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Abstract：
A genotoxic carcinogen, N-nitrosodimethylamine (NDMA), was detected as a synthesis impurity in some valsartan drugs in 2018, and other N-nitrosamines, such as N-nitrosodiethylamine (NDEA), were later detected in other sartan products. N-nitrosamines are pro-mutagens that can react with DNA following metabolism to produce DNA adducts, such as O6 -alkyl-guanine. The adducts can result in DNA replication miscoding errors leading to GC>AT mutations and increased risk of genomic instability and carcinogenesis. Both NDMA and NDEA are known rodent carcinogens in male and female rats. The DNA repair enzyme, methylguanine DNA-methyltransferase can restore DNA integrity via the removal of alkyl groups from guanine in an error-free fashion and this can result in nonlinear dose responses and a point of departure or \"practical threshold\" for mutation at low doses of exposure. Following International recommendations (ICHM7; ICHQ3C and ICHQ3D), we calculated permissible daily exposures (PDE) for NDMA and NDEA using published rodent cancer bioassay and in vivo mutagenicity data to determine benchmark dose values and define points of departure and adjusted with appropriate uncertainty factors (UFs). PDEs for NDMA were 6.2 and 0.6 μg/person/day for cancer and mutation, respectively, and for NDEA, 2.2 and 0.04 μg/person/day. Both PDEs are higher than the acceptable daily intake values (96 ng for NDMA and 26.5 ng for NDEA) calculated by regulatory authorities using simple linear extrapolation from carcinogenicity data. These PDE calculations using a bench-mark approach provide a more robust assessment of exposure limits compared with simple linear extrapolations and can better inform risk to patients exposed to the contaminated sartans.
摘要：
基因毒性致癌物,N-亚硝基二甲胺(NDMA),2018年在一些缬沙坦药物和其他N-亚硝胺中被检测为合成杂质，如N-亚硝基二乙胺（NDEA），后来在其他沙坦产品中检测到。N-亚硝胺是促诱变剂，可以在代谢后与DNA反应产生DNA加合物，例如O6-烷基-鸟嘌呤。加合物可导致DNA复制错误编码,导致GC>AT突变和增加基因组不稳定性和致癌作用的风险。NDMA和NDEA都是雄性和雌性大鼠中已知的啮齿动物致癌物。DNA修复酶,甲基鸟嘌呤DNA-甲基转移酶可以通过以无差错的方式从鸟嘌呤中去除烷基来恢复DNA完整性,这可能导致非线性剂量反应和在低剂量暴露下突变的“实际阈值”。遵循国际建议（ICHM7；ICHQ3C和ICHQ3D），我们使用已发表的啮齿动物癌症生物测定法和体内致突变性数据,计算了NDMA和NDEA的允许每日暴露量(PDE),以确定基准剂量值,确定出发点,并用适当的不确定性因子(UFs)进行调整.对于癌症和突变，NDMA的PDE为6.2和0.6μg/人/天，分别,对于NDEA来说,2.2和0.04μg/人/天。两种PDE均高于监管机构使用简单的线性外推法从致癌性数据计算得出的可接受的每日摄入量值（NDMA为96ng，NDEA为26.5ng）。与简单的线性外推相比，使用基准方法进行的PDE计算可对暴露极限进行更可靠的评估，并且可以更好地告知暴露于受污染的sartan的患者的风险。
