[Federal Register: March 3, 2003 (Volume 68, Number 41)]
[Notices]
[Page 10012-10015]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr03mr03-69]
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ENVIRONMENTAL PROTECTION AGENCY
[FRL-7457-2]
Notice of Availability and Opportunity To Provide Comment on the
Draft Final Guidelines for Carcinogen Risk Assessment and the Draft
Supplemental Guidance for Assessing Cancer Susceptibility From Early-
Life Exposure to Carcinogens
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice of availability and public comment period.
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SUMMARY: EPA is today announcing the availability of, and opportunity
to comment on, the Draft Final Guidelines for Carcinogen Risk
Assessment and the draft Supplemental Guidance for Assessing Cancer
Susceptibility from Early-Life Exposure to Carcinogens.
In 1996, EPA published for public comment proposed revisions to
EPA's 1986 Guidelines for Carcinogen Risk Assessment. Since the 1996
proposal, the Agency has benefitted from extensive public comment and
scientific peer review, including three reviews by EPA's Science
Advisory Board (SAB). The major issues currently being considered by
EPA as it proceeds to issue final Guidelines are identified in the
Supplementary Information section of this notice. As announced in
November 2001, the July 1999 draft revised Guidelines will continue to
serve as EPA's interim guidance to EPA risk assessors preparing cancer
risk assessments until final Guidelines are issued.
The Draft Final Guidelines issued today for comment explicitly call
for consideration of possible sensitive subpopulations and/or
lifestages (such as childhood). Therefore, concurrent with release of
the Draft Final Guidelines, EPA is also requesting public comment on
draft supplemental guidance describing possible approaches that could
be used to assess risks resulting from early life exposure to potential
carcinogens. This draft supplemental guidance will be peer reviewed by
the Agency's Science Advisory Board at a public meeting that will be
announced in a separate Federal Register notice. 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.
DATES: Comments must be received by Thursday, May 1, 2003.
ADDRESSES:
Document Availability
The Draft Final Guidelines for Carcinogen Risk Assessment (February
2003, NCEA-F-0644A) and the draft Supplemental Guidance for Assessing
Cancer Susceptibility from Early-Life Exposure to Carcinogens (EPA/630/
R-03/003) are available via the Internet from http://www.epa.gov/ncea/
raf/cancer2003.htm.
A limited number of paper copies of the documents
are available from the Technical Information Staff (8623D), NCEA-W,
U.S. Environmental Protection Agency, 1200 Pennsylvania Avenue NW.,
Washington, DC 20460; telephone: 202-564-3261; facsimile: 202-565-0050.
Submitting Comments
One of three methods may be chosen to submit comments, and comments
may be in electronic or paper copy format. First, comments may be
submitted through EPA's electronic public docket and comment system,
EPA Dockets. EPA Dockets is available at http://www.epa.gov/edocket/.
EPA Dockets. EPA Dockets is available at http://www.epa.gov/edocket/.
Once in the system, select ``search,'' then key in the appropriate
docket identification number (OAR-2003-0008). Second, comments may be
submitted via e-mail to ``a-and-r-Docket@epa.gov.'' Third, paper copies
of comments may be submitted (in duplicate if possible) to the Air
Docket at the Environmental Protection Agency, EPA Docket Center (EPA/
DC), Office of Air and Radiation, Mail Code 6102T, 1200 Pennsylvania
Avenue NW., Washington, DC 20460. Please refer to Public Docket Number
OAR-2003-0008 in e-mail and in paper correspondence. Acknowledgments
will not be sent for electronic or paper comment submissions. Persons
providing information or comments should not submit personal
information (such as medical data or home address), Confidential
Business Information, or information protected by copyright because all
comments will be made available for public viewing.
