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Recent Advances in Chest Medicine |

Frontiers in Occupational and Environmental Lung Disease ResearchFrontiers in Occupational Lung Disease Research FREE TO VIEW

Saeher A. F. Muzaffar, MD; David C. Christiani, MD, FCCP
Author and Funding Information

From the Division of Pulmonary, Allergy, and Critical Care Medicine (Dr Muzaffar), Hospital of the University of Pennsylvania, Philadelphia, PA; the Departments of Environmental Health and Epidemiology (Dr Christiani), Harvard School of Public Health; Harvard Medical School (Dr Christiani); and the Division of Pulmonary and Critical Care Medicine (Dr Christiani), Massachusetts General Hospital, Boston, MA.

Correspondence to: David C. Christiani, MD, FCCP, Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, 665 Huntington Ave, SPH I-1407, Boston, MA 02115; e-mail: dchris@hsph.harvard.edu


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).


© 2012 American College of Chest Physicians


Chest. 2012;141(3):772-781. doi:10.1378/chest.11-0156
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Two central challenges in the field of occupational and environmental epidemiology include accurately measuring biologic responses to exposure and preventing subsequent disease. As exposure-related lung diseases continue to be identified, advances in exposure biology have introduced toxicogenomic approaches that detect biomarkers of exposure at the gene, protein, and metabolite levels. Moreover, genetic epidemiology research has focused more recently on common, low-penetrant (ie, low-relative-risk) genetic variants that may interact with commonly encountered exposures. A number of such gene by environment interactions have been identified for airways and interstitial lung diseases, with the goal of preventing disease among susceptible populations that may not otherwise have been identified. Exhaled breath condensate analysis has provided another noninvasive means of assessing toxicant exposures and systemic effects. As these technologies become more refined, clinicians and public health practitioners will need to appreciate the social implications of the individual- and population-level risks conferred by certain genetic polymorphisms or by biomarker evidence of exposure. At present, the primary approach to occupational and environmental lung disease prevention remains elimination or reduction of known hazardous exposures and requires continued application of local and international resources toward exposure control.

The field of occupational and environmental lung disease has evolved dramatically with the advent of molecular and genetic technologies to assess exposure and disease susceptibility. These advances have transpired against a backdrop of recently recognized exposure-related diseases, novel exposures, and familiar exposures in new settings, including precarious work arrangements in both industrializing and developed countries. Challenges to refine molecular methods parallel the continuing need to anticipate and prevent hazardous exposures.

The recent identification of several exposure-related lung diseases highlights the role of specific agents contributing to otherwise “idiopathic” disease. Bronchiolitis obliterans associated with exposure to diacetyl among microwave popcorn workers1 and interstitial lung disease (ILD) among nylon flock workers2 are two examples. Others include “lifeguard lung,” a granulomatous lung disease associated with respirable bioaerosols containing nontuberculous mycobacteria and endotoxin at indoor swimming pools,3,4 and hypersensitivity pneumonitis among machine workers exposed to nontuberculous mycobacteria in metal-working fluids.5 Similarly, a sarcoid-like granulomatous lung disease among World Trade Center fire department rescue workers exposed to alkaline dusts has been reported.6 Another growing concern is new-onset and work-exacerbated asthma related to the use of cleaning products, including use by health-care professionals.7 Internationally, indoor air pollution, particularly from biomass use, has been recognized as a major cause of COPD among nonsmokers.

Among both familiar and novel exposures are manufactured nanomaterials, whose use has increased precipitously in electronics, construction, and medicine (eg, as drug-carrying devices or contrast agents). In addition, exposures continue from combustion-derived nano-sized particles such as diesel exhaust particulates and welding fumes. Despite numerous advantages, the unique properties of nanoparticles (size comparable to organelles and increased surface area) may generate adverse health effects. Such toxicity was implicated when several workers in China who were exposed to polyacrylate nanoparticles developed dyspnea and pleural effusions, with lung pathology demonstrating pulmonary fibrosis, pleural granulomatous changes, and intracytoplasmic nanoparticles.8 Once within the body, nanoparticles may translocate into the bloodstream and migrate to distant organs, including the brain. Animal studies have demonstrated acute inflammatory responses resulting in fibrosis, oxidative stress, and immunosuppressive and mutagenic effects.9 Some studies in mice suggest that longer particles produce acute effects similar to those seen with asbestos, although whether mesotheliomas develop with long-term exposure remains unclear.9 Importantly, such novel exposures may act synergistically with other toxicants, such as tobacco smoke.

Finally, known exposures in newly industrializing countries combined with increasingly decentralized work structures present further challenges to exposure control and prevention. For instance, hazardous industries and materials that are banned in developed countries have sometimes been exported to developing regions.10 Such processes include acid battery recycling, electronic waste recycling, ship breaking, asbestos mining and use by foreign companies, and the use of certain pesticides.11 Furthermore, many of these exposures occur among those in the informal sector of the economy, including home-based workers and street vendors. These less-organized work arrangements have burgeoned in concert with globalization and remain beyond the reach of surveillance programs and labor protection laws.

