Fertility and early embryonic development toxicity of penequine hydrochloride in mice.

Penequine hydrochloride, a novel anticholinergic agent, was developed as an effective treatment for organophosphorus intoxication. The potential for penequine hydrochloride to induce fertility and early embryonic developmental toxicity was evaluated in AMMS-1 mice. Totally 320 healthy, sexual mature and nulliparous AMMS-1 mice were orally treated with the chemical in drinking water at dose levels of 0, 2.5, 12.5 and 62.5 mg/L from 60 days before cohabitation to successful copulation in 160 males and from two weeks before cohabitation to GD 6 in 160 females, respectively. All the parental mice were observed for body weights, water consumption and any abnormal change during treatment period. Caesarean sections were carried out on day 14 of pregnancy in half assumed-pregnant females, and all the intrauterine data were recorded. Pups naturally delivered by the other half females were weighed, and examined for viability, sex ratio and gross malformations. About 7 days after cohabitation period, all the paternal males were examined for epididymal and testicular weights, sperm number and sperm motility. The decreases in fertility/fecundity indices and maternal weight gain were found at high-dose level in both caesarean sections and natural delivery observations. The primary developmental toxicity of the chemical included decreases in relative organ (epididymis, liver and lung) weights at mid- and high-dose levels in pups on postnatal day (PND) 35. The cause of both the decreased fertility/fecundity indices in F0 males and the decreased relative organ weights in F1 pups are not well known but are presently under investigation. Under the experimental conditions, penequine hydrochloride did not produce any adverse effects (expect the decreases in certain relative organ weights) up to and including 12.5 mg/L (2.53 mg/kg/day in males and 2.19 mg/kg/day in females) corresponding to approximately 72 times above anticipated dosage in human.     

The pre- and post-natal toxicity of penequine hydrochloride in mice

Penequine hydrochloride, a novel anticholinergic agent, was developed as an effective treatment for organophosphorus intoxication (e.g., soman poisoning). The current study was performed to assess the potential pre- and post-natal toxicity of penequine hydrochloride in mice. Approximately 120 timed-pregnant mice were assigned to four dose groups (n = 30 per group). Dams were exposed orally to 0, 2.5, 12.5, 62.5 mg/L penequine hydrochloride in drinking water from gestation day 6 to lactation day 21. The F1 generation mice, which were not exposed directly to penequine hydrochloride as pups or as adults, were bred to produce F2 generation fetuses for the fertility test of the F1 population. Various pre- and post-natal measurements, including neurobehavioral tests, were performed with the F0 and F1 mice. Among the significant findings were decreases in water consumption, viability, organ weights and delay of physical landmarks in 62.5 mg/L groups. With the exception of treatment-unrelated abnormality in surface righting reflex in the F1 generation, penequine hydrochloride did not produce any adverse effects at doses up to and including 12.5 mg/L (equal to 2.5 mg/kg/day in mice) that were at least 75 times of human therapeutic dosage.     

Developmental toxicity of benzyl benzoate in rats after maternal exposure throughout pregnancy

The maternal and fetal toxicity of benzyl benzoate, commonly used as antiparasitic insecticide, was evaluated in pregnant rats after a daily oral dose of 25 and 100 mg/kg. Biochemical, histopathological, and morphological examinations were performed. Dams were observed for maternal body weights and food and water consumption and subjected to caesarean section on (GD) 20. Maternal and fetal liver, kidney, heart, brain, and placenta were examined histopathologically under light microscope. Maternal and fetal liver and placenta were stained immunohistochemically for vascular endothelial growth factor (VEGF). Morphometric analysis of fetal body lengths, placental measurements, and fetal skeletal stainings was performed. Statistically significant alterations in biochemical parameters and placental and skeletal measurements were determined in treatment groups. In addition to histopathological changes, considerable differences were observed in the immunolocalization of VEGF in treatment groups. These results demonstrated that benzyl benzoate and its metabolites can transport to the placenta and eventually enter the fetuses. © 2011 Wiley Periodicals, Inc. Environ Toxicol 29: 40–53, 2014.     

