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Recently, through transcriptome profiling of peripheral blood mononuclear cells (PBMC), we reported dose-dependent effects of benzene exposure on gene expression and biochemical pathways in 83 workers exposed across four airborne concentration ranges (from ,1 ppm to . 10 ppm) compared with 42 subjects with non-workplace ambient exposure levels. Here, we further characterize these dosedependent effects with continuous benzene exposure in all 125 study subjects. We estimated air benzene exposure levels in the 42 environmentally-exposed subjects from their unmetabolized urinary benzene levels. We used a novel nonparametric, data-adaptive model selection method to estimate the change with dose in the expression of each gene. We describe non-parametric approaches to model pathway responses and used these to estimate the dose responses of the AML pathway and 4 other pathways of interest. The response patterns of majority of genes as captured by mean estimates of the first and second principal components of the dose-response for the five pathways and the profiles of 6 AML pathway response-representative genes (identified by clustering) exhibited similar apparent supra-linear responses. Responses at or below 0.1 ppm benzene were observed for altered expression of AML pathway genes and CYP2E1. Together, these data show that benzene alters disease-relevant pathways and genes in a dose-dependent manner, with effects apparent at doses as low as 100 ppb in air. Studies with extensive exposure assessment of subjects exposed in the low-dose range between 10 ppb and 1 ppm are needed to confirm these findings.","publication_date":"2014,,","publication_name":"PLoS ONE","grobid_abstract_attachment_id":"44881622"},"document_type":"paper","pre_hit_view_count_baseline":null,"quality":"high","language":"en","title":"Characterization of Changes in Gene Expression and Biochemical Pathways at Low Levels of Benzene Exposure","broadcastable":true,"draft":null,"has_indexable_attachment":true,"indexable":true}}["work"]; window.loswp.workCoauthors = [32943985]; window.loswp.locale = "en"; window.loswp.countryCode = "SG"; window.loswp.cwvAbTestBucket = ""; window.loswp.designVariant = "ds_vanilla"; window.loswp.fullPageMobileSutdModalVariant = "control"; window.loswp.useOptimizedScribd4genScript = false; window.loginModal = {}; window.loginModal.appleClientId = 'edu.academia.applesignon'; window.userInChina = "false";</script><script defer="" src="https://accounts.google.com/gsi/client"></script><div class="ds-loswp-container"><div class="ds-work-card--grid-container"><div class="ds-work-card--container js-loswp-work-card"><div class="ds-work-card--cover"><div class="ds-work-cover--wrapper"><div class="ds-work-cover--container"><button class="ds-work-cover--clickable js-swp-download-button" data-signup-modal="{"location":"swp-splash-paper-cover","attachmentId":44881622,"attachmentType":"pdf"}"><img alt="First page of “Characterization of Changes in Gene Expression and Biochemical Pathways at Low Levels of Benzene Exposure”" class="ds-work-cover--cover-thumbnail" src="https://0.academia-photos.com/attachment_thumbnails/44881622/mini_magick20220706-23782-1sxv6s2.png?1657118086" /><img alt="PDF Icon" class="ds-work-cover--file-icon" src="//a.academia-assets.com/images/single_work_splash/adobe_icon.svg" /><div class="ds-work-cover--hover-container"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">download</span><p>Download Free PDF</p></div><div class="ds-work-cover--ribbon-container">Download Free PDF</div><div class="ds-work-cover--ribbon-triangle"></div></button></div></div></div><div class="ds-work-card--work-information"><h1 class="ds-work-card--work-title">Characterization of Changes in Gene Expression and Biochemical Pathways at Low Levels of Benzene Exposure</h1><div class="ds-work-card--work-authors ds-work-card--detail"><a class="ds-work-card--author js-wsj-grid-card-author ds2-5-body-md ds2-5-body-link" data-author-id="32943985" href="https://independent.academia.edu/ClionaMcHale"><img alt="Profile image of Cliona McHale" class="ds-work-card--author-avatar" src="//a.academia-assets.com/images/s65_no_pic.png" />Cliona McHale</a></div><div class="ds-work-card--detail"><p class="ds-work-card--detail ds2-5-body-sm">2014, PLoS ONE</p><div class="ds-work-card--work-metadata"><div class="ds-work-card--work-metadata__stat"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">visibility</span><p class="ds2-5-body-sm" id="work-metadata-view-count">…</p></div><div class="ds-work-card--work-metadata__stat"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">description</span><p class="ds2-5-body-sm">13 pages</p></div><div class="ds-work-card--work-metadata__stat"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">link</span><p class="ds2-5-body-sm">1 file</p></div></div><script>(async () => { const workId = 13849777; 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if (!viewCountBody) { throw new Error('Failed to find work views element'); } viewCountBody.textContent = `${commaizedViewCount} views`; } catch (error) { // Remove the whole views element if there was some issue