食用竹炭粉的急性毒性与致突变性研究

目的:评价食用竹炭粉的急性毒性和致突变性。方法:采用大鼠急性经口毒性试验、Ames试验、大鼠骨髓嗜多染红细胞微核试验和小鼠体内彗星试验,参考经济合作与发展组织(OECD)相关方法进行。急性毒性试验以20 mL/kg进行灌胃;Ames试验设每皿0.008、0.04、0.2、1、5 mg剂量组,另设空白、溶剂、阳性对照;微核试验设2.81、5.62、11.24 g/kg剂量组,另设溶剂、阳性对照;彗星试验设2.81、5.62、11.24 g/kg剂量组,另设溶剂、阳性对照。结果:本实验所用食用竹炭粉(平均粒径为16.596 μm)对雌、雄性SD大鼠的LD₅₀均大于11.24 g/kg;Ames试验、大鼠骨髓嗜多染红细胞微核试验、小鼠体内彗星试验结果均为阴性。结论:微米级食用竹炭粉对大鼠的经口急性毒性属无毒级,对鼠伤寒沙门氏菌组氨酸缺陷型菌株和大、小鼠体细胞无致突变作用。     

邻苯二甲酸(2-乙基己基)酯致畸致突变实验研究

目的:本文报道了邻苯二甲酸(2-乙基己基)酯(DEHP)小鼠致畸试验、小鼠骨髓嗜多染红细胞微核试验、小鼠骨髓细胞染色体畸变试验和Ames试验的研究结果.结果与结论:DEHP大剂量(1 000 mg/kg、2 000 mg/kg)时对小鼠有明显的胚胎毒性和致畸性.DEHP对Ames试验的4个标准菌株无明显诱变作用,但可致小鼠骨髓嗜多染红细胞微核形成,并具染色体畸变效应.     

复方竹节参胶囊的毒理学试验

背景与目的： 检测复方竹节参胶囊的毒性。 材料与方法： 按照常规方法进行小鼠经口急性毒性、小鼠骨髓微核试验、小鼠精子畸形试验、Ames实验以及大鼠30 d喂养试验。小鼠骨髓微核试验、精子畸形试验均同时设阴性对照组(蒸馏水)和阳性对照组(环磷酰胺), 大鼠30 d喂养试验设阴性对照组给予蒸馏水。 结果： 复方竹节参胶囊对雌、雄性SPF级昆明种小鼠在灌胃量达 20 g/kg时,两周内动物未见明显中毒症状。微核试验、精子畸形试验和Ames实验结果均为阴性。30 d喂养试验结果表明: 给药剂量达6 g/kg复方竹节参胶囊对Wistar大鼠的行为表现、血液学、生化学、脏器重量和系数以及病理组织学等指标均未见毒性作用。 结论： 在本实验条件下,复方竹节参胶囊可以通过急性毒性、微核试验、精子畸形试验、Ames实验和30 d喂养试验的毒理学安全性评价,未见明显毒性。     

奇亚籽急性毒性及遗传毒性研究

目的： 了解奇亚籽的毒理学安全性。方法：采用小鼠急性毒性试验和遗传毒性试验(Ames试验、小鼠骨髓嗜多染红细胞微核试验、小鼠精子畸形试验)对奇亚籽进行研究,小鼠急性经口毒性试验剂量为22.5 g/kg,观察经口给予受试物后14 d内动物的死亡情况;Ames试验设5个剂量,分别为每皿0.008、0.04、0.20、1.0和5.0 mg (每皿给受试物体积为0.1mL),同时设自发回变、溶剂对照(丙酮)和阳性对照(9-芴酮、2-AF、NaN3、MMC、1.8-二羟蒽锟),接种后,在37 ℃下培养48 h,计数每皿回变菌落数;小鼠骨髓嗜多染红细胞微核试验和小鼠精子畸形试验均设3个剂量组,分别为1.875、3.750和7.500 g/kg,同时设溶剂对照组(玉米油)和阳性对照组(环磷酰胺,50 mg/kg),分别观察骨髓涂片中嗜多染红细胞中的微核发生率和精子标本中精子畸形的类型和相应的数量。结果：奇亚籽的小鼠经口最大耐受剂量(maximum tolerated dose,MTD)>22.5 g/kg,为无毒级物质;在Ames试验、小鼠骨髓嗜多染红细胞微核试验和小鼠精子畸形试验中结果均呈阴性;结论：奇亚籽属于无毒级物质,亦不具有遗传毒性。     

重质芳烃的致突变性研究

目的：用Ames试验,小鼠骨髓嗜多染红细胞微核试验,人体外周血淋巴细胞姐妹染色单体交换（SCE）试验以及小鼠精子畸形试验对重质芳烃进行了致突变性研究,结果：重质芳烃无移码突变和碱基置换效应,微核试验显示在316－1580mg/kg.bw剂量范围小鼠骨髓嗜多染红细胞微核率显著增加（与阴性对照组比较P＜0．01）;SCE试验结果显示在活化系统（S9混合液）存在的条件下,人外周血淋巴细胞SCE频率较对照组显著增高（在0．5mg/ml及5mg/ml剂量组）;小鼠精子畸形试验显示在1580m,g/kg.bw剂量水平小鼠精子畸形率显著增高,与阴性对照组比较差异有显著性（P＜0．01）,结论：重质芳烃具有间接致突变性,对其职业性接触及应用的安全性应给予,高度重视。     

