国家毒理学规划关于吸入异戊二烯对F344/N大鼠和B6C3F1小鼠毒性研究的技术报告(CAS No. 78-79-5)。

Toxicity report series Pub Date : 1995-01-01
Ronald Melnick
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Data from inhalation teratology studies of isoprene in rats and mice are also reported. In vitro genetic toxicity studies included assessments of mutagenicity in Salmonella typhimurium and sister chromatid exchanges and chromosomal aberrations in Chinese hamster ovary cells. In conjunction with the inhalation studies in mice, evaluations were also made of sister chromatid exchanges and chromosomal aberrations in bone marrow cells and micronuclei in peripheral blood of male mice exposed to isoprene for 12 days or 13 weeks. Target concentrations of isoprene in the inhalation chambers were 0, 438, 875, 1,750, 3,500, and 7,000 ppm in the 2-week studies; 0, 70, 220, 700, 2,200, and 7,000 ppm in the 13-week and stop-exposure studies; and 0, 280, 1,400, and 7,000 ppm in the teratology studies. In the 2-week studies, no changes related to chemical administration were observed in survival, body weight gain, clinical signs, hematologic or clinical chemistry parameters, or the incidence of gross or microscopic lesions in rats. In mice, there were no effects on survival; the mean body weight of males in the 7,000 ppm group was less than that of the controls. In mice, exposure to isoprene caused decreases in hematocrit values, hemoglobin concentrations, and erythrocyte counts, atrophy of the testis and thymus, cytoplasmic vacuolization of the liver, olfactory epithelial degeneration in the nasal cavity, and epithelial hyperplasia in the forestomach. Exposure to isoprene for 13 weeks produced no discernible toxicologic effects in rats. In the stop-exposure study, interstitial cell hyperplasia of the testis was observed in all male rats in the 7,000 ppm group after 6 months of exposure. Following the 6-month recovery period, male rats exposed to 700, 2,200, or 7,000 ppm isoprene had slightly greater incidences of interstitial cell adenomas of the testes than the controls. Exposure to isoprene for 13 weeks or 6 months produced no clear exposure-related effects on body weight gain in male or female mice; however, survival was decreased for male mice exposed to 7,000 ppm isoprene for 6 months. More notably, toxic and carcinogenic effects were induced at multiple organ sites in mice exposed to isoprene. After 6 months of exposure and 6 months of recovery, male mice exposed to 700 ppm or higher concentrations of isoprene had greater incidences of neoplasms of the liver (0 ppm, 7/30; 70 ppm, 3/30; 220 ppm, 7/29; 700 ppm, 15/30; 2,200 ppm, 18/30; 7,000 ppm, 17/28), lungs (2/30, 2/30, 1/29, 5/30, 10/30, 9/28), forestomach (0/30, 0/30, 0/30, 1/30, 4/30, 6/30), and harderian gland (2/30, 6/30, 4/30, 14/30, 13/30, 12/30) than the controls. In addition to the higher neoplasm incidences in male mice exposed to 700 ppm or greater, incidences of multiple neoplasms and/or neoplasms of greater malignancy were also higher than in the controls. Hematologic effects similar to those occurring in exposed mice in the 2-week study, plus greater mean cell volume values than in the controls, were observed after 24 days and after 13 weeks of exposure to isoprene. These hematologic effects, which were not accompanied by greater reticulocyte counts or a higher frequency of polychromatic erythrocytes than controls, were indicative of a nonresponsive, macrocytic anemia. In male mice in the stop-exposure study, partial hindlimb