Search

I would like to discuss (a) how important discoveries over the last 100 years help to quantify the risk of cancer in populations exposed to man-made sources of ionizing radiation, and (b) how periodic episodes of contamination of the environment with radioactive elements have created public health problems.

For decades investigators have suggested a correlation between personality (1) or emotional stress (2) and the growth of cancer. Links have been made between helpless behavior in the face of stressful impairment and reduction in clearance of tumor cells in experimental animal models (3, 4). Humans might be affected in a similar fashion but the possibilities to obtain this evidence in humans are limited. Some recent results concerning the link between stressful life events and breast cancer are contradictory and usually dependent on the different methodologies of investigation of this link (5).

In this paper, we consider the possible role of nitroarenes as causative compounds for human cancer. At the outset, it is important to recognize that adequate data to answer this question are not available. However, we will evaluate existing data with respect to three major cancer sites: lung, bladder, and breast. These sites were chosen because either experimental or epidemiologic studies, as summarized below, suggested that nitroarenes were possible etiologic agents. Our evaluation of the role of nitroarenes in each of these diseases will be based on their abilities to induce the relevant tumors in experimental animals, on their concentrations in the appropriate environments, and on data from analyses of human tissues or blood. We recognize that this approach is limited by the complex interactions that occur in environmental mixtures to which humans are exposed. Interactions between carcinogens and cocarcinogens, inhibitors, or promoters as well as host factors such as levels of carcinogen metabolizing enzymes tend to confound analyses of this type. Nevertheless, we have found it useful to focus on individual compounds within complex mixtures as this can lead to new insights regarding mechanisms of cancer induction.

Because of the unusually high reliability of short-term microbial assays for predicting the potential carcinogenicity of environmental agents, the emphasis of recent reports has been on standardization of experimental procedures, interlaboratory reproducibility, and the generation of a data base for a wide variety of chemicals (de Serres and Shelby, 1979a,b; Mattern et al., 1978; Seiler et al., 1980). Indeed, studies in this laboratory have dealt with experimental factors which may affect the mutagenic and genotoxic responses of potential carcinogens (Rosenkranz et al., 1976a,b, 1979a,b, 1980; Rosenkranz and Leifer, 1980; Rosenkranz and Poirier, 1979). All too often, however, we tend to forget that short-term assays can be used as research tools in the development of new concepts related to the molecular basis of DNA-adduct formation, its repair, and alternate mechanisms responsible for cancer Induction. In addition, the data base itself, if developed properly, may be an excellent source of information for the development of theoretical models which could form the basis of a more rational approach to risk evaluation.

Changes in genetic systems are of great importance for human life. They can, as an acute effect be responsible for the death of cells, as well as for developmental damage or death of organisms. Mutations can also be involved in late radiation effects such as cancer induction or premature ageing. Generally, one distinguishes (Fig. 1) between mutations visible through the light microscope, such as changes in the number or in the structure of chromosomes, and point or gene mutations which cannot be detected by usual microscopical methods and are caused mainly by base damage.

The dramatic progress and findings made at the molecular and cellular level, discussed in the previous chapter, now permit a molecular description of the neoplastic process that involves lower- and higher-order nuclear structures, genes and cytoskeleton, and that confirms what was believed in the early days, namely that cancer is the final product of a multistep process (Farber and Cameron, 1980; Pitot, 1979; Pontecorvo, 1975; Heston, 1975). The questions that are still unanswered or inconclusively proven are: What are the steps in the cancer process? Which of them are limiting? Which of the steps are more susceptible to intervention, either through treatment following early detection (the object of Chapter 3) or through prevention (the object of this chapter).

A number of papers in this volume have already been devoted to in vitro screening tests. They have illustrated the diversity of studies that can be made including (a) mechanisms of cancer induction (b) causes of cancer spread and metastasis, (c) screening for new drugs (d) studies on the mechanism of acquired drug resistance and (c) methods of killing resistant cells.

Somatic mutations have been a major focus of aging research for many years. Initial support for the view that aging in mammals was due to the accumulation of somatic mutations was the effect of radiation on life span (Prasad, 1974). This mutagenic effect of radiation has been established in several systems, including mammalian cells (Awa, 1975). A single dose of radiation in a young animal did not produce effects associated with aging such as graying until long after the administration of the radiation. That it did not led to the idea that aging had been accelerated by radiation (Finch, S. C., and Beebe, 1975).

Although radiation carcinogenesis was recognized some 75 years ago, we still know little about the mechanisms involved. Because of its profoundly important theoretical and practical aspects, the subject has been very extensively studied, but most of the information obtained has been of a phenomenological nature. It seems unlikely that a complete step-by-step description of radiogenic cancer induction will be possible in the foreseeable future. Merely the first purely physical process—that of energy deposition by charged particles—is highly com­plex and difficult to quantitate. There is every reason to believe that the ensuing physicochemical, biochemical, intracellular, intercellular, and systemic processes are at least as complex and that many of them are unknown at this time.

It has generally been agreed that one of the most important radiation-induced risks that must be faced on extended manned spaceflight is that of cancer induction. In this chapter, we present a brief review of the data on neoplastic cell transformation in in vitro cell lines at low dose rates for both low and high LET radiation. We discuss whether these data have implications for the very protracted periods envisaged for space missions.

Risk assessment is a complex process. It attempts to relate adverse health effects, such as cancer induction, to exposure to potentially toxic agents. The relationship between exposure and tumor incidence is studied experimentally by administering specific exposure regimens to animals followed by lifetime observation to determine tumor incidence. A pivotal issue in risk assessment centers around the estimation of risk at low exposure levels, levels significantly below those typically used in experimental toxicology studies. To quantitatively estimate risk at low exposure levels, mathematical modeling and extrapolation procedures are necessary.