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Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 41
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 42
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 43
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 44
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
×
Page 45
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 46
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 47
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 48
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 49
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 50
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 51
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
×
Page 52
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 53
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
×
Page 54
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
×
Page 55
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
×
Page 56
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
×
Page 57
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
×
Page 58
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
×
Page 59
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
×
Page 60
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 61
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 62
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 63
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
×
Page 64
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
×
Page 65
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
×
Page 66
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
×
Page 67
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
×
Page 68
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
×
Page 69
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
×
Page 70
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
×
Page 71
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 72
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
×
Page 73
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
×
Page 74
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
×
Page 75
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 76
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 78
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 79
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
×
Page 80
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 81
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
×
Page 82
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
×
Page 83
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
×
Page 84
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
×
Page 85
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
×
Page 86
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
×
Page 87
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
×
Page 88
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
×
Page 89
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
×
Page 90
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 91
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 92
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 93
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 94
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 95
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 96
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 97
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 98
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 99
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 100
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 101
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 102
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 103
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 104
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 105
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 106
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 107
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 108
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 109
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 110
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 111
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 112
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 113
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 114
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 115
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 116
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Page 117
Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Suggested Citation:"2 Evaluation of the Respiratory Diseases Research Program." National Research Council and Institute of Medicine. 2008. Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health. Washington, DC: The National Academies Press. doi: 10.17226/12171.
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Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

2 Evaluation of the Respiratory Diseases Research Program The committee was charged with reviewing the Respiratory Diseases Research Program (RDRP) of the National Institute for Occupational Safety and Health (NIOSH) to evaluate the relevance and impact of its work to reduce workplace illnesses and injuries. The committee’s review focused primarily on 1996 to the present. This time period encompasses not only the current RDRP as it was estab­ lished under the second National Occupation Research Agenda (NORA2) in 2005 but also occupational respiratory disease research as it was configured under the original NORA in 1996. The committee also notes selected activities related to respiratory disease research that occurred before 1996. As stated previously, the committee’s use of the term RDRP also indicates NIOSH activities and programs related to occupational respiratory diseases that predate formal creation of the RDRP under NORA2. The committee evaluation followed the framework document, presented in Appendix A, developed by the Committee to Review NIOSH Research Programs and referred to as the framework committee. The framework document directs individual evaluation committees to evaluate program relevance in terms of the degree to which the research is connected to improvements in workplace protec- tion. It identifies factors to be considered, including the frequency and severity of adverse health outcomes, the number of people at risk, the structure of the program, and the degree of consideration of stakeholder inputs. The framework document directs the evaluation committee to evaluate research impact in terms of the program’s contributions to improvement in worker health and safety to the 34

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 35 extent that it can be known or surmised in terms of quantifiable outcomes. This chapter presents the results of the committee’s review. RDRP GOALS, SUBGOALS, AND RESOURCES Since 2006, the RDRP has pursued the five strategic goals discussed in Chapter 1 with activities of different breadth. These goals are further subdivided into the subgoals shown in Table 2-1. NIOSH used these five strategic goals and their related subgoals to organize the primary evidence package and presentations provided to the committee. In turn, the committee used the five goals to organize its evaluation of the RDRP. While recognizing that the program did not directly use these goals during most of the period covered by the committee’s assessment, the goals are nonetheless consistent with priorities adopted by NIOSH throughout its history. These goals are also relevant for work related to the NORA priority areas of control technology and personal protective equipment, exposure assessment methods, and intervention effectiveness research. The following sections present the committee’s findings addressing both the overall program and matters concerning individual goals and their related subgoals. Funding for the program goals has varied over the past 10 years. Table 2-2 provides the budget for the RDRP classified by program goal. The largest frac- tion of the RDRP budget goes to airway diseases, followed closely by research budgeted for interstitial lung diseases. Table 2-2 also shows that malignancies and nanotechnologies are the smallest components, although spending on nanotech- nology research is rapidly increasing. Figure 2-1 shows a trend toward research in airway and interstitial disease and away from the study of occupational respiratory malignancies. EXTERNAL FACTORS AFFECTING THE RDRP The RDRP operates in an environment shaped by many factors that the pro- gram cannot control. Some factors are so fundamental to the nature of the program that the committee found it essential to keep them in mind for all aspects of its review. For example, NIOSH is primarily a research entity. Thus, although NIOSH can issue recommendations, it cannot mandate that such recommendations be implemented in the workplace. Regulatory implementation of NIOSH’s recom- mendations is left to the Occupational Safety and Health Administration (OSHA) or the Mine Safety and Health Administration (MSHA). Another important consideration is that the RDRP comprises a collection of activities that take place within the 11 organizational units of NIOSH shown in Table 2-3. The program is based on a matrix approach and does not reside within a

36 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 TABLE 2-1  Strategic Goals and Subgoals of the NIOSH RDRP, as of February 2007 Strategic Goal 1: Prevent and reduce work-related airway diseases • Prevent and reduce asthma and allergy due to natural rubber latex among health care workers • Prevent and reduce WRA in the isocyanate production industrya • Prevent and reduce WRA related to nonindustrial indoor environmental quality • Improve detection of WRA and relevant exposures • Establish the work-relatedness of COPD • Develop tools and identify at-risk workers in industries and occupations to assess the extent, severity, and burden of work-related COPD • Develop, test, and disseminate recommendations for preventing COPD in the workplace. • Prevent and reduce flavoring related bronchiolitis obliterans Strategic Goal 2: Prevent and reduce work-related interstitial lung diseases • Prevent and reduce respiratory diseases induced by coal mine dust • Prevent and reduce silica-induced respiratory diseases • Prevent and reduce fiber-induced diseases • Prevent and reduce chronic beryllium disease Strategic Goal 3: Prevent and reduce work-related infectious respiratory diseases • Maintain reductions in the incidence of occupational tuberculosis in high-risk work settings • Protect workers from bioterrorism agents • Protect workers from occupational acquisition of emerging diseases (including severe acute respiratory syndrome, avian and pandemic flu) • Protect workers from occupational exposures that make them susceptible to respiratory infections • Prevent outbreaks of occupational histoplasmosis by maintaining worker and employer awareness Strategic Goal 4: Prevent and reduce work-related respiratory malignancies • Determine occupation etiologies of lung cancer • Reduce metal-induced lung cancer (hexavalent chromium) • Prevent and reduce silica-induced lung cancer • Prevent and reduce lung cancer induced by diesel engine exhaust • Produce lung cancer diagnostic tools Strategic Goal 5: Prevent respiratory and other diseases potentially resulting from occupational exposures to nanomaterials • Determine the relative toxicity of nanomaterials • Conduct exposure assessment and engineering control evaluations in 10 nanomaterial production or use facilities by 2008 • Produce dose-response data for carbon nanotubes sufficient to conduct a quantitative risk assessment by 2008 Abbreviation: WRA, work-related asthma. aBecause workers are exposed to isocyanates in a variety of industries besides isocyanate production, the goal should probably be worded “Preventing and reducing WRA associated with isocyanate exposure.” However, to be consistent with the NIOSH terminology, NIOSH’s original wording is used in this report.

TABLE 2-2  NIOSH Respiratory Diseases Research Program Budget and Staffing by Research Goals (in Millions of Dollars) Total FY1996 FY1997 FY1998 FY1999 FY2000 FY2001 FY2002 FY2003 FY2004 FY2005 FY2006 Intramural 7.35 7.09 10.90 13.20 15.50 16.20 16.06 16.39 16.31 17.17 Extramural 2.31 3.08 4.51 7.31 7.29 8.61 10.08 10.30 8.64 11.40 14.50 Strategic Goal 1: Prevent and reduce work-related airway diseases Intramural 1.66 1.56 2.07 4.35 6.38 5.90 5.64 5.97 7.31 5.80 Extramural 0.62 1.51 2.37 3.13 3.72 3.42 3.10 2.83 2.52 2.74 2.94 Strategic Goal 2: Prevent and reduce work-related interstitial lung diseases Intramural 1.73 3.56 4.60 5.61 6.82 6.14 6.25 6.60 5.61 6.64 Extramural 0.08 0.08 0.35 0.70 0.65 1.48 0.92 1.09 0.38 0.68 0.38 Strategic Goal 3: Prevent and reduce work-related infectious respiratory diseases Intramural 2.89 1.74 3.57 1.89 1.40 3.10 3.63 3.05 2.45 2.70 Extramural 0.30 0.50 0.65 0.65 0.29 0.26 0.25 0.00 0.08 0.08 0.75 Strategic Goal 4: Prevent and reduce work-related respiratory malignancies Intramural 1.08 0.23 0.66 1.34 0.90 1.06 0.54 0.76 0.74 0.76 Extramural .043 0.19 0.09 1.68 1.68 1.19 1.25 1.91 1.78 1.40 1.35 Strategic Goal 5: Prevent respiratory and other diseases potentially resulting from occupational exposures to nanomaterials Intramural 0 0 0 0 0 0 0 0 0.67 1.27 3.31 Extramural 0.10 0.38 0.38 0.29 0.10 0.66 0.82 Abbreviations: FY, fiscal year; FTE, full-time equivalent. Source: R. Sinclair, NIOSH, unpublished material, April 7, 2007. 37

38 Percent Total Intramural 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 Fiscal Year 2-1.eps FIGURE 2-1  Proportional allocation of RDRP intramural funds by goal by fiscal year (FY). Source: R. Sinclair, NIOSH, unpublished material, April 7, 2007. bitmap w/ vector axis headers type is ~6 pt. specific division or laboratory on the NIOSH organizational chart (see Chapter 1). Although there is a Division of Respiratory Disease Studies, it is only one part of the RDRP, albeit the leading one. As with all 15 cross-sector programs under NORA2, a program manager and coordinator(s) are expected to monitor and guide the overall program effort. However, as described in Chapter 1, the organizational structure of NIOSH means that the program manager of the RDRP does not control the budget or the entire program portfolio. The program’s funding level is the sum of the financial resources that individual NIOSH organizational units apply to work on activities to monitor and prevent respiratory disease. The activities of the intra- mural program are distributed across units located in Morgantown, West Virginia; Pittsburgh, Pennsylvania; Cincinnati, Ohio; and Spokane, Washington. The selec- tion and management of extramural projects are based in Atlanta, Georgia. The portfolio, staffing, and funding levels for the RDRP also are shaped by congressional direction as to the amount of the NIOSH budget to be applied to pri- ority areas (e.g., mining safety and health). Although the NIOSH mining program no longer carries a separate line item in the federal budget, Congress has directed

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 39 TABLE 2-3  NIOSH Divisions, Laboratories, and Offices Involved in the RDRP • Division of Respiratory Disease Studies • Health Effects Laboratory Division • Division of Surveillance Hazard Evaluation and Field Studies • Division of Applied Research and Technology • Education and Information Division • Pittsburgh Research Laboratory • Spokane Research Laboratory • National Personal Protective Technology Laboratory • Office of Extramural Programs • Office of Health Communications • Office of Research and Technology Transfer NIOSH to maintain its current level of research effort in this area. In practical terms, this means that, although the RDRP receives a percentage of its budget from the mining sector program, it does not have discretion to redirect these funds to any of the program’s other activities, which may need funding, unless there is a nexus with mine safety and health. SURVEILLANCE, HEALTH HAZARD EVALUATION AND TECHNICAL ASSISTANCE PROGRAM, AND OTHER INPUT ACTIVITIES There are several NIOSH programs that support all NIOSH activities, including those of the RDRP. These programs include surveillance activities, the health hazard evaluation and technical assistance (HHE/TA) program, emergency response and disaster preparedness tasks, and the respirator program. These elements serve as critical inputs into and support for the RDRP. Because they serve many different NIOSH activities, they are not evaluated under the program goals of the RDRP. However, it is important to note how these activities help serve the RDRP. Surveillance WoRLD Reports The information gathered through surveillance helps to identify and track occupational health and exposure. This information also can provide research directions and allow for assessment of trends and impacts. One prominent sur- veillance activity is the summary of occupation respiratory disease and associated exposure data in the series of Work-Related Lung Disease (WoRLD) Surveillance Reports and the web-based eWoRLD Surveillance System. The WoRLD Surveillance

40 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 Report provides information on the frequency and trends in respiratory diseases, the industry and geographic distribution, and demographic information on those affected. Six of these reports have been released since 1991. As noted by NIOSH (2006a), the continuing challenge of such an undertaking not only is to maintain and update existing content but also to present the content in a meaningful way and to add new sources. This activity has also helped spur work in developing a standardized approach to mortality data on occupational lung disease. It has also helped give rise to NIOSH’s Worker Health Chartbook (NIOSH 2004). SENSOR Programs The SENSOR program attempts to integrate occupation health surveillance into public health activities at the state level. Using a consensus case definition of occupational asthma, SENSOR began as a sentinel event system based solely on vol- untary physician reports. It has evolved into efforts at the state level to enhance the population aspects of work-related asthma (WRA) surveillance including examina­ tion of hospital discharge data and use of capture-recapture meth­odology. The state surveillance programs were intended to be targeted programs. At its inception in 10 states in 1987, 6 states identified WRA and 4 identified silicosis for surveillance. Currently, only 4 states continue WRA surveillance ­(Massachusetts, Washington, Michigan, and California) and 2 continue silicosis surveillance (Michigan and New Jersey). The need for appropriate surveillance data for WRA is critical. Without such data, the appropriate targeting of limited resources for exposure and medical moni- toring and interventions to prevent and control disease is difficult, if not impos- sible. The SENSOR program now has a presence in only four states. Expanding the program to include additional geographic areas, and thus the broader occupational mix, would provide a larger basis to track trends and to highlight geographic varia- tion. It is difficult to confirm from external material the NIOSH conclusion that the RDRP “indirectly supports 33 states, one city, and one territory to conduct surveil- lance for WRA.” While the National Center for Environmental Health supported state asthma plans and encouraged recipient state health departments to develop methods for WRA surveillance, a nationwide standard was not implemented and data formats and quality vary. Health Hazard Evaluation and Technical Assistance Program Under its “right of entry” authority, NIOSH investigates suspected hazardous exposures in the workplace. Such investigations, known as health hazard evalua- tions, take place under the HHE/TA program. These investigations are initiated by

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 41 requests from workers, from their representatives, or from an employer. ­Because of the importance and unique character of the HHE/TA program, it will be the subject of a separate National Research Council evaluation. This section focuses on the role of the HHE/TA program insofar as it interfaces with the goals of the RDRP. As noted later in this chapter, particularly with regard to activities related to airways and infectious diseases, the RDRP appears to have effectively used the HHE/TA program to inform and extend the research program on workplace envi­ ron­mental quality. For example, the HHE of the Missouri microwave popcorn plant, which investigated flavoring-induced bronchiolitis obliterans, gave rise to a coordinated research program on flavoring-related obstructive airway disease. The response to that specific HHE request can be considered a model of how the surveillance and initial data-gathering activities related to an HHE can be used as a key production input for setting priorities and planning research objectives. A more systematic approach to the review of all investigations in the HHE/TA program related to respiratory diseases might prove useful. For example, when the outbreak of flavoring-related bronchiolitis obliterans was followed up it was learned that an HHE a decade before had examined a similar work risk. No systematic assess­ ment of HHE findings appears to be in place to identify other new occupational respiratory disease risks worthy of investigation. Similarly, the committee did not learn of any general review of reports in the HHE/TA program for WRA due to low-molecular-weight (LMW) or high-molecular-weight (HMW) sensitizers and irritants that induce new-onset asthma or for the discovery of agents that may cause work-related interstitial or airway disease, although NIOSH did undertake such a summary report with regard to isocyanates (Donovan Reh 2004). Dissemination of particularly relevant outbreak investigations pertinent to WRA or fixed-airway obstruction through mechanisms such as the Morbidity and ­Mortality Weekly Report (MMWR) or brief case reports in the peer-reviewed literature also could be carried out more effectively (e.g., glutaraldehyde in heart-valve manufac- turing workers, chlorine/sulfur dioxide/ozone in paper and pulp mill ­ workers). A successful example of such dissemination by NIOSH was a report of a cluster of cases of new-onset asthma associated with exposure to 3-amino-5-mercapto-1,2,4-triazole identified through SENSOR (Hnizdo et al. 2004a) surveillance. Emergency Response As described in the evidence package, NIOSH participates in agency-wide responses to emergencies and catastrophes. These events include the World Trade Center disaster and anthrax attacks, responses to hurricanes Katrina and Rita, and responses to outbreaks of severe acute respiratory syndrome (SARS) and avian

42 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 influenza in 2005. Activities related to emergency responses include immediate activities related to specific incidents and follow-up activities to further assess the impacts of these incidents and to help improve preparedness. Such activities are incorporated into RDRP program goals to varying degrees. For example, activities related to the goal of preventing and reducing work-related infectious respiratory diseases have been informed by the anthrax attacks of 2001 and outbreaks of SARS and avian influenza. However, no research activities related to emergency response and either WRA or chronic obstructive pulmonary disease (COPD) were reported in the airways disease section of the evidence package. Interestingly, the evidence package did not cite the ongoing medical monitoring of the World Trade Center disaster rescue and recovery workers as an example. This may reflect the somewhat compartmentalized organizational structure of NIOSH. It is unclear whether the RDRP plans to incorporate such research questions into future efforts, but such events could lead to coordinated activities between intramurally and extramurally funded NIOSH research programs. Respiratory Program Another critical element of NIOSH activities relevant to respiratory diseases is work related to respirators, including respirator policy. The evidence package provided by NIOSH (NIOSH 2006b) provides an overview of these activities, including the role NIOSH plays in having the lead responsibility for directing and carrying out the NIOSH respirator certification program and related laboratory, field, quality, and research activities. However, the integration of this activity with the program goals of the RDRP was unclear. For example, there was no discus- sion of airway-disease-specific respirator policy in the evidence package. However, NIOSH respirator development, testing, and certification efforts continue to play a crucial role in preventing both WRA and work-related COPD. The agency could better highlight the need for the respirator program by using the recent NIOSH peer-reviewed report supporting the use of respirators in emergency response situ- ations that involve exposures to irritant dust (Feldman et al. 2004). INTRODUCTION TO Relevance AND IMPACTS ASSESMENT The following sections review the five NIOSH RDRP strategic goals and pres- ent the committee’s assessments with regard to the relevance and impacts of the research completed or in progress. The committee’s evaluation of NIOSH’s target- ing of new research is discussed in Chapter 3. At the end of the review of the five strategic goals, the committee provides a quantitative and qualitative evaluation of the relevance and impacts of the RDRP. In its evaluation of the relevance of

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 43 the work of the NIOSH RDRP, the committee has assessed the degree to which the program has led and carried out research in aspects of occupationally related respiratory disease most relevant to improvements in workplace protection. As discussed in Chapter 1, the committee evaluated the RDRP by using the evidence presented by NIOSH and other stakeholders, a review of the literature, and com- mittee members’ knowledge and experience in respiratory diseases. The committee developed a consensus through deliberations at meetings and discussions of written materials, including a lengthy scoring discussion. STRATEGIC GOAL 1: PREVENT AND REDUCE WORK-RELATED AIRWAY DISEASES Introduction Obstructive airway diseases as a group comprise the most prevalent type of occupationally related chronic respiratory disease. Moreover, the contribution of occupational factors to the incidence of obstructive airway diseases is well docu- mented. Thus, the overall goal of the RDRP airway diseases component to prevent and reduce work-related airway diseases is extremely important. The supporting materials the RDRP submitted to the committee underscore the importance of this goal to NIOSH. Our assessment focuses on the ways program development and associated resource allocation can optimize the efforts being expended to achieve this goal given its relative importance to the overall NIOSH agenda. The materials devoted to airway diseases submitted by NIOSH were organized into two major disease categories: WRA and fixed obstructive airway diseases (COPD and bronchiolitis obliterans). Four specific objectives were listed by NIOSH for each of these two categories. To facilitate review, the evaluation of the relevance and impact of the RDRP airway diseases component activities follows the same organizational scheme and addresses separately the subgoals for WRA and fixed airway obstruction as formulated by NIOSH. Nonetheless, it is recognized that no rigid boundary demarcates these two broad categories of obstructive airway disease and substantial overlap can occur. Work-Related Asthma NIOSH formulated the following four subgoals for WRA: • Prevent and reduce asthma and allergy due to natural rubber latex among health care workers. • Prevent and reduce WRA in the isocyanate production industry.

44 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 • Prevent and reduce WRA related to nonindustrial indoor environmental quality. • Improve detection of WRA and relevant exposures. Ample rationale exists for including such specific objectives in an overall WRA program. The prevalence of sensitization to natural rubber latex among health care workers increased dramatically between 1987 and 1996 because of a huge increase in the use of latex gloves as part of the universal precautions for preventing exposure to blood-borne pathogens. Diisocyanates are one of the most common specific chemical causes of WRA and are used in a variety of settings and formulations. Indoor environmental quality complaints in general, and complaints specifically related to respiratory health (which include exacerbation of preexisting asthma), have led to multiple NIOSH HHEs. In response, NIOSH has developed considerable expertise related to WRA exacerbation in the context of indoor air, largely in the managerial and service sector, which is a dominant employment sector in postindustrial economies. The fourth, more general objective recognizes that ­improved surveillance for WRA is critical for identifying emergent problems, setting priorities, and tracking the effectiveness of interventions. The objectives as formulated have certain limitations. The objective related to latex asthma and allergy largely has been achieved. NIOSH deserves much credit for the documented reduction in WRA due to natural rubber latex, an end outcome among health care workers in the United States. The case for continuing this ­narrowly cast objective as a priority could have been more clearly elucidated. Latex is still used widely in applications far beyond the health care industry, such as day care and other service industries. Programmatic work on latex, a proto- typical HMW antigen, naturally extends to a variety of other important causes of WRA, such as enzyme and nonenzyme plant and animal proteins. This work also is relevant to work-related rhinitis, an airway disease apparently overlooked in the description of NIOSH goals. Similarly, the importance of diisocyanate-related asthma, a key prototype for asthma induced by LMW chemicals, goes well beyond the manufacture of this chemical (the focus of the NIOSH goal). In particular, diisocyanates are relevant to end-user sectors, especially in the construction industry. The mechanisms of immune response to these chemicals appear to differ in key ways from classic HMW sensitization, such as sensitization to latex, so the diisocyanate-specific goal may also be generalized to a far wider array of workplace LMW chemical hazards. For example, the challenges of elucidating mechanisms of disease in isocyanate- induced asthma may apply to other LMW chemicals. The NIOSH supporting materials only minimally addressed this subject.

