Notice of Availability of the Document Entitled Guidelines for Carcinogen Risk Assessment, 17766-17817 [05-6642]

Agencies

• ENVIRONMENTAL PROTECTION AGENCY

[Federal Register Volume 70, Number 66 (Thursday, April 7, 2005)]
[Notices]
[Pages 17766-17817]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 05-6642]



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Part II





Environmental Protection Agency





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Notice of Availability; Documents Entitled Guidelines for Carcinogen 
Risk Assessment and Supplemental Guidance for Assessing Susceptibility 
From Early-Life Exposure to Carcinogens; Notices

Federal Register / Vol. 70, No. 66 / Thursday, April 7, 2005 / 
Notices

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ENVIRONMENTAL PROTECTION AGENCY

[FRL-7895-2]


Notice of Availability of the Document Entitled Guidelines for 
Carcinogen Risk Assessment

AGENCY: U.S. Environmental Protection Agency (EPA).

ACTION: Notice of availability of final document.

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SUMMARY: This Notice announces the availability of the final document, 
Guidelines for Carcinogen Risk Assessment (EPA/630/P-03/001F), 
hereafter referred to as the Guidelines. These Guidelines were 
developed as part of an Agency-wide guidelines development program by a 
Technical Panel of the U.S. EPA's Risk Assessment Forum, which was 
composed of scientists from throughout the Agency. Selected drafts were 
peer reviewed internally by the U.S. EPA's Science Advisory Board, and 
by experts from universities, environmental groups, industry and other 
governmental agencies. The Guidelines were also subjected to several 
public comment periods. Issuance of these final Guidelines fulfills 
EPA's obligations under section 112(o) (7) of the Clean Air Act.

DATES: The Guidelines are available for use by EPA risk assessors as 
March 29, 2005.

ADDRESSES: This Notice contains the full Guidelines document. The 
Guidelines also are available electronically through the EPA Web site 
at https://www.epa.gov/cancerguidelines. A limited number of paper and 
CDROM copies will be available from the EPA's National Service Center 
for Environmental Publications (NSCEP), P.O. Box 42419, Cincinnati, OH 
45242; telephone: (800) 490-9198 or (513) 489-8190; facsimile: (513) 
489-8695. Please provide your name, mailing address and the title and 
number of the requested EPA publication (EPA/630/P-03-001F). 
Additionally, copies of the Guidelines will be available for inspection 
at EPA headquarters and regional libraries, through the U.S. Government 
Depository Library program.

FOR FURTHER INFORMATION CONTACT: Dr. William P. Wood, Risk Assessment 
Forum, National Center for Environmental Assessment (8601D), U.S. 
Environmental Protection Agency, Washington DC 20460, telephone: (202) 
564-3361; facsimile: (202) 565-0062; or e-mail: 
risk.forum@epamail.epa.gov.

SUPPLEMENTARY INFORMATION: In the 1983 Risk Assessment in the Federal 
Government: Managing the Process, the National Academy of Sciences 
recommended that Federal regulatory agencies establish ``inference 
guidelines'' to promote consistency and technical quality in risk 
assessment, and to ensure that the risk assessment process is 
maintained as a scientific effort separate from risk management. A task 
force within EPA accepted that recommendation and requested that EPA 
scientists begin to develop such guidelines. In 1984, EPA scientists 
began work on risk assessment guidelines for carcinogenicity, 
mutagenicity, suspect developmental toxicants, chemical mixtures and 
exposure assessment. Following extensive scientific and public review, 
these five guidelines were issued on September 24, 1986 (51 FR 33992-
34054). Since 1986, additional risk assessment guidelines have been 
developed, revised and supplemented.
    EPA continues to revisit the guidelines as experience and 
scientific consensus evolve. In 1996, the Agency published proposed 
revisions to EPA's 1986 cancer guidelines for public comment. Since the 
1996 proposal, the document has undergone extensive public comment and 
scientific peer review, including three reviews by EPA's Science 
Advisory Board (SAB) in February 1997, January 1999 and July 1999. The 
July 1999 review panel was supplemented by the EPA Children's Health 
Protection Advisory Committee. Public comments were received concurrent 
to each of these reviews. In 2001 (66 FR 59593, November 29, 2001) an 
additional public comment period was held requesting new information 
gained through the use of the July 1999 draft final revised guidelines 
on issues including, but not limited to, the nature and use of default 
assumptions; definition and application of hazard descriptors; 
identification of carcinogenic mode(s) of action and, in particular, 
consideration of relevancy for children (e.g., the potential for 
differential life stage susceptibility); and guidance on the use of the 
margin of exposure analysis. The notice also announced that the July 
1999 draft final revised guidelines would serve as EPA's interim 
guidance to EPA risk assessors preparing cancer risk assessment, until 
the issuance of final guidelines. In May 2003 EPA made available for 
public comment a revised draft of the guidelines, and in February 2005 
the guidelines underwent interagency review. The final Guidelines 
issued today are based, in part, upon the recommendations derived from 
public comments, workshops and recommendations of the SAB.
    CAA section 112(o)(7) provides ``[t]he Administrator shall 
consider, but need not adopt, the recommendations contained in the 
report of the National Academy of Sciences prepared pursuant to this 
subsection and the views of the Science Advisory Board, with respect to 
such report. Prior to the promulgation of any standard under [CAA 
section 112(f)], and after notice and opportunity for comment, the 
Administrator shall publish revised Guidelines for Carcinogenic Risk 
Assessment or a detailed explanation of the reasons that any 
recommendations contained in the report of the National Academy of 
Sciences will not be implemented.''
    In response to CAA section 112(o)(7), the 1994 National Research 
Council (NRC) report, and continuing developments in the science of 
cancer risk assessment, EPA began the process of revising its 
Guidelines for Carcinogen Risk Assessment. Revisions to the Guidelines 
were intended to make greater use of the increasing scientific 
understanding of the mechanisms that underlie the carcinogenic process. 
Several drafts of revisions to the Guidelines have been subject to 
extensive public comment and scientific peer review, including three 
reviews by EPA's SAB, as discussed above. EPA considered the 1994 
recommendations of the NRC on the Guidelines. EPA's approach to those 
NRC recommendations is reflected in the Guidelines. Draft EPA responses 
to the NRC recommendations were presented in the preamble to the 1996 
draft of these revised Guidelines (61 FR 18003, April 23, 1996). By 
issuing the final Guidelines which address the recommendations of the 
NRC, EPA has fulfilled its responsibilities under CAA section 
112(o)(7).