Current approaches to measuring exposure and outcomes in occupational and environmental lung disease range from job title assessment to sputum analysis (Tables 1, 2). Although these methods continue to be useful, they share a number of limitations, including exposure misclassification and a corresponding lack of refinement in phenotype classification. Polygenetic inheritance patterns and multiple pathophysiologic processes in the setting of varying environmental influences produce complex phenotypes within disease groups.12,13 As a result, classification of disease can be a challenge, which is reflected by the lack of consensus in diagnostic criteria for diseases, including those that are that are symptom based, lung function based, or imaging based. The International Labor Office Classification system for chest radiographs does provide a standardized approach for describing findings that can be applied epidemiologically, but it does not constitute a diagnostic algorithm. Likewise, diagnostic criteria in studies of obstructive lung disease include the GOLD (Global Initiative for Chronic Obstructive Lung Disease) guidelines, lower-limit-of-normal cutoffs, and symptom-based criteria, thus limiting the generalizability of findings. Methods that offer greater precision in detecting exposure and the resulting pathologic effect and that are feasible on a broad scale would enhance disease surveillance and classification of diverse phenotypes.

Table Graphic Jump Location
Table 1 —Traditional Epidemiologic and Biologic Exposure and Outcome Measures

In general, traditional methods lack accurate cumulative exposure data (including intensity/duration) and there is limited precision in type of particulate/chemical exposure and corresponding phenotype.

Table Graphic Jump Location
Table 2 —Emerging Molecular Exposure and Outcome Measures

In general, molecular methods have greater precision in measuring exposures and response to exposure, they are costly on large scale, and complex social ramifications must be addressed prior to widespread application.

Gene by Environment Interactions

Gene by environment (G × E) interactions have become a key area of investigation in the field of exposure-related lung disease. The concept of genetic susceptibility to environmental exposures dates at least as far back as the 1700s with the observation that asthma was associated with grain dust exposure, but only 10% of grain handlers would develop symptoms.12 Indeed, environmental and occupational exposures may play a critical role in modifying the effect of genes on phenotype, with G × E interactions accounting for a proportion of phenotypic variance that may be greater than that attributable to genetic variability or to the environment alone.14

G × E interaction research focuses on common, low-penetrant, susceptibility polymorphisms that may interact with commonly encountered exposures. The goals include identifying those at risk of exposure-related disease and tailoring interventions to prevent or reduce exposures to those most susceptible. Common genetic variants identified in noninteraction genetic studies often confer a small risk compared with subgroups in which an environmental factor modifies the effect of a gene.15 Knowledge of such interactions permits targeted prevention strategies.

In terms of G × E interaction methods, association studies assume that common genetic variants underlie common diseases, in contrast to the less powerful linkage mapping used for Mendelian traits. Candidate gene association studies select genes based on their association with disease-related traits. Increasingly common genome-wide association studies (GWASs) entail analysis of whole-genome single-nucleotide polymorphism (SNP) associations with disease,12 using high-density SNP chips and case-control design, without any specific a priori hypotheses.13 However, most chips cover only about 60% of genome,12 and large sample sizes (with replication studies) are needed for multiple comparisons. Generally, these studies perform main-effect analyses first and only test interactions for significant main effects, thus potentially overlooking G × E interactions with weak main effects, which require much larger sample sizes for detection.15 Other challenges with association studies have been reviewed elsewhere12,13,16 but generally include poor reproducibility, unclear functional mechanisms of discovered loci, and a small contribution from each polymorphism to the observed phenotype and disease development.

Alternative approaches to addressing some of these shortcomings include joint testing of main effects and interactions, and longitudinal designs with repeated-exposure measurements to decrease measurement error and bias.15,17 More-refined disease characterization using physiologic rather than symptom-based criteria, for example, would reduce phenotypic heterogeneity.15 In addition, the development of statistical methodology for gene-gene and gene-environment interactions will further facilitate these analyses.

Epigenetics

Considered the interface between the environment and the genome, the field of epigenetics involves the study of changes in gene transcription not related to DNA sequence changes.12 Epigenetic markers may be heritable and may demonstrate age, cell, or tissue specificity, with critical windows of change during development as well as later in life. Three primary epigenetic mechanisms include DNA methylation, noncoding RNAs, and histone modification, with the potential to be modified by exposures. For instance, although monozygotic twins appear epigenetically identical at birth, differences associated with changes in gene expression arise by adulthood.18

Exposure Biology

Biomarkers are commonly used as markers of exposure, early biologic effects, and disease susceptibility.19 Classically, laboratory parameters or metabolites were used. More recently, however, molecular technology in the field of toxicogenomics has produced biomarkers that measure changes in gene expression or modification, protein production, and metabolite patterns in response to drugs, chemicals, or other exposures.20 The related fields include epigenetics; transcriptomics or gene-expression profiling; proteomics; and metabolomics, the study of metabolites that may change in response to exposures such as diet, stress, or disease.20 In addition, exhaled breath condensate (EBC) has been studied as a potential noninvasive biomarker for airways and parenchymal disease that may distinguish molecular profiles reflecting oxidant stress or inflammation.21,22 EBC may also permit detection of toxic metals and trace elements, with specific profiles associated with various occupational exposures such as chromium, asbestos, and welding fumes.22,23 Analysis requires assays such as enzyme-linked immunosorbent assay or more sophisticated methods of gas chromatography-mass spectrophotometry or nuclear magnetic resonance. Challenges for this evolving methodology include oral contamination and standardization of collection and analysis, among other issues. An alternate technology, termed an “Enose,” provides a method for obtaining a “breathprint” of volatile organic compounds to distinguish disease phenotypes without requiring complex technology such as gas chromatography-mass spectrophotometry.24 Exposure biology is likely to play a role in assessing the safety of chemicals, determining susceptibility to exposures, monitoring exposures, and understanding mechanisms of disease.

