Safety" testing of carcinogenic agents.
Safety" testing of carcinogenic agents.
复制标题
致癌剂的安全性”测试。
DOI：
10.1093/jnci/27.2.455
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发表时间：
1961
期刊：
影响因子：
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通讯作者：
Bryan W. Ray
中科院分区：
文献类型：
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作者：
M. Nathan;Bryan W. Ray
确定何种剂量的药剂是安全的问题。除非首先确定某种允许的风险水平（无论多小），而不是坚持绝对安全，否则无法解决非致癌性的问题。由于实际考虑和统计差异，不能直接确定低风险剂量水平，例如1亿分之1，而必须从观察到的数据中进行外推。给出了这样做的保守方法。除了对“虚拟安全”的任意定义之外，还需要定义任意高的统计保证水平和使用任意浅的斜率进行外推的规则。Bryan和Shimkin （J. Nat. Cancer institute . 3: 503-531, 1943）关于甲基胆碱致癌作用的说明性数据显示，当统计保证水平为99%时，每只小鼠的“安全”剂量为9 × 10 - 8mg，并且使用每对数1个正态偏差的保守概率斜率进行外推。所给出的原则一般适用于其他安全测试问题，重点是由于不能直接观察到某些剂量水平的风险显然很低，因此必须制定确定低风险水平的间接保守程序。武断的风险和这样做的定义可能会随着情况而改变。该程序不需要实验方案的说明；“安全”剂量是根据现有数据确定的。然而，最低限度的协议可能是可取的，因为较大的数据量通常允许指定较大的“安全”水平。
The problem of determining what dose levels of an agent are safe,e.g., non-carcinogenic, cannot be resolved unless one first defines some level of permissible risk, no matter how small, rather than insisting on absolute safety. Both because of practical considerations and statistical variation, the determination of low-risk dose levels, for example 1/100 million, cannot be made directly but must be by extrapolation from observed data. A conservative approach for doing so is given. In addition to an arbitrary definition of “virtual safety,” it is necessary to define an arbitrarily high statistical assurance level and a rule for extrapolation by use of an arbitrarily shallow slope. Illustrative data by Bryan and Shimkin (J. Nat. Cancer Inst. 3: 503–531, 1943) on the carcinogenic action of methylcholanthrene yield a “safe,” 1/100 million, dose of 9 × 10−8mg per mouse when a statistical assurance level of 99 percent and a conservative probit slope of 1 normal deviate per log for extrapolation are used. The principles given are of general applicability in other safety-testing problems, the point of emphasis being that since direct observation cannot be made that the risk at some dose level is clearly low, indirect conservative procedures for the determination of low risk levels must be made. The arbitrary risks and definitions for so doing may change with circumstances. The procedure does not require specification of an experimental protocol; the “safe” dose is determined on the basis of whatever data are available. Minimum protocols may, however, be desirable, since greater amounts of data will ordinarily permit specifying large “safe” levels.