Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health (2008)

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3 Emerging Research and Research Issues The goal of this chapter is to assess progress in targeting new research relevant to future improvements in workplace protection from occupational respiratory dis- eases and identifying significant emerging research areas important to the mission of the National Institute for Occupational Safety and Health (NIOSH). The NIOSH evidence package (NIOSH 2006a, Chapter 13) provides a “vision for the future” statement that summarizes past accomplishments and their link with future plans in terms of their five strategic goals. This chapter serves as a useful framework within which the evaluation committee will present its findings. We first present a brief summary of the Respiratory Diseases Research Pro- gram (RDRP) presentation of important plans for its five goals, each of which is followed by the evaluation committee’s assessment; then we discuss cross-cutting issues the committee identified as important considerations for future NIOSH- RDRP research work. Strategic Goal 1: Prevent and reduce work-related airway diseases Summary The RDRP gives very high priority to this area, with a focus on improved characterization, exposure assessment, and elucidation of the mechanisms of ­action of low-molecular-weight agents and mold allergens. Within this goal are a plan to 120 

Emerging Research and Research Issues 121 implement and monitor a model screening and surveillance program for work- related asthma (WRA) in the isocyanate industry, an evaluation of the effectiveness of recommendations made in response to health hazard evaluations (HHEs), and continued development of better approaches to facilitate the use of ambulatory spirometry for assessing WRA. With regard to work-related chronic obstructive pulmonary disease (COPD), the RDRP will continue to evaluate the relation between COPD prevalence and occupation and pursue aggressive surveillance of work-related bronchiolitis obliterans. Much of this goal is a direct extension of material presented in the evidence package. The focus on mold allergen stems from the NIOSH-RDRP response to the high frequency of HHE requests triggered by asthma and asthma-like symptoms. Committee Comments Exposure and disease surveillance are critical to the objective of detecting and reducing work-related airway diseases as well as other major program goals of the RDRP. WRA is a difficult condition to identify and the RDRP should explore ways to identify new agents, outbreaks, or “hot spots” of WRA caused by known agents and trends in WRA. Furthermore, many WRA agents are present in small businesses that current surveillance methods do not identify or track effectively. Expanding the SENSOR program to include additional geographic areas and, thus, an even broader occupational mix would provide the much needed opportunity to track trends and to highlight possible geographic variation. One strength of the SENSOR program is that it does have elements that go beyond a purely passive (that is wholly voluntary) scheme. Active elements, such as mandatory physician reporting, warrant additional follow-up from the RDRP to evaluate their possible extrapolation to other geographic areas and other respiratory diseases. Without SENSOR data, the appropriate targeting of limited resources for exposure and medical monitoring and interventions to prevent and control disease is difficult, if not impossible. NIOSH should develop strategies to work with state health depart- ments to develop methods for WRA surveillance. The requirement for improved surveillance in work-related COPD parallels the need with WRA. RDRP efforts to seek new methods for conducting work- r ­ elated COPD surveillance are of great importance. Furthermore, the RDRP should  The California SENSOR program, in particular, has utilized legally required physician reporting of occupational disease (the Doctor’s First Report system) for case finding. In addition, a NIOSH- led effort exploited the multiple routes of SENSOR case detection in the Michigan program to carry out a formal “capture-recapture” analysis of case incidence, once again highlighting that this scheme transcends the strict definition of a passive surveillance program (Henneberger et al, 1999). Also in Michigan, NIOSH participated in a similar surveillance related to silicosis (Rosenman et al 2003). 