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 45 Work-aggravated asthma only recently has been recognized as a major issue in occupational airway disease, in large part through NIOSH’s leadership role. Examina­tion of indoor air quality in offices and other public buildings, highlighted in the WRA goal related to asthma exacerbations, may well be expanded to other settings, such as custodial work. Finally, the admirable, but broadly stated generic goal of improved detection, suffers when juxtaposed with the other highly focused objectives. NIOSH’s craft- ing of this goal could have benefited from concentrating on selected key examples. For example, the targeted surveillance of irritant-induced asthma is overlooked although highly appropriate to this objective. Whatever shortcomings exist in the definitions of this key goal, NIOSH has been suitably active in this area. For e ­ xample, a NIOSH investigator is one of the coauthors of the chapter on this sub- ject in a major text in the field and has been involved in important investigations of the subject (Gautrin et al. 2006). Planning and Production Inputs NIOSH-funded surveillance efforts through the SENSOR program assisted in determining the extent of the latex-induced occupational asthma problem and, importantly, identified its prominence relative to other HMW antigens for which latex can serve as a prototype. The established surveillance system can continue to provide extended tracking information for latex-caused WRA, allowing for assess- ment of intervention efforts. Although limited to four states and with an uncertain future, SENSOR for WRA has also facilitated the identification of emerging prob- lems associated with other HMW antigens. Additionally, the RDRP developed an approach to the latex problem that included collaboration with multiple federal agencies, health care industry associations, and professional organizations as well as the preparation of a widely disseminated NIOSH Alert (see below). Diisocyanates are widely used in U.S. industry and multiple studies have shown them to be one of the most commonly identified causes of LMW sensitizer-induced occupational asthma. There is no reliable biological marker of sensitization to diisocyanates and the OSHA permissible exposure limit appears to be inadequate. The RDRP recognizes both the relative importance of diisocyanates as a cause of asthma and the relative difficulty of detecting diisocyanate-induced asthma or sen- sitization at the preclinical stage. The RDRP approach to the diisocyanate problem includes supporting both intramural and extramural research, developing new exposure monitoring methods, partnering with industry to develop best practices for exposure control and medical monitoring, and using surveillance through the SENSOR program.

46 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 As highlighted above, available data suggest that improving the environmental quality of nonindustrial indoor workplaces can have major health and economic benefits. Review of the HHE program showed that there has been a tremendous in- crease in requests for HHEs related to indoor environmental quality concerns over the past three decades, with building-related asthma accounting for approximately 25% of such requests. An Institute of Medicine report (IOM 2004) documented that damp indoor spaces are associated with health risks and public health efforts should be directed toward preventing and remediating such environments. Data from the SENSOR program also identified indoor air pollutants as a category of agents frequently associated with WRA. The RDRP developed an approach to this problem that resulted in a major investment of intramural funds through the Asthma Research Program Project. The RDRP also developed collaborations in Connecticut that involved state agencies and the University of Connecticut in conducting a multiyear study of a large office building. In Maine, state agencies and the American Lung Association Maine affiliate work with the RDRP to study the relationship between school environmental quality and asthma. Other collabora- tions were formed with universities and the U.S. Environmental Protection Agency (EPA) to develop methods for assessing exposures to fungi. The asthma and COPD NORA1 team recognized the need for an improved questionnaire to ascertain probable WRA in epidemiologic studies. The RDRP also recognized the need for a portable spirometer, a personal device to record and store data electronically, that could be used to improve the detection of WRA. The RDRP developed collaborative approaches to these needs that involved working with the American Thoracic Society (ATS) and the National Center for Health S ­ tatistics (NCHS) on questionnaire development and the manufacturer of a popu- lar ­portable spirometer to improve the device for use in detecting WRA. The planning and consideration of inputs for all four subgoals appear to have been reasonable. The asthma and COPD team during NORA1 was aware of the problems of latex- and diisocyanate-induced occupational asthma and of the larger problem of inadequate surveillance for WRA. The team devoted its efforts toward addressing these and other asthma-related research and prevention issues. It is not clear how well the new industrial-sector-based approach of NORA2 will be able to address disease-specific issues. The indoor environment team during NORA1 provided a forum for addressing problems of indoor air quality common to ­office and other buildings in virtually all areas of the economy. Again, it is not clear how the NORA2 approach will address disease-related problems that are common across industrial sectors.

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 47 Activities, Outputs, and Outcomes The primary output of the natural rubber latex activity was the publication of a NIOSH Alert, “Preventing Allergic Reactions to Natural Rubber Latex in the Workplace” (NIOSH 1997a). More than 360,000 hard copies have been dissemi- nated since it was released in 1997, with easy public access to a downloadable web version. The NIOSH Alert also led to published commentaries in at least 10 health publications accessible on Pubmed (National Library of Medicine) in 1997. In addition, the RDRP conducted a research project on the efficacy of the NIOSH Alert for changing hospital policy that documented its effectiveness and led to two peer-reviewed publications (Maxfield et al. 1999, 2000). The latex reports in the SENSOR program have been analyzed systematically: a peer-reviewed publication based on SENSOR data focuses on WRA among health care workers and highlights latex among other exposures (Pechter et al. 2005). There have been other relevant information transfer efforts as well. An RDRP collaboration with the Veterans Administration health care system demonstrated that switching from powdered to nonpowdered latex gloves dramatically reduced the rate of latex sensitization (Zeiss et al. 2003). An RDRP collaboration with the Food and Drug Administra- tion (FDA) resulted in a peer-reviewed publication that analyzed FDA MedWatch data relevant to adverse events from medical gloves, primarily focusing on latex allergy (Dillard et al. 2002). Although NIOSH has never published a report specific to latex allergy in the MMWR, an outbreak of occupational asthma related to another HMW trigger (egg protein) was published (MMWR 1987). Similarly, although NIOSH has not committed substantive resources to extramural or intramural research into the biological mechanisms or outcomes of latex-induced occupational asthma, it has supported work related to allergic sensitization to egg protein and asthma asso­ ciated with crab processing as related examples of HMW protein caused WRA (Boeniger et al. 2001; Ortega et al. 2002). Intramural and extramural research support has been a major mechanism that underlies NIOSH activities and outputs relevant to diisocyanate asthma. Since 1996, RDRP intramural and NIOSH-funded extramural investigators have authored over 50 peer-reviewed publications covering toxicology, mechanisms of action, epidemiology, clinical aspects of disease and medical monitoring, sampling methods, and disease prevention and environmental controls (NIOSH 2006a). Highlights of this research output include the development of a tumor necrosis f ­ actor (TNF) receptor knockout mouse model that was used to demonstrate the role of TNF-α in diisocyanate sensitization, the first human study to confirm that dermal exposure increased the risk for pulmonary sensitization, and four pub- lished papers on 17 methods for diisocyanate exposure monitoring and analysis of

48 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 samples. In addition to peer-reviewed publications, NIOSH analytic methods for diisocyanate quantification are available through the NIOSH website. Between 1985 and 1994, NIOSH carried out 29 HHEs—identifiable by the key term search “isocyanate(s)” in the NIOSH database; between 1995 and 2004, the number fell to 11. It is not clear whether industry practices or other interventions account for this fall-off or whether other factors are responsible. In 1996, NIOSH published an important Alert, “Preventing Asthma and Death From ­Diisocyanate” (NIOSH 1996b). In 2006, a NIOSH Alert, “Preventing Asthma and Death from MDI [mineral-dust induced] Exposure During Spray-on Truck Bed Liner and R ­ elated Applications” (NIOSH 2006c), summarized four case reports: one death and several incidents of asthma or other respiratory disease that followed exposure to MDI during spray-on truck bed lining operations. In the same way that SENSOR data have allowed tracking of latex-related asthma, a new source of diisocyanate asthma has been detected by this surveillance system; the truck bed liner MDI cases were detected through the Michigan SENSOR project and reported in the MMWR. NIOSH has disseminated information about diisocyanate asthma through other routes, including two major international conferences that featured presentations on diisocyanate-related research (on occupational asthma and skin exposures) that the agency sponsored. In addition, the RDRP developed a website that provides a single source of published references on the prevention of diisocyanate-induced asthma. Another noteworthy output was a memorandum of understanding ­between NIOSH and the American Chemistry Council Diisocyanates Panel. Signed in 2003, this agreement facilitates the identification and implementation of best practices in disease prevention and medical monitoring related to diisocyanates. Although not fully described in the evidence package, NIOSH has conducted intramural research on potential mechanisms of diisocyanate-induced sensitization and asthma as well as mechanistic research on another class of LMW sensitizers, acid anhydrides (Zhang et al. 2002, 2004, 2006). In addition, an HHE of an outbreak of asthma due to another LMW sensitizer, 3-amino-5-mercapto-1,2,4-triazole, led to peer-reviewed publications, one of which documented sensitization in an animal model (Hnizdo and Sylvain 2003; Klink and Meade 2003; Hnizdo et al. 2004a). The RDRP has also played a key role in gathering, organizing, and interpreting research and case studies on the relationship between machining fluids and hypersensitiv- ity pneumonitis as well as occupational asthma. This work included an important workshop (Kreiss and Cox-Ganser 1997), development of a criteria document that was used by a federal advisory committee established by OSHA (NIOSH 1998a, Metalworking Fluids Standards Advisory Committee 1999), and an assessment of metal-working fluid exposures in small workplaces that demonstrated these loca- tions would not be adversely affected by NIOSH’s recommended exposure limit (Piacitelli et al. 2001).

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 49 The “WRA in offices and schools” project has been the largest component of the RDRP Asthma Research Program Project (funding from 2000 projected through 2010). As described by NIOSH (2006a), the project involved field investigations that included clinical assessment of building occupants, development of biomarkers for improved assessment of exposure to bioaerosols, and a longitudinal study of the efficacy of remediation work in a damp building. Collaborations were established with the University of Sydney to design a halogen immunoassay to assess personal exposures to fungi, with the University of Cincinnati to develop immunoassay- compatible sampling techniques that make it possible to differentiate fungal spores from fungal fragments, and with the EPA to develop serologic immunoassays for biomonitoring exposures to fungi. Since 1996, RDRP investigators supported through intramural and extramural funding mechanisms published multiple articles relevant to this topic, broadly defined, in the peer-reviewed literature. An RDRP investigator coauthored the relevant chapter in the latest edition of an influential textbook on occupational asthma (Menzies and Kriess 2006). Several monoclonal antibodies developed by RDRP investigators have been patented and licensed to companies for commer- cialization. An RDRP gas and vapor team established in 2001 to investigate the gas-phase and surface-phase chemistry of indoor environments has built an experi­ mental laboratory to study volatile organic compounds and oxygen radicals. In collaboration with the Harvard School of Public Health, the RDRP cosponsored an international workshop on indoor chemistry and health in 2004. The RDRP also partnered with multiple federal agencies to organize the Surgeon General’s Workshop on Healthy Indoor Environment held in 2005. The scope of work on indoor air summarized above has the potential to lose “specificity” to the question of asthma alone. For example, indoor exposures to mold and endotoxin that are subsumed within this goal are associated with impor- tant respiratory tract responses other than asthma (as well as being linked to non- respiratory tract responses). Although building-related illness can include asthma, other health effects such as “sick building syndrome” have little direct relevance to the stated goal of preventing and reducing WRA related to nonindustrial indoor environmental quality. The potential for using resources theoretically targeted to WRA for studying non-asthma health effects is underscored by the record of HHEs in this area: only 19% of all indoor air investigations since 1982 appear to promi- nently feature asthma as a suspect complaint. Although not limited to asthma, the RDRP has published a systematic evaluation of data from office buildings for which HHEs were received in a 6-month period in 1992 and 1993 (Mendell et al. 2003). Although the potential for loss of focus does exist with indoor air investiga- tions, RDRP work on bioaerosols in office buildings and schools has relevance to occupational exposures to bioaerosols in other settings—for example, from contaminated metalworking fluids and in animal confinement facilities. Thus,

50 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 on balance, although the indoor WRA asthma goal may include work on non- asthma-related issues, the benefits of this line of research outweigh this potential drawback. To address the goal of improved WRA detection, NIOSH has taken into ­account both new onset of occupational asthma and aggravation of preexisting disease. There is some overlap with the subgoal of reducing WRA associated with indoor air quality in nonindustrial settings, to the extent that the latter is perceived as an emerging asthma problem. The WRA detection goal, however, is more broadly cast. A linchpin of the RDRP effort to improve the detection of WRA has been the SENSOR program. The SENSOR case definition for WRA is cited frequently in the published literature. The contribution of SENSOR to data on latex and diisocyanate asthma was discussed above. In addition to standard surveillance reports from SENSOR, several key focused analyses based on pooled SENSOR data have been published in the peer-reviewed literature and include epidemiologic assessments of work-aggravated asthma and irritant-induced asthma (Henneberger et al. 2003a; Goe et al. 2004). Another investiga­tion that built directly on SENSOR was a project to include questions on occupational asthma in the annual Behavioral Risk Factor Surveillance System survey when it was administered in three SENSOR states in 2001 (Breton et al. 2006; Flattery et al. 2006). The RDRP also led a key methodologic assessment of asthma surveillance that built on SENSOR data from one participating state and applied an innovative capture-recapture strategy to better estimate the true inci- dence of occupational asthma (Henneberger et al. 1999). With a targeted request for applica­tion collaborative agreement strategy, the RDRP also has supported analyses of several different health care databases to better estimate the incidence of new onset occupational asthma as well as work-aggravated asthma (Henneberger et al. 2003a,b; Vollmer et al. 2005; Henneberger et al. 2006; Sama et al. 2006). The RDRP played a key role in facilitating the ATS Statement on the Occupa- tional Contribution to the Burden of Obstructive Airways Disease (Balmes et al. 2003), a frequently cited document that summarized the large body of literature (through 2000) on the work-relatedness of a substantial fraction of cases of adult asthma. The partnership between the RDRP and the ATS grew out of the NORA asthma and COPD team deliberations. This document and the RDRP-ATS part- nership are discussed below in the subsection on fixed obstructive airway disease. Beyond the activities and outputs specifically related to the subgoal of improved detection of WRA summarized above, the RDRP partnered with the ATS to ­develop a survey instrument to assess respiratory symptoms in adults that included an occu­ pational module; the RDRP cosponsored a meeting of the committee for further development of the questionnaire. After a draft questionnaire was completed, the RDRP contracted with the NCHS to conduct cognitive testing of the new core

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 51 and occupational questions. NIOSH (2006a) stated that cognitive testing of the revised adult respiratory questionnaire will be completed in 2007 and data from that testing will be used in 2008 to modify parts of the questionnaire related to occupational exposures, symptoms, and diseases. The RDRP worked to develop hardware (a “belt spirometer”) and software to facilitate the collection of serial spirometric data for use in detecting WRA; some of this work was done in col- laboration with the manufacturer of a popular portable spirometer, the EasyOne (ndd Medizintechnik AG). Assessment of Relevance Given the high prevalence of new cases of adult asthma that may be related to occupational exposures, the four WRA subgoals are highly relevant to improved occupational safety and health among the U.S. workforce. As presented by NIOSH (2006a, p. 116), WRA is the most common respiratory disease treated in occupational health clinics in the U.S., accounting for a substantial share of all asthma among adults. A 2003 statement of the American Thoracic Society indicates that 15 percent of asthma among adults is attributable to work [Balmes et al. 2003]. Under cooperative agreements, NIOSH-funded researchers have since estimated that 29 percent to 33 percent of new-onset adult asthma is attributable to work. In addition, RDRP scientists estimate that 23 per- cent of existing adult asthma is exacerbated by work. Assuming that about 25 percent of asthma is attributable to work, at least 2.25 million Ameri- cans between the ages of 15 and 65 have experienced onset or exacerbation of their asthma due to workplace conditions [Sama et al. 2006]. The planning, activities, and outputs described above are judged to be of generally high quality for each of the four subgoals. The work on latex represents a timely response to an epidemic of occupational asthma and a model of how e ­ ffective planning can lead to research targeted to generate knowledge that can be transferred to improve outcomes. The work on diisocyanates directly addressed the most common LMW sensitizing cause of asthma in the developed world and again led to important knowledge that has been used to prevent disease. While the work of the RDRP on indoor environmental quality is judged to be relevant to occupa- tional health and safety in the general sense, it is not always necessarily related to WRA. Some of the work on indoor environmental quality has a broader relevance (e.g., to residential settings). The RDRP effort to improve the detection of WRA in the broad sense is of the highest relevance. Increased awareness of this disease

52 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 has been engendered by RDRP’s support of the ATS statement, analysis of National Health and Nutrition Examination Survey (NHANES) data, and ­population-based research conducted through collaborative agreements. Assessment of Impact RDRP’s work to achieve the four WRA subgoals has had considerable impact. In the case of latex, the RDRP investigators have documented a fall in the preva- lence of latex sensitization as a result of the intervention effort begun with the 1996 NIOSH Alert. For diisocyanates, RDRP’s work has contributed to greater awareness of WRA due to this class of LMW sensitizers. This work included iden- tifying a new source of exposure, with publication of a report in the MMWR, and a new NIOSH Alert in response. With regard to WRA and indoor air quality, the greatest impact of RDRP research appears to be in the development of methods for ­improved quantitative assessment of exposure to fungi. The impact of RDRP efforts to improve detection of WRA in the broad sense is more difficult to assess given the lack of adequate surveillance data, but the quality of transfer activities in this area (e.g., the ATS statement on the “Occupational Contribution to the Burden of Obstructive Airway Disease”) is judged to be high. Fixed Obstructive Airway Diseases The four subgoals for fixed obstructive airway diseases formulated by NIOSH are as follows: • Establish the work-relatedness of COPD. • Develop tools and identify at-risk workers in industries and occupations to assess the extent, severity, and burden of work-related COPD. • Develop, test, and disseminate recommendations for preventing COPD in the workplace. • Prevent and reduce flavoring related bronchiolitis obliterans. The first three subgoals are quite broadly defined. This is appropriate, given the current state of the art in the epidemiology of work-related COPD. Moreover, an overly specific definition of COPD (e.g., based solely on a decreased FEV1/FVC ratio, where FEV1 is forced expiratory volume in the first second and FVC is forced vital capacity) could lead to the lack of consideration of certain related conditions. For example, chronic bronchitis is frequently addressed as a condition captured under the rubric of COPD. The term COPD typically is used in a way intended to include emphysema as well. Although the NIOSH goals did not explicitly endorse a

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 53 definition of COPD as a subsuming disease defined by airflow obstruction, emphy- sema (defined by loss of air-exchanging units of the lung and supporting structure), and chronic bronchitis (defined by chronic sputum production), it was implicit in the supporting materials provided. By the same token, even though “prevention” is not specifically defined in the goal, elements of secondary and tertiary as well as primary prevention are relevant. For example, efforts can be made to reduce work-related disability associated with COPD. Because of the leading role of the RDRP in the research effort to understand, control, and prevent bronchiolitis obliterans in the flavoring industry, the fourth subgoal also is consistent with the priorities of the RDRP. Although it could be construed to be cast narrowly, especially juxtaposed with the prior three subgoals, such an interpretation would overlook both the inherent importance of this disease outbreak in its own right and the application of this work to other established or emerging occupational airway disease processes characterized more by fixed than by reversible airway obstruction. Such conditions (including byssinosis and irritant inhalation-related bronchiolitis obliterans) typically are considered to be separate from WRA. By establishing a subgoal focused on flavoring-related bronchiolitis obliterans, NIOSH provides for a mechanism to prioritize research in this general area and in so doing addresses a topic that has been understudied and overlooked from a preventive standpoint. A final point to emphasize in assessing the subgoals that target work-related COPD is that the classic pneumoconioses, although leading to a restrictive ventila- tory deficit, also can be associated with COPD, chronic bronchitis, and emphysema. This is most clearly the case with coal workers’ pneumoconiosis (CWP). Although RDRP research related to CWP and other fibrotic (restrictive) lung diseases are addressed separately, activities that address airway effects of exposures to fibrotic agents are discussed in this section. Planning and Production Inputs As noted above, a partnership between the RDRP and the ATS grew out of the NORA asthma and COPD team deliberations and led to the establishment of a committee that undertook a systematic review of the published literature on the question of work relatedness of COPD as well as of asthma. Not only did the RDRP provide logistic support for the work of this committee, but three RDRP investigators were key participants directly involved in writing the report that was the committee’s main output (see below). Both before and in follow-up to publication of the ATS statement, the RDRP has approached the need for better assessment of the magnitude of the ­ burden of work-related COPD on an industry-specific and occupation-specific basis.

54 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 This ­includes conducting a series of epidemiologic studies, developing improved m ­ ethods for identifying COPD, and collaborating with extramural researchers at various universities. For example, the National Study of Coal Workers’ Pneumo- coniosis (NSCWP) included spirometry data relevant to obstruction; in follow-up to initial observations, RDRP investigators planned a series of thoughtful research investigations to answer specific questions related to coal-dust-induced COPD. Another notable example of relatively new RDRP activity that was not industrial sector based was the use of NHANES data to address the population-attributable risk of COPD due to occupational exposures and to provide support for greater preventive efforts in this area. The RDRP has approached the prevention of work-related COPD primarily through research on spirometric monitoring of lung function at the workplace. One aspect of this approach involves spirometry as a medical surveillance tool, consistent with NIOSH’s recommendations for a variety of exposures. From a production input perspective, RDRP efforts to develop standard population reference equations for predicted lung function values represent a crucial con- tribution to preventing work-related COPD. First, these equations (derived from NHANES data collected following the design by and supervision of NIOSH research scientists) allow for race/ethnicity-specific estimations for Caucasians, Blacks, and ­ Hispanics. Second, the equations facilitate the identification of e ­ xposure-associated lung function deficits within a cohort based on a reliable external comparison group, including, if needed, an external smoking adjust- ment parameter estimate. This RDRP effort also provided NCHS with prediction equations for use in settings other than the workplace, which is recognized as a highly valuable contribution. The RDRP research effort on flavoring-induced bronchiolitis obliterans began with a 2000 HHE request from the Missouri Department of Health. The results of the initial RDRP investigation led to the recognition that workers throughout the flavoring industry also might be at risk for this potentially debilitating airway disease. A multidisciplinary approach to the problem was organized and involved epidemiologists, inhalational toxicologists, industrial hygienists, and engineers. This multidisciplinary approach is similar to that used in the RDRP response to the initial report of nylon flock workers’ lung disease (see interstitial lung diseases below). The RDRP approach to these two clusters of cases of potentially severe occupational respiratory disease has been of great value in defining the scope of the threat to worker health. The response to the HHE request with regard to a cluster of cases of ­bronchiolitis obliterans from a single microwave popcorn manufacturing facility can be consid- ered a model of how an HHE (a surveillance and initial data-gathering instrument) should serve as a key production input for setting priorities and planning research

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 55 objectives relevant to detecting and preventing occupational diseases. An earlier HHE in 1985 investigated a cluster of cases of bronchiolitis obliterans in a com- mercial baking facility that used diacetyl (McConnell and Hartle 1986). The failure of the earlier HHE to trigger a deeper investigation that might have highlighted the hazards of diacetyl further underscores the point that, without a concerted effort to make fixed obstructive airway disease an RDRP priority, important surveillance “signals” can and will be lost. In follow-up planning efforts intended to better define the population of workers at risk for flavoring-induced bronchiolitis obliterans, RDRP investigators have attempted to engage the Flavor and Extract Manufactur- ing Association in industry-wide surveillance activities, have held workshops and exchanged information with specific industries, and have responded to requests for assistance from the California OSHA and Department of Health Services. Beyond the specific case of diacetyl, the more general issue of the systematic ways the RDRP could look for “signals” within the HHE program and other surveillance resources should be considered in future planning. Activities, Outputs, and Outcomes RDRP activities and outputs on coal-dust-induced COPD derived from the NSCWP have been considerable and comprehensive. The exposure-response rela­ tionship was investigated initially by relating quantitative measures of dust expo- sure to measurements of pulmonary function obtained serially in the NSCWP (Attfield and Hodous 1992). These and related data helped support an updated NIOSH criteria document for coal mine dust published in 1995. More recently, the RDRP has focused on identifying occupational and nonoccupational risk factors for excessive declines in pulmonary function among coal workers and the implica- tions of these risk factors for morbidity and mortality (Hodgins et al. 1998; Wang et al. 2005). Additional data were collected to supplement the NSCWP for these studies. Laboratory studies that included pathological evaluation of material col- lected through the National Coal Workers’ Autopsy Program and toxicologic investi­ gations that involved potential pathways by which silica can induce lung injury by generating reactive oxygen species contributed to a mechanistic understanding of coal-dust-induced COPD (Hnizdo and Vallyathan 2003). Other relevant RDRP research has included investigations of the associa- tion between excessive decline in FEV1 and retirement due to chest illness and the ­ exposure-response relationship for mortality due to chronic bronchitis or e ­ mphysema (Kuempel et al. 1995; Beeckman et al. 2001). Combined with the pathological findings from the autopsy study noted above, these results indicate that exposure to coal dust can lead to permanent and debilitating structural damage to the airways and lungs. The RDRP also has supported laboratory-based investiga- tions related to coal mining and airway disease (Cohen et al. 2002).