三七的急性毒性及致突变性试验研究

目的: 探讨三七的急性毒性和致突变性,为评价其安全性提供毒理学依据。方法: 采用小鼠急性经口毒性试验、小鼠骨髓嗜多染红细胞微核试验、小鼠精子畸形试验和Ames试验,参考《食品安全性毒理学评价程序》进行。小鼠急性经口毒性试验采用最大耐受剂量法,折合剂量为15 g/kg。小鼠骨髓嗜多染红细胞微核试验及小鼠精子畸形试验均设10.00、5.00、2.50 g/kg剂量组,另设溶剂和阳性对照组。Ames试验设2、8、40、200、1 000、5 000 μg/皿剂量组,另设自发回变组、溶剂及阳性对照组。结果: 急性毒性试验显示小鼠对三七经口灌胃的最大耐受剂量>15 g/kg。小鼠骨髓嗜多染红细胞微核试验和精子畸形试验中,各剂量组的微核率和精子畸形率与溶剂对照组比较,差异均无统计学意义(P>0.05)。Ames试验中,在加与不加S9时各剂量组回变菌落数均未超过自发回变菌落数的2倍,亦无剂量-反应关系,结果为阴性。结论: 在本实验条件下,三七对小鼠的经口急性毒性属于无毒级,对小鼠体细胞、雄性生殖细胞和鼠伤寒沙门氏菌组氨酸缺陷型菌株均未见潜在的致突变性。     

正衡片遗传毒性及致畸性实验研究

目的与方法：为保证保健食品正衡片应用的安全性，进行了Ames试验、小鼠骨髓细胞微核试验、小鼠精子畸形试验、小鼠睾丸染色体畸变试验和大鼠传统致畸试验。结果：4项遗传毒性试验均为阴性致畸试验未对大鼠母体及胚胎毒性。结论：在本受试剂量范围内，正衡片对遗传物质无损伤，对胎鼠无致畸作用。     

正衡片遗传毒性及致畸性实验研究

目的与方法 :为保证保健食品正衡片应用的安全性 ,进行了Ames试验、小鼠骨髓细胞微核试验、小鼠精子畸形试验、小鼠睾丸染色体畸变试验和大鼠传统致畸试验。结果 :4项遗传毒性试验均为阴性致畸试验未见对大鼠母体及胚胎毒性。 结论 :在本受试剂量范围内 ,正衡片对遗传物质无损伤 ,对胎鼠无致畸作用     

珍珠祛斑美容片的急性毒性和遗传毒性试验研究

背景与目的： 研究珍珠祛斑美容片的急性毒性和遗传毒性。 材料与方法： 采用大鼠、小鼠急性毒性试验、Ames试验、小鼠骨髓嗜多染红细胞微核试验和小鼠精子畸形试验对珍珠祛斑美容片进行常规安全性实验分析。 结果： 急性毒性实验结果表明,大鼠、小鼠灌胃给予珍珠祛斑美容片,其最大耐受剂量(MTD)均大于200 g/kg。Ames试验、微核试验和精子畸形试验结果均为阴性。 结论： 在人体推荐摄入剂量,每人2.0 g/d范围内使用珍珠祛斑美容片是安全可靠的。     

赛参调脂胶囊的急性和遗传毒性研究

目的 :为确保赛参调脂胶囊的食用安全 ,对其进行了急性毒性和遗传毒性试验。 方法 :小鼠和大鼠经口急性毒性试验、Ames试验、小鼠骨髓嗜多染红细胞微核计数、小鼠精子畸形试验。 结果 :受试物对两种性别小鼠和大鼠的经口急性毒性试验 ,LD50 均大于10g/kg;Ames试验在加与不加S9 混合液 ,各剂量组回复突变菌落数均未超过自发回变菌落数的2倍 ;小鼠骨髓嗜多染红细胞微核试验结果阴性 ;小鼠精子畸形试验各剂量组及阴性对照组间畸形率无显著性差异(P>0.05)。 结论 :受试物未见遗传毒性     

GP 方案和吉非替尼单药一线治疗非小细胞 肺癌疗效比较

 目的　对比分析以铂类为基础的GP(吉西他滨+ 顺铂) 联合化疗和单药吉非替尼( IRESSA) 一 线治疗ⅢB2 Ⅳ期非小细胞肺癌的近期疗效和毒副作用。方法　60 例ⅢB～ Ⅳ期从未接受过化疗的非小 细胞肺癌患者中,单用吉非替尼治疗26 例,GP 方案治疗34 例。吉非替尼组为吉非替尼250 mg/ d ; GP 组为吉西他滨1 250 mg/ m2 ,第1 ,8 天,顺铂75 mg/ m2 ,第1 天。每三周为一周期,两周期后评价客观疗 效及不良反应。结果　两组总有效率吉非替尼组26. 9 %(7/ 26) ,GP 组29. 4 %(10/ 34) , P > 0. 05 ;疾病控 制率吉非替尼组76. 9 %(20/ 26) ,GP 组50. 0 %(17/ 34) , P < 0. 05 。GP 组主要存在骨髓抑制和胃肠道反 应毒性( P < 0. 05) ,吉非替尼组的毒性反应主要为皮疹和腹泻。结论　GP 方案和吉非替尼单药一线治 疗非小细胞肺癌(NSCLC) 可获得一致的客观有效率,但吉非替尼单药的疾病控制率显著高于GP 组,且 其毒副反应较GP 组轻微,患者均可完全耐受。吉非替尼单药口服可考虑作为治疗晚期化疗难耐受的 NSCLC 患者的一线方案。     

2-(α-羟基戊基)苯甲酸钾盐的急性毒性和致突变作用研究

目的:研究2-(α-羟基戊基)苯甲酸钾盐(dl-PHPB)的急性毒性及致突变性。方法:急性毒性试验采用Bliss法,昆明小鼠分为5组,每组10只,雌雄各半,分别按256.0、286.3、320.0、357.8、400.0、447.2 mg/kg静脉注射dl-PHPB,观察注射后至给药后14 d动物的毒性反应性质及程度,计算半数致死剂量(LD₅₀)及95%可信限;Ames试验采用平板掺入预培养法,选用鼠伤寒沙门氏菌株TA97、TA98、TA100和TA102,每皿0.5～5 000.0 μg浓度范围内,检测加和不加S9条件下对Ames菌的致突变性;微核试验采用雄性昆明小鼠,分为3组,每组6只,分别按23.3、70、210 mg/kg单次静脉注射dl-PHPB,注射后24 h计数骨髓嗜多染红细胞微核率(MNPCEs);体外染色体畸变试验在加和不加S9条件下,检测11.0~88.0 μg/mL dl-PHPB对CHL细胞染色体畸变率的影响。结果:小鼠静脉注射dl-PHPB后,各剂量动物出现一过性呼吸急促、自发活动减少、俯卧少动等症状,随剂量增加至≥320.0 mg/kg时,部分动物出现濒死症状,并在给药后2~30 min内死亡,死亡率随剂量的增加而增加,256.0~447.2 mg/kg 6个剂量组死亡率依次为0、0、10%、30%、70%、100%。未死亡动物在给药30 min后逐渐恢复正常。14 d观察期期间动物未见其他异常。其LD₅₀为373.3 mg/kg,95%可信限为355.6～392.0 mg/kg;Ames试验结果显示,在每皿0.5～5 000.0 μg浓度范围内未引起4种测试菌株回复突变数增加;微核试验结果显示,dl-PHPB在23.3~210.0 mg/kg范围内,各组动物MNPCEs均低于4‰;CHL细胞体外染色体畸变试验中,dl-PHPB在 11.0～88.0 μg/mL浓度范围内致CHL细胞染色体畸变率<5%。结论:在本实验条件下,小鼠静脉注射dl-PHPB的LD₅₀为373.3 mg/kg,致突变性3项试验均为阴性结果。     