Social Implications

Although still mainly investigative, the previous methods carry implications that must be communicated clearly to the public. In developed nations, toxicogenomics and proteomics have emerged as potential avenues for identifying more-susceptible individuals as exposures are reduced. It is important to convey that a relatively large population-attributable risk often does not translate into similar individual susceptibility, because each polymorphism tends to contribute a small amount to overall disease development.16 In addition, workplace screening is generally not yet recommended, given the low-to-moderate penetrance of genes with lack of clinical interventions, the various sensitivities/specificities/positive predictive values of available tests, the risk of compromised confidentiality, the potential for ethnic/racial discrimination, and the need to consider behavioral and environmental influences on exposure control.25 Researchers will also need to address the need for meaningful community consent to population-based research.26

In terms of prevention at the population level, channeling resources toward exposure and disease prevention will continue to be a priority for known exposures, including outdoor and indoor air pollution. Likewise, in many newly industrializing countries, where exposures may exceed safe levels more commonly, the implementation of basic workplace exposure controls and the development of occupational safety and health clinical and institutional infrastructure will need to be promoted to improve working conditions.

Asthma

Asthma has increased in incidence and severity over the past 2 decades, particularly in developed countries. In addition to direct pathophysiologic effects, these trends may reflect epigenetic changes associated with evolving exposures such as air pollution, endotoxin in domestic and occupational settings, aeroallergens, smoking behavior, viruses, or immunizations against certain infections. In contrast, DNA sequence modifications generally occur over a longer period of time.12,27

More than 100 genes are thought to contribute to the development of asthma.13 A number of genetic associations have been identified that pertain to several mechanisms of disease, namely, innate immunity and immunoregulation; T-helper type 2 cell differentiation and effector functions; epithelial biology and mucosal immunity; and lung function, airway remodeling, and disease severity.14 Although genetic associations have been inconsistent in the literature, reported asthma genes include human leukocyte antigen (HLA), GSDMB, IL33, STAT6, RAD50, and IL1RL1.28 Among GWAS studies, ORMDL on chromosome 17q21 was found to be associated with childhood asthma29 and, more specifically, with early age of onset and severity of disease.30

Several G × E interactions for asthma have also been reported (Table 3). Interactions between neonatal or prenatal environmental tobacco smoke exposure and chromosome 17q21 variants, glutathione-S-transferase M1 (GSTM1)-null homozygosity, IL13 polymorphisms, and an IL-1 receptor antagonist (IL1RA) polymorphism are thought to contribute to increased risk of childhood asthma.3134 Likewise, Polonikov et al35 demonstrated significant interactions between cigarette smoke exposure and specific alleles of several xenobiotic metabolizing enzymes including CYP1A1, CYP1B1, and microsomal epoxide hydrolase (EPHX1), as well as evidence for gene-gene interactions. Among occupational exposures causing asthma, toluene diisocyanate is a component of paints, foams, and fibers and appears to interact with HLA class 2 alleles36,37 and glutathione-S-transferase (GST) polymorphisms,38,39 among other genes.40,41 Similarly, HLA class 2 alleles appear to be associated with red cedar asthma and platinum salts.42,43 Finally, several studies suggest genetic interactions with environmental tobacco smoke, outdoor air pollution, and microbial exposures, but they are somewhat limited by inconsistent findings.44

Table Graphic Jump Location
Table 3 —Genes Implicated in Exposure-Related Lung Disease

HLA = human leukocyte antigen; IPF = idiopathic pulmonary fibrosis; SNP = single-nucleotide polymorphism.

a 

Human Genome Organization nomenclature used.

Epigenetic processes have also been implicated in the pathogenesis of asthma. For instance, differential DNA methylation is associated with T-helper type 2 cell-mediated allergic airway disease in response to in utero supplementation with methyl donors in mice,45 and early studies in humans have observed an association between folic acid supplementation and asthma.46 Likewise, in utero tobacco exposure was found to alter methylation patterns of detoxification genes,47 whereas prenatal exposure to polyaromatic hydrocarbons, largely traffic derived, was associated with methylation of a fatty acid metabolism gene and development of asthma symptoms in children under 5 years old, bolstering evidence for epigenetic mechanisms contributing to asthma development in prenatally exposed children.48

Finally, advances in exposure biology have impacted asthma assessment as well. In particular, EBC may provide molecular profiles associated with isocyanate-induced asthma, among other exposures.49

COPD

As with asthma, both environmental and genetic influences appear to play a significant role in the development of COPD. Only 20% of cigarette smokers develop clinically apparent COPD, for instance, suggesting a genetic predisposition.12 Non-tobacco-related risk factors have been relatively underappreciated, with about 25% to 45% of patients with COPD having never smoked.50 Globally, exposure to biomass smoke is likely the leading contributor to COPD and accounts for up to 50% of deaths from COPD, 75% of which occur among women.50 The population-attributable fraction of occupational exposures to COPD is about 15%.51

Among genetic factors, SNPs in genes mediating a number of pathways including inflammation, oxidative stress, xenobiotic metabolism, and tissue remodeling have been associated with COPD severity and the rate of lung function decline in smokers. Some of these genes have been confirmed in several studies, such as microsomal epoxide hydrolase EPHX1, heme oxygenase-1 (HMOX1), and the GSTs.12,52 In a meta-analysis of 12 candidate genes (TNFα, TGFB1, IL6, IL1B, IL1RN, MMP9, GSTP1, GSTM1, GSTT1, EPHX1, SOD2, and SOD3), only five polymorphisms in three genes (TNFα, IL1 RN, and GSTM1) were significantly associated with COPD.53 A more recent study including seven cohorts found that an SNP for matrix metalloproteinase 12 (MMP12) was positively associated with increased FEV1 in children with asthma and in adult current and former smokers and was associated with a reduced risk of COPD.54

