A meta-analysis of asbestos-related cancer risk that addresses fiber size and mineral type

Our plain-English summary of A meta-analysis of asbestos-related cancer risk that addresses fiber size and mineral type, by D.W. Berman, K.S. Crump (Critical Reviews in Toxicology, 2008).

The study

• Authors: D.W. Berman, K.S. Crump
• Journal: Critical Reviews in Toxicology
• Published: 2008;38 Suppl 1:49-73
• Type of article: Meta-analysis
• Cited by: 184 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Quantitative estimates of the risk of lung cancer or mesothelioma in humans from asbestos exposure made by the U.S. Environmental Protection Agency (EPA) make use of estimates of potency factors based on phase-contrast microscopy (PCM) and obtained from cohorts exposed to asbestos in different occupational environments. These potency factors exhibit substantial variability. The most likely reasons for this variability appear to be differences among environments in fiber size and mineralogy not accounted for by PCM. In this article, the U.S. Environmental Protection Agency (EPA) models for asbestos-related lung cancer and mesothelioma are expanded to allow the potency of fibers to depend upon their mineralogical types and sizes. This is accomplished by positing exposure metrics composed of nonoverlapping fiber categories and assigning each category its own unique potency. These category-specific potencies are estimated in a meta-analysis that fits the expanded models to potencies for lung cancer (KL's) or mesothelioma (KM's) based on PCM that were calculated for multiple epidemiological studies in our previous paper (Berman and Crump, 2008). Epidemiological study-specific estimates of exposures to fibers in the different fiber size categories of an exposure metric are estimated using distributions for fiber size based on transmission electron microscopy (TEM) obtained from the literature and matched to the individual epidemiological studies. The fraction of total asbestos exposure in a given environment respectively represented by chrysotile and amphibole asbestos is also estimated from information in the literature for that environment. Adequate information was found to allow KL's from 15 epidemiological studies and KM's from 11 studies to be included in the meta-analysis. Since the range of exposure metrics that could be considered was severely restricted by limitations in the published TEM fiber size distributions, it was decided to focus attention on four exposure metrics distinguished by fiber width: "all widths," widths > 0.2 micro m, widths < 0.4 microm, and widths < 0.2 microm, each of which has historical relevance. Each such metric defined by width was composed of four categories of fibers: chrysotile or amphibole asbestos with lengths between 5 microm and 10 microm or longer than 10 microm. Using these metrics three parameters were estimated for lung cancer and, separately, for mesothelioma: KLA, the potency of longer (length > 10 microm) amphibole fibers; rpc, the potency of pure chrysotile (uncontaminated by amphibole) relative to amphibole asbestos; and rps, the potency of shorter fibers (5 microm < length < 10 microm) relative to longer fibers. For mesothelioma, the hypothesis that chrysotile and amphibole asbestos are equally potent (rpc = 1) was strongly rejected by every metric and the hypothesis that (pure) chrysotile is nonpotent for mesothelioma was not rejected by any metric. Best estimates for the relative potency of chrysotile ranged from zero to about 1/200th that of amphibole asbestos (depending on metric). For lung cancer, the hypothesis that chrysotile and amphibole asbestos are equally potent (rpc = 1) was rejected (p < or = .05) by the two metrics based on thin fibers (length < 0.4 microm and < 0.2 microm) but not by the metrics based on thicker fibers. The "all widths" and widths < 0.4 microm metrics provide the best fits to both the lung cancer and mesothelioma data over the other metrics evaluated, although the improvements are only marginal for lung cancer. That these two metrics provide equivalent (for mesothelioma) and nearly equivalent (for lung cancer) fits to the data suggests that the available data sets may not be sufficiently rich (in variation of exposure characteristics) to fully evaluate the effects of fiber width on potency. Compared to the metric with widths > 0.2 microm with both rps and rpc fixed at 1 (which is nominally equivalent to the traditional PCM metric), the "all widths" and widths < 0.4 microm metrics provide substantially better fits for both lung cancer and, especially, mesothelioma. Although the best estimates of the potency of shorter fibers (5 < length < 10 microm) is zero for the "all widths" and widths < 0.4 microm metrics (or a small fraction of that of longer fibers for the widths > 0.2 microm metric for mesothelioma), the hypothesis that these shorter fibers were nonpotent could not be rejected for any of these metrics. Expansion of these metrics to include a category for fibers with lengths < 5 microm did not find any consistent evidence for any potency of these shortest fibers for either lung cancer or mesothelioma. Despite the substantial improvements in fit over that provided by the traditional use of PCM, neither the "all widths" nor the widths < 0.4 microm metrics (or any of the other metrics evaluated) completely resolve the differences in potency factors estimated in different occupational studies. Unresolved in particular is the discrepancy in potency factors for lung cancer from Quebec chrysotile miners and workers at the Charleston, SC, textile mill, which mainly processed chrysotile from Quebec. A leading hypothesis for this discrepancy is limitations in the fiber size distributions available for this analysis. Dement et al. (2007) recently analyzed by TEM archived air samples from the South Carolina plant to determine a detailed distribution of fiber lengths up to lengths of 40 microm and greater. If similar data become available for Quebec, perhaps these two size distributions can be used to eliminate the discrepancy between these two studies.

