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Proposed Guidelines for Carcinogen Risk Assessment
ABSTRACT:
The Proposed Guidelines for Carcinogen Risk Assessment were published
in the Federal Register on April 23, 1996 (Federal Register: 17960-18011)
for a 120-day public review and comment period. The Proposed Guidelines
are a revision of EPA's 1986 Guidelines for Carcinogen Risk Assessment
(51 FR 33992), and when final, will replace the 1986 cancer guidelines.
The full text of the FR notice also is being made available via the
Internet.
Since the publication of the 1986 cancer guidelines, there is a
better understanding of the variety of ways in which carcinogens can
operate. Today, many laboratories are moving toward adding new test
protocols in their programs directed at mode of action questions.
Therefore, the Proposed Guidelines provide an analytical framework
that allows for the incorporation of all relevant biological information,
recognize a variety of situations regarding cancer hazard, and are
flexible enough to allow for consideration of future scientific advances.
The 1986 cancer guidelines have several limitations in addition to
their inadequacy in addressing recent gains in the understanding of
carcinogenesis. Although they called for the evaluation of all relevant
information, the classification scheme used for identifying potential
human hazard relied heavily on tumor findings, and in practice, seldom
made full use of all biological information. Moreover, the conditions
of the hazard were not taken into account. For example, it was common
to assume that if an agent was carcinogenic by one route of exposure
(e.g., inhalation), it posed a risk by any route. The 1986 cancer guidelines
are also confined in that dose-response assessment allowed for only
one default approach (i.e., the linearized multistage model for extrapolating
risk from upper-bound confidence intervals). Moreover, very little guidance
was given for risk characterization, the component of risk assessment
that describes potential human risk, strengths and weaknesses of data,
size of risk, and confidence of the conclusions for the risk manager.
The Proposed Guidelines include the following changes to address these
limitations, accommodate new information on carcinogenesis, and advance
cancer risk assessment:
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Hazard Assessment Emphasizes Analysis of All Biological Information
rather than just tumor findings.
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Agent's Mode of Action is Emphasized to reduce the uncertainty
in describing the likelihood of harm and in determining the dose response
approach(es). This emphasis should provide incentive for generating
key information needed to reduce the default assumptions used in risk
assessment.
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Hazard Characterization is Added to Integrate the Data Analysis
of all relevant studies into a weight of evidence conclusion of hazard,
to develop a working conclusion regarding the agent's mode of action
in leading to tumor development, and to describe the conditions under
which the hazard may be expressed (e.g., route, pattern, duration,
and magnitude of exposure).
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Weight of Evidence Narrative Replaces the Current Alphanumeric
Classification. The narrative is intended for the risk manager
and lays out a summary of the key evidence, describes the agent's
mode of action, characterizes the conditions of hazard expression,
and recommends appropriate dose response approach(es). Significant
strengths, weaknesses, and uncertainties of contributing evidence
are highlighted. The overall conclusion as to the likelihood of human
carcinogenicity is given by route of exposure.
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Three Descriptors for Classifying Human Carcinogenic Potential:
"known/likely", "cannot be determined", and "not likely" replace the
six alphanumeric categories (A,B1,B2,C,D,E) in the 1986 cancer guidelines.
Subdescriptors are provided under these categories to further differentiate
an agent's carcinogenic potential.
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Biologically Based Extrapolation Model is the Preferred Approach
for quantifying risk. It is anticipated, however that the necessary
data for the parameters used in such models will not be available
for most chemicals. The Proposed Guidelines allow for alternative
quantitative methods, including several default approaches.
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Dose Response Assessment is a Two Step Process. In the first
step, response data are modeled in the range of observation and in
the second step, a determination of the point of departure or range
of extrapolation below the range of observation is made. In addition
to modeling tumor data, the new guidelines call for the use and modeling
of other kinds of responses if they are considered to be measures
of carcinogenic risk.
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Three Default Approaches--Linear, Nonlinear, or Both are provided.
Curve fitting in the observed range would be used to determine the
effective dose corresponding to the lower 95% limit on a dose associated
with 10% response (LED10). The LED10 would then be used as a point
of departure for extrapolation to the origin as the linear default
or for a margin of exposure (MOE) discussion as the nonlinear default.
The LED10 is the standard point of departure, but another may be used
if more reasonable given the data set [(e.g., a no observed adverse
effect level (NOAEL)]. In support of discussion of the anticipated
decrease in risk associated with various MOEs, biological information
concerning human variation and species differences, the slope of the
dose response at the point of departure, background human exposure
(if known), and other pertinent factors would be taken into consideration.
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Descriptions of Major Default Assumptions and Criteria for Departing
From Them are described.
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Risk Characterization is More Fully Developed by providing
direction on how the overall conclusion and confidence of risk is presented
for the risk manager. The Proposed Guidelines call for assumptions and
uncertainties to be clearly explained.
Document size: 435k
Number of tables: 0
Number of figures: 7
Email contact:
cancer-guidelines@epamail.epa.gov
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