摘要:

AbstractAn accurate determination of the correlation between the carcinogenicity and the mutagenicity of chemicals has been hampered by the lack of a well‐documented list of noncarcinogens. To overcome this problem, Shelby and Stasiewicz (Environ Mutagen6:871–878, 1984) published a list of 70 chemicals that showed no evidence of carcinogenicity in the National Cancer Institute (NCI) or National Toxicology Program (NTP) rodent carcinogenesis bioassays. More recently, Tennant et al. (Science236:933–941, 1987) published a list of chemicals, including 29 noncarcinogens, that had been adequately tested for carcinogenicity by the NTP. Of the chemicals listed by Shelby and Stasiewicz or by Tennant and co‐workers as noncarcinogenic, the NTP has evaluated 25 as mutagenic inSalmonella typhimurium;48 of the noncarcinogens were evaluated as nonmutagenic. Thus, of the 73 non‐carcinogens that have been evaluated as either positive or negative for mutagenicity, 34% (25/73) were “false positives” (mutagenic non‐carcinogens) in theS. typhimuriumassay. We re‐evaluated the same mutagenicity and carcinogenicity data to determine whether the frequency of “false positives” is really as high as it appears to be.Our reevaluation of the mutagenicity data used more stringent criteria for calling a compound mutagenic than those used by the NTP, resulting in a substantial reduction in the frequency of “false positives” in theS. typhimuriummutagenicity assay. However, application of these same stringent criteria also substantially reduced the frequency of “true positives” (mutagenic carcinogens). Thus, it is concluded that modification of the evaluation criteria for the mutagenicity test can increase the specificity of the assay for the detection of carcinogens, but only at the cost of a corresponding reduction in sensitivity.We also performed a separate reevaluation of the NCI/NTP carcinogenicity data for the 25S. typhimurium“false positives,” assuming that the NTP evaluations of the mutagenicity data were correct. These reevaluations were based on the methodologies and findings of Griesemer and Cueto (In Montesano R, Bartsch H, Tomatis L (eds):Molecular and Cellular Aspects of Carcinogen Screening Tests.IARC Scientific Publication No. 27. Lyon: International Agency for Research on Cancer, pp 259–281, 1980) and those of Sontag (J Natl Cancer Inst66:591–602, 1981). Of the 25S. typhimuriummutagens among the “noncarcinogens” cited by Shelby and Stasiewicz or by Tennant and co‐workers, we concluded that two were noncarcinogenic (8‐hydroxyquinoline and 1‐nitronaphthalene), two were carcinogenic (2,4‐dinitrotoluene and 3‐nitropropionic acid), and the remaining 21 could not be classified because of the results of the rodent carcinogenesis bioassays or serious flaws in their design. The unclassifiability of chemicals generally resulted from marginal increases in tumors in treated animals as compared to controls, the failure to administer test chemicals at the maximum tolerated doses, and/

ISSN:0893-6692    

DOI:10.1002/em.2850130102

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

摘要:

AbstractIn vivo‐derivedhprt‐deficient mutant T cells isolated from three nonirradiated controls and two atomic bomb survivors were studied by Southern blot analysis to investigate the molecular spectra of the mutations. Mutant frequencies for the three controls were 1.8, 2.3, and 7.3 × 10−6, and those for the two survivors (who had received radiation doses of 2.46 and 2.15 Gy, based upon the revised atomic bomb shielded kerma estimates) were 9.3 and 14.4 × 10−6, respectively. Fourteen (13%) of 105 mutant T‐cell colonies from the controls showed various structural changes in thehprtgene. The frequency of mutants withhprtgene structural changes in one atomic bomb survivor, who exhibited a mutant frequency of 9.3 × 10−6, was 26% (16/61), which was significantly higher than that of the controls. However, the frequency of structural changes in the other survivor (14%, 8/59) was not higher than that of the controls. Two sets of mutants (in total, eight mutants) from the survivor, who showed a significantly higher frequency of mutants withhprtgross alterations than did the controls, had the samehprtchanges and the same rearrangements of T‐cell receptor (TcR) β‐ and γ‐chain genes, indicating a clonal expansion from one progenitor mutant. This phenomenon may reflect an in vivo recovery process of T cells in the periphery after exposure to atomic bomb radiation. However, when comparing the frequency of mutations, these two sets of mutants should be reduced. After reducing the total number of mutants from the number of grosshprtchanges, the frequency was not significantly higher tha

ISSN:0893-6692    

DOI:10.1002/em.2850130103

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

摘要:

AbstractThe identification of agents causing aneuploidy in humans, a condition associated with carcinogenesis and birth defects, is currently limited due to the highly skilled and time‐consuming nature of cytogenetic analyses. We report the development of a new simple and rapid assay to identify aneuploidy‐inducing agents (aneuploidogens). The assay involves the chemical‐ or radiation‐induced formation of micronuclei in cytokinesis‐blocked human lymphocytes and the use of an antikinetochore antibody to determine whether the micronuclei contain centromeres—a condition indicating a high potential for aneuploidy. All agents tested produced dose‐related increases in the frequency of micronucleated cells. The micronucleated cells induced by the known aneuploidogens—colchicine, vincristine sulfate, and diethylstilbestrol—contained kinetochore‐positive micronuclei 92, 87, and 76% of the time, respectively. In contrast, the micronucleated cells induced by the potent clastogens—ionizing radiation and sodium arsenite—contained kinetochore‐positive micronuclei only 3 and 19% of the time, respectively. These results indicate that this relatively simple assay can discriminate between aneuploidogens and clastogens and may allow a more rapid identification of environmental and therapeutic agents with aneu