56 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 While past RDRP epidemiologic research on work-related COPD extended beyond coal mining, the work was limited to industry-specific exposures or dis- crete occupations and was not framed to address more general cross-industry or cross-occupation exposures to vapors, gas, dust, and fumes. Cotton dust exposure, which is linked to fixed obstructive airway disease as a manifestation of Stage IV byssinosis, is an excellent example of such a non-coal-industry-specific research f ­ ocus. NIOSH has provided the key extramural funding for the longitudinal study of cotton dust exposure and fixed airway obstruction among textile workers in China, establishing one of the longest-followed byssinosis cohorts. This study has led to improved knowledge of both exposure-response and individual risk factors. NIOSH also has provided extramural support for studies of grain-dust- related and diesel-e­xhaust-related respiratory health effects that are highly relevant to occupationally related COPD. In addition, NIOSH’s support of the Agricul- tural Research Centers has helped to promote research relevant to organic-dust- r ­ elated ­obstruction—for example, research on the mechanisms underlying chronic b ­ ronchitis in farmers (Lambert et al. 2005). Although industry- and occupation-specific studies have provided key early evidence of the link between work-related exposures and COPD, more recently, analyses of existing data from large population-based surveys have been used to provide a more global picture of the impact of occupational exposures on the prevalence of COPD in the general population. NIOSH has supported this work through extramural support or it has been conducted internally by RDRP investi- gators. Extramural funding has supported collaborations with several universities (University of California, Los Angeles; University of Oregon; Tulane University) that provided for analysis of the effects of occupational factors on the risk of COPD in cohorts to which RDRP investigators otherwise would not have had access (e.g., the Lung Health Study, Kaiser Permanente-Northwest Region, longitudinal spirometric data from 12,000 workers in 11 industrial facilities). The results of the collaborative analyses have not been published other than as abstracts, but the a ­ pproaches taken (e.g., use of a new job-exposure matrix) should provide valu- able contributions. Another important output was a peer-reviewed paper on the costs associated with work-related COPD, which was a collaborative effort between University of California, Davis, investigators and an RDRP investigator (Leigh et al. 2002). The results of the intramural analyses of NHANES III data have been pub- lished in two peer-reviewed papers and are a major contribution to the scientific literature on COPD (Hnizdo et al. 2002, 2004b). An output with wide distribution was the ATS Policy Statement on the “Occu­ pational Contribution to the Burden of Obstructive Airway Disease” (Balmes et al. 2003) to which the RDRP made a major contribution. The RDRP cosponsored a

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 57 meeting of the international writing committee in Morgantown in 2001 that greatly facilitated the completion of this document. The RDRP development of new reference equations for spirometry, discussed previously (Hankinson et al. 1999), has been an extremely valuable contribution to the improved detection of COPD. Developed as a consequence of the RDRP’s responsibility for spirometry in NHANES surveys, these equations have become the “gold standard” in the United States. The RDRP also has activities directed toward improving lung function testing of workers, including hardware and software devel­ opment, methodologic work on analysis of longitudinal decline and identification of individuals with excessive declines, and evaluation of decision rules based on excessive decline. Since 2000, this work, in partial collaboration with Tulane Uni- versity, has led to multiple papers published in the peer-reviewed literature and represents an impressive body of work (Hnizdo et al. 2005, 2006a). Another recent paper by RDRP investigators demonstrates how different lung-function-based case definitions for COPD can influence prevalence data (Hnizdo et al. 2006b). In 2006, the RDRP also organized a workshop that reviewed the current statistical methods for longitudinal spirometry assessment. The RDRP has developed sampling methods to measure exposure to volatile chemicals, including diacetyl in facilities that process butter flavoring. A longitu- dinal investigation of the sentinel plant in Missouri and new investigations at five additional microwave popcorn plants have been conducted (Kreiss et al. 2002; Kanwal et al. 2006). These studies showed that workers were at risk throughout the industry and that the highest risk appears to be associated with peak exposures to butter flavoring chemicals due to open handling, even when ventilation maintained low average exposures. Animal inhalational toxicology studies conducted by the RDRP have demonstrated that diacetyl can injure airways, although other ingredi- ents in butter flavoring may contribute to toxicity (Hubbs et al. 2002; Fedan et al. 2006). RDRP investigators also performed laboratory analyses of emissions from bulk butter flavoring samples collected at six microwave plants and demonstrated that emissions of volatile chemicals were greater from liquids and pastes than from powders (Boylstein et al. 2006). To better assess the potential for flavoring-related lung disease in other food-production facilities, RDRP investigators have done walk-through surveys at plants that produce beverages, flavored coffee, and pack- aged oil. Presentations to the Flavor and Extract Manufacturers Association have been made in an effort to establish partnerships with member companies to work with the RDRP to assess worker risk throughout the industry. RDRP investigators also have partnered with the California OSHA and Department of Health Services to conduct surveillance for flavoring-related respiratory disease and to help develop a state-based standard for California, an ongoing process (MMWR 2007b).

58 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 Assessment of Relevance The four fixed obstructive airway disease subgoals are highly relevant to i ­ mproved occupational safety and health among the U.S. workforce in light of evidence that up to 15% of all cases of COPD may be related to occupational exposures (Balmes et al. 2003; Blanc and Torén 2007). Further, as described by NIOSH (2006a, p. 139): COPD is the fourth leading cause of death in the U.S. In 2003, 10.7 million U.S. adults were estimated to have COPD, although close to 24 million adults had evidence of impaired lung function, indicating under-diagnosis of COPD in the U.S. The cost to the nation of COPD was approximately $37.2 billion in 2004, including healthcare expenditures of $20.9 billion in direct costs, $7.4 billion in indirect morbidity costs, and $8.9 billion in indirect mortality costs [American Lung Association 2006]. The planning, activities, and outputs described above are judged to be of high quality for each of the four subgoals. RDRP efforts that included the ATS statement, industry-specific studies (especially those in coal mining), and population-based studies directly addressed underrecognition of the work relatedness of COPD. Work on spirometric methods, as well as in industry-specific and population-based s ­ tudies, also directly addressed the identification of at-risk workers and assessment of the burden of work-related COPD. Much of the work on spirometry, especially the development of equations to predict normal values, has an even broader rele- vance for preventing COPD. The work on flavoring-related bronchiolitis obliterans has been a well-coordinated and integrated multidisciplinary response to an emerg- ing problem that can be considered a model for future efforts of the RDRP. The need for improved surveillance data on work-related COPD is critical for assessing relevance. Without such data, it is difficult to appropriately allocate limited resources for exposure and medical monitoring and interventions to pre- vent and control disease. The RDRP plan to collaborate with the NCHS and the National Heart, Lung, and Blood Institute to provide support for spirometry in the 2007-2008 NHANES is of highest importance; failure to do so would be a major setback for COPD surveillance at the national level. The addition of new questions on occupational exposure to the NHANES survey is a major improvement; analysis of NHANES on the basis of occupational and industrial categories, which can be segregated with reasonable precision, has already yielded important results, as summarized previously (Hnizdo et al. 2004a). However, inadequate geographic resolution of NHANES data prevents appropriate analysis of state-level variation in COPD outcomes as opposed to large regional aggregations (e.g., the western United States). Therefore, RDRP efforts to seek new

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 59 methods for conducting work-related COPD surveillance are of great importance for understanding the relevance of COPD-related research and appropriately tar- geting resources. Assessment of Impact RDRP work to achieve the four fixed obstructive airway disease subgoals has had a considerable impact. Although the ATS statement on the “Occupational Con- tribution to the Burden of Obstructive Airways Disease” was mentioned previously in relation to WRA, its impact on increased recognition of work-related COPD should not be understated. Multiple peer-reviewed papers by RDRP ­investigators report the results of studies using NSCWP data and provide clear evidence that certain groups of U.S. underground coal miners are at risk for COPD, pneumo­ coniosis, bronchitis, and emphysema, which are associated with disability and mor- tality. Numerous investigators and policy makers have cited this body of ­research in their assessment of the links between respirable dust exposure, diesel particulate matter, and COPD, not only for this specific industry but also as a measure of biologic plausibility for COPD related to other exposures. RDRP studies using NHANES data have contributed to a greater recognition of the role of occupational factors in the burden of COPD on the U.S. population. RDRP work on spirometry, especially the development of new reference equations for normative values, has had a major impact on respiratory disease research in general and, more specifi- cally, on preventing COPD. The RDRP response to the initial outbreak of diacetyl- i ­ nduced bronchiolitis obliterans has led to surveillance efforts in multiple locations in an effort to detect and prevent disease. In large measure due to RDRP research, the California OSHA is considering establishment of a permissible exposure limit (PEL) for diacetyl. STRATEGIC GOAL 2: PREVENT AND REDUCE WORK-RELATED INTERSTITIAL LUNG DISEASES Introduction Historically, research and prevention activities, outputs, and outcomes that pertain to work-related interstitial lung diseases generally categorized as pneumo­ conioses have been a critical part of the RDRP mission. Because of the impor- tance of CWP, initial RDRP research focused on it almost entirely. A number of research, surveillance, and regulatory-related activities associated with interstitial lung diseases first mandated by the Federal Mine Health and Safety Act of 1969 were later assigned to NIOSH. Beginning in 1976, with formation of the Division

60 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 Respiratory Disease Studies, the scope of respiratory disease research extended significantly to other forms of interstitial lung disease, including silicosis, chronic beryllium disease (CBD), and asbestosis. In addition, work on organic dusts has subsumed hypersensitivity pneumonitis (also known as extrinsic allergic alveolitis), another potentially fibrotic lung condition. More recently, novel emerging occu- pational lung conditions have been recognized that also have prominent fibrotic features—for example “flock worker’s lung.” The following sections summarize the activities of the RDRP that pertain to interstitial lung diseases. The four subgoals related to the prevention and reduction of work-related interstitial disease as formulated by the RDRP are as follows: • Prevent and reduce respiratory diseases induced by coal mine dust. • Prevent and reduce silica-induced respiratory diseases. • Prevent and reduce fiber-induced diseases. • Prevent and reduce CBD. The first of these subgoals clearly remains central to core RDRP activities. Although coal mine dust had long been known to cause pneumoconiosis and chronic respiratory disease, little was done in the United States to prevent CWP until passage of the Federal Mine Health and Safety Act of 1969, as alluded to above. This legislation established the federal standard of 2 mg/m3 for respirable coal mine dust; before this standard was established, between 150,000 and 500,000 U.S. underground miners were typically exposed to respirable dust concentrations of 6-8 mg/m3 (Attfield and Sexias 1995). Moreover, new data are emerging that suggest geographic “hot spots” within certain states and even across multistate regions are linked to endemic CWP characterized by rapid progression of disease (Antao et al. 2005; MMWR 2006a, 2007a). Moreover, emerging NIOSH surveil- lance data indicate that the prevalence of CWP among workers with 25 years or more of exposure is climbing relative to the historic lows in the late 1990s (NIOSH 2006a; Ward 2007) (see further discussion below). Finally, this specific subgoal, as articulated, overlaps with the RDRP initiative on work-related COPD (addressed in the preceding section). Thus, there is more than sufficient rationale for the coal- dust-related subgoal. Silicosis, the pneumoconiosis associated with silica exposure, has been a long-recognized and continuing problem in many industrial sectors in the United States. Unlike CWP, which by definition is a mining-specific issue, silica exposure in mining and quarrying accounts for only one of multiple potential exposure venues. Traditional sources of exposure include heavy industry (such as foundry work, glass making, and pottery manufacture) as well as construction trades in which sandblasting remains an ongoing risk factor both for those directly carry­

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 61 ing out the work and for “bystander employees.” Not only do silica-containing blasting materials remain in use, but there is growing awareness (in part through research work supported by extramural NIOSH programs) that concrete finish- ing operations that have become a prominent component of construction can be asso­ciated with substantive silica exposure (Woskie et al. 2002; Croteau et al. 2004; Akbar-Khanzadeh et al. 2007). Beyond the well-defined risk of silicosis, other silica-associated adverse health effects are relevant to this subgoal, although they are not limited to interstitial processes. These effects include “acute silicosis” (which overlaps with pulmonary alveolar proteinosis), silica-promoted myco- bacterial infection (including atypical mycobacterial disease), silica-associated extrapulmonary rheumatologic disorders, and, overlapping with RDRP goals in respiratory cancer, the association between silica and bronchogenic carcinoma. Considering all these disease links, coupled with ongoing sources of exposure, this subgoal has unquestionable relevancy. The subgoal related to “fiber-induced” lung disease as formulated subsumes both inorganic and organic (naturally occurring and anthropogenic) materials that, because of their physical characteristics, may share important mechanistic pathways and may benefit from overlapping prevention strategies. Asbestos is by far the most prominent of these exposures in terms of past commercial applica- tions and ongoing and likely future respiratory morbidity and mortality. Other natural mineral fibers closely resemble commercial asbestos and also cause inter- stitial lung disease (e.g., amphibole fibers that contaminate vermiculite ore once mined in Libby, Montana). Other naturally occurring mineral fibers (including fibrous talc, wollastonite, attapulgite, and mordenite fibers) differ from asbestos and ­amphibole-contaminated vermiculite minerologically and toxicologically but nonetheless may be relevant to this subgoal. Synthetic vitreous (inorganic) fibers, including refractory ceramic fibers (RCFs), increasingly used as asbestos substitutes may be hazardous, especially if they are durable and have dimensional characteristics mimicking asbestos. Fibrous glass and mineral wool are examples of synthetic vitreous fibers that may be less ­durable but still carry lung health risks. Modern synthetic organic fibers (e.g., ­nylon, rayon, polyester, and others), depending on their processing and applications, pose a respirable fiber hazard and the potential for interstitial lung disease, of which the emerging disease flock worker’s lung appears to be prototypical. While the total population at risk for all the various fibers that may be sub- sumed under this subgoal has not been determined, it is estimated that nearly 4 mil- lion workers are at risk to a subset of these hazardous fibers (asbestos, fibrous talc, fibrous glass, wollastonite, attapulgite fibers, and RCFs) (NIOSH 1986b, 2006c). These exposure data, although fragmentary, underscore the importance of this subgoal.

62 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 Beryllium, the focus of the fourth subgoal, is a lightweight metal with proper- ties that include heat resistance and conductance, electrical conductance, flexibility, formability, neutron moderation, x-ray transparency, and lubricity. These proper- ties have led to beryllium being used in many applications in a variety of settings, including the nuclear industry, aerospace and electronics/microelectronics manu- facturing, and a variety of specialty applications, including health care. As the uses for beryllium have become increasingly diverse, exposures are more widespread. It is estimated that as many as 134,000 current U.S. workers have been or will be exposed to beryllium at some time during their working lives, which may be an all time high (Henneberger et al. 2004). Exposure to beryllium can lead to sensitization, resulting in CBD, a granulo- matous, often progressive, potentially fatal, fibrotic lung disease that is histologi- cally identical to the idiopathic disease sarcoidosis. Factors leading to sensitization and then to disease among sensitized workers have been only partially elucidated. NIOSH-supported research efforts have been pivotal in this work (see below). Through this work, it has become clear that very low levels of exposure can carry substantial risk (Henneberger et al. 2001; Day et al. 2007) and clusters of disease in work settings not previously considered at risk have been well documented in recent investigations (Sackett et al. 2004; Welch et al. 2004). The relevance of beryllium sensitization and CBD goes beyond the population directly at risk, large and growing as it may be, because the causes and prevention of this process have relevance to additional, albeit less common, metals-associated, work-related granulomatous processes (e.g., disease caused by titanium and zirconium). Fur- ther, the beryllium subgoal may also be applicable to more general epidemiologic efforts to study potential occupational associations with sarcoidosis. For example, an otherwise unexplained increased incidence of sarcoidosis has been observed in dust-exposed firefighters in follow-up to the World Trade Center disaster (Izbicki et al. 2007). The four subgoals, as formulated, are not as inclusive as they might be insofar as certain occupationally related fibrotic lung disease is concerned. For example, the previously cited group of conditions known as extrinsic alveolitis does not easily fall under any of the four stated subgoals. Organic dusts (as opposed to fi ­ bers) ­altogether seem to fall outside this particular set of subgoals. So too do gases or fumes that might lead to interstitial lung processes—for example, chemically induced bronchiolitis obliterans organizing pneumonia. We recognize that these omissions are largely an artifact of the structure of this review process rather than reflecting a fundamental lack of programmatic content on the part of the RDRP. The following sections summarize planning and production inputs; activities, outputs, and outcomes; and assessment of relevance and impact, in turn, for each of the subgoals discussed above. Where appropriate, this discussion is extended to

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 63 other selected RDRP initiatives that are relevant but may not otherwise be easily categorized within this format. Respiratory Disease Induced by Coal Mine Dust Planning and Production Inputs The work of the RDRP addresses three primary objectives directed at disease assessment and prevention of occupational lung diseases among coal miners: r ­ esearch into disease causation, disease surveillance and monitoring, and research to improve measurement and control of coal mine dust. The three major subgoals of the program translate into the following: • Verification that the currently enacted coal mine dust standard protects mine workers. • Tracking disease occurrence in coal miners to document the status of prevention and to target preventive efforts. • Improved measurement and controls to reduce exposure to coal mine dust. Since the late 1960s, the coal industry has contracted to an estimated 74,000 people, mainly men, of whom 57% are underground coal miners. CWP has been documented to occur among both underground and surface coal miners. The legacy of exposure to respirable coal mine dust has been the well-documented impairment from advanced pneumoconiosis and airway obstruction that results in significant morbidity and accompanying compensation costs. A primary planning input is tracking the occurrence of disease in coal miners that was mandated in the original Federal Coal Mine Health and Safety Act. To fulfill the mandate, the RDRP operates x-ray surveillance programs to identify those with pneumoconiosis. RDRP efforts to raise employer and miner awareness has increased employer x-ray surveil- lance program compliance from 90% to 98% (2003-2006) and has increased miner participation from 20% to 30% (1985-1999) to nearly 50% (2003-2006). NIOSH realized very early in its surveillance program that evidence of CWP suffered from variability in the classification of x-ray evidence, which led NIOSH to create the B Reader Certification Program to standardize and test physicians’ competency in CWP radiographic assessment. NIOSH has revised its B Reader Certification Pro- gram to comply with changes in the pneumoconiosis classification system of the International Labour Office (ILO). This includes collaborating in a multinational film reading trial led by RDRP scientists, which provided the basis for the ILO r ­ evision in collaboration with the American College of Radiology (NIOSH 2006a). The RDRP has held numerous workshops and major meetings that involve the

64 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 B Readers Certification Program. In addition to a continuing emphasis on CWP surveillance and associated methodology, the RDRP has successfully incorporated CWP morbidity and mortality in their series of WoRLD Surveillance Reports that have been widely disseminated nationally and internationally (see WoRLD Surveil- lance Reports 2002 [NIOSH 2003] and the eWoRLD Surveillance System, a more frequently updated web-formatted reporting system [NIOSH 2007a]). Despite significant progress in reducing CWP, surveillance reports have identi- fied rapidly progressive CWP in a geographic area that includes Eastern Kentucky and Southern West Virginia (Antao et al. 2005; MMWR 2006a, 2007a). NIOSH (2006a) stated “The reasons for this apparent rapid progression and continuing occurrence of progressive massive fibrosis are unclear. It may result from a com- bination of inadequacies in the present dust limit and its method of enforcement. These occurrences point to the need for continued surveillance and monitoring activities to track disease decline and to target enhanced exposure assessment and dust control.” The RDRP has responded by conducting special radiographic examina­tions (Miners’ Choice Program) from 1999 through 2002. The RDRP is now operating a mobile examination unit and is working with MSHA to determine hot spot surveillance that is supplemented by intense publicity and outreach efforts to enhance miner participation in these areas. Activities, Outputs, and Outcomes Research into disease causation includes assessment and verification that the enacted coal mine dust standard protects miners. The standard of 2 mg/m3 was derived from British epidemiologic research, but few of the assumptions that under­lie the 2 mg/m3 PEL have since been validated among U.S. coal miners. RDRP efforts to validate the respiratory dust standard for coal miners included a series of comprehensive cross-sectional epidemiologic surveys, the National Coal Workers’ Pneumoconiosis Study, that used standardized methodologies for chest r ­ adiography and spirometry to establish the prevalence and severity of disease in the United States; requirements that employers offer chest radiographic surveil- lance to all underground miners in the United States and that the RDRP assist in developing standardized radiographic reading methods and programs; and epi- demiologic and laboratory research to explore, examine, and evaluate knowledge and assumptions about mechanisms and progression of disease among U.S. coal miners. Led first by the Appalachian Laboratory for Occupational Respiratory Diseases, which then became the Division of Respiratory Disease Studies, the RDRP pub- lished more than 220 epidemiologic studies, surveillance laboratory-based studies, and dust control reports that documented a decreasing prevalence of CWP, declin-

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 65 ing severity of associated respiratory impairment, and improved dust control and monitoring measures. The completion of more than 300,000 radiographic surveil- lance examinations, supplemented by the serial National Coal Workers’ Pneumoco- niosis Study, provided reliable U.S. occupational dose-response data for CWP that resulted in a NIOSH criteria document, “Occupational Exposure to Respirable Coal Mine Dust” (NIOSH 1995). That document recommended a respirable coal mine dust PEL of 1 mg/m3 (NIOSH 1995, 2006a), which MSHA did not adopt. These recommendations arise from a series of RDRP peer-reviewed publications (Attfield and Morring 1992a,b). With issuance of the criteria document in 1995, the focus of RDRP fieldwork has moved toward surveillance and prevention activities. To comply with the respirable coal mine dust PEL set in the Federal Mine Safety and Health Act of 1969, the Bureau of Mines was required to improve dust exposure assessments, develop cleaner coal-cutting technology, and improve ventilation and dust suppression methods. This research included developing real-time dust moni- tors. Between 1996 and 2005, 97 publications on dust measurement and control were published by respiratory disease and mining research programs. Many of these publications are technical reports directed to the mining industry and to MSHA (Campoli et al. 1996; Cantrell et al. 1996; Belle et al. 2000; Bugarski and Gautam 2001). Development of these technologies was critical, as average production of continuous miner sections more than doubled between 1971 and 2003, and average long-wall production increased nearly 10-fold during the same period. Assessment of Relevance Current program efforts for RDRP research to further reduce pneumoconiosis among coal miners have developed the following objectives: • Improve technologies for dust assessment and dust control. • Monitor and evaluate the extent, severity, and characteristics of CWP. • Increase awareness of the occupational contribution to pulmonary impair- ment associated with CWP. • Research, document, and better understand rapidly progressive CWP. • Research, document, and recommend targeted dust-reduction strategies, dig- ital chest radiographs, and improved radiographic assessment methods for CWP. All these activities are highly relevant for reducing the incidence of CWP. The need to improve technologies to assess respirable dust and to monitor levels of respirable dust is critical to reducing the incidence and severity of CWP.  The reasons underlying MSHA’s decision were not presented to this committee for consideration.