Developmental toxicity study of CBLB502 in Wistar rats

CBLB502 is a derivative of a microbial protein that binds to Toll-like receptor 5. It is demonstrated to reduce inflammatory response from acute stresses, such as radiation in animal models. We determined the potential developmental toxicity of CBLB502 in rats. Four groups of 25 time-mated female Wistar rats/group received subcutaneously 0, 30, 100, or 300 μg/kg/day of CBLB502 from Gestation Days (GD) 6 to 17 at a dose volume of 1.0 mL/kg. Toxicokinetic evaluation was performed on GD 6 and 17. On GD 20 C-section was performed for uterine evaluation and blood samples collected from each dam for immunogenicity assay.Significant decrease in gestation body weight, weight changes and food consumption indicative of maternal toxicity were observed in all dose groups. Also adjusted body weight and weight changes were seen at 300 μg/kg/day. No external, visceral and skeletal abnormalities were observed. The NOAEL for developmental toxicity was estimated to be ≥300 μg/kg/day.     

Non-clinical single- and repeated-dose toxicity studies of ET-26 hydrochloride in rats

ET-26 hydrochloride (ET-26HCl), a novel analog of etomidate, induces as effective sedation, with good cardiac and respiratory stability, as etomidate but with mild adrenocortical suppression. The objective of this study was to evaluate the potential adverse effects of ET-26HCl in rats. In a single-dose toxicity study, abnormal urine color (red) was observed in all groups: control (100%), 8 mg/kg (10%), 16 mg/kg (50%), and 20 mg/kg (70%) ET-26HCl, which returned to normal on the day of dosing. There were no mortalities or serious toxicological signs; the maximum tolerable dose of ET-26HCl was 20 mg/kg. In the repeated-dose toxicity study, deaths occurred in the 12- (13.33% of males) and 16-mg/kg/day (20% of males and 3.33% of females) groups. Abnormal urine color (red or brown) was detected in the control group (10%) and all treatment groups (30%, 46.67%, and 40% at 8, 12 and 16 mg/kg/day, respectively), at a frequency of 1.43% in the control group, 4.76% in 8 mg/kg/day, 7.62% in 12 mg/kg/day, and 4.29% in 16 mg/kg/day. Increases in neutrophils and plasma fibrinogen were temporary and recoverable effects. Macroscopic and histopathologic changes were found only at the injection sites: abnormal skin color, scabbing, thrombus, ulceration, and inflammation. During the recovery period, there was evidence of reversibility, including fibroblast proliferation and vessel recanalization. The no-observed-adverse-effect level of ET-26HCl was 8 mg/kg/day. Toxicokinetic variables of ET-26HCl, except the calculated initial concentration in females on Day 1, showed a dose-dependent increase to exposure, with no gender difference and no evidence of accumulation.     

复方盐酸西替利嗪凝胶剂对大鼠的长期毒性试验

盐酸西替利嗪是第二代抗组胺药，为长效的具选择性的强效抗变态反应药，临床上主要用于治疗过敏性皮炎、荨麻疹及过敏性哮喘等”。目前，盐酸西替利嗪的临床使用制剂主要有片剂、胶囊、颗粒剂、口服液、滴鼻剂、滴眼液等。我院开发的复方盐酸西替利嗪凝胶剂，有效成分为盐酸西替利嗪和莫匹罗星，具有良好的抗过敏作用，副反应少且耐受性好，使用时易涂展和洗除、无油腻感、不妨碍皮肤正常功能，是值得推广的新型制剂。     