Features of the Guidelines

    The Guidelines are intended to make greater use of the increasing 
scientific understanding of the mechanisms that underlie the 
carcinogenic process. The final guidelines include discussions of all 
of the four steps of the risk assessment process and provide guidance 
to risk assessors on these steps. In applying these principles to the 
development of these Guidelines, the following key issues were 
highlighted: use of default options, the consideration of mode of 
action, understanding of biological changes, fuller characterization of 
carcinogenic potential, and consideration of differences in 
susceptibility.
    Use of default options--Default options are approaches that EPA can

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apply in risk assessments when scientific information about the effects 
of an agent on human health is unavailable, limited, or of insufficient 
quality. Under the final Guidelines, EPA's approach begins with a 
critical analysis of available information, and then invokes defaults 
if needed to address uncertainty or the absence of critical 
information.
    Consideration of mode of action--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. 
The final Guidelines emphasize the value of understanding the 
biological changes and how these changes might lead to the development 
of cancer. They also discuss ways 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 used 
to draw conclusions about the potency of a chemical, its potential 
effects at low doses, whether findings in animals are relevant to 
humans, and which populations or lifestages may be particularly 
susceptible.
    Fuller characterization of carcinogenic potential--In the final 
Guidelines, an agent's human carcinogenic potential is 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 a chemical appears to be carcinogenic by 
some routes of exposure but not by others (e.g., by inhalation but not 
ingestion). Similarly, a hazard may be attributed to exposures during 
sensitive life-stages 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 present a set of weight-
of-evidence descriptors that accompany the narratives. The Guidelines 
emphasize that risk managers should 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.
    Consideration of differences in susceptibility--The Guidelines 
explicitly recognize that variation may exist among people in their 
susceptibility to carcinogens. Some subpopulations may experience 
increased susceptibility to carcinogens throughout their life, such as 
people who have inherited predisposition to certain cancer types or 
reduced capacity to repair genetic damage. Also, during certain 
lifestages the entire 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: 
rapid growth and development that occurs prenatally and after birth, 
differences related to an immature metabolic system, and differences in 
diet and behavior patterns that may increase exposure.
    The final Guidelines explicitly call for consideration of possible 
sensitive subpopulations and/or lifestages (such as childhood). 
Therefore, concurrent with release of the final Guidelines, EPA 
published a separate guidance, entitled Supplemental Guidance for 
Assessing Susceptibility from Early-Life Exposure to Carcinogens (EPA/
630/R-03/003F), hereafter referred to as the Supplemental Guidance, 
describing possible approaches that could be used to assess risks 
resulting from early life exposure to potential carcinogens. The 
Supplemental Guidance is separate from the Guidelines so that it may be 
more easily updated in a timely manner given the expected rapid 
evolution of scientific understanding about the effects of early-life 
exposures. Availability of the Supplemental Guidance is announced in a 
separate notice, also published in today's Federal Register.

Risk Assessment Guidelines at EPA

    These Guidelines set forth principles and procedures to guide EPA 
scientists in the conduct of cancer risk assessments and to inform 
Agency decision makers and the public about these procedures. Policies 
in this document are intended as internal guidance for EPA. So risk 
assessors and risk managers at EPA are the primary audience. These 
Guidelines also provide basic information to the public about EPA's 
risk assessment methods. In particular, the Guidelines emphasize that 
risk assessments should be conducted on a case-by-case basis, giving 
full consideration to all relevant scientific information. This 
approach means that Agency experts study scientific information on each 
agent under review and use the most scientifically appropriate 
interpretation to assess risk. The Guidelines also stress that this 
information be fully presented in Agency risk assessment documents, and 
that Agency scientists identify the strengths and weaknesses of each 
assessment by describing uncertainties, assumptions and limitations, as 
well as the scientific basis and rationale for each assessment. The 
Guidelines are formulated in part to bridge gaps in risk assessment 
methodology and data. By identifying these gaps and the importance of 
the missing information to the risk assessment process, EPA wishes to 
encourage research and analysis that will lead to new risk assessment 
methods and data.
    The Guidelines are guidance only. They do not establish any 
substantive ``rules'' under the Administrative Procedure Act or any 
other law and have no binding effect on EPA or any regulated entity, 
but instead will represent a non-binding statement of policy. EPA 
believes that the Guidelines represent a sound and up-to-date approach 
to cancer risk assessment and enhance the application of the best 
available science in EPA's risk assessments. However, EPA cancer risk 
assessments may be conducted differently than envisioned in the 
Guidelines for many reasons, including (but not limited to) new 
information, new scientific understanding or new science policy 
judgment. The science of risk assessment continues to develop rapidly, 
and specific components of the Guidelines may become outdated or may 
otherwise require modification in individual settings. Use of the 
Guidelines in future risk assessments will be based on decisions by EPA 
that approaches from the Guidelines are suitable and appropriate in the 
context of those particular risk assessments. These judgments will be 
tested through peer review, and risk assessments will be modified to 
use different approaches if appropriate.
    Even though the Guidelines are not binding rules, EPA is issuing 
them in a manner consistent with the procedures in the Administrative 
Procedure Act that are generally applicable to rulemaking, including 
providing opportunity for public comment. EPA considered and responded 
to all significant public comments as it prepared the Guidelines and 
will send a copy of the final Guidelines to Congress. EPA certifies 
that the Guidelines will not have a significant impact on a substantial 
number of small entities, because the Guidelines are for the benefit of 
EPA and impose no requirements or costs on small entities.

Implementation

    Beginning today, Guidelines and Supplemental Guidance serve as 
EPA's

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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 intends to begin to use the Guidelines and 
Supplemental Guidance. EPA also intends to consider the Guidelines and 
Supplemental Guidance along with other selection factors when EPA 
selects agents for reassessment in annual IRIS agendas (see for 
example, 70 FR 10616, March 4, 2005).

    Dated: March 29, 2005.
Stephen L. Johnson,
Acting Administrator.

