A dose-response model for refractory ceramic fibers.

Refractory ceramic fibers (RCFs) are man-made vitreous fibers commonly used in insulation applications above 1000 degrees C. Although they have been subjected to considerable toxicologic evaluation, only the pooled results from two rat inhalation studies provide data that may be suitable for performing a numerical risk assessment. Even in these inhalation studies, good evidence exists that the maximum tolerated dose (MTD) was exceeded and that pulmonary overload occurred, a condition that will cause tumors whatever the dust responsible. Indeed, a significant yield of tumors was only obtained at the highest dose tested. If these results are omitted, there is no statistically significant evidence of carcinogenicity within the RCF results. Although there is little evidence that overload-related tumors are relevant to human risk, we adopted a conservative approach to obtain the estimates of risk regardless of overload, using a biologically based model, the two-stage clonal expansion model, as well as various statistical models, including the benchmark dose model. We argue that the data favor the use of a biologically based model, which gives the best fit when the highest dose RCF exposures are omitted. Continuing with this model, we show that available data from the RCF experiment, less outliers, coupled with results from other experiments with man-made mineral fibers (MMVFs), demonstrate that all MMVFs are potentially carcinogenic, with any risk mediated by the fibers' biopersistence. Application of this "all MMVF data set" model yields a maximum likely estimate for RCF excess unit risk of 4.6 x 10(-5) (95% upper confidence limit = 9.2 x 10(-5) per fiber/ml). This implies that the risk from occupational exposure to RCFs at 1 fiber/ml for a typical working lifetime would not exceed 10(-4).

An exploratory study of variations in exposure to environmental tobacco smoke in the United States.

There is considerable interest in assessing exposure to environmental tobacco smoke (ETS) and in understanding the factors that affect exposure at various venues. The impact of these complex factors can be researched only if monitoring studies are carefully designed. Prior work by Jenkins et al. gathered personal monitor and diary data from 1,564 nonsmokers in 16 metropolitan areas of the United States and compared workplace exposures to ETS with exposures away from work. In this study, these data were probed further to examine (1) the correspondence between work and away-from-work exposure concentrations of ETS; (2) the variability in exposure concentration levels across cities; and (3) the association of ETS exposure concentrations with select socioeconomic, occupation, and lifestyle variables. The results indicate (1) at the population level, there was a positive association between ETS concentrations at the work and away-from-work environments; (2) exposure concentration levels across the 16 cities under consideration were highly variable; and (3) exposure concentration levels were significantly associated with occupation, education, household income, age, and dietary factors. Workplace smoking restrictions were associated with low ETS concentration levels at work as well as away from work. Generally, the same cities that exhibited either lower or higher away-from-work exposure concentration levels also showed lower or higher work exposure concentration levels. The observations suggest that similar avoidance characteristics as well as socioeconomic and other lifestyle factors that affect exposure to ETS may have been in operation in both away-from-work and work settings.

Biopersistence, fiber length, and cancer risk assessment for inhaled fibers.

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.

The power of the European Union protocol to test for carcinogenicity of inhaled fibers.

We evaluate the power of a recent protocol proposed by the European Union (EU) for testing the carcinogenicity of inhaled fibers. We assume that every fiber has oncogenic potential determined by its biopersistence. We use a recently estimated potency for the oncogenic potential of fibers together with experimentally determined "weighted" half-lives (WHL) of a dozen fibers to generate simulations of long-term bioassays conducted according to the EU protocol. We analyze these experiments using standard statistical techniques and determine the number of tests that would have yielded significant results. We conclude that the EU protocol will readily detect the carcinogenic effect of long-lived fibers, such as amosite with a WHL of more than 450 days, and usually detect the effect of fibers, such as RCF1a, with WHL of about 40-50 days. However, the EU protocol has very low power to detect effects of short-lived fibers, such as X607, with WHL of about 10 days.

Long man-made fibers and lung cancer risk.

We show that available experimental data from long-term oncogenicity experiments in Fisher rats are consistent with the hypothesis that the oncogenic potential of long man-made mineral fibers is determined mainly by their biopersistence. We present analyses of these data within the initiation-promotion-progression paradigm of carcinogenesis. Our method of analysis can take the temporal pattern of the burden of long fibers in the lungs of individual animals into explicit account. For this analysis, the temporal pattern of lung burden for each animal was imputed from the information obtained from sacrificed animals. The data are consistent with the hypothesis that fibers act as initiators in the rat lung. We present an estimate of the dose-dependent initiation parameter that is based on all the available data.

Lung cancer risk associated with exposure to man-made fibers.

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.

Quantitative assessment of the risk of lung cancer associated with occupational exposure to refractory ceramic 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.