Takayama S, Renwick A G, Johansson S L, Thorgeirsson U P, Tsutsumi M, Dalgard D W, Sieber S M
Division of Basic Sciences, National Cancer Institute, Bethesda, Maryland 20892, USA.
Toxicol Sci. 2000 Jan;53(1):33-9. doi: 10.1093/toxsci/53.1.33.
Twenty-one monkeys (cynomolgus, rhesus, African green) were fed cyclamate (100 mg/kg and 500 mg/kg) in the diet five times per week from a few days after birth and continuing for up to 24 years. Malignant tumors were diagnosed in three 24-year-old cyclamate monkeys; these were metastatic colon carcinoma (rhesus; 500 mg/kg), metastatic hepatocellular carcinoma (cynomolgus; 500 mg/kg), and a small, well differentiated adenocarcinoma of the prostate (cynomolgus; 100 mg/kg). Benign tumors were found at necropsy in three females; these were adenoma of the thyroid gland (rhesus; 100 mg/kg) and two cases of leiomyoma of the uterus (rhesus; 100 mg/kg and 500 mg/kg). No tumors were detected in an age-matched control group of 16 monkeys. Examination of the testes revealed complete testicular atrophy in one of the old cyclamate monkeys, and focal germ cell aplasia (Sertoli-only tubules) in two other cyclamate monkeys. Focal spermatogenic interruption (maturation arrest) at various germ cell levels mixed with normal spermatogenesis was observed in both the cyclamate-treated and the control monkeys, all of which were over 20 years old. Measurements of terminal cyclohexylamine concentrations showed that three of the males dosed with cyclamate at 500 mg/kg were high converters, with plasma concentrations comparable to the levels that produce testicular atrophy in rats. However, only one of the three high converters showed histologic evidence of irregular spermatogenesis. The overall conclusion is that the testicular abnormalities and the sporadic cases of different malignancies found after more than 20 years of dosing do not provide clear evidence of a toxic or carcinogenic effect of sodium cyclamate in monkeys.
21只猴子（食蟹猴、恒河猴、非洲绿猴）从出生后几天开始，每周5次在饮食中摄入甜蜜素（100毫克/千克和500毫克/千克），持续长达24年。在3只24岁的食用甜蜜素的猴子身上诊断出恶性肿瘤；分别是转移性结肠癌（恒河猴；500毫克/千克）、转移性肝细胞癌（食蟹猴；500毫克/千克）和前列腺高分化小腺癌（食蟹猴；100毫克/千克）。尸检时在3只雌性猴子身上发现了良性肿瘤；分别是甲状腺腺瘤（恒河猴；100毫克/千克）和2例子宫平滑肌瘤（恒河猴；100毫克/千克和500毫克/千克）。在16只年龄匹配的对照猴子中未检测到肿瘤。对睾丸的检查发现，1只年老的食用甜蜜素的猴子出现完全性睾丸萎缩，另外2只食用甜蜜素的猴子出现局灶性生殖细胞发育不全（仅支持细胞小管）。在所有年龄超过20岁的食用甜蜜素处理的猴子和对照猴子中，均观察到不同生殖细胞水平的局灶性生精中断（成熟停滞）与正常生精混合存在。对终末环己胺浓度的测量表明，3只给予500毫克/千克甜蜜素的雄性猴子是高转化者，其血浆浓度与在大鼠中产生睾丸萎缩的水平相当。然而，这3只高转化者中只有1只显示出精子发生不规则的组织学证据。总体结论是，在给药20多年后发现的睾丸异常和不同恶性肿瘤的散发病例，并未提供甜蜜素钠对猴子有毒性或致癌作用的明确证据。
