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April 1992 Appearing monthly Vol. 2K1, No. 4 Completing Vol. 2SI MUTATION RESEARCH ISSN 01G3-7992 MUREAV 281(4) 227-301 (1992) International journal on mutagenesis, chromosome breakage and related subjects Editor-in-Chief: F.H. Sobels (Leiden) Managing Editors (Mutation Research Letters): S.M. Galloway, West Point, PA and J.M. Gentile, Holland, MI Board of Managing Editors J. Ashby, Macclesfield', S.M. Galloway, West Point, PA (Mutation Research Letters); J.M. Gentile, Holland, Ml (Mutation Research Letters); B.W. Glickman, Victoria, B.C.\ P.C. Hanawalt, Stanford, CA (DNA Repair); P.H.M. Lohman, Leiden (DNA Repair); K. Sankaranarayanan, Leiden', F.J. de Serrcs, Research Triangle Park, NC\ R.B. Setlow, Upton, NY (DNAging); M.D. Shelby, Research Triangle Park, NO, T. Sugimura, Tokyo (DNAging); H, Takebe, Kyoto (DNA Repair); J. Vijg, Leiden (DNAging); E. Vogel, Leiden-, J.S. Wassom, Oak Ridge, TN JAI Mutation Research Letters 4 ' Elsevier H&ES/Tox. Library APR 2 7 1992 Dow Chemical-1803 Mutation Ki'ii'urf/i. 2K1 (l`M2> 239-243 V 1992 I-Kci.tor Scit-mc I'uhli'.hcrs II.V. All rights reserved 0U>5-?`/92/`)2/S(I5.(kI MUTUiT (KKi.18 Activity of human carcinogens in the Salmonella and rodent bone marrow cytogenetic tests * Armen K. Ncrscssians K/t, I'mwrtijian Centre for Oncoiotfy Research, Yerevan 375052 (U.S.S.li.) (Received 24 July 199L) (Revision received 12 November 1991) (Accepted 14 November 1991) Ktyteords: Inorganic agents; Salmonella test; Rodent bone marrow test; Human carcinogens Recently Shelby and Zeiger (1990) have con* eluded that organic chemicals that arc carcino genic for rodents, active in the Salmonella and rodent bone marrow cytogenetic tests arc highly probably also human carcinogens. ' - The aim of this paper is to add some data to the results presented in two papers by Shelby (1988, 1990) for they did not include some data obtained by Soviet investigators and data ob tained recently. In 1990 two more drugs were added to the list of agents of group 1 - cy closporin (cyclosporin A) and thiotepa (Tomatis and Bartsch, 1990) - and the results of the inves tigations of these agents in the Ames assay and cytogenetic tests are absent in Shelby's papers (1988, 1990). I also add some other human car cinogens - ethanol, ionizing radiation - and one industrial process - aluminum production (Tomatis and Bartsch, 1990). Asbestos is inactive in the classical Ames assay (1ARC, 1987) but Soviet investigators (Frash et * Addition to the paper of M.D. Shelby and E. Zeiger, Mutation Research, 1990,224, 257-261. Correspondence: Dr. A.K. Nersessian, V.A. Fanardjian Cen tre for Oncology Research, 76 Fanardjian Street, Yerevan 52, Armenia 375052 (U.S.S.R.). al., 1990) using the modified Ames assay (hostmediated assay) have shown that chrysolite as bestos 025 mg/kg in saline, 1/5 of LDM) is mutagenic in Salmonella. The hosts were male Wistar rats which were intrapcritoncally treated-, with asbestos. 24 h later the rats were treated intrapcritoncally with Salmonella and animals were killed 6 h after that. The results show that asbestos caused a 27-fold increase in strain TA1534, a 4,2-fold increase in TAI950, but was inactive in strain TA1537 of Salmonella. Various asbestoses 24 h after intraperitoncal injection (500 mg/kg b.w. in saline) caused statistically signifi cant increases in the number of polychromatic erythrocytes with micronuclci (MN) in bone mar row of CBA mice (Vanchougova et al., 1985). Chrysotile asbestos (from Bazenovsk) induced Z63%, chrysotile A 1.0%, chrysotile B 1.04%, krokidolite 1.47%, antophylite 1.38% and amosite 1.13% cells with MN vs, 0.51% in intact controls. Under the same conditions chrysotile asbestos caused a 3.7-fold increase in the number of bone marrow cells with chromosomal aberrations (CA) of C57BI/6 mice but ccolite asbestos caused a 3*fold increase only 28 days after treatment (Doumev et al., 1990). Soviet investigators have considered that the mutagenic and clastogcnic effects of asbestos are due not to direct interac tion of fibers with target cells, but to increased R&S150752 TAULE i MUTAGENICITY