Questions and Answers: EPA's Guidelines for Carcinogen Risk Assessment and Supplemental Guidance from Assessing Susceptibility from Early-Life Exposure to Carcinogens
Risk Assessment Forum
March 29, 2005
EPA's Guidelines for Carcinogen Risk Assessment
And Supplemental Guidance from Assessing Susceptibility from Early-life
Exposure to Carcinogens
Questions and Answers
The following questions and answers provide general information and a summary of key points in EPA's "Guidelines for Carcinogen Risk Assessment", hereafter referred to as Cancer Guidelines, or Guidelines, and Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens, hereafter referred to as Supplemental Guidance.
SECTION I. GENERAL
1. What are EPA's "Guidelines for Carcinogen Risk Assessment"?
EPA's cancer guidelines set forth recommended principles and procedures to guide EPA scientists in assessing the cancer risks from chemicals or other agents in the environment. They also inform EPA decision makers and the public about these procedures. The cancer guidelines are used with other risk assessment guidelines that the Agency has developed, such as guidelines for exposure assessment, in developing an overall characterization of risk to human health. Collectively, all the risk assessment guidelines are intended to promote consistency and technical quality in EPA risk assessments while providing flexibility to utilize yet-to-be-developed information and procedures.
2. Why is EPA revising its 1986 final cancer guidelines?
EPA began revising the 1986 cancer guidelines in light of significant advances in our understanding of the processes of cancer development and the modes of actions of disease at the cellular level. The risk assessment guidelines are meant to be dynamic, flexible documents that would evolve to reflect the current state of the science and risk assessment practices.
3. What is the history of the cancer guidelines?
EPA published cancer guidelines in 1986 and interim revisions in 2001. As with other risk assessment guidelines, EPA has been working to revise the cancer guidelines to reflect advances in scientific understanding as well as experience in using them. Milestones in the revisions to the cancer guidelines include the following:
- In 1996, EPA issued proposed revisions to the cancer guidelines. The proposed guidelines have been subject to extensive public comment and scientific peer review, including three reviews by EPA's Science Advisory Board (SAB).
- In 1997, the SAB completed comments from its first review of the proposed guidelines.
- In January 1999, the SAB reviewed key sections of the proposed guidelines that had been revised to address prior SAB and public comments.
- In July 1999, the SAB began a third review that focused on revisions of the guidelines addressing risks to children. EPA received the report from this review in 2000.
- In November 2001, EPA published in the Federal Register, a Notice of Intent to finalize the cancer guidelines, and provided an opportunity to provide additional information and comment. At the same time EPA identified the draft 1999 guidelines as interim EPA guidance pending issuance of final revised guidelines.
- In March 2003, drafts of the cancer guidelines and a supplement focusing on susceptibility to cancer from early-life exposure to carcinogens were made available for public review and comment. In May 2003, the supplement underwent SAB review.
- In March 2004, EPA received SAB comments on the Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens. In response to one of their recommendations, EPA extended the analysis supporting the Supplemental Guidance. This analysis has been accepted for publication in the peer-reviewed journal, Environmental Health Perspectives. A separate peer review of this analysis was also conducted.
- In March 2005, EPA published revised Cancer Guidelines and the Supplemental Guidance.
4. How do the revised Guidelines incorporate our knowledge of how an agent causes cancer into the risk assessment process?
Cancer refers to a group of diseases involving abnormal, malignant tissue growth. Research has revealed that the development of cancer involves a complex series of steps and that carcinogens may operate in a number of different ways. Ultimately, cancer results from a series of defects in genes controlling cell growth, division, and differentiation. Genetic defects leading to cancer may occur because a chemical (or other carcinogenic agent) damages DNA directly. Alternatively, an agent may have indirect effects that increase the likelihood, or accelerate the onset, of cancer without directly interacting with DNA. For example, an agent might interfere with DNA repair mechanisms; thereby increasing the likelihood that cell division will give rise to cells with damaged DNA. An agent might also increase rates of cell division, thus increasing the potential for genetic errors to be introduced as cells replicate their DNA in preparation for division.
