ATSDR Cancer Policy Framework
January 1993
Note: While the original publication dates on some of ATSDR's documents may
not appear to be current, the information in the documents is valid and may
still provide relevant information.
Table of Contents
The Cancer Policy Framework was developed by a workgroup
comprised of the following individuals:
Christopher DeRosa, Ph.D. (Chairman)
Dennis Jones, D.V.M.
Kenneth Orloff, Ph.D.
Fred Rosenberg, D.O.
Robert Spengler, Sc.D.
Yee-Wan Stevens, M.S.
Allan Susten, Ph.D., D.A.B.T.
Steve Von Allmen, M.A.
Charles Xintaras, Sc.D.
The editorial assistance of Ms. Anne Olin and the secretarial assistance
of Ms. Markitia Hawley and Ms. Sandra Malcom are gratefully acknowledged.
Cancer remains at the forefront of public health concerns in the
United States and throughout the world. Over the past 20
years a wide range of federal agencies and other organizations
have been involved in developing policy statements,
classification strategies, and assessment methods to address
carcinogenesis and health risks. Each of these documents was
developed in response to issues confronted by those
organizations in pursuing their mission, often as a direct
function of legislative mandates.
In pursuing its mandated responsibilities, the Agency for Toxic
Substances and Disease Registry (ATSDR) must address public
health concerns associated with exposure to carcinogens in the
context of all available relevant information. This information
includes both technical data as well as science policy positions
adopted by the range of organizations with programs germane
to the assessment and/or regulation of carcinogens. Because of
distinct differences in perspective, practice, and policy
dictated
by the mandated activities of these organizations and the
rapidly evolving understanding of carcinogenesis, apparently
divergent positions may be reflected in their conclusions.
The differences outlined above, coupled with requests from the
public, other agencies, and the private sector for a statement
reflecting the Agency's position on science and science policy
issues related to cancer, prompted the development of this
policy framework. This document is intended to serve as a
framework to guide the Agency in its programs and actions
regarding carcinogens and to harmonize such efforts with
those of other federal agencies and relevant organizations.
This framework reflects an assessment of current practice
within the Agency and defines the appropriate roles of
conclusions derived by other groups, professional judgment,
and emerging scientific principles in ATSDR's public health
assessments of exposures to carcinogens.
This Cancer Policy Framework is not intended to encompass
the development of operational guidelines per se, although the
Agency recognizes the utility of such efforts. A central theme
of this Cancer Policy Framework is the use of risk analysis as
an organizing construct based on sound biomedical and other
scientific judgment to define plausible exposure ranges of
concern rather than single numerical conclusions that may
convey an artificial sense of precision. The development and
use of innovative tools for exposure and dose response
assessment (with particular emphasis on molecular
epidemiology) are also endorsed.
Barry L. Johnson, Ph.D.
Assistant Surgeon General
Assistant Administrator, ATSDR
Background
The Agency for Toxic Substances and Disease Registry
(ATSDR) pursues a range of legislatively mandated programs
that address public health concerns regarding carcinogens. The
purpose of the ATSDR Cancer Policy Framework is to define
scientifically credible, internally consistent policy positions
to
guide ATSDR's activities that address the public health
implications of exposure to carcinogens. This Cancer Policy
Framework is not intended to encompass the development of
operational guidelines per se, although ATSDR recognizes the
utility of such efforts.
A central theme of ATSDR's Cancer Policy Framework is the
use of risk analysis as an organizing construct to promote
optimal decisions in the Agency's human health assessment
programs. Risk analysis is a multidimensional endeavor
encompassing biomedical judgment, peer review, and risk
assessment (NRC 1983) as well as risk communication and risk
management (CEQ 1989). Accordingly, the Agency's Cancer
Policy Framework places emphasis on scientific judgment, peer
review, and relevant expertise/knowledge of ATSDR and other
federal agencies. As a Public Health Service agency, ATSDR
places a preeminent emphasis on disease prevention.
