Wright A S, Bradshaw T K, Watson W P
Shell Research Ltd, Sittingbourne Research Centre, Kent, UK.
IARC Sci Publ. 1988(89):237-48.
Advances in our understanding of the mechanisms of chemical carcinogenesis are now being applied to improve the quality of prospective risk assessment. The contribution of Ehrenberg and his colleagues (at the University of Stockholm) probably represents the most comprehensive application of mechanistic knowledge to this field during the past 20 years. The strategic approach developed by the Swedish group was based on the identification of differences between man and experimental risk models in factors that determine the relationships between exposure and biological response and the development of methods to compensate for these differences. Many of the critical stages in chemical carcinogenesis and the cellular determinants of these stages have now been identified. As a first step in seeking to improve risk assessment, Ehrenberg introduced the target dose concept, in which the doses of carcinogens penetrating to the cellular target (DNA) are determined. This approach provides an improved basis for determining exposures to carcinogenic agents and also for compensating for species differences in factors such as metabolism that determine the relationships between exposure dose and the dose at the critical target. The target dose concept is now widely accepted and has led to the development of new biomedical monitoring techniques, based, for example, on the measurement of haemoglobin adducts, which are now being applied to detect and identify genotoxic hazards. The introduction of the target dose concept has led to significant improvements in the quality of prospective risk assessment. Further improvements necessitate procedures to compensate for differences between man and prospective risk models in factors that determine subsequent stages of the carcinogenic process. Ehrenberg has proposed that the rad-equivalence approach may be of value in this respect. Its application has accurately predicted the incidence of leukaemias in occupational cohorts which had exposures to ethylene oxide in common. The possible general applicability of this approach is discussed.
我们对化学致癌机制认识的进展如今正被用于提高前瞻性风险评估的质量。埃伦贝格及其同事（斯德哥尔摩大学）的贡献或许代表了过去20年里机制知识在该领域最全面的应用。瑞典团队制定的战略方法基于识别在决定暴露与生物反应关系的因素方面人类与实验风险模型之间的差异，并开发弥补这些差异的方法。化学致癌过程中的许多关键阶段以及这些阶段的细胞决定因素现已被确定。作为寻求改进风险评估的第一步，埃伦贝格引入了靶剂量概念，即确定穿透到细胞靶点（DNA）的致癌物剂量。这种方法为确定致癌物暴露以及弥补诸如代谢等决定暴露剂量与关键靶点剂量之间关系的因素中的物种差异提供了更好的基础。靶剂量概念如今已被广泛接受，并催生了新的生物医学监测技术的发展，例如基于血红蛋白加合物测量的技术，这些技术现正被用于检测和识别基因毒性危害。靶剂量概念的引入已使前瞻性风险评估的质量有了显著提高。进一步的改进需要有程序来弥补人类与前瞻性风险模型在决定致癌过程后续阶段的因素方面的差异。埃伦贝格提出在这方面拉德当量方法可能有价值。其应用已准确预测了共同暴露于环氧乙烷的职业人群中白血病的发病率。本文讨论了该方法可能的普遍适用性。
