Wolkowski-Tyl R, Lawton A D, Phelps M, Hamm T E
Teratology. 1983 Apr;27(2):197-206. doi: 10.1002/tera.1420270207.
C57BL/6 female mice impregnated by C3H males mice to produce B6C3F1 fetuses were exposed daily for six hr to atmospheres containing 0, 250, 500, or 750 ppm methyl chloride, from gestation day 6 to gestation day 18. There were 74 to 77 females with copulation plugs per exposure concentration. Females exposed to 750 ppm ethyl chloride exhibited ataxia commencing on the seventh day of exposure (gestation day 12). They also showed hypersensitivity to touch or sound, tremors and convulsions. Six females in the 750 ppm group died and one was euthanized in extremis prior to scheduled sacrifice. On gestation day 18, all other females were euthanized for evaluation. Only dams exposed to 750 ppm exhibited significant decrease in body weight by gestation day 18, weight gain during the gestation period, and absolute weight gain (weight gain minus gravid uterine weight) versus controls. There were no treatment related-effects on these parameters in the other exposure groups. None of the groups exhibited exposure-related differences in pregnancy rate, gravid uterine weight, or maternal liver weight. There were no differences in the numbers of implantations, resorption, dead fetuses, nonlive (dead plus resorbed) fetuses, live fetuses, sex-ratio, or mean fetal body weight per litter. There was a significant exposure-related increase in the number and percentage of affected (nonlive plus malformed) fetuses per litter with the incidence of affected fetuses in the 750 ppm group significantly higher than controls. There was a statistically significant increase in the incidence of heart defects in the 500 and 750 ppm group relative to controls. Of the 37 fetuses in the study with heart defects, 23 were females, 14 were males. The heart defects observed included: absent or abnormal tricuspid valve, reduced number of papillary muscles and/or chordae tendineae on the right side, small right ventricle, globular heart, and white spots in the left ventricular wall. Multiple malformations were observed in one fetus from the 500 ppm group and in three fetuses in the 750 ppm group. It is concluded that methyl chloride inhalation exposure to pregnant C57BL/6 mice from gestation day 6 through gestation day 17 resulted in maternal toxicity only at the 750 ppm exposure concentration and was teratogenic to B6C3F1 conceptuses at exposure concentrations of 750 and 500 ppm, leading to fetal heart malformations. No evidence of embryo or fetotoxicity other than teratogenicity was seen at any of the exposure concentrations employed. No maternal, embryo or fetotoxicity or teratogenicity was associated with exposure of mice, during critical periods of embryo and fetal development, to 250 ppm of methyl chloride.
将C3H雄性小鼠与C57BL/6雌性小鼠交配，以产生B6C3F1胎儿，从妊娠第6天至妊娠第18天，每天将其暴露于含有0、250、500或750 ppm氯甲烷的大气中6小时。每个暴露浓度有74至77只带有交配栓的雌性小鼠。暴露于750 ppm氯乙烷的雌性小鼠在暴露第7天（妊娠第12天）开始出现共济失调。它们还表现出对触摸或声音过敏、震颤和惊厥。750 ppm组中有6只雌性小鼠死亡，1只在预定处死前濒死时实施安乐死。在妊娠第18天，对所有其他雌性小鼠实施安乐死以进行评估。与对照组相比，只有暴露于750 ppm的母鼠在妊娠第18天体重、妊娠期体重增加和绝对体重增加（体重增加减去妊娠子宫重量）显著降低。其他暴露组在这些参数上没有与处理相关的影响。各组在妊娠率、妊娠子宫重量或母体肝脏重量方面均未表现出与暴露相关的差异。在着床数、吸收数、死胎数、非活胎（死胎加吸收胎）数、活胎数、性别比例或每窝平均胎儿体重方面没有差异。每窝受影响（非活胎加畸形胎）胎儿的数量和百分比随暴露增加显著增加，750 ppm组受影响胎儿的发生率显著高于对照组。500和750 ppm组相对于对照组，心脏缺陷的发生率有统计学显著增加。在该研究中有心脏缺陷的37只胎儿中，23只为雌性，14只为雄性。观察到的心脏缺陷包括：三尖瓣缺失或异常、右侧乳头肌和/或腱索数量减少、右心室小、球形心脏以及左心室壁上的白斑。在500 ppm组的1只胎儿和750 ppm组的3只胎儿中观察到多种畸形。得出的结论是，从妊娠第6天至妊娠第17天，怀孕的C57BL/6小鼠吸入氯甲烷，仅在750 ppm暴露浓度下导致母体毒性，在750和500 ppm暴露浓度下对B6C3F1胚胎具有致畸性，导致胎儿心脏畸形。在所采用的任何暴露浓度下，除致畸性外未发现胚胎或胎儿毒性的证据。在胚胎和胎儿发育的关键时期，小鼠暴露于250 ppm氯甲烷未出现母体、胚胎或胎儿毒性或致畸性。
