Witt K L, Gulati D K, Kaur P, Shelby M D
Oak Ridge Institute for Science and Education, TN 37831-0117.
Mutat Res. 1995 Jan;341(3):151-60. doi: 10.1016/0165-1218(95)90005-5.
Phenolphthalein was tested for the induction of micronucleated erythrocytes in mice. Results of an initial investigation revealed significant, dose-related increases in micronucleated polychromatic erythrocytes (MN-PCE) and normochromatic erythrocytes (MN-NCE) in peripheral blood samples of male and female mice exposed to 0.6% to 5% phenolphthalein (approximately 1100 to 10,000 mg/kg/day) in feed for 90 days (Dietz et al., 1992). Results from a second long-term feed study with Swiss CD-1 mice confirmed this effect. However, administration of comparable doses of phenolphthalein by corn oil gavage on two consecutive days gave negative results in a mouse bone marrow micronucleus test. Subsequent tests were performed to clarify the conflicting results seen in the chronic exposure, dosed-feed, peripheral blood studies and the acute, corn oil gavage, bone marrow studies. Phenolphthalein was administered to male B6C3F1 mice in feed (3%) for 14 days. Peripheral blood samples taken at 4, 7, and 14 days all showed significant increases in micronucleated PCE; bone marrow samples taken on days 7 and 14 also were clearly positive for micronucleus induction. Therefore, comparable results were obtainable from both bone marrow and peripheral blood analyses. Because of the negative results in the two-exposure gavage test, additional tests were then designed to investigate the effects of bolus vs continuous dosing, feeding vs gavage administration, and corn oil vs feed as a carrier for phenolphthalein. Results of these tests indicated that the rate of exposure to phenolphthalein affects the frequency of induced MN-PCE and that micronucleated erythrocytes can be induced by phenolphthalein either by feeding or by corn oil gavage administration. In all the acute exposure studies, relatively high doses of phenolphthalein (2000-6000 mg/kg/day for at least 2 days) were required to induce micronuclei. The positive results obtained with phenolphthalein in vivo were consistent with the results of an in vitro chromosomal aberration test in Chinese hamster ovary cells, where dose-related increases in aberrations were noted only in cells treated in the presence of induced rat liver S9.
对酚酞进行了诱导小鼠微核红细胞的试验。初步调查结果显示，在饲料中添加0.6%至5%的酚酞（约1100至10000毫克/千克/天），喂养雄性和雌性小鼠90天，其外周血样本中的微核多染红细胞（MN-PCE）和微核正染红细胞（MN-NCE）显著增加，且呈剂量相关性（迪茨等人，1992年）。对瑞士CD-1小鼠进行的第二项长期喂养研究结果证实了这一效应。然而，连续两天通过玉米油灌胃给予相当剂量的酚酞，在小鼠骨髓微核试验中得到了阴性结果。随后进行了试验，以阐明在慢性暴露、定量喂食、外周血研究以及急性玉米油灌胃、骨髓研究中出现的相互矛盾的结果。给雄性B6C3F1小鼠喂食含3%酚酞的饲料14天。在第4、7和14天采集的外周血样本均显示微核PCE显著增加；在第7天和14天采集的骨髓样本在微核诱导方面也呈明显阳性。因此，骨髓分析和外周血分析均可获得类似结果。由于两次暴露灌胃试验结果为阴性，随后设计了额外试验，以研究大剂量给药与连续给药、喂食与灌胃给药以及玉米油与饲料作为酚酞载体的影响。这些试验结果表明，酚酞的暴露速率会影响诱导MN-PCE的频率，且喂食或玉米油灌胃给药均可诱导酚酞产生微核红细胞。在所有急性暴露研究中，需要相对高剂量的酚酞（至少2天，2000 - 6000毫克/千克/天）才能诱导微核。酚酞在体内获得的阳性结果与中国仓鼠卵巢细胞体外染色体畸变试验结果一致，在该试验中，仅在存在诱导大鼠肝S9的情况下处理的细胞中观察到与剂量相关的畸变增加。
