Carcinogen Risk Assessment

In order to place the different methods used to estimate carcinogenic risk from chemical exposure into context, and to help decide on the best approach to improve this process, it is useful to discuss carcinogenesis with an emphasis on mechanism. Although the mecha nism of action of no carcinogen is completely characterized, the efforts over the last ten years have been very fruitful, and mechanistic explanations of a number of components in the grand design that is carcinogenesis have been described in detail.

As the other chapters of this volume will attest, the area of risk analysis of chemical carcinogens is a new and emerging field of science that is intermingled with economic, societal, and political values. The concept that short-term tests, which will be defined and described later in this chapter, can affect the final outcome of a risk analysis is both recent and controversial. While we have not conducted a scientifically valid survey, we have done extensive sampling among highly credible and well regarded scientists whose pro fessional activities impinge on the boundaries of the area we call risk analysis. The question asked of them was, what is the value of short-term test data in risk assessment? Approximately 10% opined that risk analysis is valueless; the remainder were evenly divided between those believing that short-term tests have no value at all to risk analysis and those who view short-term tests as holding some promise and utility for risk analysis. Among the latter group, there were those who believed that short-term tests were useful for making qualitative judgments only and they should not have an impact on quantitative risk analysis. Others felt that the main value of short-term tests in risk assessment would be for classification purposes, that is, to determine whether a substance is a genotoxic carcinogen, thus prompting the use of a conservative nonthreshold linearized extrapolation model, as opposed to a risk extrapolation approach which envisions a threshold. Finally, there were others who said they believed that short-term test data could be valuable both for qualitative and quantitative assessments, but that it is too early and scientific experience is too limited to provide general guidance on the subject. They felt, however, that there have been and that there would be specific situations where short-term tests would prove invaluable in determining a final outcome.

Risk assessment generally comprises some or all of the following factors: hazard identification, dose-response assessment, exposure assessment, and risk characterization (National Research Council, 1983). Animal bioassays are fundamental in furnishing information directly relevant to the first two of these factors, identification of the hazard and dose-response assessment.

Risk analysis consists of two basic components, exposure assessment and health effects assessment. Exposure assessment involves determining the pathways and extent of human exposure to toxic chemicals. Because of the complex processes involved, exposure as sessment is often the most resource demanding part of evaluating the risks of human exposure to environmental pollutants (Office of Science and Technology Policy, 1985). This chapter provides an overview of some of the important aspects of exposure assessment.

An essential component of any chemical risk assessment is quantifying the nature and extent of exposure expressed in terms of concentration, dosage, or duration. In this chapter, we outline the structure of such exposure assessments using relatively simple partitioning models and provide an illustration of the underlying concepts. A full-scale exposure analysis may involve an extensive program of data collection, determination, and interpretation involving chemical analyses of various biotic and abiotic media, cal culation of the rates of emission into, and migration between, environmental media, and estimation of the toxic effects on organisms, populations, communities, and ecosystems. Examples are the series of reports published in the United States by the National Academy of Sciences/National Research Council and in Canada by the Environmental Secretariat of the National Research Council.

Growing public awareness of the potential risk to humans from hazardous chemicals in the environment has led to increased concern about the effects of these chemicals on animals and man. This awareness has generated a demand for a rational means of estimating risk and of limiting exposure where risk is judged excessive. An outcome of this awareness has been the emergence of the field of risk assessment. Risk assessment synthesizes all available data on exposure to chemicals and combines it with the best scientific judgment to estimate the associated risk.

Mathematical dose-response models are currently used to extrapolate cancer risk from the high dose levels used in laboratory bioassays to the low, environmental dose levels to which humans are generally exposed. These models are empirical in nature and lack a biological basis. It has long been recognized that the accuracy with which a mathematical model predicts cancer risks at low doses is dependent upon the validity of the underlying biological paradigm on which it is based. A model that is chosen because it provides a “best fit” to tumor data observed at high doses may greatly over- or underestimate risk at low doses. Historically, regulatory agencies have had to use the available models in the absence of more appropriate alternatives; however, this is no longer the case. Our under standing of the mechanisms of carcinogenesis has advanced to a point where use of a biologically-based cancer model is now feasible.

