Experience From a Long-Term Carcinogenicity Study With Intraperitoneal Injection of Biosoluble Synthetic Mineral Fibers

Abstract

The carcinogenic potential in the intraperitoneal cavity of three newly developed biosoluble insulation glass wool fibers (M, P, and V) and one newly developed biosoluble insulation stone wool fiber (O) was investigated and compared to that of a previously developed soluble glass fiber (B). The in vitro dissolution coefficient of the three glass wool fibers ranged from 450 to 1037 ng/cm(2) x h and was 523 ng/cm(2) x h for the stone wool fiber. The in vitro dissolution coefficient of the B fiber was 580 ng/cm(2) x h. Groups of female Wistar rats (strain Crl: Wi BR) were exposed by repeated injections to doses of 0.5, 2, and 5 x 10(9) WHO fibers, which corresponds to between 41 mg to 724 mg fiber injected. In addition, 2 groups of crocidolite were used as positive controls at doses of 0.1 x 10(9) and 1 x 10(9) WHO fibers (0.5 and 5 mg). The in vitro dissolution coefficient of crocidolite is estimated to be approximately 1 ng/cm(2) x h. The protocol of the study and the size distribution of the test samples conformed to the European Commission Protocol EUR 18748 EN, and the study was executed under Good Laboratory Practice conditions. Two of the new insulation wools, fibers M and 0, showed no statistically significant tumorigenic response even at the very high dose of 5 x 10(9) WHO fibers injected. Fibers P and V showed a small tumorigenic response in the ip cavity similar in magnitude to the B fiber, which has been declared in the German fiber regulations as a noncarcinogenic fiber. The response to the soluble insulation fibers was notably different from that of the known carcinogen crocidolite, which produced 53% tumors at a comparatively low dose of 0.1 x 10(9) WHO fibers. The incidence of mesothelioma was found to be highly correlated to the incidence of intra-abdominal nodules and masses at different sites. The incidence of abdominal nodules and masses was highly correlated to the number of animals with ascites. The incidence of chronic peritonitis with fibrotic nodules at different organs also correlated with the incidence of mesotheliomas. Differences in etiology were observed between the massive doses of the highly soluble insulation wools when injected directly into the ip cavity and the lower doses of the extremely insoluble fiber crocidolite. The variability in this reaction and the impairment of animal health put into question the value of these massive doses in evaluating the carcinogenic response of soluble insulation wools. All of the fibers tested fulfilled the exoneration criteria with respect to carcinogenicity according to the European Directive 97/69/EC ("an appropriate intra-peritoneal test has not expressed signs of excessive carcinogenicity"). The dose as defined in the EC-Protocol EUR 18748 EN was 1 x 10(9) WHO fibers with a defined geometric spectrum. The influence of fiber dimensions on the ip tumor response and the difficulty in assessing the influence of the difference in background levels between this and previous studies make direct application of the German TRGS 905 criteria difficult;...

A comparison of the results from intra-pleural and intra-peritoneal studies with those from inhalation and intratracheal tests for the assessment of pulmonary responses to inhalable dusts and fibres

“…This view has been reflected in reviews conducted by various national and international agencies, including ILSI (2005) andthe National Research Council (2000). Although inhalation testing can be expensive, time consuming and lack specificity in dose (Bernstein, 2007;Grimm et al, 2002) ability to inject/implant large fibres and particles that would not normally be inhaled into the deep lung; very high numbers/concentrations of test material at the injection site that may overwhelm defence mechanisms; targeted tissues (e.g. peritoneal mesothelium) are not the same as for inhalation exposure.…”

“…In the following sections, published toxicity data for a number of fibres and dusts obtained from inhalation (and, for some materials, intratracheal instillation) studies are compared with toxicity data for the same test materials delivered by the intraperitoneal and/or intrapleural routes. The chemical compositions of the fibres discussed in this report are detailed in Table 2 below (Bellmann et al, 1987;Bernstein, 2007;Grimm et al, 2002;Guldberg et al, 2002;Hesterberg et al, 1998;Kamstrup et al, 2001;Kamstrup et al, 2002;Kamstrup et al, 2004;Lambré et al, 1998;Roller et al, 1996;Searl et al, 1999). While full characterisation of the delivered aerosol -especially fibre/particle size distribution -is extremely important, this information is not consistently available; this is acknowledged as a possible limitation when comparing test results.…”

“…A higher tumour incidence rate was seen at the higher level of exposure of 2 mg crocidolite (87.5%) using the intraperitoneal model. Grimm et al (2002) used crocidolite at 2 different doses (0.5mg and 5mg) as a positive control in a study of biosoluble insulation glass wool fibres, injected once into the intraperitoneal cavity of female Wistar rats (strain CrL: WiBR). Pathology was carried out to determine presence of the following: mesothelioma with simultaneous abdominal tumours; other abdominal tumours with serosal spread (but no mesothelioma); and abdominal tumours with neither serosal spread nor mesothelioma.…”

“…Survival numbers were significantly reduced in the high dose crocidolite group, leading to the validity of use of the high dose being questioned. Importantly, the authors concluded that there may be different aetiologies for the production of mesothelioma by soluble and insoluble fibres following intraperitoneal injection (Grimm et al, 2002).…”