Document k62kJajk19GzygMRxvvbg8GOO

J t DR. A. FORNl, UNIVERSITY OF MILAN CLINICA DEL LAVORA Assentation on chromosome damage by chemical agents in humans (Sec attached abstract) r. Forni listed the following chemicals as capable of inducing chromosomal hanges in humans: Ethvleneimine, DMSO, benzene, arsenic, lead, cyclamate, ethylmercury and toluene-benzene. Principally a review of older data. S CO CHROMOSOME DAMAGE BY CHEMICAL AGENTS IN HUMANS Alessandro FORNl * 6seo The assessment of chromosome aberrations in human metaphase cells is one of the methods for detecting a biological effect of chemical agents on the genetic material. Numerous chemicals have been reported to induce chromosome changes in vivo and in vitro in mammalian cells. A short review of these groups of substances will be given, with special emphasis for the chemicals of industrial use. Personal data on chromosome changes observed in workers exposed to aromatic hydrocarbons and to lead will be presented, as examples of the usefulness of chromosomal studies in groups at risk. Some of the mechanisms Dossibly implicated in the production of chromosome alterations will be discussed. Chromosome aberrations are indicative of a gross damage, which may result in cell death after some mitoses. The,'absence of visible chromosome changes, however, does not mean absence of genetic effects. Some recent more r^kied techniques, such as those producing banding> patterns in oBomosomes will probably enable us in future to detect more subtle alterations of the karyotype induced by exogenous agents. ! i | - It < DR. H. ZELLER, BASK PRESENTATION OF THE MUTAGENIC EFFECTS OF CHEMICALS IN THE EVALUATION OF THE TOXICOLOGICAL RISKS (See attached abstract) Dr. Zeller reviewed the tests for mutagenesis his BASF lab is using. This includes the (1) Host-mediated Assay in Mice, (2) Micronucleus Test in Mice, (3) Dominant Lethal Test in Rats, and (4) Cytogenetic Study of Bone Marrow Cells in Various Species. ZUR PROFUNG DER MUTAGENEN WIRKUNG VON CHEMISCHEN STOFFEN IM RAHMEN DER TOXIKOLOGISCHEN RISIKOBEURTEILUNG H. ZELLER R&S 025938 Die Aufgaben der modernen Toxikologie bei der Prufung chemischer Stoffe werden umrissen. Als praktikable Basismethoden fur den Nachweis mutagener Wirkungen im Rahmen der toxikologischen Risikobeurteilung werden der dominante Letaltest, in vivo cytogenetische Methoden, in vitro cytogenetische Methoden und der hostmediated assay** an Hand von Beispielen besprochen. Es wir auf die Dosis/Wirkungsbeziehungen, auf das Zeitoptimum fur den Nachweis der mutagenen Wirkung in den einzelnen Prufsystemen. auf die unterschiedliche Empfindlichkeit der verschiedenen Prufmethoden und auf die Reaktion generativer und somatischer Zellen gegenuber mutagenen Stoffen eingegangen. Empfindlichkeit, praktische Anwendbarkeit und Relevanz der Ergebnisse fur die toxikologische Risikobeurteilung werden diskutiert. . DR. KILLIAN DOW PRESENTATION ON COLIABORATTVE INTERLABORATORY STUDY (See attached sheet) Dr, Killian's presentation was well received by the.group. coT.L//'cr y,,r~ --yT-v to :ihtdrlaboratory variations nrin sco;:t-:n c::-o:-:osomk ad erratic.ms irnusTRiAL chemicals d. y# kilia: - ..:-m ;Kx expert cytogenetic laboratories from the academic, i.ndustry, and government arcas joined in a collaborative study to measure intcrlcboratory variation in cytogenetic analysis# A preliminary v;orkshop v/ac held to resolve scoring diffe rences and to develop a joint protocol and computer aralv tical techniquueess## ;n sou;;rceo of rattss, Triethylene Melamine (TEM) lcve.1-1 was used. .. _ f _ ._ _ __ _T J_ * _ J ^ , .nalysis was acco: sage# " Results were computerised; on a .standard. 