IN SALMONELLA AND CLASTOGEN1CITY IN RODENT DONE MARROW AND CARCINOGENIC ITY IN ANIMALS OF IARC GROUP 1 CARCINOGENS Carcinogen Salmonella mu tagenicity Organic compounds, combinations or groups t anatoxins + 2 4-aminobiphenyl + 3 analgesics containing phcnacetin + 4 azathioprinc + 5 benzene - 6 benzidine -f 7 betel quid and tobacco + 8 bis(chloromcthyl)cthcr + 9 chlorambucil + IQ chlornaphaztnc + 11 cyclophosphamide + 12 cyclosporin * - 13 ethanol * 14 mclphalan + 15 MOPP + 16 mustard gas + 17 myleran + 18 2*naphthylaminc + 19 thiotepa * 20 tobacco, smokeless 21 tobacco smoke +' 22 trcosulphan ' 23 vinyl chloride + * Tan and oils 24 coaMar pitches 23 shale oil + +* Rodent bone mjrrow clastogcnicity + + + + + + + + + + + +* + + 4-t- + +* +* Otrcinogcnjcny in animals S s L L s S L S S L S L 1 S ND L L s S l s ND S s s Hormones 26 diethylstilbestrol +s Metals 27 arsenic compounds 28 chromium compounds 29 nickel and nickel compounds + + + +* L s s Fibers 30 asbestos 31 talc coallifting tabes* tiform fibers ^ ^ ' industrial process ' 32 aluminum production * * + +* 4- s 1 .1 ND Other 33 ionizing radiation * + + s Added to the list of Shelby and Zeigcr (1990). +, positive, negative and . inconclusive results in the cfcort-lcrru tests; S. sufficient, L, limited, 1, inadequate evidence of carcinogenicity; ND, no data in long-term experiments using animals. f ,f V" -f rMVreftp-\"i ' Si 9 C-Px CP 1 C3 lipiil peroxidation induced by asbestos. Ionizing radiation (Dubinin, 1 lJS6) and tliiotopa (1ARC 1987) were active in the Ames assay and cytoge netic tests. Tobacco smoke (Balunskv et al., 1988) and sulfur mustard (Ashby ct al., 1 yy 1) induced MN in bone marrow of mice. Ethanol had incon clusive activity in the Ames assay (De Flora et al., I`>84) and it induced a very low level of CA (2.0% vs. 0 in control), polyploidy (7.8% v:' 1% in control) and ancuploidy (36,(>% vs. 15.6% in con trol) m bone marrow cells of male Wist nr rats 24 h after oral administration (300(1 mg/kg b.w., 1/5 of LDS,,) (Barilyak and Kozachouk, 1085). Al best, ethanol should be considered equivocal in the rodent bone marrow test for CA, Crude shaleoil was directly mutagenic in strain TA98 (indi cated al least twice the background level) and elicited a mutagenic response in four Salmonella strains (TAOS, TA100, TA102 and TA104) with exogenous metabolic activation (indicated activity at least 1.5 times the background level) (Bogovski et al., 1990). Shale oil also increased the CA level in bone marrow cells of mice (Maync and Dcavcn, 1982). Cyclosporin is inactive in the Ames assay and cytogenetic tests (IARC, 1990). Extracts of coal tar pitches induced significant increases in. MN in bone marrow of CBA mice 24 It and 48 h after intraperitoncal injection (data were not pre sented in the paper, Frash and Vanchougova. 1987). Nickel dusts (1/2 of LD5,, in saline) statis tically significantly (2-3 times, depending on the nickel contents in the dusts) increased the fre quency of MN in bone marrow of mice 24 h after injection (Kisseliova ct al., 1989) and MN and CA in bone marrow cells of rats (data were not pre sented in the paper, Zhong ct al., 19S9). Emission dusts from aluminum plants were strongly muta genic with exogenous metabolic activation in Salmonella (Pinter ct al., 1990). Soviet investiga tors have shown that wild mice trapped in the region and in the territory of an aluminum plant had increased CA levels in the bone marrow cells (8.2% vs. 1.67% in control, Gileva ct al., 1990). In Table 1 are presented only agents which are investigated in the Ames assay and cytogenetic tests. Among 33 agents only talc containing asbestiform fibers and cyclosporin arc inactive in two tests, and ethanol gives inconclusive results. Consequently, the activity of 33 human carcino :u gens in the buttery ol two sluin-ieim tests (activ ity at least in one lest system) is 90.9-93.6';; (it depends on one ineonelusive result, ethanol). Benzene, cyclosporin, diethylstilhestrol. arsenic compounds, nickel and title containing asbcstifoim fibers are inactive in the Ames assay, as bestos and ethanol give inconclusive results. So. the sensitivity