This policy framework was developed based on an assessment
of current practice across programs within ATSDR and as such
is multifaceted encompassing aspects of exposure as well as
carcinogenicity. Collectively, the elements of the ATSDR
Cancer Policy Framework are intended to guide ATSDR's
pursuit of its mandate to assess the relationship between
exposure to hazardous substances and the effects of those
substances on human health.
Risk analysis typically involves significant uncertainty
associated with required assumptions and extrapolation.
Accordingly, it is anticipated that as knowledge and
understanding of the carcinogenic process matures, the
Agency's Cancer Policy Framework will have to be modified.
For these reasons, ATSDR's Cancer Policy Framework is best
viewed as a dynamic, continuously evolving instrument
intended to mirror the scientific community's new insights into
and understanding of carcinogenicity.
ATSDR's Cancer Policy Framework Position Statements are
listed below. Supporting documentation for these positions is
presented.
Exposure
ATSDR recognizes that, at present, no single generally
applicable procedure for exposure assessment exists, and,
therefore, exposures to carcinogens are best assessed on a
case-by-case basis with an emphasis on prevention of
exposure.
Analysis of Hazard and Risk
(a) Qualitative Issues
In conveying qualitative conclusions regarding
carcinogenicity, the Agency endorses the use of a narrative
statement incorporating weight-of-evidence conclusions in
lieu of alpha-numeric designations alone. In this regard,
ATSDR adopts the findings of the Department of Health
and Human Services' most recent Annual Report on
Carcinogens, as coordinated by the National Toxicology
Program.
Analytical epidemiologic investigations, such as case-
control or cohort studies, can provide the basis for testing
causal associations and are an invaluable resource in public
health decisions. Risk estimates derived from such studies
are useful in assessing the potential range of human health
risks.
ATSDR believes that although an agent may not have been
demonstrated to be a carcinogen in a well-designed and
well-conducted epidemiologic study, a potential association
between exposure to the agent and human cancer cannot be
ruled out.
The Agency considers that a substance which has been
shown to cause cancer in animals should be presumed to
pose a carcinogenic risk to humans in the absence of
compelling data to the contrary. ATSDR evaluates the
relevance of the animal data to humans on a case-by-case
basis.
(b) Quantitative Issues
In terms of quantitative risk assessment per se, ATSDR
does not currently engage in low-dose modeling efforts or
in the development of associated cancer potency factors or
slope estimates. In some instances, cancer potency factors,
developed by the Environmental Protection Agency (EPA),
are used by ATSDR to estimate cancer risk levels.
ATSDR recognizes that estimation of lifetime cancer risks
is further complicated when available data are derived
from less than lifetime exposures and that pharmacokinetic
insights from animal models may be of utility in
addressing this issue.
ATSDR strongly endorses the development of analytical
tools to better define exposures, effects, and risks,
including individual risk, in the broad context of risk
analysis.
Risk Analysis
Emphasis is placed on the use of risk analysis as a
decision-making construct contingent on sound biomedical
and other scientific judgment to define plausible exposure
ranges of concern.
ATSDR will employ the plausible ranges associated with
default exposure, toxicological, and other assumptions and
policy positions. These may include ranges of default
values such as the range of pulmonary ventilation rates
(i.e., 8-20 m3/day), human body weight (i.e., 10-60 or 70
kg), or ranges based on the use of low-dose extrapolation
models (i.e., logit, probit, multistage, etc.).
Although ATSDR recognizes the utility of numerical risk
estimates, the Agency considers these estimates in the
context of the variables and assumptions involved in their
derivation and in the broader context of biomedical
opinion, host factors, and actual exposure conditions.
A. Background:
The establishment of the Agency for Toxic Substances
and Disease Registry (ATSDR), a United States Public
Health Service agency, was mandated by the
Comprehensive Environmental Response, Compensation, and
Liability Act of 1980 (CERCLA) or Superfund. The
mission of ATSDR is to prevent or mitigate the adverse
human health effects and diminished quality of life
that result from exposure to hazardous substances in
the environment (ATSDR 1989).