parsing. document.getElementById('work-metadata-view-count')?.parentNode?.remove(); throw new Error(`Failed to parse view count: ${viewCount}`, error); } }; // If the DOM is still loading, wait for it to be ready before updating the view count. if (document.readyState === "loading") { document.addEventListener('DOMContentLoaded', () => { updateViewCount(viewCount); }); // Otherwise, just update it immediately. } else { updateViewCount(viewCount); } })();</script></div><p class="ds-work-card--work-abstract ds-work-card--detail ds2-5-body-md">Benzene, a ubiquitous environmental pollutant, causes acute myeloid leukemia (AML). Recently, through transcriptome profiling of peripheral blood mononuclear cells (PBMC), we reported dose-dependent effects of benzene exposure on gene expression and biochemical pathways in 83 workers exposed across four airborne concentration ranges (from ,1 ppm to . 10 ppm) compared with 42 subjects with non-workplace ambient exposure levels. Here, we further characterize these dosedependent effects with continuous benzene exposure in all 125 study subjects. We estimated air benzene exposure levels in the 42 environmentally-exposed subjects from their unmetabolized urinary benzene levels. We used a novel nonparametric, data-adaptive model selection method to estimate the change with dose in the expression of each gene. We describe non-parametric approaches to model pathway responses and used these to estimate the dose responses of the AML pathway and 4 other pathways of interest. The response patterns of majority of genes as captured by mean estimates of the first and second principal components of the dose-response for the five pathways and the profiles of 6 AML pathway response-representative genes (identified by clustering) exhibited similar apparent supra-linear responses. Responses at or below 0.1 ppm benzene were observed for altered expression of AML pathway genes and CYP2E1. Together, these data show that benzene alters disease-relevant pathways and genes in a dose-dependent manner, with effects apparent at doses as low as 100 ppb in air. Studies with extensive exposure assessment of subjects exposed in the low-dose range between 10 ppb and 1 ppm are needed to confirm these findings.</p><div class="ds-work-card--button-container"><button class="ds2-5-button js-swp-download-button" data-signup-modal="{"location":"continue-reading-button--work-card","attachmentId":44881622,"attachmentType":"pdf","workUrl":"https://www.academia.edu/13849777/Characterization_of_Changes_in_Gene_Expression_and_Biochemical_Pathways_at_Low_Levels_of_Benzene_Exposure"}">See full PDF</button><button class="ds2-5-button ds2-5-button--secondary js-swp-download-button" data-signup-modal="{"location":"download-pdf-button--work-card","attachmentId":44881622,"attachmentType":"pdf","workUrl":"https://www.academia.edu/13849777/Characterization_of_Changes_in_Gene_Expression_and_Biochemical_Pathways_at_Low_Levels_of_Benzene_Exposure"}"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">download</span>Download PDF</button></div><div class="ds-signup-banner-trigger-container"><div class="ds-signup-banner-trigger ds-signup-banner-trigger-control"></div></div><div class="ds-signup-banner ds-signup-banner-control"><div id="ds-signup-banner-close-button"><button class="ds2-5-button ds2-5-button--secondary ds2-5-button--inverse"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">close</span></button></div><div class="ds-signup-banner-ctas"><img src="//a.academia-assets.com/images/academia-logo-capital-white.svg" /><h4 class="ds2-5-heading-serif-sm">Sign up for access to the world's latest research</h4><button class="ds2-5-button ds2-5-button--inverse ds2-5-button--full-width js-swp-download-button" data-signup-modal="{"location":"signup-banner"}">Sign up for free<span class="material-symbols-outlined" style="font-size: 20px" translate="no">arrow_forward</span></button></div><div class="ds-signup-banner-divider"></div><div class="ds-signup-banner-reasons"><div class="ds-signup-banner-reasons-item"><span class="material-symbols-outlined" style="font-size: 24px" translate="no">check</span><span>Get notified about relevant papers</span></div><div class="ds-signup-banner-reasons-item"><span class="material-symbols-outlined" style="font-size: 24px" translate="no">check</span><span>Save papers to use in your research</span></div><div class="ds-signup-banner-reasons-item"><span class="material-symbols-outlined" style="font-size: 24px" translate="no">check</span><span>Join the discussion with peers</span></div><div class="ds-signup-banner-reasons-item"><span class="material-symbols-outlined" style="font-size: 24px" translate="no">check</span><span>Track your impact</span></div></div></div><script>(() => { // Set up signup banner show/hide behavior: // 1. 