DOSE-RESPONSE RELATIONSHIP FOR RAT-LIVER DNA-DAMAGE CAUSED BY 49 RODENT CARCINOGENS

被引:58
作者
KITCHIN, KT
BROWN, JL
机构
[1] Carcinogenesis and Metabolism Branch, Genetic Toxicology Division, Health Effects Research Laboratory, Research Triangle Park
关键词
DOSE-RESPONSE; THRESHOLDS; CHEMICAL CARCINOGENESIS; RISK ASSESSMENT; DNA DAMAGE; ALKALINE ELUTION;
D O I
10.1016/0300-483X(94)90109-0
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
An experimental approach was taken to the question of dose-response curves for chemical carcinogenesis, DNA damage in female rat liver was chosen as the experimental parameter because all chemicals found to damage hepatic DNA were rodent carcinogens. The lowest dose causing DNA damage was determined for the 12 active chemicals (1,2-dibromoethane, 1,2-dibromo-3-chloropropane, 1,2-dichloroethane, 1,4-dioxane, methylene chloride, auramine O, Michler's ketone, selenium sulfide, 1,3-dichloropropene, 1,2-dimethylhydrazine, N-nitrosopiperidine and butylated hydroxytoluene). The resulting dose-response curves for rat hepatic DNA damage were plotted versus log of the molar dose (all activity was in five orders of magnitude) and versus percent of chemicals' oral rat LD(50) (most of the activity was in only two orders of magnitude). Dose-response studies of the active chemicals were analyzed by regression methods. With the exception of butylated hydroxytoluene, the dose-response curves fit a linear model well (r(2) = 0.886) and a quadratic model even better (r(2) = 0.947). Based on experimental data from 11 DNA-damaging carcinogens (a dose range of 6 orders of magnitude), an equation and graph of the dose-response relationship of an 'average DNA-damaging carcinogen' is presented over the x-axis dose range of eight orders of magnitude.
引用
收藏
页码:31 / 49
页数:19
相关论文
共 30 条
[1]   CLASSIFICATION ACCORDING TO CHEMICAL-STRUCTURE, MUTAGENICITY TO SALMONELLA AND LEVEL OF CARCINOGENICITY OF A FURTHER 42 CHEMICALS TESTED FOR CARCINOGENICITY BY THE UNITED-STATES NATIONAL TOXICOLOGY PROGRAM [J].
ASHBY, J ;
TENNANT, RW ;
ZEIGER, E ;
STASIEWICZ, S .
MUTATION RESEARCH, 1989, 223 (02) :73-103
[2]   DEFINITIVE RELATIONSHIPS AMONG CHEMICAL-STRUCTURE, CARCINOGENICITY AND MUTAGENICITY FOR 301 CHEMICALS TESTED BY THE UNITED-STATES NTP [J].
ASHBY, J ;
TENNANT, RW .
MUTATION RESEARCH, 1991, 257 (03) :229-306
[3]   CHEMICAL-STRUCTURE, SALMONELLA MUTAGENICITY AND EXTENT OF CARCINOGENICITY AS INDICATORS OF GENOTOXIC CARCINOGENESIS AMONG 222 CHEMICALS TESTED IN RODENTS BY THE UNITED-STATES NCI/NTP [J].
ASHBY, J ;
TENNANT, RW .
MUTATION RESEARCH, 1988, 204 (01) :17-115
[4]   CONSIDERATION OF BOTH GENOTOXIC AND NONGENOTOXIC MECHANISMS IN PREDICTING CARCINOGENIC POTENTIAL [J].
BUTTERWORTH, BE .
MUTATION RESEARCH, 1990, 239 (02) :117-132
[5]   PROLIFERATIVE AND GENOTOXIC CELLULAR EFFECTS IN 2-ACETYLAMINOFLUORENE BLADDER AND LIVER CARCINOGENESIS - BIOLOGICAL MODELING OF THE ED01 STUDY [J].
COHEN, SM ;
ELLWEIN, LB .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 1990, 104 (01) :79-93
[6]   CELL-PROLIFERATION IN CARCINOGENESIS [J].
COHEN, SM ;
ELLWEIN, LB .
SCIENCE, 1990, 249 (4972) :1007-1011
[7]  
FARMER JH, 1979, J ENVIRON PATHOL TOX, V3, P55
[8]   A CARCINOGENIC POTENCY DATABASE OF THE STANDARDIZED RESULTS OF ANIMAL BIOASSAYS [J].
GOLD, LS ;
SAWYER, CB ;
MAGAW, R ;
BACKMAN, GM ;
DEVECIANA, M ;
LEVINSON, R ;
HOOPER, NK ;
HAVENDER, WR ;
BERNSTEIN, L ;
PETO, R ;
PIKE, MC ;
AMES, BN .
ENVIRONMENTAL HEALTH PERSPECTIVES, 1984, 58 (DEC) :9-319
[9]  
GREIM H, 1984, ACS MONOGR SER, V182, P525
[10]  
JUKES TH, 1983, CANC ENV, P147