66 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 The experience gained in the CWP program creates a highly valuable framework for better understanding and preventing the recently described rapidly progressive CWP. Efforts to understand the strengths and limitations of digital radiographs in detecting pneumoconioses and for implementing the use of digital radiography in the B Reader Certification Program are important. Assessment of Impact The impact of NIOSH’s work quantifying the cumulative incidence of respira- tory diseases induced by coal mine dust has been very high. Unfortunately, it has not solely been an exercise in documenting an ongoing reduction in the burden of disease, given the findings of hot spots of rapidly progressive CWP and the a ­ pparent increase in the prevalence of CWP across the United States (MMWR 2006a, 2007a; Ward 2007). The RDRP and the Mining Research Program have col- laborated to develop, disseminate, and significantly improve control of coal mine dust in under­ground mines. For continuous miner work, dust samples exceeding the PEL of 2 mg/m3 have dropped from 49% in 1971 to 9% in 2003. For long- wall miners, the percentage dropped from 44% to 12% over the same time period (NIOSH 2006a). Data provided to this committee (NIOSH 2006a) indicate that, between 1970 and 1999, the percentage of all underground coal miners examined with CWP (ILO category 1/0+) declined from 11% to 1.6%. As shown in Figure 2-2, for ­miners with 25 years of tenure or longer, the prevalence of CWP dropped from 35% (1983-1978) to below 5% (1997-1999) and to just over 5% in 2004 (NIOSH 2003). However, Figure 2-2 also indicates an upswing in the disease in 2004-2005. More recent data indicate further increases in the prevalence of CWP. Data from 2005 and 2006 indicate that about 9% of miners with tenure of 25 years or longer showed lung abnormalities indicating CWP. Rates among miners with 20 to 24 years of experience increased from 2.5% to about 6% over the same period (data from E. L. Petsonk, NIOSH, as cited by Ward [2007]). The geographic hot spots of cases of rapidly progressive CWP described above are also of great concern. As described by Antao et al. (2005), “cases of rapidly progressive CWP can be regarded as sentinel health events, indicating inadequate prevention measures in specific regions.” The x-ray program has resulted in 3,000 of 18,000 eligible miners with radio- graphic evidence of pneumoconiosis exercising their right to transfer to a less- dusty job. This also means that 15,000 have not transferred to jobs with reduced exposure. Moreover, as stated above, one in two miners does not even participate in the program. RDRP activities affect other issues related to lung disease in coal workers that are substantive NIOSH outputs, most notably for occupationally related COPD (see

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 67 Figure 2-2  Reductions in respirable dust concentrations derived from MSHA compliance data, 2-2.eps and prevalence of CWP among participants in the Coal Workers’ Health Surveillance Program, 1970-2005. Source: NIOSH 2006a. bitmap above). Work on isocyanate-induced asthma is noteworthy, given the application of such materials in mining (NIOSH 1994; Donovan Reh 2004). Silica-Induced Respiratory Diseases Planning and Production Inputs RDRP research on silicosis has addressed six primary objectives: • Reduce deaths due to silicosis through research and policy development. • Promote use of silica substitutes for abrasive blasting. • Assess silica exposures and controls. • Provide relevant disease progression and dose-response data for standard- setting groups.

68 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 • Demonstrate that freshly fractured silica is associated with a highly reactive dust. • Demonstrate that oxidant injury is a critical mechanism for interstitial lung disease. As late as the mid-1980s, NIOSH estimated that 2.3 to 4.3 million workers in a wide variety of mining and nonmining occupations were still at risk for occu­ pational exposure from silica dust. By 1991, the RDRP had established a system for national surveillance both to document silica exposures and to estimate the prevalence of silicosis. According to more recent NIOSH data (2006d), between 1968 and 2003 there were 15,714 certified deaths that mentioned silicosis and annually reported deaths due to silicosis decreased from 1,065 in 1969 to 179 in 2003. Mortality from silicosis has declined, with the total number of silicosis deaths from 1999 to 2003 at 52% of the corresponding number for the period 1985-1989 (NIOSH 2006d). Nonetheless, the problem persists. It has been estimated that b ­ etween 3,600 and 7,300 new cases of silicosis are recognized each year (Rosenman et al. 2003). Moreover, OSHA and MSHA silica sampling data (1999) showed that 47% of samples from construction, 38% from manufacturing, and 8% from mining exceed their PELs for silica (NIOSH 2006a). More than half the silica samples in construction and manufacturing exceed the NIOSH recommended exposure limit (REL) for silica (0.05 mg/m3) (NIOSH 2006a). Activities, Outputs, and Outcomes RDRP scientists have documented increased toxicity from freshly fractured s ­ ilica, which may elevate the risk of silicosis among miners, rock drillers, sand- blasters, and silica flour millers (Castranova et al. 1996a). They have also produced hundreds of abstracts, presentations, and publications on silica (249 published in the last 10 years) (NIOSH 2006a). On the basis of RDRP research, NIOSH has pub- lished 12 official policy documents on silica in the workplace that began with the 1974 criteria document “Occupational Exposure to Crystalline Silica” completed and disseminated in 1974 (NIOSH 1974). This document set an REL for crystal- line silica of 0.05 mg/m3. In 2002, NIOSH reassessed its silica data, updated its risk assessment, and reaffirmed the NIOSH REL of 0.05 mg/m3 for silica (half that of the OSHA PEL of 0.1 mg/m3) (NIOSH 2002a). NIOSH cosponsored International Symposia on Silica, Silicosis and Cancer in 1993 and 2002 and has used interagency agreements to conduct several research projects designed to address essential knowledge gaps in support of a new silica standard (Perry 2006). NIOSH (2006a, p. 69) states that “OSHA intends to ask RDRP scientists for an expert review of OSHA’s anticipated new silica standard prior to its release for public comment.”

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 69 In response to documented high rates of silicosis and acute silicosis arising from sandblasting, NIOSH published an alert “Request for Assistance Preventing Silicosis and Deaths from Sandblasting” (NIOSH 1992a). The alert recommended use of abrasive substitutes for sand, but the economic feasibility of substitutes and the potential for toxicity of substitute abrasives were not understood fully at the time. Substitute materials for silica sand and abrasive blasting were evaluated through controlled test blasting. The cost of substitute materials was evaluated and the effectiveness of substitute materials was determined. RDRP results documented that pulmonary toxicity of abrasive substitutes (specular hematite and steel grit) was less than that of sand (Craighead et al. 1988; Hubbs et al. 2001, 2005; Porter et al. 2002). These findings were documented in several peer-reviewed reports and three U.S. Department of Commerce National Technical Information ­Service pub- lications and were communicated to industrial hygiene professionals and govern­ ment regulatory agencies (KTA-Tator 1998). As a result of RDRP research, use of abrasive substitutes for sand increased, while the use of silica sand for sand­blasting decreased by 47% (between 1996 and 2004). OSHA considers information on the toxicity of sandblasting substitutes as critical to its ongoing effort to develop and promulgate a new silica standard (NIOSH 2006a). Consistent with NIOSH’s e ­ fforts, the National Toxicology Program (NTP) included selected abrasive blasting substitutes for a subchronic inhalation study (2002). The RDRP partnered with the American Lung Association in a joint campaign on silicosis prevention that began in 1996. This campaign engaged multiple part- ners from industry, labor, and academia throughout the United States and in several foreign countries. The RDRP developed engineering controls and recommenda- tions to reduce occupational exposures to silica that resulted in 80 publications on the control of silica exposures in several industry sectors and mining. On the basis of the RDRP joint campaign on prevention of silicosis, OSHA developed a Special Emphasis Program to reduce silicosis. Similarly, MSHA undertook efforts to reduce occupational exposures based on RDRP research that included the ­Miners Choice Examination Program for surface coal miners who are at particular risk for silicosis associated with drilling overburden rock. A World Health Organization (WHO) report authored by the RDRP was instrumental in launching the ongoing ILO/WHO International Programme on Global Elimination of Silicosis (1995). In 1998, OSHA asked NIOSH to collect data on silica exposure and engineering controls in a variety of workplaces to determine the technical feasibility of a pro- posed rule. These environmental studies, in both construction and general industry, by RDRP scientists have documented significant exceedances of the NIOSH PEL in both construction (36% of samples) and general industry (16% of samples). Therefore, RDRP studies focused on evaluating engineering controls in a variety of construction and general industry settings. Results have documented prevention

70 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 measures for silica exposures that led to peer-reviewed papers documenting the technological feasibility, cost, and impact of these measures (Echt et al. 2002, 2003; Echt and Sieber 2002). RDRP research continues to evaluate engineering control technology for selected silica-generating activities, development of a silica-focused workplace solutions document to provide practical guidance for dust control, and transfer of engineering control knowledge from mining to selected general industry applications (Flanagan et al. 2003; Flynn and Susi 2003; Croteau et al. 2004). Data used to set standards are based on available population-based studies of silicosis in working populations. The development of biomarkers may provide evidence of an even earlier stage of disease that could benefit prevention efforts. T ­ oward resolution of these issues, RDRP scientists have undertaken a major inhala- tion study of silica-induced pulmonary responses in a rat model. This multidisci- plinary study is intended to identify a threshold lung burden beyond which disease will progress without further exposure (Green et al. 1989; Kuempel et al. 2001). Studies have also been undertaken in humans and have led to the identification of genetic polymorphisms associated with an increased incidence of silicosis (Yucesoy et al. 2001). Identification of biomarkers that can indicate potential ­susceptibility to silicosis or provide early evidence of the disease is suggested as a useful adjunct to the diagnosis of silicosis. In addition to continuing consultation with OSHA, research on biomarkers continues through a collaborative study with South ­Africa’s National Center of Occupational Health and also through a collaborative study with the People’s Republic of China (silicosis in tin and ­ pottery workers) with attention to particle surface characteristics in these industries. Finally, RDRP sci- entists are investigating dose- and time-dependent silica-induced lung cancer in a susceptible mouse model and are completing a study of the role of a model gene (mineral dust-induced gene, mdig) in silica-induced lung cancer to provide mecha- nistic data on silica-induced lung cancer. It is known that certain occupations, including sandblasting, rock drilling, silica flour milling, concrete cutting, and tunneling are associated with a high incidence of silicosis. A fundamental question addressed by RDRP activities is whether this high rate is due to high concentrations of airborne dust or whether freshly fractured silica particles are inherently more toxic than aged silica ­particles. Certainly, this mecha- nism has long been suspected to be relevant to disease causation, but the question remains unsettled. In vitro exposure of lung cells to freshly fractured versus aged silica particles has revealed freshly fractured silica to be more cytotoxic (Vallyathan et al. 1995; Castranova et al. 1996b). Coating these particles with an organosaline material effectively coats freshly fractured silica and mitigates cytotoxicity and thereby represents a potential prevention strategy in certain occupational exposure settings. RDRP scientists also have worked closely with MSHA to develop engineer- ing controls in underground mines and to use dust capture technology on drills.

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 71 These control technologies have been widely disseminated in the form of technical reports and peer-reviewed publications relevant to sand­blasters, rock drillers, con- struction workers, and miners (NIOSH 1992a,b; Gulumian et al. 2006). A critical mechanistic issue addressed by the RDRP is the hypothesis that the pathogenic potency of a particle depends in part on its ability to generate reactive species on its surface or to stimulate production of reactive oxygen and nitrogen species from phagocytic cells. RDRP scientists have developed techniques to mea- sure the production of reactive oxygen species and reactive nitrogen species and have also developed techniques to monitor oxidant stress. This research has been aided by experimental in vivo exposure studies in the rat. This line of research has also demonstrated that silica-induced oxidants can activate signaling pathways for the production of inflammatory cytokines and chemokines, fibrosis, and growth factors. It is hoped that elucidation of the mechanistic role of oxidative species will result in identification of biomarkers of silicosis and silica-induced cancer. Four important peer-reviewed publications and multiple abstracts and presentations have resulted from this research (Shi et al. 1998; Castranova 2004; Zeidler and C ­ astranova 2004; Porter et al. 2006). In addition, RDRP scientists sponsored or co- sponsored three conferences on oxidant injury in 1993, 1997, and 2002. RDRP sci- entists have also cowritten four books on oxidant injury (Van Dyke and Castranova 1987; Castranova et al. 1996a; Vallyathan et al. 2002, 2004). These findings have helped the scientific community and regulatory agencies to better understand the mechanism for initiating the progression of silicosis. Oxidant stress has also been identified as an important paradigm for nanoparticle toxicity (Nel et al. 2006). RDRP expertise has been useful to external bodies, including the International Agency for Research on Cancer (IARC) monograph, “Evaluation of the Carcino- genic Risk of Chemicals to Humans. Silica, Silicate, Coal Dust, and Para-aramid Fibers” (IARC 1997), and to the EPA and the International Life Sciences Institute in their effort to develop short-term screening strategies for fiber toxicities and nanomaterials. RDRP research will continue to focus on the role of oxidant stress and occu­ pational lung disease with an emphasis on developing inhibitors, therapeutic interventions, and delivery systems to treat pulmonary disease. Current program efforts for silica-induced respiratory disease research are (1) to provide necessary research to inform OSHA in anticipation of its new silica standard; (2) to reduce silica exposures through increased substitution, development, and dissemination of guidance for dust control in at-risk industries and occupations; (3) to continue silica and silicosis surveillance; (4) to provide mechanistic data on dose- and time- dependent silica-induced lung cancer; (5) to provide mechanistic data on the role of a novel gene (mdig) in silica-induced lung cancer; and (6) to develop tools for early detection of silica-induced respiratory disease, including the use of digital

72 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 radiography in silicosis surveillance and development of a possible biomarker to help detect early development of disease. In addition, although specifically relevant to RDRP work on cancer risk gener- ally, it should be noted here that NIOSH research supported a link between silica exposure and lung cancer through numerous epidemiologic studies, HHEs, and laboratory investigations that focused on silica exposure in the 1970s and 1980s. IARC cited this research to support its determination that crystalline silica, in the form of quartz and cristobalite, were probable human carcinogens (IARC 1997). Further, interagency agreements with OSHA in 1999, 2000, and 2002 have funded RDRP projects on silicosis in an animal model to evaluate responses at the lower end of the dose-response scale and to evaluate the ability of silica to cause lung cancer in a susceptible animal model. Assessment of Relevance The wide range of occupations and activities with silica exposures, the severe health effects of silicosis, and a direct causal link to occupational exposures all underscore the high relevance of this focus area to NIOSH’s core mission and the RDRP’s specific goals. In that context, the goals of the RDRP for silica-induced lung diseases focus on key areas that can contribute to a better understanding of the adverse health effects of silica and to better protect workers. These goals i ­ nclude laboratory research on a mechanistic understanding of silica’s toxicity and applied field research relevant to silicosis surveillance and monitoring occupational exposures. Both foci should assist in the effort to develop and promulgate a revised silica standard as part of a broader effort to reduce the incidence of and mortality from the disease. Unfortunately, with the exception of cancer risk assessment, there does not appear to be a complementary epidemiologic effort targeting silicosis and other silica-associated health that is integrated with the laboratory and applied field activities delineated above. Assessment of Impact RDRP work to achieve goals related to reducing silicosis and other silica- induced respiratory diseases has had a measurable impact. As described above, NIOSH reports that, while annual silicosis deaths decreased from 1,065 in 1968 to 179 in 2003, recent estimates show that between 3,600 and 7,300 cases of silicosis are newly recognized each year. Mechanistic, dose-response, and epidemiologic research conducted or sponsored by NIOSH have enhanced the understanding of silica-related disease processes in support of the goal of reducing these diseases. The mechanisms driving disease causation have been better defined through a series of

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 73 research efforts on silica-related oxidant stress. Research on freshly fractured silica has demonstrated its enhanced toxicity, mechanisms driving that effect, and means to reduce those toxic effects. RDRP-applied research efforts have helped to reduce the use of silica in sand- blasting operations and have driven the development of alternatives for silica sand in these operations and, as described above, NIOSH (2006a) indicates that the use of silica sand for sandblasting decreased by 47% between 1996 and 2004. Nonetheless, even a 50% reduction in use means that only half the problem has been eliminated. This is particularly noteworthy since, in the same time frame, silica-based abrasive blasting has been virtually eliminated within the European Union. Furthermore, NIOSH analysis of exposure monitoring for a variety of industries has indicated that levels of exposure frequently exceed even current standards, suggesting that any new standard, absent changes in work practices and enforcement, is unlikely to achieve adequate control. Overall, deaths attributable to silica have declined substantially since 1983, but, once again, it is notable that this wholly preventable cause of mor­ tality continues to occur so frequently as appears to be documented by NIOSH. Fiber-Induced Interstitial Lung Disease Planning and Production Inputs NIOSH’s very first criteria document was “Criteria for a Recommended S ­ tandard: Occupational Exposure to Asbestos” (NIOSH 1972). This criteria docu- ment was instrumental in moving OSHA and MSHA to establish occupational PELs for asbestos. Despite regulations and because of the thousands of products and processes that use asbestos, even as late as the 1980s, NIOSH estimated that 1.5 million workers remained at-risk for asbestosis (NIOSH 1986b). National mortality data documented that asbestosis mortality increased in the United States from 100 deaths in 1968 to nearly 1,500 in 2002, likely, in part, to a long latency and also to increased recognition and diagnosis of the disease. OSHA and MSHA documented substantial declines in exposure for manufacturing, construction, and mining over the past two decades (NIOSH 2003). After tackling asbestos early on, NIOSH later shifted focus to emerging fiber-induced lung diseases from RCFs and carbon nanotubes, asbestos-contaminated vermiculite, and respirable nylon flock fibers. Long-standing NIOSH research strategies include the “NIOSH Inter­ divisional Fiber Subcommittee Final Report” (Baron et al. 1999): • Validate animal models to provide a quantitative relationship between animal and human responses to fiber exposures. • Characterize and quantify fiber exposure in the workplace.

74 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 • Design size-selective technology to produce homogeneous fiber samples for study. • Determine mechanisms of action, rates of dissolution, and dose-response relationships for various homogeneous fiber samples. Although a great deal is known about the adverse health effects of inhaled fibers, much of it with asbestos as a prototype hazard, new exposures continue to emerge that may put workers at risk. At issue is the development of a universal definition for fibers and standard criteria for measuring them. Methods for produc- ing fiber samples of uniform dimensions are an intermediate objective as it would facilitate experimental toxicology research. Activities, Outputs, and Outcomes Vermiculite The vermiculite episode serves as a good illustration of a key set of NIOSH a ­ ctivities and outcomes in relation to fibers. A now closed mine near Libby, M ­ ontana, accounted for three-fourths of the worldwide vermiculite production for many decades during the last century. Vermiculite, once expanded, was used as loose-fill thermal insulation in residential and commercial buildings and was also used in horticulture and many other applications. This vermiculate ore was later documented to be substantially contaminated with actinolite-tremolite asbestos and other closely related asbestiform amphibole fibers. RDRP engagement in this research began as far back as 1979 (NIOSH 2006a). Since that time, RDRP staff have worked with the EPA and the Agency for Toxic Substances and Disease Registry to communicate and to assess potential community health risks from asbestos- contaminated vermiculite. At OSHA’s request, RDRP investigators undertook field studies to determine current levels of occupational exposure to vermiculite through asbestos fibers in expansion plants for agricultural uses. More recently, RDRP scientists used findings from their studies of asbestos-contaminated vermiculite to document and support development of a MSHA PEL for asbestos applicable to the mining industry to bring it in line with the more protective OSHA PEL for asbestos in general industry. RDRP staff continue to support MSHA in the current effort to establish a more protective “Proposed Rule on Asbestos Exposure Limit” (NIOSH 2005a). The RDRP is now engaged in updating and expanding its 1980s cohort mortality study of vermiculite workers to examine a broader range of exposures, including short-term workers with low cumulative exposures to fiber, to examine disease out- comes not previously documented, and to provide more precise risk estimates for

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 75 low-level exposures to fiber. This research has implications for both occupational and selected community exposures. Nylon Flock In 1996, an employer used the HHE/TA to request that the RDRP investigate multiple cases of biopsy-documented interstitial lung disease among workers at a small Rhode Island textile plant that produced nylon flock and flock-coated upholstery fabric (Washko et al. 1998). RDRP investigators conducted a compre- hensive environmental sampling and medical survey, and RDRP laboratory-based investigators analyzed the airborne dust and conducted animal studies to char- acterize its respiratory toxicity. Brown University and RDRP scientists reported a new interstitial lung disease in MMWR, a disease dubbed “flock worker’s lung” (MMWR 1997). RDRP investigators later conducted additional HHEs at other U.S. flock plants and documented that subclinical disease among these workers was both widespread and associated with time worked per week, specifically in flock- ing processes that used compressed air between production runs (Daroowalla et al. 1998a,b; Antao and ­Piacitelli 2004; Piacitelli and Antao 2006). RDRP laboratory research documented that respirable fibers were arising from cutting nylon tow filaments when rotary cutters were not optimally sharpened and aligned, which resulted in melting and tailing nylon ends of cut flock becoming airborne with subsequent milling (Burkhart et al. 1999). Animal models documented an intense inflammatory response in their lungs (Porter et al. 1999). Other RDRP investiga- tors recommended prevention measures including improved maintenance, exhaust ventilation, limited use of compressed air, and a respiratory surveillance program with ongoing medical screening. After the initial MMWR article, RDRP investigators completed additional HHEs. They also published several peer-reviewed papers pertaining to flock expo- sures and interstitial lung disease (Burkhart et al. 1999; Porter et al. 1999; Washko et al. 2000; Daroowalla et al. 2005) and hosted a workshop on “Flock Worker’s Lung” that was summarized in two published papers (Boag et al. 1999; Eschenbacher et al. 1999). RDRP investigators also hosted several meetings with representatives of the major domestic producers of nylon tow to inform them of this newly recog- nized hazard and discussed product stewardship. In addition, they made several presentations to annual meetings of the American Flock Association and at an international trade association meeting on flock. Follow-up by RDRP investigators at the Rhode Island textile mill found no new cases of flock worker’s lung after exposure controls were implemented.