122 R e s p i r ato ry D i s e a s e s R e s e a r c h at NIOSH e ­ xplore ways to identify new agents or occurrences of work-related COPD. Efforts to ensure spirometry in the next round of the National Health and Nutrition Examina­tion Survey (NHANES) are encouraged, as the lack of lung function would be a major setback for COPD surveillance at the national level. The ability to detect work-related COPD requires including new questions on occupational exposures as well as spirometry in the NHANES survey. An important area of work-related COPD research is the development of improved methods for analyzing pulmonary function data from longitudinal studies. Finally the committee notes that, while the RDRP has made critically important contributions to preventing exposure to latex and considering isocyanate as a cause of WRA, the program has not used these successes to develop a more systematic approach to the classes of high- and low-molecular-weight sensitizers. The com- mittee considers this to be an area that should be articulated more coherently. Such a conceptualization is well suited to the matrix organization under the second National Occupational Research Agenda (NORA2). Strategic Goal 2: Prevent and reduce work-related interstitial lung diseases Summary Because of the recent identification of clusters of miners with progressive massive fibrosis, the RDRP plans to work on further technological improvements to reduce exposure, ensure the availability and use of personal dust monitors, and investigate the nature and causes of hot spots of coal workers’ pneumoconiosis (CWP). A move to digital radiography for application of the International Labour Office (ILO) classification of CWP will not occur until there is further assessment, validation, and acceptance of digitized films for use in the ILO classification. Work will continue on the development of molecular biomarkers for silica exposure for early detection. The new digital radiography programs are seen as being relevant to more intense medical screening and surveillance of silicosis. Collaboration with Brush Wellman will continue with the collection of additional data allowing for reanalysis of epidemiologic findings to examine dose-response relations in light of the estimated dose of dissolved beryllium and dermal exposure. This effort is motivated by analyses that suggest mass-based exposure is not optimal for predict- ing disease risk. The RDRP will create transgenic mice to examine the impact of dose, form, and route and associated pathology and pathophysiology. These mice will be made available to other investigators. 

Emerging Research and Research Issues 123 Committee Comments The committee’s review of the RDRP’s research on interstitial lung disease generally documents a sustained, thoughtful, and effective research program that has had a marked impact on respiratory exposures and the incidence of ­interstitial diseases in the numerous workplaces where these diseases occur. Much of the r ­ esearch and surveillance activities dealing with CWP was mandated by the Federal Coalmine Health and Safety Act of 1969. These programs, which were established in the 1970s, led to a marked reduction in miners’ exposure to respirable coalmine dust and until recently have decreased the annual prevalence of pneumoconiosis. Measures have been taken to improve the participation of miners in mandated surveillance efforts. Surveillance data have recently identified a cluster of rapidly progressing CWP in Southern West Virginia and Eastern Kentucky. Targeted hot spot surveillance has been undertaken to further elucidate the reasons for rapid progression of CWP among miners with relatively short exposures. This experience should lead to a full reexamination of the organization and efficacy of the CWP surveillance program that includes the interaction between NIOSH and the Mine Safety and Health Administration (MSHA), with additional focus on the adequacy of exposure assessment and compliance determination. Additional factors that need better understanding include the possible role of coal rank, silica level, and duration of exposure in the mines producing these rapidly progressive cases of CWP. These issues need to be assessed further epide- miologically and even experimentally. Assessment of digital radiography in CWP surveillance is also an important continuing research priority. Other emerging i ­ ssues more directly tied to CWP include exposure levels in light of changing work patterns underground, especially longer work shifts; the impact of deeper under- ground mining conditions on dust exposures and lung health; and the respiratory risks (beyond physical trauma) that may result from “retreat mining.” The RDRP’s work related to pulmonary toxicity from silica, which includes traditional and innovative approaches to silica control and exposure assessment, and work on the basic mechanisms of oxidant injury resulting in interstitial lung disease have been important contributions by RDRP scientists. More work remains to be done with regard to elucidating the toxic and genetic mechanisms of silicosis and the issue of lung cancer arising from exposure to silica. A strong and continuing emphasis is needed on control technology and on efforts to reduce silica exposures in multiple mining and nonmining workplaces. NIOSH also has played an important role in contributing to our understanding of the epidemiology of exposure to commercial asbestos products. This work led to a revised NIOSH recommended exposure limit in 1976 and recommendations with regard to asbestos substitute materials. Despite the well-understood epidemiology 