80 column IDM unch fF inal card and biostatistically evaluated* '-AAa A> by^pAAAbAapAv^^ '-A. a,;-1 results revealed an excellent cor-rclation between interlaboratory scoring and also dose relationship# ,, ; - ''S;g I: DR. PEH, BASF PRESENTATION ON STUDY OF MUTAGENIC EFFECTS OF ETHYLENEIMINE (See attached abstract) Dr. Peh described the BASF mutagenic studies of El animals. Data were indicative El was mutagenic under some test conditions. "- PROFUMG VCM ^TMYLT.'C'aM AUF MUTAGENE WIRKUNG UNTER VERV/ENDUNG VERSCHIEDENER IN - VIVO - TESTMETHODEN JUTTA PEH Athylenimin (Al) v/urde auf mutagene Wirkung im deminanten Letaltest, Mikronukleus-Test und bone-marrow-Test cepruft. Das Mutagen 2,3.5-Trisathylenimino-benzochinon-(1,4) (Trenimon;\ Handelsprodukt der Fa. Bayer. Leverkusen) wards als positive KontrcHsubstanz in gleicher VVeise untersuchL A!s Versuchstiere dienten NMRl'-Mause und Sprague-Dawley-RaUen. Der dominante Letaltest wurde durchgcfuhrt nach ROHRBORN und VOGEL (1967) bzw. den Err.pfohfungen der WHO (1971). der Mikronukleus-Test nach BOLLER und SCHMID (1970) und der bone-marrow-Test nach Report of the Ad Hoc Research- (1972). Die Dosis fur Al betrug im dominanten Letaltest bei einmsliger intraperitonealer Gabe 1.6 pl/kg Korpergewicht, im Mikronukleus-Test und bone-marrow-Test bei einmaliger Oder 5maliger intraperitonealer Applikation 1.16 und 2,9 ul/kg Korpergewicht. Die Dosis fur Trenimon betrug im deminanten Letaltest 0.125 mg. im Mikronukleus-Test und bone-marrow-Test bei einmaliger intraperitonealer Gabe 0.05 mg bzw. 0,125 mg/kg und bei 5rhaligeri;intrapericonealer Gabe 0,025 bzw. 0,05 mg/kg Korpergewicht. Wahrend Trenimon in alien Testsystemen eine mutagene, Wirkung zeigte, wurden nach Gabe won ; Athyienimin keine sicheren Hinwelse ^ fiir eine mutagene Wirkung gefunden. Versuchsdurchfuhrung und Ergebnisse werden dargestellt und diskutiert. : 1 ;,. . yy- ' . ,, 7 'y 7 . ` y "7 r>i: R&S 025940 DR. KILBEY, EDINBURGH UNIVERSITY PRESENTATION ON ENVIRONMENTAL MUTAGENIC AGENTS (Sec attached abstract) Dr. Kilbey suggested the use of a "Tier" system of evaluating results of mutagenic tests. Initial tests would be conducted in the Ames bacterial system. Subsequent tests would be conducted with mammalian tissues. Risk/ benefit evaluations would be used in dealing with positive results obtained with the testing of compounds vital for certain uses. ENVIROMENTAL MUTAGENIC AGENTS - B.J. KILBEY Genetic damage is fundamentally different from other types of damage. A brief summary will be given of the classes of genetic damage which probably constitute a hazard to the human population. Although very few data exist from which the incidence of the various types of damage can be estimated for the DOpulation as a whole. It is nevertheless possible to discusse the probable consequences for the human population if there is an increase in the frequency of these different classes of demage. Methods are available fo the assessment of the mutagenic potential of new compounds and some of these will be referred to. However, it is important that they be used in a rational way and that the results obtained can be translated into sensible policies regarding mutagenic agents. These problems will be discussed. (ONO>l R&S 025942 DR. PEH, BASF PRESENTATION ON MUTAGENIC STUDIES OF FORMAMIDE. ACETAMIDE, MONOMETUYLFORMAMIDE, I)IMETHYLFORtlAMIDE AND~DIMETHYLACETTCTniE (See attached abstract) These compounds were negative when tested in the Dominant Lethal Test System. prUfumg von Fcnr.'AT.'iDEN u:;o acetamiden auf mutagene wirkung IM DOMINANTEN L3TAL7GST - J'JTTA PEH Die Saureamide Formamid (F), Acetamid (A), Monomethylformamid (MMF). Monomethylacetamid (MMA), Dimethylformamib (DMF) und Dimethyilacetamid (DMA) warden vergleichend auf mutagene Wirkung im dominanten Letaitest an mannlichen NMRPMausen gepruft. Das Mutagen 2.3,5-Tris-Athyleniminobenzochinon-(1,4) (Trenimon*. Handelsprodukt der Fa. Bayer, Leverkusen) wurde als positive Kontrollsubstanz in gleicher Weise untersucht. Die Durchfuhrung der vergleichenden Prufungen erfolgte nach R0HRBORN und VOGEL (1967) bzw. den Empfehlungen der WHO (1971). Die einmal intraperitoneal applizierten Substanzmengen entsprachen jeweils 1/5 LD5o und betrugen fur F - 364 pi, A - 1700 mg, MMF - 560 pi, MMA - 700 pi, DMF 400 ul und DMA - 680 pi bezogen auf kg Korpergewicht. Trenimon3 wurde in einer Dosis von 0,125 mg/kg