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An Exposure-Response Threshold for Lung Diseases and Lung Cancer Caused by Crystalline Silica
Whether crystalline silica (CS) exposure increases risk of lung cancer in humans without silicosis, and, if so, whether the exposure‐response relation has a threshold, have been much debated. Epidemiological evidence is ambiguous and conflicting. Experimental data show that high levels of CS cause l...
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Published in: | Risk analysis 2011-10, Vol.31 (10), p.1543-1560 |
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description | Whether crystalline silica (CS) exposure increases risk of lung cancer in humans without silicosis, and, if so, whether the exposure‐response relation has a threshold, have been much debated. Epidemiological evidence is ambiguous and conflicting. Experimental data show that high levels of CS cause lung cancer in rats, although not in other species, including mice, guinea pigs, or hamsters; but the relevance of such animal data to humans has been uncertain. This article applies recent insights into the toxicology of lung diseases caused by poorly soluble particles (PSPs), and by CS in particular, to model the exposure‐response relation between CS and risk of lung pathologies such as chronic inflammation, silicosis, fibrosis, and lung cancer. An inflammatory mode of action is described, having substantial empirical support, in which exposure increases alveolar macrophages and neutrophils in the alveolar epithelium, leading to increased reactive oxygen species (ROS) and nitrogen species (RNS), pro‐inflammatory mediators such as TNF‐alpha, and eventual damage to lung tissue and epithelial hyperplasia, resulting in fibrosis and increased lung cancer risk among silicotics. This mode of action involves several positive feedback loops. Exposures that increase the gain factors around such loops can create a disease state with elevated levels of ROS, TNF‐alpha, TGF‐beta, alveolar macrophages, and neutrophils. This mechanism implies a “tipping point” threshold for the exposure‐response relation. Applying this new model to epidemiological data, we conclude that current permissible exposure levels, on the order of 0.1 mg/m3, are probably below the threshold for triggering lung diseases in humans. |
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Epidemiological evidence is ambiguous and conflicting. Experimental data show that high levels of CS cause lung cancer in rats, although not in other species, including mice, guinea pigs, or hamsters; but the relevance of such animal data to humans has been uncertain. This article applies recent insights into the toxicology of lung diseases caused by poorly soluble particles (PSPs), and by CS in particular, to model the exposure‐response relation between CS and risk of lung pathologies such as chronic inflammation, silicosis, fibrosis, and lung cancer. An inflammatory mode of action is described, having substantial empirical support, in which exposure increases alveolar macrophages and neutrophils in the alveolar epithelium, leading to increased reactive oxygen species (ROS) and nitrogen species (RNS), pro‐inflammatory mediators such as TNF‐alpha, and eventual damage to lung tissue and epithelial hyperplasia, resulting in fibrosis and increased lung cancer risk among silicotics. 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Applying this new model to epidemiological data, we conclude that current permissible exposure levels, on the order of 0.1 mg/m3, are probably below the threshold for triggering lung diseases in humans.</description><subject>Analysis</subject><subject>Cancer</subject><subject>Crystalline silica</subject><subject>Crystallization</subject><subject>Diseases</subject><subject>dose-response model</subject><subject>Dose-Response Relationship, Drug</subject><subject>Epidemiology</subject><subject>exposure-response</subject><subject>Hazardous products</subject><subject>Human exposure</subject><subject>Humans</subject><subject>Lung - metabolism</subject><subject>Lung cancer</subject><subject>lung cancer risk</subject><subject>Lung diseases</subject><subject>Lung Diseases - chemically induced</subject><subject>Lung Diseases - metabolism</subject><subject>mathematical model</subject><subject>Neutrophils</subject><subject>Occupational Exposure</subject><subject>Reactive Nitrogen Species - metabolism</subject><subject>Reactive Oxygen Species</subject><subject>Risk</subject><subject>Risk management</subject><subject>Silicon Dioxide - chemistry</subject><subject>Silicon Dioxide - toxicity</subject><subject>Silicosis</subject><subject>Studies</subject><subject>Toxicity</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><issn>0272-4332</issn><issn>1539-6924</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>8BJ</sourceid><recordid>eNqNkU2L2zAQhkVp6abb_oUieunJ6UiWLelSCOl-QdjCfrDLQhGKPe46dexUE7PJv69cb3PopRWCEZpnHpBexriAqYjr02oqstQmuZVqKkGIKYg89nYv2OTQeMkmILVMVJrKI_aGaAUgADL9mh1JobQGoybs26zlJ7tNR33A5App07WE_OYxID12TcmrLvBF337nX2pCT0jct-V4M_dtgSGWnrDkyz2fhz1tfdPULfLruqkL_5a9qnxD-O65HrPb05Ob-Xmy-Hp2MZ8tkkLlOSSZBkTU1lSprEqhK1tIJVFIUGJpZCkrg5kHaUApVJXG3OIScl8oqwzaPD1mH0fvJnQ_e6StW9dUYNP4FruenBVa2rj_TRprTGqEHsgPf5Grrg9tfMYAqfjF1kbIjFAROqKAlduEeu3D3glwQ1Ru5YZE3JCIG6Jyv6Nyuzj6_tnfL9dYHgb_ZBOBzyPwVDe4_2-xu7q4ng3HKEhGQU1b3B0EPvxwuU515u4uz9wd3N_rS3HuHtJfy8avug</recordid><startdate>201110</startdate><enddate>201110</enddate><creator>Cox, Jr, Louis Anthony (Tony)</creator><general>Blackwell Publishing