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This paper reexamines the animal-based risk assessments for benzene using physiologically-based pharmacokinetic (PBPK) models of benzene metabolism in animals and humans. It demonstrates that internal doses (interpreted as total benzene metabolites formed) from oral gavage experiments in mice are well predicted by a PBPK model developed by Travis et al. Both the data and the model outputs can also be accurately described by the simple nonlinear regression model total metabolites = 76.4x/(80.75 + x), where x = administered dose in mg/kg/day. Thus, PBPK modeling validates the use of such nonlinear regression models, previously used by Bailer and Hoel. An important finding is that refitting the linearized multistage (LMS) model family to internal doses and observed responses changes the maximum-likelihood estimate (MLE) dose-response curve for mice from linear-quadratic to cubic, leading to low-dose risk estimates smaller than in previous risk assessments. This is consistent with the conclusion for mice from the Bailer and Hoel analysis. An innovation in this paper is estimation of internal doses for humans based on a PBPK model (and the regression model approximating it) rather than on interspecies dose conversions. Estimates of human risks at low doses are reduced by the use of internal dose estimates when the estimates are obtained from a PBPK model, in contrast to Bailer and Hoel&amp;#39;s findings based on interspecies dose conversion. Sensitivity analyses and comparisons with epidemiological data and risk models suggest that our finding of a nonlinear MLE dose-response curve at low doses is robust to changes in assumptions and more consistent with epidemiological data than earlier risk models.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Reassessing Benzene Cancer Risks Using Internal Doses","attachmentId":42101612,"attachmentType":"pdf","work_url":"https://www.academia.edu/19259983/Reassessing_Benzene_Cancer_Risks_Using_Internal_Doses","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/19259983/Reassessing_Benzene_Cancer_Risks_Using_Internal_Doses"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="1" data-entity-id="63035039" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/63035039/The_Impact_of_Saturable_Metabolism_on_Exposure_Response_Relations_in_2_Studies_of_Benzene_induced_Leukemia">The Impact of Saturable Metabolism on Exposure-Response Relations in 2 Studies of Benzene-induced Leukemia</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="36175191" href="https://independent.academia.edu/DGlass1">D. Glass</a></div><p class="ds-related-work--metadata ds2-5-body-xs">American Journal of Epidemiology, 2011</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"The Impact of Saturable Metabolism on Exposure-Response Relations in 2 Studies of Benzene-induced Leukemia","attachmentId":76128053,"attachmentType":"pdf","work_url":"https://www.academia.edu/63035039/The_Impact_of_Saturable_Metabolism_on_Exposure_Response_Relations_in_2_Studies_of_Benzene_induced_Leukemia","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/63035039/The_Impact_of_Saturable_Metabolism_on_Exposure_Response_Relations_in_2_Studies_of_Benzene_induced_Leukemia"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="2" data-entity-id="18453272" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/18453272/Alternative_Testing_Methods_for_Predicting_Health_Risk_from_Environmental_Exposures">Alternative Testing Methods for Predicting Health Risk from Environmental Exposures</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="38461379" href="https://independent.academia.edu/VaccariMonica">Monica Vaccari</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Sustainability, 2014</p><p class="ds-related-work--abstract ds2-5-body-sm">ABSTRACT Alternative methods to animal testing are considered as promising tools to support the prediction of toxicological risks from environmental exposure. Among the alternative testing methods, the cell transformation assay (CTA) appears to be one of the most appropriate approaches to predict the carcinogenic properties of single chemicals, complex mixtures and environmental pollutants. The BALB/c 3T3 CTA shows a good degree of concordance with the in vivo rodent carcinogenesis tests. Whole-genome transcriptomic profiling is performed to identify genes that are transcriptionally regulated by different kinds of exposures. Its use in cell models representative of target organs may help in understanding the mode of action and predicting the risk for human health. Aiming at associating the environmental exposure to health-adverse outcomes, we used an integrated approach including the 3T3 CTA and transcriptomics on target cells, in order to evaluate the effects of airborne particulate matter (PM) on toxicological complex endpoints. Organic extracts obtained from PM2.5 and PM1 samples were evaluated in the 3T3 CTA in order to identify effects possibly associated with different aerodynamic diameters or airborne chemical components. The effects of the PM2.5 extracts on human health were assessed by using whole-genome 44 K oligo-microarray slides. Statistical analysis by GeneSpring GX identified genes whose expression was modulated in response to the cell treatment. Then, modulated genes were associated with pathways, biological processes and diseases through an extensive biological analysis. Data derived from in vitro methods and omics techniques could be valuable for monitoring the exposure to toxicants, understanding the modes of action via exposure-associated gene expression patterns and to highlight the role of genes in key events related to adversity.