Particulate-state carcinogenesis: a survey of recent studies on the mechanisms of action of fibres.

Animal experiments using, in addition to asbestos, erionite and manmade mineral fibres, have confirmed that fibre dimension is an important factor in the carcinogenic potency of fibres. However, it seems to be established that it is not the only parameter of importance and that fibre type and physicochemistry play a role. In vitro experiments have provided new information on the relationship between fibre size and effect: long, thin fibres are more effective in inducing the transformation of certain cell types and in producing injury arising from oxygen species. Different in vitro experiments have tested chromosomal and genetic damage induced by fibres, especially asbestos. Depending on the cell type, chromosomal damage and aneuploidy have been observed and interactions with the genomic material have been demonstrated. Some conflicting data in this area might be explained by differences in cell type used or in methods used to prepare the asbestos samples. At present, a working hypothesis for the mechanisms of carcinogenesis induced by fibres can be suggested. Mineral or synthetic fibres deposited in the lung are first processed by macrophages, which eliminate short fibres. The remaining fibres may be ingested by cells that are potentially transformable, the longest fibres possibly being phagocytosed preferentially. Ingested fibres may produce DNA damage in both resting and dividing cells, either by the direct production of oxygen radicals, by the formation of clastogenic factor or by direct chromosome interaction in cells in mitosis. A missegregation of chromosomes can result from interactions between fibres and the mitotic spindle. Even if these processes take place slowly, they can occur over a long period of time due to the persistence of the fibres in the tissue. The carcinogenic potency of a fibre, therefore, will be dependent on its durability, its dimensions and its physicochemical properties. Asbestos fibres appear to be pluripotent in inducing chromosome abnormalities as well as some responses shared with compounds such as promoters. Thus, these fibres can be considered as potent complete carcinogens. The potency of a given fibre in a specific target tissue will be the sum of both its initiating and its promoting effects. It seems that new concepts must be formulated to account for the mechanisms of action of fibres. 'Particulate state' carcinogenesis includes the possibility of multiple hits occurring during the time that the particles remain within the target tissue and will therefore be time-dependent.