Toxicology and carcinogenesis studies of sodium dichromate dihydrate (Cas No. 7789-12-0) in F344/N rats and B6C3F1 mice (drinking water studies).
Toxicology and carcinogenesis studies of sodium dichromate dihydrate (Cas No. 7789-12-0) in F344/N rats and B6C3F1 mice (drinking water studies).
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2008
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未标记的二水合重铬酸钠是饮用水源中发现的多种含有六价铬 (Cr VI) 的无机化合物之一，是电镀操作、皮革鞣制和纺织品制造等各种工业过程中产生的污染物。由于缺乏足够的关于口服六价铬的毒性和致癌性的实验数据，并且在饮用水源供应中发现了六价铬，加州国会代表团、加州环境保护局和加州卫生服务部提名六价铬进入国家毒理学计划进行研究。 F344/N 大鼠和 B6C3F1、BALB/c 和 am3-C57BL/6 小鼠的 3 个月毒性研究结果已在 NTP 毒性报告 72 中报道。在本研究中，雄性和雌性 F344/N 大鼠和 B6C3F1 小鼠在饮用水中暴露于二水合重铬酸钠（纯度大于 99.7%）2 年。大鼠为期 2 年的研究：50 只雄性和 50 只雌性大鼠组暴露于含有 0、14.3、57.3、172 或 516 mg/L 二水合重铬酸钠（相当于 0、5、20、60 或 180 mg/L 铬）的饮用水，持续 2 年（相当于平均每日剂量约 0.6、男性为 2.2、6 或 17 毫克二水合重铬酸钠/公斤体重，女性为 0.7、2.7、7 或 20 毫克/公斤体重。暴露组的存活率与对照组相似。在整个研究过程中，516 mg/L 的雄性和雌性的平均体重低于对照组。体重较低的部分原因是所配水的适口性较差以及随之而来的水消耗量的减少。在整个研究过程中，172 mg/L 和 516 mg/L 大鼠的饮水量低于对照组。暴露于二水合重铬酸钠会导致大鼠出现小细胞低色素性贫血，但随着时间的推移会有所改善。接触二水合重铬酸钠会导致口腔粘膜和舌头上的鳞状上皮发生肿瘤。 516mg/L雄性和雌性大鼠口腔黏膜鳞状细胞癌的发生率显着高于对照组。 172 mg/L 女性的发病率超出了饮用水研究和所有给药途径的历史控制范围。 516 mg/L雄性和雌性大鼠口腔粘膜或舌鳞状细胞乳头状瘤或鳞状细胞癌（合并）的发生率显着高于对照组。在暴露于 57.3 mg/L 或更高浓度的男性和女性中观察到与暴露浓度相关的非肿瘤性肝脏病变。这些包括组织细胞浸润、慢性炎症、脂肪变（女性）、嗜碱性病灶（男性）和透明细胞病灶（女性）。暴露于 57.3 mg/L 或更高浓度的男性和/或女性的小肠（十二指肠）、肠系膜淋巴结和胰腺淋巴结中组织细胞浸润的发生率也增加。小鼠为期 2 年的研究：50 只雄性小鼠组暴露于含有 0、14.3、28.6、85.7 或 257.4 mg/L 二水合重铬酸钠（相当于 0、5、10、30 或 90 mg/L 铬）的饮用水，持续 2 年（相当于平均每日剂量约 1.1、 2.6、7 或 17 毫克二水合重铬酸钠/公斤体重）。每组 50 只雌性小鼠连续 2 年接触含有 0、14.3、57.3、172 或 516 mg/L 二水合重铬酸钠（相当于 0、5、20、60 或 180 mg/L 铬）的饮用水（相当于平均日剂量约为 1.1、3.9、9 或 25 mg/kg）。暴露组的存活率与对照组相似。从研究的第 2 个月到第 6 个月，257.4 mg/L 雄性的平均体重低于对照组，但到研究结束时，257.4 mg/L 雄性的平均体重仅略低于对照组。从研究的第 3 个月到第 12 个月，172 mg/L 的女性平均体重低于对照组，从第 2 个月到研究结束，516 mg/L 的女性平均体重低于对照组。到研究结束时，172 mg/L 的女性平均体重比对照组低 8%，516 mg/L 的女性平均体重比对照组低 15%。体重较低的部分原因是所配水的适口性较差以及随之而来的水消耗量的减少。在整个研究过程中，85.7 和 257.4 mg/L 的雄性以及 172 和 516 mg/L 的雌性的耗水量低于对照组。暴露的小鼠出现了与治疗相关的小红细胞增多症；小鼠受到的影响比大鼠小。在暴露组的雄性和雌性小鼠中，小肠（十二指肠、空肠或回肠）肿瘤的发生率增加。 257.4 mg/L的男性和172、516 mg/L的女性十二指肠腺瘤的发病率显着高于对照组。 516mg/L的女性十二指肠癌的发病率显着增加。与对照组相比，516 mg/L 的女性空肠腺瘤的发生率显着增加。当小肠所有部位的腺瘤和癌的发病率合并时，与对照组相比，男性85.7和257.4 mg/L以及女性172和516 mg/L的发病率显着增加。 57.3 mg/L 女性的发病率超出了饮用水研究和所有给药途径的历史控制范围。所有暴露组的雄性和雌性小鼠十二指肠弥漫性上皮增生的发生率均显着增加。 85.7和257.4 mg/L的男性以及172和516 mg/L的女性十二指肠组织细胞浸润的发生率显着增加。在空肠中，516mg/L雌性中弥漫性上皮增生和组织细胞浸润的发生率显着增加。所有女性暴露组中肝脏组织细胞浸润的发生率、男性和女性所有暴露组中肠系膜淋巴结的发生率以及85.7和257.4mg/L男性和172和516mg/L女性胰腺淋巴结的组织细胞浸润发生率均显着增加。组织分布研究表明，总铬浓度随着暴露浓度和暴露时间的增加而增加。结论 在这些为期 2 年的饮用水研究条件下，基于口腔鳞状细胞肿瘤发生率的增加，有明确的证据表明二水合重铬酸钠对雄性和雌性 F344/N 大鼠具有致癌活性。根据小肠（十二指肠、空肠或回肠）肿瘤发生率的增加，有明确的证据表明二水合重铬酸钠对雄性和雌性 B6C3F1 小鼠具有致癌活性。接触二水合重铬酸钠会导致大鼠和小鼠的肝脏、小肠、胰腺和肠系膜淋巴结出现组织细胞浸润，并导致雄性和雌性小鼠的小肠出现弥漫性上皮增生。
UNLABELLED Sodium dichromate dihydrate is one of a number of inorganic compounds containing hexavalent chromium (Cr VI) found in drinking water source supplies as a contaminant resulting from various industrial processes including electroplating operations, leather tanning, and textile manufacturing. Because of the lack of adequate experimental data on the toxicity and carcinogenicity of hexavalent chromium ingested orally and because hexavalent chromium has been found in drinking water source supplies, the California Congressional Delegation, the California Environmental Protection Agency, and the California Department of Health Services nominated hexavalent chromium to the National Toxicology Program for study. Results of 3 month toxicity studies in F344/N rats and B6C3F1, BALB/c, and am3-C57BL/6 mice were reported earlier in NTP Toxicity Report 72. In the current study, male and female F344/N rats and B6C3F1 mice were exposed to sodium dichromate dihydrate (greater than 99.7% pure) in drinking water for 2 years. