Calabrese Edward J
Environmental Health Sciences, School of Public Health, Morrill I, N344, University of Massachusetts, Amherst, MA 01003, USA.
Environ Pollut. 2005 Dec;138(3):379-411. doi: 10.1016/j.envpol.2004.10.001.
This paper provides an assessment of the toxicological basis of the hormetic dose-response relationship including issues relating to its reproducibility, frequency, and generalizability across biological models, endpoints measured and chemical class/physical stressors and implications for risk assessment. The quantitative features of the hormetic dose response are described and placed within toxicological context that considers study design, temporal assessment, mechanism, and experimental model/population heterogeneity. Particular emphasis is placed on an historical evaluation of why the field of toxicology rejected hormesis in favor of dose response models such as the threshold model for assessing non-carcinogens and linear no threshold (LNT) models for assessing carcinogens. The paper argues that such decisions were principally based on complex historical factors that emerged from the intense and protracted conflict between what is now called traditional medicine and homeopathy and the overly dominating influence of regulatory agencies on the toxicological intellectual agenda. Such regulatory agency influence emphasized hazard/risk assessment goals such as the derivation of no observed adverse effect levels (NOAELs) and the lowest observed adverse effect levels (LOAELs) which were derived principally from high dose studies using few doses, a feature which restricted perceptions and distorted judgments of several generations of toxicologists concerning the nature of the dose-response continuum. Such historical and technical blind spots lead the field of toxicology to not only reject an established dose-response model (hormesis), but also the model that was more common and fundamental than those that the field accepted.
本文对兴奋效应剂量反应关系的毒理学基础进行了评估，包括其在不同生物模型、所测量的终点、化学类别/物理应激源之间的可重复性、出现频率和普遍性问题，以及对风险评估的影响。文中描述了兴奋效应剂量反应的定量特征，并将其置于毒理学背景中进行考量，该背景涵盖研究设计、时间评估、作用机制以及实验模型/群体的异质性。特别强调对毒理学领域拒绝兴奋效应而青睐剂量反应模型（如用于评估非致癌物的阈值模型和用于评估致癌物的线性无阈值模型）的历史评估。本文认为，这些决策主要基于复杂的历史因素，这些因素源于现在所谓的传统医学与顺势疗法之间激烈而持久的冲突，以及监管机构对毒理学知识议程的过度主导影响。这种监管机构的影响强调了危害/风险评估目标，如未观察到不良反应水平（NOAELs）和最低观察到不良反应水平（LOAELs）的推导，这些主要来自使用少量剂量的高剂量研究，这一特征限制了几代毒理学家对剂量反应连续体性质的认知并扭曲了他们的判断。这些历史和技术盲点导致毒理学领域不仅拒绝了一种既定的剂量反应模型（兴奋效应），还拒绝了比该领域所接受的模型更常见、更基本的模型。