Contents

1. Introduction
    1.1. Purpose and Scope of the Guidelines
    1.2. Organization and Application of the Guidelines
    1.2.1. Organization
    1.2.2. Application
    1.3. Key Features of the Cancer Guidelines
    1.3.1. Critical Analysis of Available Information as the 
Starting Point for Evaluation
    1.3.2. Mode of Action
    1.3.3. Weight of Evidence Narrative
    1.3.4. Dose-response Assessment
    1.3.5. Susceptible Populations and Lifestages
    1.3.6. Evaluating Risks from Childhood Exposures
    1.3.7. Emphasis on Characterization
2. Hazard Assessment
    2.1. Overview of Hazard Assessment and Characterization
    2.1.1. Analyses of Data
    2.1.2. Presentation of Results
    2.2. Analysis of Tumor Data
    2.2.1. Human Data
    2.2.1.1. Assessment of Evidence of Carcinogenicity From Human 
Data
    2.2.1.2. Types of Studies
    2.2.1.3. Exposure Issues
    2.2.1.4. Biological Markers
    2.2.1.5. Confounding Actors
    2.2.1.6. Statistical Considerations
    2.2.1.6.1. Likelihood of Observing an Effect
    2.2.1.6.2. Sampling and Other Bias Issues
    2.2.1.6.3. Combining Statistical Evidence Across Studies
    2.2.1.7. Evidence for Causality
    2.2.2. Animal Data
    2.2.2.1. Long-term Carcinogenicity Studies
    2.2.2.1.1. Dosing Issues
    2.2.2.1.2. Statistical Considerations
    2.2.2.1.3. Concurrent and Historical Controls
    2.2.2.1.4. Assessment of Evidence of Carcinogenicity From Long-
term Animal Studies
    2.2.2.1.5. Site Concordance
    2.2.2.2. Perinatal Carcinogenicity Studies
    2.2.2.3. Other Studies
    2.2.3. Structural Analogue Data
    2.3. Analysis of Other Key Data
    2.3.1. Physicochemical Properties
    2.3.2. Structure-Activity Relationships
    2.3.3. Comparative Metabolism and Toxicokinetics
    2.3.4. Toxicological and Clinical Findings
    2.3.5. Events Relevant to Mode of Carcinogenic Action
    2.3.5.1. Direct DNA-Reactive Effects
    2.3.5.2. Indirect DNA Effects or Other Effects on Genes/Gene 
Expression
    2.3.5.3. Precursor Events and Biomarker Information
    2.3.5.4. Judging Data
    2.4. Mode of Action--General Considerations and Framework for 
Analysis
    2.4.1. General Considerations
    2.4.2. Evaluating a Hypothesized Mode of Action
    2.4.2.1. Peer Review
    2.4.2.2. Use of the Framework
    2.4.3. Framework for Evaluating Each Hypothesized Carcinogenic 
Mode of Action
    2.4.3.1. Description of the Hypothesized Mode of Action
    2.4.3.2. Discussion of the Experimental Support for the 
Hypothesized Mode of Action
    2.4.3.3. Consideration of the Possibility of Other Modes of 
Action
    2.4.3.4. Conclusions About the Hypothesized Mode of Action
    2.4.4. Evolution with Experience
    2.5. Weight of Evidence Narrative
    2.6. Hazard Characterization
3. Dose-Response Assessment
    3.1. Analysis of Dose
    3.1.1. Standardizing Different Experimental Dosing Regimens
    3.1.2. Toxicokinetic Data and Modeling
    3.1.3. Cross-species Scaling Procedures
    3.1.3.1. Oral Exposures
    3.1.3.2. Inhalation Exposures
    3.1.4. Route Extrapolation
    3.2. Analysis in the Range of Observation
    3.2.1. Epidemiologic Studies
    3.2.2. Toxicodynamic (``Biologically Based'') Modeling
    3.2.3. Empirical Modeling (``Curve Fitting'')
    3.2.4. Point of Departure (POD)
    3.2.5. Characterizing the POD: The POD Narrative
    3.2.6. Relative Potency Factors
    3.3. Extrapolation to Lower Doses
    3.3.1. Choosing an Extrapolation Approach
    3.3.2. Extrapolation Using a Toxicodynamic Model
    3.3.3. Extrapolation Using a Low-dose Linear Model
    3.3.4. Nonlinear Extrapolation to Lower Doses
    3.3.5. Comparing and Combining Multiple Extrapolations
    3.4. Extrapolation to Different Human Exposure Scenarios
    3.5. Extrapolation to Susceptible Populations and Lifestages
    3.6. Uncertainty
    3.7. Dose-Response Characterization
4. Exposure Assessment
    4.1. Defining the Assessment Questions
    4.2. Selecting or Developing the Conceptual and Mathematical 
Models
    4.3. Collecting Data or Selecting and Evaluating Available Data
    4.3.1. Adjusting Unit Risks for Highly Exposed Populations and 
Lifestages
    4.4. Exposure Characterization
5. Risk Characterization
    5.1. Purpose
    5.2. Application
    5.3. Presentation of the Risk Characterization Summary
    5.4. Content of the Risk Characterization Summary
Appendix: Major Default Options
Appendix B: EPA's Guidance for Data Quality Assessment
References

List of Figures

Figure 1-1. Flow chart for early-life risk assessment using mode of 
action framework
Figure 3-1. Compatibility of Alternative Points of Departure with 
Observed and Modeled Tumor Incidences
Figure 3-2. Crossing between 10% and 1% Dose-Response Curves for 
Bladder Carcinomas and Liver Carcinomas Induced by 2-AAF

1. Introduction

1.1. Purpose and Scope of the Guidelines

    These guidelines revise and replace the U.S. Environmental 
Protection Agency's (EPA's, or the Agency's) Guidelines for Carcinogen 
Risk Assessment, published in 51 FR 33992, September 24, 1986 (U.S. 
EPA, 1986a) and the 1999 interim final guidelines (U.S. EPA, 1999a; see 
U.S. EPA 2001b). They provide EPA staff with guidance for developing 
and using risk assessments. They also provide basic information to the 
public about the Agency's risk assessment methods.
    These cancer guidelines are used with other risk assessment 
guidelines, such as the Guidelines for Mutagenicity Risk Assessment 
(U.S. EPA, 1986b) and the Guidelines for Exposure Assessment (U.S. EPA, 
1992a). Consideration of other Agency guidance documents is also 
important in assessing cancer risks where procedures for evaluating 
specific target organ effects have been developed (e.g., assessment of 
thyroid follicular cell tumors, U.S. EPA, 1998a). All of EPA's 
guidelines should be consulted when conducting a risk assessment in 
order to ensure that information from studies on carcinogenesis and 
other health effects are considered together in the overall 
characterization of risk. This is particularly true in the case in 
which a precursor effect for a tumor is also a precursor or endpoint of 
other health effects or when there is a concern for a particular 
susceptible life-stage for which the Agency has developed guidance, for 
example, Guidelines for Developmental Toxicity Risk Assessment (U.S. 
EPA, 1991a). The developmental guidelines discuss hazards to children 
that may result from exposures during preconception and prenatal or 
postnatal development to

