NORA Manufacturing Sector Strategic Goals
927ZBEH - Pathophysiology of Popcorn Workers' LungStart Date: 10/1/2007
End Date: 9/30/2011
Principal Investigator (PI)Name: Ann Hubbs
Funded By: NIOSH
Primary Goal Addressed5.0
Secondary Goal Addressed
Attributed to Manufacturing
Inhalation of microwave popcorn butter flavoring by food manufacturing workers causes "Popcorn Workers' Lung," an emerging, life-threatening lung disease characterized by fixed airways obstruction. The purpose of this study is to investigate the hypothesis, Popcorn Workers' Lung is an expression of the toxicity of flavoring vapors on the airway epithelium. Using in vivo and in vitro animal models, this project's purpose is to investigate the dose-response relationship for individual flavorings and mixtures to identify hazards, define No Observable Effect Levels, and to determine the pathophysiologic mechanism(s) for the airway epithelial toxicity of flavorings, thus, supporting exposure assessment and engineering control. Through publication in the literature and close communication with partners and stakeholders, this project will provide data for hazard identification, risk assessment and recommending workplace exposure standards for the NORA Respiratory Diseases cross sector and Manufacturing sectors.
Popcorn Workers' Lung is an emerging, potentially fatal, lung disease characterized by fixed airway obstruction caused by inhalation of microwave popcorn butter flavoring vapors. The respiratory epithelium is implicated in the etiology of popcorn workers' lung. Therefore, the hypothesis of this project is: Popcorn workers' lung is an expression of the toxicity of flavoring vapors on the airway epithelium. This project, involving an intramural team of 12 collaborators and one university partner, responds to many stakeholder requests for investigation into the pathophysiologic effects of butter flavorings. The broad, long-term objective of this 4-year NORA project is to identify the pathophysiologic basis of this devastating disease so that it can be prevented. The goals are to: 1) provide data on the acute inhalation toxicity of acetoin and diacetyl and their mixtures for use in hazard identification and risk assessment, 2) establish No Observable Effect Levels for inhaled diacetyl and acetoin and mixtures using in vitro and in vivo models, 3) identify mechanisms of toxicity of flavorings in airways, and 4) develop high throughput models for more rapid identification of flavoring toxicity in the airways. The research design and methods will involve in vivo and novel in vitro models of flavoring exposure to establish dose-response relationships to define No Observable Effect Levels and to establish the mechanisms of the disease. First, the relative toxicities of diacetyl, acetoin, acetic acid, and mixtures of these flavorings will be compared by quantifying epithelial degeneration and necrotic/apoptotic cell death using histopathology, morphometry, immunohistochemistry, TUNEL assays, and electron microscopy. Second, the effects of in vivo inhaled flavor vapors on airway epithelial cells, bronchus-associated lymphoid tissue, pulmonary function and airway reactivity to methacholine will be determined. Exposures will be conducted in vitro using air-filled isolated, perfused tracheas and epithelial cell culture to develop high throughput screening of flavoring effects on cell function. Third, whether the toxicity from diacetyl is dependent upon the site of initial absorbance in the airways and/or airway diameter, and the importance of nose breathing, will be investigated. Fourth, the sensitivity of epithelial ion transport to flavorings will be ascertained as a marker for early flavoring effects. Fifth, the effects of flavorings on sensory nerves, which regulate airway diameter, will be determined. Because the role of the site initial absorbance and airway diameter may inform the design of the other goals in this project as well the design of studies planned by the National Toxicology Program, the rat studies in the third goal will be largely completed in the first two years of the study, while remaining goals will be completed throughout the four years of the study. The findings will be translated into practice by providing data for hazard identification, risk assessment and assisting with recommendations for workplace exposure standards to our partners and stakeholders to assist in the development of engineering controls to protect workers. The impact of these efforts will be to protect worker health in plants where flavorings are used. This will occur both through publication in the literature and subsequent direct communication with our stakeholders.
This proposal investigates the pathophysiology of popcorn workers lung, an emerging, life-threatening lung disease characterized by fixed airways obstruction. This proposal responds to stakeholder and press requests for data needed to fill gaps in our understanding of this devastating condition. The hypothesis of the project is: Popcorn Workers' Lung is an expression of the toxicity of flavor vapors on the airway epithelium.
The long-term objective of this project is to identify the pathophysiologic basis for Popcorn Workers' Lung so that this devastating disease can be prevented. The specific aims are to: 1) investigate the acute toxicity of inhaled acetoin and acetoin/diacetyl mixtures; 2) establish dose-response relationships for the morphologic and pathophysiologic effects of flavor vapors on airways; and 3) ascertain the role of airway diameter and neural regulators in airway toxicity due to butter flavoring vapors.
