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Pathogenetische und immunbiologische Untersuchungen zur Frage: Ist die Extrapolation der Staubkanzerogenität von der Ratte auf den Menschen gerechtfertigt? Teil II: Histologie

Abschlussbericht
 
: Ernst, H.; Kolling, A.; Bellmann, B.; Rittinghausen, S.; Heinrich, U.; Pott, F.
: Umweltbundesamt -UBA-, Berlin

:
Fulltext (PDF; )

Hannover, 2005, 75 pp.
UBA-FB, 20361215
Reportnr.: UBA-FB-000903
German
Report, Electronic Publication
Fraunhofer ITEM ()
Amorphous SiO2; Poly-2-vinylpyridine-N-oxide; PVNO; dust; lung; rat; quartz; carbon black; histology; pathological

Abstract
Fragestellungen eines Kanzerogenitätsversuchs mit intratracheal instillierten Stäuben an Wistar-Ratten:
1. Erzeugt nicht bio-beständiges amorphes SiO2 bei chronischer Entzündung durch viele kleine Dosen Tumoren? - 2. Wirkt Ruß-UF (mittl. D. 0.014 µm, BET-Oberfl. ~300m²/g) in der Nähe des Staubvolumengrenzwerts ( 1 µL/g Kontrolllunge; Kontrolllunge 1,3 g) kanzerogen (geschätzte Lungendosis 1,8 µL, Oberfl. 1 m²)? - 3. Ist eine nie
Ergebnisse liegen von 17 Ratten jeder Gruppe vor (Kontrolle: 22), die länger als 2 Jahre im Versuch waren:
1. Amorphes SiO2: 2 Tumortiere mit RH, 6 mit IH plus 7 mit Präneoplasien; Entzündungsgrad nach 9 Mon. wie Ruß-UF; PMN höher und Fibrose stärker als beim Ruß, dennoch durch Ruß mehr Tumoren. (Kontr. kein Tumor, 1 Präneoplasie) - 2. Ruß-UF: 6 Tumortiere mit RH. Vergleich RH mit IH bei 7 Ratten: Verhältnis der Tumortiere 1 zu 3, der Tumoranzahl 4 zu 10. - 3. Kohlenstaub: Kein Tumor mit IH, 3 Präneoplasien. Dosisvergleich Kohle zu Ruß: Vol. 2,7 zu 1, Oberfl. 1 zu 37; Durchm.verhältnis 1 zu 286. - 4. Mäßige Reduktion der Kanzerogenität durch PVNO; PVNO-Hemmeffekte nach wie vor durch Adsorption an Quarzoberfläche erklärbar. - 5. Im Bereich der Nachweisgrenze einer Kanzerogenität kann die IH entscheidend höhere Tumorhäufigkeiten bringen.

 

The carcinogenicity experiment with rats, as the last part of a series of investigations, was to provide information on dust carcinogenicity. Quartz and ultrafine amorphous SiO2 as specifically toxic dusts were selected for this experiment, and in addition two granular dusts without known specific toxicity, but with marked differences in particle size and specific surface: ultrafine industrial carbon black (mean size 0.014 µm, BET surface approx. 300 m²/g) and non-quartz-containing coal dust (mean size 4 µm, BET surface 4.1 m²/g). In addition, one quartz group was treated with the silicosis inhibitor poly-2-vinylpyridine-N-oxide (PVNO), so as to verify whether PVNO also does not inhibit quartz-induced carcinogenesis at low quartz doses, as previously observed with high quartz doses.
The dusts, suspended in NaCl solution, were instilled to the trachea of Wistar rats at relatively low doses: 3 mg quartz, 15 mg amorphous SiO2 (split between 30 instillations of 0.5 mg each at intervals of 2 weeks because of the short retention time in the lung), 5 mg UF carbon black and 10 mg coal dust (split between 10 instillations at weekly intervals). After 9 months, 10 animals of each group were killed and examined for cells in the bronchoalveolar lavage fluid and for pulmonary lesions. All other animals lived for their normal lifetime until termination of the experiment in month 29 after the experimental start date.
Out of the animals that had reached an old age, only 17 from each group could be examined, and investigations were performed at different levels of intensity. In three groups (amorphous SiO2, coal dust, control), 60 sections per lung, instead of the routine 6 sections, were investigated for tumors and preneoplastic lesions, aiming to detect all tumor-bearing animals in particular in the group treated with amorphous SiO2, which so far had produced "negative“ results. The results obtained are in line with the expected differences between intensive (60 sections investigated, 6 animals with lung tumors, 7 with preneoplastic lesions) and routine histological analyses (only every 10th section analyzed, 2 animals with lung tumors, no preneoplastic lesions). The non-significant carcinogenicity indicated by the routine investigation, however, is in contrast to the findings of inflammation and fibrosis, which were found at degrees roughly corresponding to those in the two groups treated with quartz and PVNO and with carbon black, where carcinogenicity (47 % and 35 %, respectively) was also clearly in the positive range. The number of neutrophil granulocytes (PMN) in lung lavage fluid was even 66 % higher with amorphous SiO2 than in the group treated with quartz but not with PVNO. The question thus arises as to whether there is an additional factor contributing to tumor induction in the case of dusts that persist in the lung. This factor could e.g. lie in a different type of inflammation. Several authors have concluded from their findings that the epithelial cells absorb particles, leading to a direct toxic effect which may also occur without inflammation or in parallel with it. The new results do not support the hypothesis that chronic inflammation of any origin acts to the lung as a carcinogenic agent whose potency could be quantified with the presently common diagnostic methods.
PVNO, in principle, inhibited quartz carcinogenicity, but quantitatively the effect was only moderate. There is a difference here compared to previous investigations, in which the inhibitory effect of PVNO on the cytotoxic and fibrogenic actions of quartz had been stronger, resulting in a reduction even to the effect of "inert dust".
Ultrafine carbon black produced tumors in 35 % of the 17 animals examined with the routine diagnostic methods, and this result was obtained with a lung dust dose that was only about 1.5 times the volume limit value for fine dust defined by the MAK commission. Coal dust, whose calculated mean particle size is larger by a factor of almost 300, induced no tumors at the low dosage in the 17 animals examined. This non-positive finding though cannot be interpreted in the sense of a tolerable cancer risk of less than 1 : 1.000 if the MAK value is complied with, because an approx. 7-fold dose proved to be strongly carcinogenic in a previous experiment with a tumor incidence of 57 % and the confidence interval is large with so small a number of animals.

: http://publica.fraunhofer.de/documents/N-48711.html