76 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 Refractory Ceramic Fibers Manufactured RCFs are increasingly used as substitutes for asbestos in many industrial products and applications. RCFs have been shown to cause m ­ esothelioma and lung cancer in animal models and have been associated with pleural plaques and reduced lung function among exposed workers in a cross- sectional study ­ (Lemasters et al. 1998). An estimated 31,000 workers in the United States are exposed to RCFs. RDRP investigators have studied airborne RCFs since the early 1980s but more recently developed and disseminated a NIOSH criteria document “Criteria for Recommended Standard: Occupational Exposure to Refractory ­Ceramic Fibers” (NIOSH 2006e) and have communicated their findings to industry, academia, organized labor, and other federal agencies. This document recommends a comprehensive worker health protection program and an exposure guideline of 0.5 fiber/cm3. Further, NIOSH has supported both the EPA and OSHA in monitoring exposure and the RCF industries’ efforts to reduce exposures. RDRP scientists have documented the efficacy of engineering controls and have transferred their findings to fiber-manufacturing industries, labor interests, academia, and OSHA (Dunn et al. 2004). RDRP staff contributed to the development of an industry product stewardship program that provided guidelines for exposure monitoring, a medical surveillance program, and a rec- ommended exposure guideline for RCFs. The RCF coalition has reportedly met or exceeded all product stewardship plan requirements and annually reports its progress to RDRP scientists. The RDRP plans to continue to monitor progress of the stewardship plan and participate in annual briefings. As a result, RDRP scientists have documented a dramatic decrease in exposure (NIOSH 2006a) and improved lung function among workers who manufacture RCFs in a longitudinal study (Lockey et al. 1998). Mechanisms of Fiber Toxicity RDRP scientists have continued to study asbestos mechanisms from both a mechanistic and an applied field research perspective. For example, they have published scientific papers on the role of oxygen radicals in asbestos toxicity on a ­ dielectrophoresis method for sorting fibers by length and on the relationship b ­ etween fiber toxicity and fiber length (Simeonova et al. 1997; Blake et al. 1998; Deye et al. 1999). RDRP staff have also participated in numerous panels and workshops and have provided technical advice to the EPA, the Agency for Toxic Substances and Disease Registry, and WHO. The EPA has adopted long-term and short-term fiber-testing strategies to which RDRP scientists have contributed, and a new EPA standard is being formulated. RDRP scientific outputs have also influ- enced IARC ranking of fibers as to carcinogenicity in humans. Current initiatives

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 77 include RDRP efforts to reanalyze an unspecified “cohort mortality study of asbes- tos textile workers originally published decades ago” with characterization of expo- sures to include additional information on fiber dimensions using stored air sample filters (NIOSH 2006a). RDRP scientists are also engaged in drafting a white paper on nonasbestiform mineral “cleavage fragments.” This white paper is intended to drive policy and to recommend research to identify gaps in knowledge. Assessment of Relevance Fiber-induced diseases have long been a serious heath risk in occupational settings. Research on occupational exposures resulting in fiber-induced disease and the underlying biologic mechanisms is unquestionably of high relevance to occupational safely and health. Fibrotic lung disease, pleural disease, and thoracic malignancies are strongly related to exposure to asbestos fibers, and, unfortunately, it is clear that this is not the only occupational fiber with potential risk of lung fibrosis. The RDRP’s research on occupational exposures to asbestiform fibers at a Libby, Montana, vermiculite mine (and industries using the ore) proved immensely important in stemming exposures and disease related to asbestos-contaminated vermiculite. The RDRP’s evaluation of lung disease in textile workers exposed to nylon fibers in dust from nylon flock is also an important study area because of unknown disease etiology, occurrence, and applicability of the findings to other sites. Efforts to document lung disease from exposure to other synthetic fibers are also highly relevant RDRP research on natural and synthetic fibers likely to elicit toxicity; to identify the biologic mechanisms driving that toxicity, it is necessary to better understand disease causation and develop protective measures. Assessment of Impacts The RDRP’s efforts related to fiber-induced diseases have had a substantial impact on worker safety and health, with decreases in exposures to causative agents, decreases in disease incidence, important findings about the etiology and biology of these lung diseases, and improvements in worker health and safety. Research on a cluster of workers with pleural disease contributed to the finding that vermiculite ore from a Libby, Montana, mine was contaminated with asbestos. The mine was later closed based partly on these findings and on RDRP research on exposures and epidemiology at the mine site. RDRP research also resulted in the determination that exposure to nylon fibers was associated with lung disease in nylon flock workers. Beyond the original site that was investigated, additional cases of “flock worker’s lung” were identified. Nylon flock dust exposures are now recognized as a preventable health hazard. NIOSH reports that the lack of new

78 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 cases of “flock ­worker’s lung” from the company initially investigated and among U.S. flock ­workers suggests that incidence of the disease has been reduced (NIOSH 2006a), ­although additional surveillance is clearly warranted. RDRP projects on engineering controls to reduce exposure to flock dust have also helped reduce RCF exposures to workers and show promise for further reducing the incidence of disease. An RCF product stewardship program contains exposure monitoring, medical surveillance, and exposure guidelines. NIOSH states that RCF fiber con- centrations in manufacturing settings have declined dramatically and that these reduced exposures have been reflected in improved pulmonary function tests by workers (NIOSH 2006a). Here too, further follow-up is particularly relevant. Chronic Beryllium Disease Planning and Production Inputs It is known that compliance with the current OSHA PEL does not ensure pre- vention of beryllium sensitization or progression to CBD. The relationship between exposure and disease, still not fully understood, suggests that other characteristics of beryllium exposure (particle size, chemical form, and the contributions of d ­ ermal contact) are likely relevant. It is also recognized that field portable detection methods for beryllium are needed for fast, on-site analysis. In an effort to study the determinants of both beryllium sensitization and progression to CBD among exposed workers, NIOSH has supported multiple extramural epidemiologic studies (Newman et al. 2005; Rosenman et al. 2005). From an intramural perspective, RDRP scientists have collaborated with Brush Wellman Inc., the sole manufacturer of beryllium in the United States, to conduct epidemiologic studies, collect airborne and other work process samples, and ­assess transfer of their research to practice. This program has three major initiatives: medical surveillance and epidemiology, exposure assessment and bioavailability, and genetic studies. Activities, Outputs, and Outcomes Since 1996, the beryllium disease program has produced 54 peer-reviewed jour- nal articles and has presented its findings through several national and international meetings. Epidemiology and medical surveillance research has documented that copper-beryllium alloys make up the most widely used form of beryllium. Studies of workers with exposure to copper-beryllium alloy show low levels of sensitization and CBD together with relatively low concentrations of airborne beryllium (Schuler et al. 2005). RDRP scientists have also documented that the comprehensive preven-

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 79 tion program implemented by Brush Wellman in 2000 has successfully reduced, albeit not eliminated, the incidence of beryllium sensitization compared with the preintervention sensitization rate (Cummings et al. 2007). These findings suggest that a comprehensive approach to beryllium control and prevention, including dermal protection, is essential for effective worker protection. RDRP research on physicochemical characterization of airborne beryllium has been widely recognized for its characterization of particle behavior (Stefaniak et al. 2003, 2004). RDRP scientists have also developed a highly sensitive, field portable analytical method for determining trace beryllium in workplace air and in surface samples (Agrawal et al. 2006). RDRP research has provided a new understanding of the underlying basis for immunogenetic observations of CBD risk (Snyder et al. 2003; Weston et al. 2005). This body of research has uncovered a hierarchy of risk among exposed workers with the single genetic polymorphism most frequently associated with CBD. To better understand this hierarchy of risk, RDRP scientists have collaborated with investigators at Lawrence Berkeley National Laboratory to develop transgenic mouse models with different degrees of risk for beryllium sensitization and granu- lomatous inflammation that will allow experimental gene-exposure and gene-gene interaction studies to be conducted. RDRP researchers have forged an innovative partnership with Brush Wellman that could serve as a model for cooperative NIOSH-industry research activities in other sectors. RDRP investigators communicate their findings in regular meetings with Brush Wellman but also via peer-reviewed publications and technical reports to other interested parties including unions, other industries dealing with similar workplace issues, government agencies, and university researchers. RDRP staff have also worked with Brush Wellman to develop computer-based decision-making software to help assess exposure factors and workplace-specific decisions. According to the evidence package (NIOSH 2006a), RDRP is producing a NIOSH Alert “Preventing Beryllium Sensitization and Chronic Beryllium Dis- ease” that will be mailed to all known workplaces that use beryllium and will be posted on the NIOSH website. RDRP scientists have cosponsored several beryllium conferences, including a Department of Energy Beryllium Research Symposium, a ­National Jewish Research Center Conference, and an international beryllium ­research conference in Montreal. OSHA is in the process of develop- ing a standard for beryllium for which OSHA analysts have access to NIOSH epidemiologic data. In 2006, RDRP scientists submitted a program proposal for funding through fiscal year 2010 that includes four projects: (1) continued epidemiologic analysis of the Brush Wellman Preventive Program to extend the assessment of the risk of sensitization at other facilities, the risk of CBD at low levels of sensitization, and the

80 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 relationship between genetic markers and disease risk; (2) completion of physico- chemical characterization of beryllium materials with the goal of determining the bioavailability of beryllium to the body and development of a better approach to assess the risk of sensitization and CBD risk; (3) continued analysis of alternative exposure pathways, specifically the dermal route of exposure and its relationship to sensitization risk; and (4) a set of experimental studies with a transgenic mouse model (NIOSH 2006a). Assessment of Relevance This is a highly focused objective. However, in the broader sense, understand- ing sensitization to beryllium, as well as the progression to CBD, is highly relevant in occupational safety and health for a number of reasons. Significant numbers of workers are exposed to beryllium, leading to a severe, potentially lethal disease. In addition, CBD can serve as a model for studying granulomatous lung disease in general. This is relevant to other workplace metals as well as to sarcoidosis, an other­ wise idiopathic lung disease. The RDRP beryllium research program includes the necessary components—medical surveillance and epidemiology, exposure assess­ ment and bioavailability, and genetic markers—to better understand disease causa- tion and to protect worker health. Assessment of Impact The RDRP’s research has been of great importance in understanding the devel- opment of CBD and in protecting workers. The work has resulted in a better under- standing of the complexities of beryllium’s dose-response on exposed individuals. The RDRP has developed analytical technologies for determining trace beryllium concentrations in the workplace, has focused on genetic markers responsible for increased risk and sensitization to beryllium, and has collaborated in the develop- ment of transgenic mouse models with different susceptibility to sensitization. The program has contributed substantially to the peer-reviewed literature on multiple aspects of beryllium exposure and disease. An innovative cooperative research program with the country’s major beryllium producer, which includes applying findings in that producer’s facilities, has showed promising results in decreasing beryllium sensitization to workers; the improvement presumably results from engineering controls and use of protective equipment to control exposures. An important but major challenge will be to extend this model to exposure to other metals and, potentially, to unexplained occupational clusters of sarcoidosis.

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 81 Strategic Goal 3: Prevent and reduce work-related infectious respiratory diseases Introduction This section reviews the Infectious Diseases Program (IDP) of the NIOSH RDRP. To facilitate the review, we treat the tuberculosis (TB) program and the engineer­ing controls/respirator technology as separate entities, since the TB pro- gram has a long history of accomplishment and engineering controls/respirator technology affects all RDPD programs. All other subprograms are considered as a group, since they are newer (anthrax, emerging infections, understanding the e ­ ffect of occupational exposures on pulmonary susceptibility to infection) or are of historical interest only (histoplasmosis). The RDRP strategic goal is to prevent and reduce occupationally related respiratory infectious diseases. To achieve this strate- gic goal, the following intermediate goals have been developed (NIOSH 2006a): • Maintain reductions in occupational incidence of TB in high-risk work settings. • Protect workers from bioterrorism agents. • Protect workers from occupational acquisition of emerging diseases (includ­ ing SARS, avian flu, and pandemic flu). • Protect workers from occupational exposures that make them susceptible to respiratory infections. • Prevent outbreaks of occupational histoplasmosis by maintaining worker and employer awareness. Table 2-4 summarizes the outputs, intermediate outcomes, and end outcomes for each of these intermediate goals. The various subgoals relating to specific diseases (TB, bioterrorism agents, SARS, avian and pandemic influenza, and histoplasmosis) under this strategic goal do not provide an overarching program structure for preventing emerging infectious diseases within work environments. However, several themes would provide such structure. For example, work on engineering controls and personal respirator technology, the current subgoal to understand mechanisms of pulmo- nary susceptibility to infection resulting from occupational exposures, and the need for surveillance to detect work-related infectious respiratory diseases extend across the disease-specific subgoals.  It is unclear why histoplasmosis is included as part of the strategic goal. No further research is planned, nor are there specific surveillance programs targeted toward identifying outbreaks.

82 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 TABLE 2-4  Summary of IDP Outputs and Outcomesa Area Outputs and Transfer TB – 135 reports, abstracts, chapters, documents, videos, and other reports published and disseminated. – International training activities conducted in collaboration with other parts of CDC included environmental controls. – Protect yourself against TB, a respiratory protection guide for health care workers (94,935 copies distributed). – TB respiratory protection program in health care facilities, administrator’s guide (12,839 video, 55,413 print copies distributed). – TB prevention and control in correctional and detention facilities (2006). – >100 HHEs since 1990. Anthrax – 46 journal articles, chapters, HHE reports published. – Recommendations for personal protective equipment (PPE) and engineering controls developed and disseminated to stakeholders. – Developed sampling methods including B. anthracis culture. – Conducted remediation (USPS and Capitol Hill), provided technical support for decontamination workers, and trained FBI and Coast Guard staff. – Validated a new biological detection system (BDS) and a new ventilation- filtration system (VFS) for USPS facilities. – Contributed to development of many educational products disseminated by the CDC. – Developed two major guidance documents on building protection against chemical, biological, radiological, and nuclear (CBRN) attacks. – Developed standards for CBRN certification of respirators. SARS, – Through direct involvement on CDC’s SARS teams: Avian and • Responded to requests for help from Canada and Taiwan. Pandemic • Screened incoming passengers at domestic airports. Influenza • Developed and disseminated information, including 8 documents and 7 websites. – Through direct involvement with other groups in the CDC and beyond (e.g., OSHA), helped to develop a range of recommendations that have been disseminated in the form of 5 documents and 9 websites. Occupational – 33 peer-reviewed publications showing that diesel exhaust, welding fumes, exposures and and silica exposures increase susceptibility of rodents to experimental susceptibility respiratory infections. to infections – Welding fume generator with robotic welding arm developed to produce controlled exposures for animal studies. – DoD entered into inter-agency agreement to determine effect of mixed dusts on asthma and lung infection. Histoplasmosis – 2 HHE reports, 2 peer-reviewed reports, an MMWR report, a trade journal report, an English/Spanish fact sheet, and a NIOSH numbered publication (“Histoplasmosis: Protecting Workers at Risk”) published. aMost of the data in this table were supplied by NIOSH in response to a specific request from the committee. Data were supplemented from other materials, as appropriate.

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 83 Intermediate Outcomes End Outcomes and External Factors – CDC incorporated recommendations on – Overall number of TB cases in U.S. declined environmental controls into guidance by 46% between 1992 and 2004. on TB prevention for the health care and – Incidence of active TB among health care correctional and detention settings. workers declined from 5.6 to 4.6 per 100,000 – Influenced guidance from the American (1994-1998). Institute of Architects and the American – No good data for assessing occupationally Society of Heating, Refrigerating, and Air- related TB in other worker groups and conditioning Engineers. settings. – Influenced standards used by the Joint Commission on Accreditation of Healthcare Organizations and by OSHA. – The CDC and Health and Human Services – While it is impossible to be certain, it is rapidly adopted and posted preventive likely that the death toll from the “anthrax recommendations in the immediate attacks” would have been more than 5 had aftermath of the “anthrax attacks.” comprehensive preventive guidance not been – USPS facilities were decontaminated developed. following recommendations and the – Though not measurable, preventive guidance recommended VFSs and BDSs were is also intended to contribute to safer installed promptly. workplaces in the event of future biological attacks. – OSHA and others used CDC guidance in – Only 8 people in the U.S. contracted SARS. developing their recommendations. – If prevention guidelines are followed, some – Avian influenza guidelines implemented by impact on reducing morbidity and mortality poultry producers. of avian-pandemic flu can be expected if it WHO revised recommendations to include strikes the U.S. population. use of designated disposable respirators – Revised WHO respirator recommendations that provide protection equivalent to reduce the potential risk of overrunning the NIOSH-certified N95 respirators. supply of NIOSH-certified N95 respirators should pandemic influenza occur. – The EPA produced “Health Assessment – Findings of research on increased Document for Diesel Engine Exhaust.” susceptibility to lung infection can be expected – NTP plans to use welding fume generator to lead to improved protections for workers, system for chronic exposure studies. with resulting reductions in lung disease among workers at risk. – Recommendations adopted as guidance by – Occupational outbreaks of histoplasmosis are OSHA, Center to Protect Workers’ Rights, infrequent. various state health departments, and – Established prevention recommendations company occupational safety and health remain relevant. programs.

84 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 Tuberculosis Although not stated in formal terms, the goal of the TB program is to “pre- vent and reduce occupationally related TB within the context of the broader CDC [Centers for Disease Control and Prevention] response to eliminate TB in the U.S.” and follows the strategic plan for TB set out, updated, and implemented by the CDC (MMWR 1989a, 1992). In addition to other CDC guidance documents (CDC 2002; MMWR 2005, 2006b), a 2001 report of the Institute of Medicine has served to provide program objectives (IOM 2001). Taken together, these sources provide an extensive body of guidance for the NIOSH TB program. To a large extent, these strategic goals appear to be driven largely, and appropriately, toward national priorities that were established through the CDC. The NIOSH TB program has brought specific expertise to the occupational setting, especially in areas of respirators and environmental controls. Lack of specific occupational TB surveillance programs represents a major challenge to the RDRP goal. Moreover, many of the surveillance systems on which the TB program relies (e.g., Bureau of Labor Statistics Surveys) do not provide detailed information about specific occupations in their electronic databases. Given the continued immigration of documented and undocumented laborers from areas of TB endemicity, more specific occupational TB surveillance could help better target NIOSH’s resources. The lack of such information remains a critical unmet need. The NIOSH FY2007 project planning guidance document does not list any specific program related to TB. In the evidence package, respirator research is listed as a major priority area. This narrow focus carries over into the TB program’s role in the IDP environmental microbiology program. In addition, there is no other mention that future research plans are emerging in areas that are unique to the TB program. Planning and Production Inputs The TB program has functioned in the context of the CDC’s overall program for surveillance and prevention of the spread of TB, as noted in the preceding paragraph. In addition, appendix material that accompanied the evidence pack- age documents 22 HHEs from 1994 to 2004 that were completed in response to stakeholder requests related to TB. Over the period of evaluation, the TB program has responded to more than 100 requests for help in TB control, which include 43 HHEs. Requests have come from health care facilities, homeless shelters, and correctional and social service facilities.

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 85 Activities, Outputs, and Outcomes The program lists a large number of outputs and transfers in the form of publi- cations, abstracts, book chapters, videos, and a variety of other reports (135 in all). Of particular note were contributions to the development of environmental con- trols with respect to respiratory technology and use of an upper-room ultraviolet germicidal irradiation (UVGI) system to inactivate or kill airborne TB bacteria (and molds/spores) (Miller et al. 2002; Xu et al. 2003, 2005) and work on respiratory protection focused on surgical masks (Qian et al. 1997, 1998; Johnson et al. 1998) and fitting characteristics of face pieces (Coffey et al. 2004, 2006). Publications related to exposure assessment have reported the development of rapid detection methods for Mycobacterium tuberculosis and methods to document concentration and size distribution of infectious particles. Although the IDP has identified health care, correctional, and migrant ­workers as occupational groups of special interest with respect to occupational TB, the IDP does not supervise its surveillance activities with respect to these groups. The general issue of surveillance is addressed in the context of the overall evaluation of the IDP (see below). However, the IDP has worked with health departments to address these issues in particular cases. For example, NIOSH SENSOR (NIOSH 1997b) supported the California Department of Health Services in a program of targeted TB surveillance among prison and other correctional employees during the resurgence of TB associated with the human immunodeficiency virus in the mid-1990s. Nonetheless, systematic TB surveillance in high-risk occupational set- tings depends on other programs for data. Intermediate outcomes are listed in Table 2-4. The American Institute of A ­ rchitects adopted and updated CDC “Guidelines for Design and Construction of Hospitals and Health Care Facilities” to which the IDP provided expertise on isola- tion rooms to prevent the spread of infections in these facilities (AIA/FGI 2006). CDC guidance documents for preventing the spread of TB have been prepared with input from the IDP (MMWR 2005, 2006b) and, with respect to specific IDP inputs, these documents contain information on respirator protective gear and ventilation systems in health care facilities. In terms of end outcomes, much of the IDP TB control efforts exist within the context of broader efforts by the CDC and other agencies. Therefore, it is not possible to provide a quantitative estimate for what percentage of the decline in TB, in general and in occupational settings, can be attributed to the IDP. However, it is reasonable to presume that these programs depend on the unique expertise of the IDP with respect to controlling TB in occupational settings. Insight into the type of impact the TB program is having can been found in a response to an outbreak of 19 cases of active TB in a homeless shelter in St. Louis, Missouri (Martin and

86 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 Coffey 2005). After engineering controls (upper air and in-duct UVGI), increased fresh air, and RDRP-recommended improved maintenance practices were insti- tuted, the outbreak ended. Assessment of Relevance The work of the TB program is highly relevant. RDRP work on respirators and environmental controls is at the forefront of such work, and the program clearly is a leader in this area. The numerous documents cited above and the RDRP’s obvious role in that work supports this conclusion. Assessment of Impact The beneficial impact of the RDRP’s TB work is very high. While it is not possible to quantify the extent to which the RDRP’s work has reduced TB cases in occupational settings, on the basis of its work with engineering controls and respirators and the guidelines to which it has contributed, there can be little doubt that the program has substantially contributed to preventing TB transmission in a number of occupational settings (e.g., health care, correctional, and detention facilities, as noted previously). One threat to ongoing impact assessment is the lack of a formal occupational survey for TB and the RDRP’s dependence on other CDC programs for these data (addressed in detail below). Engineering Controls and Respirator Technology In the evidence package materials, this area is presented as part of the IDP’s TB control program. However, since environmental controls and respirator technol- ogy (particularly the latter) have implications for almost all occupational exposure sources, the area is given its own section here for evaluation. Engineering control research focuses on ventilation and UVGI and ventilation systems. The personal respirator program focuses on bioaerosol filter efficiency, filter reuse, and fit testing. Some details that are relevant to this section were pre- sented in the section on TB; others are included in the sections on anthrax and emerging infectious diseases. This section presents selected details that can be expected to have generic applications to many infectious diseases in occupational settings, particularly in health care facilities. Planning and Production Inputs Much of the work for engineering controls and personal respirator tech­nology is driven by need, reflected by requests to control the spread of microbes in occu­

