Müller Lutz, Gocke Elmar
F. Hoffmann-La Roche Ltd., Nonclinical Safety, Grenzacher Strasse, 4070 Basel, Switzerland.
Toxicol Lett. 2009 Nov 12;190(3):330-2. doi: 10.1016/j.toxlet.2009.03.015. Epub 2009 Mar 27.
Specification of human exposure limits to compounds with toxicities based on modes of action that allow considerations of a threshold and the safe estimation of a no-observed-effect level (NOEL) is normally based on acceptable daily intake (ADI) or permitted daily exposure (PDE) calculations using appropriate safety factors to account for differences between species, populations, length of observation and severity of lesions. In view of the reliable experimental evidence for a thresholded dose response of the genotoxicity of ethyl methanesulfonate (EMS) as reported in this special issue of Toxicology Letters such an acceptable daily intake proposal is made using the approach for setting permitted daily exposure limits outlined in appendix 3 of the ICH Q3C consensus guideline on residual solvents in pharmaceuticals (ICH, 2005). Up to now the specification of EMS exposure limits was based on the generic threshold of toxicological concern (TTC)-derived limit of 1.5mug/person/day as advocated by the CHMP [CHMP, 2006. Guideline on the limits of genotoxic impurities. www.emea.europa.eu/pdfs/human/swp/519902en.pdf (June 28, 2006) with Q&A www.emea.europa.eu/pdfs/human/swp/43199407en.pdf (June 25, 2008)] or on as low as technically achievable criteria. Such limits have been based on conservative linear dose-effect extrapolations corresponding to an excess cancer risk of 1 in 100,000. We now present an EMS-specific PDE based on the reliable demonstration of a NOEL for induction of mutations in vivo of 25mg/kg/day. Using the most conservative safety factors described in ICH Q3C we derive a PDE of approximately 100 microg/person/day using product safety factors still amounting to 12,000.
基于作用模式对具有毒性的化合物规定人体暴露限值，从而能够考虑阈值并安全估算未观察到效应水平（NOEL），通常是基于每日允许摄入量（ADI）或允许日暴露量（PDE）的计算，并使用适当的安全系数来考虑物种、人群、观察时长和损伤严重程度之间的差异。鉴于本期《毒理学快报》报道了甲磺酸乙酯（EMS）遗传毒性的阈值剂量反应的可靠实验证据，故采用《人用药品注册技术要求国际协调会（ICH）关于药品中残留溶剂的Q3C共识指南》（ICH，2005年）附录3中概述的设定允许日暴露限值的方法，提出了这样一个每日允许摄入量建议。到目前为止，EMS暴露限值的规定是基于欧洲药品管理局人用药品委员会（CHMP）所倡导的毒理学关注通用阈值（TTC）推导得出的1.5μg/人/天的限值[CHMP，2006年。遗传毒性杂质限度指南。www.emea.europa.eu/pdfs/human/swp/519902en.pdf（2006年6月28日）及问答www.emea.europa.eu/pdfs/human/swp/43199407en.pdf（2008年6月25日）]或基于尽可能低的技术可行标准。此类限值基于对应于十万分之一额外癌症风险的保守线性剂量效应外推法。我们现在基于体内诱导突变的NOEL为25mg/kg/天的可靠论证，提出了一个特定于EMS的PDE。使用ICH Q3C中描述的最保守安全系数，我们得出约100μg/人/天的PDE，此时产品安全系数仍达12,000。
