Short, thin asbestos fibers contribute to the development of human malignant mesothelioma: pathological evidence

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Abstract

Based on animal studies, long and thin asbestos fibers (⩾8 μm in length and ⩽0.25 μm in width) have been postulated to be strongly carcinogenic inducing pleural malignant mesothelioma, while shorter, thicker fibers have been postulated to pose a lesser risk (Stanton hypothesis). The objective of this study is to test the validity of the Stanton hypothesis through direct pathologic analysis of human mesothelioma tissue. Digested bulk tissue samples, or ashed 25 μm thick sections, or both, were prepared from lung and mesothelial tissues taken from 168 cases of human malignant mesothelioma. In these tissues, 10,575 asbestos fibers (4820 in the lung and 5755 in mesothelial tissues (1259 in fibrotic serosa and 4496 in mesotheliomatous tissue)) were identified by high-resolution analytical electron microscopy. Dimensions of these asbestos fibers were measured in printed electron micrographs. Results were as follows: (1) long, thin asbestos fibers c onsistent with the Stanton hypothesis comprised only 2.3% of total fibers (247/10,575) in these tissues; (2) the majority (89.4%) of the fibers in the tissues examined were shorter than or equal to 5 μm in length (9454 of 10,575), and generally (92.7%) smaller than or equal to 0.25 μm in width (9808 of 10,575). (3) Among asbestos types detected in the lung and mesothelial tissues, chrysotile was the most common asbestos type to be categorized as short, thin asbestos fibers. (4) Compared with digestion technique of the bulk tissue, ashing technique of the tissue section was more effective to detect short, thin fibers. We conclude that contrary to the Stanton hypothesis, short, thin, asbestos fibers appear to contribute to the causation of human malignant mesothelioma. Such fibers were the predominant fiber type detected in lung and mesothelial tissues from human mesothelioma patients. These findings suggest that it is not prudent to take the position that short asbestos fibers convey little risk of disease.

Introduction

Stanton et al. (1981) concluded from experimental data using rats that long (greater than and equal to 8 μm in length) and thin (less than and equal to 0.25 μm in width) asbestos fibers were strongly carcinogenic in the experimental induction of malignant mesothelioma and that shorter and thicker fibers posed less risk (Stanton's hypothesis). In their study, Stanton et al. used three subtypes of amphibole fibers: crocidolite, tremolite and amosite. Chrysotile fibers were excluded, although Stanton and Wrench (1972) had previously observed a high incidence of mesothelioma in rats exposed to chrysotile fibers. Stanton and Wrench (1972) stated that direct application of their results to the problem of human carcinogenesis would be unwise. Nevertheless, Stanton's model has been directly applied to the counting of the asbestos fibers in man, and certain scientists have claimed that short, thin asbestos fibers pose little or no risk to human health (McDonald et al., 1989; ASTDR Report, 2003).

Additionally, the US Occupational Safety and Health Administration (OSHA) has accepted the argument that short, thin asbestos fibers pose little risk. Accordingly, the current OSHA methodology for evaluating airborne fibrous dusts in an industrial atmosphere uses light microscopy (phase microscopy) and counts only those asbestos fibers that are longer than 5 μm with an aspect ration larger than 3 to 1. This methodology considers that fibers shorter than 5 μm may not be carcinogenic.

Our previous studies have revealed that a disparity is frequently present in both the type and number of asbestos fibers between the lung and mesothelial tissues. We have hypothesized that such a disparity might be caused by chrysotile fiber's strong capacity to translocate from the lung into the pleura and peritoneum (Kohyama and Suzuki, 1991; Suzuki and Yuen, 2001, Suzuki and Yuen, 2002). We have also suggested that short, thin asbestos fibers can contribute to the causation of human malignant mesothelioma, since these fibers were the principal type of asbestos fibers encountered in the mesothelial tissues from the mesothelioma patients (Suzuki and Yuen, 2001, Suzuki and Yuen, 2002). This suggestion was based on our preliminary study of the dimensions of 10,575 asbestos fibers detected in both the lung and mesothelial tissues from168 cases of human malignant mesothelioma (Suzuki and Yuen, 2002).

To further validate our above claim, we have performed additional analyses of these 10,575 asbestos fibers. Type, dimension (length and width) and numerical proportion in two tissue sites including lung and mesothelial tissues were clarified in each of these fibers. Furthermore, we have compared the detection sensitivity of short, thin asbestos fibers between two distinct techniques, the digestion technique of bulk tissue samples and the ashing technique of tissue section samples.

As results, we concluded that as previously suggested, short, thin asbestos fibers appeared to contribute to the causation of human malignant mesothelioma since they were the majority seen in the two tissues and that the ashing technique of tissue sections was more effective to demonstrate such submicroscopic fibers.

Section snippets

Materials and methods

Lung and mesothelial tissues (fibroplastic pleural and peritoneal, pleural hyaline plaque and pleural and/or peritoneal mesotheliomatous tissue) from 168 cases of human malignant mesothelioma (164 males and 4 females; 156 pleural and 12 peritoneal; definite or probable diagnostic certainty) were used. These tissues were of autopsy or biopsy samples that had been sent to the principal author for pathological review over a 15-year period and subsequently archived at the Mount Sinai School of

Results

Dimensions of asbestos fibers detected in lung and mesothelial tissues are shown in Table 1A. Maximum length and width was found in amosite fibers, although minimum length and width were seen in chrysotile. Chrysotile fibers were generally shorter and thinner (Table 1B). Other amphibole fibers, such as crocidolite, tremolite and anthophyllite were smaller in number in these tissues, but also longer and thicker, compared with the dimensions of the chrysotile fibers (Table 1B).

Discussion

Since it has been reported that asbestos fibers, particularly short thin chrysotile fibers can be found in water, food and indoor air pollution, as well as in paraffin (Chesson et al., 1990; Melino et al., 1991; Addison et al., 1993; Lee et al., 1995; Kashansky and Slyshkina, 2002) we have examined control samples which proved to be free from asbestos fibers including short, thin chrysotile fibers.

Therefore, we conclude that the short, thin chrysotile fibers detected in the lung and mesothelial

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