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sexual maturity. Similar guidelines exist for reproductive toxicant 
risk assessments (U.S. EPA, 1996a) and for neurotoxicity risk 
assessment (U.S. EPA, 1998b). The overall characterization of risk is 
conducted within the context of broader policies and guidance such as 
Executive Order 13045, ``Protection of Children From Environmental 
Health Risks and Safety Risks'' (Executive Order 13045, 1997) which is 
the primary directive to Federal agencies and departments to identify 
and assess environmental health risks and safety risks that may 
disproportionately affect children.
    The cancer guidelines encourage both consistency in the procedures 
that support scientific components of Agency decision making and 
flexibility to allow incorporation of innovations and contemporaneous 
scientific concepts. In balancing these goals, the Agency relies on 
established scientific peer review processes (U.S. EPA, 2000a; OMB 
2004). The cancer guidelines incorporate basic principles and science 
policies based on evaluation of the currently available information. 
The Agency intends to revise these cancer guidelines when substantial 
changes are necessary. As more information about carcinogenesis 
develops, the need may arise to make appropriate changes in risk 
assessment guidance. In the interim, the Agency intends to issue 
special reports, after appropriate peer review, to supplement and 
update guidance on single topics (e.g., U.S. EPA, 1991b). One such 
guidance document, Supplemental Guidance for Assessing Susceptibility 
from Early-Life Exposure to Carcinogens (``Supplemental Guidance''), 
was developed in conjunction with these cancer guidelines (U.S. EPA., 
2005). Because both the methodology and the data in the Supplemental 
Guidance (see Section 1.3.6) are expected to evolve more rapidly than 
the issues addressed in these cancer guidelines, the two were developed 
as separate documents. The Supplemental Guidance, however, as well as 
any other relevant (including subsequent) guidance documents, should be 
considered along with these cancer guidelines as risk assessments for 
carcinogens are generated. The use of supplemental guidance, such as 
the Supplemental Guidance for Assessing Cancer Susceptibility from 
Early-life Exposure to Carcinogens, has the advantage of allowing the 
Supplemental Guidance to be modified as more data become available. 
Thus, the consideration of new, peer-reviewed scientific understanding 
and data in an assessment can always be consistent with the purposes of 
these cancer guidelines.
    These cancer guidelines are intended as guidance only. They do not 
establish any substantive ``rules'' under the Administrative Procedure 
Act or any other law and have no binding effect on EPA or any regulated 
entity, but instead represent a non-binding statement of policy. EPA 
believes that the cancer guidelines represent a sound and up-to-date 
approach to cancer risk assessment, and the cancer guidelines enhance 
the application of the best available science in EPA's risk 
assessments. However, EPA cancer risk assessments may be conducted 
differently than envisioned in the cancer guidelines for many reasons, 
including (but not limited to) new information, new scientific 
understanding, or new science policy judgment. The science of risk 
assessment continues to develop rapidly, and specific components of the 
cancer guidelines may become outdated or may otherwise require 
modification in individual settings. Use of the cancer guidelines in 
future risk assessments will be based on decisions by EPA that the 
approaches are suitable and appropriate in the context of those 
particular risk assessments. These judgments will be tested through 
peer review, and risk assessments will be modified to use different 
approaches if appropriate.

1.2. Organization and Application of the Cancer Guidelines

1.2.1. Organization
    Publications by the Office of Science and Technology (OSTP, 1985) 
and the National Research Council (NRC) (NRC, 1983, 1994) provide 
information and general principles about risk assessment. Risk 
assessment uses available scientific information on the properties of 
an agent \1\ and its effects in biological systems to provide an 
evaluation of the potential for harm as a consequence of environmental 
exposure. The 1983 and 1994 NRC documents organize risk assessment 
information into four areas: Hazard identification, dose-response 
assessment, exposure assessment, and risk characterization. This 
structure appears in these cancer guidelines, with additional emphasis 
placed on characterization of evidence and conclusions in each area of 
the assessment. In particular, the cancer guidelines adopt the approach 
of the NRC's 1994 report in adding a dimension of characterization to 
the hazard identification step: an evaluation of the conditions under 
which its expression is anticipated. Risk assessment questions 
addressed in these cancer guidelines are as follows.
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    \1\ The term ``agent'' refers generally to any chemical 
substance, mixture, or physical or biological entity being assessed, 
unless otherwise noted (See Section 1.2.2 for a note on radiation.).
---------------------------------------------------------------------------

     For hazard--Can the identified agent present a 
carcinogenic hazard to humans and, if so, under what circumstances?
     For dose response--At what levels of exposure might 
effects occur?
     For exposure--What are the conditions of human exposure?
     For risk--What is the character of the risk? How well do 
data support conclusions about the nature and extent of the risk from 
various exposures?
    The risk characterization process first summarizes findings on 
hazard, dose response, and exposure characterizations and then develops 
an integrative analysis of the whole risk case. It ends in the writing 
of a technical risk characterization. Other documents, such as 
summaries for the risk managers and the public, reflecting the key 
points of the risk characterization are usually written. A summary for 
managers is a presentation for those who may or may not be familiar 
with the scientific details of cancer assessment. It also provides 
information for other interested readers. The initial steps in the risk 
characterization process are to make building blocks in the form of 
characterizations of the assessments of hazard, dose response, and 
exposure. The individual assessments and characterizations are then 
integrated to arrive at risk estimates for exposure scenarios of 
interest. As part of the characterization process, explicit evaluations 
are made of the hazard and risk potential for susceptible lifestages, 
including children (U.S. EPA, 1995, 2000b).
    The 1994 NRC document also explicitly called attention to the role 
of the risk assessment process in identifying scientific uncertainties 
that, if addressed, could serve to reduce their uncertainty in future 
iterations of the risk assessment. NRC recommended that when the Agency 
``reports estimates of risk to decisions-makers and the public, it 
should present not only point estimates of risk, but also the sources 
and magnitudes of uncertainty associated with these estimates'' (p. 
15). Thus, the identified uncertainties serve as a feedback loop to the 
research community and decisionmakers, specifying areas and types of 
information that would be particularly useful.
    There are several reasons for individually characterizing the 
hazard, dose response, and exposure