Other G × E interaction studies suggest an association between smoking addiction and SNPs in nicotine-metabolizing cytochrome P450 enzymes, opiate receptors, and dopamine pathway genes.55 In addition, a GWAS identified two SNPs near the nicotinic acetylcholine receptor locus on chromosome 15, suggesting an interaction with cigarette smoking.56

EBC analysis has also been applied to exposure-related COPD, with findings of higher levels of toxic metals, such as lead, cadmium, and aluminum, and lower levels of elements mediating antioxidant responses, such as iron and copper, in patients with COPD (among both smokers and exsmokers) compared with nonsmoking control subjects.57 The results suggest that EBC may serve as a marker of exposure to, and cumulative dose of, toxic elements in tobacco smoke, workplaces, or outdoor air, as well as a potential marker of susceptibility to chronic oxidative stress.

Interstitial Lung Disease

Although some newly described ILDs have been associated with exposure to toxicants such as nylon flock, evidence suggests that environmental and occupational exposures may also contribute to more familiar ILDs considered “idiopathic,” such as idiopathic pulmonary fibrosis and sarcoidosis. Genetic variation in susceptibility complicates the challenge of identifying specific causative exposures for such diseases.

Familial interstitial pneumonia arises in families with two or more cases of ILD. Several genes, including those encoding lung surfactant proteins C and A2 (SFTPC and SFTPA2), telomerase (TERT and TERC), and MUC5 have been identified in familial cases of pulmonary fibrosis and less commonly in sporadic cases.58,59 However, environmental influences appear to contribute to phenotypic variation, because multiple phenotypes of ILD are commonly associated with a given locus within the same family.60 Tobacco smoke, in particular, appears to contribute most strongly to familial interstitial pneumonia risk,60 in addition to fibrogenic exposures such as metal and wood dust, bird antigens, and certain medications,58 suggesting the occurrence of G × E interactions. Likewise, an MMP1 polymorphism has been associated with idiopathic pulmonary fibrosis and appears to interact with exposure to tobacco smoke.61

Metal, Mineral, and Organic Dust-Related Diseases

A number of genes also appear to predispose individuals to pneumoconiosis. For instance, in chronic beryllium disease, a major histocompatibility complex class 2 HLA allele with a lysine-to-glutamic acid change at position 69 (HLADPB1 Glu69) is strongly associated with disease susceptibility; 97% of cases were found to be positive for the polymorphism.62 However, given the longitudinal positive predictive value of only 12%, other mechanisms of disease are likely involved,25,63 as well as several other genes, such as TGFB1, IL1A, CCR5, and HLADRB1.6467

Similarly, silicosis has been associated with polymorphisms in the IL-1 receptor antagonist (Il1 RA) and TNFα genes, which appear to predict disease severity and risk,68,69 as well as the NFKB and Fas genes.70 In coal workers’ pneumoconiosis, TNFα, IL18, chemokine, and chemokine receptor genes have been associated with susceptibility and chest CT scan progression.7173

HLA class 2 alleles are also implicated in silicosis and several other exposure-related lung diseases, including hypersensitivity pneumonitis and hard metal lung disease.7476 Among those exposed to endotoxin in organic dusts such as cotton, EPHX1, TNFα, and lymphotoxin A (LTA) polymorphisms are associated with the rate of lung function decline.77,78

A number of institutions are promoting the genetic and molecular technologies discussed previously, as well as epidemiologic efforts in this field. For instance, the National Institute of Environmental Health Sciences developed the Environmental Genome Project in 1997, with a long-term goal of characterizing how polymorphisms contribute to environmentally induced disease susceptibility.79

In 2007, the National Institutes of Health developed the Genes, Environment and Health Initiative, which includes two components: the Genetics Program and the Exposure Biology Program, led by the National Institutes of Health’s National Human Genome Research Institute and the National Institute of Environmental Health Sciences, respectively.80 The former includes a focus on GWASs, and the latter aims to develop technologies including sensors and biomarkers to measure environmental exposures and biologic responses. Sensors under investigation include those that can detect both acute and chronic exposures to chemical toxicants or particulate matter.

The Human Toxicogenomics Initiative was proposed by a National Academy of Science study in the 2007 report Applications of Toxicogenomic Technologies to Predictive Toxicology and Risk Assessment. The Human Toxicogenomics Initiative goals include developing a national database of toxicogenomic and toxicologic data.20 In addition, the Human Epigenome Project represents a public/private collaboration to identify, catalog. and interpret genome-wide DNA methylation patterns.81

The National Institute for Occupational Safety and Health (NIOSH) has also outlined a number of priorities, including research on gene-occupational exposure interactions, use of genetic markers to assess the health effects of occupational exposures, and development of guidance information for the use of genetics in occupational safety and health.82 In addition, NIOSH has established an Occupational Health Disparities program to further investigate exposures and disease among vulnerable working populations.83

At the international level, the World Health Organization has established the Global Network of World Health Organization Collaborating Centers in Occupational Health, which aims to improve occupational health globally. The Network has undertaken several hundred projects in priority areas and facilitates skills exchange between institutions in developing and industrialized countries.84

Until the biomedical advances discussed previously become refined as feasible, long-term exposure measures, classic epidemiologic approaches will remain the mainstay of exposure and disease assessment. A number of challenges remain to be addressed, however.

