National Academies Press: OpenBook

Issues in Risk Assessment (1993)


Suggested Citation:"BIOLOGIC CONSIDERATIONS." National Research Council. 1993. Issues in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2078.

workshop summary appears in Appendix A. Postworkshop discussions were also held with the workshop speakers and with representatives of the federal liaison group to clarify the issues. However, this report and its recommendations were prepared solely by the committee.


Clinicians and pathologists have long recognized that cancer formation in humans is often preceded by a series of preneoplastic changes. Confirmation of the multistage nature of certain human cancers has been obtained by studies of the role of changes in oncogenes and suppressor genes in human colon cancer (Hollstein et al., 1991). Similar observations have been made on laboratory animals that were exposed to carcinogens experimentally (Barbacid, 1987; Balmain and Brown, 1988). Morphologic or histopathologic studies do not always lend themselves well, however, to conclusions as to the biologic potential or ultimate fate of individual precancerous lesions. Some uncertainty exists about the identification of particular lesions as part of a neoplastic process, their place in the pathologic sequence, the inevitability of their progression to the next stage, and the rate of transition when they progress. For risk assessment, it is important to be able to distinguish lesions that are reversible from lesions that will irreversibly lead to neoplastic disease. The frequency with which most preneoplastic lesions pass from stage to stage appears to be low. In such model systems as the production of hepatic tumors in rats that are given known hepatic carcinogens, one can typically produce around thousands of biochemically altered cell foci per liver, which will be followed by the appearance of several adenomas and then by one or two hepatocarcinomas (Moolgavkar et al., 1990a; Cohen and Ellwein, 1991; Luebeck et al., 1991). In examples of that sort, almost all the early lesions do not progress to cancer, but remain the same or regress; thus cancer is a rare biologic outcome. Nevertheless, the consistent association of altered cell foci with later cancer formation has prognostic value and may help in developing preventive measures.

Underlying the structural stages are molecular events, or steps, that define the beginning and end of each stage. As noted before, cancer involves a disturbance of cell growth and cell growth is under genetic regulation, so genetic damage is likely to be important in carcinogenesis.

Suggested Citation:"BIOLOGIC CONSIDERATIONS." National Research Council. 1993. Issues in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2078.

Target genes include those related to cell division and proliferation (pro-to-oncogenes) or those which cause cells to stop dividing (anti-oncogenes or tumor-suppressor genes). The available evidence strongly supports the general concept that the cells of some cancers in humans and laboratory animals contain activated or mutated oncogenes and, in some cancer cells, tumor-suppressor genes are inactive or missing (Weinberg, 1988; 1989). Under active investigation are the extent to which those genetic events are necessary and sufficient to result in cancer and whether the sequence of genetic events is important if more than one genetic event is necessary. Other possible target genes, such as the genes that contribute to cell division cycles or the genes that affect the microenvironment in which developing cancer cell clones might be inhibited or selectively enhanced, have received less attention. It is generally assumed, too, that cell proliferation in general increases the probability of inheritance of random mutations by somatic cells, thus contributing indirectly to the carcinogenic process (Cohen et al., 1991).

The concept of two-stage models emerged from Knudson's studies of heritable childhood cancers (Moolgavkar and Knudson, 1981), and was an extension of the work of Armitage and Doll (1957). For retinoblastoma in particular, the relation of tumor incidence to age suggested that one event is necessary in the somatic cells of hereditary carriers and two events are necessary in nonhereditary carriers. Molecular genetic analyses of cells from affected children have revealed that the critical event can be the loss or inactivation of both alleles of the retinoblastoma tumor-suppressor gene (RB1) (Gaillie et al., 1990). The developing retina might contain three types of cells: normal retinoblasts with two normal RB1 alleles, intermediate retinoblasts with one altered or lost RB1 gene, and retinoblasts with both RB1 genes altered. In the herediary form in which one parentally acquired allele is altered, the probability of retinoblastoma is increased, because all the developing retinoblasts have an abnormal RB1 gene and are at risk of a second event. That three or four tumors develop in the typical gene carrier suggests that the second event is not very common. The process is limited, as a child ages, by differentiation of the entire embryonal retinoblast pool into adult nondividing retinal cells.

Other cancers appear more complicated. For example, mutations in both RB1 and p53 suppressor genes are thought to be involved, with a third presumed suppressor gene, in small-cell lung tumors (Takahashi et

Suggested Citation:"BIOLOGIC CONSIDERATIONS." National Research Council. 1993. Issues in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2078.
Page 188
Suggested Citation:"BIOLOGIC CONSIDERATIONS." National Research Council. 1993. Issues in Risk Assessment. Washington, DC: The National Academies Press. doi: 10.17226/2078.
Page 189
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The scientific basis, inference assumptions, regulatory uses, and research needs in risk assessment are considered in this two-part volume.

The first part, Use of Maximum Tolerated Dose in Animal Bioassays for Carcinogenicity, focuses on whether the maximum tolerated dose should continue to be used in carcinogenesis bioassays. The committee considers several options for modifying current bioassay procedures.

The second part, Two-Stage Models of Carcinogenesis, stems from efforts to identify improved means of cancer risk assessment that have resulted in the development of a mathematical dose-response model based on a paradigm for the biologic phenomena thought to be associated with carcinogenesis.

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