甲氧化三丁基锡的急性毒性和遗传毒性研究

目的:研究甲氧化三丁基锡(tributyltin methoxide,TBTMO)对小鼠的急性毒性和遗传毒性。方法:选取昆明种小鼠110只,随机分为11组(TBTMO 420、286、194、180、132、90、73、61、41.5、28 mg/kg及阴性对照组),一次性灌胃给药进行急性毒性测试;另取昆明种小鼠50只随机分成5组(TBTMO 80、40、20 mg/kg组,阴性对照组和阳性对照组),各剂量组和阴性对照组均连续给药2 d,阳性对照组连续给药5 d,均连续观察35d,处死小鼠取双侧附睾制片进行精子畸形试验;并取昆明种小鼠50只随机分成5组(TBTMO 80、40、20 mg/kg组,阴性对照组和阳性对照组),灌胃给药30 h后处死小鼠取胸骨骨髓进行微核试验;取GFP转基因小鼠50只随机分成5组(TBTMO 80、40、20 mg/kg组,阴性对照组和阳性对照组),收集每只小鼠的脾淋巴细胞进行hprt基因突变试验。然后用不同浓度TBTMO(69.4、48.6、34.0、23.8、16.6、0μg/ml)分别处理中国仓鼠肺成纤维细胞(Chinesehamster lung,CHL)进行染色体畸变试验;用不同浓度TBTMO(每皿5×10~5、5×10~4、5×10~3、5×10~2、50、5、0.5、0.05、5×10~-3、5×10~-4μg)分别处理TA97、TA98、TA100、TA102 4种菌株进行Ames试验。结果:TBTMO对小鼠的半数致死量(LD_(50))为98 mg/kg。与阴性对照组比较,TBTMO可致小鼠精子畸形(P0.05或P0.01),且有剂量依赖趋势,其余4项遗传毒性试验结果均为阴性。结论:在本实验条件下,TBTMO对小鼠的急性经口毒性属于中等毒性,可能具有一定的遗传毒性。     

NTP 3-month toxicity studies of estragole (CAS No. 140-67-0) administered by gavage to F344/N rats and B6C3F1 mice

