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Current issues in Mutagenesis and Carcinogenesis
Mutation Research, 171 (1986)61-62 Elsevier
61
MTR 01105
Editorial Current issues in Mutagenesis and Carcinogenesis A large number of mutagenicity/genotoxicity systems are now in routine use around the world and most of the major environmental/industrial chemicals have been evaluated in at least some of them. Further, increasingly detailed mechanistic studies are being undertaken on selected chemicals. The magnitude of the data base accrued as the result of these endeavours sometimes makes it difficult to discern the salient trends of this science. Already it is evident that the relationship between mutagenicity and carcinogenicity is not always straightforward, even at the empirical level, and the prospect of a new generation of molecular mutagenicity data is evident. With such rapid progress the danger exists that seminal observations will be missed by at least some investigators, or that crucial experiments may be delayed because the need for them might not be perceived by those with the resources or expertise to undertake them. Within this context a part of each issue of the Genetic Toxicology Testing section of Mutation Research will in future be devoted to the highlighting of current advances, issues and needs of this science. It is not intended that long debates should be published. Contributions should not exceed about 200-300 words in length and be accompanied by sufficient evidence to support publication. This could normally be limited to minimal literature referencing or to a description the extent of a literature search undertaken. Essential references should be contracted and incorporated into the text. Editorial discretion in publication will be limited to that required to maintain interest whilst preventing false alerts or incorrect assertions from being made. The name of sponsors of information will be published unless requested otherwise. Publication times will be kept to the minimum in order to enhance topicality. A measure of the success of this endeavour will be the extent to which research is inspired by
it. In such cases it is hoped that investigators will mention the results of such studies in these columns, concomitant with formal publication. This will provide a sense of direction. Contributions will be numbered sequentially upon publication to enable the linking of future topics with past ones. Contributions should be sent to Dr. J. Ashby, ICI PLC, Central Toxicology Laboratory, Macclesfield, Cheshire SK10 4TJ (Great Britain). There should be no shortage of topics because many vital and provocative findings have recently been reported. The following examples prepared by Ashby were selected to illustrate the intention and proposed format of this new sub-section of Mutation Research. Frits Sobels
Leiden, 9 May 1986
The genotoxicity of thiourea Thiourea is regarded by many as an archetypal non-genotoxic carcinogen. Thus, Rubin (Cancer Res., 45 (1985) 2935) recently presented a detailed discussion of this agent as an hormonal carcinogen. Also in 1985, Zeigler-Skylakakis et al. (Arch. Toxicol., 58 (1985) 5) presented evidence for the genotoxicity and gene mutagenicity of this chemical. The effects reported were weak and unusual in several respects. Some previous negative data reported for thiourea in the literature were assessed by the authors as being possibly positive (e.g. those of Lonati-Gallinani et al., Mutation Res., 113 (1983) 145). Independent confirmation of the genotoxic status of thiourea would provide important information regarding the validity of a non-genotoxic mechanism of carcinogenesis in this case.
0165-1218/86/$03.50 © 1986 ElsevierSciencePublishers B.V.(BiomedicalDivision)
62 Is the rodent germ cell mutagen acrylamide really non-mutagenic to Salmonella?
Activity of M N N G in the mouse bone marrow micronucleus assay
Shelby et al. and Smith et al. (Mutation Res., 173 (1985) 35, 273) have reported acrylamide monomer to be a germ cell mutagen to mice (i.p. injection) and rats (oral), respectively. Also, Solomon et al. (Cancer Res., 45 (1985) 3465) have confirmed the direct (Michael Reaction) reactivity of this agent to calf-thymus DNA in vitro. The reported inactivity of acrylamide as a mutagen to Salmonella (2 studies referenced in Shelby et al.) is therefore unexpected and worthy of further detailed study.
Probably because of its hydrolytic instability, MNNG gives a negative response in in vivo genotoxicity assays unless cells are sampled proximal to the site of exposure (reviewed in Mutation Res., 128 (1984) 173, 150 (1985) 383). Thus, it is reported as being either negative or weakly and unreproducibly positive in the mouse bone marrow micronucleus assay (Bruce and Heddle, Can. J. Genet. Cytol., 21 (1978) 319; Matter and Grauwiler, Mutation Res., 23 (1974) 239; Watanabe et al., Mutation Res., 97 (1982) 43, respectively). The recent report by Aeschbacher (Mutation Res., 164 (1986) 109) that MNNG gave a clear positive response in 6 strains of mice is therefore noteworthy. The author employed freshly prepared solutions, but this cannot be the only reason for these activities because Yamamoto and Kikuchi (Mutation Res., 128 (1984) 173) have reported a negative result in a very similar experiment which also defined the use of fresh solutions. Aeschbacher's success may be due to the use of a second dose of MNNG 24 h after the first dose and 6 h before sacrifice. Perhaps the hydrolytic instability of MNNG gives an instantaneous pulse dose to the bone marrow which yields micronucleated erythrocytes 6 h later. The timing of the second dose seems to be illogical, but it may have been propitious.
Clastogenicity of benzene in vitro
Benzene is a well established and potent rodent peripheral lymphocyte and bone marrow clastogen. However, it has proven difficult to detect reproducibly as a clastogen in vitro (e.g. Progr. Mutation Res., Vol. 5, 1985). Procter et al. (Mutation Res., 160 (1986) 259) may have found the main reason for this by their demonstration that 90% of the benzene in a sealed solution of benzene is lost to the head space within 1 h at room temperature. Similar effects have been reported by Forster for benzyl chloride (Mutagenesis, 1 (1986) 72). Procter et al. also demonstrated the extreme reactivity of formaldehyde to serum. Such reports indicate that caution is required when pooling the published genotoxicity data for a chemical - apparent genetic specificity of action may only be the result of varying test protocols.
