NTP technical report on the toxicity studies of Pesticide/Fertilizer Mixtures Administered in Drinking Water to F344/N Rats and B6C3F1 Mice.

Toxicity report series Pub Date : 1993-08-01
R. Yang
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This report focuses primarily on 26-week toxicity studies describing histopathology, clinical pathology, neurobehavior/neuropathology, and reproductive system effects. The genetic toxicity of the mixtures was assessed by determining the frequency of micronuclei in peripheral blood of mice and evaluating micronuclei and sister chromatid exchanges in splenocytes from female mice and male rats. Additional studies with these mixtures that are briefly reviewed in this report include teratology studies with Sprague-Dawley rats and continuous breeding studies with CD-1 Swiss mice. In 26-week drinking water studies of the California and the Iowa mixtures, all rats (10 per sex and group) survived to the end of the studies, and there were no significant effects on body weight gains. Water consumption was not affected by the pesticide/fertilizer contaminants, and there were no clinical signs of toxicity or neurobehavioral effects as measured by a functional observational battery, motor activity evaluations, thermal sensitivity evaluations, and startle response. There were no clear adverse effects noted in clinical pathology (including serum cholinesterase activity), organ weight, reproductive system, or histopathologic evaluations, although absolute and relative liver weights were marginally increased with increasing exposure concentration in both male and female rats consuming the Iowa mixture. In 26-week drinking water studies in mice, one male receiving the California mixture at 100x died during the study, and one control female and one female in the 100x group in the Iowa mixture study also died early. It could not be determined if the death of either of the mice in the 100x groups was related to consumption of the pesticide/fertilizer mixtures. 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Abstract

Toxicity studies were performed with pesticide and fertilizer mixtures representative of groundwater contamination found in California and Iowa. The California mixture was composed of aldicarb, atrazine, 1,2-dibromo-3-chloropropane, 1,2- dichloropropane, ethylene dibromide, simazine, and ammonium nitrate. The Iowa mixture contained alachlor, atrazine, cyanazine, metolachlor, metribuzin, and ammonium nitrate. The mixtures were administered in drinking water (with 512 ppm propylene glycol) to F344/N rats and B6C3F1 mice of each sex at concentrations ranging from 0.1x to 100x, where 1x represented the median concentrations of the individual chemicals found in studies of groundwater contamination from normal agricultural activities. This report focuses primarily on 26-week toxicity studies describing histopathology, clinical pathology, neurobehavior/neuropathology, and reproductive system effects. The genetic toxicity of the mixtures was assessed by determining the frequency of micronuclei in peripheral blood of mice and evaluating micronuclei and sister chromatid exchanges in splenocytes from female mice and male rats. Additional studies with these mixtures that are briefly reviewed in this report include teratology studies with Sprague-Dawley rats and continuous breeding studies with CD-1 Swiss mice. In 26-week drinking water studies of the California and the Iowa mixtures, all rats (10 per sex and group) survived to the end of the studies, and there were no significant effects on body weight gains. Water consumption was not affected by the pesticide/fertilizer contaminants, and there were no clinical signs of toxicity or neurobehavioral effects as measured by a functional observational battery, motor activity evaluations, thermal sensitivity evaluations, and startle response. There were no clear adverse effects noted in clinical pathology (including serum cholinesterase activity), organ weight, reproductive system, or histopathologic evaluations, although absolute and relative liver weights were marginally increased with increasing exposure concentration in both male and female rats consuming the Iowa mixture. In 26-week drinking water studies in mice, one male receiving the California mixture at 100x died during the study, and one control female and one female in the 100x group in the Iowa mixture study also died early. It could not be determined if the death of either of the mice in the 100x groups was related to consumption of the pesticide/fertilizer mixtures. Water consumption and body weight gains were not affected in these studies, and no signs of toxicity were noted in clinical observations or in neurobehavioral assessments. No clear adverse effects were noted in clinical pathology, reproductive system, organ weight, or histopathologic evaluations of exposed mice. The pesticide/fertilizer mixtures, when tested over a concentration range similar to that used in the 26-week studies, were found to have no effects in teratology studies or in a continuous breeding assay examining reproductive and developmental toxicity. The California and Iowa pesticide mixtures were tested for induction of micronuclei in peripheral blood erythrocytes of female mice. Results of tests with the California mixture were negative. Significant increases in micronucleated normochromatic erythrocytes were seen at the two-highest concentrations (10x and 100x) of the Iowa mixture, but the increases were within the normal range of micronuclei in historical control animals. Splenocytes of male rats and female mice exposed to these mixtures were examined for micronucleus and sister chromatid exchange frequencies. Sister chromatid exchange frequencies were marginally increased in rats and mice receiving the California mixture, but neither species exhibited increased frequencies of micronucleated splenocytes. None of these changes were considered to have biological importance. In summary, studies of potential toxicity associated with the consumption of mixtures of pesticides and a fertilizer representative of groundwater contamination in agriculturative of groundwater contamination in agricultural areas of Iowa and California failed to demonstrate any significant adverse effects in rats or mice receiving the mixtures in drinking water at concentrations as high as 100 times the median concentrations of the individual chemicals determined by groundwater surveys. NOTE: These studies were supported in part by funds from the Comprehensive Environmental Response, Compensation, and Liability Act trust fund (Superfund) by an interagency agreement with the Agency for Toxic Substances and Disease Registry, U.S. Public Health Service.