As discussed previously, exposure assessment often relies on crude or proxy measures of exposure. More-refined estimates of biologically effective doses given time-activity and spatial patterns of exposure are needed. Examples include the particulate matter measures undertaken by Ezzati et al85 to estimate biomass exposure in Kenya. Next, study designs should address the synergy between likely risk factors for disease, such as tobacco and certain occupational exposures, malnutrition, air pollution, and sanitation, in studies of COPD, for instance. Such investigation may provide insight into the susceptibility of certain populations. Better accuracy in surveys and occupational or medical records, and inquiry into the use of personal protective equipment (PPE) and availability of occupational health and safety training are also needed. In particular, the use of job titles alone is known to result in exposure misclassification, whereas assessing categories of work arrangement, including permanent and contingent forms of employment, would permit analysis of another occupational dimension affecting exposure risk. Incorporating gender-specific differences in exposure assessment remains elusive. Studies have yet to account for the impact of gender-related anatomic differences in particle deposition and comorbidities, smoking behavior, nutritional status, immunologic factors, or hormonal actions on the metabolism of toxins and biologically effective doses. The fit, training, and use of PPE also varies: respirators have been found to fit women more poorly, and women are less likely to receive training in the use of PPE, because of part-time/temporary employment patterns.86

In terms of disease assessment, enhanced surveillance and country-specific estimates of exposure-related disease burden are needed. The development of population-specific job exposure matrices may permit a gross estimation of disease risk according to exposure type. However, job exposure matrices may be significantly limited by exposure misclassification. The technologies discussed previously, including genotyping and biomarker detection, provide much greater precision in estimating exposure and response to exposure. The challenge lies in designing cost-effective methods that can apply such technology at the population level while addressing the potential social implications discussed previously. In the meantime, surveillance in hard-to-reach populations both within the United States and internationally will require awareness of the hazards among such populations concomitant with resources to strengthen current surveillance infrastructure. The NIOSH program on Occupational Health Disparities exemplifies efforts to address such issues.

The advances in molecular technologies are transforming our ability to define the pathogenesis of, and susceptibility to, occupational and environmental lung disease. In parallel with endeavors to advance this field of science, continuing to reduce known and emerging hazardous environmental and occupational exposures through local and international collaborative resources will be essential to mitigate the burden of disease.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

EBC

exhaled breath condensate

G × E

gene by environment

GWAS

genome-wide association study

HLA

human leukocyte antigen

ILD

interstitial lung disease

NIOSH

National Institute for Occupational Safety and Health

PPE

personal protective equipment

SNP

single-nucleotide polymorphism

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Wikman H, Piirilä P, Rosenberg C, et al. N-Acetyltransferase genotypes as modifiers of diisocyanate exposure-associated asthma risk. Pharmacogenetics. 2002;123:227-233. [PubMed]
 
Kim SH, Cho BY, Park CS, et al. Alpha-T-catenin (CTNNA3) gene was identified as a risk variant for toluene diisocyanate-induced asthma by genome-wide association analysis. Clin Exp Allergy. 2009;392:203-212. [PubMed]
 
Horne C, Quintana PJ, Keown PA, Dimich-Ward H, Chan-Yeung M. Distribution of DRB1 and DQB1 HLA class II alleles in occupational asthma due to western red cedar. Eur Respir J. 2000;155:911-914. [PubMed]
 
Newman Taylor AJ, Cullinan P, Lympany PA, Harris JM, Dowdeswell RJ, du Bois RM. Interaction of HLA phenotype and exposure intensity in sensitization to complex platinum salts. Am J Respir Crit Care Med. 1999;1602:435-438. [PubMed]
 
London SJ, Romieu I. Gene by environment interaction in asthma. Annu Rev Public Health. 2009;30:55-80. [PubMed]
 
Hollingsworth JW, Maruoka S, Boon K, et al. In utero supplementation with methyl donors enhances allergic airway disease in mice. J Clin Invest. 2008;11810:3462-3469. [PubMed]
 
Whitrow MJ, Moore VM, Rumbold AR, Davies MJ. Effect of supplemental folic acid in pregnancy on childhood asthma: a prospective birth cohort study. Am J Epidemiol. 2009;17012:1486-1493. [PubMed]
 
Breton CV, Byun HM, Wenten M, Pan F, Yang A, Gilliland FD. Prenatal tobacco smoke exposure affects global and gene-specific DNA methylation. Am J Respir Crit Care Med. 2009;1805:462-467. [PubMed]
 
Perera F, Tang WY, Herbstman J, et al. Relation of DNA methylation of 5′-CpG island of ACSL3 to transplacental exposure to airborne polycyclic aromatic hydrocarbons and childhood asthma. PLoS ONE. 2009;42:e4488. [PubMed]
 
Ferrazzoni S, Scarpa MC, Guarnieri G, Corradi M, Mutti A, Maestrelli P. Exhaled nitric oxide and breath condensate ph in asthmatic reactions induced by isocyanates. Chest. 2009;1361:155-162. [PubMed]
 
Salvi SS, Barnes PJ. Chronic obstructive pulmonary disease in non-smokers. Lancet. 2009;3749691:733-743. [PubMed]
 
Balmes J, Becklake M, Blanc P, et al; Environmental and Occupational Health Assembly, American Thoracic Society Environmental and Occupational Health Assembly, American Thoracic Society American Thoracic Society Statement: Occupational contribution to the burden of airway disease. Am J Respir Crit Care Med. 2003;1675:787-797. [PubMed]
 
Silverman EK, Spira A, Paré PD. Genetics and genomics of chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2009;66:539-542. [PubMed]
 
