The re-emergence of silicosis in Australia associated with the widespread use of engineered stone has highlighted the limited understanding of the pathogenesis of this disease. Industrial exposure to respirable crystalline silica (RCS) results in the rapid development of accelerated silicosis (AS), leading to lung fibrosis and respiratory failure (1). Current knowledge of silicosis disease is largely based on mouse and rat models that deliver a single large dose of silica (up to 20 mg) to the lungs and examine the effects soon after (2, 3). These are not representative of human exposure or the course of clinical silicosis disease. Human studies have generally examined changes in patients with advanced disease, and thus the early events in the pathogenesis is a critically understudied aspect of silicosis. As the cumulative dose of silica over time and the amounts retained in the lung are major factors that drive progressive human AS (4), we have developed a repeated low-dose RCS exposure model in mice to examine early-stage inflammatory, cellular and transcriptional changes in the lungs, as well as lung function and gas exchange measures, including forced oscillations and diffusing capacity for carbon monoxide (DLCO), similar to those measured in patients. Using this model to examine dose-response kinetics, we found that repeated exposure to as little as 1 mg RCS over two weeks induces significant cellular infiltration in the lungs, highly elevated TNF, IL-6 and MCP-1 levels in bronchoalveolar lavage fluid, and lung dysfunction in the form of significantly decreased DLCO. Extended RCS accumulation over longer periods of time induced macroscopically evident pulmonary nodules, increased cellular and cytokine involvement, further lung dysfunction and widespread transcriptional changes. As such, this study maps the pulmonary immunological developments during AS onset to facilitate the discovery of early interventions for a major and debilitating occupational lung disease.