Tyl R W, Ballantyne B, Fisher L C, Fait D L, Savine T A, Pritts I M, Dodd D E
Bushy Run Research Center, Export, Pennsylvania.
Fundam Appl Toxicol. 1994 Aug;23(2):251-60. doi: 10.1006/faat.1994.1103.
This study was performed to evaluate the effects of nose-only restraint versus whole-body exposure procedures in the absence of test chemical, and to determine the appropriate control environment (water aerosol or air) for subsequent developmental toxicity studies of test materials administered as aerosols. Timed-pregnant CD-1 mice, 30/group, were exposed to high concentrations of water aerosol or to air by whole-body or nose-only inhalation procedures on Gestational Days (GD) 6 through 15 for 6 hr per day. The group exposed to air by whole-body procedures was designated as the control group. Clinical observations and maternal body weights were recorded throughout gestation. At scheduled necropsy on GD 18, maternal animals were evaluated for body weight, gravid uterine weight, liver weight, number of ovarian corpora lutea, and status of uterine implantation sites. Fetuses were counted, weighed, and sexed and were examined for external, visceral (including craniofacial), and skeletal alterations. Indices of maternal toxicity were affected in both nose-only groups. Maternal body weights were reduced during and after the exposure period; maternal weight gain was reduced during the exposure period. Clinical signs observed, from animals struggling during restraint, were resolved by GD 18. At sacrifice on GD 18, maternal body weights and maternal gestational weight gains (both corrected for gravid uterine weights) and absolute liver weights were reduced in both nose-only groups. Four females died (13.3%, all pregnant) in the air nose-only group, and maternal liver weight (relative to body weight) was reduced in the aerosol nose-only group. Gestational parameters were unaffected by any of the treatments. There were no statistically significant differences in the incidences of any individual malformations or malformations by category (external, visceral, or skeletal) or of total malformations. However, exencephaly, low set ears, cleft palate and ventricular septal defect were observed only in both aerosol-exposed groups (whole-body and nose-only exposed). The incidences of individual external or visceral variations or of variations by category or of total variations were unaffected. The incidence of one skeletal variation, poorly ossified supraoccipital skull bone, was significantly increased in the aerosol nose-only group relative to the air whole-body controls. There were also increased incidences (not statistically significant) of extra (14th) ribs in both aerosol groups. Therefore, maternal restraint (in both nose-only groups) during organogenesis produced indications of maternal toxicity, but restraint did not appear to affect normal embryo/fetal morphologic development.(ABSTRACT TRUNCATED AT 400 WORDS)
本研究旨在评估在无受试化学物质的情况下，仅限制鼻子暴露与全身暴露程序的影响，并确定适用于后续以气雾剂形式给药的受试物质发育毒性研究的对照环境（水雾或空气）。将30只妊娠定时的CD-1小鼠分为一组，在妊娠第6至15天，通过全身或仅限制鼻子吸入程序，每天暴露于高浓度水雾或空气中6小时。通过全身程序暴露于空气的组被指定为对照组。在整个妊娠期记录临床观察结果和母鼠体重。在妊娠第18天按计划进行剖检时，评估母鼠的体重、妊娠子宫重量、肝脏重量、卵巢黄体数量以及子宫着床部位的状况。对胎儿进行计数、称重和性别鉴定，并检查其外部、内脏（包括颅面）和骨骼有无异常。两个仅限制鼻子暴露的组中，母鼠毒性指标均受到影响。暴露期间及之后母鼠体重下降；暴露期间母鼠体重增加减少。观察到的临床症状，即动物在限制过程中挣扎，在妊娠第18天消失。在妊娠第18天处死时，两个仅限制鼻子暴露的组中母鼠体重、母鼠妊娠体重增加（均校正妊娠子宫重量）和绝对肝脏重量均降低。仅限制鼻子暴露于空气的组中有4只雌性死亡（13.3%，均为怀孕母鼠），仅限制鼻子暴露于气雾剂的组中母鼠肝脏重量（相对于体重）降低。任何处理均未影响妊娠参数。任何个体畸形、按类别（外部、内脏或骨骼）的畸形或总畸形发生率均无统计学显著差异。然而，仅在两个气雾剂暴露组（全身暴露和仅限制鼻子暴露）中观察到无脑儿、低位耳、腭裂和室间隔缺损。个体外部或内脏变异、按类别变异或总变异发生率均未受影响。仅限制鼻子暴露于气雾剂的组中，一种骨骼变异，即枕骨上颅骨骨化不良的发生率相对于空气全身对照组显著增加。两个气雾剂组中额外（第14根）肋骨的发生率也有所增加（无统计学显著差异）。因此，在器官发生期母鼠受到限制（两个仅限制鼻子暴露的组）产生了母鼠毒性迹象，但限制似乎并未影响正常胚胎/胎儿的形态发育。（摘要截断于400字）