Smolonska J, Wijmenga C, Postma DS, Boezen HM. Meta-analyses on suspected chronic obstructive pulmonary disease genes: a summary of 20 years’ research. Am J Respir Crit Care Med. 2009;1807:618-631. [PubMed]
 
Hunninghake GM, Cho MH, Tesfaigzi Y, et al. MMP12, lung function, and COPD in high-risk populations. N Engl J Med. 2009;36127:2599-2608. [PubMed]
 
Quaak M, van Schayck CP, Knaapen AM, van Schooten FJ. Implications of gene-drug interactions in smoking cessation for improving the prevention of chronic degenerative diseases. Mutat Res. 2009;6671-2:44-57. [PubMed]
 
Pillai SG, Ge D, Zhu G, et al; ICGN Investigators ICGN Investigators A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci. PLoS Genet. 2009;53:e1000421. [PubMed]
 
Mutti A, Corradi M, Goldoni M, Vettori MV, Bernard A, Apostoli P. Exhaled metallic elements and serum pneumoproteins in asymptomatic smokers and patients with COPD or asthma. Chest. 2006;1295:1288-1297. [PubMed]
 
Garcia CK. Idiopathic pulmonary fibrosis: update on genetic discoveries. Proc Am Thorac Soc. 2011;82:158-162. [PubMed]
 
Seibold MA, Wise AL, Speer MC, et al. A common MUC5B promoter polymorphism and pulmonary fibrosis. N Engl J Med. 2011;36416:1503-1512. [PubMed]
 
Steele MP, Speer MC, Loyd JE, et al. Clinical and pathologic features of familial interstitial pneumonia. Am J Respir Crit Care Med. 2005;1729:1146-1152. [PubMed]
 
Checa M, Ruiz V, Montaño M, Velázquez-Cruz R, Selman M, Pardo A. MMP-1 polymorphisms and the risk of idiopathic pulmonary fibrosis. Hum Genet. 2008;1245:465-472. [PubMed]
 
Richeldi L, Sorrentino R, Saltini C. HLA-DPB1 glutamate 69: a genetic marker of beryllium disease. Science. 1993;2625131:242-244. [PubMed]
 
Silver K, Sharp RR. Ethical considerations in testing workers for the -Glu69 marker of genetic susceptibility to chronic beryllium disease. J Occup Environ Med. 2006;484:434-443. [PubMed]
 
Jonth AC, Silveira L, Fingerlin TE, et al; ACCESS Group ACCESS Group TGF-beta 1 variants in chronic beryllium disease and sarcoidosis. J Immunol. 2007;1796:4255-4262. [PubMed]
 
McCanlies EC, Yucesoy B, Mnatsakanova A, et al. Association between IL-1A single nucleotide polymorphisms and chronic beryllium disease and beryllium sensitization. J Occup Environ Med. 2010;527:680-684. [PubMed]
 
Sato H, Silveira L, Spagnolo P, et al. CC chemokine receptor 5 gene polymorphisms in beryllium disease. Eur Respir J. 2010;362:331-338. [PubMed]
 
Rosenman KD, Rossman M, Hertzberg V, et al. HLA class II DPB1 and DRB1 polymorphisms associated with genetic susceptibility to beryllium toxicity. Occup Environ Med. 2011;687:487-493. [PubMed]
 
Yucesoy B, Vallyathan V, Landsittel DP, et al. Association of tumor necrosis factor-alpha and interleukin-1 gene polymorphisms with silicosis. Toxicol Appl Pharmacol. 2001;1721:75-82. [PubMed]
 
Corbett EL, Mozzato-Chamay N, Butterworth AE, et al. Polymorphisms in the tumor necrosis factor-alpha gene promoter may predispose to severe silicosis in black South African miners. Am J Respir Crit Care Med. 2002;1655:690-693. [PubMed]
 
Wu F, Xia Z, Qu Y, et al. Genetic polymorphisms of IL-1A, IL-1B, IL-1RN, NFKB1, FAS, and FASL, and risk of silicosis in a Chinese occupational population. Am J Ind Med. 2008;5111:843-851. [PubMed]
 
Zhai R, Jetten M, Schins RP, Franssen H, Borm PJ. Polymorphisms in the promoter of the tumor necrosis factor-alpha gene in coal miners. Am J Ind Med. 1998;344:318-324. [PubMed]
 
Nadif R, Mintz M, Marzec J, Jedlicka A, Kauffmann F, Kleeberger SR. IL18 and IL18R1 polymorphisms, lung CT and fibrosis: a longitudinal study in coal miners. Eur Respir J. 2006;286:1100-1105. [PubMed]
 
Nadif R, Mintz M, Rivas-Fuentes S, et al. Polymorphisms in chemokine and chemokine receptor genes and the development of coal workers’ pneumoconiosis. Cytokine. 2006;333:171-178. [PubMed]
 
Saltini C, Amicosante M, Franchi A, Lombardi G, Richeldi L. Immunogenetic basis of environmental lung disease: lessons from the berylliosis model. Eur Respir J. 1998;126:1463-1475. [PubMed]
 
Camarena A, Juárez A, Mejía M, et al. Major histocompatibility complex and tumor necrosis factor-alpha polymorphisms in pigeon breeder’s disease. Am J Respir Crit Care Med. 2001;1637:1528-1533. [PubMed]
 
Potolicchio I, Mosconi G, Forni A, Nemery B, Seghizzi P, Sorrentino R. Susceptibility to hard metal lung disease is strongly associated with the presence of glutamate 69 in HLA-DP beta chain. Eur J Immunol. 1997;2710:2741-2743. [PubMed]
 
Hang J, Zhou W, Wang X, et al. Microsomal epoxide hydrolase, endotoxin, and lung function decline in cotton textile workers. Am J Respir Crit Care Med. 2005;1712:165-170. [PubMed]
 
Zhang H, Hang J, Wang X, et al. TNF polymorphisms modify endotoxin exposure-associated longitudinal lung function decline. Occup Environ Med. 2007;646:409-413. [PubMed]
 
Environmental Genome Project: program description. National Institute of Environmental Health Sciences Web site.http://www.niehs.nih.gov/research/supported/programs/egp/. Accessed March 16, 2010.
 