paralysis in the 7,000 ppm group and a dose-related decrease in grip strength were observed near the end of the 6-month exposure period. Other nonneoplastic effects in mice exposed to isoprene included spinal cord and sciatic nerve degeneration, skeletal muscle atrophy, degeneration of the olfactory epithelium, epithelial hyperplasia of the forestomach, increased estrous cycle length, testicular atrophy, and decreased epididymal weight, sperm head count, sperm concentration, and sperm motility. The inhalation teratology studies did not show maternal or developmental toxicity in Sprague-Dawley rats at exposures of up to 7,000 ppm isoprene; in CD-1&reg; Swiss mice, exposure to isoprene resulted in lower fetal weights and a higher percentage of fetuses per litter with supernumerary ribs. Isoprene was not mutagenic in Salmonella typhimurium and did not induce sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells with or without exogenous metabolic activation; however, in mice, isoprene induced increases in the frequency of sister chromatid exchanges in bone marrow cells and in the frequency of micronucleated erythrocytes in peripheral blood. These inhalation studies showed that isoprene caused toxic effects in the testis of rats and at multiple organ sites in mice. In F344/N rats, exposure to 7,000 ppm isoprene for 6 months caused an increase in the incidence of testicular interstitial cell hyperplasia, and after 6 months of recovery there was a marginally increased incidence of benign testicular adenomas that may have been related to isoprene administration. No-observable-adverse-effect levels (NOAELs) for isoprene-induced toxic lesions in mice were: 70 ppm for nonresponsive, macrocytic anemia, decreased hindlimb grip strength, olfactory epithelial degeneration, and decreases in epididymal weights, spermatid head counts, sperm concentration, and sperm motility; 220 ppm for forestomach epithelial hyperplasia; 700 ppm for increased estrous cycle length; and 2,200 ppm for testicular atrophy, sciatic nerve degeneration, and muscle atrophy. A NOAEL was not achieved for spinal cord degeneration (less than 70 ppm) or developmental toxicity (less than 280 ppm, based on lower body weights of female fetuses). In addition, the 6-month inhalation exposure plus 6-month recovery (stop-exposure) study provided clear evidence of carcinogenicity of isoprene in the liver, lung, forestomach, and harderian gland of mice. Because these studies involved exposures of male rats and male mice to isoprene for only 6 months, they do not necessarily reveal the full carcinogenic potential of isoprene in these species. Most of the toxic and carcinogenic effects seen with isoprene were also caused by inhalation exposure to 1,3-butadiene. Synonyms: isopentadiene; 2-methyl-1,3-butadiene; beta-methylbivinyl.</p>","PeriodicalId":23116,"journal":{"name":"Toxicity report series","volume":"31 ","pages":"1-G5"},"PeriodicalIF":0.0000,"publicationDate":"1995-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"NTP technical report on the toxicity studies of Isoprene (CAS No. 78-79-5) Administered by Inhalation to F344/N Rats and B6C3F1 Mice.