Estragole is a natural organic compound that is used as an additive, flavoring agent, or fragrance in a variety of food, cleaning, and cosmetic products; as an herbal medicine; as an antimicrobial agent against acid-tolerant food microflora; and to produce synthetic anise oil. Estragole was nominated for toxicity testing by the National Institute of Environmental Health Sciences to characterize its toxicity when administered by gavage to F344/N rats and B6C3F1 mice and to determine how similar its effects might be to those of the structurally related compound, methyleugenol. Male and female F344/N rats and B6C3F1 mice were given estragole (greater than 99% pure) in corn oil by gavage for 3 months. Genetic toxicology studies were conducted in Salmonella typhimurium and mouse peripheral blood erythrocytes. Core and special study (rats only) groups of 10 male and 10 female rats and mice were administered 37.5, 75, 150, 300, or 600 mg estragole/kg body weight in corn oil by gavage, 5 days per week. The core study groups were given estragole for 3 months and the special study groups for 30 days. All core study rats survived the 3-month exposure period. Mean body weights of the 300 and 600 mg/kg groups were 73% to 92%, respectively, of those of the vehicle control groups. A staining pattern on the ventral surface anterior to the genitalia beginning at week 9 in the 300 and 600 mg/kg groups was attributed to residue of estragole or metabolites in the urine. Alterations in the erythron related to estragole administration occurred in male and female rats; male rats demonstrated a stronger response. The changes in the erythron were characterized as a microcytic, normochromic, nonresponsive anemia. There were decreases in serum iron concentration in the 300 mg/kg females and 600 mg/kg males and females. The average percent saturation of total iron binding capacity was decreased in the 600 mg/kg males and females. Dose-related increases in platelet counts occurred in most of the dosed groups of rats; the effect appeared to be stronger in males. The increase could be consistent with a reactive thrombocytosis. Increases in the serum alanine aminotransferase and sorbitol dehydrogenase activities suggested a hepatocellular effect (increased leakage) and were consistent with the morphological liver changes observed. There were dose-related increases in serum bile salt concentration in most treated male rats at all time points; females were less affected. Absolute and relative liver weights were significantly increased in 300 and 600 mg/kg males and in 75 mg/kg or greater females. Relative kidney weights were significantly increased in all dosed groups of male rats and in female rats given 75 mg/kg or greater. Absolute and relative testis weights of 300 and 600 mg/kg males were significantly decreased. Two 600 mg/kg male rats had multiple cholangiocarcinomas in the liver and a third had an hepatocellular adenoma. All 600 mg/kg males exhibited cholangiofibrosis. All 75 mg/kg or greater males and all 150 mg/kg or greater females had hepatocellular hypertrophy. Incidences of bile duct hyperplasia, oval cell hyperplasia, and chronic periportal inflammation were significantly increased in all dosed groups. Incidences of basophilic and mixed cell foci were significantly increased in 150 mg/kg or greater males and females. Incidences of eosinophilic focus were significantly increased in 300 and 600 mg/kg males and 600 mg/kg females. Incidences of cellular infiltration of the periportal region by histiocytes increased significantly in all dosed groups of males and in 150 mg/kg or greater females. Incidences of bone marrow hyperplasia were significantly increased in 75, 300, and 600 mg/kg male rats. Incidences of renal tubule papillary mineralization were significantly increased in 300 mg/kg males and females and 600 mg/kg males. Incidences of cortical renal tubule pigmentation were significantly increased in 150 mg/kg or greater males, and the incidence of renal tubule regeneration was significantly increased in 600 mg/kg females. Incidences of degeneration of the olfactory epithelium in the nose were significantly increased in 300 and 600 mg/kg rats. Incidences of hypertrophied chromophobe cells in the pars distalis of the pituitary gland were significantly increased in 300 and 600 mg/kg males. Cytoplasmic alteration of the submandibular salivary gland occurred in all 75 mg/kg or greater rats. Incidences of atrophy of the gastric glands in the stomach were significantly increased in 150 mg/kg or greater rats. Bilateral degeneration of the germinal epithelium in the testes and bilateral hypospermia of the epididymis occurred in all 300 and 600 mg/kg males. In the special study, serum gastrin concentration and stomach pH were significantly increased in rats exposed to 600 mg/kg for 30 days. Gastric gland atrophy was significantly increased in the stomach of 300 and 600 mg/kg rats. Hepatic 7-pentoxyresorufin-O-deethylase activity was significantly increased in all exposed groups except 37.5 mg/kg females, and the increases were generally dose related. In the mouse core study, a 600 mg/kg male died during week 9, and all 600 mg/kg female mice died during week 1; the female deaths were attributed to liver necrosis caused by estragole exposure. Mean body weights of 300 and 600 mg/kg males and 75 mg/kg or greater females were 79% to 89% those of the vehicle control groups. Liver weights were generally increased in 75 mg/kg or greater males and in 300 mg/kg females. Relative thymus weights were significantly increased in all dosed groups of female mice. The incidences of hepatocellular hypertrophy and hepatocellular degeneration were significantly increased in 300 and 600 mg/kg male mice and 150 and 300 mg/kg female mice. Incidences of oval cell hyperplasia were significantly increased in 300 and 600 mg/kg males and in 75 mg/kg or greater females. Liver necrosis occurred in all 600 mg/kg female mice, along with a significant increase in the incidence of diffuse fatty change. In addition, 600 mg/kg females exhibited significant increases in the incidences of degeneration of the gastric glands of the glandular stomach, as well as squamous hyperplasia, mineralization, and ulcer in the forestomach. Degeneration of the olfactory epithelium in the nose occurred in all 300 and 600 mg/kg mice. Estragole was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 when tested in the presence or absence of exogenous metabolic activation enzymes. No increases in the frequencies of micronucleated normochromatic erythrocytes were observed in peripheral blood samples from male and female mice in the 3-month study. Under the conditions of these 3-month studies, estragole showed carcinogenic activity based on the occurrence of two cholangiocarcinomas and one hepatocellular adenoma in the liver of three of 10 male F344/N rats in the high dose group. Because rats and mice were exposed for only 3 months, these studies do not access the full carcinogenic potential of estragole. Nonneoplastic effects were observed in the liver, glandular stomach, nose, kidney, and salivary gland of male and female rats and in the testes, epididymides, and pituitary gland of male rats. Nonneoplastic effects were also observed in the liver and nose of male and female mice and in the stomach of female mice.     

NTP report on the toxicology studies of dichloroacetic acid (CAS No. 79-43-6) in genetically modified (FVB Tg.AC hemizygous) mice (dermal and drinking water studies) and carcinogenicity studies of dichloroacetic acid in genetically modified [B6.129-Trp53(tm1Brd) (N5) haploinsufficient] mice (drinking water studies)