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Alternative Testing Methods for Predicting Health Risk from Environmental Exposures","attachmentId":42168121,"attachmentType":"pdf","work_url":"https://www.academia.edu/18453272/Alternative_Testing_Methods_for_Predicting_Health_Risk_from_Environmental_Exposures","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/18453272/Alternative_Testing_Methods_for_Predicting_Health_Risk_from_Environmental_Exposures"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="3" data-entity-id="29673478" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/29673478/Commentary_Biological_Effects_of_Low_Level_Exposures_A_Perspective_from_U_S_EPA_Scientists">Commentary: Biological Effects of Low-Level Exposures: A Perspective from U.S. EPA Scientists</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="56130807" href="https://colostate.academia.edu/WFarland">W. Farland</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Environmental Health Perspectives, 1998</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Commentary: Biological Effects of Low-Level Exposures: A Perspective from U.S. EPA Scientists","attachmentId":50107762,"attachmentType":"pdf","work_url":"https://www.academia.edu/29673478/Commentary_Biological_Effects_of_Low_Level_Exposures_A_Perspective_from_U_S_EPA_Scientists","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/29673478/Commentary_Biological_Effects_of_Low_Level_Exposures_A_Perspective_from_U_S_EPA_Scientists"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="4" data-entity-id="93358078" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/93358078/Global_Gene_Expression_Profiling_of_a_Population_Exposed_to_a_Range_of_Benzene_Levels">Global Gene Expression Profiling of a Population Exposed to a Range of Benzene Levels</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="32943985" href="https://independent.academia.edu/ClionaMcHale">Cliona McHale</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Environmental Health Perspectives, 2010</p><p class="ds-related-work--abstract ds2-5-body-sm">Petroleum Institute for consulting on benzene-related health research. S.M.R. has received consulting and expert testimony fees from law firms representing plaintiffs' cases involving exposure to benzene and has received research support from the American Petroleum Institute and the American Chemistry Council. M.T.S. has received consulting and expert testimony fees from law firms representing both plaintiffs and defendants in cases involving exposure to benzene. The other authors declare they have no actual or potential competing financial interests.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Global Gene Expression Profiling of a Population Exposed to a Range of Benzene Levels","attachmentId":96117546,"attachmentType":"pdf","work_url":"https://www.academia.edu/93358078/Global_Gene_Expression_Profiling_of_a_Population_Exposed_to_a_Range_of_Benzene_Levels","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/93358078/Global_Gene_Expression_Profiling_of_a_Population_Exposed_to_a_Range_of_Benzene_Levels"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="5" data-entity-id="118616792" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/118616792/Modes_of_action_considerations_in_threshold_expectations_for_health_effects_of_benzene">Modes of action considerations in threshold expectations for health effects of benzene</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="32793437" href="https://independent.academia.edu/NeslihanKocabas">Neslihan Kocabas</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Toxicology Letters, 2020</p><p class="ds-related-work--abstract ds2-5-body-sm">Understanding the Mode of Action (MOA) for a chemical can help guide decisions in development of Occupational Exposure Limits (OELs). Where sufficient information exists, it can provide the OEL developer the basis for selecting either a health-based or risk-based approach. To support the development of an OEL for benzene, scientific information relevant to MOA assessment for risk-based and health-based OEL approaches was reviewed. Direct-acting mutagenicity was considered as a basis for a risk-based OEL, versus MOAs consistent with a health-based approach: indirect mutagenicity via topoisomerase II inhibition, indirect mutagenicity via reactive oxygen species generation, or an immune-based bone marrow dysfunction. Based on the evidence against direct DNA reactivity, threshold expectations for remaining MOAs, and evidence for dose rate affecting acute myeloid leukemia and myelodysplastic syndrome risk, the weight of evidence favors a health-based OEL approach. In the case of benzene, development of an OEL based on observations of earlier key events (i.e., hematologic changes and genetic toxicity) is anticipated to provide protection from later adverse outcomes such as leukemia.