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to drinking water containing 0, 14.3, 57.3, 172, or 516 mg/L sodium dichromate dihydrate (equivalent to 0, 5, 20, 60, or 180 mg/L chromium) for 2 years (equivalent to average daily doses of approximately 0.6, 2.2, 6, or 17 mg sodium dichromate dihydrate/kg body weight for males and 0.7, 2.7, 7, or 20 mg/kg for females). Survival of exposed groups was similar to that of the control groups. Mean body weights of 516 mg/L males and females were less than those of the controls throughout the study. The lower body weights were partly attributed to poor palatability of the dosed water and consequent reductions in water consumption. Water consumption by 172 and 516 mg/L rats was less than that by the controls throughout the study. Exposure to sodium dichromate dihydrate caused a microcytic hypochromic anemia in rats that ameliorated with time. Exposure to sodium dichromate dihydrate resulted in the development of neoplasms of the squamous epithelium that lines the oral mucosa and tongue. The incidences of squamous cell carcinoma in the oral mucosa of 516 mg/L male and female rats were significantly greater than those in the controls. The incidence in 172 mg/L females exceeded the historical control ranges for drinking water studies and for all routes of administration. The incidences of squamous cell papilloma or squamous cell carcinoma (combined) of the oral mucosa or tongue of 516 mg/L male and female rats were significantly greater than those in the controls. Exposure concentration-related nonneoplastic liver lesions were observed in males and females exposed to 57.3 mg/L or greater. These included histiocytic cellular infiltration, chronic inflammation, fatty change (females), basophilic focus (males), and clear cell focus (females). Increased incidences of histiocytic cellular infiltration also occurred in the small intestine (duodenum), mesenteric lymph node, and pancreatic lymph node of males and/or females exposed to 57.3 mg/L or greater. 2-YEAR STUDY IN MICE: Groups of 50 male mice were exposed to drinking water containing 0, 14.3, 28.6, 85.7, or 257.4 mg/L sodium dichromate dihydrate (equivalent to 0, 5, 10, 30, or 90 mg/L chromium) for 2 years (equivalent to average daily doses of approximately 1.1, 2.6, 7, or 17 mg sodium dichromate dihydrate/kg body weight). Groups of 50 female mice were exposed to drinking water containing 0, 14.3, 57.3, 172, or 516 mg/L sodium dichromate dihydrate (equivalent to 0, 5, 20, 60, or 180 mg/L chromium) for 2 years (equivalent to average daily doses of approximately 1.1, 3.9, 9, or 25 mg/kg). Survival of exposed groups was similar to that of the control groups. Mean body weights of 257.4 mg/L males were less than those of controls from months 2 through 6 of the study, but by the end of the study, the mean body weight of 257.4 mg/L males was only slightly less than that of