124 R e s p i r ato ry D i s e a s e s R e s e a r c h at NIOSH of asbestos exposure and significant progress in the control of commercial asbestos exposures, there remains a very important need for RDRP scientists to be engaged in understanding the differential risk from exposure to specific subtypes of asbes- tos as well as methods for surveillance of asbestosis and cancer related to asbestos exposures as these conditions continue to be reported in exposed workers. NIOSH appropriately has concentrated its efforts on asbestos exposures in a ­ sbestos-contaminated vermiculite that was widely used in housing and commercial building insulation and for many commercial products. This RDRP research has led directly to controlling these exposures through regulation and ultimately closing the mine that provided this contaminated vermiculite for commercial use. NIOSH has contributed to our understanding of respiratory disease among nylon flock workers. Description of this interstitial lung disease arose from col- laborative research with university investigators and appropriately included epide- miology, industrial hygiene, control technology, and experimental studies leading to a well-documented newly described interstitial lung disease. RDRP investiga- tors have worked effectively with the flock industry to implement controls. While surveillance of this industry apparently shows no new cases, subclinical cases have been found and continued surveillance is needed. NIOSH has also contributed to our understanding of possible pulmonary con- sequences arising from refractory ceramic fibers (RCFs). Monitoring of exposure and control technology research has led to a product stewardship program, which RDRP scientists continue to monitor. This voluntary program with the Occupa- tional Safety and Health Administration (OSHA) that arose in conjunction with the NIOSH RCF criteria document is an alternative to the traditional regulatory approach and is innovative, but it needs continuing evaluation of its efficacy in documenting and controlling risk. RDRP research on fiber characterization and toxicity also is appropriate and has aided regulatory and other federal agencies and international bodies in their assessment of fiber ranking with regard to carci- nogenicity in humans. These efforts should continue with attention to low-level exposures and unresolved issues such as cleavage fragments. Overall, the RDRP’s documentation of health effects from respirable fibers demonstrates the importance of surveillance to detect effects and research to understand the processes resulting in exposures. The experience with nylon flock shows the potential for the emergence of previously unknown fiber-related diseases and, ultimately, the importance of evaluating the potential negative consequences of new fibers or new uses of fibers in occupational settings. NIOSH is encouraged to continue and expand its surveillance activities to evaluate the potential effects of synthetic fibers such as nylon flock and RCF. NIOSH has made substantial contributions to our understanding of sensitiza- tion and the risk of chronic beryllium disease from industrial exposures. Indus- 

Emerging Research and Research Issues 125 trial exposure to beryllium continues to be widespread and the population at risk is relatively large. NIOSH epidemiologic work has documented that the OSHA permissible exposure limit (PEL) does not prevent sensitization or the onset of chronic beryllium disease. This highlights the need for OSHA to recommend a new PEL based on RDRP research that will satisfactorily protect workers. NIOSH’s col- laboration with Brush Wellman appears to provide incentives for the industry and high-quality research for NIOSH and the research and regulatory communities. NIOSH has evaluated the importance of the interaction of occupational expo- sures and genetic factors by looking specifically at the influence of genetic variation on chronic beryllium disease. The research has been productive and it is tempt- ing to consider this relationship as a model for understanding gene-­environment interactions in disease causation. However, the committee recognizes that research on both genetic and epigenetic relationships to the environment is likely to prove much more complex than this one example (Kelsey 2007; Schulte 2007; Vainio 2007). Furthermore, how research on these interactions (whether on beryllium or other toxicants) can be applied to protect exposed workers or assist in protect- ing susceptible subpopulations of workers remains unclear (Palmer et al. 2004), although the research will likely lead to better understanding of the molecular mechanisms driving workplace-related disease. The current program articulated by RDRP scientists is appropriate but should not lose sight of the need for an OSHA-recommended standard and a mandated comprehensive beryllium control program for all workplaces where this exposure occurs. Strategic Goal 3: Prevent and reduce work-related infectious respiratory diseaseS Summary Future efforts in this area largely are a continuation of the work being carried out by the RDRP. Engineering controls, improved personal respirator protection, and preparation for possible pandemic and bioterrorism events remain the focus. Surprisingly, the efforts directed toward understanding the effects and mechanisms of exposures such as diesel exhaust particles on pulmonary susceptibility to infec- tion are scarcely mentioned, despite the considerable emphasis placed on them in the evidence package. Committee Comments One important area that is missing from this strategic goal relates to surveil- lance activities. While surveillance for the occurrence of infectious diseases is 

