Failure of the standard battery of short-term tests in detecting some rodent and human genotoxic carcinogens

被引:28
作者
Brambilla, G [1 ]
Martelli, A [1 ]
机构
[1] Univ Genoa, Dept Internal Med, Div Clin Pharmacol & Toxicol, I-16132 Genoa, Italy
关键词
genotoxic carcinogens; genotoxicity assays; limits of the standard three-test battery;
D O I
10.1016/j.tox.2003.11.003
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Theoretical reasons and experimental evidence indicate that a no-effect level generally cannot be expected for genotoxic carcinogens; as a consequence, in quantitative risk assessment the capability of distinguishing genotoxic from non-genotoxic carcinogens is of fundamental importance in order to identify relevant levels of human exposure. According to generally accepted guidelines, the standard three-test battery for the detection of genotoxic compounds consists of: (i) an in vitro test for gene mutation in bacteria; (ii) an in vitro test in mammalian cells with cytogenetic evaluation of chromosomal damage and/or a test that detects gene mutations; (iii) an in vivo test for chromosomal damage using rodent hematopoietic cells. This test battery is designed to avoid the risk of false negative results for compounds with genotoxic potential, but it cannot be taken for granted that the risk is completely eliminated. As a matter of fact there are some chemicals, classified by the International Agency for Research on Cancer (IARC) as probably or possibly carcinogenic to humans, which gave consistent negative results in this test battery, and in contrast provided positive results in other not routinely employed genotoxicity assays. The failure of the standard test battery in detecting some genotoxic carcinogens is attributable to several causes, but the principal of them are the following ones: in vitro, the artificial metabolic activity of the liver S9-mix, and the different biotransformation of chemicals in cells of different type and from different animal species; in vivo, the pharmacokinetic behaviour of the test compound, and its possible species-, sex- and tissue-specificity. (C) 2003 Elsevier Ireland Ltd. All rights reserved.
引用
收藏
页码:1 / 19
页数:19
相关论文
共 143 条
[11]   Chloroform, carbon tetrachloride and glutathione depletion induce secondary genotoxicity in liver cells via oxidative stress [J].
Beddowes, EJ ;
Faux, SP ;
Chipman, JK .
TOXICOLOGY, 2003, 187 (2-3) :101-115
[12]  
BIGGER CAH, 1980, CANCER RES, V40, P655
[13]   NEPHROTOXIC AND GENOTOXIC N-ACETYL-S-DICHLOROVINYL-L-CYSTEINE IS A URINARY METABOLITE AFTER OCCUPATIONAL 1,1,2-TRICHLOROETHENE EXPOSURE IN HUMANS - IMPLICATIONS FOR THE RISK OF TRICHLOROETHENE EXPOSURE [J].
BIRNER, G ;
VAMVAKAS, S ;
WOLFGANG, D ;
HENSCHLER, D .
ENVIRONMENTAL HEALTH PERSPECTIVES, 1993, 99 :281-284
[14]   INVITRO AND INVIVO STUDIES ON THE METABOLISM OF 1,3-DIAMINOBENZENE - COMPARISON OF METABOLITES FORMED BY THE PERFUSED RAT-LIVER, PRIMARY RAT HEPATOCYTE CULTURES, HEPATIC RAT MICROSOMES AND THE WHOLE RAT [J].
BISGAARD, HC ;
LAM, HR .
TOXICOLOGY IN VITRO, 1989, 3 (03) :167-174
[15]   Study on the cytochrome P-450-and glutathione-dependent biotransformation of trichloroethylene in humans [J].
Bloemen, LJ ;
Monster, AC ;
Kezic, S ;
Commandeur, JNM ;
Veulemans, H ;
Vermeulen, NPE ;
Wilmer, JW .
INTERNATIONAL ARCHIVES OF OCCUPATIONAL AND ENVIRONMENTAL HEALTH, 2001, 74 (02) :102-108
[16]  
Boll M, 2001, Z NATURFORSCH C, V56, P649
[17]   DNA adducts in cultures of polychlorinated biphenyl-treated human hepatocytes [J].
Borlak, R ;
Hock, A ;
Hansen, T ;
Richter, E .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 2003, 188 (02) :81-91
[18]   INVITRO METABOLISM OF (C-14)4-CHLOROBIPHENYL AND (C-14)2,2',5,5'-TETRACHLOROBIPHENYL BY HEPATIC MICROSOMES FROM RATS AND PIGEONS - EVIDENCE AGAINST AN OBLIGATORY ARENE OXIDE IN AROMATIC HYDROXYLATION REACTIONS [J].
BORLAKOGLU, JT ;
HAEGELE, KD ;
REICH, HJ ;
DILS, RR ;
WILKINS, JPG .
INTERNATIONAL JOURNAL OF BIOCHEMISTRY, 1991, 23 (12) :1427-1437
[19]   MUTAGENESIS BY CHEMICAL-AGENTS IN V79 CHINESE-HAMSTER CELLS - A REVIEW AND ANALYSIS OF THE LITERATURE - A REPORT OF THE GENE-TOX PROGRAM [J].
BRADLEY, MO ;
BHUYAN, B ;
FRANCIS, MC ;
LANGENBACH, R ;
PETERSON, A ;
HUBERMAN, E .
MUTATION RESEARCH, 1981, 87 (02) :81-142
[20]   GENOTOXIC EFFECTS IN RODENTS GIVEN HIGH ORAL DOSES OF RANITIDINE AND SODIUM-NITRITE [J].
BRAMBILLA, G ;
CAVANNA, M ;
FAGGIN, P ;
MAURA, A ;
PINO, A ;
RICCI, R ;
ROBBIANO, L .
CARCINOGENESIS, 1983, 4 (10) :1281-1285