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 87 pational settings. In this sense, the work is extremely responsive to the needs of stakeholders (health care workers, workers in prisons and detention facilities, health care workers and coworkers exposed to a large number of newly arrived immigrants from regions where TB is endemic). Integral to this work are risk assess­ments re- lated to specific exposures. For example, NIOSH-funded, extramural investigators developed methods to document the concentration and size distribution of viable cough-generated M. tuberculosis from patients with TB (Fennely et al. 2004). A sampling and detection method for TB based on polymerase chain reaction was developed and published in the NIOSH Manual of Analytical Methods (NIOSH 1998b) and allows for determining the concentration and aerodynamic size of airborne mycobacteria. Activities, Outputs, and Outcomes Many of these elements are described in the section on TB. In addition, the RDRP has provided guidance on respirator use in relation to bioterrorism threats (NIOSH 2002b) and emerging infections (e.g., SARS and avian influenza) (CDC 2004a,b). Almost all guidance documents in the latter areas include recommenda- tions for personal protection that directly reflect RDRP investigations into personal and building environmental controls to minimize transmission and infection. The RDRP contracted with the U.S Army’s Dugway Proving Ground to evaluate the protective efficacy of surgical masks and dust/mist, dust/fume/mist, and high- e ­ fficiency particulate air (powered and nonpowered) respirators against ­Bacillus subtilis and NaCl aerosol. This work showed that these devices were equally pro- tective against biological and nonbiological aerosols. Additional tests included filter efficiency, micro­organism survival, mold and fungal contamination, and contamination due to handling. This work confirmed that Part 84 filters could be safely reused (Johnson et al. 1998). The RDRP also documented that passing of some fit tests listed in the OSHA respirator standard (29 CFR 1910.134) with N95 filtering face pieces does not guarantee an acceptable level of protection in the workplace (Coffey et al. 2004, 2006). This work was disseminated in comments to the docket on the proposed OSHA rule on occupational exposure to TB (see NIOSH 1998c). Assessment of Relevance The engineering control work is extremely relevant to protection of workers and minimization of the contamination of work facilities by highly infectious and lethal microbial agents. The RDRP is a leader in this area, as evidenced by the inclusion of the outputs from this work in virtually all CDC guidance on the

88 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 protection from and spread of infectious agents in the workplace. This relevance is particularly true in health care settings and for first responders to real or potential bioterrorism or outbreak events. Assessment of Impacts As was the case for TB, there is no way to quantify specifically the impacts that work on personal respirators and environmental controls have had on reductions in the occurrence of respiratory infections. Clearly, in the case of the anthrax contami- nation of the U.S. Postal Service (USPS) facilities and the Senate Office Building, the use of the outputs of this work were integral to the protection of responders and decontamination teams. It seems fair to say that direct quantitative assessment of the impacts will never be possible, since the counterfactual experiment (exposure of the same workers without protection) would be unethical and immoral. Other Components of the Infectious Diseases Program Goal The evidence package presented several other elements of the RDRP ­ under the headings of “anthrax,” “emerging infectious diseases,” and “understanding mechanisms of occupational exposures on pulmonary susceptibility.” These do not ­represent a coherent related set of programs, but they are presented together here for the following reasons: (1) Anthrax presented a unique event that likely contributed to the RDRP’s capacity to handle such events but does not represent an ongoing research program apart from its work on respirators and engineering controls. (2) A similar case can be made for SARS under the emerging infections. (3) Work on pandemic and avian influenza is largely preparatory and also depends heavily on work related to respirators and engineering controls. (4) The mecha- nisms component is not connected directly to other programs. The anthrax program was developed in response to the anthrax attacks in 2001 that exposed postal workers to Bacillus anthracis. The IDP goal was to participate in the investigation of the exposures and to protect postal workers during the 2001 attack and in any future attacks. The closest that any statement comes to defining goals and objectives for any ongoing program is: “NIOSH and RDRP will maintain a state of readiness to respond within the context of CDC and PHS [Public Health Service] actions in the event of future attacks” (NIOSH 2006a, p. 196). This rubric of emerging infectious diseases forms a core of current and future research activities and challenges for the IDP. The strategic goal is best expressed in a recent request for proposal (RFA-OH-06-002) “Prevention of Airborne Infections in Occupational Settings” (NIH 2006):

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 89 Transmission of airborne infections to early responders, health care ­workers, and other occupational groups such as postal workers has ­ become an important­ public health concern. . . . The objective of this RFA is to ­improve prevention of airborne infectious diseases in occupational settings. Examples of the types of research of interest in the request for application (RFA) are as follows: • Development of improved strategies for early identification and isolation of infectious cases. • Development of improved approaches to detect and quantify airborne i ­ nfectious agents and settled infectious agents with potential for re-aerosolization. • Studies establishing exposure-response relationships for induction of dis- ease by airborne infectious agents. • Characterization of infectious aerosols generated by infected people, bio- logical weapons systems, or other sources. Determination of infectious aerosol size distribution and impact of factors such as temperature, humidity, and ultraviolet irradiation on aerodynamic properties, viability, and infectivity of these ­aerosols. Elucidating factors that affect re-aerosolization of settled agents. Developing a ­ pproaches to predicting the relative importance of airborne and contact disease transmission. • Engineering controls such as optimization of ventilation and other build- ing characteristics, and UVGI. • Issues in the use of respirators to prevent transmission of airborne infec- tious diseases such as fit testing methods and interpretation, respirator selection, and innovative approaches to enable longer use or reuse of respirators when they are in short supply. A section on histoplasmosis was provided in the evidence package (NIOSH 2006a). This program appears to be of interest historically since “no new RDRP research is planned or anticipated at this time. . . .” Ample documentation was provided about the success of the RDRP efforts to protect workers in environments were the fungus is common and where outbreaks represent a threat. The evidence package states further that “we intend to continue dissemination of relevant infor- mation to prevent outbreaks of occupational histoplasmosis by maintaining aware- ness. . . . [I]nitiatives would only be undertaken should recurrence or worsening of the problem occur as documented by surveillance or disease outbreaks.” However, in the absence of an operational definition of “awareness” and the documented lack of adequate resources for specific surveillance activities, the inevitable conclusion is that only the emergence of an outbreak or notification of suspicion of a problem

90 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 by employees or management will trigger further activity in this area. This is far from satisfactory, but it is difficult to see how the RDRP could justify allocating scarce resources to a more proactive approach. No further comments are made about this program in the following sections. Planning and Production Inputs Anthrax The RDRP played a major role in the national effort to protect workers from the threat of anthrax-contaminated mail by sending personnel to staff the CDC and Department of Health and Human Services Emergency Operations Centers and to the six locations where workers were at risk. The RDRP devel- oped sampling procedures, recommended effective interim protective measures, safeguarded workers who decontaminated affected workplaces, assessed the ef- fectiveness of decontamination, and disseminated information on protection. Sampling technologies were used in innovative ways, such as adapting a vacuum- ing technique using an “allergy sock,” a method originally developed to measure allergens, to provide a more sensitive, comprehensive way to collect anthrax samples at large postal facilities. The RDRP and partner agencies provided information to USPS managers, workers, and unions to help assess exposures at postal facilities and on Capitol Hill. The RDRP sampled numerous sites where contamination was known or suspected. The RDRP provided technical assistance on workplace sampling procedures and personal protective equipment for decontamination workers to aid in the EPA’s clean-up of contaminated government buildings and worked with the EPA and others to determine when remediated congressional buildings were ready for r ­ eoccupancy by performing surface sampling after the clean-up and decontamina- tion were completed. Several ongoing projects are listed with respect to developing better under- standing of how mail becomes cross-contaminated and of spore migration patterns in buildings; however, their relation to the “readiness” goal is not obvious. A more obvious realization of the readiness goal is a collaboration with Battelle Corpora- tion to develop a database for anthrax sampling methods (collection and analytic methods) that is being made available to the public. No specific NIOSH extramural funds have been set aside since 2001 for ­anthrax- specific research activities. However, as described above, a more general RFA was issued in 2006 that would permit such research.

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 91 Emerging Infectious Diseases (SARS, Pandemic, and Avian Influenza) With respect to SARS, these activities are listed in Table 2-4. Of particular note is the RDRP’s support role for the CDC’s assistance (in the form of on-site investigations) to Canada and Taiwan during the SARS outbreaks in those coun- tries. The RDRP also contributed staff to the CDC’s airport operations related to the arrival of international flights in U.S. airports. The IDP contributed to two comprehensive CDC guidance publications that contained specific reference to transmission in occupational settings (CDC 2004a; NIOSH 2007b). An additional guidance document was prepared specifically for flight crews on commercial air- lines (CDC 2004b). With respect to influenza, the RDRP functions in the context of the CDC’s overall program to deal with these issues. The IDP is taking the lead in workplace safety and industrial hygiene issues in several work groups: the non­pharmaceutical intervention work group, the working group for avian influenza (nonpandemic), respirator use for pandemic influenza, and technical assistance to OSHA in col- laboration with the OSHA medical director. The IDP presents information on emerging issues to appropriate groups, such as the poultry industry (NIOSH 2006b). Therefore, in this context the CDC can be viewed as a major stakeholder to which the RDRP has been responsive. Understanding the Effects and Mechanisms of Occupational Exposures and Pulmonary Susceptibility Under the overall strategic goal of preventing and reducing occupational respi- ratory infectious diseases, the intermediate goal relevant to this work is to protect workers from occupational exposures making them susceptible to respiratory infections. NIOSH states that “Because this work is at the more basic end of the research to practice spectrum, its intermediate outcomes relate to influencing the thoughts and actions of others” (NIOSH 2006a). The committee queried NIOSH about whether this research is appropriate when other agencies (e.g., the National Institute of Allergy and Infectious Diseases [NIAID]) carry out similar research and what is unique to the occupational environment that requires their involve- ment in mechanistic research. NIOSH replied (NIOSH 2006b) that they are the only federal agency mandated to conduct occupational safety and health research, that their mechanistic research is consistent with that role, and that it complements the activities of other agencies. Further, the RDRP’s mechanistic studies differ from those of NIAID, which focus more on elucidating mechanisms of host defense against microorganisms and developing clinical responses such as vaccines and treatments, and the research is within the NIOSH mission as it studies an impor-

92 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 tant aspect of the toxicologic effects of occupational chemicals and exposures. The evaluation committee agreed that this is a reasonable and compelling rationale for the existence of this program. Activities Outputs and Outcomes Anthrax Specific responses to stakeholders are listed in the preceding section and constitute important activities. A number of specific outputs and transfers have r ­ esulted from these activities (Table 2-4). A substantial number of technical papers, books and book chapters, numbered NIOSH publications, control tech- nology, and HHE reports and presentations at conferences and meetings were produced. Worker fact sheets (paper and web-based) (NIOSH 2002c; CDC 2007b) were produced for use by first responders, workers, and investigators. Recom- mendations were published in conjunction within the larger CDC effort (CDC 2001), with specific IDP contributions related to engineering controls and pro- tective equipment for personnel. The IDP contributed to the NIOSH publication related to procedures for collecting and analyzing samples to detect B. anthracis (NIOSH 2002c; Teshale et al. 2002; CDC 2007a). IDP staff also helped to train the Federal Bureau of Investigation, U.S. Coast Guard, independent contractors, and other personnel in appropriate procedures for anthrax decontamination and to determine when decontaminated buildings are safe for reoccupancy. Symptom surveys among exposed workers and air monitoring also were conducted followed by release of relevant reports (Hall and Bernard 2002; Hall and Hess 2002; Hall et al. 2002). One of the most important outputs to which the IDP contributed was the 2002 emergency preparedness plan developed in collaboration with the USPS (USPS 2002) and its associated biological detection system (USPS 2005) and the development and installation (four distribution centers) of new venti- lation and filtration systems to capture releases of bioterrorism agents during mail processing. Guidance documents for protecting buildings from future bio­ terrorism attacks and filtration and air cleaning systems to protect buildings were also released (NIOSH 2002b). Emerging Infectious Diseases With respect to SARS, the main outputs have been guidance documents (CDC 2004a,b; NIOSH 2007b). In addition, the evidence package lists seven URLs on the CDC website to which it has made contributions with respect to workplace protec- tion (e.g., respirators, schools, air transport, health care). RDRP staff published one peer-reviewed (Christian et al. 2004) paper and contributed to a CDC document that provides specific guidance for flight crews on commercial aircraft (CDC 2004b).

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 93 The RDRP has been highly productive with respect to planning for outbreaks of pandemic or avian influenza. As described by NIOSH (2006a), a number of specific guidance documents have been developed: • Guidelines for Protecting Healthcare Workers Caring for Patients with Avian Influenza (CDC 2004c). • Respiratory Hygiene/Cough Etiquette in Healthcare Settings (CDC 2003). • Guidance on occupational health and safety aspects of avian influenza. (CDC 2007b). • The NIOSH topic page covers occupational aspects of avian influenza (NIOSH 2007c). • Pandemic Preparedness Checklist. • Toolkit for Business Pandemic Flu Planning. • CDCIDEOC Plans and Exercises: The CDC CONPLAN (internal opera- tions plan for pandemic influenza) was released in February 2006. • HHS Worker/Employee Protection Guidelines and Policy. Extramural RDRP research on the efficacy of N95 respirators against virus- sized particles (University of Cincinnati) was completed (Lee et al. 2005). Various technical presentations, meeting disseminations, NIOSH interagency work group meetings, and meetings with the FDA have occurred. The Institute of Medicine was contracted to review the availability of surgical masks in the event of a pandemic and various use characteristics of personal respirators. The report was completed in 2006 (IOM 2006). Research efforts are also under way to assess the reusability of disposable filtering face piece respirators to protect against infectious aerosols (71 Fed. Reg. 56151[2006]). The IDP conducted a review of the Department of Homeland Security (Coast Guard) internal pandemic flu plan with regard to protecting department personnel. The IDP is working with the Department of Homeland Security on this issue. The most notable intermediate outcome relates to meetings with respirator manufacturers to address concern about the demand for NIOSH-certified N95 disposable respirators. RDRP scientists played a role in the effort to convince WHO to revise the posted recommendations for respiratory protection by noting which other disposable respirators are comparable to the N95. Understanding the Effects and Mechanisms of Occupational Exposures and Pulmonary Susceptibility Activities, outputs, and outcomes are summarized in Table 2-4. Several findings from RDRP studies can be highlighted. Studies have found that exposing rats to diesel exhaust particulate matter but not carbon black (the carbonaceous core of

94 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 diesel exhaust particulate matter without the organic compounds adsorbed onto it) significantly increased the susceptibility of their lungs to infection with Listeria monocytogenes (Antonini et al. 2001a). Other studies have addressed lung clearance function and the pulmonary clearance of L. monocytogenes after exposure to diesel exhaust particles, different welding fumes, and silica (Antonini et al. 2001b, 2004; Yang et al. 2001). Although L. monocytogenes is not an important pathogen in the occupational setting, the choice of it as a test organism is justified because host defense responses after intrapulmonary deposition of the organism have been well characterized and involve an initial antigen-nonspecific host defense mediated by alveolar macrophages, followed by development of adaptive cell-mediated immune responses in which T cells network with alveolar macrophages and other cells for host defense. RDRP scientists have developed an innovative, automated, robotic welding fume generator and inhalation exposure system for use with laboratory animals to simulate real workplace exposures (Antonini et al. 2006). RDRP sci- entists have determined the mechanisms of how workers such as welders in con- struction and boilermakers who have inhaled metal-containing particles of mixed composition become more susceptible to infection than the general population. The RDRP research on occupational respiratory diseases in welders won the 2006 American Welding Society Safety and Health Award. The major intermediate outcome related to partnerships with other federal agencies involves an interagency agreement with the Department of Defense (DOD) entitled, “Effects of Mixed Dusts on Asthma and Pulmonary Infectivity.” Results from this work may contribute to DOD’s development of an exposure standard for diesel exhaust particulate matter. A second project with DOD involves pulmonary and central nervous system toxicity associated with welding fumes. The relevance of this project to the IDP cannot be ascertained from the documentation m ­ aterials supplied to the committee. The NTP has funded the RDRP to study im- mune ­response in the lungs associated with exposure to welding fumes. The NTP plans to use the RDRP model for welding fume generation and inhalation for its chronic neurotoxicity and carcinogenicity studies in addition to those related to immune function in the lung. Assessment of Relevance Anthrax Unquestionably, the work carried out by the RDRP was very relevant to con- trolling the spread of anthrax within USPS facilities and the Senate Office Build- ing and the protection of workers during decontamination work. The activities of research and testing of respirators and engineering controls were an important factor in the effectiveness of the RDRP’s efforts. The CDC advisories to which the

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 95 RDRP contributed are highly relevant to worker protection should any such con- tamination occur in the future. Emerging Infectious Diseases The relevance of the work related to SARS and influenza can be considered together. Again, this work is highly relevant and rests on the RDRP’s capacity to develop rapid methods of detection and worker protection through respirators and engineering controls for workplace facilities. Understanding the Effects and Mechanisms of Occupational Exposures and Pulmonary Susceptibility As described above, the committee determined that the RDRP’s research is distinct from that of other federal agencies. This focus area is relevant and will sup- port the missions of other federal agencies as evidenced by the previously described interagency agreements with DOD. What appears to be lacking is a cogent strategy for determining which specific elements of host defense are going to be addressed, in what priority, and in relation to which exposures. Although some future projects are identified, the RDRP does not state how the program has and will complement, rather than duplicate, research being done by other federal agencies on similar e ­ xposures (e.g., the EPA-funded research on the toxicity and health effects of diesel particulate matter). Thus, to ensure the relevance of this component, there is a need to develop a more explicit overall program of research and to clarify its rela- tion to studies being carried out by other federal agencies. Assessment of Impacts Anthrax It is nearly impossible to disentangle the specific role of the IDP or, for that matter, any other agency involved in limiting the spread of B. anthracis and, thereby, decreasing the risk of infection and death in exposed workers and investigators. However, insofar as IDP plays a major role in the development and dissemination of personal and building respiratory protection systems, it is fair to credit the IDP with helping to contain what could have been a larger disaster with greater cost of human lives.  One example of a more specific line of inquiry might be to investigate the potential mechanisms underlying the increased risk of bacterial pneumonia among welders and how it might relate to iron particulates and facilitating infectivity or virulence. Similarly, mechanistic questions about silica’s promotion of atypical mycobacterial disease remain to be fully elucidated.

96 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 Emerging Infectious Diseases Similarly, with regard to SARS, it is nearly impossible to disentangle the spe- cific role of the IDP or, for that matter, any other agency involved in limiting the spread of SARS and, thereby, decreasing the risk of infection and death among the public and in exposed health care workers and workers in the airline industry. However, insofar as the IDP plays a major role in the development and dissemi- nation of important guidance documents for preventing the transmission of the SARS ­coronavirus, it is fair to credit the IDP with helping to contain what could have been a larger disaster with greater cost of human lives. Since there has not been an influenza pandemic or a large outbreak of avian influenza in the United States or other parts of the world, there are no outcomes by which this program can be evaluated. There are, however, some important challenges related to likely future impacts noted by the committee. Successful completion of these challenges could be used as appropriate impacts in advance of any outbreaks. RFA-OH-06-002 (NIH 2006) has already been mentioned to solicit extramural research in a host of areas related to emerging infections, including the identification, characterization, and control of infectious agents. This RFA represents an important step to engage extramural researchers in the IDP emerging infections program and appears to be an appropriate prioritization of extramural funding in the face of limited budgetary resources. However, the evidence package does not explicitly indicate how the RDRP intends to integrate the research generated. The IDP is to be commended for its work on personal respirators and engineer- ing controls relevant to previous transmission of infectious agents to workers. The RDRP through the IDP has played a leading role in the CDC’s efforts to evaluate and disseminate these technologies. A major challenge to the IDP is the limited availability of BSL-3 labora- tory space in which to carry out studies of aerobiology, transmission potential, exposure assessment methods, engineering controls, and personal protective equipment. Efforts are under way through the CDC to establish an appropri- ate facility to be located on the National Biodefense Research Campus in Fort Detrick, Maryland. Understanding the Effects and Mechanisms of Occupational Exposures and Pulmonary Susceptibility No overall statement of possible end outcomes was provided in the docu- mentation materials in response to the committee’s queries about this program. Outcomes for specific research projects are noted, but they are not integrated into

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 97 a coherent set of program outcome criteria that could be used to evaluate impact. However, insofar as the studies have improved our understanding of susceptibility and immune mechanisms, it is fair to credit the RDRP with contributing to our understanding of lung defenses related to a variety of respiratory infections. Strategic Goal 4: Prevent and reduce work-related respiratory malignancies Introduction Within the overall RDRP mission the goal of this component is to “prevent and reduce work-related respiratory malignancies.” Before NORA, the strategic plan for preventing occupational lung diseases did not include lung cancer as a specific disease target. While occupational cancer was a general NIOSH priority, this work was performed by investigators in the Division of Surveillance, Field Studies and Hazard Evaluation. When the NORA priorities were established, attention to respiratory malignancies was located in the priority Cancer Research Methods. Assessments of the overall cancer burden, at that time, drew attention to the estimated annual occupational lung cancer burden of 9,000-10,000 men and 900-1,900 women. Half of this burden was attributed to asbestos-related bronchogenic carcinoma. Furthermore, a much larger number of workers were noted to be or to have been exposed to known human respiratory carcinogens, not to mention the millions exposed to substances that are probable or possible human carcinogens, some of which carry risk specific to the respiratory tract (Toraason et al. 2004). To address the RDRP subgoal of preventing and reducing work-related respira- tory malignancies, the RDRP selected the following targets as most relevant. • Determine occupation etiologies of lung cancer. • Reduce metal-induced lung cancer (hexavalent chromium). • Prevent and reduce silica-induced lung cancer. • Prevent and reduce lung cancer induced by diesel engine exhaust. • Produce lung cancer diagnostic tools. Our comments in this chapter address the planning and production inputs for all five of these goals, followed by a review of the activities and outputs for the same issues. We follow these reviews by assessing the relevance of these materials and the impacts of the RDRP’s lung cancer research effort.

