Subchronic Oral Toxicity Evaluation of Lanthanum： A 90-day, Repeated Dose Study in Rats

Objective The present study was undertaken to evaluate the subchronic toxicity of lanthanum and to determine the no observed adverse effect level（NOAEL）,which is a critical factor in the establishment of an acceptable dietary intake（ADI）.Methods In accordance with the Organization for Economic Co-operation and Development（OECD） testing guidelines,lanthanum nitrate was administered once daily by gavage to Sprague-Dawley（SD） rats at dose levels of 0,1.5,6.0,24.0,and 144.0 mg/kg body weight（BW） per day for 90 days,followed by a recovery period of 4 weeks in the 144.0 mg/kg BW per day and normal control groups.Outcome parameters were mortality,clinical symptoms,body and organ weights,serum chemistry,and food consumption,as well as ophthalmic,urinary,hematologic,and histopathologic indicators.The benchmark dose（BMD） approach was applied to estimate a point of departure for the hazard risk assessment of lanthanum.Results Significant decreases were found in the 144.0 mg/kg BW group in the growth index,including body weight,organ weights,and food consumption.This study suggests that the NOAEL of lanthanum nitrate is 24.0 mg/kg BW per day.Importantly,the 95% lower confidence value of the benchmark dose（BMDL） was estimated as 9.4 mg/kg BW per day in females and 19.3 mg/kg BW per day in males.Conclusion The present subchronic oral exposure toxicity study may provide scientific data for the risk assessment of lanthanum and other rare earth elements（REEs）.

Combined Subchronic Toxicity of Bisphenol A and Dibutyl Phthalate on Male Rats

Objective To evaluate the combined subchronic toxicity of bisphenol A（BPA） and dibutyl phthalate（DBP） in male Sprague Dawley（SD） rats.Methods Forty 4‐week‐old male rats weighing 115‐125 g were randomly divided into BPA‐treated,DBP‐treated group,BPA＋DBP‐treated and control groups and fed with a soy‐ and alfalfa‐free diet containing 285.4 ppm BPA,285.4 ppm DBP,285.4 ppm BPA plus 285.4 ppm DBP,and a control diet,respectively,for 90 consecutive days.At the end of the study,the animals were sacrificed by exsanguination via the carotid artery under diethyl etherane aesthesia and weighed.Organs,including liver,kidneys,spleen,thymus,heart,brain,and testis underwent pathological examination.The androgen receptor（AR）,gonadotropin‐releasing hormone receptor（GNRHR）,and progesterone hormone receptor（PR） genes from the hypothalamus were detected by real‐time PCR.The biomedical parameters were analyzed.Results No significant difference was found in food intake,body weight,tissue weight,organ/brain weight ratio,and biomedical parameters among the four groups（P〉0.05）.However,BPA and DBP up‐regulated AR,PR and GNRHR expression levels in rats and showed a synergistic or an additive effect in the BPA＋DBP group.Conclusion The combined subchronic toxicity of BPA and DBP is synergistic or additive in male SD rats.

Acute and subchronic toxicity as well as evaluation of safety pharmacology of modified pulsatilla granules

The present study investigated acute and subchronic toxicity and safety pharmacology of modified pulsatilla granules（MPG）to provide a basis for a comprehensive understanding of MPG toxicity.The results of acute toxicity testing showed that the median lethal dose of MPG was more than 5 000 mg kg^-1,suggesting that MPG was considered as practically non-toxic.The subchronic toxicity study for 30 days was conducted by daily oral administration at doses of 375,750 and 1 500 mg kg^-1 in Sprague-Dawley rats.The results of subchronic toxicity study showed that the body weight and relative organ weight were not significantly changed by administration of MPG.The clinical chemistry study showed that MPG could induce kidney and liver damages.In histopathological,mild lesions in liver and kidney were also observed,suggesting that the liver and kidney might be potential target organs of MPG.In the safety pharmacology study,MPG did not exhibited any side effects to rats in cardiovascular system,respiratory system and central nervous system.These results suggested that MPG could be considered safe for veterinary use.

