Mail Drop B143-06, Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
Chem Res Toxicol. 2010 Feb 15;23(2):327-35. doi: 10.1021/tx900343d.
Exposure to inorganic arsenic (iAs) induces cancer in human lungs, urinary bladder, skin, kidney, and liver, with the majority of deaths from lung and bladder cancer. To date, cancer risk assessments for iAs have not relied on mechanistic data, as we have lacked sufficient understanding of arsenic's pharmacokinetics and mode(s) of carcinogenic action (MOA). Furthermore, while there are vast amounts of toxicological data on iAs, relatively little of it has been collected using experimental designs that efficiently support development of biologically based dose-response (BBDR) models and subsequently risk assessment. This review outlines an efficient approach to the development of a BBDR model for iAs that would reduce uncertainties in its cancer risk assessment. This BBDR-based approach is illustrated by using oxidative stress as the carcinogenic MOA for iAs but would be generically applicable to other MOAs. Six major research needs that will facilitate BBDR model development for arsenic-induced cancer are (1) MOA research, which is needed to reduce the uncertainty in risk assessment; (2) development and integration of the pharmacodynamic component (MOA) of the BBDR model; (3) dose-response and extrapolation model selection; (4) the determination of internal human speciated arsenical concentrations to improve physiologically based pharmacokinetic (PBPK) models; (5) animal models of arsenic carcinogenesis; and (6) the determination of the low dose human relationship for death from cancer, particularly in lungs and urinary bladder. The major parts of the BBDR model are arsenic exposure, a physiologically based pharmacokinetic model, reactive species, antioxidant defenses, oxidative stress, cytotoxicity, growth factors, transcription factors, DNA damage, chromosome damage, cell proliferation, mutation accumulation, and cancer. The BBDR model will need to be developed concurrently with data collection so that model uncertainties can be identified and addressed through an iterative process of targeted additional research.
暴露于无机砷（iAs）会导致人类肺部、膀胱、皮肤、肾脏和肝脏癌症，其中大多数死亡是由肺癌和膀胱癌引起的。迄今为止，iAs 的癌症风险评估并未依赖于机制数据，因为我们对砷的药代动力学和致癌作用模式（MOA）了解不足。此外，尽管有大量关于 iAs 的毒理学数据，但相对较少的数据是使用能够有效地支持基于生物学的剂量反应（BBDR）模型开发和随后的风险评估的实验设计收集的。
本综述概述了开发 iAs 的 BBDR 模型的有效方法，该方法可以减少其癌症风险评估中的不确定性。这种基于 BBDR 的方法通过将氧化应激作为 iAs 的致癌 MOA 来说明，但也将普遍适用于其他 MOA。促进砷诱导癌症的 BBDR 模型开发的六个主要研究需求是：
MOA 研究，这是减少风险评估不确定性所必需的；
开发和整合 BBDR 模型的药效学成分（MOA）；
剂量反应和外推模型选择；
确定人体种特异性砷浓度以改善基于生理学的药代动力学（PBPK）模型；
砷致癌作用的动物模型；
确定癌症死亡的低剂量人体关系，特别是在肺部和膀胱。
BBDR 模型的主要部分包括砷暴露、基于生理学的药代动力学模型、活性物质、抗氧化防御、氧化应激、细胞毒性、生长因子、转录因子、DNA 损伤、染色体损伤、细胞增殖、突变积累和癌症。BBDR 模型将需要与数据收集同时开发，以便通过迭代过程识别和解决模型不确定性，该过程通过有针对性的额外研究进行。