There are a number of biological factors which may enhance one’s susceptibility to experience adverse health effects from exposure to toxic substances, including car cinogens. These include one’s age, sex, genetic composition, nutritional status, and preexisting disease conditions (Calabrese, 1978, 1984, 1985, 1986; Propping, 1978).

Traditionally, the field of chemical carcinogenesis has relied upon estimates of adminis tered dose and/or human exposure in constructing dose-response curves and assessing cancer risk. Of far greater relevance to risk is the actual amount of carcinogen that has interracted with target cellular molecules such as DNA, RNA, or protein—the biologically effective dose of the carcinogenic substance.

A world with acute health problems, economic depression, war or the threat of nuclear annihilation, and high injury rates is not one where environmental issues are likely to be the focus of attention. Only when short-term health problems are under control, income is at a high level, and other immediate threats such as war are viewed as being under control is the environment likely to emerge as a major social concern (Lave, 1980a). The late 1960s was such a time in the United States and in much of the developed world. Spectacular progress had been made in lowering the infant mortality rate and vanquishing infectious disease. Trauma was viewed as basically being under control, due in part to the creation of the National Highway Transportation Safety Administration and Occupational Safety and Health Administration (OSHA). The perceived threat of nuclear war had receded far from the preoccupation of the early 1950s. Per capita income had increased steadily in the post-war period and fears of a deep depression had evaporated with the steady performance of the economy over two and a half decades. In short, immediate, high-level concerns had been satisfied and other issues might emerge to take their place.

The acceptability of risk is a complex subject. Judgments of acceptability are made at many levels—by individuals, families and other groups, and by the society at large. A risk may be acceptable to the consumer of a product or technology, but those who receive no benefit but some risk from the technology may disagree. A risk which was accepted in prospect may become unacceptable in hindsight.

In industrialized societies, the question “How safe is safe enough?” has emerged as one of the major policy issues of the 1980s. The frequent discovery of new hazards and the widespread publicity they receive is causing more and more individuals to see themselves as the victims, rather than as the beneficiaries, of technology. These fears and the opposition to technology that they produce have puzzled and frustrated industrialists and regulators and have led numerous observers to argue that the public’s apparent pursuit of a “zero-risk society” threatens the nation’s political and economic stability. Political Sci entist Aaron Wildavsky commented on this state of affairs (Wildavsky, 1979):

How extraordinary! The richest, longest-lived, best-protected, most resourceful civilization, with the highest degree of insight into its own technology, is on its way to becoming the most frightened.

Is it our environment or ourselves that have changed? Would people like us have had this sort of concern in the past? … today, there are risks from numerous small dams far exceeding those from nuclear reactors. Why is the one feared and not the other? Is it just that we are used to the old or are some of us looking differently at essentially the same sorts of experience?

Every day we take risks and avoid others. It starts as soon as we wake up. One of us lives in an old house that had old wiring. Each time he turned on the light, there was a small risk of electrocution. Every year about 200 people are electrocuted in the United States in accidents involving home wiring or appliances, representing a risk of death of about 10^-6 per year, or 7 × 10^-5 per lifetime. To reduce this risk, he got the wiring replaced. When we walk downstairs, we recall that 7000 people die each year in falls in U.S. homes. But most are over 65, so we pay little attention to this risk since both of us are younger than that.

Risk communication takes place in a variety of forms, ranging from warning labels on consumer products to interactions among governmental officials, industry representatives, the media, and members of the public on such highly charged situations as Love Canal, ethylene dibromide (EDB) contamination of food, Three Mile Island, cigarette smoking, asbestos in school buildings, and Chernobyl. Experience has shown that risk communication efforts are a source of frustration for both risk communicators and for the intended recipients of the information. Government officials, industry representatives, and scientists note that laypeople frequently do not understand highly technical risk information and that individual biases and limitations may lead to distorted and inaccurate perceptions of many risk problems. Representatives of citizen groups and individual citizens are often equally frustrated, perceiving risk communicators and risk assessment experts to be uninterested in their concerns and unwilling to take immediate and direct actions to solve seemingly straightforward health, safety, and environmental problems. In this context, the media often plays the role of transmitter and translator of information between risk communicators and the public. But the media has been criticized for exaggerating risks and for emphasizing drama over scientific facts.