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assessments. One is that they are often done by different people than 
those who do the integrative analyses. The second is that there is very 
often a lapse of time between the conduct of hazard and dose-response 
analyses and the conduct of exposure assessment and integrative 
analysis. Thus, it is important to capture characterizations of 
assessments as the assessments are done to avoid the need to go back 
and reconstruct them. Finally, frequently a single hazard assessment is 
used by several programs for several different exposure scenarios. 
There may be one or several documents involved. ``Integrative 
analysis'' is a generic term; and many documents that have other titles 
may contain integrative analyses. In the following sections, the 
elements of these characterizations are discussed.
1.2.2. Application
    The cancer guidelines apply within the framework of policies 
provided by applicable EPA statutes and do not alter such policies.
     The cancer guidelines cover the assessment of available 
data. They do not imply that one kind of data or another is 
prerequisite for regulatory action concerning any agent. It is 
important that, when evaluating and considering the use of any data, 
EPA analysts incorporate the basic standards of quality, as defined by 
the EPA Information Quality Guidelines (U.S. EPA, 2002a see Appendix B) 
and other Agency guidance on data quality such as the EPA Quality 
Manual for Environmental Programs (U.S. EPA, 2000e), as well as OMB 
Guidelines for Ensuring and Maximizing the Quality, Utility, and 
Integrity of Information Disseminated by Federal Agencies (OMB, 2002). 
It is very important that all analyses consider the basic standards of 
quality, including objectivity, utility, and integrity. A summary of 
the factors and considerations generally used by the Agency when 
evaluating and considering the use of scientific and technical 
information is contained in EPA's A Summary of General Assessment 
Factors for Evaluating the Quality of Scientific and Technical 
Information (U.S. EPA, 2003).
     Risk management applies directives in statutes, which may 
require consideration of potential risk or solely hazard or exposure 
potential, along with social, economic, technical, and other factors in 
decision making. Risk assessments may be used to support decisions, but 
in order to maintain their integrity as decision-making tools, they are 
not influenced by consideration of the social or economic consequences 
of regulatory action.
    The assessment of risk from radiation sources is informed by the 
continuing examination of human data by the National Academy of 
Sciences/NRC in its series of numbered reports: ``Biological Effects of 
Ionizing Radiation.'' Although some of the general principles of these 
cancer guidelines may also apply to radiation risk assessments, some of 
the details of their risk assessment procedures may not, as they are 
most focused on other kinds of agents. Therefore, these cancer 
guidelines are not intended to provide the primary source of, or 
guidance for, the Agency's evaluation of the carcinogenic risks of 
radiation.
    Not every EPA assessment has the same scope or depth, a factor 
recognized by the National Academy of Sciences (NRC, 1996). For 
example, EPA's Information Quality Guidelines (U.S. EPA, 2002a, see 
Appendix B) discuss influential information that ``will have or does 
have a clear and substantial impact * * * on important public policies 
or private sector decisions * * * that should adhere to a rigorous 
standard of quality.'' It is often difficult to know a priori how the 
results of a risk assessment are likely to be used by the Agency. Some 
risk assessments may be used by Agency economists and policy analysts, 
and the necessary information for such analyses, as discussed in detail 
later in this document, should be included when practicable (U.S. EPA, 
2002a). On the other hand, Agency staff often conduct screening-level 
assessments for priority setting or separate assessments of hazard or 
exposure for ranking purposes or to decide whether to invest resources 
in collecting data for a full assessment. Moreover, a given assessment 
of hazard and dose response may be used with more than one exposure 
assessment that may be conducted separately and at different times as 
the need arises in studying environmental problems related to various 
exposure media. The cancer guidelines apply to these various situations 
in appropriate detail, given the scope and depth of the particular 
assessment. For example, a screening assessment may be based almost 
entirely on structure-activity relationships (SARs) and default 
options, when other data are not readily available. When more data and 
resources are readily available, assessments can use a critical 
analysis of all of the available data as the starting point of the risk 
assessment. Under these conditions, default options would only be used 
to address uncertainties or the absence of critical data. Default 
options are inferences based on general scientific knowledge of the 
phenomena in question and are also matters of policy concerning the 
appropriate way to bridge uncertainties that concern potential risk to 
human health.
    These cancer guidelines do not suggest that all of the kinds of 
data covered here will need to be available or used for either 
assessment or decision making. The level of detail of an assessment is 
a matter of Agency management discretion regarding applicable decision-
making needs. The Agency generally presumes that key cancer information 
(e.g., assessments contained in the Agency's Integrated Risk 
Information System) is ``influential information'' as defined by the 
EPA Information Quality Guidelines and ``highly influential'' as 
defined by OMB's Information Quality Bulletin for Peer Review (OMB 
2004).

1.3. Key Features of the Cancer Guidelines

1.3.1. Critical Analysis of Available Information as the Starting Point 
for Evaluation
    As an increasing understanding of carcinogenesis is becoming 
available, these cancer guidelines adopt a view of default options that 
is consistent with EPA's mission to protect human health while adhering 
to the tenets of sound science. Rather than viewing default options as 
the starting point from which departures may be justified by new 
scientific information, these cancer guidelines view a critical 
analysis of all of the available information that is relevant to 
assessing the carcinogenic risk as the starting point from which a 
default option may be invoked if needed to address uncertainty or the 
absence of critical information. Preference is given to using 
information that has been peer reviewed, e.g., reported in peer-
reviewed scientific journals. The primary goal of EPA actions is 
protection of human health; accordingly, as an Agency policy, risk 
assessment procedures, including default options that are used in the 
absence of scientific data to the contrary, should be health protective 
(U.S. EPA, 1999b).
    Use of health protective risk assessment procedures as described in 
these cancer guidelines means that estimates, while uncertain, are more 
likely to overstate than understate hazard and/or risk. NRC (1994) 
reaffirmed the use of default options as ``a reasonable way to cope 
with uncertainty about the choice of appropriate models or theory'' (p. 
104). NRC saw the need to treat uncertainty in a predictable way that 
is

[[Page 17771]]