In plain English

This meta-analysis used potency estimates for occupational cohorts from the authors' earlier paper. The authors expanded U.S. EPA cancer models so potency could differ by fiber type (chrysotile or amphibole asbestos), length and width. Each study was matched to published fiber-size data, sometimes from other sites, and amphibole content was estimated from the literature. Fifteen studies were used for lung cancer and 11 for mesothelioma. All chrysotile estimates meant pure chrysotile, without amphibole contamination. For mesothelioma, equal potency of the two types was strongly rejected under every metric; zero chrysotile potency could not be ruled out, except with the lowest amphibole estimates. For lung cancer, long chrysotile was estimated 6 to 60 times less potent than long amphibole, but equal potency was rejected only for two thin-fiber metrics. Under the best-fitting metrics, fibers 5 to 10 µm long had a best-estimate potency of zero. No metric resolved the lung cancer gap between Quebec miners and South Carolina textile workers. With cautions on where they apply, the authors proposed the metrics as interim alternatives to the traditional PCM metric.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Meta-analysis (statistical modeling) that fitted expanded versions of the U.S. EPA lung cancer and mesothelioma models to potency factors previously estimated for individual epidemiological studies
• Who was studied: Occupational cohorts exposed to asbestos, including:
• Quebec chrysotile miners and millers
• South Carolina textile workers
• Wittenoom, Australia crocidolite miners
• cement, friction product, textile and insulation workers
  Lung cancer potency factors came from 15 studies and mesothelioma potency factors from 11 studies. All were taken from the authors' previous paper.
• Exposure: Chrysotile (estimated as pure chrysotile, uncontaminated by amphibole) and amphibole asbestos. Fibers were divided into two length categories (5 to 10 µm and longer than 10 µm) within four width metrics: all widths, widths greater than 0.2 µm, widths less than 0.4 µm, and widths less than 0.2 µm. A further analysis added fibers shorter than 5 µm.
• Main results:
  • All chrysotile potency estimates refer to pure chrysotile uncontaminated by amphibole. Contaminating amphibole asbestos would have to be added explicitly to estimate risk in real environments.
  • Mesothelioma, main analyses:
• Equal potency of chrysotile and amphibole asbestos was strongly rejected for all metrics.
• Chrysotile was estimated as nonpotent for three metrics and as 900 or 2000 times less potent than amphibole asbestos in the other two.
• The hypothesis that chrysotile has zero potency for mesothelioma was accepted for all metrics.
  • Mesothelioma, sensitivity analysis using the lower bounds of percent amphibole:
• The potency of long chrysotile rose from zero to 1/350th that of long amphibole asbestos.
• The hypothesis that chrysotile is non-potent was rejected.
  The authors attributed this to lower bounds of zero amphibole in several chrysotile studies, which they called clearly an underestimate.
  • Mesothelioma, across all analyses: best estimates of chrysotile potency ranged from zero up to 1/200th of the potency of amphibole asbestos.
  • Lung cancer: long (pure) chrysotile was estimated as 6 to 60 times less potent than long amphibole asbestos. The confidence intervals for the two potencies overlapped for all metrics except the one based on widths less than 0.2 µm.
  • Lung cancer, test of equal potency for the two fiber types:
• Rejected for the two thin-fiber metrics (widths less than 0.4 µm or less than 0.2 µm).
• Nearly rejected for the all-widths metric (p less than .07).
• Not rejected for the metrics based on widths greater than 0.2 µm.
  • Compared with the all-widths and widths-less-than-0.4-µm metrics, the traditional PCM metric fitted the mesothelioma data substantially worse and the lung cancer data somewhat worse.
  • Shorter fibers (5 to 10 µm long) under the best-fitting all-widths and widths-less-than-0.4-µm metrics:
• The best estimate of their potency was zero.
• Equal potency of shorter and longer fibers was rejected for the widths-less-than-0.4-µm metric for lung cancer.
• It was nearly rejected for the all-widths metric for lung cancer and for both metrics for mesothelioma.
  • Fibers shorter than 5 µm: potency was estimated as zero for both diseases under all metrics except the widths-greater-than-0.2-µm metric. The hypothesis that these fibers are nonpotent could not be rejected in any case.
  • No metric reconciled the difference in lung cancer potency between the Quebec chrysotile miners and millers and the South Carolina textile plant workers.
• The authors' conclusion: The authors concluded that the metrics should be considered as interim alternatives to the traditional PCM metric, within stated cautions, while further refinements are developed. They noted that the metrics improve the fit to the data, substantially so for mesothelioma, but do not fully resolve differences between studies.
• Limitations the authors state:
  • Except for one South Carolina data set, the published fiber-size data had no length cut point above 10 µm, so effects of longer length categories could not be explored.
  • Some electron microscopy procedures were poorly documented, and some size distributions came from locations other than where the epidemiological studies were done.
  • The analysis had to assume that PCM fiber concentrations equal the PCM-equivalent concentrations measured by TEM.
  • The fiber-size studies gave no information on chrysotile versus amphibole content, so the amphibole fractions had to be estimated separately from other literature.
  • The fiber-size data came from air samples taken over a narrow time span, but were used to represent exposure periods that often covered many years.
  • The available cohort studies may not vary enough in exposure characteristics to fully evaluate the effect of fiber width.
  • The metrics should not be applied in environments whose exposure characteristics differ radically from those of the studies used to define them.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Chrysotile, Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Meta-Analysis, Lung Cancer, Mesothelioma, Asbestos Exposure, Mineralogy, Transmission Electron Microscopy (TEM), Chrysotile, Amphibole Asbestos.

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