Conolly Rory B, Lutz Werner K
CIIT Centers for Health Research, Research Triangle Park, North Carolina 27709, USA.
Toxicol Sci. 2004 Jan;77(1):151-7. doi: 10.1093/toxsci/kfh007. Epub 2003 Nov 4.
Dose-response curves for the first interaction of a chemical with a biochemical target molecule are usually monotonic; i.e., they increase or decrease over the entire dose range. However, for reactions of a complex biological system to a toxicant, nonmonotonic (biphasic) dose-effect relationships can be observed, showing a decrease at low dose followed by an increase at high dose, or vice versa. We present four examples to demonstrate that nonmonotonic dose-response relationships can result from superimposition of monotonic dose responses of component biological reactions. Examples include (i) a membrane-receptor model with receptor subtypes of different ligand affinity and opposing downstream effects (adenosine receptors A1 vs. A2), (ii) androgen receptor-mediated gene expression driven by homodimers, but not mixed-ligand dimers, (iii) repair of background DNA damage by enzymatic activity induced by adducts formed by a xenobiotic, (iv) rate of mutation as a consequence of DNA damage times rate of cell division, the latter being modulated by cell-cycle delay at low-level DNA damage, and cell-cycle acceleration due to regenerative hyperplasia at cytotoxic dose levels. Quantitative analyses based on biological models are shown, and factors that affect the degree of nonmonotonicity are identified. It is noted that threshold-type dose-response curves could in fact be nonmonotonic. Our analysis should promote a scientific discussion of biphasic dose responses and the concept termed "hormesis," and of default procedures for low-dose extrapolation in toxicological risk assessment.
化学物质与生物化学靶分子的首次相互作用的剂量-反应曲线通常是单调的；也就是说，它们在整个剂量范围内增加或减少。然而，对于复杂生物系统对毒物的反应，可以观察到非单调（双相）剂量-效应关系，即在低剂量时下降，随后在高剂量时上升，反之亦然。我们给出四个例子来证明非单调剂量-反应关系可能是由组成生物反应的单调剂量反应叠加导致的。例子包括：（i）具有不同配体亲和力和相反下游效应的受体亚型的膜受体模型（腺苷受体A1与A2）；（ii）由同型二聚体而非混合配体二聚体驱动的雄激素受体介导的基因表达；（iii）由异生物素形成的加合物诱导的酶活性对背景DNA损伤的修复；（iv）DNA损伤导致的突变率乘以细胞分裂率，后者在低水平DNA损伤时受细胞周期延迟调节，在细胞毒性剂量水平时由于再生性增生导致细胞周期加速。展示了基于生物学模型的定量分析，并确定了影响非单调性程度的因素。需要注意的是，阈值型剂量-反应曲线实际上可能是非单调的。我们的分析应促进对双相剂量反应和“兴奋效应”概念以及毒理学风险评估中低剂量外推的默认程序进行科学讨论。