``scientifically defensible, consistent with the agency's statutory 
mission, and responsive to the needs of decision-makers'' (p. 86). The 
extent of health protection provided to the public ultimately depends 
upon what risk managers decide is the appropriate course of regulatory 
action. When risk assessments are performed using only one set of 
procedures, it may be difficult for risk managers to determine how much 
health protectiveness is built into a particular hazard determination 
or risk characterization. When there are alternative procedures having 
significant biological support, the Agency encourages assessments to be 
performed using these alternative procedures, if feasible, in order to 
shed light on the uncertainties in the assessment, recognizing that the 
Agency may decide to give greater weight to one set of procedures than 
another in a specific assessment or management decision.
    Encouraging risk assessors to be receptive to new scientific 
information, NRC discussed the need for departures from default options 
when a ``sufficient showing'' is made. It called on EPA to articulate 
clearly its criteria for a departure so that decisions to depart from 
default options would be ``scientifically credible and receive public 
acceptance'' (p. 91). It was concerned that ad hoc departures would 
undercut the scientific credibility of a risk assessment. NRC 
envisioned that principles for choosing and departing from default 
options would balance several objectives, including ``protecting the 
public health, ensuring scientific validity, minimizing serious errors 
in estimating risks, maximizing incentives for research, creating an 
orderly and predictable process, and fostering openness and 
trustworthiness'' (p. 81).
    Appendices N-1 and N-2 of NRC (1994) discussed two competing 
standards for choosing default options articulated by members of the 
committee. One suggested approach would evaluate a departure in terms 
of whether ``it is scientifically plausible'' and whether it ``tends to 
protect public health in the face of scientific uncertainty'' (p. 601). 
An alternative approach ``emphasizes scientific plausibility with 
regard to the use of alternative models'' (p. 631). Reaching no 
consensus on a single approach, NRC recognized that developing criteria 
for departures is an EPA policy matter.
    The basis for invoking a default option depends on the 
circumstances. Generally, if a gap in basic understanding exists or if 
agent-specific information is missing, a default option may be used. If 
agent-specific information is present but critical analysis reveals 
inadequacies, a default option may also be used. If critical analysis 
of agent-specific information is consistent with one or more 
biologically based models as well as with the default option, the 
alternative models and the default option are both carried through the 
assessment and characterized for the risk manager. In this case, the 
default model not only fits the data, but also serves as a benchmark 
for comparison with other analyses. This case also highlights the 
importance of extensive experimentation to support a conclusion about 
mode of action, including addressing the issue of whether alternative 
modes of action are also plausible. Section 2.4 provides a framework 
for critical analysis of mode of action information to address the 
extent to which the available information supports the hypothesized 
mode of action, whether alternative modes of action are also plausible, 
and whether there is confidence that the same inferences can be 
extended to populations and lifestages that are not represented among 
the experimental data.
    Generally, cancer risk decisions strive to be ``scientifically 
defensible, consistent with the agency's statutory mission, and 
responsive to the needs of decision-makers'' (NRC, 1994). Scientific 
defensibility would be evaluated through use of EPA's Science Advisory 
Board, EPA's Office of Pesticide Programs' Scientific Advisory Panel, 
or other independent expert peer review panels to determine whether a 
consensus among scientific experts exists. Consistency with the 
Agency's statutory mission would consider whether the risk assessment 
overall supports EPA's mission to protect human health and safeguard 
the natural environment. Responsiveness to the needs of decisionmakers 
would take into account pragmatic considerations such as the nature of 
the decision; the required depth of analysis; the utility, time, and 
cost of generating new scientific data; and the time, personnel, and 
resources allotted to the risk assessment.
    With a multitude of types of data, analyses, and risk assessments, 
as well as the diversity of needs of decisionmakers, it is neither 
possible nor desirable to specify step-by-step criteria for decisions 
to invoke a default option. A discussion of major default options 
appears in the Appendix. Screening-level assessments may more readily 
use default parameters, even worst-case assumptions, that would not be 
appropriate in a full-scale assessment. On the other hand, significant 
risk management decisions will often benefit from a more comprehensive 
assessment, including alternative risk models having significant 
biological support. To the extent practicable, such assessments should 
provide central estimates of potential risks in conjunction with lower 
and upper bounds (e.g., confidence limits) and a clear statement of the 
uncertainty associated with these estimates.
    In the absence of sufficient data or understanding to develop of a 
robust, biologically based model, an appropriate policy choice is to 
have a single preferred curve-fitting model for each type of data set. 
Many different curve-fitting models have been developed, and those that 
fit the observed data reasonably well may lead to several-fold 
differences in estimated risk at the lower end of the observed range. 
In addition, goodness-of-fit to the experimental observations is not by 
itself an effective means of discriminating among models that 
adequately fit the data (OSTP, 1985). To provide some measure of 
consistency across different carcinogen assessments, EPA uses a 
standard curve-fitting procedure for tumor incidence data. Assessments 
that include a different approach should provide an adequate 
justification and compare their results with those from the standard 
procedure. Application of models to data should be conducted in an open 
and transparent manner.
1.3.2. Mode of Action
    The use of mode of action \2\ in the assessment of potential 
carcinogens is a main focus of these cancer guidelines. This area of 
emphasis arose because of the significant scientific advances that have 
developed concerning the causes of cancer induction. Elucidation of a 
mode of action for a particular cancer response in animals or humans is 
a data-rich determination. Significant

[[Page 17772]]

information should be developed to ensure that a scientifically 
justifiable mode of action underlies the process leading to cancer at a 
given site. In the absence of sufficiently, scientifically justifiable 
mode of action information, EPA generally takes public health-
protective, default positions regarding the interpretation of 
toxicologic and epidemiologic data: Animal tumor findings are judged to 
be relevant to humans, and cancer risks are assumed to conform with low 
dose linearity.
---------------------------------------------------------------------------

    \2\ The term ``mode of action'' is defined as a sequence of key 
events and processes, starting with interaction of an agent with a 
cell, proceeding through operational and anatomical changes, and 
resulting in cancer formation. A ``key event'' is an empirically 
observable precursor step that is itself a necessary element of the 
mode of action or is a biologically based marker for such an 
element. Mode of action is contrasted with ``mechanism of action,'' 
which implies a more detailed understanding and description of 
events, often at the molecular level, than is meant by mode of 
action. The toxicokinetic processes that lead to formation or 
distribution of the active agent to the target tissue are considered 
in estimating dose but are not part of the mode of action as the 
term is used here. There are many examples of possible modes of 
carcinogenic action, such as mutagenicity, mitogenesis, inhibition 
of cell death, cytotoxicity with reparative cell proliferation, and 
immune suppression.
---------------------------------------------------------------------------

    Understanding of mode of action can be a key to identifying 
processes that may cause chemical exposures to differentially affect a 
particular population segment or lifestage. Some modes of action are 
anticipated to be mutagenic and are assessed with a linear approach. 
This is the mode of action of radiation and several other agents that 
are known carcinogens. Other modes of action may be modeled with either 
linear or nonlinear \3\ approaches after a rigorous analysis of 
available data under the guidance provided in the framework for mode of 
action analysis (see Section 2.4.3).
---------------------------------------------------------------------------

    \3\ The term ``nonlinear'' is used here in a narrower sense than 
its usual meaning in the field of mathematical modeling. In these 
cancer guidelines, the term ``nonlinear'' refers to threshold models 
(which show no response over a range of low doses that include zero) 
and some nonthreshold models (e.g., a quadractic model, which shows 
some response at all doses above zero). In these cancer guidelines, 
a nonlinear model is one whose slope is zero at (and perhaps above) 
a dose of zero. A low-dose-linear model is one whose slope is 
greater than zero at a dose of zero. A low-dose-linear model 
approximates a straight line only at very low doses; at higher doses 
near the observed data, a low-dose-linear model can display 
curvature. The term ``low-dose-linear'' is often abbreviated 
``linear,'' although a low-dose-linear model is not linear at all 
doses. Use of nonlinear approaches does not imply a biological 
threshold dose below which the response is zero. Estimating 
thresholds can be problematic; for example, a response that is not 
statistically significant can be consistent with a small risk that 
falls below an experiment's power of detection.
---------------------------------------------------------------------------