\",\"authors\":\"Ronald Melnick\",\"doi\":\"\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Isoprene, the 2-methyl analogue of 1,3-butadiene, has a high production volume and is used largely in the manufacture of synthetic rubber. Isoprene is also the major endogenous hydrocarbon exhaled in human breath. Two-week and 13-week inhalation toxicology studies were conducted in male and female F344/N rats and B6C3F1 mice to characterize potential adverse effects of isoprene. Male rats and male mice were also exposed to isoprene vapors for 6 months followed by a 6-month recovery period (stop- exposure protocol) to determine if isoprene produces a carcinogenic response similar to that of 1,3-butadiene after intermediate exposure durations. In addition to histopathology, evaluations included clinical pathology, tissue glutathione analyses, forelimb and hindlimb grip strength analyses, and sperm motility and vaginal cytology. Data from inhalation teratology studies of isoprene in rats and mice are also reported. In vitro genetic toxicity studies included assessments of mutagenicity in Salmonella typhimurium and sister chromatid exchanges and chromosomal aberrations in Chinese hamster ovary cells. In conjunction with the inhalation studies in mice, evaluations were also made of sister chromatid exchanges and chromosomal aberrations in bone marrow cells and micronuclei in peripheral blood of male mice exposed to isoprene for 12 days or 13 weeks. 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Exposure to isoprene for 13 weeks produced no discernible toxicologic effects in rats. In the stop-exposure study, interstitial cell hyperplasia of the testis was observed in all male rats in the 7,000 ppm group after 6 months of exposure. Following the 6-month recovery period, male rats exposed to 700, 2,200, or 7,000 ppm isoprene had slightly greater incidences of interstitial cell adenomas of the testes than the controls. Exposure to isoprene for 13 weeks or 6 months produced no clear exposure-related effects on body weight gain in male or female mice; however, survival was decreased for male mice exposed to 7,000 ppm isoprene for 6 months. More notably, toxic and carcinogenic effects were induced at multiple organ sites in mice exposed to isoprene. After 6 months of exposure and 6 months of recovery, male mice exposed to 700 ppm or higher concentrations of isoprene had greater incidences of neoplasms of the liver (0 ppm, 7/30; 70 ppm, 3/30; 220 ppm, 7/29; 700 ppm, 15/30; 2,200 ppm, 18/30; 7,000 ppm, 17/28), lungs (2/30, 2/30, 1/29, 5/30, 10/30, 9/28), forestomach (0/30, 0/30, 0/30, 1/30, 4/30, 6/30), and harderian gland (2/30, 6/30, 4/30, 14/30, 13/30, 12/30) than the controls. In addition to the higher neoplasm incidences in male mice exposed to 700 ppm or greater, incidences of multiple neoplasms and/or neoplasms of greater malignancy were also higher than in the controls. Hematologic effects similar to those occurring in exposed mice in the 2-week study, plus greater mean cell volume values than in the controls, were observed after 24 days and after 13 weeks of exposure to isoprene. 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The inhalation teratology studies did not show maternal or developmental toxicity in Sprague-Dawley rats at exposures of up to 7,000 ppm isoprene; in CD-1&reg; Swiss mice, exposure to isoprene resulted in lower fetal weights and a higher percentage of fetuses per litter with supernumerary ribs. Isoprene was not mutagenic in Salmonella typhimurium and did not induce sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells with or without exogenous metabolic activation; however, in mice, isoprene induced increases in the frequency of sister chromatid exchanges in bone marrow cells and in the frequency of micronucleated erythrocytes in peripheral blood. These inhalation studies