THE DETECTION OF INCREASED MUTATION RATES IN HUMAN POPULATIONS* JAMES V. NEEL, M.D., Ph.D.] Introduction This presentation will assume that a sufficient case has already been made for studying human mutation rates—either spontaneous, as a basic parameter ofhuman genetics, or induced, as an indicator of the effect on the germ plasm ofa wide variety ofnoxious agents to which human populations are increasingly exposed. With respect to induced mutations and their possible deleterious effects, the early concerns of twenty to forty years ago were, of course, primarily directed toward radiation, with the late Professor H.J. Müller their most eloquent spokesman. More recently, although interest in radiation effects remains very real, the subject of chemical mutagenesis has moved center stage. Detailed reasons for the concern for man on this point will be found in a number ofrecent publications [1-9]. In addition, the bulletins of the newly organized Environmental Mutagen Society are quite instructive. A partial list of the chemicals now in our environment which, for one reason or another, could be mutagenic for man includes the fungicide, captan; the plant-growth inhibitor , maleic hydrazide; the artifical sweetener, cyclamate; the food preservatives, sodium nitrite and sodium nitrate; certain of the streptomyces -derived antibiotics; various insect chemosterilants, such as triethylene phosphoramide and triethylene melamine; pesticides, such as the mercurials, the carbamates and thiocarbamates, the organophosphates, and the unsaturated "rings" with —OH or -SH groups; the benzepyrine found in smog; and a variety ofalkylating agents. There seems no reason to belabor the possibility that human exposures to radiation and chemical * Submitted October 6, 1970 as a position paper for the Conference on Genetic Disease Control, held in Washington, D.C, December 3-5, 1970. This work was supported by Atomic Energy Commission grant no. AT(n-i)-i552. t Lee R. Dice Professor ofHuman Genetics,University ofMichigan,Ann Arbor, Michigan 48104. 522 James V. Neel · Mutation Rates in Humans Perspectives in Biology and Medicine · Summer 10.71 mutagens may be increasing mutation rates; the problem to be considered here is how we proceed to evaluate this possibility. A voluminous literature on the genetic effects of radiation on experimental organisms has already accumulated, and an equally voluminous literature on chemical mutagens is building up rapidly. There is, ofcourse, absolutely no question that experimental models are indispensable in screening potential mutagens and that the results of these screens will, in many instances, be adequate to forestall public exposure to a variety of agents. However, a potential mutagen could pass reasonable screening tests, and yet, alone or in combination with other agents, be mutagenic in man. Furthermore, some agents could have such beneficial effects as pesticides or herbicides that—as in the case of radiation—some genetic risks may be accepted in return for the benefits conferred. Finally, we may inadvertently introduce unrecognized mutagens into the environment. Thus, it is clear that no matter how extensive the screening programs may become, the final test will be what is happening to the germinal tissue of human populations. It will be the thesis ofthis presentation that the technological advances of the last twenty years permit new and much more refined approaches to monitoring human populations than have been true in the past. The Approaches to Monitoring Human Populations There are three principal approaches to detecting an increased mutation rate in human populations. i. The use ofpopulation characteristics.—This approach utilizes as indicators ofan increase (or decrease) in mutation rates changes in such parameters ofhuman populations as stillbirth frequency, birth weight, frequency of congenital defect, the sex ratio, death rates during the early years of life, and physical growth and development during infancy and childhood. The argument that an increased mutation rate should be reflected in these indicators is simple and solid. However, the relationship between any given change in the indicator and the underlying change in mutation rate is not clear. Furthermore, we know that all these indicators are influenced by many exogenous factors operating on both mother and child. A suitable control population must be available, and, especially as it concerns the matter of chemical mutagenesis, establishing such a control group becomes increasingly difficult. 523 This approach was employed in the principal opportunity...
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