Subchronic Toxicity Study on Soy Isoflavones in Rats

Objective To investigate the subchronic toxicity of soy isoflavones （SIF） in male rats. Method Fifty Sprague-Dawley rats were randomly divided into 5 groups, 10 rats per group. SIF were given to rats in different groups by gavage at dose of 0, 0.2, 0.5, 1.5, and 4.5 g/kg bw, respectively for 13 weeks. Clinical manifestations, body weight, and food consumption were observed weekly. At the end of the study, urinalysis, hematology, clinical chemistry, total testosterone, and follicle-stimulating hormone were tested, and histopathological examinations were performed. Results No mortality, ophthalmic abnormalities or treatment-related clinical signs were identified during the study. As compared with the control group, significantly lower body weights and food consumption were observed in 1.5 and 4.5 g/kg bw groups. In clinical chemistry tests, triglyceride was significantly decreased and high-density lipoprotein cholesterol was significantly increased in all SIF-treated groups. Total testosterone levels were significantly lower in 0.50, 1.50, and 4.5 g/kg bw dose groups than in the control group. Microscopic examination showed that the mammary glands exhibited hyperplasia and excreted latex in rats of the 4.5 g/kg bw group. No changes attributable to treatment of SIF in other parameters were found. Conclusion SIF at high dosages caused significant endocrine disruption in male rats. The no observed adverse effect level （NOAEL） of SIF to male rats in this study is considered to be 0.20 g/kg bw.

Subchronic Oral Toxicity of Silica Nanoparticles and Silica Microparticles in Rats

Objective To investigate the subchronic oral toxicity of silica nanoparticles（NPs） and silica microparticles（MPs） in rats and to compare the difference in toxicity between two particle sizes.Methods Sprague-Dawley rats were randomly divided into seven groups： the control group; the silica NPs low-, middle-, and high-dose groups; and the silica MPs low-, middle-, and high-dose groups [166.7,500, and 1,500 mg/（kg·bw·day）]. All rats were gavaged daily for 90 days, and deionized water was administered to the control group. Clinical observations were made daily, and body weights and food consumption were determined weekly. Blood samples were collected on day 91 for measurement of hematology and clinical biochemistry. Animals were euthanized for necropsy, and selected organs were weighed and fixed for histological examination. The tissue distribution of silicon in the blood, liver,kidneys, and testis were determined.Results There were no toxicologically significant changes in mortality, clinical signs, body weight,food consumption, necropsy findings, and organ weights. Differences between the silica groups and the control group in some hematological and clinical biochemical values and histopathological findings were not considered treatment related. The tissue distribution of silicon was comparable across all groups.Conclusion Our study demonstrated that neither silica NPs nor silica MPs induced toxicological effects after subchronic oral exposure in rats.

Acute and subchronic toxicity of hydroxylammonium nitrate in Wistar rats

Hydroxylammonium nitrate(HAN) is a major constituent in a class of liquid monopropellants and is extensively used in nuclear industry and space propulsion.Previous toxicological studies have focused on oral,inhalation and dermal routes of exposure to HAN-based propellant blends.In this study,acute and subchronic toxicity of HAN in Wistar rats by intraperitoneal injections were evaluated.In this acute study,doses of HAN at 115,125,135,147,160 or 174 mg/kg were administered.No adverse effects were observed during a 14-day period and at gross histopathological examination.In the subchronic study,HAN at 7,14 or 28 mg/kg were administered for 13 weeks.The treatment with HAN caused significant changes in the weight of spleen,in the level of hematological parameters,total bilirubin,direct bilirubin,uric acid and carbondioxidecombining power and histopathological damages of the lung,liver,spleen and kidney.Overall,the study suggests that 13-week HAN treatment caused abnormal hematological changes and tissue lesions,and the risk of toxicity to mammals is not negligible.

A Subchronic Toxicity Study on Lactobacillus Fermentum GM 090 in Rat

Lactobacillus fermentum （L. fermentum） is one of seven species in the genus Lactobacillus[1]. With a long history of safe use in fermented food production, Lactobacillus is considered as one of the most beneficial probiotics[23]. The most well-known potential health benefit is improving digestion and immune function[4.s]. Other beneficial functions of Lactobacillus strains include managing lactose intoleranceIs], lowering cholesterol and blood pressureIs], reducing inflammation[~], and prevention of cancerIs＇7]. L. fermentum is usually found during malt whisky fermentation]8]. L. fermentum CP34 was found to have the significant effect of decreasing the serum antigen-specific IgE levels compared to a control group[9].