98 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 Planning and Production Inputs Determination of Occupation Etiologies of Lung Cancer The relevance of the overall goal of prevention and reduction of work-related respiratory malignancies is well established and appropriately documented in the RDRP evidence package. In particular, NIOSH references the CDC’s Healthy People 2010 goal to reduce further the nation’s cancer burden (CDC 2000), the primary importance of lung cancer due to its rank as the leading cause of deaths from cancer in the United States, the substantive attributable fraction for lung cancer due to occupational exposures (Steenland et al. 1996), and the large number of workers in the United States thought to be exposed to known or suspected carcinogens at work. RDRP scientists have been key authors or contributors of many publications that have established these estimates, which in turn provided the rationale to make preventing occupationally related lung cancer a priority for the program. The RDRP has participated in several planning processes in reference to occu­ pational cancers including lung cancer. A comprehensive occupational cancer- planning process was conducted by the Industry Wide Studies Branch (Ward et al. 1993) and later through the NORA committee process (Ward et al. 2003). The latter report is very comprehensive, although it focuses on priorities for research methods rather than specific etiologic research needs. An earlier planning docu- ment on the prevention of occupational lung diseases in general limited its focus on cancer to those associated with asbestos (NIOSH 1986a). These planning processes provide a basis for ensuring that the research activi- ties undertaken by the RDRP are relevant to the overall NIOSH research agenda; however, the linkage between the planning documents and the five subgoals and the myriad specific activities is not clear. In contrast, the project estimating the a ­ ttributable fraction and mortality rate in the United States (Steenland et al. 1996) and worldwide (Driscoll et al. 2005b) is highly relevant to the mission. The RDRP mentions significant focused efforts on lung carcinogenic effects of cadmium, ethylene oxide, chrysotile asbestos, beryllium, uranium, and radiation among exposed workers as well as an evaluation of cancer risk among construction painters. The specific program inputs and activities for these studies, however, are not addressed in detail. Including specific respiratory cancers as a part of the RDRP portfolio rather than in a program addressing occupational cancers in general appears somewhat arbitrary and awkward. Presumably, their inclusion in the RDRP stems from the major involvement of Division of Respiratory Disease Studies personnel in these programs (e.g., silica and diesel exhaust) rather than from an explicit strategic deci- sion. In fact, with the exception of these two specific topics, the respiratory cancers

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 99 are included under the general occupational carcinogens planning documents and NORA agenda. Because of the commonality of methods and expertise used for studying occupational cancers, assigning respiratory cancer into a separate program area may create counterproductive divisions among researchers. On the other hand, the management of respiratory malignancies in the new matrix structure of the RDRP may ensure better communication among units in different cities within the reorganized RDRP programs. Although the choice of the three exposure-specific subgoals—chromium, silica, and diesel exhaust—appears to be highly relevant, the rationale for choosing these particular risks over other ongoing lung carcinogen exposures, or other non­ respiratory occupational carcinogens, is not addressed. Reduce Metal-Induced Lung Cancer (Hexavalent Chromium) Hexavalent chromium (chromium VI) has been long recognized as a lung c ­ arcinogen and NIOSH addressed the problem in an early criteria document in 1975 (NIOSH 1975). Despite this recognition, OSHA did not begin to regu- late chromium VI exposure as a carcinogen until 2001. As NIOSH is expected to ­ respond to an OSHA need for the best evidence base to guide its regulatory actions, the RDRP placed a priority on addressing OSHA’s need for additional information and technology in support of a possible revision of its existing stan- dard for exposure to chromium VI. The RDRP developed projects on quantitative epidemiology and risk assessment and the development of sensitive and rapid and field-portable detection methodology for chromium VI. In both areas, the RDRP’s contributions demonstrate the special expertise available within the program. RDRP epidemiologists and biostatisticians were able to exploit established cohorts with well-characterized chromium exposures to explore quantitative aspects of the exposure-response relationships and to use them to model risk in exposed populations. RDRP scientists also overcame a significant hurdle in relation to field monitoring for exposures to chromium VI. The problem existed for settings where exposure to chromium VI is possible but levels are low—for example, in the con- struction industry. The RDRP succeeded in developing environmental monitoring technologies to determine trace levels of chromium VI with sufficient sensitivity for detection where low-level exposures occur. Prevent and Reduce Silica-Induced Lung Cancer In the case of silica-induced lung cancer, OSHA has sought guidance from NIOSH for regulation of exposures to silica but has been inconsistent in developing its regulatory approach to silica. However, the RDRP has recognized the potential

100 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 importance of the issue because of the ubiquity of the exposure and the mount- ing evidence for carcinogenicity. In addition, the RDRP’s long-standing interest in silica exposures in a variety of relatively high exposure settings provided the basis for addressing the emerging recognition of the association between silica and lung cancer. NIOSH responded with two major epidemiologic studies that helped pro- vide evidence on this issue. The first, a study of gold miners, indicated excess risk for silica-exposed workers but exposure information was not sufficiently detailed to document an exposure-response relationship. The second was a study of Vermont granite workers where, with higher-quality exposure information, the excess risk was shown to increase with exposure level (Steenland and Brown 1995; Attfield and Costello 2004). NIOSH’s ability to respond was clearly related to long-standing familiarity with both silica exposures and cancer epidemiology expertise. Prevent and Reduce Lung Cancer Induced by Diesel Engine Exhaust The issue of the association of diesel exposure with lung cancer risk provides an especially revealing picture of the RDRP’s relevance and impact. NIOSH first published a document assessing diesel exhaust as a probable human carcinogen in 1988 (CDC 1988). In a sense, this current intelligence bulletin served as a plan- ning document and provided evidence for the importance of the issue. Similar conclusions were published by IARC (1989), WHO (1996), NTP (1998), California Environmental Protection Agency (CalEPA 1998), and EPA (2002). In 1997, the National Cancer Institute and NIOSH agreed on an interagency project protocol for two studies—a cohort mortality study with a nested case-control study of lung cancer and diesel exhaust among nonmetal ­miners. These studies are close to completion (see below). MSHA promulgated comprehensive standards to control diesel exhaust in under­ground mines in 2001. In addition to contributing to the development of these standards, the RDRP has also responded with a series of projects and studies to comprehensively respond to several challenges. The studies include detailed quantitative epidemiologic and risk assessment studies; development of air-­sampling technologies suitable for monitoring diesel exhaust in the presence of other carbon-containing particulate matter, such as that found in underground coal mines; and studies of alternative approaches to control technologies for diesel exhaust. There are significant nondiesel sources of carbon particles in mines that interfere with attempts to measure the concentrations of diesel particulate matter. As a result, NIOSH has worked with the mining community to develop methods of measuring tail-pipe emissions of diesel engines in coal mines and of measuring environmental concentrations of diesel particulate matter in other (e.g., metal and

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 101 nonmetal) mines that have led to exposure regulations (see http://www.cdc.gov/ niosh/nas/mining/potentialintermediateoutcome5.htm). Produce Lung Cancer Diagnostic Tools The fifth subgoal addresses lung cancer diagnostic tools. The rationale for these activities is based on the significance of lung cancer in the general population and the importance of early detection and staging in secondary prevention. The linkage of these activities to the RDRP planning processes and stakeholder input is ­ unclear. In fact, the current planning document on priorities for developing research methods in occupational cancer (Ward et al. 2003) places an appropriate focus on workplace exposure and workforce approaches but makes no mention of the priority for developing lung cancer diagnostic markers. For example, the docu- ment addresses the importance of intervention studies among high-risk cohorts but does not mention early detection methods as an important area for develop- ment. Although RDRP scientists may make significant contributions to this area of lung cancer research, NIOSH’s mission to address work-related injury and illness does not provide a clear rationale for this activity. Other research agencies may be better suited to these issues, permitting NIOSH to allocate these resources to laboratory explorations directly related to cancer detection even if the tool could be applied in cohorts with elevated risk of occupationally related cancer. Activities and Outputs The impact of the RDRP work under the stated subgoals has been evaluated in terms of the transfer of the outputs to the broad audience of potential users or partners as well as in terms of evidence that intermediate or end outcomes have been accomplished. For each of the five goals associated with the prevention of occupational respiratory malignancy (determination of occupational etiologies; reduction of metal-induced lung cancer, silica-induced lung cancer, and diesel exhaust-induced lung cancer; and development of diagnostic tools) consideration was given to evidence of impact in terms of intermediate end points and current program activities. Not considered here are the major contributions by NIOSH to the study of lung cancer related to asbestos exposures and to radon daughters among uranium miners. This work is no longer considered high priority and, for the most part, studies of these risks were completed before the original NORA. While the end impact of each of these goals is a reduction in the incidence of or mortality from respiratory cancer, the long latency between exposure and cancer onset makes it unrealistic to gather adequate direct evidence of impact. Therefore,

102 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 the committee considers evidence of impact on intermediate outcomes as provid- ing adequate support for an impact on morbidity and mortality. Determine Occupational Etiologies of Lung Cancer During the past 10 years, RDRP scientists have published at least 200 peer- r ­ eviewed articles and book chapters (127 since 2001) on occupationally related lung cancer. More than 90% of those published after 2000 were peer-reviewed journal articles. They have contributed valuable scientific research findings to the scientific literature. The RDRP’s engagement in the transfer of these published research findings has been primarily through the standard routes of public pre- sentations at scientific and professional meetings. There are some notable specific efforts, including testimony at an executive branch effort in 1994 to assess the role of government agencies in the research mission of the National Cancer Program (L. L. Fine, NIOSH, testimony before the President’s Cancer Panel, January 31, 1994). At that time, the director of the Division of Surveillance Hazard Evaluation and Field Studies was primarily responsible for the strategic planning and priority setting concerning occupational cancer. Although not a stated priority effort, RDRP scientists contributed to the ­efforts to control secondhand cigarette smoke both through solicited commentary in the June 2006 Surgeon General’s Report on the Health Consequences of Second-hand Smoke” (DHHS 2006) and through the development of a number of fact sheets based on the content of the report for dissemination to a wide variety of stake­ holders and customers: legislators, employers, unions, physicians, parents, and oth- ers. Although this risk is not only an occupational risk, it certainly is an important risk in work environments. A long-standing and remarkable program of the RDRP is its effort to directly notify individual workers who were part of cancer epidemiology studies of the study findings; this is in accordance with the NIOSH Worker Notification Program (NIOSH 2007d). The RDRP estimates that it has successfully notified more than 48,900 workers about lung cancer hazards (NIOSH 2006a). In recent years, regulatory agencies have taken much less advantage of NIOSH research findings than was the case in the early years of NIOSH’s existence. Two important exceptions are the OSHA cadmium standard (29 CFR 1910.1027) issued in 1992, which relied on RDRP findings especially with respect to risk assessment (58 Fed Reg. 21778 [1993]), and the final OSHA rule on hexavalent chromium, which relied on both the epidemiologic research and the risk assessment findings of NIOSH. Other agencies, however, have made good use of the NIOSH research to affect public policy, as evidenced by the California Air Resources Board action on diesel particulate matter (see below).

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 103 RDRP studies and risk assessments have contributed to evidence used by IARC in classifying agents as carcinogenic, including beryllium, cadmium, silica, and chromium (IARC 1993). IARC has included evidence on excess risk for lung cancer from the RDRP when categorizing 13 agents as Group 1 (carcinogenic to humans), 10 as Group 2A or 2B (probably carcinogenic [2A] or possibly carcino- genic [2B]), and 1 as Group 3 (not classifiable with respect to carcinogenicity). Since IARC does not identify the relative importance of individual studies, it is not possible to measure how large an impact specific NIOSH studies had in affecting the IARC determination. Nonetheless, several of the IARC determinations include a substantial number of NIOSH references, indicating they were a major factor. In the case of beryllium, however, it is clear that NIOSH’s research was seminal in the determination that this metal is a human carcinogen. For the most part, the major occupational carcinogen classifications by IARC classification occurred before this century; however, NIOSH continues to study the agents in an effort to improve understanding of detection and control. Reduce Metal-Induced Lung Cancer (Hexavalent Chromium) The Occupational Safety and Health Act of 1970 (29 USC 671) authorized NIOSH to “develop and establish recommended occupational safety and health standards” [Section 22(c)(1)] as well as “to conduct such research and experimental programs as he determines are necessary for the development of criteria for new and improved occupational safety and health standards, and . . . after consideration of the results of such research and experimental programs make recommendations concerning new or improved occupational safety and health standards” [Section 22(d)]. The RDRP risk assessment contributed significantly to OSHA rulemaking that resulted in a revised chromium VI (hexavalent chromium) standard promulgated in early 2006 (71 Fed. Reg. 10099[2006]). The RDRP risk assessment estimated that exposure corresponding to a lifetime risk of 1/1,000 was 0.2 μg/m3 (Park et al. 2004). Furthermore, the assessment found no evidence to support a threshold in the intensity effects of chromium VI and no evidence to suggest saturation of defense mechanisms (such as extracellular reduction of chromium VI deposited on the lung epithelium) (Park and Stayner 2006). While OSHA found the NIOSH risk assessment compelling, the agency determined that considerations of technological and economic feasibility led them to set the PEL at 5 μg/m3, which is associated with an excess lifetime risk per 1,000 exposed persons of 10-45 lung cancer deaths compared with 2-9 cancers per 1,000 per lifetime at the NIOSH recommended PEL of 1 μg/m3. The seven RDRP publications relating to chromium VI are listed

104 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 elsewhere (Wang et al. 1997; Boiano et al. 2000; Ding et al. 2000; Ashley et al. 2003; Park et al. 2004, 2006; Park and Stayner 2006). The work of RDRP scientists is cited in OSHA’s “Final Rule on Occupational Exposure to Hexavalent Chromium” along with the work of others (71 Fed. Reg. 10099 [2006]). OSHA had originally argued against including the construction industry within the scope of the proposed rule, citing the lack of field-portable analytic capability. As part of the effort to assist OSHA in improving the feasi- bility of controlling exposures to hexavalent chromium, NIOSH developed and patented (U.S. Patent 6,808,931) a field-portable, rapid chromium VI detection method [NMAM (Method 7703)]. The field technique allows for the measure- ment of chromium VI at levels well below the new OSHA PEL and thus permits assessment in occupations that are not normally monitored, such as construction (Boiano et al. 2000; Wang and Ashley 2004). Largely as a result of this new method, OSHA ultimately included construction within the scope of the final rule that was ­promulgated. The U.S. Air Force is already using the RDRP-developed field- portable rapid chromium VI detection method in aircraft painting/maintenance operations (Aizenberg et al. 2000). NIOSH anticipates that applications of the field chromium VI method will become more widespread now that the new OSHA rule has been promulgated. RDRP scientists continue to be funded by OSHA to investigate some of the mechanistic issues that might prove relevant to chromium VI risk management and permit a more nuanced regulation of chromium VI exposures. These efforts are now laboratory based; the study of mechanisms of carcinogenesis and the role of genetic polymorphism are also areas of considerable interest. Silica-Induced Lung Cancer Publications from the RDRP on lung cancer among workers exposed to silica (Costello and Graham 1988; Steenland and Brown 1995; Attfield and Costello 2004) have been influential in the ongoing debate on the carcinogenicity of silica dust. They were among the 10 most-influential studies for its evaluation of silica dust in 1997 when IARC designated crystalline silica as a Group I carcinogen (IARC 1997). These publications continue to inform discussion about silica-related cancer risk and were featured and discussed in an international workshop organized by a European industry group in 2005. Studies of silica-associated oxidative DNA damage, gene activation, and carci- nogenesis in a p53-deficient mouse model are ongoing (see Chapter 3). Given the extensive work NIOSH has conducted on silica carcinogenesis, it may be reason- able to ask if the work could be extended to address the potential carcinogenicity of other fibrogenic dusts.

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 105 Lung Cancer Induced by Diesel Engine Exhaust NIOSH’s responsibility to MSHA is similar to its responsibility to OSHA— u ­ ndertaking research and developing proposals for health standards for submission to the assistant secretary. Several developments regarding a MSHA rulemaking on diesel exhaust exposures in underground mines have relied on products of the work of the RDRP. MSHA does not have sufficient in-house scientific personnel to undertake such studies on its own. RDRP scientists published two key studies that were important to MSHA in their risk assessment for their final rulemaking for diesel exhaust. NIOSH con- tributed one major epidemiologic study to the evidence base for associating diesel particulate matter with lung cancer (Steenland et al. 1998). In addition, NIOSH’s risk assessment paper (Stayner et al. 1998) provided essential assistance to MSHA in arriving at their conclusion about preventable lung cancer risk. As a result of research by the RDRP, MSHA’s final rule changed the interim standard’s surrogate for measuring diesel exhaust particulate matter in metal/non- metal mines from total carbon to elemental carbon (Birch and Noll 2004; 71 Fed. Reg. 33387 [2006]). Similarly, RDRP research documenting the likely success when available control technologies for diesel particulate matter were applied in metal/nonmetal mines was important in gaining acceptance of the new MSHA rule. The research results, in addition to being published, have been shared at two workshops and partnership meetings attended by representatives of industry, labor, and gov- ernment (Bugarski and Schnakenberg 2001, 2003; Schnakenberg and Bugarski 2002, 2004; Bugarski 2004; Bugarski et al. 2004a, 2005, 2006; Schnakenberg et al. 2005). On January 19, 2001, MSHA promulgated final rules to control exposures to diesel exhaust in underground coal mines (66 Fed. Reg. 5526 [2001]; 30 CFR 72) and in underground metal and nonmetal mines (66 Fed. Reg. 5706 [2001]; 30 CFR 57). The RDRP, MSHA, and a private company (SKC Inc.) engaged in research on a new commercially available sampler. Keeping industry and labor groups i ­ nformed throughout development of the sampler facilitated both the transfer and acceptance of the new technology, which is now the MSHA-required sampler for  Incoal mines and metal and nonmetal mines, there are significant nondiesel sources of carbon particulate matter that interferes with efforts to measure the concentration of diesel particulate matter, most of which is elemental carbon. This problem is solved in coal mines by measuring tail- pipe emissions of diesel engines and, in metal and nonmetal mines, by measuring environmental concentrations. NIOSH has developed methods for making both types of measurements and for developing technology for achieving these limits. A lingering question is whether these two very dif- ferent approaches provide equally safe environments.

106 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 measuring diesel particulate matter in metal/nonmetal mines (Noll et al. 2005). MSHA relied on RDRP research (Bugarski et al. 2004b) as part of the evidence that available technologies are capable of reducing the amount of particulate matter in diesel exhaust. In a separate arena, NIOSH contributed important evidence to the California Air Resources Board proceedings that led to the decision to list diesel particulate matter as a “toxic air contaminant.” The same two papers that MSHA relied on for its action were considered relevant in California as well. NIOSH and the National Cancer Institute are now in the process of complet- ing a major epidemiologic study of diesel exhaust and mortality (particularly from lung cancer). The study includes a large cohort mortality study, a nested case-control study, and an extensive effort to retrospectively estimate job-specific exposure over a wide range using historical records and new industrial hygiene surveys. The study seeks to characterize the quantitative relationships between diesel exhaust and cancer and, therefore, is focused on nonmetal miners, where exposure levels are probably the highest and there is little exposure to other lung carcinogens. It is reasonable to expect that this study will provide the most detailed and comprehensive assessment to date of lung cancer risk from exposures to diesel particulate matter. The study’s progress has been affected by intensive scrutiny and legal action by industry. Legal challenges to the process that initiated the study required NIOSH and the National Cancer Institute to repeat the protocol peer-review process from the beginning (Monforten 2006). This, too, was challenged. The consequence was substantial added delay in progress as well as a court order to require the govern- ment to refrain from publicly releasing all information submitted to the House Committee for a 90-day period. Work is proceeding and will be completed under the terms of this court order. The MSHA final rule still presents assessment problems at the lower range of exposures due to technical limitations of the exposure assessment methodology. A key to addressing this is the RDRP’s ongoing work on finding a reliable ratio between elemental carbon and total carbon at these measurement levels to allow MSHA to establish an elemental carbon surrogate for total carbon at these lower limits and thus enable MSHA to enforce the new exposure limit. Research, expected to begin soon, is being planned by RDRP scientists to address long-term implementation issues relating to the MSHA diesel exhaust rule. NIOSH estimates that approximately 1.35 million workers are occupation- ally exposed to diesel exhaust particulate matter in about 80,000 workplaces in the United States (MMWR 1989b). Exposed workers outside of mining include railroad workers, bus garage workers, trucking company workers, forklift truck operators, firefighters, lumberjacks, tollbooth and parking garage attendants, and

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 107 many professions that service or handle automobiles (car mechanics, professional drivers) (NTP 2005). Lung Cancer Diagnostic Tools The RDRP research on spectral karyotyping and comparative genomic hybrid- ization has been applied to identifying genetic changes that occur during the general progression of lung cancer. In addition to published reports (Sargent et al. 2002; Yuan et al. 2004) a cooperative research and development agreement with Spectral Genomics, Inc., has resulted in development of a syntenic genomic chip and a patent is pending (2004-025124). This mouse-human chip will be used to allow direct comparisons between mouse and human lung adenocarcinomas. This RDRP research has led to generalizable knowledge about the mechanisms of lung cancer that is valuable to other lung cancer researchers. The syntenic chip is the forerunner of a human chip that will be used to diagnose and stage lung adenocarcinomas in humans. The RDRP believes that these findings can be applied to mouse and human studies to establish biomarkers for occupational exposure to lung carcinogens and the early detection and staging of lung cancer. The cooperative research and devel- opment agreement established with Spectral Genomics will assess the applicability of the observed gene expression and gene copy number changes detected in RDRP studies to aid in the early detection, diagnosis, and staging of lung cancer. While the committee found evidence of the impact of the RDRP research effort in addressing the development of early markers for lung cancer starting with a mouse model, the potential for this work to lead to biomarkers of occupational exposures was not documented or explained. The research appears to the committee to be distant from addressing occupationally related respiratory malignancies and might equally well be carried out by the National Cancer Institute or the National Institute of Environmental Health Sciences, each of which has significantly more research resources and a mandate closer to this particular goal. Assessment of Relevance The RDRP has addressed several of the key occupational lung cancer risks in substantial and relatively comprehensive ways. The relevance of the work address- ing the three carcinogen-specific exposure goals—silica, hexavalent chromium, and diesel exhaust—is unquestioned. These three carcinogens carry a significant risk, expose large occupational populations, and are highly amenable to control. In fact, the programs addressing these goals may have been motivated both by internal scientists’ recognition of the problem and by external opportunities for having

108 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 impact. Although the committee has no specific concerns related to the choice of these three exposures’ programmatic priorities, the rationale for their prioritization over other possible important lung carcinogens is not evident. NIOSH has also conducted very significant work on the contribution of occu­ pational exposures to lung cancer risk in working populations. To some degree, the relevance of these efforts has been aided by substantial planning documents produced in 1993 (occupational cancer in general) and in 2003 as part of the NORA process addressing occupational cancer research methods. However, as stated pre- viously, although there are some advantages for RDRP involvement in respiratory cancer, respiratory concerns should be included in a broader program addressing occupational cancers in general. The NORA team and the planning documents cited earlier addressed occupational cancers but did not separate lung cancer for attention by a different program. Furthermore, the degree to which information from surveillance activities, HHE/TA projects, or reports from the field contribute to the planning of priority areas for research on lung cancer is not clear. While the relevance of early detection methods for lung cancer is not disputed, the relevance of this area of investigation to NIOSH’s unique mission within the federal health research apparatus is questionable. A closer link between the bio- medical research activities of the RDRP and the unique problems associated with occupational exposures, populations, or research methods is needed. It is important to reiterate a key characteristic of the RDRP’s three areas of exposure-specific subgoals. In each case, the RDRP has responded to a need recog- nized by either the scientific community or specific regulatory agencies, responding with multiple approaches to address the complexity of exposure and risk in the workplace. The ability to conduct quantitative epidemiology and risk assessment, while also addressing chemical and technological challenges of exposure assessment and exposure controls is an unusually effective approach for a scientific or govern- mental agency. The multidisciplinary and comprehensive approach to addressing risks in the workplace is a hallmark of the RDRP and NIOSH’s contribution to public health. Assessment of Impact After review of the contributions presented by the RDRP and the input of stakeholders, there is evidence of solid and effective research that has had a direct impact on the control of occupationally related cancer risk in today’s workplaces. There is current evidence that the research products have been of direct use both to OSHA and to MSHA in their standard-setting process as seen in the value of the RDRP risk assessments for both hexavalent chromium and for diesel exhaust particulate matter. The positive impact of the RDRP transfer efforts is also evident in the importance the agencies place on RDRP research that has been called for and

