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Issues in Risk Assessment
Executive Summary
Risk assessment is a relatively new and rapidly developing science. Indeed, most federal agencies for which risk assessment is an important tool for decision-making or a subject of research were established only within the last quarter-century. Among those are the Environmental Protection Agency (EPA), Occupational Safety and Health Administration (OSHA), Consumer Product Safety Commission (CPSC), National Institute of Environmental Health Sciences (NIEHS), National Institute for Occupational Safety and Health (NIOSH), Food and Drug Administration (FDA), and Agency for Toxic Substances and Disease Registry (ATSDR). Mantel and Bryan published in 1961 the first paper on estimation of low dose risk based on data obtained from tests in which animals were exposed at high doses; formal procedures for performing animal bioassays, which are critically important for gathering information for risk assessment, had been standardized only in the 1960s and 1970s; and formal risk assessment began to be conducted regularly in the late 1970s. It was not until 1983, when the National Research Council (NRC) committee that prepared Risk Assessment in the Federal Government: Managing the Process defined the steps in risk assessment, that a generally accepted nomenclature for risk assessment was established.
Now, after this short time, risk assessment scientists study the details and argue the relative merits of different approaches to the performance and interpretation of studies; learned societies publish journals to communicate these deliberations; and national and international meetings are
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convened to discuss specific issues or to write the blueprints for new programs. New concepts are being rapidly explored, such as the use of pharmacokinetic studies of the fate of a chemical agent in the body; and some of the practices and principles established only a few years ago are already being re-evaluated. In addition, whereas almost all efforts were once directed toward determining the carcinogenic potential of an agent, scientists are now equally interested in assessing the potential of mixtures of agents to produce not only cancer, but reproductive, neurotoxic, developmental, and immunologic effects.
This volume contains the first three reports the Committee on Risk Assessment Methodology (CRAM) in the National Research Council (NRC) Board on Environmental Studies and Toxicology. The committee's work was sponsored by a consortium of federal agencies and private organizations, including EPA, NIOSH, the U.S. Army Biomedical Research and Development Laboratory, the American Petroleum Institute, and the American Industrial Health Council. The committee was charged to assess the scientific basis, inference assumptions, and regulatory uses of and research need in risk assessment. The committee has investigated these issues partly through a series of narrowly focused workshops. Topics were chosen in consultation with federal regulatory agencies on the basis of scientific considerations and the needs of the agencies. One source is a list of subjects that appeared in Risk Assessment if the Federal Government, which has become known as the Red Book. CRAM's reports are intended to provide guidance to regulatory decision-makers on specific questions; they are not broad, thorough scientific analyses, as are many NRC reports. The committee has focused on methodology; accordingly, its deliberations on each topic takes into account not only potential problems with existing methods, but also the suitability of alternative methods for risk assessment.
The committee consulted closely with federal agencies whose mission is to make decisions based on risk assessment of environmental and human health hazards. Representatives of 11 federal agencies organized themselves as a federal liaison group, and the committee consulted with the group in selecting workshop topics and participants and in preparing workshop summaries. However, in accordance with NRC policy, the members of the federal liaison group did not take part in the committee's deliberations or in the preparation of its reports. The workshop presentations, commissioned papers, and extensive committee deliberations formed the basis for the findings in the reports.
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The committee began meeting in January 1990 and selected as its first topic of study and use of the maximum tolerated dose (MTD) in animal bioassays, with emphasis on the relationship between the MTD and the carcinogenic potency of a test chemical. The second topic was the two-stage model of carcinogenesis, with a focus on data requirements for regulatory application. The third topic was a conceptual framework for ecologic risk assessment. The committee's reports on those three subjects make up this volume. Two other topics that have been selected are exposure assessment and developmental toxicity; workshops on these topics have been held, and reports are in preparation.
Use of the Maximum Tolerated Dose in Animal Bioassays for Carcinogenicity
Long-term animal bioassays for carcinogenicity are used regularly to determine whether chemical agents are capable of inducing cancer in exposed animals. Two important aspects of current bioassays are that testing covers a substantial portion of the lifespan of the test species and that high doses are used. The highest dose tested (HDT) is an approximation of the maximum tolerated dose (MTD), which is roughly described as the highest dose that does not alter the test animal's longevity or well-being because of noncancer effects.
