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Risk Assessment for Carcinogens
EPA's first carcinogen risk assessment guidelines [1], published in 1986, were the product of nearly two decades of experience and scientific consensus building. EPA has since gained considerable experience in applying cancer risk assessment approaches. Concurrently, the science of risk assessment and toxicological testing has continued to evolve, and EPA has had to address situations not explicitly discussed in the 1986 guidelines, e.g., children's risk assessment. The revision of EPA's 1986 carcinogen risk assessment guidelines, currently underway, will consolidate the Agency's experience, provide more comprehensive and transparent guidance on topics not fully developed in the original guidelines, and provide flexibility to accommodate anticipated advances in the science.
Since 1996 EPA has applied the principles and procedures of the draft revised guidelines on a case-by-case basis for new hazard identifications and dose-response assessments. EPA now uses the most recent 1999 draft guidelines [2] in this regard. These interim guidelines represent the evolution of risk assessment methods rather than a dramatic shift in methodology. Application of the guidelines reflects EPA's accumulated experience and advances in our knowledge on cancer assessment. On the other hand, assessments for many substances that were prepared under the 1986 guidelines continue to be valid. Therefore, the dose-response assessments of carcinogens reflect a mixture of the application of 1986 guidelines and the 1999 interim guidelines.
Hazard Identification for Carcinogens. The 1986 guidelines recognized three broad categories of data: (1) human data (primarily epidemiological); (2) results of long-term experimental animal bioassays; and (3) supporting data, including a variety of short-term tests for genotoxicity and other relevant properties, pharmacokinetic and metabolic studies, and structure-activity relationships. In hazard identification of carcinogens under the 1986 guidelines, human data, animal data, and supporting evidence are combined to characterize the weight-of-evidence (WOE) regarding the agent's potential as a human carcinogen into one of several hierarchic categories [1]:
Group A -- Carcinogenic to Humans: Agents with adequate human data to demonstrate the causal association of the agent with human cancer (typically epidemiologic data).
Group B -- Probably Carcinogenic to Humans: Agents with sufficient evidence (i.e., indicative of a causal relationship) from animal bioassay data, but either limited human evidence (i.e., indicative of a possible causal relationship, but not exclusive of alternative explanations; Group B1), or with little or no human data (Group B2).
Group C -- Possibly Carcinogenic to Humans: Agents with limited animal evidence and little or no human data.
Group D -- Not Classifiable as to Human Carcinogenicity: Agents without adequate data either to support or refute human carcinogenicity.
Group E -- Evidence of Non-carcinogenicity for Humans: Agents that show no evidence for carcinogenicity in at least two adequate animal tests in different species or in both adequate epidemiologic and animal studies.
It is important to note that these WOE categories express only a relative level of certainty that these agents may cause cancer in humans. The categories specifically do not connote relative levels of hazard or degree of conservatism applied in developing a dose-response assessment. For example, a substance in group C (possible human carcinogen) may very well impart a greater cancer risk to more people than another substance in group A (known human carcinogen). EPA has classified substances as "possible" carcinogens only because the amount and quality of evidence were insufficient to place them in a higher group, not because EPA believes they necessarily present less risk.
The 1999 draft guidelines recommend expressing WOE by narrative statements rather than hierarchical categories, and expressing them separately for the oral and inhalation routes. While the 1999 guidelines remain in interim form EPA's practice has been for its assessment to include WOE evaluations using both the 1986 and 1999 guidelines. Table 1 has for the time being retained the alphanumeric category labels. At some point in the future, the table will also include excerpts of narrative WOEs.
Dose-Response Assessment for Carcinogens. EPA's 1986 cancer guidelines [1] adopted a default assumption that chemical carcinogens would exhibit risks at any dose. Linear extrapolation of risk in the low dose region was proposed as a reasonable upper-bound on risk (i.e., the true value of the risk is unknown, and may be as low as zero). This linear approach has been used to extrapolate the dose-response curve for most chemicals with adequate data.
Since the publication of EPA's original cancer guidelines in 1986, considerable new knowledge has been developed regarding the processes of chemical carcinogenesis and the evaluation of human cancer risk. The 1999 interim revised guidelines [2] depart from the original guidelines by identifying the presence of both linear and nonlinear modes of action for carcinogens. Cancer data in the observable range are analyzed using a dose-response model similar to the models used for noncancer effects. The method of extrapolation to lower doses from the point of departure may vary depending on whether the available data indicate a linear or nonlinear mode of action.
Under the 1999 guidelines, linear extrapolation remains appropriate when the evidence supports the mode of action of gene mutation due to direct DNA reactivity or another mode of action that is thought to be linear in the low dose region. A linear mode of action will also be the default when available evidence is not sufficient to support a nonlinear extrapolation procedure, even in the absence of evidence of DNA reactivity. Nonlinear methods are to be used if there is sufficient evidence to support a nonlinear mode of action.
The 1999 guidelines also revised and simplified the linear extrapolation methods presented in the 1986 guidance. For linear carcinogens, EPA's current process of estimating cancer risk is based on the unit risk estimate (URE) for inhalation, and the carcinogenic potency slope (CPS) for ingestion. The URE represents the upper-bound excess lifetime cancer risk estimated to result from continuous exposure to an agent at a concentration of 1 µg/m3 in air. The interpretation of the URE would be as follows: if the URE = 1.5 x 10-6 µg/m3, no more than 1.5 excess tumors are expected to develop per 1,000,000 people if exposed daily for a lifetime to a concentration of 1 µg of the chemical per cubic meter of air. The CPS is an upper bound, usually approximating a 95% confidence limit, on the increased cancer risk from a lifetime oral exposure to an agent. This estimate, usually expressed in units of proportion (of a population) affected per mg/kg/day, is generally reserved for use in the low-dose region of the dose-response relationship, that is, for exposures corresponding to risks less than 1 in 100.
The URE and CPS are plausible upper-bound estimates of the risk (i.e., the actual risk is likely to be lower, but may be greater). However, because the URE and CPS reflect unquantifiable assumptions about effects at low doses, their upper bounds are not true statistical confidence limits. The tabulated UREs and CPSs were developed by EPA and the California EPA, and were selected for use by a priority system.
References
- U.S. EPA. 1986. Guidelines for Carcinogen Risk Assessment. 51 FR 33992-34003.
- US EPA. 1999. Proposed Guidelines for Carcinogen Risk Assessment. NCEA-F-0644, available on-line at http://www.epa.gov/ncea/raf/car2sab/preamble.pdf