We analyzed mesothelioma incidence in the Surveillance, Epidemiology, and End Results (SEER) database over the period 1973-2005 using extensions of the age-period-cohort (APC) models. In these analyses, the usual non-specific age effects of the conventional APC models were replaced by hazard functions derived from two multistage models of carcinogenesis, the Armitage-Doll model and the two-stage clonal expansion (TSCE) model. The extended APC models described the incidence data on pleural and peritoneal mesotheliomas well. After adjustment for temporal trends, the data suggest that the age-specific incidence rates of both pleural and peritoneal mesotheliomas are identical in men and women. Driven largely by birth cohort effects, age-adjusted rates of pleural mesothelioma among men rose from about 7.5 per million person-years in 1973 to about 20 per million person-years in the early 1990s and appear to be stable or declining thereafter. Age-adjusted rates of pleural mesothelioma among women have remained more or less constant at about 2.5 per million person-years over the period 1973-2005. Age-adjusted rates for peritoneal mesothelioma in both men (1.2 per million person-years) and women (0.8 per million person-years) exhibit no temporal trends over the period of the study. We estimate that approximately 94,000 cases of pleural and 15,000 cases of peritoneal mesothelioma will occur in the US over the period 2005-2050.

We briefly review the evidence that the carcinogenic risk posed by inhaled fibers depends principally on the lung burden of long fibers. We use a deposition clearance model to generate time-dependent lung burdens in rats of a dozen long fibers for various exposure concentrations. Together with a previously estimated potency factor for long fibers, we use the generated lung burdens to estimate risks of lung cancer associated with inhaled fibers in rats. Over a broad range of exposure concentrations, excess risk is a linear function of exposure concentration. Excess risk of lung cancer is also a linear function of weighted half-life for fibers for which the weighted half-life is short compared to the life span of the rat. We propose an approach to estimating human lung cancer risk associated with inhaled fibers from animal studies.

We show that available experimental data from long-term experiments are consistent with the hypothesis that the oncogenic potential of man-made fibers is determined completely by their biopersistence. We present an analysis of these data within the initiation-promotion-progression paradigm of carcinogenesis. Our method of analysis takes explicit account of the temporal pattern of fiber burden in the rat lung, and suggests that fibers act as initiators in the lung. We estimate a dose-dependent initiation parameter and show how it can be transported to human populations for assessment of the risk of lung cancer following exposure to man-made fibers.

We present the results of a quantitative assessment of the lung cancer risk associated with occupational exposure to refractory ceramic fibers (RCF). The primary sources of data for our risk assessment were two long-term oncogenicity studies in male Fischer rats conducted to assess the potential pathogenic effects associated with prolonged inhalation of RCF. An interesting feature of the data was the availability of the temporal profile of fiber burden in the lungs of experimental animals. Because of this information, we were able to conduct both exposure-response and dose-response analyses. Our risk assessment was conducted within the framework of a biologically based model for carcinogenesis, the two-stage clonal expansion model, which allows for the explicit incorporation of the concepts of initiation and promotion in the analyses. We found that a model positing that RCF was an initiator had the highest likelihood. We proposed an approach based on biological considerations for the extrapolation of risk to humans. This approach requires estimation of human lung burdens for specific exposure scenarios, which we did by using an extension of a model due to Yu. Our approach acknowledges that the risk associated with exposure to RCF depends on exposure to other lung carcinogens. We present estimates of risk in two populations: (1) a population of nonsmokers and (2) an occupational cohort of steelworkers not exposed to coke oven emissions, a mixed population that includes both smokers and nonsmokers.