Arnold Lora L, Eldan Michal, Nyska Abraham, van Gemert Marcia, Cohen Samuel M
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
Toxicology. 2006 Jun 1;223(1-2):82-100. doi: 10.1016/j.tox.2006.03.013. Epub 2006 Mar 29.
Dimethylarsinic acid (DMA(V), cacodylic acid), a foliar herbicide, was administered in the diet to B6C3F1 mice (at dose levels of 0, 8, 40, 200, and 500 ppm) and to F344 rats (at dose levels of 0, 2, 10, 40, and 100 ppm) for 2 years, according to US EPA guidelines. In mice, there were no treatment-related tumors observed at any site. Treatment-related progressive glomerulonephropathy and nephrocalcinosis were observed in the kidneys in both sexes. The incidence of vacuolation of the epithelium in the urinary bladder was increased in both sexes, but was not associated with cytotoxicity, necrosis or hyperplasia. Based on non-neoplastic lesions found in the urinary bladder, the NOEL for mice was assessed to be 40 ppm in males and 8 ppm in females. In rats, treatment-related mortality occurred early in the study in five males in the 100 ppm group and in one male in the 40 ppm group. Papillomas and carcinomas with degeneration of the urothelium, necrosis and urothelial cell hyperplasia, were found in the urinary bladders of both sexes. In male rats, one papilloma was found in each of the 10 and 40 ppm groups; one urothelial cell carcinoma was found in the 2 ppm group and two in the 100 ppm group. Four papillomas and six urothelial cell carcinomas were found in the female 100 ppm group. Non-neoplastic treatment-related kidney lesions were confined to the 40 and 100 ppm levels and included necrosis, pyelonephritis, medullary nephrocalcinosis and tubular cystic dilation, hyperplasia of the epithelial lining of the papilla, and pelvic urothelial cell hyperplasia. All of these kidney changes appear to be related to an increase in the aging nephropathy of the rat. Dose-related increases in the height of the thyroid follicular epithelium were also noted in males and females, however, such changes reflect an adaptive response of the thyroid to decreased levels of circulating thyroid hormone, rather than an adverse effect. Based on the kidney and bladder lesions, the NOEL for non-neoplastic and neoplastic lesions was considered to be 10 ppm in males and females. Based on these studies, DMA(V) is carcinogenic only in rats and only at relatively high doses, with the urinary bladder as the target organ. Female rats appear to be more sensitive to the effects of DMA(V) than male rats. DMA(V) is not carcinogenic in mice.
根据美国环境保护局（US EPA）的指导方针，将叶面除草剂二甲基胂酸（DMA(V)，卡可基酸）添加到饮食中，以0、8、40、200和500 ppm的剂量水平投喂B6C3F1小鼠，以0、2、10、40和100 ppm的剂量水平投喂F344大鼠，为期2年。在小鼠中，未在任何部位观察到与处理相关的肿瘤。在两性的肾脏中均观察到与处理相关的进行性肾小球肾炎和肾钙质沉着症。两性膀胱上皮空泡化的发生率均增加，但与细胞毒性、坏死或增生无关。基于在膀胱中发现的非肿瘤性病变，评估雄性小鼠的无观察到有害作用水平（NOEL）为40 ppm，雌性为8 ppm。在大鼠中，100 ppm组的5只雄性和40 ppm组的1只雄性在研究早期出现了与处理相关的死亡。在两性的膀胱中均发现了伴有尿路上皮变性、坏死和尿路上皮细胞增生的乳头状瘤和癌。在雄性大鼠中，10 ppm组和40 ppm组各发现1个乳头状瘤；2 ppm组发现1例尿路上皮细胞癌，100 ppm组发现2例。在雌性100 ppm组中发现4个乳头状瘤和6例尿路上皮细胞癌。与处理相关的非肿瘤性肾脏病变仅限于40和100 ppm剂量水平，包括坏死、肾盂肾炎、髓质肾钙质沉着症和肾小管囊性扩张、乳头上皮衬里增生以及肾盂尿路上皮细胞增生。所有这些肾脏变化似乎都与大鼠衰老性肾病的增加有关。在雄性和雌性中还注意到甲状腺滤泡上皮高度的剂量相关增加，然而，这种变化反映了甲状腺对循环甲状腺激素水平降低的适应性反应，而不是不良反应。基于肾脏和膀胱病变，非肿瘤性和肿瘤性病变的NOEL被认为在雄性和雌性中均为10 ppm。基于这些研究，DMA(V)仅在大鼠中具有致癌性，且仅在相对高剂量下具有致癌性，靶器官为膀胱。雌性大鼠似乎比雄性大鼠对DMA(V)的影响更敏感。DMA(V)在小鼠中不具有致癌性。