The committee chose as its first task to address the use and limitations of MTD testing in long-term animal bioassays for carcinogenicity. The first report focuses specifically on whether the MTD should continue to be used in carcinogenicity bioassays, and it does not address all the issues related to performing carcinogenicity bioassay or interpreting their results.
In particular, the committee chose to investigate the observation that statistical analyses of the results of bioassays of many chemicals have shown strong correlations between measures of carcinogenic potency, such as the TD50 (the dose that causes tumors in 50% of test animals that would otherwise be tumor-free), and measures of toxicity, including the MTD. The strength of the correlations suggests that carcinogenicity is inherently related in some way to other toxic effects produced by a chemical, although dependence on such factors as the bioassay design and the mathematical and statistical methods used to estimate potency and investigate the correlations has also been proposed.
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The committee concluded that the correlations are not wholly mathematical or statistical artifacts, but are due partially to an underlying relationship between measures of general toxicity (e.g., the MTD) and measures of carcinogenic potency. The relationship can be expressed as follows: increases in cancer incidence large enough to be detected (i.e., to be statistically significant) in standard bioassays generally occur only at doses near the MTD. The committee suggests that because of the relationship between TD50s and the MTDs, a preliminary (and perhaps uncertain) estimate of the potential carcinogenic potency of an untested chemical can be derived from its MTD. Such an estimate is a plausible upper bound on the carcinogenic potency of a chemical, if in fact it is a carcinogen. Such estimates can prove useful in setting priorities for carcinogenicity testing and in estimating cancer risk when carcinogenicity data are not available. If an upper-bound estimate predicts a small human risk, a chemical could be given a low priority for carcinogenicity testing or might be deemed suitable for use with less extensive testing than might otherwise be required.
The committee noted that because specific criteria for selecting the HDT vary, even under the current guidelines, reports of bioassay results should include a clearly stated rationale for dose selection and a summary of the toxicity information important for evaluating the dose selection to facilitate interpretation.
The usefulness of information from bioassays conducted at the MTD has been questioned for several reasons. First, some believe that the proportion of compounds found to be carcinogenic at the MTD is so large that regulatory attention and public concern might be applies to agents that pose only trivial hazards. (The committee did not review such regulatory attention.) Second, it has been argued that some agents induce cancer at the MTD through mechanisms that do not occur at lower doses. Several mechanisms of carcinogenesis have been hypothesized to be effective only at high doses, such as increased cell proliferation rates in response to high dose toxicity or as a result of receptor complex-mediated alterations in cell growth control. According to these hypotheses, exposure at lower doses, where these mechanisms are inactive, would not result in a carcinogenic response. (The committee noted several examples of agents for which these hypotheses had been proposed, but did not reach conclusions on their proof or consensus on the generality of their application.) Third, it has been asserted that current
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bioassays, which generally involve only doses at or near the MTD, provide little information that is useful for defining the dose-response relationship. Defining the shape of the dose-response curve at lower doses would provide information that has greater relevance to human exposures and consequent risks. (The committee noted that validation of methods for extrapolation of dose-response relationship over wide ranges was beyond the scope of the study, although human exposure to some carcinogens at doses approximating those used in bioassays is known to occur.)
The committee noted several limitations in the information provided by current bioassays that use the MTD. Those assays often do not incorporate doses smaller than one-fourth of the MTD, so they do not provide direct information on the carcinogenic potential of a test substance at lower doses. But tests conducted at lower doses will probably have little power to detect carcinogenic effects, unless the number of animals tested is increased immensely, which would increase the cost of a bioassay commensurately; the large number of animals required for detection of the smaller increase in tumors incidence that might occur at low doses is one of the primary reasons for use of the MTD in carcinogenicity bioassays. Testing at doses that induce overt toxicity, however, can lead to changes in an animal's food consumption, recurrent cytotoxicity, and hormonal imbalance, all of which an increase or decrease carcinogenic responses at particular target sites. A rodent bioassay might yield information whether a chemical produces tumors in rodents, but generally can provide only scanty information on whether it produces tumors through generalized indirect mechanisms or directly as a result of its specific properties. Other data are required for extrapolating bioassay results to other doses or from animals to humans or for evaluating the possibility that indirect mechanisms of carcinogenesis can contribute to the results.