The Guidelines emphasize the value of understanding the biological changes that the agent can cause and how these changes might lead to the development of cancer. They also discuss methods to evaluate and use such information, including information about an agent's postulated mode of action, or the series of steps and processes that lead to cancer formation. Mode-of-action data, when available and of sufficient quality, may be useful in drawing conclusions about the potency of an agent, its potential effects at low doses, whether findings in animals are relevant to humans, and which populations or lifestages may be particularly susceptible. In the absence of mode-of-action information, default options are available to allow the risk assessment to proceed.
5. What is the approach used in the Guidelines for "default optionsv?
Default options are approaches that EPA can apply in risk assessments when critical information about the effects of an agent on human health is unavailable, limited, or of insufficient quality. For example, if no information is available on the effects of an agent on humans, a common default option is that adverse effects observed in animals due to chemical exposure have the potential to occur in humans as well. In the Guidelines, EPA has articulated its policy regarding when it is appropriate to invoke various default assumptions, based on comments from the SAB and others. EPA's recommended approach is to begin with a critical analysis of available information, and then only invoke default options if needed to address uncertainty or the absence of critical information.
6. How do the Guidelines account for the variability in susceptibility to carcinogens among the human population?
EPA's Guidelines explicitly recognize that variability can exist among people in their susceptibility to carcinogens. Individuals in some subpopulations may experience increased susceptibility to carcinogens throughout their lives, such as people who have an inherited predisposition to certain cancer types or reduced capacity to repair genetic damage. Also, during certain lifestages the population may experience heightened susceptibility to carcinogens. In particular, EPA notes that childhood may be a lifestage of greater susceptibility for a number of reasons, such as that related to the rapid growth and development that occurs prenatally and after birth. Some of the aspects of the Guidelines that account for potentially susceptible subpopulations and lifestages include the following:
- The Guidelines recommend estimating the internal dose experienced by children to predict the toxic effects from such doses.
- The Guidelines encourage and provide guidance for developing separate risk estimates for children when pertinent data are available.
- The Guidelines encourage consideration of differences in diet and behavior patterns among subpopulations and lifestages that may increase exposure to potential carcinogens.
7. How does EPA characterize an agent's potential for human carcinogenicity under the Guidelines?
The Guidelines recommend that an agent's human carcinogenic potential be described in a weight-of-evidence narrative. The narrative summarizes the full range of available evidence and describes any conditions associated with conclusions about an agent's hazard potential. For example, the narrative may explain that an agent appears to be carcinogenic by some routes of exposure but not others (e.g., by inhalation but not ingestion). Similarly, a hazard may be attributed to exposures during sensitive lifestages of development but not at other times. The narrative also summarizes uncertainties and key default options that have been invoked.
To provide additional clarity and consistency in weight-of-evidence narratives, the Guidelines suggest a set of weight-of-evidence descriptors to accompany the narratives. The Guidelines emphasize that risk managers consider the full range of information in the narratives and not focus exclusively on the descriptors. As in the case of the narratives, descriptors may apply only to certain routes of exposure, dose ranges, and durations of exposure. The five descriptors are:
- Carcinogenic to Humans
- Likely to be Carcinogenic to Humans
- Suggestive Evidence of Carcinogenic Potential
- Inadequate Information to Assess Carcinogenic Potential
- Not Likely to be Carcinogenic to Humans
8. What is new in the Guidelines issued in March 2005 when compared to the interim guidance provided in the July 1999 Draft Revised Guidelines?
The revised Guidelines reflect public comments received in response to the March 2003 Federal Register notice, the November 2001 Federal Register notice, as well as EPA's experience in applying the July 1999 Draft Revised Guidelines.
Specific changes include:
- Clarification that EPA recommends that assessments begin with a critical analysis of the available data and that default options be invoked on an as needed basis when there is too much uncertainty or critical data are missing.
- Refinement of the guidance addressing the weight of evidence narrative and use of the associated descriptors. The Guidelines emphasize the importance of weighing all of the evidence in reaching conclusions about the human carcinogenic potential of agents. The Guidelines recommend this be accomplished in a single step after assessing all of the individual lines of evidence. Examples of the kinds of results that can lead to the use of a particular descriptor are included in the Guidelines.
