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NIOSH Respiratory Diseases Research Program

Evidence Package for the National Academies' Review 2006-2007

NIOSH Programs > Respiratory Diseases > Evidence Package > 3. Interstitial Lung Diseases > 3.2 Silica-Induced Respiratory Diseases

3.2d) Provision of Relevant Mechanistic and Dose-Response Data to Standard-Setting Bodies

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Although inhalation of silica has been linked with occupational silicosis, mechanistic information concerning the initiation and progression of silicosis is still needed to support refined risk assessment and promulgation of new, more protective standards. It is also needed to develop biomarkers to identify workers with very early stage disease who may benefit from targeted prevention and treatment efforts. More accurate dose-response data are required to determine the existence of a threshold lung burden upon which to set new exposure standards. In addition, the link between silica and cancer requires more research.71


The two major RDRP planning efforts relating to silica resulted in activities that included research on dose-response relationships and time course of silicosis in animal models and the developments of biometric models to relate such results to human exposure-response; and on mechanisms of disease initiation and progression to support risk assessment and development of biomarkers for early detection of disease in the treatable state.

RDRP scientists conducted a major inhalation study of silica-induced pulmonary responses in a rat model. This multi-disciplinary study involved inhalation technologists, toxicologists, biochemists, microscopists, pathologists, and statistical modelers. This project characterized the dose-response and time course of inflammation, damage, and fibrosis resulting from silica exposure. It identified a threshold lung burden of silica beyond which disease will progress without further exposure (5, A3-58).

These data relating silica lung burden and pulmonary response were also used to develop a model predictive of silica-induced lung disease in humans (6, 7, A3-59, A3-60). RDRP conducted numerous studies to elucidate signaling pathways for the initiation and progression of silicosis and identify the inflammatory and fibrogenic mediators induced by these signaling pathways. Such studies have led to identification of genetic polymorphisms associated with an increased incidence of silicosis (8, A3-61).The discovery of other biomarkers has demonstrated the feasibility of diagnosing of early disease (9, A3-62).

OSHA sought our data to fill essential knowledge gaps which must be resolved to support a new silica standard. Through Interagency Agreements in 1999, 2000, and 2002, OSHA funded RDRP projects to evaluate the time-course of development of silicosis in an animal model, to evaluate dose-response at the lower end of the scale and evaluate the threshold burden, to develop a model comparing rat and human data, and to evaluate the ability of silica to cause lung cancer using susceptible animal models (Perry letter A3-63). OSHA intends to ask RDRP scientists for an expert review of OSHA’s anticipated new silica standard prior to its release for public comment (Schuman letter A3-42).

Outputs and Transfers

RDRP assumed a leadership role in evaluating existing knowledge of silicosis, and identifying research needs and prevention strategies. In this role, RDRP co-sponsored the second and third International Symposia on Silica, Silicosis and Cancer, in 1993 and 2002, respectively. These conferences brought together leading international scientists to present the state of knowledge of silicosis.

RDRP scientists co-edited a book on silica and silica-induced lung diseases, which presents state-of-the art information concerning particle characteristics and biological signaling pathways involved in the initiation and progression of silicosis.72 In 2002, RDRP scientists also prepared a NIOSH Hazard Review, “Health Effects of Occupational Exposure to Respirable Crystalline Silica” (A3-37) (cited at least 49 times). It is a comprehensive review of literature in silica-induced lung disease and the risk assessment based on these data that supports NIOSH REL of 0.05 mg/m3. This recent review included citation of over 75 RDRP publications, indicating the extensive contribution of our research to scientific understanding of silicosis.

In addition, we disseminated information in the lay press via an article concerning the dose-response and threshold for the development of silicosis, which appeared in “Columns-Silica” in 2002 (A3-64).

Intermediate Outcomes

Mechanistic, dose-response, and epidemiologic data generated by RDRP scientists directly influence decisions by OSHA on exposure standards for silica. This is evidenced by the OSHA document “Preliminary Health Effects Discussion on Silica” (June 2006), which is an update concerning the PEL for silica (A3-65). It reviews the state of science concerning risks of pulmonary disease due to exposure to silica. To support their conclusions, OSHA cites key publications in the field of silica research. Publications by RDRP scientists were cited 59 times. Mechanistic data have also driven new research by the scientific community into the initiation and progression of silicosis (Donaldson letter A3-66).

In the planning of a research initiative relating to silicosis in South African gold miners, South Africa’s National Center of Occupational Health formed an advisory panel of four international experts. Two RDRP scientists served on this panel. The panel gave advice and helped plan a research program to monitor blood biomarkers as an early indicator of silica-induced disease in miners. This project is intended to provide a scientific basis for removing workers from dusty jobs at an early reaction stage before disease is irreversible (Murray letter A3-44).

What’s Ahead

The strategic goal is to contribute to the prevention and reduction of silica-induced respiratory diseases. Several research activities are underway to address this goal.

Biomarkers for early detection of the silicosis disease process are being developed. This will be accomplished through a collaborative study with South Africa’s National Center of Occupational Health on “A Biomarker Study for Silicosis in Gold Miners” (Murray letter A3-44).

In addition, we have a collaborative study with researchers in the People’s Republic of China relating the incidence of silicosis in tin miners and pottery workers to particle surface characteristics of the silica dust in these industries.

In the laboratory we are investigating dose- and time-dependence of silica-induced lung cancer using a DNA-repair and apoptosis compromised (p53 deficient) susceptible mouse strain for which we will submit a report to OSHA. We will also complete a study of the role of a novel gene (mineral dust-induced gene, mdig) in silica-induced lung cancer and will submit a final report to OSHA before peer-review publication.

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