Inc</general><general>Blackwell Publishing Ltd</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7ST</scope><scope>7U7</scope><scope>7U9</scope><scope>8BJ</scope><scope>8FD</scope><scope>C1K</scope><scope>FQK</scope><scope>FR3</scope><scope>H94</scope><scope>JBE</scope><scope>JQ2</scope><scope>KR7</scope><scope>M7N</scope><scope>SOI</scope><scope>7X8</scope></search><sort><creationdate>201110</creationdate><title>An Exposure-Response Threshold for Lung Diseases and Lung Cancer Caused by Crystalline Silica</title><author>Cox, Jr, Louis Anthony (Tony)</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4660-570eee798f32fd17f9c242e12041b82d2f8e5a028044e4f7e69eb06ac4948e963</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Analysis</topic><topic>Cancer</topic><topic>Crystalline silica</topic><topic>Crystallization</topic><topic>Diseases</topic><topic>dose-response model</topic><topic>Dose-Response Relationship, Drug</topic><topic>Epidemiology</topic><topic>exposure-response</topic><topic>Hazardous products</topic><topic>Human exposure</topic><topic>Humans</topic><topic>Lung - metabolism</topic><topic>Lung cancer</topic><topic>lung cancer risk</topic><topic>Lung diseases</topic><topic>Lung Diseases - chemically induced</topic><topic>Lung Diseases - metabolism</topic><topic>mathematical model</topic><topic>Neutrophils</topic><topic>Occupational Exposure</topic><topic>Reactive Nitrogen Species - metabolism</topic><topic>Reactive Oxygen Species</topic><topic>Risk</topic><topic>Risk management</topic><topic>Silicon Dioxide - chemistry</topic><topic>Silicon Dioxide - toxicity</topic><topic>Silicosis</topic><topic>Studies</topic><topic>Toxicity</topic><topic>Tumor Necrosis Factor-alpha - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cox, Jr, Louis Anthony (Tony)</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Environment Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>International Bibliography of the Social Sciences (IBSS)</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>International Bibliography of the Social Sciences</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>International Bibliography of the Social Sciences</collection><collection>ProQuest Computer Science Collection</collection><collection>Civil Engineering Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Environment Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Risk analysis</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cox, Jr, Louis Anthony (Tony)</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>An Exposure-Response Threshold for Lung Diseases and Lung Cancer Caused by Crystalline Silica</atitle><jtitle>Risk analysis</jtitle><addtitle>Risk Anal</addtitle><date>2011-10</date><risdate>2011</risdate><volume>31</volume><issue>10</issue><spage>1543</spage><epage>1560</epage><pages>1543-1560</pages><issn>0272-4332</issn><eissn>1539-6924</eissn><abstract>Whether crystalline silica (CS) exposure increases risk of lung cancer in humans without silicosis, and, if so, whether the exposure‐response relation has a threshold, have been much debated. Epidemiological evidence is ambiguous and conflicting. Experimental data show that high levels of CS cause lung cancer in rats, although not in other species, including mice, guinea pigs, or hamsters; but the relevance of such animal data to humans has been uncertain. This article applies recent insights into the toxicology of lung diseases caused by poorly soluble particles (PSPs), and by CS in particular, to model the exposure‐response relation between CS and risk of lung pathologies such as chronic inflammation, silicosis, fibrosis, and lung cancer. An inflammatory mode of action is described, having substantial empirical support, in which exposure increases alveolar macrophages and neutrophils in the alveolar epithelium, leading to increased reactive oxygen species (ROS) and nitrogen species (RNS), pro‐inflammatory mediators such as TNF‐alpha, and eventual damage to lung tissue and epithelial hyperplasia, resulting in fibrosis and increased lung cancer risk among silicotics. This mode of action involves several positive feedback loops. Exposures that increase the gain factors around such loops can create a disease state with elevated levels of ROS, TNF‐alpha, TGF‐beta, alveolar macrophages, and neutrophils. This mechanism implies a “tipping point” threshold for the exposure‐response relation. Applying this new model to epidemiological data, we conclude that current permissible exposure levels, on the order of 0.1 mg/m3, are probably below the threshold for triggering lung diseases in humans.</abstract><cop>Malden, USA</cop><pub>Blackwell Publishing Inc</pub><pmid>21477084</pmid><doi>10.1111/j.1539-6924.2011.01610.x</doi><tpages>18</tpages></addata></record> |
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subjects | Analysis Cancer Crystalline silica Crystallization Diseases dose-response model Dose-Response Relationship, Drug Epidemiology exposure-response Hazardous products Human exposure Humans Lung - metabolism Lung cancer lung cancer risk Lung diseases Lung Diseases - chemically induced Lung Diseases - metabolism mathematical model Neutrophils Occupational Exposure Reactive Nitrogen Species - metabolism Reactive Oxygen Species Risk Risk management Silicon Dioxide - chemistry Silicon Dioxide - toxicity Silicosis Studies Toxicity Tumor Necrosis Factor-alpha - metabolism |
title | An Exposure-Response Threshold for Lung Diseases and Lung Cancer Caused by Crystalline Silica |
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