Abstract
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1.
The results of experiments with graduated doses of alkylating agents, antimetabolites and cytotoxic environmental substances in mammalian test systems so far indicate that mutagenic effects like other toxic reactions are dose dependent.
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2.
In the dominant lethal test system and in in vivo cytogenetic investigations the optimal time of investigation, with regard to the last application, depends on the animal species involved, the type of cell system examined and the substances tested. The mutagenic effect varies according to the sensitivity of the cell system, the cell cycle and the pharmacokinetic behaviour of the substance.
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3.
The current results of comparative experiments with single administration of large or several applications of smaller doses of mutagenic substances do not answer the question, whether long term studies are necessary in mutagenicity testing.
Zusammenfassung
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1.
Die Ergebnisse von Mutagenitätsversuchen in SäugetierTestsystemen, mit abgestuften Dosen von alkylierenden Stoffen, Antimetaboliten und cytotoxischen Stoffen vorgenommen, weisen aus, daß mutagene Effekte in gleicher Weise wie andere toxische Wirkungen dosisabhängig sind.
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2.
Im „dominant lethal test” und bei in vivo cytogenetischen Untersuchungen hängt das Zeitoptimum der Prüfung im Hinblick auf die letzte voraufgehende Applikation von der augewendeten Tierspezies, dem Typ des untersuchten Zellsystems und von der Prüfsubstanz ab. Der mutagene Effekt ändert sich mit der Empfindlichkeit des Zellsystems, dem Zellcyclus und dem pharmakokinetischen Verhalten des Stoffes.
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3.
Die Frage, ob Langzeitstudien in Mutageneseprüfungen erforderlich sind oder nicht, wird durch die vorliegenden Ergebnisse aus vergleichenden Untersuchungen mit einmaliger Administration sehr hoher oder wiederholter Applikation kleinerer Dosen mutagener Stoffe nicht beantwortet.
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References
Adler, I. D.: (1) Cytogenetic effect of mitomycin C on mouse spermatogonia. Mutation Res. 21, 20–21 (1973)
Adler, I. D.: (2) Cytogenetic analysis of meiotic chromosomes of male mice after treatment with mitomycin C. Third. Ann. Meeting of the Environmental Mutagen Society, European Branch (EEMS) Uppsala June 4–7, 1973
Bauchinger, M., Sohmid, E., Schmidt, D.: Chromosomenanalyse bei Verkehrspolizisten mit erhöhter Bleilast. Mutation Res. 16, 407–412 (1972)
Cole, J. F., Lynam, D. R.: ILZRO's research to define lead's impact on man. International Symposium: Environmental health aspects of lead. Amsterdam October 2–6, 1972
Datta, P. K., Schleiermacher, E.: The effects of cytoxan on the chromosomes of mouse bone marrow. Mutation Res. 8, 623–628 (1969)
Ehling, U. H., Cumming, R. B., Malling, H. V.: Induction of dominant lethal muta tions by alkylating agents in male mice. Mutation Res. 5, 417–428 (1968).
Ehling, U. H.: Comparison of radiation and chemically-induced dominant lethal mutations in male mice. Mutation Res. 11, 35–44 (1971)
Ehling, U. H., Neuhäuser, A.: Induction of specific locus mutations by tumor in hibitors in male mice. In: The laboratory animal in drug testing (Spiegel, A., Ed.). Stuttgart: Fischer 1973
Epstein, S. S., Shafner, H.: Chemical mutagens in the human environment. Nature (Lond.) 219, 385–387 (1968)
Epstein, S. S., Arnold, E., Steinberg, K., Mackingtosh, D., Shafner, H., Bishop, Y.: (1) Mutagenic and antifertility effects of TEPA and METEPA in mice. Toxicol. appl. Pharmacol. 17, 23–40 (1970)
Epstein, S. S., Bass, W., Arnold, E., Bishop, Y.: (2) Mutagenicity of bimethylphosphate in mice. Science 168, 584–586 (1970)