Despite those limitations, the majority of the committee concluded that current bioassays that incorporate the MTD provide some information that is useful for hazard identification and risk assessment. The assays identify substances that do or do not increase the incidence of cancer under standardized test conditions; in the case of substances that do not increase the incidence, the assays provide an operational definition of noncarcinogen. They identify target organs that show which tumor types are associated with exposure, thereby providing guidance
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for epidemiologic studies, although concordance among species is often absent. They also provide a basis for interspecies comparisons and they provide useful information on the carcinogenic potency of a chemical at high doses, as well as on differences in sensitivity between the sexes and among different strains and species of rodents, which are the test animals almost universally used.
The committee recognizes that bioassays conducted at the MTD are not designed to provide information on a biochemical and physiologic mechanisms of tumors production. Nor do they provide direct information on the shape of the dose-response curve at doses below the lowest experimental dose, which often include doses to which humans are exposed.
The committee considered four major options for modification of current bioassay procedures: (1) retain the status quo, possibly with the addition of doses lower than the MTD; (2) use a high dose that is an arbitrary fraction of the estimated maximum tolerated dose; (3) redefine the MTD, basing it on studies of the dose dependence of physiologic effects expected to alter carcinogenic response; and (4) use MTD testing as part of an overall testing strategy that separates carcinogens from noncarcinogens but also provides additional information useful for determining human relevance.
After extensive deliberation and consideration of those options, the committee was unable to come to a unanimous decision on a recommendation. Two points of view emerged. The majority of the committee considered option 4 (which recommends that the MTD, as currently defined, continue to be one of the doses used in carcinogenicity bioassays) to be appropriate and prudent. However, a sizable minority (six of the 17 committee members) did not fully agree with the conclusions and recommendations reached by the majority and prepared an alternative recommendation. The two groups' recommendations are summarized below.
The majority of the committee prefers option 4 and recommends that the MTD, as currently defined, continue to be one of the doses used in carcinogenicity bioassays. Other doses, from one-half to possibly one-tenth of the MTD or even smaller, should also be used, taking into account the capacity of the test animals to metabolize the test substance. If bioassay results are negative in both sexes of two species, generally no additional tests related to carcinogenicity are required. If the results
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are positive, additional studies should be performed to reduce uncertainties in the prediction of human responses to the material and in the quantification of human risk. The additional studies should address mechanisms of cancer induction, toxicokinetics and metabolism of the substance, and physiologic responses induced by the substance. The committee notes that regulation of a chemical can be instituted (for public health reasons and to protect human lives while more data are being collected) at almost any stage of data collection and that regulation can be modified as additional data become available.
The minority of the committee believes that the process for selecting doses to be used in a carcinogenicity bioassay should be modified (option 3). Specifically, the minority recommends that dose selection be done by a panel of experts on the basis of careful evaluation of appropriate subchronic studies conducted before the bioassay is initiated. The HDT should be chosen as the highest dose that can be expected to yield results relevant to humans, not simply the highest dose that can be administered to animals without causing early mortality from causes other than cancer (i.e., the MTD as currently defined). (In contrast, the majority believes that the decision regarding results obtained with the MTD can best be made after the MTD data are collected and that future decisions—regarding either regulation or additional studies—are better grounded if these data are present than if they are absent. The minority recognizes that chronic animal bioassays were originally designed to answer a simple question: Can chemicals cause cancer in animals? It is clear that the primary motivation for conducting the chronic bioassay today, however, is to determine whether the substances tested are likely to pose a substantial cancer risk to human populations. Therefore, the minority finds that a core of basic information should be gathered before the chronic bioassay is initiated, so that the study can be designed to achieve its objective.