showed that isoprene caused toxic effects in the testis of rats and at multiple organ sites in mice. In F344/N rats, exposure to 7,000 ppm isoprene for 6 months caused an increase in the incidence of testicular interstitial cell hyperplasia, and after 6 months of recovery there was a marginally increased incidence of benign testicular adenomas that may have been related to isoprene administration. No-observable-adverse-effect levels (NOAELs) for isoprene-induced toxic lesions in mice were: 70 ppm for nonresponsive, macrocytic anemia, decreased hindlimb grip strength, olfactory epithelial degeneration, and decreases in epididymal weights, spermatid head counts, sperm concentration, and sperm motility; 220 ppm for forestomach epithelial hyperplasia; 700 ppm for increased estrous cycle length; and 2,200 ppm for testicular atrophy, sciatic nerve degeneration, and muscle atrophy. A NOAEL was not achieved for spinal cord degeneration (less than 70 ppm) or developmental toxicity (less than 280 ppm, based on lower body weights of female fetuses). 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引用次数: 0

摘要

异戊二烯是1,3-丁二烯的2-甲基类似物,产量很高,主要用于制造合成橡胶。异戊二烯也是人体呼出的主要内源性烃。对雄性和雌性F344/N大鼠和B6C3F1小鼠进行了为期两周和13周的吸入毒理学研究,以表征异戊二烯的潜在不良反应。雄性大鼠和雄性小鼠也暴露在异戊二烯蒸气中6个月,然后是6个月的恢复期(停止暴露方案),以确定异戊二烯在中等暴露时间后是否产生类似于1,3-丁二烯的致癌反应。除组织病理学外,评估还包括临床病理学、组织谷胱甘肽分析、前肢和后肢握力分析、精子活力和阴道细胞学。还报道了大鼠和小鼠吸入异戊二烯致畸学研究的数据。鼠伤寒沙门菌的体外遗传毒性研究包括鼠伤寒沙门菌的致突变性、姊妹染色单体交换和中国仓鼠卵巢细胞的染色体畸变。在对小鼠进行吸入研究的同时,还对暴露于异戊二烯12天或13周的雄性小鼠骨髓细胞和外周血微核中的姐妹染色单体交换和染色体畸变进行了评估。在为期2周的研究中,吸入室中异戊二烯的目标浓度分别为0、438、875、1750、3500和7000 ppm;13周和停止接触研究中的0,70,220,700,2200和7,000 PPM;致畸学研究中的0,280,1,400和7,000 PPM。在为期2周的研究中,在大鼠的生存、体重增加、临床体征、血液学或临床化学参数或肉眼或显微镜下病变发生率方面,没有观察到与化学给药相关的变化。在小鼠中,对存活率没有影响;7000 PPM组男性的平均体重低于对照组。在小鼠中,暴露于异戊二烯会导致红细胞压积值、血红蛋白浓度和红细胞计数下降,睾丸和胸腺萎缩,肝脏细胞质空泡化,鼻腔嗅上皮变性和前胃上皮增生。暴露于异戊二烯13周对大鼠没有明显的毒理学影响。在停止暴露研究中,暴露6个月后,7000 ppm组所有雄性大鼠的睾丸间质细胞增生。在6个月的恢复期后,暴露于700、2200或7000 ppm异戊二烯的雄性大鼠睾丸间质细胞腺瘤的发生率略高于对照组。暴露于异戊二烯13周或6个月对雄性或雌性小鼠的体重增加没有明显的影响;然而,暴露于7000 PPM异戊二烯6个月的雄性小鼠存活率下降。更值得注意的是,暴露于异戊二烯的小鼠在多个器官部位产生了毒性和致癌作用。暴露6个月和恢复6个月后,暴露于700 ppm或更高浓度异戊二烯的雄性小鼠肝脏肿瘤发生率更高(0 ppm, 7/30;70 ppm, 3/30;220 ppm, 7/29;700 ppm, 15/30;2,200 ppm, 18/30;7000 ppm, 17/28),肺(2/30,2/30,1/29,5/30,10/30,9/28),前胃(0/30,0/30,0/30,1/30,4/30,6/30),和哈德氏腺(2/30,6/30,4/30,14/30,13/30,12/30)。除了暴露于700ppm或更高浓度的雄性小鼠的肿瘤发病率更高外,多发性肿瘤和/或恶性程度更高的肿瘤的发病率也高于对照组。在暴露于异戊二烯24天和13周后,观察到的血液学影响与暴露于异戊二烯2周研究中小鼠的血液学影响相似,而且平均细胞体积值高于对照组。这些血液学上的影响,没有伴随着比对照组更高的网织红细胞计数或更高频率的多染红细胞,表明无反应性大细胞性贫血。在停止暴露研究中的雄性小鼠中,在6个月的暴露期结束时,观察到7000 ppm组的部分后肢瘫痪和剂量相关的握力下降。暴露于异戊二烯的小鼠的其他非肿瘤效应包括脊髓和坐骨神经变性、骨骼肌萎缩、嗅觉上皮变性、前胃上皮增生、动情周期长度增加、睾丸萎缩、附睾重量、精子头数、精子浓度和精子活力降低。吸入致畸学研究并未显示暴露于高达7000 ppm异戊二烯的Sprague-Dawley大鼠的母体或发育毒性;在CD-1&reg;瑞士小鼠,暴露于异戊二烯导致胎儿体重较低,每胎胎儿多肋的比例较高。 异戊二烯对鼠伤寒沙门菌无诱变作用,在有无外源性代谢激活的情况下均不会引起中国仓鼠卵巢细胞姊妹染色单体交换或染色体畸变;然而,在小鼠中,异戊二烯诱导骨髓细胞姐妹染色单体交换频率和外周血微核红细胞频率增加。这些吸入研究表明异戊二烯在大鼠睾丸和小鼠多个器官部位引起毒性作用。在F344/N大鼠中,暴露于7000 ppm异戊二烯6个月导致睾丸间质细胞增生的发生率增加,恢复6个月后,良性睾丸腺瘤的发生率略有增加,这可能与异戊二烯的使用有关。异戊二烯引起的小鼠毒性病变的无观察不良反应水平(NOAELs)为:无反应、大细胞性贫血、后肢握力下降、嗅觉上皮变性、附睾重量、精子头数、精子浓度和精子活力下降的70 ppm;前胃上皮增生220 PPM;700 PPM增加发情周期长度;2200 PPM用于睾丸萎缩,坐骨神经退化和肌肉萎缩。脊髓变性(小于70 ppm)或发育毒性(小于280 ppm,基于女性胎儿较低的体重)未达到NOAEL。此外,6个月的吸入暴露加6个月的恢复(停止暴露)研究提供了异戊二烯对小鼠肝脏、肺、前胃和硬腺的致癌性的明确证据。由于这些研究只涉及雄性大鼠和雄性小鼠暴露于异戊二烯6个月,因此它们不一定能揭示异戊二烯在这些物种中的全部致癌潜力。异戊二烯的大多数毒性和致癌作用也是由吸入接触1,3-丁二烯引起的。同义词:isopentadiene;三丁基2-methyl-1;beta-methylbivinyl。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
NTP technical report on the toxicity studies of Isoprene (CAS No. 78-79-5) Administered by Inhalation to F344/N Rats and B6C3F1 Mice.