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Modes of action considerations in threshold expectations for health effects of benzene","attachmentId":114199655,"attachmentType":"pdf","work_url":"https://www.academia.edu/118616792/Modes_of_action_considerations_in_threshold_expectations_for_health_effects_of_benzene","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/118616792/Modes_of_action_considerations_in_threshold_expectations_for_health_effects_of_benzene"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="6" data-entity-id="96222341" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/96222341/A_Quantitative_Meta_Analysis_of_the_Relation_between_Occupational_Benzene_Exposure_and_Biomarkers_of_Cytogenetic_Damage">A Quantitative Meta-Analysis of the Relation between Occupational Benzene Exposure and Biomarkers of Cytogenetic Damage</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="199497754" href="https://independent.academia.edu/BerniceScholten">Bernice Scholten</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Environmental Health Perspectives, 2020</p><p class="ds-related-work--abstract ds2-5-body-sm">BACKGROUND: The genotoxicity of benzene has been investigated in dozens of biomonitoring studies, mainly by studying (classical) chromosomal aberrations (CAs) or micronuclei (MN) as markers of DNA damage. Both have been shown to be predictive of future cancer risk in cohort studies and could, therefore, potentially be used for risk assessment of genotoxicity-mediated cancers. OBJECTIVES: We sought to estimate an exposure-response curve (ERC) and quantify between-study heterogeneity using all available quantitative evidence on the cytogenetic effects of benzene exposure on CAs and MN respectively. METHODS: We carried out a systematic literature review and summarized all available data of sufficient quality using meta-analyses. We assessed the heterogeneity in slope estimates between studies and conducted additional sensitivity analyses to assess how various study characteristics impacted the estimated ERC. RESULTS: Sixteen CA (1,356 individuals) and 13 MN studies (2,097 individuals) were found to be eligible for inclusion in a meta-analysis. Studies where benzene was the primary genotoxic exposure and that had adequate assessment of both exposure and outcomes were used for the primary analysis. Estimated slope estimates were an increase of 0.27% CA [(95% CI: 0.08%, 0.47%); based on the results from 4 studies] and 0.27% MN [(95% CI: −0:23%, 0.76%); based on the results from 7 studies] per parts-per-million benzene exposure. We observed considerable between-study heterogeneity for both end points (I 2 > 90%). DISCUSSION: Our study provides a systematic, transparent, and quantitative summary of the literature describing the strong association between benzene exposure and accepted markers of genotoxicity in humans. The derived consensus slope can be used as a best estimate of the quantitative relationship between real-life benzene exposure and genetic damage in future risk assessment. We also quantitate the large between-study heterogeneity that exists in this literature, a factor which is crucial for the interpretation of single-study or consensus slopes.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"A Quantitative Meta-Analysis of the Relation between Occupational Benzene Exposure and Biomarkers of Cytogenetic Damage","attachmentId":98180825,"attachmentType":"pdf","work_url":"https://www.academia.edu/96222341/A_Quantitative_Meta_Analysis_of_the_Relation_between_Occupational_Benzene_Exposure_and_Biomarkers_of_Cytogenetic_Damage","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/96222341/A_Quantitative_Meta_Analysis_of_the_Relation_between_Occupational_Benzene_Exposure_and_Biomarkers_of_Cytogenetic_Damage"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="7" data-entity-id="66387668" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/66387668/Felter_et_al_Crit_Rev_Toxicol_2011">Felter et al Crit Rev Toxicol 2011</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="62617641" href="https://independent.academia.edu/PMichaelBolger">P. Michael Bolger</a></div><p class="ds-related-work--abstract ds2-5-body-sm">Quantitative methods for estimation of cancer risk have been developed for daily, lifetime human exposures. There are a variety of studies or methodologies available to address less-than-lifetime exposures. However, a common framework for evaluating risk from less-than-lifetime exposures (including short-term and/or intermittent exposures) does not exist, which could result in inconsistencies in risk assessment practice. To address this risk assessment need, a committee of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute conducted a multisector workshop in late 2009 to discuss available literature, different methodologies, and a proposed framework. The proposed framework provides a decision tree and guidance for cancer risk assessments for less-than-lifetime exposures based on current knowledge of mode of action and dose-response. Available data from rodent studies and epidemiological studies involving less-than-lifetime exposures are considered, in addition to statistical approaches described in the literature for evaluating the impact of changing the dose rate and exposure duration for exposure to carcinogens. The decision tree also provides for scenarios in which an assumption of potential carcinogenicity is appropriate (e.g., based on structural alerts or genotoxicity data), but bioassay or other data are lacking from which a chemical-specific cancer potency can be determined. This paper presents an overview of the rationale for the workshop, reviews historical background, describes the proposed framework for assessing less-than-lifetime exposures to potential human carcinogens, and suggests next steps.