Occupational exposure limits in the context of solvent mixtures, consumption of ethanol, and target tissue dose
Occupational exposure limits in the context of solvent mixtures, consumption of ethanol, and target tissue dose
复制标题
DOI：
10.1191/0748233704th203oa
复制
发表时间：
2004-09-01
影响因子：
1.9
通讯作者：
Andersen, ME
中科院分区：
文献类型：
--
作者：
Dennison, JE;Bigelow, PL;Andersen, ME
个人接触的是混合物，而不是单一的化学品。根据混合物元素的组成，各组分之间可能会发生重大的毒理相互作用。这些相互作用是复杂的，往往难以预测，从协同作用到相加和次相加的相互作用。相互作用的性质需要作为每种化学物质活性形式的目标组织剂量进行评估。当数据可用于模型开发时，PBPK模型是确定目标组织剂量和评估这些相互作用的有效工具。其中一些相互作用本质上是药代动力学的，影响体内其他化学物质的处置。其他相互作用在本质上可能是药效学的，改变了其他化学物质对生物体的影响。对于许多有机溶剂，这些相互作用主要发生在代谢酶细胞色素P-450 2E1(CYP2E1)的水平上。已知许多溶剂可以诱导或抑制CYP2EI，或两者兼而有之。混合物可由接触化学品或分别在工作、非工作、饮食和其他方面遇到的成分组成。将讨论在工作之外暴露于分离组分的混合物的例子，特别强调乙醇消耗作为溶剂药代动力学的调节剂。对目前在解释职业接触限值时对个别混合物组分的毒性进行线性外推的做法也将提出批评。
Individuals are exposed to mixtures, and never to single chemicals. Depending on the composition of the elements of mixtures, significant toxicological interactions between the components may occur. These interactions are complex and often difficult to predict, ranging from synergistic to additive and subadditive interactions. The nature of the interactions needs to be evaluated as the target tissue dose of the active form of each chemical. PBPK modeling is an effective tool for determining the target tissue dose and evaluating these interactions when data are available for model development. Some of the interactions are pharmacokinetic in nature, affecting the disposition of other chemicals in the body. Other interactions can be pharmacodynamic in nature, altering the effects that other chemicals have on the organism. For many organic solvents, these interactions occur principally at the level of the metabolizing enzyme, cytochrome P-450 2E1 (CYP2E1). Many solvents are known to induce or inhibit CYP2EI, or both. Mixtures may be comprised of concomitant exposures to chemicals or from components encountered separately on-the-job, off-the-Job, through the diet, and otherwise. Examples of mixtures where the exposure to separate components occurs off the job will be discussed, with special emphasis on ethanol consumption as a modifier of solvent pharmacokinetics. The present practice of the linear extrapolation of the toxicity of individual mixture components in the interpretation of occupational exposure limits will also be critiqued.