The Genes, Environment and Health Initiative (GEI). National Institutes of Health Web site.http://www.gei.nih.gov. Accessed March 16, 2010.
 
Human Epigenome Project Human Epigenome Project Web site.http://www.epigenome.org/index.php. Accessed March 16, 2010.
 
Public health genomics at CDC: accomplishments and priorities 2004. Centers for Disease Control and Prevention Web site.http://www.cdc.gov/genomics/about/reports/2004/niosh.htm. Accessed March 16, 2010.
 
NIOSH program portfolio: occupational health disparities. Centers for Disease Control and Prevention Web site.http://www.cdc.gov/niosh/programs/ohd/. Accessed March 16, 2010.
 
Network of WHO Collaborating Centres in Occupational Health World Health Organization Web site.http://www.who.int/occupational_health/network/en/index.html. Accessed March 16, 2010.
 
Ezzati M, Saleh H, Kammen DM. The contributions of emissions and spatial microenvironments to exposure to indoor air pollution from biomass combustion in Kenya. Environ Health Perspect. 2000;1089:833-839. [PubMed]
 
Camp PG, Dimich-Ward H, Kennedy SM. Women and occupational lung disease: sex differences and gender influences on research and disease outcomes. Clin Chest Med. 2004;252:269-279. [PubMed]
 

Figures

Tables

Table Graphic Jump Location
Table 1 —Traditional Epidemiologic and Biologic Exposure and Outcome Measures

In general, traditional methods lack accurate cumulative exposure data (including intensity/duration) and there is limited precision in type of particulate/chemical exposure and corresponding phenotype.

Table Graphic Jump Location
Table 2 —Emerging Molecular Exposure and Outcome Measures

In general, molecular methods have greater precision in measuring exposures and response to exposure, they are costly on large scale, and complex social ramifications must be addressed prior to widespread application.

Table Graphic Jump Location
Table 3 —Genes Implicated in Exposure-Related Lung Disease

HLA = human leukocyte antigen; IPF = idiopathic pulmonary fibrosis; SNP = single-nucleotide polymorphism.

a 

Human Genome Organization nomenclature used.

References

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Choi JH, Lee KW, Kim CW, et al. The HLA DRB1*1501-DQB1*0602-DPB1*0501 haplotype is a risk factor for toluene diisocyanate-induced occupational asthma. Int Arch Allergy Immunol. 2009;1502:156-163. [PubMed]
 
Piirilä P, Wikman H, Luukkonen R, et al. Glutathione S-transferase genotypes and allergic responses to diisocyanate exposure. Pharmacogenetics. 2001;115:437-445. [PubMed]
 
Mapp CE, Fryer AA, De Marzo N, et al. Glutathione S-transferase GSTP1 is a susceptibility gene for occupational asthma induced by isocyanates. J Allergy Clin Immunol. 2002;1095:867-872. [PubMed]
 
Wikman H, Piirilä P, Rosenberg C, et al. N-Acetyltransferase genotypes as modifiers of diisocyanate exposure-associated asthma risk. Pharmacogenetics. 2002;123:227-233. [PubMed]
 
Kim SH, Cho BY, Park CS, et al. Alpha-T-catenin (CTNNA3) gene was identified as a risk variant for toluene diisocyanate-induced asthma by genome-wide association analysis. Clin Exp Allergy. 2009;392:203-212. [PubMed]
 
Horne C, Quintana PJ, Keown PA, Dimich-Ward H, Chan-Yeung M. Distribution of DRB1 and DQB1 HLA class II alleles in occupational asthma due to western red cedar. Eur Respir J. 2000;155:911-914. [PubMed]
 
Newman Taylor AJ, Cullinan P, Lympany PA, Harris JM, Dowdeswell RJ, du Bois RM. Interaction of HLA phenotype and exposure intensity in sensitization to complex platinum salts. Am J Respir Crit Care Med. 1999;1602:435-438. [PubMed]
 
London SJ, Romieu I. Gene by environment interaction in asthma. Annu Rev Public Health. 2009;30:55-80. [PubMed]
 
Hollingsworth JW, Maruoka S, Boon K, et al. In utero supplementation with methyl donors enhances allergic airway disease in mice. J Clin Invest. 2008;11810:3462-3469. [PubMed]
 
Whitrow MJ, Moore VM, Rumbold AR, Davies MJ. Effect of supplemental folic acid in pregnancy on childhood asthma: a prospective birth cohort study. Am J Epidemiol. 2009;17012:1486-1493. [PubMed]
 
Breton CV, Byun HM, Wenten M, Pan F, Yang A, Gilliland FD. Prenatal tobacco smoke exposure affects global and gene-specific DNA methylation. Am J Respir Crit Care Med. 2009;1805:462-467. [PubMed]
 
Perera F, Tang WY, Herbstman J, et al. Relation of DNA methylation of 5′-CpG island of ACSL3 to transplacental exposure to airborne polycyclic aromatic hydrocarbons and childhood asthma. PLoS ONE. 2009;42:e4488. [PubMed]
 