61
MTR 01105
Editorial Current issues in Mutagenesis and Carcinogenesis A large number of mutagenicity/genotoxicity systems are now in routine use around the world and most of the major environmental/industrial chemicals have been evaluated in at least some of them. Further, increasingly detailed mechanistic studies are being undertaken on selected chemicals. The magnitude of the data base accrued as the result of these endeavours sometimes makes it difficult to discern the salient trends of this science. Already it is evident that the relationship between mutagenicity and carcinogenicity is not always straightforward, even at the empirical level, and the prospect of a new generation of molecular mutagenicity data is evident. With such rapid progress the danger exists that seminal observations will be missed by at least some investigators, or that crucial experiments may be delayed because the need for them might not be perceived by those with the resources or expertise to undertake them. Within this context a part of each issue of the Genetic Toxicology Testing section of Mutation Research will in future be devoted to the highlighting of current advances, issues and needs of this science. It is not intended that long debates should be published. Contributions should not exceed about 200-300 words in length and be accompanied by sufficient evidence to support publication. This could normally be limited to minimal literature referencing or to a description the extent of a literature search undertaken. Essential references should be contracted and incorporated into the text. Editorial discretion in publication will be limited to that required to maintain interest whilst preventing false alerts or incorrect assertions from being made. The name of sponsors of information will be published unless requested otherwise. Publication times will be kept to the minimum in order to enhance topicality. A measure of the success of this endeavour will be the extent to which research is inspired by
it. In such cases it is hoped that investigators will mention the results of such studies in these columns, concomitant with formal publication. This will provide a sense of direction. Contributions will be numbered sequentially upon publication to enable the linking of future topics with past ones. Contributions should be sent to Dr. J. Ashby, ICI PLC, Central Toxicology Laboratory, Macclesfield, Cheshire SK10 4TJ (Great Britain). There should be no shortage of topics because many vital and provocative findings have recently been reported. The following examples prepared by Ashby were selected to illustrate the intention and proposed format of this new sub-section of Mutation Research. Frits Sobels
Leiden, 9 May 1986
The genotoxicity of thiourea Thiourea is regarded by many as an archetypal non-genotoxic carcinogen. Thus, Rubin (Cancer Res., 45 (1985) 2935) recently presented a detailed discussion of this agent as an hormonal carcinogen. Also in 1985, Zeigler-Skylakakis et al. (Arch. Toxicol., 58 (1985) 5) presented evidence for the genotoxicity and gene mutagenicity of this chemical. The effects reported were weak and unusual in several respects. Some previous negative data reported for thiourea in the literature were assessed by the authors as being possibly positive (e.g. those of Lonati-Gallinani et al., Mutation Res., 113 (1983) 145). Independent confirmation of the genotoxic status of thiourea would provide important information regarding the validity of a non-genotoxic mechanism of carcinogenesis in this case.
0165-1218/86/$03.50 © 1986 ElsevierSciencePublishers B.V.(BiomedicalDivision)
62 Is the rodent germ cell mutagen acrylamide really non-mutagenic to Salmonella?
Activity of M N N G in the mouse bone marrow micronucleus assay
Shelby et al. and Smith et al. (Mutation Res., 173 (1985) 35, 273) have reported acrylamide monomer to be a germ cell mutagen to mice (i.p. injection) and rats (oral), respectively. Also, Solomon et al. (Cancer Res., 45 (1985) 3465) have confirmed the direct (Michael Reaction) reactivity of this agent to calf-thymus DNA in vitro. The reported inactivity of acrylamide as a mutagen to Salmonella (2 studies referenced in Shelby et al.) is therefore unexpected and worthy of further detailed study.
Probably because of its hydrolytic instability, MNNG gives a negative response in in vivo genotoxicity assays unless cells are sampled proximal to the site of exposure (reviewed in Mutation Res., 128 (1984) 173, 150 (1985) 383). Thus, it is reported as being either negative or weakly and unreproducibly positive in the mouse bone marrow micronucleus assay (Bruce and Heddle, Can. J. Genet. Cytol., 21 (1978) 319; Matter and Grauwiler, Mutation Res., 23 (1974) 239; Watanabe et al., Mutation Res., 97 (1982) 43, respectively). The recent report by Aeschbacher (Mutation Res., 164 (1986) 109) that MNNG gave a clear positive response in 6 strains of mice is therefore noteworthy. The author employed freshly prepared solutions, but this cannot be the only reason for these activities because Yamamoto and Kikuchi (Mutation Res., 128 (1984) 173) have reported a negative result in a very similar experiment which also defined the use of fresh solutions. Aeschbacher's success may be due to the use of a second dose of MNNG 24 h after the first dose and 6 h before sacrifice. Perhaps the hydrolytic instability of MNNG gives an instantaneous pulse dose to the bone marrow which yields micronucleated erythrocytes 6 h later. The timing of the second dose seems to be illogical, but it may have been propitious.
Clastogenicity of benzene in vitro
Benzene is a well established and potent rodent peripheral lymphocyte and bone marrow clastogen. However, it has proven difficult to detect reproducibly as a clastogen in vitro (e.g. Progr. Mutation Res., Vol. 5, 1985). Procter et al. (Mutation Res., 160 (1986) 259) may have found the main reason for this by their demonstration that 90% of the benzene in a sealed solution of benzene is lost to the head space within 1 h at room temperature. Similar effects have been reported by Forster for benzyl chloride (Mutagenesis, 1 (1986) 72). Procter et al. also demonstrated the extreme reactivity of formaldehyde to serum. Such reports indicate that caution is required when pooling the published genotoxicity data for a chemical - apparent genetic specificity of action may only be the result of varying test protocols.