1.3.3. Weight of Evidence Narrative
    The cancer guidelines emphasize the importance of weighing all of 
the evidence in reaching conclusions about the human carcinogenic 
potential of agents. This is accomplished in a single integrative step 
after assessing all of the individual lines of evidence, which is in 
contrast to the step-wise approach in the 1986 cancer guidelines. 
Evidence considered includes tumor findings, or lack thereof, in humans 
and laboratory animals; an agent's chemical and physical properties; 
its structure-activity relationships (SARs) as compared with other 
carcinogenic agents; and studies addressing potential carcinogenic 
processes and mode(s) of action, either in vivo or in vitro. Data from 
epidemiologic studies are generally preferred for characterizing human 
cancer hazard and risk. However, all of the information discussed above 
could provide valuable insights into the possible mode(s) of action and 
likelihood of human cancer hazard and risk. The cancer guidelines 
recognize the growing sophistication of research methods, particularly 
in their ability to reveal the modes of action of carcinogenic agents 
at cellular and subcellular levels as well as toxicokinetic processes.
    Weighing of the evidence includes addressing not only the 
likelihood of human carcinogenic effects of the agent but also the 
conditions under which such effects may be expressed, to the extent 
that these are revealed in the toxicological and other biologically 
important features of the agent.
    The weight of evidence narrative to characterize hazard summarizes 
the results of the hazard assessment and provides a conclusion with 
regard to human carcinogenic potential. The narrative explains the 
kinds of evidence available and how they fit together in drawing 
conclusions, and it points out significant issues/strengths/limitations 
of the data and conclusions. Because the narrative also summarizes the 
mode of action information, it sets the stage for the discussion of the 
rationale underlying a recommended approach to dose-response 
assessment.
    In order to provide some measure of clarity and consistency in an 
otherwise free-form, narrative characterization, standard descriptors 
are used as part of the hazard narrative to express the conclusion 
regarding the weight of evidence for carcinogenic hazard potential. 
There are five recommended standard hazard descriptors: ``Carcinogenic 
to Humans,'' ``Likely to Be Carcinogenic to Humans,'' ``Suggestive 
Evidence of Carcinogenic Potential,'' ``Inadequate Information to 
Assess Carcinogenic Potential,'' and ``Not Likely to Be Carcinogenic to 
Humans.'' Each standard descriptor may be applicable to a wide variety 
of data sets and weights of evidence and is presented only in the 
context of a weight of evidence narrative. Furthermore, as described in 
Section 2.5 of these cancer guidelines, more than one conclusion may be 
reached for an agent.
1.3.4. Dose-Response Assessment
    Dose-response assessment evaluates potential risks to humans at 
particular exposure levels. The approach to dose-response assessment 
for a particular agent is based on the conclusion reached as to its 
potential mode(s) of action for each tumor type. Because an agent may 
induce multiple tumor types, the dose-response assessment includes an 
analysis of all tumor types, followed by an overall synthesis that 
includes a characterization of the risk estimates across tumor types, 
the strength of the mode of action information of each tumor type, and 
the anticipated relevance of each tumor type to humans, including 
susceptible populations and lifestages (e.g., childhood).
    Dose-response assessment for each tumor type is performed in two 
steps: assessment of observed data to derive a point of departure 
(POD),\4\ followed by extrapolation to lower exposures to the extent 
that is necessary. Data from epidemiologic studies, of sufficient 
quality, are generally preferred for estimating risks. When animal 
studies are the basis of the analysis, the estimation of a human-
equivalent dose should utilize toxicokinetic data to inform cross-
species dose scaling if appropriate and if adequate data are available. 
Otherwise, default procedures should be applied. For oral dose, based 
on current science, an appropriate default option is to scale daily 
applied doses experienced for a lifetime in proportion to body weight 
raised to the \3/4\ power (U.S. EPA, 1992b). For inhalation dose, based 
on current science, an appropriate default methodology estimates 
respiratory deposition of particles and gases and estimates internal 
doses of gases with different absorption characteristics. When 
toxicokinetic modeling (see Section 3.1.2) is used without 
toxicodynamic modeling (see Section 3.2.2), the dose-response 
assessment develops and supports an approach for addressing 
toxicodynamic equivalence, perhaps by retaining some of the cross-
species scaling factor (see Section 3.1.3). Guidance is also provided 
for adjustment of dose from adults to children (see Section 4.3.1).
---------------------------------------------------------------------------

    \4\ A ``point of departure'' (POD) marks the beginning of 
extrapolation to lower doses. The POD is an estimated dose (usually 
expressed in human-equivalent terms) near the lower end of the 
observed range, without significant extrapolation to lower doses.
---------------------------------------------------------------------------

    Response data on effects of the agent on carcinogenic processes are 
analyzed (nontumor data) in addition to data on tumor incidence. If 
appropriate, the analyses of data on tumor incidence and on precursor 
effects may be used in combination. To the extent the relationship 
between precursor effects and tumor incidence are known, precursor data 
may be used to estimate a dose-response function below the observable 
tumor data. Study of the dose-response function for effects

[[Page 17773]]