ISSN:0893-6692    

DOI:10.1002/em.2850130104

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

摘要:

AbstractA deviation from physiological osmolality (300 mOsm/kg H2O) can lead to genotoxic effects. A 30‐min treatment of V79 hamster cells with hy‐potonic sodium chloride of 60 mOsm/kg H2O or with diluted culture medium of the same osmolality induces extraordinarily high frequencies of chromosomal aberrations. In this study, multiple fixation times over a 24‐hr period were used to identify cells in various stages of the cell cycle at the time of treatment and to find out whether or not hypotonic conditions are able to induce aberrations in all cell cycle stages. Because of the aberration pattern observed, it is suggested that hypotonic treatment acts as an S‐independent agent, like X‐rays or restriction endonucleases. Whether the aberrations originate from directly induced DNA damage or from a release of DNase after lysosomal breakdown is

ISSN:0893-6692    

DOI:10.1002/em.2850130105

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

摘要:

AbstractICR 2A frog cells and two solar ultraviolet (UV)‐sensitive cell lines, DRP 36 and DRP 153, were irradiated with 150 kj/m2of the UV radiation produced by a fluorescent sun lamp, the radiation from which was passed through a sheet of 48A Mylar (DuPont, Wilmington, DE) to eliminate wavelengths shorter than approximately 315 nm. The irradiated cultures were also exposed to photoreactivating light (PRL), resulting in the removal of most of the pyrimidine dimers induced by the sun lamp UV irradiation, and then incubated 0–4 hr. At the end of the incubations, the cells were subjected to the alkaline elution assay. In these elutions, the cell lysates were either treated with proteinase K (proK) to eliminate any DNA‐protein crosslinks (DPC) that may be present in the cells, or left untreated with proK. For the ICR 2A cells, the level of apparent DNA single‐strand breaks (ssb) detected in elutions using proK increased with the incubation time after irradiation and remained high. However, when the DNA was eluted without proK pretreat‐ment, the number of ssb fell rapidly. In contrast, the levels of ssb decreased in the DRP 36 and DRP 153 cells regardless of the use of proK in the elutions. Hence, this differential response in ssb induction may be indicative of a system involved with recovery following irradiation with solar UV wa

ISSN:0893-6692    

DOI:10.1002/em.2850130106

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

摘要:

AbstractCigarette smoke has been reported to contain free radicals and free radical generators in both the gas and particulate phases. Studies in our laboratory have shown that both cigarette smoke condensate (CSC) and smoke bubbled through phosphate buffered saline solution (smoke‐PBS) increased sister chromatid exchanges (SCE) in Chinese hamster ovary cells in a dose‐dependent manner. Since oxygen free radicals have been shown to cause SCEs and other chromosomal damage, we investigated the role of these radicals in the induction of SCEs by CSC and smoke‐PBS. Addition of the antioxidant enzymes catalase and superoxide dismutase or the oxygen‐radical scavenger ascorbic acid failed to reduce the SCE frequency in the presence of either CSC or smoke‐PBS. Additional studies indicated that the quantity of hydrogen peroxide produced in CSC or smoke‐PBS is too small to account for the observed SCE induction. It appears, therefore, that SCE induction by CSC or smoke‐PBS does not involve the participation of oxygen

ISSN:0893-6692    

DOI:10.1002/em.2850130107

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

摘要:

AbstractTwenty chemicals were tested for their ability to induce sister chromatid exchanges (SCEs) and chromosomal aberrations (ABs) in cultured Chinese hamster ovary cells (CHO). These chemicals were tested with and without an added metabolic activation system (rat liver S9 fraction). Four chemicals were negative in both assays, 1 induced ABs only, and 15 were positive for SCEs; 6 of these 15 also induced ABs.The effect of cell harvest time on the ability to detect the induction of chromosomal aberrations was examined for six chemicals. Five of these had caused at least one of the following: cell cycle delay, aberrations observed in first division metaphase cells in the SCE assay, or a weak response in the standard AB assay (10–12‐hr growth period). Three chemicals, chlorinated tri‐sodium phosphate, 1, 2‐dibromo‐3‐chloropro‐pane, and tetrakis(hydroxymethyl)phosphonium chloride, were positive using both the standard and extended harvest times. N‐Nitrosodimethyl‐amine and diphenhydramine HCI were only positive using an extended harvest time, and malo‐naldehyde was negative using both standard and ext

ISSN:0893-6692    

DOI:10.1002/em.2850130108

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

ISSN:0893-6692    

DOI:10.1002/em.2850130109

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY

ISSN:0893-6692    

DOI:10.1002/em.2850130101

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1989

数据来源: WILEY