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NIOSH Respiratory Diseases Research Program

Evidence Package for the National Academies' Review 2006-2007

NIOSH Programs > Respiratory Diseases > Evidence Package > 3. Interstitial Lung Diseases > 3.3 Fiber-Induced Diseases

3.3d) Define Determinants of Fiber Toxicity

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Issue

While much knowledge had been developed concerning the adverse health effects of asbestos and some other fibers, critical scientific research gaps remain. Specifically, laboratory and field research is needed to define mechanisms of fiber toxicity and impacts of fiber dimension, bio-persistence, and composition on fiber toxicity. Protective occupational health guidelines are needed that are applicable to the wide range of (natural and synthetic, mineral and organic) fibers to which workers are exposed in a myriad variety of industrial settings. Issues to be addressed include developing a universal definition for fibers and standard criteria for measuring fibers. Development of a method for producing fiber samples of uniform dimensions is an intermediate objective, as it would facilitate needed experimental toxicology research.

Approach

Recent planning efforts for this RDRP research include two strategic plans. First, in the early 1990s, RDRP scientists reviewed the available literature, including the recommendations of a NIEHS-sponsored Fiber Toxicology Research Needs workshop. Then they developed an internal document entitled “Fiber Exposures and Lung Disease Research Strategy.”83 It included the following objectives:

  • Identify fiber types/parameters of consequence
  • Discern fiber characteristics responsible for disease
  • Develop means of generating homogeneous fiber samples (for lab-based studies)
  • Establish a repository of fibrous material samples
  • Develop/establish standard tests of fiber durability
  • Elucidate basic mechanisms of diseases

More recently, production and use of synthetic vitreous fibers has increased. There is also growing evidence that certain non-asbestos fibers can have fibrogenic and carcinogenic effects on animals. Those factors influenced a group of RDRP scientists to identify priority areas for research addressing occupational exposure to fibers.

The final report on this effort (“NIOSH Interdivisional Fiber Subcommittee Final Report,” 1999, A3-86) identified critical gaps in knowledge and including the following objectives:

  • Validate animal models—provide quantitative relationship between animal and human responses to fiber exposures characterize and quantitate fiber exposures in the workplace
  • 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

RDRP researchers have worked to address the research objectives identified in both of these reports.

Outputs and Transfer

RDRP scientists have published notable scientific papers on the role of oxygen radicals in asbestos toxicity (13, A3-109), on a dielectrophoresis method for sorting fibers by length (14, A3-110), and on the relationship of fiber toxicity to fiber length (15-19, A3-111, A3-112, A3-113, A3-114, A3-115).

RDRP staff recently participated on a variety of panels and workshops. In so doing, they provided comments and advice to EPA, ATSDR, and WHO. Groups included:

  • EPA Panel. “Test Guidelines for Chronic Inhalation Toxicity and Carcinogenicity of Fibrous Particles,” (SAP Report No. 2001-01). This panel’s report represents a proposed strategy for chronic animal testing of fibers under the Toxic Substances Control Act. Two RDRP scientists participated.
  • EPA Working Group, “Testing of Fibrous Particles: Short-term Assays and Strategies.” (Inhal Toxicol. 2005 Sep;17(10):497-537). This report represents a proposed strategy for short-term testing of fibers to complement the EPA Panel’s review of chronic carcinogenicity assays for fibers. The report was co-authored by a RDRP researcher who participated in the working group. The report cited 10 papers published by our researchers and has been cited at least 254 times.
  • EPA Panel, “Report of the Peer Consultative Workshop on a Proposed Asbestos-Cancer Risk Assessment,” 2003. This report presents advice offered by a panel of experts advising EPA on mechanism of action, dose-response, and risk assessment, as these issues relate to a new risk-assessment protocol being considered by EPA which weights risk by fiber length. One current and one former RDRP researcher participated.
  • IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. “Man-Made Vitreous Fibers,” 2002. For this respected international guidance on the risks associated with occupational exposure, IARC cited RDRP outputs to establish that specified man-made fibers are carcinogenic.
  • ATSDR “Expert Panel on Biomarkers of Asbestos Exposure,” 2006. This panel advised ATSDR concerning that agency’s effort to identify at-risk individuals associated with community exposures to asbestiform fibers in Libby and California.
  • WHO “Workshop on Mechanisms of Fiber Carcinogenesis and Assessment of Chrysotile Asbestos Substitutes,” 2005. This workshop established a framework for hazard assessment and grouped asbestos substitutes into groupings of high, medium, and low relative hazard, as well as into an indeterminate grouping when sufficient data did not exist to specify relative hazard (http://www.who.int/ipcs/publications/new_issues/summary_report.pdf [External link]).