126 R e s p i r ato ry D i s e a s e s R e s e a r c h at NIOSH acknowledged as an important component of preventing and reducing infectious diseases (particularly for tuberculosis), the RDRP has not proposed a plan to a ­ ddress the lack of surveillance for infectious diseases in occupational settings. The SENSOR program, described in Chapter 2, attempted to address some of these surveillance deficits. However, the program did not appear to have a specific infectious disease component. Moreover, the SENSOR program is being downsized. The RDRP Infectious Diseases Program does not appear to have the resources to develop alternatives to offset the loss of this program and will have to depend on surveillance data from programs not directly under its control. Another component of effective surveillance is the rapid detection and iden- tification of disease causing agents when they are present. Although NIOSH has made some efforts in this regard, such as developing sampling procedures and tech- nologies for anthrax, other federal groups, such as the Department of Homeland Security (DHS), support and conduct extensive research to develop technologies for the rapid detection of bioterrorism agents (see, for example, the DHS technol- ogy forecast [HSRC 2006] and its “lab-in-a-box” technology that could be adapted to the RDRP mission; the technology is briefly described in USDHS [2007]). It is important that NIOSH participate in initiatives within the federal complex that keep it informed of detection methods under development within other federal agencies. As these technologies become available, it will be necessary to extend their use to protect and reduce infectious diseases in workers. Three strategies—preventing infection with respirator controls, understand- ing the mechanisms that underlie susceptibility, and conducting robust surveil- lance for disease outbreaks—represent NIOSH’s primary tools to prevent and reduce known and unknown (emerging) respiratory infectious diseases. Support for ­respirator control and understanding susceptibility is encouraged to maximize worker protection from emerging diseases, and these areas should remain a high priority, while surveillance activities for infectious diseases in occupational settings need to be increased.  NIOSH explained that there are several sources of data (e.g., data collected by OSHA or compo- nents of the Centers for Disease Control and Prevention) that can be used in general surveillance for occupational infectious diseases, but these data-collection activities are not managed under a single programmatic umbrella (NIOSH 2006b). Several relevant data sources are described in Appendix A of the NIOSH Worker Health Chartbook (NIOSH 2004); however, the availability and content of these resources are limited (Sepkowitz and Eisenberg 2005). 

Emerging Research and Research Issues 127 Strategic Goal 4: Prevent and reduce work-related respiratory malignancies Summary Work to reduce exposure to silica will continue. In addition, diesel exhaust and mineral fibers are targeted for future focus. Cooperation with the National Cancer Institute (NCI) epidemiologic study of diesel-exhaust-related mortality is identi- fied as a source of exposure-response data with respect to lung cancer. Electron microscopy will be used to reassess exposure-response relations that account for asbestos fibers that could not be observed with light-microscopy-based methods to assess exposure; data from previously studied cohorts will be used to provide new exposure-response estimates for cancer development. Laboratory studies will be conducted to evaluate the impact of fiber characteristics on carcinogenesis. Such studies are considered particularly important for nonasbestos fibers. Committee Comments The evaluation committee finds that the RDRP has provided evidence for a solid research program that has had a direct impact on the control of occupational cancers. This work has been of direct use to OSHA and MSHA in their standard- setting processes, particularly for hexavalent chromium and diesel particulate, as well as to the International Agency for Research on Cancer in developing its assess­ment of cancer risk from occupational exposures. The work on silica also is considered very strong. Ongoing research continues to address challenging problems related to the risk of occupational lung cancer, and the RDRP has been effective in engaging stake- holders from industry and the workforce. In particular, the RDRP’s efforts have added substantially to dissemination of research findings from cohort studies to individual workers. Collaboration with industry is often the only way to understand workplace exposures that lead to cancer. The committee supports ongoing and encourages future collaborations in studies of occupational lung cancers, particu- larly in the face of emerging evidence of the link between exposure and outcome. For some time, the epidemiologic literature from cohort studies of textile workers has provided evidence that workers exposed to cotton dust have lower than expected rates of lung cancer (Henderson and Enterline 1973; Merchant and Ortmeyer 1981; Hodgson and Jones 1990; Wernli et al. 2006). In the 1980s, endo- toxin was suggested as the source of reduced risk (Enterline et al. 1985). Recently, interest in this association resurfaced when deficits in lung cancer were observed in a large cohort study of cotton workers in China and the deficit was found to be 

