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Research Article

Update of Potency Factors for Asbestos-Related Lung Cancer and Mesothelioma

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Pages 1-47 | Published online: 20 Oct 2008
 

Abstract

The most recent update of the U.S. Environmental Protection Agency (EPA) health assessment document for asbestos (Citation, referred to as “the EPA 1986 update”) is now 20 years old. That document contains estimates of “potency factors” for asbestos in causing lung cancer (KL's) and mesothelioma (KM's) derived by fitting mathematical models to data from studies of occupational cohorts. The present paper provides a parallel analysis that incorporates data from studies published since the EPA 1986 update.

The EPA lung cancer model assumes that the relative risk varies linearly with cumulative exposure lagged 10 years. This implies that the relative risk remains constant after 10 years from last exposure. The EPA mesothelioma model predicts that the mortality rate from mesothelioma increases linearly with the intensity of exposure and, for a given intensity, increases indefinitely after exposure ceases, approximately as the square of time since first exposure lagged 10 years. These assumptions were evaluated using raw data from cohorts where exposures were principally to chrysotile (South Carolina textile workers, Citation; mesothelioma only data from Quebec miners and millers, Citation) and crocidolite (Wittenoom Gorge, Australia miners and millers, Citation) and using published data from a cohort exposed to amosite (Paterson, NJ, insulation manufacturers, Citation).

Although the linear EPA model generally provided a good description of exposure response for lung cancer, in some cases it did so only by estimating a large background risk relative to the comparison population. Some of these relative risks seem too large to be due to differences in smoking rates and are probably due at least in part to errors in exposure estimates. There was some equivocal evidence that the relative risk decreased with increasing time since last exposure in the Wittenoom cohort, but none either in the South Carolina cohort up to 50 years from last exposure or in the New Jersey cohort up to 35 years from last exposure.

The mesothelioma model provided good descriptions of the observed patterns of mortality after exposure ends, with no evidence that risk increases with long times since last exposure at rates that vary from that predicted by the model (i.e., with the square of time). In particular, the model adequately described the mortality rate in Quebec chrysotile miners and millers up through >50 years from last exposure. There was statistically significant evidence in both the Wittenoom and Quebec cohorts that the exposure intensity-response is supralinear1 rather than linear. The best-fitting models predicted that the mortality rate varies as [intensity]0.47 for Wittenoom and as [intensity]0.19 for Quebec and, in both cases, the exponent was significantly less than 1 (p< .0001).

Using the EPA models, KL's and KM's were estimated from the three sets of raw data and also from published data covering a broader range of environments than those originally addressed in the EPA 1986 update. Uncertainty in these estimates was quantified using “uncertainty bounds” that reflect both statistical and nonstatistical uncertainties. Lung cancer potency factors (KL's) were developed from 20 studies from 18 locations, compared to 13 locations covered in the EPA 1986 update. Mesothelioma potency factors (KM's) were developed for 12 locations compared to four locations in the EPA 1986 update. Although the 4 locations used to calculate KM in the EPA 1986 update include one location with exposures to amosite and three with exposures to mixed fiber types, the 14 KM's derived in the present analysis also include 6 locations in which exposures were predominantly to chrysotile and 1 where exposures were only to crocidolite.

The KM's showed evidence of a trend, with lowest KM's obtained from cohorts exposed predominantly to chrysotile and highest KM's from cohorts exposed only to amphibole asbestos, with KM's from cohorts exposed to mixed fiber types being intermediate between the KM's obtained from chrysotile and amphibole environments. Despite the considerable uncertainty in the KM estimates, the KM from the Quebec mines and mills was clearly smaller than those from several cohorts exposed to amphibole asbestos or a mixture of amphibole asbestos and chrysotile.

For lung cancer, although there is some evidence of larger KL's from amphibole asbestos exposure, there is a good deal of dispersion in the data, and one of the largest KL's is from the South Carolina textile mill where exposures were almost exclusively to chrysotile. This KL is clearly inconsistent with the KL obtained from the cohort of Quebec chrysotile miners and millers.

The KL's and KM's derived herein are defined in terms of concentrations of airborne fibers measured by phase-contrast microscopy (PCM), which only counts all structures longer than 5 μm, thicker than about 0.25 μ m, and with an aspect ratio ≥3:1. Moreover, PCM does not distinguish between asbestos and nonasbestos particles. One possible reason for the discrepancies between the KL's and KM's from different studies is that the category of structures included in PCM counts does not correspond closely to biological activity. In the accompanying article (Citation) the KL's and KM's and related uncertainty bounds obtained in this article are paired with fiber size distributions from the literature obtained using transmission electron microscopy (TEM). The resulting database is used to define KL's and KM's that depend on both the size (e.g., length and width) and mineralogical type (e.g., chrysotile or crocidolite) of an asbestos structure. An analysis is conducted to determine how well different KL and KM definitions are able to reconcile the discrepancies observed herein among values obtained from different environments.

ACKNOWLEDGMENTS

We thank Corbett McDonald and acknowledge the help of Douglass Liddell (deceased) for making available the raw data on mesothelioma mortality for the cohort of Quebec chrysotile miners and millers. We thank Nicholas de Klerk for making available the raw data for the cohort of Wittenoom, Australia, crocidolite miners. We thank NIOSH, and Everett (Chip) Lehman in particular, for making available the raw data for the cohort of workers from the textile plant in Charleston, SC. We thank Misty Hein for her valuable and very timely assistance in providing data on background cancer rates and additional information on the South Carolina cohort. We gratefully acknowledge the guidance and support provided by Aparna Koppikar, Richard Troast, Chris Weis, and Paul Peronard. We are indebted to John Addison, John Dement, Agnes Kane, Bruce Case, Michel Camus, and Vanessa Vu for their input and assistance. We thank Phillip Benge for his technical assistance and careful reading of the final manuscript. Finally, we gratefully acknowledge the financial support for the earlier work provided by the U.S. EPA and the grant provided by the National Stone Sand and Gravel Association to prepare this manuscript. This project was supported in part by an appointment to the Research Participation Program at the National Center for Environmental Assessment, U.S. EPA, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the EPA. The financial support provided by any group should not be construed as endorsement of the results of this work.

Notes

1. “Supralinear” refers to an exposure response whose slope decreases as exposure increases (e.g., [exposure]K with K< 1). A linear model fit to data that exhibit supralinearity will generally underestimate the response at low exposures and overestimate at high exposures.

2. Although the term “fiber type” typically includes consideration of both mineralogy and crystalline habit, we have focused primarily on mineralogy here due to an almost complete lack of data informative of crystalline habit among published epidemiological studies.

3. As used here, the term, “fiber” is intended to include not only single fibers (fibrils), but the bundles, clusters, and matrices that make up the set of fibrous particles in an asbestos dust (ISO, 1995).

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