国家毒理学规划关于饮用水中施用农药/肥料混合物对F344/N大鼠和B6C3F1小鼠毒性研究的技术报告。
对加利福尼亚和爱荷华州发现的具有代表性的地下水污染的农药和肥料混合物进行了毒性研究。加州混合物由涕灭威、阿特拉津、1,2-二溴-3-氯丙烷、1,2-二氯丙烷、二溴乙烯、辛嗪和硝酸铵组成。爱荷华州的混合物含有甲草胺、阿特拉津、氰嗪、甲草胺、甲曲霉嗪和硝酸铵。这些混合物在饮用水中(含512 ppm丙二醇)以0.1倍至100倍的浓度给F344/N大鼠和B6C3F1雌雄小鼠,其中1x代表在正常农业活动引起的地下水污染研究中发现的每种化学物质的中位数浓度。本报告主要关注26周的毒性研究,描述组织病理学、临床病理学、神经行为/神经病理学和生殖系统的影响。通过测定小鼠外周血微核频率和雌雄大鼠脾细胞微核和姐妹染色单体交换来评估混合物的遗传毒性。本报告简要回顾了这些混合物的其他研究,包括对Sprague-Dawley大鼠的致畸学研究和对CD-1瑞士小鼠的连续育种研究。在为期26周的加利福尼亚和爱荷华混合饮用水研究中,所有老鼠(每性别和每组10只)都存活到研究结束,并且对体重增加没有显著影响。用水量不受农药/肥料污染物的影响,通过功能观察电池、运动活动评估、热敏性评估和惊吓反应测量,没有毒性或神经行为影响的临床迹象。在临床病理学(包括血清胆碱酯酶活性)、器官重量、生殖系统或组织病理学评估中没有发现明显的不良反应,尽管在摄入爱荷华州混合物的雄性和雌性大鼠中,肝脏的绝对和相对重量随着暴露浓度的增加而轻微增加。在为期26周的小鼠饮用水研究中,一只雄性小鼠在研究期间死亡,一只对照雌性小鼠和一只雌性小鼠在爱荷华州混合物研究中过早死亡。无法确定100x组中任何一只小鼠的死亡是否与食用农药/肥料混合物有关。在这些研究中,水的消耗和体重增加没有受到影响,在临床观察或神经行为评估中也没有发现毒性迹象。暴露小鼠的临床病理、生殖系统、器官重量或组织病理学评估均未发现明显的不良反应。在与26周研究中使用的浓度范围相似的浓度范围内对农药/肥料混合物进行测试时,在致畸学研究或检查生殖和发育毒性的连续育种试验中发现没有影响。研究了加州和爱荷华混合农药对雌鼠外周血红细胞微核的诱导作用。加州混合物的测试结果为阴性。在爱荷华混合物的两个最高浓度(10倍和100倍)下,微核正染色红细胞显著增加,但在历史对照动物中,微核增加在正常范围内。暴露于这些混合物的雄性大鼠和雌性小鼠的脾细胞检测微核和姐妹染色单体交换频率。姐妹染色单体交换频率在接受加州混合物的大鼠和小鼠中略有增加,但两个物种都没有表现出微核脾细胞的频率增加。这些变化都不被认为具有生物学上的重要性。总而言之,对农药和化肥混合物的潜在毒性的研究表明,在爱荷华州和加利福尼亚州的农业地区,地下水污染代表了地下水污染的农业地区,在饮用浓度高达地下水调查确定的个别化学品中位数浓度100倍的混合物的大鼠或小鼠中,没有发现任何显著的不良影响。注:这些研究部分由综合环境反应、赔偿和责任法案信托基金(超级基金)提供资金支持,并与美国公共卫生服务局有毒物质和疾病登记处达成机构间协议。
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