Contrera J F, DeGeorge J J
Office of Testing and Research, U.S. Food and Drug Administration Center for Drug Evaluation and Research, Rockville, MD 20857, USA.
Environ Health Perspect. 1998 Feb;106 Suppl 1(Suppl 1):71-80. doi: 10.1289/ehp.98106s171.
There is general agreement in the scientific community on the need to improve carcinogenicity testing and the assessment of human carcinogenic risk and to incorporate more information on mechanisms and modes of action into the risk assessment process. Advances in molecular biology have identified a growing number of genes such as protooncogenes and tumor-suppressor genes that are highly conserved across species and are associated with a wide variety of human and animal cancers. In vivo transgenic rodent models incorporating such mechanisms are used to identify mechanisms involved in tumor formation and as selective tests for carcinogens. Transgenic methods can be considered an extension of genetic manipulation by selective breeding, which long has been employed in science and agriculture. The use of two rodent species in carcinogenicity testing is especially important for identifying transspecies carcinogens. The capacity of a substance to induce neoplasia across species suggests that the mechanism(s) involved in the induction of the neoplasia are conserved and therefore may have significance for humans. Based on available information there is sufficient experience with some in vivo transgenic rodent carcinogenicity models to support their application as complementary second species studies in conjunction with a single 2-year rodent carcinogenicity study. The optional substitution of a second 2-year rodent carcinogenicity study with an alternative study such as an in vivo transgenic carcinogenicity study is part of the International Conference on Harmonization guidance S1B: Testing for Carcinogenicity of Pharmaceuticals. This guidance is intended to be flexible enough to accommodate a wide range of possible carcinogenicity assessment models currently under consideration or models that may be developed in the future. The use of an in vivo transgenic mouse model in place of a second 2-year mouse study will improve the assessment of carcinogenic risk by contributing insights into the mechanisms of tumorigenesis and potential human relevance not available from a standard 2-year bioassay. It is envisioned that this will stimulate the further development of more efficient and relevant methods for identifying and assessing potential human carcinogenic risk, which will benefit public health.
科学界普遍认为有必要改进致癌性测试和人类致癌风险评估，并将更多关于作用机制和作用方式的信息纳入风险评估过程。分子生物学的进展已鉴定出越来越多的基因，如原癌基因和肿瘤抑制基因，这些基因在物种间高度保守，并与多种人类和动物癌症相关。纳入此类机制的体内转基因啮齿动物模型用于确定肿瘤形成所涉及的机制，并作为致癌物的选择性检测方法。转基因方法可被视为选择性育种遗传操作的延伸，而选择性育种长期以来一直在科学和农业中使用。在致癌性测试中使用两种啮齿动物物种对于识别跨物种致癌物尤为重要。一种物质在不同物种间诱导肿瘤形成的能力表明，诱导肿瘤形成所涉及的机制是保守的，因此可能对人类具有重要意义。根据现有信息，一些体内转基因啮齿动物致癌性模型有足够的经验支持其作为补充的第二种物种研究，与单一的两年期啮齿动物致癌性研究一起应用。用替代研究（如体内转基因致癌性研究）替代第二个两年期啮齿动物致癌性研究是国际协调会议指南S1B：药物致癌性测试的一部分。该指南旨在足够灵活，以适应目前正在考虑的各种可能的致癌性评估模型或未来可能开发的模型。使用体内转基因小鼠模型代替第二个两年期小鼠研究将通过提供对肿瘤发生机制和潜在人类相关性的见解来改进致癌风险评估，而这些见解是标准的两年期生物测定所无法提供的。预计这将刺激进一步开发更有效和相关的方法来识别和评估潜在的人类致癌风险，这将有益于公众健康。