Subchronic Oral Toxicity of Pyridostigmine Bromide in Rats

This study evaluated the oral toxicity of pyridostigmine bromide in Sprague-Dawley rats when administered for 13 weeks by daily gavage. Groups of 10 rats/sex received doses of 0, 5, 15, 30, or 60 mg/kg/day. Toxicity was limited to exaggerated cholinergic stimulation at doses of 15 mg/kg/day or greater. Significant findings included tremors and inhibition of RBC acetylcholinesterase. Thus, 5 mg/kg/day of pyridostigmine bromide appears to be the no observed toxic effect level under the conditions of the present investigation.

A 180-Day Subchronic Oral Toxicity Study of Total Flavones of <i>E. leptorrhizum</i>Stearn in Rats

A subchronic oral toxicity was conducted to evaluate the safety of total flavones of E. leptorrhizum Stearn in Sprague-Dawley rats. The test article was administered once daily by gavage in male and female rats at dose levels of 24, 48, and 96 mg/kg body weight/day for 180 days. 90 and 180 days after administration, ten and tweedy animals (each half of male and female) of each group were tested. 28 days after withdrawal, five male and female rats were tested. There were no significant toxicological changes shown in daily clinical signs, body weight, food consumption, hematology parameters, blood biochemistry, organ weights and histopathological examination except leukocyte differential count. It was concluded that the no-observed-effect level (NOEL) for total flavones of E. leptorrhizum Stearn was >96 mg/kg in SD rats.

2C-B的亚慢性毒性研究

研究4-溴-2,5-二甲氧基苯乙胺(4-bromo-2,5-dimethoxyphenethylamine,2C-B)的亚慢性毒性.通过对大鼠进行长期连续染毒,以体重变化、脏器系数、病理学检查及肝肾生化酶水平的影响探讨2C-B对机体造成损伤的情况.综合各指标结果分析长期服用2C-B会对心脏、肝脏、肺脏、肾脏、大脑产生损害,上述器官可能是2C-B毒性的靶器官.

樟树籽仁油的90 d亚慢性经口毒性评价

为评价樟树籽仁油的食用安全性,以4.0、2.0、1.0、0.0 mL/kg剂量的樟树籽仁油对4组SPF级SD大鼠(20只/组、雌雄各半)连续灌胃90 d,研究樟树籽仁油的亚慢性经口毒性,探明其剂量-反应关系,毒作用靶器官和可逆性。结果表明:90 d经口毒性试验期间,大鼠的活动和生长均正常;除高剂量组雌、雄性大鼠的血糖显著低于对照组外(p<0.05),各剂量组雌、雄性大鼠的体质量及其增量、进食量及食物利用率、脏体比、血常规、血生化、血电解质和尿液等指标与对照组均无显著性差异(p>0.05);病理检查未见樟树籽仁油对大鼠的作用靶器官产生有意义的病理变化。综上,樟树籽仁油对大鼠生长和生理的影响无剂量-反应关系,对大鼠的作用靶器官无毒害作用且无剂量-反应关系,樟树籽仁油无亚慢性经口毒性,其未观察到毒效应的剂量(NOAEL)大于4.0 mL/kg,食用安全性高。

樟树籽仁油的急性及42d高剂量经口毒性评价

为评价樟树籽仁油的食用安全性,以ICR小鼠为试验动物,通过急性经口毒性试验确定樟树籽仁油的急性毒性剂量和分级;以SD大鼠为试验动物,进行42 d高剂量(4.0 mL/kg)经口毒性试验评价樟树籽仁油的亚慢性经口毒性。结果表明:ICR小鼠生理和活动均正常,无中毒和死亡现象,其组织器官均没有肉眼可见病变且无剂量-反应关系,樟树籽仁油对ICR小鼠急性经口毒性半数致死量(LD50)大于21.5 g/kg,根据急性毒性剂量分级标准判定樟树籽仁油无急性经口毒性,属实际无毒级;樟树籽仁油对SD大鼠的生长和生理没有影响,对SD大鼠的作用靶器官无毒害作用,表明樟树籽仁油在连续42 d饲喂期内没有呈现出亚慢性经口毒性。综上,樟树籽仁油无急性经口毒性,也无42 d高剂量经口毒性,食用安全性高。