Comparative subcutaneous repeated toxicity study of enoxaparin products in rats

Enoxaparin is a low-molecular-weight heparin widely used for the prevention and treatment of thromboembolism. With the development of several enoxaparin biosimilars, real medical concerns about their safety and efficacy have been raised. This repeated dose toxicity study consists of preclinical toxicological evaluation of a biosimilar biological version of enoxaparin, the drug product “Enoxa”, compared to the enoxaparin reference drug product, “Lovenox”. Eighty white Wistar rats were treated with “Enoxa” versus the reference product, using subcutaneous therapeutic and toxic doses, varying from 3.5 to 100 mg/kg/day. Dose levels were adjusted and ultimately fixed at 3.5 and 20 mg/kg/day as therapeutic and toxic doses, respectively. A sodium chloride solution (0.9%) was used as the control, and the comparative study was conducted over periods of 14 and 28 days. Comparable effects were observed with few adverse effects at the administration dose of 20 mg/kg/day, for both enoxaparin biosimilar and reference products. Interestingly, mortality started only at high doses of 40 mg/kg/day and reached 25% at 100 mg/kg/day for both products. These results, as part of the recommended biosimilarity monitoring, demonstrated comparable toxicity profiles of “Enoxa” and “Lovenox” products in rats. Continuing investigation of biosimilarity on humans to confirm safety and efficacy is suggested.     

Evaluation of the developmental toxicity of isoeugenol in Sprague-Dawley (CD) rats.

Isoeugenol, used as a perfumery and flavoring agent, was evaluated for developmental toxicity. Timed-pregnant CD((R)) outbred albino Sprague-Dawley rats received isoeugenol (250, 500, or 1000 mg/kg/day) or vehicle (5 ml/kg corn oil) by gavage on gestational days (gd) 6 through 19. Maternal food and water consumption, body weight, and clinical signs were monitored at regular intervals throughout gestation. At termination (gd 20), confirmed-pregnant females (23-25 per group) were evaluated for gestational outcome. All live fetuses were weighed and examined for external malformations, and approximately 50% were evaluated for visceral or skeletal malformations. There were no treatment-related maternal deaths. Clinical signs associated with isoeugenol exposure included dose-related evidence of sedation and aversion to treatment (rooting behavior) in all isoeugenol groups, as well as an increased incidence of piloerection at >/= 500 mg/kg/day. Maternal body weight, weight gain, and gestational weight gain (corrected for gravid uterine weight) were reduced at all doses in a dose-related manner. Gravid uterine weight was significantly decreased at the mid and high doses, whereas maternal relative liver weight was increased at all three dose levels. During treatment (gd 6 to 20), maternal relative food consumption was significantly decreased at the high dose, and maternal relative water consumption was elevated in the mid- and high-dose groups. Prenatal mortality (resorption or late fetal death) was unaffected. At 1000 mg/kg/day, average fetal body weight/litter was decreased by 7% (male) or 9% (female). Incidences of fetal morphological anomalies were statistically equivalent among groups, except for an increase in the incidence of unossified sternebra(e), a skeletal variation, at the high dose. In summary, the maternal toxicity lowest observed adverse effect level (LOAEL) was 250 mg/kg/day based primarily on reduced body weight and gestational weight gain (corrected for gravid uterine weight), and the maternal toxicity no observed adverse effect level (NOAEL) was not determined in this study. The developmental toxicity LOAEL was 1000 mg/kg/day based on intrauterine growth retardation and mildly delayed skeletal ossification. The developmental toxicity NOAEL was 500 mg/kg/day.     

Evaluation of the developmental toxicity of formamide in Sprague-Dawley (CD) rats.

Timed-pregnant CD(R) outbred albino Sprague-Dawley rats received formamide (50, 100, or 200 mg/kg/day) or vehicle (5 ml/kg deionized/distilled water, po) on gestational days (gd) 6 through 19. Maternal food and water consumption (absolute and relative), body weight, and clinical signs were monitored at regular intervals throughout gestation. At termination (gd 20), confirmed-pregnant females (21-23 per group) were evaluated for clinical status and gestational outcome; live fetuses were examined for external, visceral, and skeletal malformations and variations. There were no maternal deaths and no dose-related clinical signs. At 200 mg/kg/day, maternal body weight on gd 20, weight gain, and gravid uterine weight were significantly decreased. Maternal weight gain, corrected for gravid uterine weight, liver weight (absolute or relative), and food and water consumption (absolute or relative), were not affected. Formamide did not affect prenatal viability or incidences of fetal malformations or variations. Average fetal body weight/litter was decreased at 100 and 200 mg/kg/day. Fetal body weight was affected at lower daily doses than in previously published studies, possibly due to the longer total exposure period and/or lack of a recovery period between cessation of exposure and termination. In summary, the maternal toxicity no-observed-adverse-effect level (NOAEL) was 100 mg/kg/day and the low observed adverse effect level (LOAEL) was 200 mg/kg/day under the conditions of this study. Similarly, the developmental toxicity NOAEL was 50 mg/kg/day and the LOAEL was 100 mg/kg/day.     

