Genotoxic Potential of Mixed Dust Exposures

在建筑物拆除、补救和施工过程中产生的粉尘可能受到有毒颗粒物的污染，包括金属和石棉纤维。三种形式的石棉被列入CERCLA危险物质优先清单，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的不良影响， 地点不详。过渡金属，特别是铁，参与氧化还原的可用性 循环导致自由基的产生已被假设在石棉引起的肺病中起重要作用。据推测，与铁和石棉纤维的污染将加强混合粉尘暴露的毒性，由于增强铁动员，氧化还原循环，并产生活性氧。该项目的最终目标是开发一组细胞和分子终点，可将其纳入短期筛选战略，以识别有毒混合粉尘。实现这一目标的具体目标是：a）生成和表征由惰性颗粒、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的体外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）使用短期体外试验探索混合粉尘-纤维毒性的机制;以及e）在慢性致癌性试验中验证该测试策略。

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.