天冬对大鼠的亚慢性和致畸毒性研究

目的:研究天冬对大鼠经口重复给药的亚慢性毒性和致畸毒性。方法:90天经口毒性试验采用SD大鼠80只,雌雄各半,体质量65.4~94.0 g,拌饲法设2 000、4 000、8 000 mg/kg共3个剂量组和1个阴性对照组,连续给予受试物90天,观察动物一般状况,记录动物体质量、摄食量,计算食物利用率,并进行血液学、血生化及病理学检测,从而评价其亚慢性毒性。传统致畸试验采用雌性SD孕鼠,剂量为1 000、2 000、4 000 mg/kg共3个剂量组,另设阴性对照组(蒸馏水),每组22只,经口灌胃给药,于孕第20天处死母体,检查受孕情况和胎仔发育,观察胎仔外观,检查骨骼及内脏,以评估致畸毒性。结果:90天经口毒性试验中大鼠未出现中毒症状及死亡,试验组大鼠组织病理学检查未见毒性损伤作用。致畸试验中低、中剂量组胎仔胸骨发育不全发生率分别为21.49%和26.32%,与对照组(6.25%)相比显著升高(P<0.01),未见其他异常。结论:在本试验条件下,90天经口毒性试验中天冬对大鼠的未观察到有害作用剂量(NOAEL)为8 000 mg/kg;在致畸试验中,未观察到与染毒剂量相关的效应,天冬对SD大鼠无致畸性。

苍朴乌梅散对大鼠的急性毒性及亚慢性毒性研究

为了评价苍朴乌梅散的安全性,分别进行了苍朴乌梅散的急性毒性试验以及亚慢性毒性试验。在急性毒性试验中,各组SD大鼠在经口灌胃给药后,连续7 d观察大鼠的采食和精神状态。在亚慢性毒性试验中,80只SD大鼠(雌雄各半)被随机分为空白对照组以及苍朴乌梅散低、中、高剂量组,连续给药30 d后,检测各组大鼠的血常规、血液生化指标,并对脏器进行组织病理学分析。结果显示,在急性毒性试验中均无大鼠死亡;在亚慢性毒性试验中,中、高剂量组在体重增长率、血液学和生化检测中有个别指标与空白对照组有显著差异(P<0.05);而低剂量组10 g/kg在体重增长率、生理生化指标、脏器指数和组织病理学差异不显著(P>0.05)。研究表明,苍朴乌梅散对大鼠的LD_(50)>5 000 mg/kg,以10 g/kg(临床推荐剂量的25倍)连续给药SD大鼠30 d安全性好。

波棱瓜子总木脂素的急性和亚慢性毒性试验

旨在用小鼠急性毒性试验和大鼠亚慢性毒性试验评价波棱瓜子总木脂素的安全性。在24只ICR小鼠急性经口毒性试验中,设单次最大给药量(5000 mg/kg),给药后连续观察7 d;在亚慢性毒性试验中,40只SD大鼠分为对照组(0.5%羧甲基纤维素钠)和波棱瓜子总木脂素低(100 mg/kg)、中(200 mg/kg)和高(400 mg/kg)剂量组进行灌胃给药,每天1次,连续给药30 d,灌胃结束后测定大鼠体重、采食量、血液指标、生化指标、脏器系数和病理组织学变化。结果:在小鼠急性毒性试验中,波棱瓜子总木脂素对ICR小鼠的LD50>5000 mg/kg,按照外源化合物急性毒性分级标准波棱瓜子总木脂素属于实际无毒;大鼠亚慢性毒性试验中,与对照组比较,波棱瓜子总木脂素各剂量组体重、采食量、血液学、血液生化学、脏器系数均无显著差异(P>0.05),组织病理学检查结果未见与波棱瓜子总木脂素毒性有关的病理变化。综上,波棱瓜子总木脂素临床合理剂量使用安全性高。

溴氰菊酯不同暴露时间对小鼠神经行为的毒性作用研究

目的:探究溴氰菊酯(DM)不同暴露时间对小鼠神经行为的毒性作用。方法:将32只成年雄性C57BL/6J小鼠随机分为30 d(对照组、DM组)和90 d(对照组、DM组)4组,每组8只。DM组经口灌胃4.5 mg/kg(1/20 LD_(50))30 d或90 d,对照组给予等容量玉米油。采用Morris水迷宫(MWM)检测小鼠的学习记忆能力;苏木精—伊红(HE)染色及尼氏染色观察小鼠皮层组织病理学变化;检测皮层组织还原型谷胱甘肽(GSH)、超氧化物歧化酶(SOD)、过氧化氢酶(CAT)、丙二醛(MDA)的含量。结果:MWM实验结果,30 d的DM组与对照组相比无显著性差异(P<0.05)。90 d的DM组小鼠在目标象限时间、目标象限路程和穿越平台次数均显著少于对照组(P<0.01)。大脑皮层组织GSH的含量,DM 90 d组低于对照组(P<0.05);SOD活力变化,DM 30 d组低于对照组(P<0.01);CAT活力变化,DM 90 d组低于对照组(P<0.01)。结论:低剂量DM不同暴露时间对成年雄性小鼠的学习记忆能力及抗氧化能力具有不良影响,且这种影响随暴露时间的延长而加剧,应重视DM长期低剂量暴露对神经行为的影响。