- Understanding of mode of action can be a key to identifying processes that may cause agent exposures to differentially affect a particular population segment or lifestage. The framework for analysis of mode of action data has been revised to recommend consideration of any populations or lifestages that can be particularly sensitive in light of the hypothesized mode of action.
- Because the Guidelines recommend consideration of possible sensitive subpopulations and lifestages (such as childhood), EPA developed a supplemental guidance, entitled, "Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens." This Supplemental Guidance describes approaches that could be used to assess risks resulting from early life exposure to environmental contaminants (Supplemental Guidance is discussed in more detail in Section II). As with the Guidelines, the Supplemental Guidance is intended as a non-binding statement of policy. Risk assessments may employ different methods for a variety of reasons, including new information, methods, or scientific judgment.
- In keeping with the goal of harmonizing cancer and noncancer risk assessment practices, the Guidelines recommend the use of EPA's approach to setting noncancer reference values (oral reference doses [RfD] and inhalation reference concentrations [RfC]) in situations where the carcinogenic mode of action is determined to be nonlinear.
SECTION II. SUPPLEMENTAL GUIDANCE ON EARLY-LIFE EXPOSURE
9. What is the Supplemental Guidance? Why is it necessary?
The document entitled, "Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens," describes approaches that EPA could use in assessing risks from early-life exposure to potential carcinogens. This guidance reflects public comments and recommendations from the SAB's review of the external review draft (March 2003).
The Supplemental Guidance is part of EPA's response to the recommendation of the National Research Council (1994) that "EPA should assess risks to infants and children whenever it appears that their risks might be greater than those of adults." For several potential carcinogens, there is some evidence of higher cancer risks following early-life exposure. Accordingly, the potential for higher risks from early-life exposure warrants explicit consideration in each assessment.
10. What does the Supplemental Guidance contain? How will it be used?
The Supplemental Guidance describes the approaches that EPA could use in assessing cancer risks following early-life exposures. The Supplemental Guidance also summarizes the results of the cancer studies that investigated early-life exposure, along with EPA's analysis of those studies.
EPA's headquarters and regional offices intend to refer to the Supplemental Guidance when assessing exposure scenarios that include exposure during childhood. Several examples in the Supplemental Guidance illustrate how early-life exposures can be assessed.
11. Why has the Supplemental Guidance been issued separately rather than included in the final Guidelines?
The Supplemental Guidance focuses on assessing the effects of early lifestage exposure and includes a review of existing scientific literature on chemical effects in animals and human exposure. Because the areas of carcinogenicity, genesis of disease, and effects on susceptible life stages and populations are constantly and quickly evolving, the EPA expects that this will be the first of several supplemental guidance documents to the Guidelines. These companion documents will provide additional information on how to address certain aspects of children's risk to the cancer causing effects of some chemicals.
12. Does the Supplemental Guidance address all potential carcinogens?
The Supplemental Guidance recommends consideration of all studies on the effects of early-life exposures. For the common case where there are no early-life studies on a potential carcinogen, the final Guidelines suggest consideration of the carcinogen's mode of action. The Supplemental Guidance addresses carcinogens with a mutagenic mode of action in detail because currently most early-life studies are for carcinogens with a mutagenic mode of action. As new research leads to more conclusive evidence, EPA intends to update this guidance to address other modes of action.
13. Do the revised Guidelines or the Supplemental Guidance recommend development of specific data on children's risk?
Both the Guidelines and the Supplemental Guidance discuss general ways of proceeding when there are no early-life studies on a potential carcinogen. Nonetheless, there may be cases where these general approaches may not adequately reflect differential risks to children. As in all cases, specific data on the effects of early-life exposures is valuable in improving the assessment.
14. The Supplemental Guidance states that the data and analyses used in deriving the adjustments to potency are available on EPA's web site. Which site? What is available on that site?
Access to data and other information relating to the Cancer Guidelines and Supplemental Guidance will be through EPA's Risk Assessment Forum website, under Publications, Guidelines, Guidelines for Cancer Risk Assessment. The URL is http://epa.gov/cancerguidelines/. The data and results of analyses are available in spreadsheets.