Dichloroacetic acid was nominated for study by the United States Environmental Protection Agency (EPA) and by the National Institute of Environmental Health Sciences because of its widespread occurrence in drinking water as a by-product of water disinfection using chlorination. It was also nominated because dichloroacetic acid is the most studied representative of the class of haloacetic acids and has been shown to cause liver tumors in both rats and mice. Haloacetic acids are second only to trihalomethanes as a family of disinfection by-products found in many drinking water supplies. Dichloroacetic acid is one of several disinfection by-products being evaluated to determine whether genetically modified mouse models can serve as a more rapid and cost-effective means of evaluating and ranking potential hazards of disinfection by-products. The NTP has explored the use of genetically altered mouse models as adjuncts to 2-year rodent cancer assays. These models may prove to be more rapid, use fewer animals, and provide some mechanistic insights into neoplastic responses. As part of the evaluation of new mouse cancer screening models, dichloroacetic acid was tested for potential toxicity and carcinogenicity in two relatively well-studied models, the Tg.AC hemizygous strain and the p53 haploinsufficient strain. Male and female Tg.AC hemizygous and p53 haploinsufficient mice were exposed to dichloroacetic acid in the drinking water (greater than 98% pure) for 26 or 39 weeks. Genetic toxicology studies were conducted in Salmonella typhimurium strains TA98, TA100, and TA1535 and in mouse peripheral blood erythrocytes. 26- AND 39-WEEK DERMAL STUDIES IN Tg.AC HEMIZYGOUS MICE Groups of 15 male and 15 female Tg.AC hemizygous mice were administered 0, 31.25, 125, or 500 mg dichloroacetic acid/kg body weight 5 days per week for 26 weeks with additional groups of 10 males and 10 females continued on treatment for 39 weeks. Survival of dosed males and females was similar to that of the vehicle control groups for both studies. Mean body weights of dosed males and females in the 26-week study were similar to those of the vehicle control groups. Mean body weights of dosed males in the 39-week study were similar to those of the vehicle control groups. Mean body weights of the 500 mg/kg females were greater than those of the vehicle controls in the 39-week study. The absolute liver weights were increased by greater than 50% compared to the vehicle controls for the 500 mg/kg males and females in both studies. At the site of application, the incidences of squamous cell papilloma were significantly increased in 500 mg/kg males and females at 39 weeks. In addition, one 125 mg/kg male, two 500 mg/kg males, and two 500 mg/kg females had squamous cell papillomas at 26 weeks. The incidences of epidermal hyperplasia and hyperkeratosis were significantly increased at the site of application in the 125 and 500 mg/kg males and females at 26 weeks. At 39 weeks, the incidence of epidermal hyperkeratosis was increased in the 31.25 mg/kg males, but in females, increased epidermal hyperkeratosis and hyperplasia occurred only in the 500 mg/kg group. There was a modest increase in pulmonary adenomas at 39 weeks that may have been related to the dichloroacetic acid exposure in males and females exposed to 125 or 500 mg/kg. In both studies, there was a dose-related increase in the mean severity of hepatocyte cytoplasmic vacuolization in males and females, and the incidence of nephropathy was increased in 500 mg/kg males. 26- AND 41-WEEK DRINKING WATER STUDIES IN Tg.AC HEMIZYGOUS MICE: Groups of 15 male and 15 female Tg.AC hemizygous mice were exposed to drinking water containing 0, 500, 1,000, or 2,000 mg/L dichloroacetic acid for 26 weeks with additional groups of 10 males and 10 females exposed for 41 weeks. The equivalent average daily doses were approximately 75, 145, and 235 mg dichloroacetic acid/kg body weight to males and approximately 100, 185, and 285 mg/kg to females. Survival of exposed males was similar in both studies. In the females, survival was decreased in the 26-week but not the 41-week study. While there was some variability, the mean body weights of mice exposed to dichloroacetic acid tended to be similar to those of the control groups. In the 41-week study, mean body weights of exposed males and females tended to be less than those of the control groups. Water consumption by males and females exposed to 1,000 and 2,000 mg/L was less than that by the controls throughout both studies. The incidences and/or severity of hepatocyte cytoplasmic vacuolization were increased in males and females in both studies. The incidence of pulmonary adenoma was increased in the male mice exposed to 1,000 mg/L dichloroacetic acid for 41 weeks. Two pulmonary adenomas were found in the 2,000 mg/L females at 41 weeks. At 26 weeks, a pulmonary carcinoma was found in one 1,000 mg/L male, one 500 mg/L female, and one 2,000 mg/L female. 26- AND 41-WEEK DRINKING WATER STUDIES IN p53 HAPLOINSUFFICIENT MICE: Groups of 15 male and 15 female p53 haploinsufficient mice were exposed to drinking water containing 0, 500, 1,000, or 2,000 mg/L dichloroacetic acid for 26 weeks with additional groups of 10 males and 10 females exposed for 41 weeks. The equivalent average daily doses were approximately 45, 80, and 145 mg/kg to males and approximately 75, 145, and 220 mg/kg to females. Survival of all exposed groups was similar to that of the control groups in both studies. Mean body weights of 1,000 and 2,000 mg/L males and females were generally less than those of the control groups throughout most of both studies; mean body weights of 500 mg/L males and females were less than those of the controls for much of the 41-week study. Water consumption by 1,000 and 2,000 mg/L males and females was less than that by the control groups throughout both studies. The incidences and/or severities of hepatocyte cytoplasmic vacuolization were increased in males in the 26-week study and females in both studies. GENETIC TOXICOLOGY: Dichloroacetic acid was mutagenic in Salmonella typhimurium strains TA100 and TA1535 in tests conducted in the absence of S9 liver activation enzymes; no increase in mutations was observed in either strain in the presence of rat or hamster liver S9. Dichloroacetic acid was not mutagenic in S. typhimurium strain TA98 with or without S9. Dichloroacetic acid was also tested for micronucleus induction in peripheral blood erythrocytes of male and female Tg.AC hemizygous and p53 haploinsufficient mice treated by drinking water or dermal application for 26 weeks. No induction of micronuclei was seen in Tg.AC hemizygous mice treated by either route or in the p53 haploinsufficient mice, which were exposed only by the drinking water route. In another study, analysis of peripheral blood samples for frequency of micronucleated erythrocytes in male and female B6C3F1 mice exposed to dichloroacetic acid in drinking water for 3 months revealed no alteration in micronucleus frequencies in male mice; a small increase seen in females was judged to be equivocal. CONCLUSIONS: Under the conditions of these drinking water studies, there was no evidence of carcinogenic activity of dichloroacetic acid in male or female p53 haploinsufficient mice exposed to 0, 500, 1,000, or 2,000 mg/L for 26 or 41 weeks. The incidences and/or severities of cytoplasmic vacuolization of the hepatocyte were increased in males and females exposed to dichloroacetic acid for 26 or 41 weeks. Under the conditions of these dermal studies, there were increased incidences of squamous cell papillomas at the site of application in male and female Tg.AC hemizygous mice exposed to 500 mg/kg for 39 weeks. There were dose-related increased incidences of epidermal hyperkeratosis and hyperplasia at the site of application in both male and female mice exposed to dichloroacetic acid for 26 or 39 weeks. Under the conditions of these drinking water studies, there was an increase in the incidence of alveolar/bronchiolar adenoma in male Tg.AC hemizygous mice exposed to 1,000 mg/L for 41 weeks. There were a few bronchiolar/alveolar carcinomas in males and females exposed to dichloroacetic acid in the drinking water for 26 weeks and a few bronchiolar/alveolar adenomas in females exposed to dichloroacetic acid in the drinking water for 41 weeks. There were increased incidences and/or severities of cytoplasmic vacuolization of the hepatocyte in male and female Tg.AC hemizygous mice exposed to dichloroacetic acid in the drinking water study for 26 or 41 weeks. The marginally increased incidences of pulmonary adenomas and/or carcinomas compared to the unexposed groups found in both the dermal and drinking water studies at 39 or 41 weeks were considered to be related to dichloroacetic acid exposure.     