Korpergewicht verabreicht. Das injizierte Volumen betrug 100 uI/Tier. Die Auswertung der Untersuchungen erstreckte sich auf den klinischen Verlauf, Konzeptionsrate, durchschnittliche Zahl der Implantate und prozentualen Anteil abgestorbener Implantate (= Mutagenitatsindex). Fur jede der acht Paarungswochen wurden die Parameter Konzeptionsrate, durchschnittliche Zahl/der Impiantate und prozentualer Anteil abgestorbener Implantate mittels Chr-T.est zwischen den einzelnen Versuchsgruppen hinsichtlich ihrer Signifikanz untersucht. Wahrend.Trenimon eine starke mutagene Wirkung besaG, lieBen die gepruften Saureamide keine Anzeichen einer mutaaenen Wirkung in dom verwendeten Testsystem erkennen. / Versuchsdurchfiihrung und Ergebnisse werden dargestellt und diskutiert. 7: ;i "if7 V ; "" '* DR. LEONARD, ITALY PRESENTATION ON CYTOGENETIC HAZARDS OF LEAD AND CADMIUM TO MAN AND CATTLE (See attached abstract) Dr, Leonard reported chromosomal changes in workers exposed to undetermined levels of Lead and Cadmium. No chromosomal changes were detected in cattle grazing on pasture adjacent to a metal refinery. Some cattle had died of heavy metal intoxication previous to this study. CYTOGENETIC HAZARDS OF LEAD AND CADMIUM IN MAMMALS A. LEONARD, GH. DEKNUDT R&S 025943 Clinical observations have been performed on peripheral blood lymphocytes of workers from zinc industry who presented signs of lead poisoning of different degrees as well as on peripheral blood lymphocytes off workers from cadmium industry. Chromatid (gaps, breaks and exchanges) aberrations as well as chromosome aberrations (gaps, fragments, disturbances of spiralisation, rings and dicentrics) were observed in most of the workers. Negative results, however, were obtained on peripheral blood lymphocytes of cows intoxicated by the ingestion of hay /^\ which had been harvested near a plant refining metals. Six animals (on a total J. of 15) died within a few days and the lead content in the cadavers was markedly increased. FurthermoreTchemical analysis performed on soils around the plant showed that the level of many other metals was very high (lead, 2-60 times higher than normal: chronium, dA 80 times; cadmium, * 50 times; cobalt, 7 times: zinc. 50-4C0 times; cooper,:12 times). The amount of arsenic in the grass was 50 to 2C0 times above normal. Nevertheless, no severe chromosome abnormalities were observed in the survivors. The results are discussed in relation with the chromosoma morphology of the two species ' R&S 025944 PRESENTATION ON MUTAGENICITY OF VINYL CHLORIDE (See attached publication and abstract) Atmospheres containing 20% (V/V) Vinyl Chloride were mutagenic to Ames* Salmonella typhimuriurn TA1535. Metabolic activation (via addition of liver microsomes) was required in order to demonstrate mutagenic effects. The positive mutagenic effect seen in TA1535 is interpreted to indicate base substitution in DNA. Tests with strains TA1536, TA1537, and 1538 were negative. Additional studies in the Host-mediated assay (mice exposed to 2% VC for 2i^hrs.) and in the micromonucleus test (mice exposed to up to 10% VC for 1 hr.) have not shown mutagenic effects. THE MUTAGENICITY OF VINYL CLORIDE AFTER METABOLIC ACTIVATION U. RANNUG, A. JOHANSSON, C. RAMEL and C.A. MACHTMEISfER In order to study the mutagenicity of vinyl chloride four different strains of Salmonella typhimuriurn has been used (TA 1535 - TA 1523). These auxotrophic strains revert to histidine independence either due to base-pair substitution (TA 1535) or base-pair addition or deletion (TA 1536 - TA 1538). The bacteria were plated with or without liver cell preparations containing microsomes from rats according to Ames system. vinyl chloride caused point mutations, but only at the presence of liver microsomes. indicating that the mutagenic action of vinyl chloride requires a metabolic activation.. From the data cn the different strains of Salmonella it can be concluded that vinyl chloride causes base-pair substitution in DNA but. no deletions! or insertions of bases.