Butterworth B E, Templin M V, Constan A A, Sprankle C S, Wong B A, Pluta L J, Everitt J I, Recio L
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709, USA.
Environ Mol Mutagen. 1998;31(3):248-56. doi: 10.1002/(sici)1098-2280(1998)31:3<248::aid-em6>3.0.co;2-g.
The weight of evidence indicates that chloroform induces cancer in the female B6C3F1 mouse liver via a nongenotoxic-cytotoxic mode of action. However, it is probable that DNA damage occurs secondary to events associated with cytolethality and regenerative cell proliferation. The purpose of the present study was to evaluate the potential mutagenic activity of chloroform in the B6C3F1 lacI transgenic mouse liver mutagenesis assay including mutagenic events that might occur secondary to cytolethality. The positive control, dimethylnitrosamine (DMN) is a DNA-reactive mutagen and carcinogen. DMN-induced mutations were anticipated to require only a brief exposure and without further treatment were predicted to remain unchanged over time at those frequencies. Chloroform-induced mutations secondary to toxicity were anticipated to require longer exposure periods and to occur only under conditions that produced sustained cytolethality and regenerative cell proliferation. Female B6C3F1 lacI transgenic mice were treated with daily doses of 2, 4, or 8 mg/kg of DMN by gavage for 4 days and then held until analysis 10, 30, 90, and 180 days postexposure. Livers from DMN-treated mice exhibited a dose-related 2- to 5-fold increase over control mutant frequencies and remained at those levels for 10 through 180 days postexposure. Thus, following the initial induction by DMN no selective mutation amplification or loss was seen for this extended period of time. Female B6C3F1 lacI mice were exposed daily for 6 hr/day 7 days/week to 0, 10, 30, or 90 ppm chloroform by inhalation, representing nonhepatotoxic, borderline, or overtly hepatotoxic chloroform exposures. Timepoints for determination of lacI mutant frequency were 10, 30, 90, and 180 days of exposure. No increase in lacI mutant frequency in the liver was observed at any dose or timepoint with chloroform, indicating a lack of DNA reactivity. DNA alterations secondary to toxicity either did not occur or were of a type not detectable by lacI mutant frequency analysis, such as large deletions.
大量证据表明，氯仿通过非遗传毒性 - 细胞毒性作用模式诱导雌性B6C3F1小鼠肝脏发生癌症。然而，DNA损伤可能继发于与细胞致死率和再生细胞增殖相关的事件。本研究的目的是在B6C3F1 lacI转基因小鼠肝脏诱变试验中评估氯仿的潜在诱变活性，包括可能继发于细胞致死率的诱变事件。阳性对照二甲基亚硝胺（DMN）是一种DNA反应性诱变剂和致癌物。预计DMN诱导的突变仅需短暂暴露，且在未进行进一步处理的情况下，预计这些频率会随时间保持不变。预计氯仿毒性继发的突变需要更长的暴露时间，并且仅在产生持续细胞致死率和再生细胞增殖的条件下发生。雌性B6C3F1 lacI转基因小鼠每天通过灌胃给予2、4或8 mg/kg的DMN，持续4天，然后在暴露后10、30、90和180天进行分析。经DMN处理的小鼠肝脏的突变频率比对照增加了2至5倍，且与剂量相关，并在暴露后10至180天保持在这些水平。因此，在DMN最初诱导后，在这段延长的时间内未观察到选择性突变扩增或丢失。雌性B6C3F1 lacI小鼠每周7天、每天6小时吸入0、10、30或90 ppm氯仿，分别代表非肝毒性、临界或明显肝毒性的氯仿暴露。测定lacI突变频率的时间点为暴露后10、30、90和180天。氯仿在任何剂量或时间点均未观察到肝脏中lacI突变频率增加，表明缺乏DNA反应性。毒性继发的DNA改变要么未发生，要么是lacI突变频率分析无法检测到的类型，如大片段缺失。