NTP report on the toxicology studies of aspartame (CAS No. 22839-47-0) in genetically modified (FVB Tg.AC hemizygous) and B6.129-Cdkn2atm1Rdp (N2) deficient mice and carcinogenicity studies of aspartame in genetically modified [B6.129-Trp53tm1Brd (N5) haploinsufficient] mice (feed studies)

Aspartame is an artificial sweetener used throughout the world in food and beverages. Conventional 2-year rodent cancer studies of aspartame are considered negative, although a small number of neoplasms of the brain were observed in a rat study (Fed. Regist., 1981a,b). The NTP has explored the use of genetically altered mouse models as adjuncts to the 2-year rodent cancer assay. These models may prove to be more rapid, use fewer animals, and provide some mechanistic insights into neoplastic responses. As part of the evaluation of new mouse cancer screening models, aspartame was tested for potential toxicity and carcinogenicity in two relatively well-studied models, the Tg.AC hemizygous strain and the p53 haploinsufficient strain, and an uncharacterized model, the Cdkn2a deficient strain. Male and female Tg.AC hemizygous, p53 haploinsufficient, and Cdkn2a deficient mice were given feed containing aspartame (greater than 98% pure) for 9 months. Genetic toxicology studies were conducted in Salmonella typhimurium, rat bone marrow cells, and mouse peripheral blood erythrocytes. 9-MONTH STUDY IN Tg.AC HEMIZYGOUS MICE: Groups of 15 male and 15 female Tg.AC hemizygous mice were fed diets containing 0, 3,125, 6,250, 12,500, 25,000, or 50,000 ppm aspartame (equivalent to average daily doses of approximately 490, 980, 1,960, 3,960, or 7,660 mg aspartame/kg body weight to males and 550, 1,100, 2,260, 4,420, or 8,180 mg/kg to females) for 40 weeks. Exposure to aspartame had no effect on survival. The mean body weights of 50,000 ppm females were greater than those of the controls from week 15 until the end of the study. Feed consumption by the exposed groups was similar to that by the control groups throughout the study. There were no neoplasms or nonneoplastic lesions that were attributed to exposure to aspartame. 9-MONTH STUDY IN p53 HAPLOINSUFFICIENT MICE: Groups of 15 male and 15 female p53 haploinsufficient mice were fed diets containing 0, 3,125, 6,250, 12,500, 25,000, or 50,000 ppm aspartame (equivalent to average daily doses of approximately 490, 970, 1,860, 3,800, or 7,280 mg/kg to males and 630, 1,210, 2,490, 5,020, or 9,620 mg/kg to females) for 40 weeks. Exposure to aspartame had no effect on survival or mean body weights. Feed consumption by the exposed groups was similar to that by the control groups throughout the study. No neoplasms or nonneoplastic lesions were attributed to exposure to aspartame. 9-MONTH STUDY IN Cdkn2a DEFICIENT MICE: Groups of 15 male and 15 female Cdkn2a deficient mice were fed diets containing 0, 3,125, 6,250, 12,500, 25,000, or 50,000 ppm aspartame for 40 weeks (equivalent to average daily doses of approximately of approximately 490, 960, 1,900, 3,700, and 7,400 mg/kg to males and 610, 1,200, 2,390, 4,850, and 9,560 mg/kg to females). Survival of all exposed groups was similar to that of the control groups. Mean body weights of 3,125 and 6,250 ppm males were less than those of the controls after weeks 29 and 16, respectively. Mean body weights of female mice were similar to those of the controls throughout the study. The incidences of minimal to mild cytoplasmic vacuolization of periportal hepatocytes were significantly greater than controls in males exposed to 6,250, 25,000, or 50,000 ppm aspartame. GENETIC TOXICOLOGY: Aspartame was tested for induction of gene mutations in Salmonella typhimurium. No mutagenicity was detected in strains TA98, TA100, or TA1535 with or without exogenous metabolic activation (S9). In addition, a single test in TA1537 with 30% rat liver S9 gave negative results. In TA97 with 30% rat liver S9, however, a reproducible small increase in mutant colonies was observed, and this response was judged to be equivocal. No mutagenicity was detected in TA97 without S9 or with hamster liver S9. An acute bone marrow micronucleus test was conducted with aspartame administered by gavage to male F344/N rats. No increase in micronucleated polychromatic erythrocytes was observed at any dose level. Peripheral blood micronucleus tests were conducted after 9 months exposure of Tg.AC hemizygous, p53 haploinsufficient, and Cdkn2a deficient mice to aspartame in dosed feed. Negative results were obtained in male and female Tg.AC hemizygous and Cdkn2a deficient mice. Negative results were also obtained with male p53 haploinsufficient mice. In female p53 haploinsufficient mice, the results of the micronucleus test were judged to be positive, based on a significant trend test and a small but statistically significant increased frequency of micronucleated erythrocytes in the 50,000 ppm group. CONCLUSIONS Under the conditions of this 9-month feed study, there was no evidence of carcinogenic activity of aspartame in male or female p53 haploinsufficient mice exposed to 3,125, 6,250, 12,500, 25,000, or 50,000 ppm. Because this is a new model, there is uncertainty whether the study possessed sufficient sensitivity to detect a carcinogenic effect.     

紫荷植物固体饮料的急性毒性和遗传毒性试验研究

目的：对紫荷植物固体饮料的急性毒性和遗传毒性进行评价。方法：急性毒性试验,采用限量法,设雌雄2组,每组10只SPF级昆明小鼠,累积剂量为10 g/（kg·d）。Ames试验,采用平板掺入法,设5000、1000、200、40、8μg/皿共5个剂量组;小鼠精原细胞染色体畸变试验,设2000、1000、500 mg/（kg·d）剂量组;哺乳动物红细胞微核试验,设2000、1000、500 mg/（kg·d）剂量组。3个遗传毒性试验均另设置阴性对照组和阳性对照组。结果：在14 d观察期内受试动物未见任何急性毒性反应,根据急性毒性分级,属于实际无毒级。Ames试验结果显示,该固体饮料属无致突变性。小鼠精原细胞染色体畸变试验结果显示,各剂量组小鼠染色体畸变率（0～1.6%）,与阴性对照组（0.6%）比较,差异无统计学意义（P>0.05）。哺乳动物红细胞微核试验结果显示,各剂量组雌雄性小鼠骨髓嗜多染红细胞微核率与阴性对照组比较,差异无统计学意义（P>0.05）。3项遗传毒性试验结果显示该固体饮料未见遗传毒性。结论：在本实验条件下,紫荷植物固体饮料无明显急性毒性反应和遗传毒性。     

