Are non-mutagenic carcinogens merely cryptomutagens?

Mutation Research, 216 (1989) 267-317 Elsevier

267

MUTENV 08730

European Environmental Mutagen Society Selected abstracts of the 18th Annual Meeting 3 - 8 October 1988, Varna (Bulgaria)

Keywords: European Environmental Mutagen Society; Abstracts, Annual Meeting 1988

1

Ashby, J., ICI Central Toxicology Laboratory, Macclesfield, Cheshire (U.K.) Are non-mutagenic carcinogens merely cryptomutagens? Two debates presently dominate genetic toxicology - - how m a n y genotoxicity tests are required to detect genotoxins, and how to respond to the apparent existence of several classes of non-genotoxic carcinogen. The latter debate is of general significance as it implies access to carcinogenicity by chemicals that are unable to affect the integrity of the genome. The first debate, that regarding strategies for the detection and assessment of genotoxins, is waning. Not that general agreement on this matter has yet been reached, but the essence of a common approach is emerging. The question of non-genotoxic carcinogens has yet to be seriously considered by a wide audience. The apparent existence of such agents can be supported by several independent lines of evidence, but there remains the possibility that they induce selective and subtle changes in D N A that are not detected by the present mutagenicity/ genotoxicity assays. But this in turn opens the door to poorly defined and inadequately validated

Due to the large number of abstracts presented, some could not be included. The following criteria were employed for exclusion: (a) abstracts for which no posters were presented, (b) abstracts not containing sufficient meaningful information and (c) abstracts containing only material derived from already published papers. , A.T. Natarajan (Editor)

assays that may detect a few of such carcinogens as positive, perhaps only by chance. These matters will be discussed within the context of the viewpoints and data available in October 1988.

2 Vogel, E.W., Department of Radiation Genetics and Chemical Mutagenesis, State University of Leiden, Sylvius Laboratories, Wassenaarseweg 72, Leiden (The Netherlands) Genotoxic profile of chemicals in relation to their carcinogenic potency The aim of this paper is to review results of recent studies on the genotoxic profile of small alkylating agents in relation to their carcinogenic potency. The general trend observed in both Drosophila and the mouse is that alkylating agents (AAs) which primarily react with ring nitrogens in D N A tend to be poor mutagens or are even inactive in repair-competent (early) germ cells. This parallels the observation that strong N-alkylators are likewise weak carcinogens in rodents in comparison to agents more efficient in O-alkylation in D N A , such as ethylnitrosourea (ENU). Another striking finding concerns the strong ' h y p e r m u t a bility effect' seen with effective N-alkylators in cells defective in excision repair (mei-9, mus(2)201 ) of Drosophila. All this has led to the hypothesis that in rodents, it is efficient error-free repair o f N-alkylation damage which makes necessary the use of high exposure doses for tumor initiation. In support of this hypothesis, there is indirect but nevertheless good evidence for eukaryotes that

0165-1161/89/$03.50 © 1989 Elsevier Science Publishers B.V. (Biomedical Division)