Embryo-fetal development toxicity of honokiol microemulsion intravenously administered to pregnant rats

The aim of this study was to evaluate the embryo-fetal development toxicity of honokiol microemulsion. The drug was intravenously injected to pregnant SD rats at dose levels of 0, 200, 600 and 2000 μg/kg/day from day 6–15 of gestation. All the pregnant animals were observed for body weights and any abnormal changes and subjected to caesarean-section on gestation day (GD) 20; all fetuses obtained from caesarean-section were assessed by external inspection, visceral and skeletal examinations. No treatment-related external alterations as well as visceral and skeletal malformations were observed in honokiol microemulsion groups. There was no significant difference in the body weight gain of the pregnant rats, average number of corpora lutea, and the gravid uterus weight in the honokiol microemulsion groups compared with the vehicle control group. However, at a dose level of 2000 μg/kg/day, there was embryo-fetal developmental toxicity observed, including a decrease in the body length and tail length of fetuses. In conclusion, the no-observed–adverse-effect level (NOAEL) of honokiol microemulsion is 600 μg/kg/day, 75 times above the therapeutic dosage and it has embryo-fetal toxicity at a dose level of 2000 μg/kg/day, which is approximately 250 times above the therapeutic dosage.     

人脐带间质干细胞对大鼠的免疫毒性研究

目的:研究人脐带间质干细胞(UCMSC)对Wistar大鼠的免疫毒性作用。方法:SPF级Wistar大鼠112只分为4组:溶媒组(给予溶媒5 ml/kg)、低剂量组(给予人UCMSC 1×107个/kg)、高剂量组(给予人UCMSC 5×107个/kg)和对照组(给予大鼠UCMSC 1×107个/kg)。每组28只大鼠,雌雄各14只。大鼠尾静脉注射给药,2周1次,共注射4次。给UCMSC后每周进行受体鼠临床移植物抗宿主病(GVHD)评分,末次注射UCMSC后1、13周检测血IgG、IgM含量,CD3+、CD4+、CD8+T细胞数量,并对大鼠淋巴结、胸腺、脾脏进行脏器系数计算和组织病理学检查。结果:给予UCMSC后,各组大鼠的GVHD评分值均为0。末次给予UCMSC后1周,低、高剂量组雌性大鼠IgG[(0.65±0.12)、(0.63±0.14)g/L]和IgM含量[(0.06±0.01)、(0.06±0.01)g/L]明显高于溶媒组雄性大鼠[(0.41±0.17)g/L、(0.04±0.01)g/L,P<0.01或P<0.05];高剂量组雄性大鼠IgM含量[(0.05±0.01)g/L]明显高于溶媒组雄性大鼠[(0.03±0.01)g/L,P<0.01];对照组雌性、雄性大鼠IgM[(0.06±0.02)、(0.05±0.02)g/L]也明显高于溶媒组(P<0.01或P<0.05)。末次给予UCMSC后13周,各剂量组雌、雄性大鼠IgG、IgM与溶媒组相比差异均无统计学意义(均P>0.05)。末次给予UCMSC后1周,低、高剂量组雌性大鼠的脾脏系数[分别为(0.274±0.016)%、(0.294±0.019)%]明显高于溶媒组[(0.232±0.012)%,P<0.01];高剂量组雄性大鼠的脾脏系数[(0.242±0.027)%]明显高于溶媒组[(0.202±0.012)%,P<0.01];对照组雌、雄性大鼠脾脏系数[分别为(0.261±0.019)%、(0.236±0.014)%]也明显高于溶媒组(P<0.05或P<0.01)。末次给予UCMSC后13周各组大鼠的脾脏和胸腺系数差异均无统计学意义(均P>0.05)。各组大鼠CD3+、CD4+、CD8+T细胞百分比及CD4+/CD8+比值均在正常范围内。各组大鼠胸腺、脾脏和肠系膜淋巴结组织病理学检查均未见明显异常。结论:人脐带间质干细胞可引起正常Wistar大鼠免疫球蛋白含量和脾脏系数的升高,该作用具有一过性和可逆性。     

