Bogen Kenneth T
Exponent Inc., Health Sciences Group, 500 1th Street, Oakland, CA 94607, USA.
Risk Anal. 2008 Aug;28(4):1033-51. doi: 10.1111/j.1539-6924.2008.01066.x. Epub 2008 Jun 28.
The U.S. Environmental Protection Agency (USEPA) guidelines for cancer risk assessment recognize that some chemical carcinogens may have a site-specific mode of action (MOA) involving mutation and cell-killing-induced hyperplasia. The guidelines recommend that for such dual MOA (DMOA) carcinogens, judgment should be used to compare and assess results using separate "linear" (genotoxic) versus "nonlinear" (nongenotoxic) approaches to low-level risk extrapolation. Because the guidelines allow this only when evidence supports reliable risk extrapolation using a validated mechanistic model, they effectively prevent addressing MOA uncertainty when data do not fully validate such a model but otherwise clearly support a DMOA. An adjustment-factor approach is proposed to address this gap, analogous to reference-dose procedures used for classic toxicity endpoints. By this method, even when a "nonlinear" toxicokinetic model cannot be fully validated, the effect of DMOA uncertainty on low-dose risk can be addressed. Application of the proposed approach was illustrated for the case of risk extrapolation from bioassay data on rat nasal tumors induced by chronic lifetime exposure to naphthalene. Bioassay data, toxicokinetic data, and pharmacokinetic analyses were determined to indicate that naphthalene is almost certainly a DMOA carcinogen. Plausibility bounds on rat-tumor-type-specific DMOA-related uncertainty were obtained using a mechanistic two-stage cancer risk model adapted to reflect the empirical link between genotoxic and cytotoxic effects of the most potent identified genotoxic naphthalene metabolites, 1,2- and 1,4-naphthoquinone. Bound-specific adjustment factors were then used to reduce naphthalene risk estimated by linear extrapolation (under the default genotoxic MOA assumption), to account for the DMOA exhibited by this compound.
美国环境保护局（USEPA）的癌症风险评估指南认识到，一些化学致癌物可能具有特定部位的作用模式（MOA），涉及突变和细胞杀伤诱导的增生。该指南建议，对于此类双重作用模式（DMOA）致癌物，应运用判断力，使用单独的“线性”（遗传毒性）与“非线性”（非遗传毒性）方法进行低水平风险外推，以比较和评估结果。由于该指南仅在有证据支持使用经过验证的机制模型进行可靠的风险外推时才允许这样做，因此当数据不能完全验证此类模型但在其他方面明确支持DMOA时，它们有效地阻止了对作用模式不确定性的处理。本文提出了一种调整因子方法来弥补这一差距，类似于用于经典毒性终点的参考剂量程序。通过这种方法，即使“非线性”毒代动力学模型不能得到充分验证，也可以处理DMOA不确定性对低剂量风险的影响。本文以慢性终生暴露于萘诱导的大鼠鼻腔肿瘤生物测定数据的风险外推为例，说明了所提出方法的应用。生物测定数据、毒代动力学数据和药代动力学分析表明，萘几乎肯定是一种DMOA致癌物。使用一个机制性的两阶段癌症风险模型，获得了大鼠肿瘤类型特异性DMOA相关不确定性的合理性界限，该模型经过调整以反映最有效的已鉴定遗传毒性萘代谢物1,2-萘醌和1,4-萘醌的遗传毒性和细胞毒性效应之间的经验联系。然后使用特定界限的调整因子来降低线性外推法（在默认的遗传毒性MOA假设下）估计的萘风险，以考虑该化合物表现出的DMOA。
