作为新化学品（药物，农药等）安全评估的一部分，目前建议采用分层的遗传毒性方法（DNA损伤）测试。这种方法旨在防止人类对可能损害DNA的药物的暴露，因为DNA损伤与癌症的发展密切相关。分层方法涉及所有进入第1阶段测试的化学物质，其中在实验室培养的细胞中评估了DNA损伤诱导。这些测试中的负面结果使制造商保证，该试剂不太可能诱导DNA损伤。但是，通常将这些测试中的任何化学物质测试呈阳性，然后进行第二阶段测试，这些测试在动物（通常是小鼠）中进行。这可能涉及每年在英国进行数千种此类动物测试。第2阶段测试旨在克服可能在第1阶段测试中发生的假阳性结果的问题，并更严格地评估人类健康的风险。由于使用了高剂量的化学物质，通常会在第1阶段测试中进行假阳性结果。传统上，高剂量的化学物质被用来确保鉴定出DNA损伤效应，并广泛认为该作用是以线性方式诱导的。也就是说，如果高剂量为阳性，那么低剂量也将是阳性的。 We have recently shown how important dose can be in terms of DNA damage. We uniquely demonstrated that DNA damaging agents whilst giving positive results at high doses, are not DNA damaging at low doses. This confirms that "safe" doses exist, even for potent DNA damaging agents which are known to induce cancer. Hence, identifying these critical dose ranges is vital if we are to assess the effects of dose on DNA damage. If chemicals in stage 1 tests are only positive at high doses and not at low doses, and these positive effects were seen at doses estimated to be well above human exposures, then this would suggest that these chemicals would not be a human health risk. Importantly, the progression of these chemicals into stage 2 (animal) tests might not be necessary. Hence, by changing the testing strategy to consider the effects of dose, we could reduce the numbers of animal tests in toxicology. To add weight to the argument that DNA damaging thresholds exist and can be fully explained, we need high quality, cell-based studies of DNA damage induction for a wide range of chemicals. This application is aimed at supplying new knowledge in this field to impact on the testing strategies for DNA damage assessment with the ultimate aim of reducing the number of animal tests.
