Gastel J A, Sutter T R
Department of Environmental Health Sciences, Johns Hopkins School of Hygiene and Public Health, Baltimore, Maryland 21205-2179, USA.
Regul Toxicol Pharmacol. 1995 Dec;22(3):273-82. doi: 10.1006/rtph.1995.0010.
We have developed a biologically bounded marginal effect model for use in risk assessment of human exposure to receptor-mediated nongenotoxic carcinogens. Schematically this model can be reduced to four components: CI, the absence of an observable biological response; CII, observable biochemical responses but no observable pathology; CIII, observable pathology; and CIV, both observable pathology and lethality. The inflection point in the marginal response curve between CI and CII is defined as the biologically evaluated scientifically tested no observable effect level (BESTNOEL). We demonstrate the utility of this approach by applying it to the well-studied nongenotoxic carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Using a well-developed mechanistic understanding of the initial interactions of TCDD with the cell, we justify the selection of the minimal effective dose for CYP1A1 mRNA induction as the BESTNOEL. With allowance for variation in human sensitivity to TCDD, the BESTNOEL is assigned a human liver tissue burden of approximately 0.25-25 ppt and an allowable daily intake level in the range of 15-1500 fg/kg/day. In the future, the BESTNOEL can help establish a lower boundary for acceptable extrapolation when using either statistical or biologically based attributable risk models.
我们开发了一种生物界定的边际效应模型，用于人类暴露于受体介导的非遗传毒性致癌物的风险评估。示意性地，该模型可简化为四个组成部分：CI，无明显生物反应；CII，可观察到生化反应但无明显病理学改变；CIII，可观察到病理学改变；以及CIV，既有可观察到的病理学改变又有致死性。CI和CII之间边际反应曲线的拐点定义为经生物学评估和科学测试的无明显效应水平（BESTNOEL）。我们通过将其应用于充分研究的非遗传毒性致癌物2,3,7,8-四氯二苯并对二恶英（TCDD）来证明这种方法的实用性。利用对TCDD与细胞初始相互作用的深入机制理解，我们将CYP1A1 mRNA诱导的最小有效剂量的选择作为BESTNOEL的依据。考虑到人类对TCDD敏感性的差异，BESTNOEL对应的人体肝脏组织负荷约为0.25 - 25 ppt，每日允许摄入量范围为15 - 1500 fg/kg/天。未来，BESTNOEL在使用统计或基于生物学的归因风险模型时，可有助于为可接受的外推建立一个下限。