坤灵丸对雌性大鼠生育力及胚胎-胎仔发育影响的研究

目的 评价坤灵丸对雌性大鼠的生育力及胚胎发育的影响。方法 在生育力及早期胚胎发育毒性研究中,每组25只雌性SD大鼠从交配前14 d开始,每天ig给予1次坤灵丸（0.875、1.750、3.500 g制剂/kg）或去离子水至妊娠第7天,评价雌鼠症状、体质量、摄食量、生殖能力和早期胚胎发育情况;在胚胎-胎仔发育毒性研究中,每组25只雌性SD大鼠从妊娠第6~15天每天ig给予坤灵丸（0.875、1.750、3.500 g制剂/kg）或去离子水1次,评价妊娠母鼠的症状、体质量、摄食量、生殖能力及胎仔的体质量、性别和外观、内脏、骨胳发育的畸形或变异。结果 在生育力及早期胚胎发育毒性研究和胚胎-胎仔发育毒性研究中,坤灵丸给药剂量达到3.500 g/kg时未产生任何药物相关的母体毒性和胚胎毒性。结论 本试验条件下,雌鼠生育力及胚胎发育毒性的安全剂量为3.500 g/kg,按照体质量计算,该剂量相当于人用最大临床使用剂量的43.2倍。     

In utero and lactation exposure of rats to 1R4F reference cigarette mainstream smoke: effect on prenatal and postnatal development.

Childhood cognitive and behavioral deficits have been reported in children born to mothers who smoked during pregnancy (Institute of Medicine, 2001). To investigate these potential responses in an animal model, reproductive and neurotoxicity evaluations based on the U.S. FDA guidelines were used to examine the offspring of male and female Sprague-Dawley rats exposed 2 h/day, 7 days/week by nose-only inhalation to whole mainstream smoke total particulate matter (TPM). Concentrations of 150, 300, or 600 mg/m(3) were used (males: 4 weeks prior to and during mating; and females: 2 weeks prior to mating, during mating, and through weaning at postnatal day 21). Sham air controls receiving filtered air and cage controls were also maintained. F(1) rats were weighed, identified by gender, examined for clinical signs of toxicity, and evaluated for neurobehavioral effects through postnatal day 65. Parental exposure was evidenced by smoke concentration-related increases in blood carboxyhemoglobin, nicotine, and cotinine and by characteristic cigarette smoke-related rodent respiratory tract histopathology. Also, nicotine and cotinine were found in F(1) blood through the lactation period. Maternal toxicity occurred at concentrations of 300 and 600 mg TPM/m(3), where total body weight gain during gestation was significantly (p < or = 0.05) decreased compared to sham controls. While smoke concentration-related decreases in F(1) birth weight and growth were evident (600 mg TPM/m(3), significantly different from sham at all time points), no adverse effects on developmental landmarks, including age at vaginal patency or preputial separation, motor activity, acoustic startle response or learning, and memory, were observed in the F(1) generation. This study confirmed that maternal exposure to high levels of mainstream cigarette smoke during gestation and lactation reduces birth weight and retards growth in the rat neonate; however, the developmental and neurobehavioral testing methodologies employed did not appear to be sensitive for an evaluation of neonatal behavioral effects following parental smoke exposure.     