believed to be part of the carcinogenic process influenced by the agent 
may also assist in evaluating the relationship of exposure and response 
in the range of observation and at exposure levels below the range of 
observation.
    The first step of dose-response assessment is evaluation within the 
range of observation. Approaches to analysis of the range of 
observation of epidemiologic studies are determined by the type of 
study and how dose and response are measured in the study. In the 
absence of adequate human data for dose-response analysis, animal data 
are generally used. If there are sufficient quantitative data and 
adequate understanding of the carcinogenic process, a biologically 
based model may be developed to relate dose and response data on an 
agent-specific basis. Otherwise, as a default procedure, a standard 
model can be used to curve-fit the data.
    The POD for extrapolating the relationship to environmental 
exposure levels of interest, when the latter are outside the range of 
observed data, is generally the lower 95% confidence limit on the 
lowest dose level that can be supported for modeling by the data. SAB 
(1997) suggested that, ``it may be appropriate to emphasize lower 
statistical bounds in screening analyses and in activities designed to 
develop an appropriate human exposure value, since such activities 
require accounting for various types of uncertainties and a lower bound 
on the central estimate is a scientifically-based approach accounting 
for the uncertainty in the true value of the ED10 [or 
central estimate].'' However, the consensus of the SAB (1997) was that, 
``both point estimates and statistical bounds can be useful in 
different circumstances, and recommended that the Agency routinely 
calculate and present the point estimate of the ED10 [or 
central estimate] and the corresponding upper and lower 95% statistical 
bounds.'' For example, it may be appropriate to emphasize the central 
estimate in activities that involve formal uncertainty analysis that 
are required by OMB Circular A-4 (OMB, 2003) as well as ranking agents 
as to their carcinogenic hazard. Thus, risk assessors should calculate, 
to the extent practicable, and present the central estimate and the 
corresponding upper and lower statistical bounds (such as confidence 
limits) to inform decisionmakers.
    The second step of dose-response assessment is extrapolation to 
lower dose levels, if needed. This extrapolation is based on extension 
of a biologically based model if supported by substantial data (see 
Section 3.3.2). Otherwise, default approaches can be applied that are 
consistent with current understanding of mode(s) of action of the 
agent, including approaches that assume linearity or nonlinearity of 
the dose-response relationship, or both. A default approach for 
linearity extends a straight line from the POD to zero dose/zero 
response (see Section 3.3.3). The linear approach is used when: (1) 
There is an absence of sufficient information on modes of action or (2) 
the mode of action information indicates that the dose-response curve 
at low dose is or is expected to be linear. Where alternative 
approaches have significant biological support, and no scientific 
consensus favors a single approach, an assessment may present results 
using alternative approaches. A nonlinear approach can be used to 
develop a reference dose or a reference concentration (see Section 
3.3.4).
1.3.5. Susceptible Populations and Lifestages
    An important use of mode of action information is to identify 
susceptible populations and lifestages. It is rare to have 
epidemiologic studies or animal bioassays conducted in susceptible 
individuals. This information need can be filled by identifying the key 
events of the mode of action and then identifying risk factors, such as 
differences due to genetic polymorphisms, disease, altered organ 
function, lifestyle, and lifestage, that can augment these key events. 
To do this, the information about the key precursor events is reviewed 
to identify particular populations or lifestages that can be 
particularly susceptible to their occurrence (see Section 2.4.3.4). Any 
information suggesting quantitative differences between populations or 
lifestages is flagged for consideration in the dose-response assessment 
(see Section 3.5 and U.S. EPA 2002b).
1.3.6. Evaluating Risks From Childhood Exposures
    NRC (1994) recommended that ``EPA should assess risks to infants 
and children whenever it appears that their risks might be greater than 
those of adults.'' Executive Order 13045 (1997) requires that ``each 
Federal Agency shall make it a high priority to identify and assess 
environmental health and safety risks that may disproportionately 
affect children, and shall ensure that their policies, programs, and 
standards address disproportionate risks that result from environmental 
health risks or safety risks.'' In assessing risks to children, EPA 
considers both effects manifest during childhood and early-life 
exposures that can contribute to effects at any time later in life.
    These cancer guidelines view childhood as a sequence of lifestages 
rather than viewing children as a subpopulation, the distinction being 
that a subpopulation refers to a portion of the population, whereas a 
lifestage is inclusive of the entire population. Exposures that are of 
concern extend from conception through adolescence and also include 
pre-conception exposures of both parents. These cancer guidelines use 
the term ``childhood'' in this more inclusive sense.
    Rarely are there studies that directly evaluate risks following 
early-life exposure. Epidemiologic studies of early-life exposure to 
environmental agents are seldom available. Standard animal bioassays 
generally begin dosing after the animals are several weeks old, when 
many organ systems are mature. This could lead to an understatement of 
risk, because an accepted concept in the science of carcinogenesis is 
that young animals are usually more susceptible to the carcinogenic 
activity of a chemical than are mature animals (McConnell, 1992).
    At this time, there is some evidence of higher cancer risks 
following early-life exposure. For radiation carcinogenesis, data 
indicate that risks for several forms of cancer are highest following 
childhood exposure (NRC, 1990; Miller, 1995; U.S. EPA, 1999c). These 
human results are supported by the few animal bioassays that include 
perinatal (prenatal or early postnatal) exposure. Perinatal exposure to 
some agents can induce higher incidences of the tumors seen in standard 
bioassays; some examples include vinyl chloride (Maltoni et al., 1981), 
diethylnitrosamine (Peto et al., 1984), benzidine, DDT, dieldrin, and 
safrole (Vesselinovitch et al., 1979). Moreover, perinatal exposure to 
some agents, including vinyl chloride (Maltoni et al., 1981) and 
saccharin (Cohen, 1995; Whysner and Williams, 1996), can induce 
different tumors that are not seen in standard bioassays. Surveys 
comparing perinatal carcinogenesis bioassays with standard bioassays 
for a limited number of chemicals (McConnell, 1992; U.S. EPA, 1996b) 
have concluded that
     The same tumor sites are usually observed following either 
perinatal or adult exposure, and
     Perinatal exposure in conjunction with adult exposure 
usually increases the incidence of tumors or reduces the latent period 
before tumors are observed.
    The risk attributable to early-life exposure often appears modest 
compared with the risk from lifetime exposure, but it can be about 10-
fold

[[Page 17774]]

higher than the risk from an exposure of similar duration occurring 
later in life (Ginsberg, 2003). Further research is warranted to 
investigate the extent to which these findings apply to specific 
agents, chemical classes, and modes of action or in general.
    These empirical results are consistent with current understanding 
of the biological processes involved in carcinogenesis, which leads to 
a reasonable expectation that children can be more susceptible to many 
carcinogenic agents (Anderson et al., 2000; Birnbaum and Fenton, 2003; 
Ginsberg, 2003; Miller et al., 2002; Scheuplein et al., 2002). Some 
aspects potentially leading to childhood susceptibility are listed 
below.
     Differences in the capacity to metabolize and clear 
chemicals can result in larger or smaller internal doses of the active 
agent(s).
     More frequent cell division during development can result 
in enhanced expression of mutations due to the reduced time available 
for repair of DNA lesions (Slikker et al., 2004).
     Some embryonic cells, such as brain cells, lack key DNA 
repair enzymes.
     More frequent cell division during development can result 
in clonal expansion of cells with mutations from prior unrepaired DNA 
damage (Slikker et al., 2004).
     Some components of the immune system are not fully 
functional during development (Holladay and Smialowicz, 2000; Holsapple 
et al., 2003).
     Hormonal systems operate at different levels during 
different lifestages.
     Induction of developmental abnormalities can result in a 
predisposition to carcinogenic effects later in life (Anderson et al., 
2000; Birnbaum and Fenton, 2003; Fenton and Davis, 2002).
    To evaluate risks from early-life exposure, these cancer guidelines 
emphasize the role of toxicokinetic information to estimate levels of 
the active agent in children and toxicodynamic information to identify 
whether any key events of the mode of action are of increased concern 
early in life. Developmental toxicity studies can provide information 
on critical periods of exposure for particular targets of toxicity.
    An approach to assessing risks from early-life exposure is 
presented in Figure 1-1. In the hazard assessment, when there are mode 
of action data, the assessment considers whether these data have 
special relevance during childhood, considering the various aspects of 
development listed above. Examples of such data include toxicokinetics 
that predict a sufficiently large internal dose in children or a mode 
of action where a key precursor event is more likely to occur during 
childhood. There is no recommended default to settle the question of 
whether tumors arising through a mode of action are relevant during 
childhood; and adequate understanding the mode of action implies that 
there are sufficient data (on either the specific agent or the general 
mode of action) to form a confident conclusion about relevance during 
childhood (see Section 2.4.3.4).
    In the dose-response assessment, the potential for susceptibility 
during childhood warrants explicit consideration in