Ferrazzoni S, Scarpa MC, Guarnieri G, Corradi M, Mutti A, Maestrelli P. Exhaled nitric oxide and breath condensate ph in asthmatic reactions induced by isocyanates. Chest. 2009;1361:155-162. [PubMed]
 
Salvi SS, Barnes PJ. Chronic obstructive pulmonary disease in non-smokers. Lancet. 2009;3749691:733-743. [PubMed]
 
Balmes J, Becklake M, Blanc P, et al; Environmental and Occupational Health Assembly, American Thoracic Society Environmental and Occupational Health Assembly, American Thoracic Society American Thoracic Society Statement: Occupational contribution to the burden of airway disease. Am J Respir Crit Care Med. 2003;1675:787-797. [PubMed]
 
Silverman EK, Spira A, Paré PD. Genetics and genomics of chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2009;66:539-542. [PubMed]
 
Smolonska J, Wijmenga C, Postma DS, Boezen HM. Meta-analyses on suspected chronic obstructive pulmonary disease genes: a summary of 20 years’ research. Am J Respir Crit Care Med. 2009;1807:618-631. [PubMed]
 
Hunninghake GM, Cho MH, Tesfaigzi Y, et al. MMP12, lung function, and COPD in high-risk populations. N Engl J Med. 2009;36127:2599-2608. [PubMed]
 
Quaak M, van Schayck CP, Knaapen AM, van Schooten FJ. Implications of gene-drug interactions in smoking cessation for improving the prevention of chronic degenerative diseases. Mutat Res. 2009;6671-2:44-57. [PubMed]
 
Pillai SG, Ge D, Zhu G, et al; ICGN Investigators ICGN Investigators A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci. PLoS Genet. 2009;53:e1000421. [PubMed]
 
Mutti A, Corradi M, Goldoni M, Vettori MV, Bernard A, Apostoli P. Exhaled metallic elements and serum pneumoproteins in asymptomatic smokers and patients with COPD or asthma. Chest. 2006;1295:1288-1297. [PubMed]
 
Garcia CK. Idiopathic pulmonary fibrosis: update on genetic discoveries. Proc Am Thorac Soc. 2011;82:158-162. [PubMed]
 
Seibold MA, Wise AL, Speer MC, et al. A common MUC5B promoter polymorphism and pulmonary fibrosis. N Engl J Med. 2011;36416:1503-1512. [PubMed]
 
Steele MP, Speer MC, Loyd JE, et al. Clinical and pathologic features of familial interstitial pneumonia. Am J Respir Crit Care Med. 2005;1729:1146-1152. [PubMed]
 
Checa M, Ruiz V, Montaño M, Velázquez-Cruz R, Selman M, Pardo A. MMP-1 polymorphisms and the risk of idiopathic pulmonary fibrosis. Hum Genet. 2008;1245:465-472. [PubMed]
 
Richeldi L, Sorrentino R, Saltini C. HLA-DPB1 glutamate 69: a genetic marker of beryllium disease. Science. 1993;2625131:242-244. [PubMed]
 
Silver K, Sharp RR. Ethical considerations in testing workers for the -Glu69 marker of genetic susceptibility to chronic beryllium disease. J Occup Environ Med. 2006;484:434-443. [PubMed]
 
Jonth AC, Silveira L, Fingerlin TE, et al; ACCESS Group ACCESS Group TGF-beta 1 variants in chronic beryllium disease and sarcoidosis. J Immunol. 2007;1796:4255-4262. [PubMed]
 
McCanlies EC, Yucesoy B, Mnatsakanova A, et al. Association between IL-1A single nucleotide polymorphisms and chronic beryllium disease and beryllium sensitization. J Occup Environ Med. 2010;527:680-684. [PubMed]
 
Sato H, Silveira L, Spagnolo P, et al. CC chemokine receptor 5 gene polymorphisms in beryllium disease. Eur Respir J. 2010;362:331-338. [PubMed]
 
Rosenman KD, Rossman M, Hertzberg V, et al. HLA class II DPB1 and DRB1 polymorphisms associated with genetic susceptibility to beryllium toxicity. Occup Environ Med. 2011;687:487-493. [PubMed]
 
Yucesoy B, Vallyathan V, Landsittel DP, et al. Association of tumor necrosis factor-alpha and interleukin-1 gene polymorphisms with silicosis. Toxicol Appl Pharmacol. 2001;1721:75-82. [PubMed]
 
Corbett EL, Mozzato-Chamay N, Butterworth AE, et al. Polymorphisms in the tumor necrosis factor-alpha gene promoter may predispose to severe silicosis in black South African miners. Am J Respir Crit Care Med. 2002;1655:690-693. [PubMed]
 
Wu F, Xia Z, Qu Y, et al. Genetic polymorphisms of IL-1A, IL-1B, IL-1RN, NFKB1, FAS, and FASL, and risk of silicosis in a Chinese occupational population. Am J Ind Med. 2008;5111:843-851. [PubMed]
 
Zhai R, Jetten M, Schins RP, Franssen H, Borm PJ. Polymorphisms in the promoter of the tumor necrosis factor-alpha gene in coal miners. Am J Ind Med. 1998;344:318-324. [PubMed]
 
Nadif R, Mintz M, Marzec J, Jedlicka A, Kauffmann F, Kleeberger SR. IL18 and IL18R1 polymorphisms, lung CT and fibrosis: a longitudinal study in coal miners. Eur Respir J. 2006;286:1100-1105. [PubMed]
 
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