One-generation reproductive toxicity study of epichlorohydrin in Sprague-Dawley rats

This study was conducted to evaluate the potential reproductive toxicity of epichlorohydrin in a one-generation reproduction toxicity study in compliance with OECD Test Guideline 415. Twenty-four male and female rats per group were given epichlorohydrin by gavage at 0, 3.3, 10, and 30?mg/kg/day. Males were dosed for 10 weeks prior to and during mating. Females were dosed from 2 weeks before mating to day 21 of lactation. At 30?mg/kg, an increase in the incidence of clinical signs (i.e., nasal discharge, soft feces, depression, and piloerection), gross necropsy findings (i.e., cystic pustule of the epididymidis and enlargement of the kidney) and the weights of heart, liver, and epididymidis, a decrease in male fertility, and an increased incidence of histopathological changes of the testis, epididymidis, and kidney were observed. At 10?mg/kg, decreased male fertility and increased kidney weight and incidence of histopathological changes of the epididymidis were found. There was a slight, but nonsignificant, reduction in the male fertility index at the dose of 3.3?mg/ kg. Under these experimental conditions, the lowest-observed-adverse-effect level of epichlorohydrin was 3.3?mg/kg/day for parent animals and their offspring. The absolute toxic dose for parent animals and their offspring was estimated to be 10?mg/kg/day.     

Repeated dose inhalation developmental toxicity study in rats exposed to cellulose insulation with boric acid additive

Abstract

Cellulose insulation (CI), a common building material, is a mixture of cellulose fibers and borates. Borates are approximately 20% of the product weight and act as a flame retardant. Given possible exposure to workers and consumers, an inhalation toxicity study was conducted following Organization for Economic Co-operation and Development (OECD) 414 for Prenatal Development Toxicity to evaluate if CI is a developmental toxicant. Pregnant female rats were exposed by nose-only inhalation to CI aerosols containing 20% boric acid for six h/day, from gestational day (GD) 6–19, and fetuses were evaluated for developmental parameters. Respirable CI was produced by grinding to produce respirable particles (MMAD 2.7–2.9?µm, geometric standard deviations (GSD) 1.9–2.6), which were then aerosolized. Target air concentrations were 15, 90, and 270?mg CI/m³. Controls were exposed to air only. Slight body weight reductions (average decrease <7% vs. control) were observed in male and female GD 20 fetuses in the mid and high dose groups. No embryo/fetal developmental toxicity or alterations in any other measured variable were reported at any dose. The no observed adverse effect level (NOAEL) for developmental outcomes was 270?mg/m³.     

A ninety-day toxicity study of semicarbazide hydrochloride in Wistar Hannover GALAS rats

A ninety-day toxicity study of semicarbazide hydrochloride (SEM-HCl) was conducted in male and female Wistar Hannover GALAS rats fed diet containing the compound at concentration of 0, 250, 500 and 1000 ppm. Suppression of body weight gain and food consumption was found in both sexes at 1000 ppm throughout the study. Enlargement and deformation of knee joints were obvious at 500 and 1000 ppm from week 3, together with deformation of the thorax and tail. Histopathologically, disarrangement of chondrocytes and fissures in the cartilage matrix were apparent at all doses tested in epiphyseal and articular cartilage. The severity of these lesions increased dose-dependently, accompanied by increased connective tissues and bone deformation at high doses. Additionally, compact bones at 1000 ppm became thin, suggesting loss of bone mass. In the thoracic aorta, the edges of elastic laminae became rough and the interlaminar spaces were altered from a fibrillar to a rod or globular appearance. No abnormalities were detected in any other organs. Taken together, toxicological effects of subchronic exposure to SEM-HCI were mainly observed in bone, cartilage and the aorta, with the no-observed-adverse-effect-level estimated from the present histopathological examination of less than 250 ppm in both sexes.     