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Felter et al Crit Rev Toxicol 2011","attachmentId":77598812,"attachmentType":"pdf","work_url":"https://www.academia.edu/66387668/Felter_et_al_Crit_Rev_Toxicol_2011","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/66387668/Felter_et_al_Crit_Rev_Toxicol_2011"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="8" data-entity-id="13849772" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/13849772/Use_of_Omic_technologies_to_study_humans_exposed_to_benzene">Use of ‘Omic’ technologies to study humans exposed to benzene</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="32943985" href="https://independent.academia.edu/ClionaMcHale">Cliona McHale</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Chemico-Biological Interactions, 2005</p><p class="ds-related-work--abstract ds2-5-body-sm">Omic' technologies include genomics, transcriptomics (gene expression profiling), proteomics and metabolomics. We are utilizing these new technologies in an effort to develop novel biomarkers of exposure, susceptibility and response to benzene. Advances in genomics allow one to study hundreds to thousands of single nucleotide polymorphisms simultaneously on small quantities of DNA using array-based technologies. We are currently utilizing these technologies to examine genetic variation in pathways relating to biotransformation, DNA repair, folate metabolism and immune response with the goal of finding biomarkers of susceptibility to benzene hematotoxicity. Transcriptomics is used to measure the full complement of activated genes, mRNAs or transcripts in a particular tissue at a particular time typically using microarray technology. We have applied microarrays to the study of global gene expression in the peripheral blood cells of benzene-exposed workers. More than 100 genes were identified as being potentially differentially expressed, with genes related to apoptosis and immune function being the most significantly affected. Initial studies employing proteomics have also shown that several proteins are altered in the serum of exposed compared to control subjects and these proteins are potential biomarkers of benzene exposure. Omic technologies therefore have significant potential in generating novel biomarkers of exposure, susceptibility and response to benzene.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Use of ‘Omic’ technologies to study humans exposed to benzene","attachmentId":44881608,"attachmentType":"pdf","work_url":"https://www.academia.edu/13849772/Use_of_Omic_technologies_to_study_humans_exposed_to_benzene","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/13849772/Use_of_Omic_technologies_to_study_humans_exposed_to_benzene"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="9" data-entity-id="12478255" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/12478255/Low_air_levels_of_benzene_Correlation_between_biomarkers_of_exposure_and_genotoxic_effects">Low air levels of benzene: Correlation between biomarkers of exposure and genotoxic effects</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="31324191" href="https://independent.academia.edu/PieroLovreglio">Piero Lovreglio</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Toxicology Letters, 2010</p><p class="ds-related-work--abstract ds2-5-body-sm">This study was aimed to identify useful biomarkers of exposure and effect in workers exposed to low levels of benzene, and to evaluate any correlations existing between these parameters.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Low air levels of benzene: Correlation between biomarkers of exposure and genotoxic effects","attachmentId":46153583,"attachmentType":"pdf","work_url":"https://www.academia.edu/12478255/Low_air_levels_of_benzene_Correlation_between_biomarkers_of_exposure_and_genotoxic_effects","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/12478255/Low_air_levels_of_benzene_Correlation_between_biomarkers_of_exposure_and_genotoxic_effects"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div></div></div><div class="ds-sticky-ctas--wrapper js-loswp-sticky-ctas hidden"><div class="ds-sticky-ctas--grid-container"><div class="ds-sticky-ctas--container"><button class="ds2-5-button js-swp-download-button" data-signup-modal="{"location":"continue-reading-button--sticky-ctas","attachmentId":44881622,"attachmentType":"pdf","workUrl":null}">See full PDF</button><button class="ds2-5-button ds2-5-button--secondary js-swp-download-button" data-signup-modal="{"location":"download-pdf-button--sticky-ctas","attachmentId":44881622,"attachmentType":"pdf","workUrl":null}"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">download</span>Download PDF</button></div></div></div><div class="ds-below-fold--grid-container"><div class="ds-work--container js-loswp-embedded-document"><div class="attachment_preview" data-attachment="Attachment_44881622" style="display: none"><div class="js-scribd-document-container"><div class="scribd--document-loading js-scribd-document-loader" style="display: block;"><img alt="Loading..." src="//a.academia-assets.com/images/loaders/paper-load.gif" /><p>Loading Preview</p></div></div><div style="text-align: center;"><div class="scribd--no-preview-alert js-preview-unavailable"><p>Sorry, preview is currently unavailable. You can download the paper by clicking the button above.