鸿茅药酒对大鼠的急性和亚慢性毒性研究

目的:研究鸿茅药酒的急性和亚慢性毒性反应,为评价其安全性提供试验依据.方法:对鸿茅药酒(上市品)进行大鼠单次和13周经口毒性试验.结果:大鼠单次给予鸿茅药酒超过20mL/kg,可引起步态不稳、嗜睡、俯卧、侧躺、死亡等严重毒性反应.连续13周给予鸿茅药酒,与灭菌注射用水对照组动物比较,1、3、6 mL/kg组大鼠的每周体重、摄食量,给药末期及恢复期的血液学、血生化指标、脏器重量,均无明显差异;除动物自发病变,6mL/kg鸿茅药酒组动物未见明显毒性病理改变.结论:鸿茅药酒对大鼠急性经口最大耐受剂量约为20mL/kg;大鼠连续13周每日给予6mL/kg鸿茅药酒,未见明显不良反应.

鸿茅药酒浓缩液的急性和亚慢性毒性研究

目的:研究鸿茅药酒浓缩液的急性和亚慢性毒性反应,为评价其安全性提供试验依据。方法:对鸿茅药酒浓缩液(上市品的5.5倍浓缩液)进行大鼠单次和13周经口毒性试验。结果:大鼠单次给予鸿茅药酒浓缩液最大达1600 mg/kg,未见不良毒性反应。连续13周给予鸿茅药酒浓缩液,与灭菌注射用水对照组动物比较,200、400、800 mg/kg组大鼠的每周体重、摄食量,给药末期及恢复期的血液学、血生化指标、脏器重量,均无统计学差异;800 mg/kg剂量组雄鼠可见体重、摄食的降低及血糖值轻微降低,停药后可恢复;除动物自发病变,800 mg/kg鸿茅药酒浓缩液组动物未见明显毒性病理改变。结论:鸿茅药酒浓缩液对大鼠急性经口最大耐受剂量大于1600 mg/kg;大鼠连续13周给予鸿茅药酒浓缩液,未观察到临床不良反应的剂量为400 mg/kg(以生药量计,约为人用剂量的10倍)。

三氯卡班对海水青鳉鱼生命发育初期的亚慢性毒性研究

研究了三氯卡班(TCC)对海水青鳉生命初期阶段的亚慢性毒性影响。结果表明,TCC会降低胚胎的心率和孵化率,并降低仔鱼的存活率。典型生物标志物测定发现,TCC会对胚胎的抗氧化系统和神经系统造成损伤。通过亚慢性毒性研究,可以进一步认识三氯卡班对海洋生物初期的潜在毒性影响和毒性机理,为TCC毒性的早期风险预警和控制提供了重要的理论指导。

金莲花饲用安全性评价

试验旨在探究金莲花饲用安全性,对金莲花进行急性毒性试验、遗传毒性试验(细菌回复突变试验、哺乳动物红细胞微核试验、小鼠精母细胞染色体畸变)和亚慢性毒性试验。结果显示,昆明小鼠半数致死量(LD50)大于10.0 g/kg·BW。遗传毒性试验结果未见金莲花对试验动物致突变作用。大鼠致畸试验结果显示,各剂量组孕鼠未出现中毒体征,未观察到大鼠的生殖毒性,未见致畸作用。亚慢性毒性试验未见大鼠出现中毒表现以及死亡发生,各剂量组大鼠的体重、增重、进食量、食物利用率、脏体比与阴性对照相比差异均不显著(P>0.05)。各组大鼠的血常规、血液生化、尿常规等指标均在正常范围内,心脏、肝脏、胰脏、肺、肾脏、脑、胃、睾丸和子宫等脏器的色泽、大小和形态结构均未见明显异常。研究表明,金莲花毒性小,饲用安全性较高。