The research plan and methods involve animal inhalation exposures to flavorings and innovative in vitro techniques. First, we will expose rats to acetoin, diacetyl, acetoin/diacetyl mixtures, and acetoin/diacetyl/acetic acid mixtures to provide acute toxicologic pathology data on the airway effects of acetoin and its influence upon diacetyl toxicity. The outcome will be establishment of No Observable Adverse Effect Levels and pathogenesis for acute diacetyl and acetoin toxicity and characterization of the toxic effects of mixed exposures to diacetyl, acetoin and acetic acid. Second, the effects of inhaled flavor vapors on airway epithelial cells, pulmonary function and airway reactivity to methacholine and other bronchoactive drugs will be determined in vitro using air-filled isolated, perfused tracheas and epithelial cell culture. These findings will be compared with in vivo function testing. The outcome of these experiments will be dose-response data for risk assessment, including establishing No Observable Adverse Effect Levels, and validation of a high throughput technique for hazard identification of vapor phase reactive chemicals. Third, the sensitivity of epithelial ion transport to flavorings will be ascertained as a marker of their toxic effects. The outcome of these experiments is that a very sensitive biomarker of toxicity may be identified for screening. Fourth, we will determine whether the toxicity from diacetyl is dependent upon the site of initial absorbance in the airways and/or airway diameter. The outcome from these experiments will be to define the importance of airway diameter to the site of toxic action, and to fill gaps related to the appropriateness of animal species as models of toxicity. Fifth, we will determine the role of neural regulators in airway toxicity of butter flavoring vapors. In combination with our other experiments, the outcome of this experiment will be to identify mechanisms of flavoring-induced lung disease.
Goals and performance measures for this project include:
1. Provide data on the acute inhalation toxicity of acetoin and diacetyl and their mixtures to stakeholders for use in hazard identification and risk assessment.
2. Establish No Observable Adverse Effect Levels for inhaled diacetyl and acetoin and mixtures using in vivo and in vitro animal models.
3. Identify mechanisms of toxicity of flavorings in airways.
4. Develop high throughput models for more rapid identification of flavoring toxicity in the airways.
Annual goals and performance measures:
1. Publication in peer-reviewed biomedical journals will disseminate our findings to the basic research and occupational health research communities.
2. Presentation at professional meetings/conferences will disseminate our findings to the basic research and occupational health research communities.
Popcorn Workers' Lung is a debilitating lung disease triggered by inhaling butter flavorings. The disease is characterized by impaired pulmonary function and airways obstruction in workers. The most severely affected workers have a devastating condition characterized by fixed airways obstruction on spirometry with air trapping and bronchial thickening on expiratory computer tomography scans and some cases of bronchiectasis. The disease clinically resembles bronchiolitis obliterans and changes consistent with constrictive bronchiolitis obliterans were demonstrated in two of three reported lung biopsies. Epidemiology studies, and Health Hazard Investigations of effected plants conducted principally from the Field Studies Branch in DRDS, NIOSH, show an association between Popcorn Workers' Lung and diacetyl, a volatile ketone in butter flavoring. While the disease is now widely recognized by occupational health professionals, researchers, labor, industry and the press, the dose-response relationships for flavoring-induced airway damage have not been established, nor are the biological mechanisms related to toxicity known. The epithelial cell layer of the airways appears to be a target of flavoring-induced lung disease, and the epithelium is regarded as key to development of bronchiolitis obliterans from other causes. Using animal inhalation exposures to flavorings and novel, high throughput in vitro models, this project will fill several critical gaps in our knowledge that are relevant to NIOSH's mission. First, it will establish dose-response relationships for toxicity, with the goal of identifying No Observable Effect Levels. Second, it will clarify the relative toxicities of several suspect flavorings among the many components of butter flavoring vapors. Filling these critical gaps will identify specific hazards and enable recommendations for engineering controls to protect workers. A third critical gap exists in our knowledge of the mechanisms whereby diacetyl and other flavorings cause marked damage and destruction of airway epithelium. Therefore, this project will clarify the relationship between flavoring toxicity and airway diameter and reveal the pathophysiological effects of flavorings on respiratory epithelium. This proposal is responsive to the requests and needs of NIOSH stakeholders including labor, other government agencies and manufacturers, who recognize the importance of these studies. Because the findings will inform worker protection strategies, this project is perfectly aligned with a goal of the manufacturing sector (100%) goal 1 (09PPMNFSG5) to "reduce the number of respiratory conditions and diseases due to exposures in the manufacturing sector"; The Respiratory disease cross sector (100%) goal 1 (09PPRDSG1) "Prevent and reduce work-related airways disease" Intermediate Goal 1.3 (09PPRDRIG1.3) "Prevent and reduce flavoring-induced obstructive lung disease" Activity/Output goals 1.3.5 (09PPRDRAOG1.3.5) to conduct basic toxicology research, including inhalation toxicology studies to better characterize the toxic potential and mechanisms of toxicity of diacetyl and other potentially toxic artificial flavorings. It also supports the exposure assessment cross sector (25%) goal 1 (09PPEXASG1) "develop or improve exposure assessment strategies to understand and prevent work-related illness and injuries; Strategic Goal 2 (09PPEXASG2): Develop or improve specific methods and tools to assess worker exposures to critical occupational agents and stressors.; Intermediate Goal 2.3 (09PPEXAIG2.3): Develop and evaluate new or improved methods for assessing exposure to workplace chemicals and occupational health stressors either singly or as mixtures, including both prospective and retrospective methods; engineered control cross sector (25%) goal 4 (09PPENGSG4) "reduce health and safety hazards by providing expert consultation to elements of NIOSH, other agencies, and external partners in the applications of engineering controls for hazard prevention and the formation of occupational criteria".
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