The minority therefore recommends that the HDT in a bioassay be selected after a careful evaluation of results of subchronic studies conducted before the 2 year bioassay (option 3). In option 3, a core of basic information gathered before the bioassay would include information about the mechanisms of toxicity in test animals and an elucidation of the dose-response curve for such toxicity. That information is important because there is concern that induction of substantial toxicity throughout the lifetime of an animal might affect the rate at which tu-
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mors develop. Information would also be required on how dosage (including repeated exposures) affects biochemical and physiologic processes that are responsible for homeostasis, cell proliferation, hormonal balance, and the uptake and metabolism of the test chemical. All those processes are known to influence cancer incidence.
In some circumstances, adoption of option 3 would not change the magnitude of the HDT. For example, if human populations were exposed to high concentrations of the test substance, the HDT might be the MTD. However, in many cases, the HDT could be much lower than the current MDT, and the range of doses tested might be much wider than that used in current studies.
The principles recommended by Sontag et al. in 1976 (and endorsed by the majority of the committee) were designed to minimize the frequency of false-negative results (i.e., to maximize the sensitivity of the bioassay). The minority believes that the changes it recommends would improve the relevance of the bioassay for human populations by increasing the specificity of the test. (The majority points out that any increase in specificity resulting from the change proposed by the minority would be accompanied by a decrease in sensitivity, and the committee did not investigate the extent to which the change would allow human carcinogenicity to go undetected.)
The minority recognizes the implementation of option 3 would not be trivial. Guidelines for the amount of information required before bioassays are initiated would have to be modified. Criteria for dose selection would vary from chemical to chemical. It is clearly beyond the scope of the minority recommendation to specify all the details for this paradigm shift. However, the minority believes that implementation of its recommendation is feasible within the current testing framework. For example, review of scientific criteria for selection of bioassay doses by the National Toxicology Program (NTP) could be carried out by its Board on Scientific Counselors. (The board currently reviews the selection of compounds to be tested by NTP and reviews NTP's reports, but does not review the selection of doses for testing by NTP.) Other testing organizations might use other review boards before commencing studies.
The inability of the committee to come to unanimity on its primary recommendations reflects differing judgments on which approach to
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carcinogenicity testing would be most effective in providing information to assist risk managers, given the incomplete scientific understanding of chemical carcinogenesis in rodents and humans.
The Two-Stage Model of Carcinogenesis
Efforts to improve cancer risk assessment have resulted in the development of a mathematical dose-response model, called the two-stage model, that is based on a two-stage paradigm for the biologic phenomena thought to be associated with carcinogenesis. This paradigm is based on the relationship between tumor incidence and age, which suggests that at least two critical cellular changes are necessary for the development of many nonhereditary tumors. Current evidence suggests that some tumors might require more than two critical events to be expressed as human cancer. More complex models might be needed to describe multistage carcinogenesis accurately; however, it is hoped that the two-stage model will provide more accurate estimates of the cancer potency of chemicals that the multistage models currently in use by regulatory agencies.
Applying the two-stage model requires more extensive biologic data than current procedures; and because its feasibility as a tool for routine regulatory use has been questioned CRAM chose as its second task to evaluate the data needs and regulatory applicability of two-stage models of carcinogenesis. The committee considered several applications of the two-stage model to rodent carcinogens with different mechanisms of action and different quantities of available data. The committee noted that numerous assumptions were required to apply the model in each case. Assumptions must be made about mechanisms of action, appropriate target cells, time dependence, and the shape of the dose-response relationship. Extensive data would have to be obtained to reduce the current uncertainty in these assumptions. In fact, for very few chemicals are data sufficient to support the use of this model.
By studying specific application of the two-stage model, the committee determined that when different forms of the model are consistent with a particular data set, risk estimates can differ by several orders of magnitude. Therefore, the committee concluded that even if an agent's
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mechanisms of action are well understood, it will be still be very difficult to determine its dose-response relationship accurately enough to predict doses that correspond to risk as low as one in a million.