of this assay is 75.8-81,8% (it de pends on two ineonelusive results). In the cytoge netic tests only talc containing asbestiform fibcis and cyclosporin are inactive, bis(chloroinethyl)ether and ethanol give ineonelusive results. So. the sensitivity of cytogenetic tests in identification of 33 human carcinogens is 87.9-93.9%' (it de pends on two inconclusive results). Cytogenetic tests are more sensitive in the identification of carcinogens than the Ames assay at least for this group of agents. It is interesting that some car cinogens inactive in the Ames assay or cytoge netic tests or giving inconclusive results increased the CA level in the lymphocytes of humans ex posed to these agents. Such agents arc benzene, nickel, arsenic compounds, bis(chloromcthyl)cthcr (IARC, 1987), cyclosporin (IARC, 1990), ethanol, (Obc ct al., 1986). asbestos (Ressner ct al., 1990). So I think that if an agent is inactive in the Ames assay or cytogenetic tests in rodents, the reaction of human somatic cells to this agent is very im portant. I suppose that cyclosporin induces CA in hu man lymphocytes not via genotoxic mechanisms but via its immunosuppressive property. It is known that genome instability is connected with immune system abnormalities (Ilyinshikh, 1990) and cyclosporin-induced immunosuppression leads to the elevation of the number of mutant cells. Increased numbers of lymphocytes with CA were observed only after 1 year of cyclosporin therapy. But investigations concerning clasiogenicity in rodents were performed 24-48 h after, cyclosporin treatment. Voogt (19S9) also con cluded that another immunosuppressive agent, azathioprine, induces tumors in humans via its immunosuppressive property but not via genotoxicity. So the Ames assay and cytogenetic tests in rodents cannot identify the gcnotoxicity of any hormonal and some inorganic agents as described by Shelby and Zciger (1990), nor immunosup pressive agents with mechanisms of action other R&S150754 i V 242 than gcnotoxicity. i suppose that the gcnotoxicity of some such agents is identified in short-term tests only by chance. It would be of interest to compare the results of long-term studies of carcinogenicity in anim, .s (Tomati:. and Barisch, 1990) and the activity of carcinogens in two short-term tests. Only 30 of the 33 carcinogens were studied in long-term studies. Three agents showed inadequate evi dence of carcinogenicity in animals (ethanol, smokeless tobacco and talc containing asbestiform fibers) and eight agents had limited evi dence of carcinogenicity (analgesics containing phcnacctin, azathioprinc, betel quid with to bacco. chlornaphazinc, cyclosporin, mustard gas, mylcran and arsenic compounds). Only 19 agents (63.3%) had sufficient evidence of carcinogenicity in animals and altogether 27 agents (90%) had sufficient or limited evidence of carcinogenicity. Consequently the sensitivity of long-term experi ments using animals is almost the same as for batteries of short-term test including the Ames assay and cytogenetic tests (at least for this group of agents). Conclusion The additional data have confirmed the con clusion of Shelby and Zeiger (1990) than the greatest concern should center on agents that are carcinogenic for animals, mutagenic in Salmonella and rodent clastogens. In the case of inconclusive or negative results in rodent clastogcnicity or in the Ames assay the reaction of human somatic cells to this agent is very important. I agree with Ashby and Tennant (1991) that `non-genotoxic rodent carcinogens cannot be automatically ne glected as possible human carcinogens' and T suppose that all hormonal or immunosuppressive agents that arc carcinogenic for animals (suffi cient or limited evidence) but inactive in short term tests may be carcinogenic for humans, be cause they induce tumors not via genotoxic mech anisms. The battery consisting of two short-term tests (the Ames assay and rodent clastogcnicity) is very' sensitive in identification of genotoxic carcino gens. It is very important for genotoxic agents are prevalent among human carcinogens and also among agents probably and possibly carcinogenic for