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 109 effective in addressing complex issues related to methods to permit field assessment of low-level exposure to hexavalent chromium and relatively low-level exposure to diesel exhaust particulate matter. While the RDRP work on silica and respiratory malignancies has not penetrated as well into affecting agency rules and stakeholder practices, the reasons for this are beyond NIOSH’s control. Ongoing research continues to address some of the challenging problems related to occupational lung cancer risk. The RDRP has effectively engaged with stakeholders from both the workforce and the industry. This appears to be impor- tant in gaining acceptance of the research findings as well as adopting the methods and technology that were the subject of the research. It is important to note the unusual and successful efforts the RDRP has directed at informing, individually, all subjects of cohort studies about the findings from these studies and what meaning it could have to each worker. This attention to communicating to occupationally exposed populations is a model for investigators both within and outside government. The impact of the respiratory malignancies program is particularly strong in those specific areas where NIOSH applies its special expertise and mandate, comprehensively addressing specific carcinogenic exposures in the workplace. This strength is well demonstrated in the case of silica and chromium VI exposures. The work in diesel exposures has been completed, and it is expected to be integrated into this highly relevant exposure and risk assessment. The program components that address the contribution of occupational exposures to the burden of cancer in general are very significant. However, this contribution is not particular to respiratory cancers and it is unclear that the program is well served by separat- ing these particular outcomes from other important occupational cancer risks. Finally, the committee questions the specific relevance to the NIOSH mission of the research directed at diagnostic tools for early detection of lung cancer. While this area of investigation is relevant to lung cancer in general, there is little advantage of having this work located at NIOSH. Focusing the early detection biomarkers on workplace-specific prevention efforts would make these efforts more relevant to NIOSH’s mission and would increase the likelihood of the program’s having a significant impact. Strategic Goal 5: Prevent respiratory and other diseases potentially resulting from occupational exposures to nanomaterials Introduction The overarching theme for the NIOSH Nanotechnology Research Program is to understand and prevent injuries and illnesses due to occupational exposure to

110 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 nanomaterials in the workplace environment. This is a relatively new program that was implemented before any relationship was observed between nanotechnology and occupational lung disease. Thus, it is a proactive program rather than one that attempts to resolve problems after they have occurred. It includes specific concern with potential risks to the respiratory system as a natural extension of the previous research by NIOSH on the occupational hazards associated with inhaled dusts. NIOSH has indicated the following specific goals for the program: • To conduct research aimed at understanding and preventing work-related injuries and illnesses due to the use of nanotechnology products. This involves determining the toxicity of nanomaterials, identifying potential health outcomes from the use of these materials, and monitoring the health of individuals who work with these materials. NIOSH will also serve a major role in disseminating guidance information related to engineered nanomaterials. • To conduct research to prevent work-related injuries and illnesses due to the application of nanotechnology products. Nanotechnology-based sensors and communication devices may help in handling emergencies and in empowering workers to take preventive steps for reducing the risk of injury. Nanotechnology- based fuel cells, lab-on-chip analyzers, and optoelectronic devices have the potential to be useful in making the workplace safe and healthful. • To promote healthful workplaces through intervention, recommenda- tion, and capacity building. This involves developing and evaluating engineer- ing controls, personal protective equipment, and guidance on safe handling of nanomaterials. • To enhance global workplace health and safety through national and inter- national collaborations. This involves growing existing partnerships and developing new ones to identify research needs, approaches, and results to ensure worker health and safety. • Within the context of this program, the potential for disease and injury evaluated by NIOSH goes beyond just consideration of the respiratory tract. How- ever, because respiratory issues are highly integrated within the program as a whole, this section provides an assessment of the entire program and is not limited to respiratory outcomes. Planning and Production Inputs To help to achieve its goals, NIOSH has developed a strategic plan to guide the program. NIOSH is also working to coordinate its goals with other research groups, government agencies, and industries. To coordinate nanotechnology ­research within the Institute, the virtual Nanotechnology Research Center (NTRC) was established

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 111 in 2004. The NTRC and its steering committee is composed of NIOSH scientists from various disciplines. The role of this committee is to develop and guide the Institute’s plan for health research related to nanomaterials in the workplace as well as to guide research on the application and utilization of nanomaterials in occu- pational safety and health. The project activities managed and coordinated by the NTRC contribute to several sector, cross-sector, and coordinated emphasis areas, including respiratory disease, manufacturing, exposure assessment, personal pro- tective technology, and engineering controls. In keeping with the NORA ­approach, the nanotechnology research program is managed across the Institute in a matrix fashion through NTRC. Various members of the nanotechnology research program meet annually to update strategic planning and to review the critical occupational safety and health issues arising from nanotechnology. The latter is a list developed by the NTRC to identify critical issues that may arise from nanotechnology in various areas, includ- ing exposure, toxicity, measurement, and control. NIOSH is a member of the Nanoscale Science, Engineering and Technology Subcommittee (NSET) of the National Science and Technology Council (NSTC) and participates in the National Nanotechnology Initiative (NNI) strategic and ­budget- planning processes. Through the NSET Nanotechnology Environmental and Health Implications Working Group, NIOSH coordinates research related to the occupa- tional health and safety of nanotechnology with other federal agencies. Activity, Outputs, and Outcomes As part of its nanomaterial research effort, in 2004, NIOSH funded the Nano- technology Safety and Health Research Program, which consisted initially of six research projects aimed at issues of exposure measurement, nanoparticle charac- terization, and biological effects of exposure in the pulmonary and cardiovascular systems. An additional four projects, aimed at issues related to exposure surveillance, exposure control, risk assessment, and risk dissemination, were added in 2005, and it is anticipated that a further increase in the research portfolio will be forth­coming to address issues of safe handling of nanomaterials, exposure mitigation, and ­toxicity to workers that may go beyond the respiratory tract as a target organ. Since this review began, an NTRC progress report for the years 2004-2006 has been released (NIOSH 2007e). The report lists 10 topic research areas that are the core of the NTRC research program to address occupational safety and health issues: toxicity and internal dose, risk assessment, epidemiology and surveillance, engineering controls and personal protective equipment, measurement methods, exposure assessment, fire and explosion safety, recommendations and guidance, communication and education, and applications.

112 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 The NIOSH research program related to nanomaterials consists of intramural and extramural activities. Extramural funding for nanomaterial research began in FY2000, and these projects accounted for 3.1% of total extramural funding from that time to FY2006. Funding for extramural projects in FY2007 is lower than that in FY2006, at about $700,000. On the other hand, intramural funding has been increasing rapidly since 2003, and FY2007 funding is $4.6 million. Activities: Intramural Research Program The intramural program is concerned with determining nanomaterial expo- sure concentrations in occupational environments and potential adverse health outcomes from exposure as well as assessing appropriate engineering controls. These activities are reviewed and prioritized by the NTRC Steering Committee and are funded through various sources, including the NORA program, NTRC ­projects, and supplemental NORA funding. Several projects are listed in the “Strategic Plan for NIOSH Nanotechnology Research” (NIOSH 2005b) and in the ­recently released progress report (NIOSH 2007e). Funded projects include those on gen- eration and characterization of occupationally relevant airborne nanoparticles, pulmonary toxicity of carbon nanotube particles, the role of carbon nanotubes in cardio­pulmonary inflammation and COPD-related diseases, particle surface area as a dose metric, ultrafine aerosols from diesel-powered equipment, nanotech- nology safety and health research coordination, nanoparticle dosimetry and risk assessment, nanoparticles in the workplace, web-based nanoinformation library implementation, an ultrafine particle intervention study in automotive production plants, and the filter efficiency of typical respirator filters for nanoscale particles. Given the diversity of types of nanoparticles that may be encountered in occupa- tional settings, it is likely that there will be quantitative and qualitative differences in the manner by which they may affect human health. Furthermore, a wide range of organizations are conducting research on the toxicity of various nanoparticles. Thus, it will be critical for NIOSH to prioritize the areas of research that are most important for its specific consideration. Activities: Extramural Research Program Extramural activities are aimed at supporting the strategic plan through r ­ esearch, education, and training. Some of these activities involve collaborating with other agencies, including the National Center for Environmental Research of the EPA, the National Science Foundation, and the National Institute of Environ- mental Health Sciences of the National Institutes of Health (NIH). As of FY2006, the extramural research project had funded seven projects. Some are joint solicita-

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 113 tions from NIOSH and other funding agencies. The proposals are treated as NIH R01 or small business innovation research (SBIR) applications and are reviewed by the NIOSH study section. Research (R01) studies include assessment methods for nanoparticles in the workplace, monitoring and characterizing airborne ­carbon nanotube particles, lung oxidative stress/inflammation by carbon nanotubes, and the role of surface chemistry in the toxicologic properties of manufactured nanoparticles. Two SBIR studies were funded on new nanostructured sensor arrays for hydride detection and using nanoparticles in lightweight permeable textiles to improve the ability of protective garments to protect against toxic gases. There are also a number of cross-cutting projects that have some utility for evaluating risks from exposure to nanosized particles, although they may not be specifically engineered materials. Other Activities A number of activities serve to disseminate information about nano­tech­nology. They have often been produced in collaboration with NIOSH partners in nano- technology health and safety research. • NNI: NIOSH is a member of the NSET of NSTC and participates in the NNI strategic and budget-planning processes. Through the NSET Nano­tech­ nology Environmental and Health Implications Working Group, NIOSH coordi- nates ­ research related to the occupational health and safety of nanotechnology with other federal agencies. • NIOSH cosponsored the International Conference on Nano­tech­nology Occu­pational and Environmental Health and Safety: Research to Practice in D ­ ecember 2006. This conference addressed the impact of nanotechnology on occu­pational and environmental health and safety from two perspectives: the promotion and protection of individual heath and safety along the life cycle of nanobased products, and the use of emerging technology in preventing, detecting, and treating occupational and environmental diseases related to nanomaterials. • NIOSH cosponsored an international symposium, Nano-Toxicology: Bio- medical Aspects, in January and February 2006. • NIOSH cosponsored the Second International Symposium on Nanotech- nology and Occupational Health in October 2005. • NIOSH cosponsored the First International Symposium on Nanotechnol- ogy and Occupational Health in October 2004. • NIOSH published the document “Approaches to Safe Nanotechnology” in 2005 with an update in 2006 (NIOSH 2006f) as an informational exchange to discuss health and safety concerns from exposure to nanomaterials.

114 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 Outputs Safety Document NIOSH has published a highly requested document on “Approaches to Safe Nanotechnology: An Information Exchange with NIOSH” (NIOSH 2006f), which provides practical advice on the safe handling of nanomaterials by anyone working with the substances. NIOSH has a website to answer frequently asked questions. Research Publications NIOSH is just getting started in publishing in this emerging, fast-moving field. Three peer-reviewed articles were mentioned in the evidence package (Maynard and Kuempel 2005; Shvedova et al. 2005; Oberdorster et al. 2005). There were also six abstracts and six proceedings documents relating to manufactured nano­ particles. The agency indicated a much higher number of publications, but they appear to be based on work with diesel particles, and not specifically with manu- factured nanoparticles. The recently released progress report of the NTRC indicates that the number of peer-reviewed publications has increased, with more abstracts and proceedings documents. Sponsored Conferences NIOSH has sponsored or cosponsored at least five nanotechnology conferences at the national and international levels. Invited Talks NIOSH staff have given about 50 invited talks on nanotechnology at national and international conferences. Outcomes This is a fairly new program for NIOSH so outcomes are limited. On an inter- mediate outcome level, an ISO Technical Committee on Nanotechnology that was established in 2005 has the United States as the leader in the committee’s Working Group on Health, Safety and the Environment.

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 115 Assessment of Relevance The nanomaterial research program, as outlined in the “Strategic Plan for NIOSH Nanotechnology Research-Filling the Knowledge Gaps” (NIOSH 2005b), is a highly relevant component of their overall research efforts. The research ­addresses an important and pressing need to determine the potential toxicity of and methods to monitor and control a newly discovered, highly useful material at the onset of its extensive use in industry. NIOSH has taken the initiative to develop a strategic plan to guide efforts and to allow more effective collaborations with other agencies both nationally and internationally. The focus of the NIOSH nanotechnology program is engineered nanoparticles, but the NTRC supports work within the Institute that can contribute to a better understanding of the behavior, measurement, toxicity, and control of other types of ultrafine particles such as those generated from occu­ pational activities such as welding, diesel engines, and fires. Thus, the work in the nanotechnology program has implications for utility in other aspects of NIOSH. Assessment of Impacts This program is dealing with materials having a potential health effect, so measures of any reduction in health effects are not yet determinable. The expected impact is to prevent future health effects that might occur if this research were not done. The committee agrees that NIOSH is very proactive in this area of occupational health, helping to anticipate the need to protect occupationally exposed individuals. This proactivity is manifested both in the development of their research program on nanomaterials as well as in significant outreach as exemplified by publication of the “Approaches to Safe Nanotechnology” document (NIOSH 2006f). Successful development and implementation of this program will provide NIOSH with the opportunity to develop a paradigm to prevent occupa- tionally related illness due to exposure to nanomaterials before their widespread use in industry. This provides NIOSH with a unique opportunity to prevent dis- ease before it occurs rather than to control it after workers develop occupationally related pathology. Intermediate Impacts The NIOSH program should ultimately have an impact on setting federal regu- lations as well as voluntary and professional standards for handling nanomaterials. NIOSH is also having an impact on the education and training for monitoring and controlling nanomaterials in occupational settings. A major contribution of NIOSH to the latter was the timely publication of the document, “Approaches to Safe Nanotechnology: An Information Exchange with

116 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 NIOSH” (NIOSH 2006f), a valuable guide for anyone working with nanomaterials. The leadership of NIOSH in developing this safety manual strongly influenced the appointment of the United States as chair of the Working Group on Safety and Health Standards of the International Standards Organization Technical Commit- tee on Nanotechnologies. NIOSH staff also have helped the EPA to develop a pilot program on the toxicity of nanomaterials and work with the National Institute of Standards and Technology to set standards for nanomaterials. NIOSH is a leader in providing forums for discussion of the potential health problems associated with the use of nanomaterials and has set up several confer- ences on the topic. The conference proceedings have been published and the impact of these conferences has been to stimulate further research in the field. NIOSH has interacted well with various stakeholders, including other government agencies and industry, to explore problems associated with nanotechnology. The output of the NIOSH basic research program on the toxicity of nano­ particles in biological systems is less impressive in that only a few open literature publications have been completed. This probably reflects the newness of the field and the fact that NIOSH, with limited funds, has placed higher priority in areas where NIOSH is particularly well suited to have an impact—that is, in continuing successful research into methods to monitor exposures to nanomaterials and to develop appropriate engineering controls to prevent such exposures. The com- mittee thinks this is appropriate because many other agencies, particularly NIH, are conducting basic research on the health effects of engineered nanomaterials. N ­ evertheless, the committee encourages continued research efforts on the ­toxicity of nanomaterials in biological systems as a part of the RDRP program (see emerg- ing issues section). One listed goal is to explore how various applications of nano- materials might improve workplace safety. This is a limited program confined to a few SBIR extramural projects. The committee agrees that this area should not have a high priority for the RDRP. End Impacts It is not possible at this time to assess end outcomes since nanotechnology is a fairly new field and occupational disease has not yet been attributed to exposure to nanomaterials. However, the use of manufactured nanomaterials is expected to grow, and the available database from toxicology studies suggests that nanoparticles may be a potential occupational health hazard. Since there is a potential impact on thousands of workers, it is admirable that NIOSH has taken the lead before development of disease in the workplace; by continuing a leadership role, NIOSH has had and will have a major influence on policy setting.

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 117 OVERALL ASSESSMENT OF THE RDRP RELEVANCE AND IMPACTS A central part of the charge to the committee is to provide a quantitative assessment of the overall relevance and impacts of the RDRP’s activities. Using scoring criteria the National Research Council framework committee developed, the committee was tasked with rating the relevance of the RDRP’s activities for improving occupational health on a scale of 1 (lowest) to 5 (highest) and rating the impacts of the program’s research for reducing work-related hazardous exposures and illnesses on a similar scale. Box 2-1 shows the scoring criteria for relevance and impacts, which was also shown in Chapter 1. To develop scores for the program as a whole, the committee considered its assessment of the relevance and impacts of NIOSH activities directed at the indi- vidual program subgoals described previously. It then weighted these qualitatively to arrive at an overall program assessment. The framework committee recognized the substantial differences among the types of research programs that will be reviewed by the various evaluation committees. It thus declined to provide an explicit instruction on how an evaluation committee should implement the scoring system and weigh the various programs and instead called for individual commit- tees to use their expert judgment to develop its scores. Relevance Score As noted earlier, the RDRP is a large program, using nearly $30 million in 2005 in pursuit of its program goals and subgoals. Not surprisingly, the committee found variability in the degree to which individual activities might be relevant to the overall program goals of the RDRP. For example, although the individual activi- ties related to indoor air quality likely contribute to better overall understanding of this issue, their relationship to occupational asthma is not necessarily straight- forward. However, there are clearly a large number of programs that are directly relevant to the individual goals. It also is important to note how some activities, especially those that occur outside the Division of Respiratory Disease Studies, may have other NIOSH goals as their primary motivators. For example, RDRP-related activities that occur at the Pittsburgh Research Laboratory must also be relevant to NIOSH’s goal of improving mine safety and health. The committee has assigned a score of 5 in its rating of relevance. This reflects the judgment of the committee that the activities related to most of the subgoals are in the highest-priority subject areas and highly relevant to improvements in workplace protection and that the RDRP is engaged in transfer activities at a sig- nificant level. This is particularly true for its activities related to interstitial lung disease as well as many parts of the activities related to airways and infectious

118 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 BOX 2-1 Scoring Criteria for NIOSH Program Reviews from Framework Document Rating of Impact 5 = Research program has made a major contribution to worker health and safety on the basis of end outcomes or well-accepted intermediate outcomes. 4 = Research program has made a moderate contribution on the basis of end outcomes or well-accepted intermediate outcomes; research program generated important new knowledge and is engaged in transfer activities, but well-accepted intermediate out- comes or end outcomes have not been documented. 3 = Research program activities or outputs are going on and are likely to produce improve- ments in worker health and safety (with explanation of why not rated higher). 2 = Research program activities or outputs are going on and may result in new knowledge or technology, but only limited application is expected. 1 = Research activities and outputs are NOT likely to have any application. NA = Impact cannot be assessed; program not mature enough. Rating of Relevance 5 = Research is in highest-priority subject areas and highly relevant to improvements in workplace protection; research results in, and NIOSH is engaged in, transfer activities at a significant level (highest rating). 4 = Research is in high-priority subject area and adequately connected to improvements in workplace protection; research results in, and NIOSH is engaged in, transfer activities. 3 = Research focuses on lesser priorities and is loosely or only indirectly connected to workplace protection; NIOSH is not significantly involved in transfer activities. 2 = Research program is not well integrated or well focused on priorities and is not clearly connected to workplace protection and is inadequately connected to transfer activities. 1 = Research in the research program is an ad hoc collection of projects, is not integrated into a program, and is not likely to improve workplace safety or health. diseases and malignancies. The committee also noted that the activities related to nanotechnology were highly relevant, even though this emerging area has yet to see any impacts related to intermediate or end outcomes. Activities related to parts of some subprograms, including some of the activities related to malignancies and infectious diseases, do not reach this highest level of relevance as reflected in the assessment of the subprograms earlier in this chapter. But those NIOSH activities

E va l u at i o n of the R e s p i r ato ry D i s e a s e s R e s e a r c h P r o g r a m 119 were still in important research areas with some connection to improvements in workplace protection. Impact Score There is variability in the impacts of RDRP activities on end outcomes or well-accepted intermediate outcomes. Some activities may have large and well- documented impacts, whereas others are smaller and less easily discernable. Again, given the size of the RDRP and the notion that some elements of the RDRP have objectives besides respiratory diseases, the outcome is not surprising. For example, the committee notes that activities related to the development of diagnostic tools for early detection of lung cancer, while relevant to lung cancer in general, have no effect on the program goal associated with work-related respiratory malignan- cies. The committee recognized that, in terms of assessing measurable impacts, any programmatic efforts of only 10 years’ duration could not be expected to be reflected in changing incidence data for respiratory tract diseases with long latency, most notably respiratory tract malignancies. Thus the absence of data for indicating such impacts was not weighted as a “negative” finding. Where appropriate, however, exposure or other risk factor reductions for disease processes with long latencies were considered. Further, there is no way for NIOSH to quantify specifically the impacts that work on personal respirators and environmental controls have had on reductions in the occurrence of TB and other respiratory infections. However, the activities of the RDRP have clearly played major roles in reducing the occurrence of and mortality from CWP. It also played a major role in reducing the prevalence of latex sensitization as a result of the intervention effort that began with the 1996 NIOSH Alert. The committee has assigned a score of 4 in its rating of impact, reflecting the committee’s judgment that most of the subprograms within the RDRP have made major contributions to worker health and safety on the basis of end and well- a ­ ccepted intermediate outcomes. It represents the consensus of the committee on the degree to which the overall program, which is still in its infancy, meets the goals and has had the impacts set out by NIOSH. After much deliberation on how to weigh the assessments of different subprograms, the committee assigned a score of 4 for the program as a whole. Had the committee been given the option of provid- ing non-integer scores, the score for program impact would have been between 4 and 5, based on consensus that the program was clearly better than that called for in a score of 4 but not in sum what the committee would rate a 5.

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Respiratory diseases caused by exposures to dangerous materials in the workplace have tremendous implications for worker health and, by extension, the national economy. The National Institute for Occupational Safety and Health (NIOSH) estimates that deaths from work-related respiratory diseases and cancers account for about 70% of all occupational disease deaths. NIOSH conducts research in order to detect and reduce work-related hazardous exposures, injuries, and diseases; its Respiratory Disease Research Program (RDRP) focuses on respiratory diseases. This National Research Council book reviews the RDRP to evaluate the 1) relevance of its work to improvements in occupational safety and health and 2) the impact of research in reducing workplace respiratory illnesses. The assessment reveals that the program has made essential contributions to preventing occupational respiratory disease. The National Research Council has rated the Program a 5 out of 5 for relevance, and a 4 out of 5 for impact. To further increase its effectiveness, the Respiratory Disease Research Program should continue and expand its current efforts, provide resources for occupational disease surveillance, and include exposure assessment scientists in its activities.

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