AN INTEGRATIVE MODEL

An integrative theory is proposed in which environmental carcinogenesis is viewed as a process by which the genetic control of cell divzsion and differentiation is altered by carcinogens. In thzs theory, carcinogens include physical, chemical, and viral "mutagens," as well as chemical and viral gene modulators. Existing explanations of carcinogenesis can be considered either as somatic mutation theories or as epigenetic theories. Evidence seems to support the hypothesis that both mutations and epigenetic processes are components of carcinogenesis. The mutational basis of cancer is supported by the clonal nature of tumors, the mutagenicity of most carcinogens, high mutationfrequencies in cells of cancer-prone human fibroblasts lacking DNA repair enzymes, the correlation of in vitro DNA damage and in vitro mutation and transformationfrequencies with in vivo tumorigenesis, age-related incidences of various hereditary tumors, and the correlation between photoreactivation of DNA damage and the biological amelioration of UV-induced neoplasms. Since both mutagens and gene modulators can be carcinogenic it may be that carcinogens affect genes which control cell division. An integration of the mutation and epigenetic theories of cancer with the "two-stage" theory and Comings's general theory of carcinogenesis is proposed. This integrative theory postulates that carcinogens can affect regulatory genes which control a series of "transforming genes. A general hypothesis is advanced that involves a common mechanism of somatic mutagenesis via error-prone repair of DNA damage which links carcinogenesis, teratogenesis, atherosclerosis and aging. Various concepts are presented to provide aframework for evaluating the scientific, medical, and social implications of cancer. "This innerfragmentation of man mirrors his view of the world 'outside' which is seen as a multitude of separate objects and events. The natural environment is treated as if it consisted of separate parts to be exploited by different interest groups. The fragmented view is further extended to society which is split into different nations, races, religious and political groups. The belief that all thesefragments - in ourselves, in our environment and in our society - are really separate can be seen as the essential reason for the present series of social, ecological, and cultural crises. It has alienated us from nature andfrom our fellow human beings. It has brought a grossly unjust distribution of natural resources creating economic and political dzsorder; an ever rising wave of violence both spontaneous and