疏肝健脾抑癌汤对原发性肝癌的辅助疗效观察

 目的 观察疏肝健脾抑癌汤对原发性肝癌的辅助疗效。方法 将60例原发性肝癌患者随机分为治疗组(疏肝健脾抑癌汤+化疗)和对照姐(化疗)。各组30例，均治一个疗程。结果 治疗后两组在癌灶和延长生存期方面无明显差别(P>0．05)，在改善临床症状、提高生存质量及减少白细胞抑制方面治疗组优于对照姐(P<0．05)。结论 疏肝健脾抑癌汤可改善肝癌患者的临床症状、提高生存质量并可减轻化疗药物的毒性。     

重组人血管内皮抑制素治疗人乳腺癌裸鼠模型的实验研究

目的 探讨重组人血管内皮抑制素注射液(恩度,YH-16)对人乳腺癌细胞株MCF-7裸鼠移植瘤的抑制作用.方法 建立人乳腺癌裸鼠模型,随机分成4组,每组10只,接种人乳腺癌细胞悬液,瘤体达1.0 cm3时,于种植部位皮下注射药物:阴性对照组生理盐水0.2 mg/kg体重,阳性对照组顺铂(DDP)1 ms/ks体重,YH-16组YH-16 20 ms/kg体重,DDP联合YH-16组为DDP1 mg/kg体重和YH-16 20 ms/ks体重,隔日一次,20 d后颈椎脱位处死裸鼠,检测裸鼠体重、肿瘤体积、抑瘤率、血管内皮生长因子(VEGF)、癌细胞凋亡率、肺转移率.结果 DDP联合YH-16组、阳性对照组、YH-16单药组、阴性对照组肿瘤体积分别为(0.686±0.229)、(1.258±0.101)、(1.888±0.215)、(3.366±0.284)cm3;抑瘤率分别为92.1%、57.3%、36.5%、0;肺转移率分别为0、10%、20%、90%;癌细胞凋亡率分别为31.6%±2.7%、28.1%±2.7%、19.4%±2.9%、15.7%±3.2%;RT-PCR检测VEGF表达,吸光度(A)比值均数分别为0.530±0.164、0.759±0.210、1.063±0.295、1.268±0.145,Western blot检测结果为0.260±0.0820、0.348±0.085、0.461±0.099、0.556±0.113,以上各组间差异均有统计学意义(P<0.05).结论 YH-16对人乳腺癌裸鼠肿瘤生长及远处转移均有抑制作用,不良反应小;YH-16联合DDP有协同增效作用.     

Toxicology studies of bromodichloromethane (CAS No. 75-27-4) in genetically modified (FVB Tg.AC Hemizygous) mice (dermal, drinking water, and gavage studies) and carcinogenicity studies of bromodichloromethane in genetically modified [B6.129-Trp53(tm1Brd) (N5) haploinsufficient] mice (drinking water and gavage studies)