Intermediate Outcomes

EPA has adopted long-term and short-term fiber testing strategies derived from the above panel and workshop reports that involved RDRP scientists.95 EPA is also using recommendations from the above panel and workshop reports in assessing the need for new environmental standards for asbestos fibers. Formulation of a new EPA standard is in progress.

Based in part on RDRP scientific outputs, IARC has formally ranked the following fibers as to carcinogenicity in humans: ceramic fibers, rock wool, fibrous glasses, etc.

EPA will apply the newly developed adopted strategies for testing fibers, which involved RDRP scientists, with the expectation that such testing will prevent some hazardous fibers from entering commerce.

Progress Towards End Outcomes

End outcomes in terms of observed reductions in morbidity and mortality due to fiber exposure may be achievable after formulation, implementation, and enforcement of a new standard. RDRP has provided EPA and OSHA with mechanistic data that could be used to support promulgation of a new standard.

What’s Ahead

In addition to continuing laboratory research aimed at further addressing mechanisms of fiber toxicity and the controversial issue of the role of fiber length in determining fiber toxicity, RDRP experts in epidemiology and risk assessment will refine asbestos risk assessment with completion of a current RDRP effort to reanalyze an influential cohort mortality study of asbestos textile workers originally published decades ago. The reanalysis will include updated data on mortality of the cohort from lung cancer and asbestosis and new characterization of worker exposures. The characterization of exposures will include additional information on fiber dimensions (length and width) obtained from a reanalysis using transmission electron microscopy of stored air sampling filters collected from the original study.

A committee of intramural RDRP scientists is currently engaged in drafting a white paper to address controversial asbestos definitional issues, particularly the issue of non-asbestiform mineral “cleavage fragments.” Cleavage fragments meet dimensional criteria set out in the comprehensive OSHA asbestos standard, but are explicitly excluded from the standards. However, both asbestiform and non-asbestiform (“blocky”) mineral analogues exist for the six asbestos minerals, and distinguishing an individual fiber on an air sample filter as an asbestiform fiber or a cleavage fragment presents a formidable technical challenge. Moreover, little is known about the toxicity of such fibrous cleavage fragments. The anticipated white paper is intended to drive policy and recommend research to address identified voids in knowledge. The white paper will be shared with stakeholders, federal agencies, industry associations, labor organizations, and other interested parties for review and comment.

Objective and Aims Moving Forward

Our objective in this area is to develop an approach for assessing relative potential toxicity and establishing relative limits for occupational exposure to various fibers types (man-made and synthetic, organic and mineral, and of varying composition and structure). Some of the aims by which to achieve this objective include the following: 

  • Validate animal models—provide quantitative relationship between animal and human responses to fiber exposures, where possible
  • Design size-selective technology to produce dimensionally homogeneous fiber samples for experimental studies
  • Determine mechanisms of action, rates of dissolution, and dose-response relationships for various homogeneous fiber samples
  • Discern characteristics of fibers responsible for disease
  • Develop standard tests for assessing toxicity of various fibers
  • Characterize and quantitate fiber exposures in established work settings, and (where anticipation is possible) characterize potential toxicity of fibers before they are introduced in commercial scale processes
  • Develop a “white paper” on “cleavage fragments” to help move RDRP towards development of a universally applicable approach for assessment and control of fiber-related hazards
  • Development of the "Asbestos Road-Map" (A3-115s)

95. EPA Health Effects Test Guidelines [2001]. Combined Chronic Toxicity/Carcinogenicity Testing of Respirable Fibrous Particles (OPPTS 870.8355). 12-C-01-352.

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