Comparison of various methodological approaches to model asbestos thresholds for mesothelioma

Abstract

Background: There is evidence to support several modes of action (MoAs), and particularly non-genotoxic MoAs, for mesothelioma induced by asbestiform elongate mineral particles (EMPs). In turn, these MoAs provide biological support for dose-response relationships that are non-linear and that include a threshold. However, statistical models of human data have not adequately addressed threshold dose-response relationships for asbestiform EMPs and mesothelioma. In addition, unlike other carcinogens, asbestiform EMPs are not uniform materials and display a range of properties.

Objectives: Our objective was to review various approaches for applying threshold dose-response models to asbestiform EMPs and mesothelioma.

Materials and methods: We collected data from several sources, including the Surveillance, Epidemiology, and End Results (SEER) Program and published case-control studies, cohort studies, and a meta-analysis that evaluated various mineral types of asbestos and mesothelioma risk. Several threshold-based models were fit to the available data. We also evaluated thresholds for certain fiber characteristics.

Results: Certain characteristics of asbestiform EMPs, such as width, length, and surface area, likely have thresholds for mesothelioma. Theoretical models and models based on epidemiology data supported thresholds. A Monte Carlo evaluation of the threshold hypothesis for mesothelioma in a meta-analysis of occupational exposures to various mineral fiber types, using a cumulative exposure metric, demonstrated the likelihood of a threshold to be 72% for non-textile chrysotile, 80.9% for textile chrysotile, 84% for amosite, and 60% for crocidolite. A multi-stage clonal expansion (MSCE) model applied to the SEER mesothelioma registry data demonstrated a good fit with the inclusion of a threshold by a surrogate predictor of cumulative exposure to amphiboles. Finally, lung burden studies also support a threshold. Our preliminary estimate of a central-tendency cumulative exposure threshold level for non-textile chrysotile is ~90 f/cc-years. Based on our proposed approach, we suggest thresholds of 1.04 f/cc-years for amosite, 0.25 f/cc-years for crocidolite, and 4.3-10.9 f/cc-years for tremolite. Future studies should be conducted to support these estimates.

Conclusions: While uncertainties remain, many angles of scientific evidence support the existence of mineral-specific thresholds for mesothelioma.

Keywords: amphibole; asbestos; chrysotile; dose-response; mesothelioma; threshold.

Figure 1

The illustration of the conceptual model of mesothelioma threshold. Blue line—Excess mesothelioma rate. Green line—Probability of inflammation. Red line—Probability of cell survival. Magenta line—Probability of immunosuppression (cell immortalization).

Figure 2

The distribution of threshold levels for non-textile chrysotile cohorts.

Figure 3

Observed and predicted excess mesothelioma mortality estimated using a threshold-based exposure intensity and duration model.

Figure 4

Survival function and its second derivative in relationship to cumulative exposure to non-textile chrysotile asbestos. Blue circles—Datapoints for cumulative exposure and mesothelioma mortality. Blue line—Survival rate function (left Y axis). Red line—Second derivative of the survival rate (right Y axis).