Proposed Guidelines for Carcinogen Risk Assessment
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The Proposed Guidelines for Carcinogen Risk Assessment were published in the Federal Register on April 23, 1996 (Federal Register: 17960-18011) for a 120-day public review and comment period. The Proposed Guidelines are a revision of EPA's 1986 Guidelines for Carcinogen Risk Assessment (51 FR 33992), and when final, will replace the 1986 cancer guidelines. The full text of the FR notice also is being made available via the Internet.
Since the publication of the 1986 cancer guidelines, there is a better understanding of the variety of ways in which carcinogens can operate. Today, many laboratories are moving toward adding new test protocols in their programs directed at mode of action questions. Therefore, the Proposed Guidelines provide an analytical framework that allows for the incorporation of all relevant biological information, recognize a variety of situations regarding cancer hazard, and are flexible enough to allow for consideration of future scientific advances.
The 1986 cancer guidelines have several limitations in addition to their inadequacy in addressing recent gains in the understanding of carcinogenesis. Although they called for the evaluation of all relevant information, the classification scheme used for identifying potential human hazard relied heavily on tumor findings, and in practice, seldom made full use of all biological information. Moreover, the conditions of the hazard were not taken into account. For example, it was common to assume that if an agent was carcinogenic by one route of exposure (e.g., inhalation), it posed a risk by any route. The 1986 cancer guidelines are also confined in that dose-response assessment allowed for only one default approach (i.e., the linearized multistage model for extrapolating risk from upper-bound confidence intervals). Moreover, very little guidance was given for risk characterization, the component of risk assessment that describes potential human risk, strengths and weaknesses of data, size of risk, and confidence of the conclusions for the risk manager. The Proposed Guidelines include the following changes to address these limitations, accommodate new information on carcinogenesis, and advance cancer risk assessment:
- Hazard Assessment Emphasizes Analysis of All Biological Information rather than just tumor findings.
- Agent's Mode of Action is Emphasized to reduce the uncertainty in describing the likelihood of harm and in determining the dose response approach(es). This emphasis should provide incentive for generating key information needed to reduce the default assumptions used in risk assessment.
- Hazard Characterization is Added to Integrate the Data Analysis of all relevant studies into a weight of evidence conclusion of hazard, to develop a working conclusion regarding the agent's mode of action in leading to tumor development, and to describe the conditions under which the hazard may be expressed (e.g., route, pattern, duration, and magnitude of exposure).
- Weight of Evidence Narrative Replaces the Current Alphanumeric Classification. The narrative is intended for the risk manager and lays out a summary of the key evidence, describes the agent's mode of action, characterizes the conditions of hazard expression, and recommends appropriate dose response approach(es). Significant strengths, weaknesses, and uncertainties of contributing evidence are highlighted. The overall conclusion as to the likelihood of human carcinogenicity is given by route of exposure.
- Three Descriptors for Classifying Human Carcinogenic Potential: "known/likely", "cannot be determined", and "not likely" replace the six alphanumeric categories (A,B1,B2,C,D,E) in the 1986 cancer guidelines. Subdescriptors are provided under these categories to further differentiate an agent's carcinogenic potential.
- Biologically Based Extrapolation Model is the Preferred Approach for quantifying risk. It is anticipated, however that the necessary data for the parameters used in suchmodelswill not be available for most chemicals. The Proposed Guidelines allow for alternative quantitative methods, including several default approaches.
- Dose Response Assessment is a Two Step Process. In the first step, response data are modeled in the range of observation and in the second step, a determination of the point of departure or range of extrapolation below the range of observation is made. In addition to modeling tumor data, the new guidelines call for the use and modeling of other kinds of responses if they are considered to be measures of carcinogenic risk.
- Three Default Approaches--Linear, Nonlinear, or Both are provided. Curve fitting in the observed range would be used to determine the effective dose corresponding to the lower 95% limit on a dose associated with 10% response (LED10). The LED10 would then be used as a point of departure for extrapolation to the origin as the linear default or for a margin of exposure (MOE) discussion as the nonlinear default. The LED10 is the standard point of departure, but another may be used if more reasonable given the data set [(e.g., a no observed adverse effect level (NOAEL)]. In support of discussion of the anticipated decrease in risk associated with various MOEs, biological information concerning human variation and species differences, the slope of the dose response at the point of departure, background human exposure (if known), and other pertinent factors would be taken into consideration.
- Descriptions of Major Default Assumptions and Criteria for Departing From Them are described.
- Risk Characterization is More Fully Developed by providing direction on how the overall conclusion and confidence of risk is presented for the risk manager. The Proposed Guidelines call for assumptions and uncertainties to be clearly explained.