MUTAGENS OF POTENTIAL SIGNIFICANCE 177 



load due to spontaneous mutation, perhaps several mutations per 

 gamete. What are the sources of the spontaneous mutation rate? 



There is agreement that all sources of radiation, including cosmic 

 radiation, natural radioactivity in our earthly background, the slight 

 additions as a result of fallout in recent years, and also the effects of 

 transmutation of naturally occurring C^^ in DNA — that all these 

 could account for less than 10 per cent of the estimated spontaneous 

 rate in man (47, 56) . Then 90 per cent must be attributed either to un- 

 defined instability of the genes or to chemical mutagenesis, caused by 

 endogenous or exogenous substances. A major role of chemical muta- 

 genesis in spontaneous mutation is suggested by Novick's (43) finding 

 with E. coli that two-thirds of the spontaneous rate could be sup- 

 pressed by an antimutagenic nucleoside. 



It is at least within the realm of possibility that exogenous mutagens 

 are making a major contribution to the present spontaneous rate in 

 man, and have made a significant contribution to the existing genetic 

 load of deleterious mutations. Finally, we must recognize that no 

 mutation rate estimates in man have ever been made in the absence 

 of exposure to exogenous substances, some at least of which are 

 known to be mutagenic in other species. 



I should like to go on now to a general feature of the mechanism of 

 drug action which has certain implications for any possible genetic 

 hazard of drugs. With the exception of a very few compounds (like 

 the alkylating agents) drugs are remarkably unreactive in the or- 

 dinary chemical sense, but owe their biological effects to highly 

 specific reversible combinations with functionally important tissue 

 macromolecules ("receptors"). These drug-receptor interactions de- 

 pend upon electrostatic bonding, hydrogen bonds, and above all Van 

 der Waals' forces, which are so sensitive to small configurational dif- 

 ferences between closely similar drug molecules. It is therefore un- 

 likely that most drugs, no matter how biologically potent they may 

 be, could directly attack and chemically alter the DNA or associated 

 structures of the genetic apparatus. 



We should distinguish here between two principal modes of chemical 

 mutagenesis. On the one hand there is direct chemical modification of 

 the gene, as in the deamination of nucleic bases by nitrous acid or the 

 alkylation of guanine by diethylsulfate (see p. 101). Such alterations 

 of the DNA can be effected even in vitro, so that active replication 

 is by no means a prerequisite. On the other hand, genetic alterations 

 can be induced by intervention in the replicative process, either 

 through incorporation of abnormal base analogues or by otherwise 