Viewing Public Comments
Public comments pertaining to this notice may be viewed by using
EPA Dockets, or by visiting EPA's Air Docket. EPA intends to make all
comments received in response to this Federal Register Notice available
in EPA Dockets (http://www.epa.gov/edocket/), including documents
in EPA Dockets (http://www.epa.gov/edocket/), including documents
originally submitted in paper format. To view comments select
``search,'' then key in the appropriate docket identification number
(OAR-2003-0008). Also, paper copies of materials related to this notice
are available for review under Public Docket No. OAR-2003-0008 at EPA's
Air Docket. EPA's Air Docket also makes available for review the
comments received on the 1996 Proposed Guidelines under Public Docket
No. ORD-CAN-96-02 and comments received on the 1999 draft revised
Guidelines during the November 2001 public comment period under Public
Docket No. ORD-CAN-2001. EPA's Air Docket is located at the following
address: U.S. Environmental Protection Agency (EPA), Public Reading
Room, Room B102 EPA West Building, 1301 Constitution Avenue NW.,
Washington, DC 20460. The Reading Room is open between 8 a.m. and 4:30
p.m., Monday through Friday, except on legal holidays. Visitors to the
Public Reading Room are required to show photographic identification
and sign the Agency's visitor log. There may be a reasonable fee for
copying docket materials, as provided in 40 CFR part 2. You can reach
the Air Docket by telephone at 202-566-1742, and by facsimile at 202-
566-1741.
FOR FURTHER INFORMATION CONTACT: Dr. William P. Wood, Risk Assessment
Forum (mail code 8601D), U.S. Environmental Protection Agency, 1200
Pennsylvania Avenue NW., Washington, DC 20460, telephone 202-564-3361,
or send electronic mail inquiries to risk.forum@epa.gov.
SUPPLEMENTARY INFORMATION:
Background
In 1983, the National Academy of Sciences/National Research Council
(NRC) published its report entitled, Risk Assessment in the Federal
Government: Managing the Process. In that report, the NRC recommended
that Federal regulatory agencies establish ``inference guidelines'' to
promote consistency and
[[Page 10013]]
technical quality in risk assessments and to ensure that the risk
assessment process was maintained as a scientific effort separate from
risk management. EPA responded to this recommendation by publishing a
set of risk assessment guidelines in 1986, including Guidelines for
Carcinogen Risk Assessment (51 FR 33992, September 24, 1986). These
Guidelines set forth principles and procedures to guide EPA scientists
in assessing the cancer risks from chemicals or other agents in the
environment and to inform the public about these procedures. EPA
continues to revise its risk assessment guidelines and to develop new
guidelines as experience and scientific understanding evolve. Revisions
to the Guidelines for Carcinogen Risk Assessment are intended to make
greater use of the increasing scientific understanding of the
mechanisms that underlie the carcinogenic process. As part of that
process, the Agency published Proposed Guidelines for Carcinogen Risk
Assessment in 1996 (61 FR 17960, April 23, 1996).
The draft revisions to the Guidelines have been subject to
extensive public comment and scientific peer review, including three
reviews by EPA's Science Advisory Board (SAB). In 2001, EPA published a
notice (66 FR 59593, November 29, 2001) providing an additional
opportunity for public comment on a 1999 draft of the Guidelines.
Comments were invited on experience gained in applying previous draft
revised Guidelines and on issues raised in previous comments by the SAB
and the public. EPA has also considered the recommendations of the NRC
(Science and Judgment in Risk Assessment, 1994) in revising the
Guidelines. EPA's approach to the recommendations is reflected in the
Guidelines themselves. 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). EPA anticipates issuing final
responses to the NRC recommendations when it issues final Guidelines.
Role of Risk Assessment Guidelines at EPA
The final Guidelines will be guidance only. They will not establish
any substantive ``rules'' under the Administrative Procedure Act or any
other law and will have no binding effect on EPA or any regulated
entity, but instead will represent a non-binding statement of policy.
EPA believes that the Draft Final Guidelines represent a sound and up-
to-date approach to cancer risk assessment, and the final Guidelines
will 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 final 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
final Guidelines may become outdated or may otherwise require
modification in individual settings. Use of the final Guidelines in
future risk assessments will be based on decisions by EPA that
approaches from the final 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 final Guidelines will not be 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 an opportunity for public comment. EPA
will consider and respond to all significant public comments as it
prepares the final Guidelines, and will send a copy of the final
Guidelines to Congress. EPA certifies that the Draft Final 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.
