach. J. Toxicol. Pub. Health, 20(1): 1-11 
    50. Gad, S.C. and C.G. Rousseaux (2002) Use and misuse of statistics in the design and interpretation of studies. In: Handbook of toxicologic pathology 
    51. Lang, P.L. (1991) Changes in life span of research animals leading to questions about validity of toxicologic studies. Chem. Reg. Rep. 14:1518-1520 
    52. Williams, G.M. (1986) Epigenetic promoting effects of butylated hydroxyanisole. Food. Chem. Toxicol. 24: 1163-1166 
    53. Gopinath, C. (1999) Comparative endocrine carcinogenesis. In. Endocrine and hormonal toxicology, (PW Harvey, K Rush, A Cockburn, eds.) Wiley, Chichester. pp.155-167 
    54. Mastorides, S. and R.R. Maronpot (2002) Carcinogenesis. In: Haschek WM, Rousseaux CG, Wallig MA: Handbook of toxicologic pathology. Vol. 1, pp. 83-122 
    55. EMEA(The European Agency for the Evaluation of medicinal products Evaluation of medicines for human use London) (2004) CPMP/SWP/1094/04/Corr: Guideline on the evalution of control samples for toxicokinetic parameters in toxicology studies: checking for contamination with the test substance 
    56. CD(SD)IGS study group (1999) Biological reference data on CD(SD)IGS rats. 1999. (Matsuzawa T, Hiroyuki Inoue, ed). Yamanouchi Phannaceutical Co. Ltd., Japan 
    57. Gopinath, C. (1995) The predictive value of pathological findings in animal toxicity studies. J. Toxicol. Pathol. 8: 89-100 
    58. Masoro, E.J. (1992) Restriction of aging processes by food restriction: An experimental tool. Am. J. Clin. Nutr. 55:12505-12525 
    59. Thomas, G.A. and E.D. Williams (1991) Evidence for possible mechanisms for nongenotoxic carcinogens in the rodent thyroid. Mutat. Res. 248: 357-370 
    60. U.S. Environmental Protection Agency(EPA) (1994): Pesticide Regulation (PR) Notice 94 5, Notice to Registration of Pesticide Products(issued Aug., 24, 1994) 
    61. The OECD guideline, (1999): ENV/JlM/MONO(99)4, Series on pesticides No. 14, Environment directorate joint meeting of the committee and the working party on chemicals. Environmental health and safety publications. Guidance notes for analysis and evaluations of chronic toxicity and carcinogenicity studies. (issued 17 Feb., 1999) 
    62. Bode, G. (1994) Toxicokinetics in long tenn toxicity and carcinogenicity studies. Drug Information Journal 28: 213-220 
    63. Keenan K. P. (1992) The effects of diet and calorically optimization (calorically restriction) on rat survival and carcinogenicity. Proceeding from the 43rd annual meeting of the American college of veterinary pathologists, San Diego, CA, November 15-21, p. 227 

 저자의 다른 논문

  • 장동덕 (4)

    1. 2001 "다장기 중기발암성 시험법을 이용한 셀렌염의 대장암 억제효과에 대한 연구" 한국수의병리학회지 = Korean journal of veterinary pathology 5 (1): 23~28    
    2. 2001 "실험적 대장암 모델에서 키토산의 발암 억제효과에 관한 연구" 한국수의병리학회지 = Korean journal of veterinary pathology 5 (1): 29~34    
    3. 2005 "형질전환 마우스 모델 발암성 평가의 최신 지견" Journal of toxicology and public health : an official journal of the Korean Society of Toxicology 21 (1): 1~14    
    4. 2009 "Safety Assessment of Chromium by Exposure from Cosmetic Products" Archives of pharmacal research : a publication of the Pharmaceutical Society of Korea 32 (2): 235~241    
  • Kim, Jong-Choon (78)

  • 이제봉 (12)

  • 신진섭 (19)

  • 김형진 (12)

 활용도 분석

  • 상세보기

    amChart 영역
  • 원문보기

    amChart 영역

원문보기

무료다운로드
  • NDSL :
  • 한국농약과학회 : 저널
유료다운로드

유료 다운로드의 경우 해당 사이트의 정책에 따라 신규 회원가입, 로그인, 유료 구매 등이 필요할 수 있습니다. 해당 사이트에서 발생하는 귀하의 모든 정보활동은 NDSL의 서비스 정책과 무관합니다.

원문복사신청을 하시면, 일부 해외 인쇄학술지의 경우 외국학술지지원센터(FRIC)에서
무료 원문복사 서비스를 제공합니다.

NDSL에서는 해당 원문을 복사서비스하고 있습니다. 위의 원문복사신청 또는 장바구니 담기를 통하여 원문복사서비스 이용이 가능합니다.

이 논문과 함께 출판된 논문 + 더보기