128 R e s p i r ato ry D i s e a s e s R e s e a r c h at NIOSH dose-related based on quantitative estimates of historic exposures to endotoxin (Wernli et al. 2003; Astrakianakis et al. 2007). These findings, although intriguing, suggest that further work is necessary to understand the potential mechanisms of the cancer-preventive action of endotoxins, if they exist (Boffetta 2007). Exposure to endotoxin is sufficiently common in a wide range of industrial settings (ranging from agriculture to metal machining) to warrant consideration by the RDRP of what it might be able to contribute to understanding the nature and importance of the interaction of endotoxin and cancer. NIOSH’s long-term interest in the ­effects of cotton dust and the measurement of endotoxin suggests this as a potential fruit- ful area for research. As described in Chapter 2, NIOSH and the NCI have undertaken a major epi- demiologic study of diesel exhaust and mortality to provide essential epidemiologic information on the quantitative relationships between diesel exhaust and cancer, particularly lung cancer. Progress in the study, however, has been affected by ­intensive scrutiny and legal action by the industry and congressional intervention ­(Monforton 2006). The number of workers exposed to diesel exhaust and the ­potential for this study to provide significantly improved information about the nature and extent of the risk requires that the study be completed with deliberate speed. The design and conduct of the NIOSH-NCI diesel study are meeting high levels of scientific quality. It is important that the peer review process proceed ­unhindered to allow data to be used by the scientific and regulatory community. Strategic Goal 5: Prevent respiratory and other diseases potentially resulting from occupational exposures to nanomaterials Summary The RDRP plans to focus its attention on the relative toxicities of different nanomaterials in biological systems. The RDRP plans to develop and validate methods of exposure assessment and recommendations for appropriate medical monitoring and surveillance and indicates that it will consider recommendations for engineering controls but does not articulate a specific research program. Committee Comments The growing recognition of the usefulness of nanomaterials in various indus- trial applications and their increased prevalence has created an urgent need to study (1) the potential health effects of exposures to nanoparticles, and (2) methods to control exposures to nanoparticles during manufacturing processes. The RDRP 

Emerging Research and Research Issues 129 has taken a lead at the national and international levels to address these questions. Such studies require a multidisciplinary approach that includes expertise in the physical and biological sciences to develop methods to characterize the particles physically and chemically, methods to develop adequate protective gear to prevent exposures, methods to maintain the characteristics of the particles during inha- lation exposures of test animals, and methods to detect biological responses to exposure to the particles. NIOSH is one of only a few facilities with such a broad multidisciplinary expertise in one agency. The RDRP proposes to conduct a dose-response inhalation toxicology study in animals with engineered nanoparticles. This should be a valuable contribution and provide the information needed to develop a quantitative risk assessment model. The RDRP also plans to continue to conduct exposure assessments and engineering control evaluations in nanomaterial production facilities. These areas of work should provide valuable information. The committee finds that these are commendable and appropriate future plans that appropriately seek to assess and address the potential emerging effects of nanoparticles. Cross-Cutting Issues: Continuing and Emerging Issues Cutting Across Multiple Program Goals During its deliberations and review of the materials present in the evidence package and in several in-person presentations, the committee identified several continuing and emerging issues that cut across all program goals. These issues include surveillance, exposure assessment, emergency response, respirator policy, and the RDRP’s resource allocation. In some instances, the committee thought that the RDRP’s attention to these issues was not articulated very clearly or in ways that could motivate and strengthen current and future research programs. The commit- tee will provide recommendations with regard to cross-cutting issues in Chapter 4. Here, we provide a brief summary of these issues. Surveillance The evidence package and public presentations made by NIOSH-RDRP i ­ ndicate clearly the importance of surveillance to the research, dissemination, and prevention activities of the RDRP and the limitations with respect to resources for surveillance under which the RDRP is constrained to operate. The com­mittee understands that a lack of financial and personnel resources and not a lack of awareness or expertise are the major causes of inadequate surveillance. While the needed resources are not likely to emerge in the near future, the committee thinks that it is important to highlight the limitation as a continuing and emerg- 