the control group. Mean body weights of 172 mg/L females were less than those of the controls from months 3 through 12 of the study, and mean body weights of 516 mg/L females were less than those of the controls from month 2 until the end of the study. By the end of the study, the mean body weight of 172 mg/L females was 8% less than that of the controls, and the mean body weight of 516 mg/L females was 15% less than that of the controls. The lower body weights were partly attributed to poor palatability of the dosed water and consequent reductions in water consumption. Water consumption by 85.7 and 257.4 mg/L males and 172 and 516 mg/L females was less than that by the controls throughout the study. A treatment-related microcytosis occurred in exposed mice; the mice were less affected than the rats. The incidences of neoplasms of the small intestine (duodenum, jejunum, or ileum) were increased in exposed groups of male and female mice. The incidences of adenoma of the duodenum in 257.4 mg/L males and 172 and 516 mg/L females were significantly greater than those in the controls. The incidence of carcinoma of the duodenum was significantly increased in 516 mg/L females. The incidence of adenoma of the jejunum in 516 mg/L females was significantly increased compared to that in the controls. When the incidences of adenoma and carcinoma were combined for all sites of the small intestine, the incidences were significantly increased in 85.7 and 257.4 mg/L males and 172 and 516 mg/L females compared to those in the controls. The incidences in 57.3 mg/L females exceeded the historical control ranges for drinking water studies and for all routes of administration. The incidences of diffuse epithelial hyperplasia were significantly increased in the duodenum of all exposed groups of male and female mice. The incidences of histiocytic cellular infiltration were significantly increased in the duodenum of 85.7 and 257.4 mg/L males and in 172 and 516 mg/L females. In the jejunum, the incidences of diffuse epithelial hyperplasia and histiocytic cellular infiltration were significantly increased in 516 mg/L females. The incidences of histiocytic cellular infiltration of the liver in all exposed groups of females, of the mesenteric lymph node in all exposed groups of males and females, and of the pancreatic lymph node of 85.7 and 257.4 mg/L males and 172 and 516 mg/L females were significantly increased. Tissue distribution studies showed that total chromium concentrations tended to increase with increasing exposure concentration and duration of exposure. CONCLUSIONS Under the conditions of these 2-year drinking water studies, there was clear evidence of carcinogenic activity of sodium dichromate dihydrate in male and female F344/N rats based on increased incidences of squamous cell neoplasms of the oral cavity. There was clear evidence of carcinogenic activity of sodium dichromate dihydrate in male and female B6C3F1 mice based on increased incidences of neoplasms of the small intestine (duodenum, jejunum, or ileum). Exposure to sodium dichromate dihydrate resulted in histiocytic cellular infiltration in the liver, small intestine, and pancreatic and mesenteric lymph nodes of rats and mice and diffuse epithelial hyperplasia in the small intestine of male and female mice.