The strength of the two-stage model for application in cancer risk assessment is its ability to use information about intermediate steps in carcinogenesis; however, it is difficult to characterize these steps. Few experimental data sets now available provide all the types of data required. Before the two-stage model can be adopted for routine health risk assessments, it will be necessary to expand current rodent bioassay methods so that the necessary data are generated. The two-stage model can be used now to gain insights into induced carcinogenesis, such as identifying and characterizing the critical events, as well as to examine the ranges of assumptions. The committee strongly encourages further development and continued applications of the two-stage model to gain insight into its usefulness.
Two general approaches have been used for fitting two-stage models to data. One involves specifying trial values of parameters and simulating the subsequent tumor response. Values are then varied until the realizations conform to the data. The second approach involves applying standard statistical data-fitting methods (e.g., the methods of maximum likelihood). The former approach can be quite useful in some circumstances (such as exploratory data analysis). However, the committee encourages the use of formal statistical methods, whenever possible, to estimate values of parameters, assess goodness of fit, calculate statistical confidence-intervals for values of parameter sand risk estimates, and determine the extent to which the model is consistent with other mathematical representations and ranges of risk.
Two-stage models can be used as a basis for decision-making if there is sufficient mechanistic understanding and a sufficient data base for the chemical in question. At present, it is recommended that the two-stage model be used primarily to increase understanding. For health risk assessments, the two-stage model can be used with other models to add perspective and scope to the evaluation.
A Paradigm for Ecologic Risk Assessment
The third issue addressed by the committee and the subject of the last
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report in this volume is a conceptual framework for ecologic risk assessment, defined as the characterization of the adverse ecologic effects of environmental exposures to hazards imposed by human activities. The workshop held on this subject had three principal goals: (1) to survey existing approaches to ecologic risk assessment through case studies representing various types of environmental stresses, (2) to consider the feasibility of developing a consistent framework for ecologic risk assessment analogous to the four-part health risk assessment framework proposed in the 1983 NRC report, and (3) to identify major scientific uncertainties and research needs common to many types of ecologic risk assessments.
The committee's principal conclusion is that, despite the diversity of subject matter and approaches taken in many different studies of ecologic stresses, a conceptual framework similar in form to that of the 1983 framework is applicable to ecologic risk assessments. However, for general applicability to ecologic assessments, the 1983 scheme requires augmentation to address some common grounds between science and management, primarily because of the need to focus on appropriate questions relevant to applicable environmental law and policy under different circumstances. Specifically, the scheme needs to address the influence of legal and regulatory considerations on the initial stages of ecologic risk assessment and the importance of characterizing ecologic risks in terms that are intelligible to risk managers. The committee's opinion is that such augmentation is as important for human health risk assessment as it is for ecologic risk assessment.
Although ecologic risk assessment and human health risk assessment differ substantially in their scientific disciplines and technical problems, the committee believes that the underlying decision process is the same for both. Therefore, the committee recommends that a uniform framework be adopted and applied to ecologic and human health risk assessment—a framework that is flexible and able to facilitate communication between scientists and risk managers. The committee extends the 1983 framework to satisfy those requirements.
The committee recommends that the use of risk assessment in strategic planning and priority-setting be expanded so that financial resources of state and federal environmental agencies can be focused on critical environmental problems and uncertainties.
The committee also recommends that research programs be estab-
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lished and maintained to improve the credibility of ecologic risk assessments and that ecologic risk assessments be followed by systematic research and monitoring to determine the accuracy of their predictions and to resolve remaining uncertainties.
The committee identified the following kinds of research as likely to provide major opportunities for advancement of ecologic risk assessment:
Extrapolation across scales of time, space, and ecologic organization.
Quantification of uncertainty.
Validation of predictive tools.
Valuation, especially quantification of ''nonuse" values (values for environmental attributes that cannot be bought or sold).
Finally, the committee recommends that expert committees drawn from the academic community, the private sector, and regulatory agencies develop technical guidance on the scientific conduct of ecologic risk assessments.
Representative terms from entire chapter:
risk assessments
