The use of biochemical and molecular parameters to estimate dose-response relationships at low levels of exposure.
The use of biochemical and molecular parameters to estimate dose-response relationships at low levels of exposure.
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DOI：
10.1289/ehp.98106s1349
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发表时间：
1998-02
影响因子：
10.4
通讯作者：
Barton HA
中科院分区：
文献类型：
--
作者：
Andersen ME;Barton HA
基于分子和生化参数变化的生物标记物可能有助于进行化学风险评估，以确定暴露的存在，对暴露个人的相对风险进行排名，并估计低水平暴露的风险。由于毒性反应和生物标记物变化程度之间的关系不太可能在所有剂量下都相同，因此使用这些生物标记物进行外推，在低水平下量化风险不一定更准确。以2，3，7，8-四氯二苯并对二恶英(TCDD)为例，讨论了响应生物标志物在低水平暴露风险评估中的应用，TCDD是一种在肝脏和其他组织中引起细胞色素CYP1A1和CYP1A2诱导的化合物。肝脏中细胞色素P1A1的诱导量随TCDD剂量的增加而单调增加；然而，TCDD对肝脏影响的剂量-反应曲线中有几条呈U型。由于综合毒理学反应依赖于多种潜在的过程--有丝分裂抑制、毒性和细胞增殖--对于TCDD，每个过程都有不同的剂量-反应关系，所以产生了促进肝脏肿瘤的U型剂量-反应曲线。尽管生物标记物的剂量-反应关系预计不会复制综合反应中看到的复杂形状，但对这些分子和生化参数变化的测量和药效学建模仍然有助于在低暴露水平下获得上行风险估计。
Biomarkers based on alterations in molecular and biochemical parameters may be useful in chemical risk assessment for establishing the presence of an exposure, ranking relative risks among exposed individuals, and estimating risks at low levels of exposure. Because it is unlikely that the relation between toxic responses and the degree of alteration in the biomarker is equivalent at all doses, quantification of risks at low levels is not necessarily more accurate using these biomarkers for extrapolation. The application of response biomarkers for risk evaluation at low levels of exposure is discussed in relation to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a compound that causes induction of cytochromes CYP1A1 and CYP1A2 in liver and other tissues. CYP1A1 induction in liver increases monotonically with TCDD dosage; however, several of the dose-response curves for hepatic effects of TCDD are U-shaped. The U-shaped dose-response curve for hepatic tumor promotion appears to result because the integrated toxicologic response depends on multiple underlying processes--mitosuppression, toxicity, and cell proliferation--each of which has a different dose-response relationship with respect to TCDD. Although dose-response relationships for the biomarkers are not expected to duplicate the complex shapes seen with the integrated responses, measurements and pharmacodynamic modeling of the changes in these molecular and biochemical parameters can still be useful for obtaining an upperbound risk estimate at low levels of exposure.