Issues Identified in 2001 Public Comments
A range of views were expressed in the comments submitted to EPA in
response to the 2001 notice (66 FR 59593, November 29, 2001) (see the
Addresses section for information on viewing these comments). Comments
on four issues of interest identified by EPA in the 2001 notice
included the following:
(1) Default assumptions. Default assumptions are options that EPA
can apply in risk assessments when information about the effects of a
substance on human health is unavailable, limited, or of insufficient
quality. (For example, if no information is available on the effects of
a chemical on humans, a common default assumption is that adverse
effects observed in animals due to chemical exposure have the potential
to occur in humans as well.) Commenters differed on whether default
assumptions should be (a) built into each risk assessment unless
sufficient evidence is available to depart from them, or (b) invoked
only when determined to be necessary given the data available in a
particular risk assessment. Commenters also differed on whether EPA's
proposed default assumptions should be more protective of public health
versus already being excessively conservative.
(2) Hazard descriptors. Under the 1999 draft Guidelines, one or
more standard descriptors (e.g., ``Likely to be Carcinogenic to
Humans'') were used to express conclusions about the weight of evidence
for human carcinogenic potential. Many commenters generally agreed with
EPA's approach for the descriptors, but most recommended that EPA
refine the phrases and descriptions to enhance their clarity. Two
commenters preferred that descriptors not be used at all. A number of
commenters advised the Agency to use the ``Carcinogenic to Humans''
descriptor only when epidemiological evidence of carcinogenicity is
conclusive.
(3) Mode of action. EPA's draft 1999 Guidelines emphasized the
value of understanding a chemical's ``mode of action,'' which refers to
the series of steps and processes that lead to cancer formation. Many
commenters disagreed with EPA's proposal that confirmatory data be
available or a ``cogent biological rationale'' be developed before a
mode of action identified in adults (or mature animals) could be
considered applicable to children as well. On the other hand, several
commenters stated that EPA should require much stronger evidence before
concluding that a particular mode of action operates in both adults and
children.
(4) Margin of exposure analysis. A margin of exposure analysis is
an approach described in the 1999 draft Guidelines to inform decision-
makers about cancer risks at relatively low levels of exposure. The
1999 draft Guidelines suggested its use in the case of certain
carcinogens where mode of action data support a nonlinear approach for
describing the relationship between dose and response for the chemical.
Several commenters expressed concern that the margin of exposure
analysis as described by EPA would not be sufficiently protective of
public health. Other commenters stated that it inappropriately mixed
risk assessment and risk management considerations and was problematic
because it removed quantitative estimation of cancer risk from risk
assessment.
[[Page 10014]]
Key Features of the Draft Final Guidelines
EPA's guiding principle for revisions to the Guidelines is that
Agency cancer risk assessments be both public health protective and
scientifically sound. By public health protective, EPA means that risk
assessments should consider a range of susceptibilities among the human
population and, in the absence of complete knowledge, employ
assumptions that will reflect the risks to susceptible subpopulations
and lifestages. By scientifically sound, EPA means that risk
assessments should reflect current and evolving scientific practice and
describe risks in a clear, consistent, and reasonable manner. In
particular, the revisions to the Guidelines are intended to make
greater use of the increasing scientific understanding of the
mechanisms that underlie the carcinogenic process. EPA has also
designed the Guidelines to be flexible enough to accommodate future
scientific advances in science and risk assessment practices. EPA is
particularly interested in public comments on the following areas that
have been the focus of the Agency's attention in preparing today's
Draft Final Guidelines:
(1) Use of default options. The Draft Final Guidelines clarify the
role of default options (default assumptions) in the Agency's risk
assessments. Rather than view default options as the starting point
from which departures may be justified by new scientific information,
the Guidelines emphasize that assessments begin with a critical
analysis of the available data, and defaults would be invoked as needed
when too much uncertainty exists or critical data are missing. In
keeping with EPA's mission and the advice of numerous scientific
advisory panels, the Agency's default options are constructed to be
public health protective. The decision to invoke a default option would
be determined on a case-by-case basis. Given the multitude of different
types of risk assessments and potential default options, it is neither
possible nor desirable to specify step-by-step criteria for decisions
to invoke a default option. The Guidelines, however, identify general
principles for invoking default options (as originally articulated by
the National Research Council): Such decisions should be scientifically
defensible, consistent with EPA's statutory mission, and responsive to
the needs of decision-makers.
