Genotoxic Potential of Mixed Dust Exposures

拆除建筑物、修复和施工过程中产生的粉尘可能会被有毒颗粒污染，包括金属和石棉纤维。在CERCLA的危险物质优先清单上有三种形式的石棉，它是前工业场所和军事基地的常见污染物。然而，吸入这些石棉污染的混合粉尘可能对健康造成不利影响 具体地点尚不清楚。参与氧化还原的过渡金属，尤其是铁的可用性 循环导致自由基的产生被认为在石棉引起的肺部疾病中起着重要作用。据推测，铁和石棉纤维的污染将增强混合粉尘暴露的毒性，因为它增强了铁的动员、氧化还原循环和活性氧物种的产生。该项目的最终目标是开发一组细胞和分子端点，这些端点可以整合到短期筛选策略中，以识别有毒的混合粉尘。实现这一目标的具体目标是：a)产生和表征由惰性颗粒、金属污染颗粒和石棉纤维组成的模型粉尘样品；b)评估这些模型粉尘样品在体外的过渡金属动员和氧化还原活性；c)开发区分无毒和有毒粉尘的基因表达谱；d)使用短期体外测试来探索粉尘和纤维混合毒性的机制；以及e)在慢性致癌试验中验证这一测试策略。

Dusts generated during demolition of buildings, remediation, and construction may be contaminated with toxic particulates including metals and asbestos fibers. Three forms of asbestos are on the CERCLA Priority List of Hazardous Substances and it is a common contaminant at former industrial sites and military bases. However, the potential adverse health effects resulting from inhalation of mixed dusts from these asbestos-contaminated sites are unknown. The availability of transition metals, especially iron, to participate in redox cycling leading to generation of free radicals has been hypothesized to play an important role in asbestos-induced lung diseases. It is hypothesized that contamination with iron and asbestos fibers will potentiate the toxicity of mixed dust exposures due to enhanced iron mobilization, redox cycling, and generation of reactive oxygen species. The ultimate goal of this project is to develop a panel of cellular and molecular endpoints that can be integrated into a short-term screening strategy to identify toxic mixed dusts. The Specific Aims to achieve this goal are: a) To generate and characterize model dust samples composed of inert particles, metal-contaminated particles, and asbestos fibers; b) To assess mobilization of transition metals and redox activity of these model dust samples in vitro; c) To develop a gene expression profile that will differentiate between nontoxic and toxic dusts; d) To explore the mechanisms of mixed dust-fiber toxicity using short-term in vitro assays; and e) To validate this testing strategy in a chronic carcinogenicity assay.