</p></div></div></div></div><div class="ds-sidebar--container js-work-sidebar"><div class="ds-related-content--container"><h2 class="ds-related-content--heading">Related papers</h2><div class="ds-related-work--container js-related-work-sidebar-card" data-collection-position="0" data-entity-id="125186993" data-sort-order="default"><a class="ds-related-work--title js-related-work-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/125186993/The_Use_of_Biochemical_and_Molecular_Parameters_to_Estimate_Dose_Response_Relationships_at_Low_Levels_of_Exposure">The Use of Biochemical and Molecular Parameters to Estimate Dose-Response Relationships at Low Levels of Exposure</a><div class="ds-related-work--metadata"><a class="js-related-work-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="139624241" href="https://independent.academia.edu/AndersenMelvin">Melvin Andersen</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Environmental Health Perspectives, 1998</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"The Use of Biochemical and Molecular Parameters to Estimate Dose-Response Relationships at Low Levels of Exposure","attachmentId":119274772,"attachmentType":"pdf","work_url":"https://www.academia.edu/125186993/The_Use_of_Biochemical_and_Molecular_Parameters_to_Estimate_Dose_Response_Relationships_at_Low_Levels_of_Exposure","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-related-work-grid-card-view-pdf" href="https://www.academia.edu/125186993/The_Use_of_Biochemical_and_Molecular_Parameters_to_Estimate_Dose_Response_Relationships_at_Low_Levels_of_Exposure"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-related-work-sidebar-card" data-collection-position="1" data-entity-id="23170718" data-sort-order="default"><a class="ds-related-work--title js-related-work-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/23170718/A_Paradigm_Shift_is_Required_for_the_Risk_Assessment_of_Potential_Human_Health_After_Exposure_to_Low_Level_Chemical_Exposures_A_Response_to_the_Toxicity_Testing_in_the_21st_Century_Report">A Paradigm Shift is Required for the Risk Assessment of Potential Human Health After Exposure to Low Level Chemical Exposures: A Response to the Toxicity Testing in the 21st Century Report</a><div class="ds-related-work--metadata"><a class="js-related-work-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="44960707" href="https://independent.academia.edu/JamesTrosko">James Trosko</a></div><p class="ds-related-work--metadata ds2-5-body-xs">International Journal of Toxicology, 2010</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"A Paradigm Shift is Required for the Risk Assessment of Potential Human Health After Exposure to Low Level Chemical Exposures: A Response to the Toxicity Testing in the 21st Century 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class="ds-related-work--container js-related-work-sidebar-card" data-collection-position="2" data-entity-id="110190983" data-sort-order="default"><a class="ds-related-work--title js-related-work-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/110190983/Consistencies_and_inconsistencies_underlying_the_quantitative_assessment_of_leukemia_risk_from_benzene_exposure">Consistencies and inconsistencies underlying the quantitative assessment of leukemia risk from benzene exposure</a><div class="ds-related-work--metadata"><a class="js-related-work-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="65350228" href="https://independent.academia.edu/StevenLamm1">Steven Lamm</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Environmental Health Perspectives, 1989</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" 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translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-related-work-sidebar-card" data-collection-position="3" data-entity-id="78578340" data-sort-order="default"><a class="ds-related-work--title js-related-work-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/78578340/Guidelines_to_Evaluate_Human_Observational_Studies_for_Quantitative_Risk_Assessment">Guidelines to Evaluate Human Observational Studies for Quantitative Risk Assessment</a><div class="ds-related-work--metadata"><a class="js-related-work-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="170659432" href="https://uu.academia.edu/HansKromhout">Hans Kromhout</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Environmental Health Perspectives, 2008</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" 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