130 R e s p i r ato ry D i s e a s e s R e s e a r c h at NIOSH ing issue. The performance assessment of current and future RDRP activities and the identification of new respiratory disease issues depend on having an effective surveillance program. Exposure Assessment Exposure assessment is a core component of occupational respiratory disease research and prevention activities. The field of exposure assessment incorporates several closely related areas that include instrument development, modeling, and the use of exposure biomarkers. The RDRP evidence package includes excellent examples of relevant and high-impact contributions in all these areas as well as spe- cific future goals related to exposure assessment, as noted previously. However, the RDRP does not present these exposure assessment activities as part of an explicit or comprehensive focus on exposure assessment methods, leaving it to the reader to make the extrapolation. Further, while a number of RDRP scientists focused on exposure assessment research in the past, current or future staffing and program- matic needs for exposure assessment activities are not specifically mentioned. Emergency Response It is unclear whether the RDRP plans to incorporate research activities related to emergency responses into future efforts. In particular, much could be learned about exposure-response relationships, and ultimately protecting emergency responders and exposed populations, if appropriate resources were devoted to careful modeling of spatial-temporal toxicant concentrations and estimation of personal exposures for longitudinal cohort studies of individuals involved in cata- strophic events (e.g., those from the World Trade Center [WTC] or work settings where sudden exposures to high levels of irritants are experienced [see Chapter 2, “Emergency Response,” for further discussion]). In follow-up studies, data derived from emergency responses to toxicant exposures should be applicable to models of irritant-induced asthma, fixed airway obstruction, interstitial lung disease, and possibly even malignancies. The RDRP is encouraged to explore research strategies in their emergency response efforts. Respirator Policy NIOSH respirator development, testing, and certification efforts continue to play a crucial role in preventing WRA and work-related COPD. This includes protection from tuberculosis and protection from pandemic and avian influenza and microbial agents that could be used in a terrorist attack. No discussion of 

Emerging Research and Research Issues 131 airway-disease-specific respirator policy was included in the evidence package, although examples of RDRP work on improvements in the fit and availability of personal respirators were documented. A NIOSH report in the peer-reviewed literature that supported the use of respirators in emergency response situations that involve irritant dust exposures (e.g., the WTC disaster) is an example of how the agency can highlight the importance of effective respirator policy in preventing work-related airway disease (Feldman et al. 2004). Given the need for respirators in such situations as well as for their possible use against other agents, the develop- ment of policies related to respirator use is a continuing issue. A separate National Research Council committee is reviewing NIOSH’s personal protective technology research program; therefore, recommendations on this topic will be addressed by that committee and are not discussed in Chapter 4. RDRP Resource Allocation As noted earlier in this report, the formal RDRP is a recent creation organized during the NORA2 process. Given that the NORA2 process emphasized sector- based as opposed to disease-based research, an emerging issue is how research priorities for respiratory diseases that cut across sectors will be treated. Further, although the focus of respiratory disease research remains within NIOSH’s Division of Respiratory Studies, the RDRP encompasses many divisions and laboratories across NIOSH. For researchers who are part of the RDRP but outside the Division of Respiratory Studies, an issue will be how well their activities can be coordinated and prioritized within the RDRP. Further, the new RDRP is faced with the need for systems to govern the awarding of extramural grants, contracts, and cooperative agreements and integrating the results of this external research into the intramural program.