15. Has the Supplemental Guidance undergone any reviews prior to being issued?
Yes. In March 2003, EPA began to receive public comment on an external review draft of the Supplemental Guidance. In May 2003, the EPA's Science Advisory Board reviewed the external review draft, and considered public comments in their review. The SAB issued their letter review in March 2004. In response to one of the SAB's recommendations, EPA developed additional statistical analyses. The analysis has been accepted for publication in the National Institute of Environmental Health Sciences' peer-reviewed journal, Environmental Health Perspectives. This article is expected to be in a Spring 2005 issue of the journal. An independent peer review of the additional analysis was also conducted earlier in 2005.
SECTION III. IRIS AND THE CANCER GUIDELINES
16. What is IRIS (www.epa.gov/IRIS)?
IRIS, the Integrated Risk Information System, is an EPA database containing EPA's position on the potential adverse human health effects that may result from chronic (or lifetime) exposure to specified chemical substances found in the environment. IRIS currently provides health effects information on over 500 specific chemical substances. IRIS contains chemical specific summaries of qualitative and quantitative health information in support of the first two steps of the risk assessment process, i.e., hazard identification and dose response evaluation. IRIS information includes the reference dose for noncancer health effects resulting from oral exposure, the reference concentration for noncancer health effects resulting from inhalation exposure, and the cancer assessment for both oral and inhalation exposure. Combined with specific situational exposure assessment information, the summary health hazard information in IRIS may be used as a source in evaluating potential public health risks from chemical substances found in the environment.
17. How is the information in IRIS developed?
EPA's current process for developing IRIS information consists of: (1) an annual Federal Register announcement of EPA's IRIS agenda and call for scientific information from the public on the selected chemical substances, (2) a search of the current literature, (3) development of health assessments and draft IRIS summaries, (4) peer review within EPA, (5) peer review outside EPA and solicitation of public comment, (6) EPA management review and approval, (7) preparation of final IRIS summaries and supporting documents, and (8) entry of summaries and supporting documents into the IRIS database.
18. What is the relationship between EPA's IRIS and the cancer guidelines?
An IRIS file may include descriptive and quantitative human health risk information on both noncancer and cancer effects. EPA's cancer guidelines provide guidance to Agency risk assessors in developing the cancer risk assessment portion of the IRIS file. Since the mid-1980s, when IRIS was developed, the cancer summary files were guided first by the 1984 proposed cancer guidelines and then by the 1986 final Guidelines. While the 1986 guidelines have guided the development of the IRIS cancer risk information for many years, cancer risk assessments have been informed by other considerations such as evolving science, the facts of the particular case, and scientific judgment. On November 29, 2001, EPA announced in the Federal Register that the July 1999 Draft Final Revised Guidelines would serve as interim guidance, and this is reflected in IRIS assessments developed since that time. The IRIS program will begin using the Guidelines in new or revised assessments.
19. What will be EPA's approach to implementing the revised Guidelines and the supplemental guidance?
Effective immediately, the Guidelines and Supplemental Guidance will serve as EPA's recommendation to Agency risk assessors preparing cancer risk assessments. As EPA prepares cancer assessments under the Integrated Risk Information System (IRIS) program, as well as in other EPA programs, the Agency will begin to use the Guidelines and Supplemental Guidance. EPA also will consider the Guidelines and Supplemental Guidance along with other selection factors when EPA selects substances for reassessment in annual IRIS agendas (see for example, 70 FR 10616, March 4, 2005).
SECTION IV. CANCER RESEARCH ACTIVITIES
20. What is EPA doing to reduce both its reliance on default options and the uncertainties that, to date, have been inherent in human health risk assessment?
EPA began revising the 1986 cancer guidelines in light of significant advances in our understanding of the processes of carcinogenesis and the modes of action of disease at the cellular level. Some of the work in these areas that led to advances is the result of EPA research efforts over the past several years. Because our understanding of carcinogenicity, causation of disease, and effects on susceptible lifestages and populations are constantly and quickly evolving, EPA intends to continue research work in this area, as well as collaborate with other research organizations to produce research that ultimately serves to reduce both uncertainties in cancer risk assessments and reduce EPA's reliance on default options.
21. Does EPA intend to continue conducting cancer research?
Yes. To enhance the understanding of the biological processes of cancer and age-related cancer sensitivity to environmental factors, EPA will continue to collaborate with other federal agencies, academia and the private sector to address these critical research issues.