Bromodichloromethane is a by-product of the chlorination of drinking water. It is formed by the halogen substitution and oxidation reactions of chlorine and naturally occurring organic matter (e.g., humic or fluvic acids) in water containing bromide. Bromodichloromethane was nominated to the NTP by the United States Environmental Protection Agency for toxicology and carcinogenicity studies. Male and female Tg.AC hemizygous mice received bromodichloromethane (at least 98%pure) by dermal application for 26 or 39 weeks, in drinking water for 26 or 42 weeks, or by gavage for 26 or 41 weeks. p53 Haploinsufficient mice received bromodichloromethane in drinking water for 26 or 42 weeks or by gavage for 26 or 41 weeks. Genetic toxicology studies were conducted in mouse peripheral blood erythrocytes. 26- and 39-WEEK DERMAL STUDIES IN Tg.AC HEMIZYGOUS MICE: Groups of 15 male and 15 female Tg.AC hemizygous mice were dermally administered 0, 64, 128, or 256 mg bromodichloromethane/kg body weight in acetone, 5 days per week for 26 weeks, and groups of 10 male and 10 female Tg.AC hemizygous mice were dermally administered the same doses 5 days per week for 39 weeks. The survival and mean body and organ weights of all dosed groups of males and females were similar to those of the vehicle controls. There were no statistically or biologically significant increases in the incidences of neoplasms or nonneoplastic lesions. 26- AND 42-WEEK DRINKING WATER STUDIES IN TG.AC HEMIZYGOUS MICE: Groups of 15 male and 15 female Tg.AC hemizygous mice were exposed to drinking water containing 0, 175, 350, or 700 mg/L bromodichloromethane for 26 weeks (equivalent to average daily doses of approximately 20, 36, or 61 mg bromodichloromethane/kg body weight to males and 31, 61, or 130 mg/kg to females). The survival of exposed males and females was similar to that of the control groups. Mean body weights of males exposed to 350 or 700 mg/L were less than those of the controls during most of the study. Mean body weights of 175, 350, and 700 mg/L females were greater than those of the controls after weeks 10, 22, and 23, respectively. In exposed males, water consumption declined with increasing exposure concentration. Water consumption by exposed females was less at the beginning of the study, but was similar to that by controls at the end of the study. The decreased water consumption was related to poor palatability. Absolute heart and right kidney weights of exposed males were significantly less than those of the control group. The incidences of hepatocyte fatty change and hypertrophy in 350 and 700 mg/L females and cytoplasmic vacuolization in 700 mg/L females were significantly greater than those in the control group. Incidences of renal tubule dilatation in males exposed to 175 mg/L or greater, renal tubule hypertrophy in 350 and 700 mg/L males, and nephropathy and renal tubule degeneration in 700 mg/L males were also increased. Groups of 10 male and 10 female Tg.AC hemizygous mice were exposed to drinking water containing 0, 175, 350, or 700 mg/L bromodichloromethane for 42 weeks (equivalent to average daily doses of approximately 18, 33, or 64 mg/kg to males and 28, 49, or 111 mg/kg to females). The survival of exposed males and females was similar to that of the control groups. Mean body weights of 350 and 700 mg/L males were less than those of the controls at the end of the study. Due to poor palatability, water consumption decreased with increasing exposure concentration. Absolute right kidney weights of 350 and 700 mg/L males were significantly less than those of the control group. The incidences of hepatocyte fatty change in all exposed groups of females, renal tubule dilatation in all exposed groups of males, and nephropathy in 700 mg/L males were significantly increased. 26- AND 41-WEEK GAVAGE STUDIES IN TG.AC HEMIZYGOUS MICE: Groups of 15 male and 15 female Tg.AC hemizygous mice were administered 0, 25, 50, or 100 mg bromodichloromethane/kg body weight in corn oil by gavage, 5 days per week for 26 weeks. The survival of dosed males and females was similar to that of the vehicle control groups. Mean body weights of dosed females were generally greater than those of the vehicle controls at the end of the study. The incidence of multiple squamous cell papilloma of the forestomach in 100 mg/kg females was significantly greater than that in the vehicle controls. The incidences of hepatocyte fatty change in all dosed groups of females, hepatocyte cytoplasmic vacuolization in 25 and 50 mg/kg females, renal tubule hypertrophy in 100 mg/kg females, and renal tubule degeneration in 100 mg/kg males were significantly increased. Groups of 10 male and 10 female Tg.AC hemizygous mice were administered 0, 25, 50, or 100 mg/kg in corn oil by gavage, 5 days per week for 41 weeks. The survival of dosed males and females was similar to that of the control groups. Mean body weights of 25 mg/kg males and 100 mg/kg females were greater than those of the vehicle controls at the end of the study. The incidences of multiple squamous cell papilloma of the forestomach in 25 and 100 mg/kg females and of all squamous cell papillomas of the forestomach in 100 mg/kg females were significantly greater than those of the vehicle controls. The incidences of hepatocyte cytoplasmic vacuolization in 50 mg/kg females and hepatocyte fatty change in 50 and 100 mg/L females were significantly increased; the incidences of renal tubule degeneration in 100 mg/kg males was also significantly greater than that in the vehicle control group. 26- AND 42-WEEK DRINKING WATER STUDIES IN P53 HAPLOINSUFFICIENT MICE: Groups of 15 male and 15 female p53 haploinsufficient mice were exposed to drinking water containing 0, 175, 350, or 700 mg/L bromodichloromethane for 26 weeks (equivalent to average daily doses of approximately 16, 31, or 65 mg/kg to males and 26, 50, or 100 mg/kg to females). The survival of exposed males and females was similar to that of the control groups. Mean body weights of 350 and 700 mg/L males were less than those of the controls throughout most of the study. Mean body weights of 175, 350, and 700 mg/L females were less than control body weights after weeks 15, 23, and 18, respectively. In exposed males, water consumption declined with increasing exposure concentration. Water consumption by exposed females was similar to that by controls by the end of the study. The absolute heart weight of 700 mg/L males and absolute right kidney and liver weights of 350 and 700 mg/L males were significantly less than those of the control group. The incidences of renal tubule dilatation in all exposed groups of males, renal tubule degeneration in 350 and 700 mg/L males, and the incidence of fatty change in hepatocytes of 700 mg/L females were significantly greater than those in the control groups. Groups of 10 male and 10 female p53 haploinsufficient mice were exposed to drinking water containing 0, 175, 350, or 700 mg/L for 42 weeks (equivalent to approximately 14, 30, or 55 mg/kg to males and 22, 43, or 98 mg/kg to females). The survival of exposed males and females was similar to that in the control groups. Mean body weights of males exposed to 350 or 700 mg/L were less than those of the controls. Mean body weights in 700 mg/L females were less during the last three weeks of the study. Water consumption by exposed males was less than that by controls. The absolute right kidney weights in 350 and 700 mg/L males were significantly less than those of the control group. The incidences of renal tubule degeneration in 350 and 700 mg/L males were significantly greater than that in the control group. 26- AND 41-WEEK GAVAGE STUDIES IN P53 HAPLOINSUFFICIENT MICE: Groups of 15 male and 15 female p53 haploinsufficient mice were administered 0, 25, 50, or 100 mg bromodichloromethane/kg body weight in corn oil by gavage for 26 weeks. The survival of dosed males and females was similar to that of the vehicle control groups. The mean body weights of males administered 50 or 100 mg/kg and females administered 50 mg/kg were less than those of the vehicle controls during most of the study. The absolute heart, right kidney, and right testis weights in 100 mg/kg males were significantly less than those of the vehicle controls. The absolute liver weight of 100 mg/kg females was significantly greater. The incidences of fatty change in hepatocytes of 100 mg/kg females and renal tubule degeneration in 100 mg/kg males were significantly greater than those in the vehicle control groups. Groups of 10 male and 10 female p53 haploinsufficient mice were administered 0, 25, 50, or 100 mg/kg in corn oil by gavage for 41 weeks. The survival of dosed males and females was similar to that of the vehicle control groups. Mean body weights of 50 and 100 mg/kg males were less than those of the vehicle controls throughout the study and those of 25, 50, and 100 mg/kg females were less after weeks 9, 14, and 24, respectively. The absolute liver weight of 100 mg/kg females was increased with respect to the vehicle controls, and the absolute heart and right kidney weights of 100 mg/kg males were decreased. The incidences of hepatocyte fatty change in 100 mg/kg males and females and renal tubule degeneration and nephropathy in 100 mg/kg males were significantly greater than those in the vehicle controls. GENETIC TOXICOLOGY: Peripheral blood micronucleus tests on male and female Tg.AC hemizygous and p53 haploinsufficient mice exposed to bromodichloromethane in drinking water, by dermal application, and by gavage for 26 weeks yielded mixed results but no clearly positive responses. Results in Tg.AC hemizygous mice were judged to be equivocal for both males and females in the drinking water study, equivocal in males and negative in females treated by dermal application, and negative in males and females treated by gavage. (ABSTRACT TRUNCATED)