Epstein, S. S., Arnold, E., Andrea, J., Bass, W., Bishop, Y.: Detection of chemical mutagens by the dominant lethal assay in the mouse. Toxicol. appl. Pharmacol. 23, 288–325 (1972)
Fritz, H., Müller, D., Hess, R.: Embryolethality in the mouse following treatment of males with cyclophosphamide at specific germ cell stages. Agents and Ac tions 3/1, 35–37 (1973)
Frohberg, H.: The evaluation of mutagenicity tests within the scope of toxicological trials. Arch. Toxikol. 28, 135–148 (1971)
Frohberg, H., Bauer, A.: Mutagenicity trials under toxicological aspects. Arznei mittel-Forsch. 23, 230–236 (1973)
Generoso, W. M., Russel, W. L., Huff, S. W., Stout, S. K.: Effect of dose on the in duction of chromosome aberrations with ethyl methanesulfonate (EMS) in male mice. Mutation Res. 21, 32–33 (1973)
Goldwater, L. J., Hoover, A. W.: An international study of “normal” levels of lead in blood and urine. Arch. environm. Hlth 15, 60–63 (1967)
Kato, R., Braze, M., Tegner, Y.: Chromosome breakage induced in vivo by a car cinogenic hydrocarbon in bone marrow cells of the Chinese hamster. Hereditas (Lund) 61, 1–8 (1969)
Kennedy, G. L., Arnold, D. W.: Absence of mutagenic effects after treatment of mice with lead compounds. EMS Newsletter 5, 37 (1971)
Kissling, M., Speck, B.: Chromosome aberrations in experimental benzene intoxication. Helv. med. Acta 36, 59–66 (1971)
Krogh Jensen, M., Philip, P.: The cytogenetic effect of rubidomycin in vivo in rats. Mutation Res. 12, 91–96 (1971)
Lehnert, G., Mastall, H., Szadkowski, D., Schaller, K. H.: Berufliche Bleibelastung durch Autoabgase in Großstadtstraßen. Dtsch. med. Wschr. 20, 1097–1099 (1970)
Leonard, A., Linden, G., Gerber, G. B.: Etude, chez la souris, des effets génétiques et cytogénétiques d'une contamination par le plomb. Intern. Symp. “Environ mental health aspects of lead”, Amsterdam, October 2–6, 1972
Matter, B., Schmid, W.: Trenimon induced chromosomal damage in bone marrow cells of six mammalian species. Mutation Res. 12, 417–425 (1971)
Matter, B. F., Generoso, W. M.: Dose-response studies on the induction of dominant lethal mutations in postspermatogonial stages of the mouse treated with trie thylenemelamine (TEM). Mutation Res. 21, 41–42 (1973)
Muro, L. A., Goyer, R. A.: Chromosome damage in experimental lead poisoning. Arch. Path. 87, 660–663 (1969)
Philip, P., Jensen, M. K.: Benzene induced chromosome abnormalities in rat bone marrow cells. Acta path. microbiol. scand., Sect. A 78, 489 (1970)
Röhrborn, G.: Die mutagene Wirkung von Trenimon bei der männlichen Maus. Hum. Genet. 1, 576–578 (1965)
Rozmiarek, H., Capizzi, R. L., Papirmeister, B., Fuhrman, W. H., Smith, W. J.: Mutagenic activity in somatic and germ cells following chronic inhalation of sulfur mustard. Mutation Res. 21, 13–14 (1973)
Schmid, E., Bauchinger, M., Pietruck, S., Hall, G.: Die cytogenetische Wirkung von Blei in menschlichen peripheren Lymphocyten in vitro und in vivo. Mutation Res. 16, 401–406 (1972)
Schmid, W., Arakaki, D. T., Breslau, N. A., Culbertson, J. C.: Chemical muta genesis. The Chinese hamster bone marrow as an in vivo test system. I. Cyto genetic results on basic aspects of the methodology, obtained with alkylating agents. Hum. Genet. 11, 103–118 (1971)
Schwanitz, G., Lehnert, G., Gebhardt, E.: Chromosomenschäden bei beruflicher Bleibelastung. Dtsch. med. Wschr. 95, 1636–1641, 1646–1647 (1970)
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Based on a lecture held on the “14. Frühjahrstagung der Deutschen Pharmakologischen Gesellschaft” in Mainz, Germany, March 18–21, 1973.
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Frohberg, H., Schencking, M.S. Recent findings concerning dose response relationship in mutagenicity testing of chemicals. Arch. Toxicol. 32, 1–17 (1974). https://doi.org/10.1007/BF00334607
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DOI: https://doi.org/10.1007/BF00334607
Key words
- In vivo Cytogenetics
- Mouse, Chinese Hamster, Rat
- Dose Response Relationship
- Time Factor
- Single and Repeated Administration
- Alkylating Agents
- Antimetabolites