Isoprene, the 2-methyl analogue of 1,3-butadiene, has a high production volume and is used largely in the manufacture of synthetic rubber. Isoprene is also the major endogenous hydrocarbon exhaled in human breath. Two-week and 13-week inhalation toxicology studies were conducted in male and female F344/N rats and B6C3F1 mice to characterize potential adverse effects of isoprene. Male rats and male mice were also exposed to isoprene vapors for 6 months followed by a 6-month recovery period (stop- exposure protocol) to determine if isoprene produces a carcinogenic response similar to that of 1,3-butadiene after intermediate exposure durations. In addition to histopathology, evaluations included clinical pathology, tissue glutathione analyses, forelimb and hindlimb grip strength analyses, and sperm motility and vaginal cytology. Data from inhalation teratology studies of isoprene in rats and mice are also reported. In vitro genetic toxicity studies included assessments of mutagenicity in Salmonella typhimurium and sister chromatid exchanges and chromosomal aberrations in Chinese hamster ovary cells. In conjunction with the inhalation studies in mice, evaluations were also made of sister chromatid exchanges and chromosomal aberrations in bone marrow cells and micronuclei in peripheral blood of male mice exposed to isoprene for 12 days or 13 weeks. Target concentrations of isoprene in the inhalation chambers were 0, 438, 875, 1,750, 3,500, and 7,000 ppm in the 2-week studies; 0, 70, 220, 700, 2,200, and 7,000 ppm in the 13-week and stop-exposure studies; and 0, 280, 1,400, and 7,000 ppm in the teratology studies. In the 2-week studies, no changes related to chemical administration were observed in survival, body weight gain, clinical signs, hematologic or clinical chemistry parameters, or the incidence of gross or microscopic lesions in rats. In mice, there were no effects on survival; the mean body weight of males in the 7,000 ppm group was less than that of the controls. In mice, exposure to isoprene caused decreases in hematocrit values, hemoglobin concentrations, and erythrocyte counts, atrophy of the testis and thymus, cytoplasmic vacuolization of the liver, olfactory epithelial degeneration in the nasal cavity, and epithelial hyperplasia in the forestomach. Exposure to isoprene for 13 weeks produced no discernible toxicologic effects in rats. In the stop-exposure study, interstitial cell hyperplasia of the testis was observed in all male rats in the 7,000 ppm group after 6 months of exposure. Following the 6-month recovery period, male rats exposed to 700, 2,200, or 7,000 ppm isoprene had slightly greater incidences of interstitial cell adenomas of the testes than the controls. Exposure to isoprene for 13 weeks or 6 months produced no clear exposure-related effects on body weight gain in male or female mice; however, survival was decreased for male mice exposed to 7,000 ppm isoprene for 6 months. More notably, toxic and carcinogenic effects were induced at multiple organ sites in mice exposed to isoprene. After 6 months of exposure and 6 months of recovery, male mice exposed to 700 ppm or higher concentrations of isoprene had greater incidences of neoplasms of the liver (0 ppm, 7/30; 70 ppm, 3/30; 220 ppm, 7/29; 700 ppm, 15/30; 2,200 ppm, 18/30; 7,000 ppm, 17/28), lungs (2/30, 2/30, 1/29, 5/30, 10/30, 9/28), forestomach (0/30, 0/30, 0/30, 1/30, 4/30, 6/30), and harderian gland (2/30, 6/30, 4/30, 14/30, 13/30, 12/30) than the controls. In addition to the higher neoplasm incidences