(2) Hazard descriptors. The Draft Final Guidelines continue to
emphasize the importance of weighing all of the evidence in reaching
conclusions about the human carcinogenic potential of agents, with
hazard descriptors used to facilitate clarity in describing
carcinogenicity conclusions. Several of the hazard descriptors
presented in the Draft Final Guidelines have been modified from
previous drafts of the Guidelines, and the discussion of when they
would apply has been strengthened. Descriptors may apply only to
certain routes of exposure, dose ranges, and durations of exposure. The
following five descriptors are discussed in the Guidelines:
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.
(3) Mode of action. The use of mode of action in the assessment of
potential carcinogens is the main thrust of the Draft Final Guidelines.
This area of emphasis arose because of scientific breakthroughs
concerning the causes of cancer induction. As discussed in the Draft
Final Guidelines, an important use of mode-of-action information is to
identify susceptible populations and lifestages. Because it is rare to
have epidemiologic studies or animal bioassays conducted in susceptible
individuals, identifying the key events of the mode of action and the
risk factors that can augment these key events can be critical in
understanding risks to susceptible populations.
(4) Extrapolation to lower doses. An important issue to address in
most EPA risk assessments is the estimation of risks at levels of
environmental exposure (doses) that are lower than the levels at which
adverse effects (responses) have been observed. Historically, EPA used
an approach known as linear extrapolation for all potential
carcinogens, which involves modeling risk in an approximately straight
line extrapolation from a particular dose level (the point of
departure) to the zero dose/zero response point. This approach differs
from that used by EPA in assessing risks in the case of most noncancer
effects, which typically involve nonlinear extrapolation. The Draft
Final Guidelines generally reaffirm the use of a linear extrapolation
approach for carcinogens when mode of action information is limited or
indicates a linear dose-response relationship, such as in the case of
mutagenic agents. The Draft Final Guidelines also discuss potential
uses of nonlinear extrapolation when consistent with understanding of
the mode of action, and recommend the development of a reference dose
(or reference concentration) as established by EPA for effects other
than cancer. This default approach is in keeping with the Agency's goal
of harmonizing the assessment of risks from agents, whether carcinogens
or not, that operate by a nonlinear mode of action.
(5) Susceptible populations and lifestages. The Draft Final
Guidelines explicitly recognize that variability exists among people in
their susceptibility to carcinogens and emphasize that this variability
should be considered in risk assessment. Some subpopulations may
experience increased susceptibility to carcinogens throughout their
lives, such as people who have inherited a 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, the Guidelines note that
childhood may be a lifestage of greater susceptibility for a number of
reasons, such as susceptibility related to the rapid growth and
development that occurs prenatally and after birth.
Supplemental Guidance on Early-Life Exposure
The discussion of consideration of childhood risks in the Draft
Final Guidelines has been augmented by the development of the separate
draft document entitled ``Supplemental Guidance for Assessing Cancer
Susceptibility from Early-Life Exposure to Carcinogens.'' This document
contains an analysis of studies and a possible approach for how
quantitative scientific data could inform risk assessments when
exposure to carcinogens occurring during childhood is considered. The
draft document will be reviewed by EPA's Science Advisory Board
following the public comment period. After SAB recommendations and
public comments are incorporated into the document, the supplemental
guidance will be issued separately from the final Cancer 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.
Request for Comment
EPA requests comments on today's Draft Final Guidelines and will
consider all comments in completing final Guidelines. Comments on
earlier drafts of the revised Guidelines already submitted to EPA need
not be resubmitted. Public comments are also invited on the draft
supplemental guidance on early-life exposure to carcinogens. Following
the public
[[Page 10015]]
comment period, EPA's SAB will peer-review the supplemental guidance. A
separate notice of the planned SAB meeting will also appear in the
Federal Register.
Dated: February 25, 2003.
Paul Gilman,
Assistant Administrator for Research and Development.
[FR Doc. 03-4912 Filed 2-28-03; 8:45 am]
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