Effects of low-level arsenic exposure on the developmental toxicity of anilofos in rats

In view of the increased use of anilofos for crop protection and ever increasing arsenic levels in drinking water in many countries, the coexistence of arsenic and anilofos in the environment is a reality and simultaneous exposure of humans and animals to these contaminants could be potentially hazardous. The aim of the present study was to examine whether coexposure to arsenic at the groundwater contamination level could alter the embryofetal toxicity of anilofos in rat model. Anilofos (100 mg kg(-1) day(-1)) and sodium arsenite (1 mg arsenic kg(-1) day(-1)) were administered by gavage either individually or in combination to the pregnant rats from day 6 to day 15 of gestation. Arsenic did not produce any significant effects either on maternal or fetal parameters at the given dose. Anilofos alone significantly decreased maternal weight gain, feed and water intakes, gravid uterine weights, number of live fetuses and fetal body weights and increased resorptions. There were increased incidences of gross, skeletal and visceral anomalies in the fetuses of anilofos-treated group. The main skeletal abnormality was increased intercostal space, while the visceral anomaly was an interventricular septal defect. Treatment with the combination of arsenic and anilofos significantly enhanced the fetal changes with much greater magnitude compared with the effects produced by anilofos alone. Anomalies such as midfacial cleft, exencephaly and anophthalmia were seen only in the fetuses of the combination group. The results show that anilofos interferes with embryofetal development and coexposure with arsenic at environmentally realistic concentrations produces additive or synergistic effects on the developmental toxicity of anilofos in rats.     

大鼠肌注伤寒Vi多糖蛋白结合疫苗的长期毒性

目的观察SD大鼠肌注伤寒Vi多糖蛋白结合疫苗的长期毒性.方法疫苗组大鼠(n=24)免疫3针,每次每只25/μg(以多糖量计),第1剂免疫后2周,第3剂免疫后1,3和5周各处死6只大鼠,测血常规、血清测特异性抗体、血清生化,并进行组织器官病检.结果疫苗组大鼠血液学白细胞分类出现可逆性的变化(P＜0.05,P＜0.01),但无明显毒性,血清特异性抗体阳性大鼠病理组织检查未见免疫毒理学损伤.结论伤寒Vi结合疫苗对大鼠有明显的免疫原性,但无明显毒性和局部刺激性.     

The effects of perinatal tebuconazole exposure on adult neurological, immunological, and reproductive function in rats.

Studies are under way to address concerns of potential persistent immunotoxic, reproductive, and neurotoxic effects of perinatal exposure to several pesticides. Tebuconazole, a triazole fungicide, was evaluated as part of this project. Sprague-Dawley dams were administered tebuconazole (0, 6, 20, or 60 mg/kg) by oral gavage daily from gestational day 14 to postnatal day (PND)7; the pups were then dosed daily at the same levels from PND7-42. Separate groups of rats were used for testing of immunological parameters, neurobehavioral testing using a screening battery of functional tests, and cognitive evaluations. Other groups of rats were evaluated for reproductive development and function, while yet others were sacrificed at the end of the dosing period for histological analyses of major organs systems, including neuropathological assessments. Pup viability and body weight were decreased in the highest dose group. There were no differences in the fertility indices in the exposed rats mated as adults. In the sheep RBC-immunized high-dose rats, spleen weights and cellularity were increased, and the ratio of cell types was altered compared to controls. There were, however, no biologically significant changes in the immune function of these rats. At necropsy on PND46 or 152, kidney, liver, and spleen weights were altered by tebuconazole treatment, but a dose-response relationship was not clear for most organs; only decreased kidney and increased liver weights were consistent in both sexes. Histological analyses were generally unremarkable outside of the brain. One month after the end of dosing, acquisition of learning the platform location in a water tank (i.e., Morris water maze) was impaired in the high-dose group; there were no differences in neuromuscular ability, motor activity, or swim speed to account for this finding. Furthermore, there was no effect on recall of the position during a free-swim trial. Neuropathological evaluations revealed pyknotic cells across hippocampal cell fields in animals of all tebuconazole treatment groups, with the highest incidence in the 20 and 60 mg/kg/day dose groups, coincident with cell loss within pyramidal cell layer of CA3-4 cell fields of the hippocampus and layer V of the neocortex. Thus, perinatal exposure to tebuconazole produced neurobehavioral deficits and neuropathology in rats, but did not alter immunological or reproductive function.