humans (Tomatis and Barisch, 1990). References Ashby, J., and R.W. Tennant (1991) Definitive relationships among chemical structure, carcinogenicity and mutagenic ity for 301 chemical tested hy the U.S. NTP. Mutation Res., 257, 229-306. Ashby, J., H. Tinwcll, R.D. Callander and N. Clare (1991) Genetic activity of the numan carcinogen sulphur mustard towards Salmonella and the mouse bone marrow. Muta tion Res,, 257, 307-311- Ralansky, R,M,, P.M. Blagocva and Z,l, Mircheva (1988) The mutagenic and clastogcnic activity of tobacco smoke. Mu tation Res., 20S, 237-241. Burilyak. I.R., and S.Yu. Kozachouk (1985) Mutagenic action of some alcohols in experiments, Cytol. Genet., 19,436-422 (in Russian). Bogovski, P,, T. Vcidebaum. J. Tamme and E, Poldverc (1990) Carcinogenicity and mutagenicity of shale oil produced in the Estonian Kivitcr retort, in: IL Vainio, M. Sorsa and AJ, McMichacl (Eds.), Complex Mixtures and Cancer Risk, IARC Sci. Publ. No 104, IARC, Lyon, pp. 354-362. De Flora, S., A. Camoirano, P. Zanacchi and C Bcnnicelli (1984) Mutagenicity testing with TA97 and TAIQ2 of 30 DNA-damaging compounds negative with other Salmo* nella strains. Mutation Res.. 134, 159-165. Dournev, A.D., N.O. Daugcl-Daugc and L.G. Korkina (1990) Mutagenic properties of chrysolite asbestos and ccolitc, in; N.N, llyinskikh (Ed.), Some Aspects of Genetics, Tomsk, pp. 73-81 (in Russian). Dubinin, N.P. (1986) The news in current genetics, Nauka, Moscow, 220 pp. (in Russian). Frash, V.N., and N.N. Vanchougova (1987) The micronudeus test as a short-term test to detect potential carcinogenicity of different groups of chemicals, Exp. Oncol.. 9, 8-14 (in Russian). Frash, V.N., N.N. Vanchougova and A.V. Karaulov (1990) Use of microbial test for detecting mutagenic effect of industrial mineral dust, Bull, Exp. Biol, Med., 60, 522-525 (in Russian). Gileva, E.A^ N-L. Kosareva and M.F. Bahtiyarova (1990^ Cytogenetic anomalies in wild mice trapped in the region of aluminium plant, in: N.N. Dubinin (Ed.), Ecological and Genctical Monitoring of Environment, Karaganda, p. 36 (in Russian). IARC (1987) Monographs on the Evaluation of Carcinogenic Risks to Humans, Genetic and Related Effects, Supp). 6, IARC, Lyon. IARC (1990) IARC Monographs on the Evaluation of Car cinogenic Risks to Humans, Vol. 50, Pharmaceutical Drugs, IARC, Lyon. llyinskikh, N.N. (1990) Genome instability as a consequence of DNA-repair and immune system abnormalities, Acta Biol. Hung., 41, 101-103. ID (Z> oUi mCn 9m Kisscliova, A.A.. C.Ya. Lipatov, L.N. Pylcv and O.Ya Beres neva (1989) On the nickclou.s dusts' potential carcinogenic ity assessment with micronuclcus test, Work 1 lygicnc Prof Dis., 9, 31-32 (in Russian). Maync, i., and L-L Deaven (1982) Cytogenetic effects of shale oils in murine bone marrow, Environ. Mutagen., 4, 639-645. Pinter, A., K. Bejezi, M. Csik ct al. (1990) Mutagenicity of emissions and immissions samples around industrial areas, in: H. Vainio, M. Sorsa and AJ, McMichaci (Eds.), Com plex Mixtures and Cancer Risk, IARC Sci. Puhl. No. 104, IARC, Lyon, pp. 269-276. Ressner, P., M. Cherna and V.S. Zhurkov (1990) Analysis of gcnotoxic effects in the professional contingents, Hygiene Sanitary, 6, 55-57 (in Russian). Shelby, M,D. (1988) The genetic toxicity of human carcino gens and its implications, Mutation Res., 204, 3-15. 243 Shelby, M.D., and E. Zeiger (1990) Activity of human carcino gens in the Salmonella and rodent bone marrow cytoge netic tests, Mutation Res., 234, 257-261, Tomatis, L., and H. Bartsch (1990) The contribution of exper imental studies to risk assessment of carcinogenic agents in humans, Exp. Pathol., 40, 251-266. Vanchougova, N.N., V.N, Frash and F.M. Kogan (19X5) The micronuclcus test as a rapid method for detection of potential carcinogenicity of asbestos containing and other mineral fibers, Work Hygiene Prof. Dis., 6, 45-48 (in Russian). Zhnng, tt.-Z., Z.-Q- Li and G.-Y. Ma (1989) Study of the mutagenicity and carcinogenicity of produced nickel dusts, Environ. Mol. Mutagen., 14 Suppt., 230. Communicated by F.H. Sobcls 'V ` I i. >3 '-7' ',*&? . -V;V Cr . 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