in male mice exposed to 700 ppm or greater, incidences of multiple neoplasms and/or neoplasms of greater malignancy were also higher than in the controls. Hematologic effects similar to those occurring in exposed mice in the 2-week study, plus greater mean cell volume values than in the controls, were observed after 24 days and after 13 weeks of exposure to isoprene. These hematologic effects, which were not accompanied by greater reticulocyte counts or a higher frequency of polychromatic erythrocytes than controls, were indicative of a nonresponsive, macrocytic anemia. In male mice in the stop-exposure study, partial hindlimb paralysis in the 7,000 ppm group and a dose-related decrease in grip strength were observed near the end of the 6-month exposure period. Other nonneoplastic effects in mice exposed to isoprene included spinal cord and sciatic nerve degeneration, skeletal muscle atrophy, degeneration of the olfactory epithelium, epithelial hyperplasia of the forestomach, increased estrous cycle length, testicular atrophy, and decreased epididymal weight, sperm head count, sperm concentration, and sperm motility. The inhalation teratology studies did not show maternal or developmental toxicity in Sprague-Dawley rats at exposures of up to 7,000 ppm isoprene; in CD-1® Swiss mice, exposure to isoprene resulted in lower fetal weights and a higher percentage of fetuses per litter with supernumerary ribs. Isoprene was not mutagenic in Salmonella typhimurium and did not induce sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells with or without exogenous metabolic activation; however, in mice, isoprene induced increases in the frequency of sister chromatid exchanges in bone marrow cells and in the frequency of micronucleated erythrocytes in peripheral blood. These inhalation studies showed that isoprene caused toxic effects in the testis of rats and at multiple organ sites in mice. In F344/N rats, exposure to 7,000 ppm isoprene for 6 months caused an increase in the incidence of testicular interstitial cell hyperplasia, and after 6 months of recovery there was a marginally increased incidence of benign testicular adenomas that may have been related to isoprene administration. No-observable-adverse-effect levels (NOAELs) for isoprene-induced toxic lesions in mice were: 70 ppm for nonresponsive, macrocytic anemia, decreased hindlimb grip strength, olfactory epithelial degeneration, and decreases in epididymal weights, spermatid head counts, sperm concentration, and sperm motility; 220 ppm for forestomach epithelial hyperplasia; 700 ppm for increased estrous cycle length; and 2,200 ppm for testicular atrophy, sciatic nerve degeneration, and muscle atrophy. A NOAEL was not achieved for spinal cord degeneration (less than 70 ppm) or developmental toxicity (less than 280 ppm, based on lower body weights of female fetuses). In addition, the 6-month inhalation exposure plus 6-month recovery (stop-exposure) study provided clear evidence of carcinogenicity of isoprene in the liver, lung, forestomach, and harderian gland of mice. Because these studies involved exposures of male rats and male mice to isoprene for only 6 months, they do not necessarily reveal the full carcinogenic potential of isoprene in these species. Most of the toxic and carcinogenic effects seen with isoprene were also caused by inhalation exposure to 1,3-butadiene. Synonyms: isopentadiene; 2-methyl-1,3-butadiene; beta-methylbivinyl.

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