Influence of Metal-Working Fluid Formulations on Dermal Absorption of Biocides

金属加工液配方对杀菌剂皮肤吸收的影响

• 批准号: 7887567
• 负责人: Ronald E Baynes
• 金额: $ 22.04万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7887567
• 关键词: Influence; Metal; Working; Fluid; Formulations

DESCRIPTION (provided by applicant): The long-term goal is to understand physicochemical and chemical-biological interactions in a metal-working fluid (MWF) formulation in order to be able to predict quantitatively how these formulations influence dermal absorption of industrial biocides used as additives in these chemically complex formulations. Current dermal risk assessments only evaluate dermal absorption of single chemicals which has limited use in occupational exposure to chemically complex MWF formulations. The primary objective of this research project is to utilize the membrane-coated fibers (MCF) to characterize the distribution behavior between a defined MWF formulation, a MWF biocide, and an inert membrane and to relate this phase distribution to solvation parameters within a linear solvation energy relationship (LSER) framework that is also applicable to dermal permeability. The central hypothesis to be tested is that the presence of MWF formulations will alter the phase distribution of biocides between the formulation and the MCF and/or skin. These changes in biocide distribution can be expressed in terms of interaction coefficients ( values) that can be used in future extrapolations to a defined formulation scenario and thus can be of value to MWF formulators and metal fabrication workers by indicating what formulations are more likely to promote skin penetration and possibly adverse occupational effects. The rationale for this approach is that MWF formulations can modulate biocide partitioning and diffusion by quantifiable physicochemical interactions ( values). The MCF approach within the LSER framework allows for a physicochemical examination of these formulation effects using a multi-fiber MCF array system and validated in porcine skin diffusion cells and finally validated in vivo for systemic absorption. The following three specific aims will be pursued to accomplish the stated objectives: 1) To quantify mixture interactions influencing transport of MWF biocides between MWF formulations and the membrane coated fibers (MCF). This first involves calibration of a diverse series of fibers followed by exposure of a 5-component MCF array to MWF formulations to provide interaction coefficients ( values) for a defined formulation. 2) To quantify chemical-biological interactions in a biological membrane system following exposure to MWF formulations in porcine skin flow-through diffusion cell. Dermal in vitro experiments will calibrate permeability in the biological system and validate formulation interaction coefficients in the MCF array for the biocides. 3) To quantify the effect of MWF formulations on the in vivo dermal absorption of MWF biocides. This involves comparative analysis of interaction coefficients between the MCF array and the two biological systems (in vitro and in vivo) and will validate the proposed MCF- array approach within the LSER framework to predict the dermal permeability of occupationally relevant toxicants such as MWF biocides in a defined in MWF formulations. PUBLIC HEALTH RELEVANCE: Workers in the metal fabrication industry are more often exposed to metal working fluids (MWF) and its components such as biocides via the skin that can cause harm to the skin and/or the entire body if absorbed by the dermal route. Many of these workers are exposed to more than one chemical additive in any given MWF formulation, and there is little or no means of estimating what class of MWF formulations can result in increased or decreased absorption of biocides across skin. Our proposal describes a novel technique that models biocide absorption in skin on the basis of quantitative changes in physicochemical properties associated with the formulation interacting with a model membrane and then validated in skin in vitro and in vivo to determine validity of these models in an occupational dermal exposure. Ultimately, the products of this research will help inform the development and risk assessment of formulations that afford greater protection.

描述（由申请人提供）：长期目标是了解金属加工液（MWF）配方中的物理化学和化学-生物相互作用，以便能够定量预测这些配方如何影响这些化学复杂配方中用作添加剂的工业杀生物剂的皮肤吸收。目前的皮肤风险评估仅评估了单一化学品的皮肤吸收，这些化学品在化学复杂的MWF制剂的职业暴露中的使用有限。本研究项目的主要目的是利用膜涂层纤维（MCF）来表征定义的MWF制剂，MWF杀菌剂和惰性膜之间的分布行为，并将该相分布与线性溶剂化能量关系（LSER）框架内的溶剂化参数相关联，该框架也适用于皮肤渗透性。待测试的中心假设是MWF制剂的存在将改变制剂与MCF和/或皮肤之间的杀生物剂的相分布。杀生物剂分布的这些变化可以用相互作用系数（值）来表示，这些相互作用系数（值）可以用于将来对定义的制剂方案的外推，因此可以通过指示哪些制剂更可能促进皮肤渗透和可能的不良职业影响而对MWF制剂设计师和金属加工工人具有价值。这种方法的基本原理是MWF制剂可以通过可量化的物理化学相互作用（值）调节杀生物剂分配和扩散。LSER框架内的MCF方法允许使用多纤维MCF阵列系统对这些制剂效应进行理化检查，并在猪皮扩散池中进行验证，最终在体内验证全身吸收。将追求以下三个具体目标以实现所述目标：1）量化影响MWF杀生物剂在MWF制剂和膜涂覆纤维（MCF）之间的运输的混合物相互作用。这首先涉及校准不同系列的纤维，然后将5组分MCF阵列暴露于MWF制剂，以提供定义制剂的相互作用系数（值）。2)在猪皮流通扩散池中暴露于MWF制剂后，定量生物膜系统中的化学-生物相互作用。体外皮肤实验将校准生物系统中的渗透性，并验证杀生物剂MCF阵列中的制剂相互作用系数。3)量化MWF制剂对MWF杀生物剂体内皮肤吸收的影响。这涉及MCF阵列和两种生物系统（体外和体内）之间相互作用系数的比较分析，并将验证LSER框架内提出的MCF阵列方法，以预测职业相关毒物（如MWF制剂中定义的MWF杀生物剂）的皮肤渗透性。 公共卫生相关性：金属加工行业的工人更经常地通过皮肤接触金属加工液（MWF）及其成分，例如杀生物剂，如果通过皮肤途径吸收，则可能对皮肤和/或整个身体造成伤害。这些工人中的许多人在任何给定的MWF制剂中暴露于一种以上的化学添加剂，并且几乎没有或没有方法估计哪类MWF制剂可以导致皮肤对杀生物剂的吸收增加或减少。我们的建议描述了一种新的技术，模型杀菌剂在皮肤中的吸收的基础上的定量变化的物理化学性质与制剂相互作用的模型膜，然后在皮肤中验证在体外和体内，以确定这些模型的有效性在职业皮肤暴露。最终，这项研究的产品将有助于为提供更大保护的配方的开发和风险评估提供信息。