Biopersistence of synthetic mineral fibers as a predictor of chronic inhalation toxicity in rats.

In December 1997 the European Commission (EC) adopted Directive 97/69/EC (O.J. L 343/19 of 13 December 1997) in which criteria were established for the classification and labeling of synthetic mineral fibers. This directive was derived based upon an extensive program evaluating current scientific knowledge on fiber pathogenicity and its relationship to the biopersistence of long fibers. Within this context, the biopersistence of fibers longer than 20 microm was found to be a good predictor of the lung burden and early pathological changes in chronic inhalation studies with fibers as well as of the tumor response in chronic intraperitoneal studies with fibers. The analysis that provided the scientific basis for the relationship of biopersistence to the chronic inhalation results is presented in detail. Proportional odds regression techniques were used to determine the relationship between both inhalation and intratracheal instillation biopersistence clearance half-times and the collagen deposition at the broncho-alveolar junction as determined following 24 mo in chronic inhalation toxicity studies. The results indicate all the indicators of biopersistence considered are equally good predictors of the early long-term change that occurs in the lung in response to more durable fibers. This change, the collagen deposition at the broncho-alveolar junction, is a precursor of interstitial fibrosis, which has been shown to be associated with tumor response in fiber-exposed animals. The results show that the clearance half-times set in the EC directive are within the baseline for this parameter.

Biopersistence of synthetic mineral fibers as a predictor of chronic intraperitoneal injection tumor response in rats.

In December 1997 the European Commission (EC) adopted Directive 97/69/EC (O.J. L 343/19 of 13 December 1997), in which criteria were established for the classification and labeling of synthetic mineral fibers. This directive was derived based upon an extensive program evaluating current scientific knowledge on fiber pathogenicity and its relationship to the biopersistence of long fibers. Within this context, the biopersistence of fibers longer than 20 microm was found to be a good predictor of the lung burden and early pathological changes in chronic inhalation studies with fibers as well as of the tumor response in chronic intraperitoneal studies with fibers. The analysis that provided the scientific basis for the relationship of biopersistence to the chronic intraperitoneal (ip) results is presented in detail. Analysis of the relationship of biopersistence clearance half-times to ip tumor response shows a statistically significant relationship of ip tumor response to not only the number of fibers injected, but also the median length of the fibers injected and their solubility (clearance half-time). The results show that the biopersistence half-times as determined by intratracheal instillation (T(1/2) of WHO fibers or weighted T(1/2) of fibers with L > 20 microm) and as determined by inhalation (weighted T(1/2) of fibers with L > 20 microm) are equivalent predictors of the ip results. From these ip studies, fibers that can be exonerated from classification as carcinogens in Europe have a relative tumorigenic potency in the ip cavity of between 66 and 2500 times less than fibers that have been shown to produce a significant increase in tumors following chronic inhalation exposure. In addition, based upon the ip results, there is no statistical difference between the EC and the other fiber exoneration criteria, such as the German Gefahrstoffverordnung of 1999.