In pursuing its legislatively mandated
responsibilities, ATSDR engages in activities in the
following general program areas:
- Public health assessment of hazardous waste sites
- Health consultations regarding specific hazardous
waste sites and substances
- Health investigations, including the development
of exposure and disease registries
- Emergency response to releases of hazardous
substances
- Applied research to enhance its health assessment
capabilities
- Identification, prioritization, and critical
assessment of hazardous substances
- Education and training of health care providers
and communities potentially exposed to hazardous
wastes
Public health concerns arising from past, ongoing,
and/or potential exposures to carcinogens are attendant
to each program area pursued by ATSDR.
B. Purpose:
Although ATSDR uses all relevant and available
information on the health effects of carcinogens, the
Agency has no formal statement or policy regarding:
- Current cancer assessment practice within ATSDR
programs
- Human exposure to carcinogens
- Reliance on or use of existing programs and
institutional experience germane to cancer policy
principles and guidance in cancer health
assessment
- Criteria/principles to be used in resolving
divergent conclusions derived from cancer
assessments conducted by other organizations
- Definition of environmental levels of concern for
purposes of screening human exposures to
carcinogens
- ATSDR's appropriate role as a practitioner/client
of risk assessments for carcinogens
- The appropriate role of peer review and use of
emerging scientific principles, methods, and
techniques in cancer health assessment
- Its long-term involvement/responsibility in
harmonizing cancer policy issues across federal
agencies
The purpose of this Cancer Policy Framework is to set
forth scientifically credible, and internally
consistent, policy positions to guide ATSDR's
activities that address the public health implications
of exposure to carcinogens and to harmonize those
activities with related activities of other federal
agencies and relevant organizations.
C. Scope:
As described above, ATSDR's Cancer Policy Framework is
intended to define a general structure to facilitate
technical and administrative decisions within programs,
all of which have developed and implemented relevant
guideline-like efforts or are in the process of so
doing. This policy framework is not intended to
encompass the development of prescriptive guidelines
for the purpose of public health or risk assessment,
although the merit and value of such endeavors are
recognized. ATSDR also recognizes the existence of a
wealth of experience accrued by its programs, other
groups, and institutions with significant programs in
the area of health and risk assessment. ATSDR intends
to reference and build on such experience where
applicable.
Collectively, the elements of this Cancer Policy
Framework are intended to guide ATSDR's pursuit of its
mandate to assess the relationship between exposure to
hazardous substances and the effects of those
substances on human health, in this case, cancer.
Emphasis is placed on the use of risk analysis as an
organizing construct contingent on sound biomedical and
other scientific judgment to define plausible exposure
ranges of concern rather than single numeric
conclusions that may convey an artificial sense of
precision. The development and utilization of
innovative tools for exposure and dose-response
assessment are also endorsed.
A. Qualitative Practice:
ATSDR's qualitative conclusions regarding
carcinogenicity are presented in the Agency's
toxicological profiles in which a weight-of-evidence
approach is used. This approach relies upon the
Department of Health and Human Services' most recent
Annual Report on Carcinogens (NTP 1991). Conclusions
of the International Agency for Research on Cancer
(IARC 1987), the U.S. Environmental Protection Agency
(EPA 1986a), and the Occupational Safety and Health
Administration (OSHA 1980) are also considered and
presented as appropriate (see Appendix A).
Discrepancies are resolved based on ATSDR's evaluation
of data used by different organizations and scientific
peer review. In the absence of toxicological profiles,
relevant peer-reviewed literature, EPA documents, and
on-line data bases, such as TOXNET and TOXLINE, are
consulted.
B. Quantitative Practice:
In terms of quantitative risk assessment per se, ATSDR
does not currently engage in low-dose modeling efforts
or in the development of cancer potency factors. In
some instances, cancer potency factors, derived by EPA,
are employed to estimate cancer risk levels. These, in
turn, are used by ATSDR internally in combination with
broader professional judgment to define exposure levels
of concern (i.e., those presenting a potentially
significant human health hazard).
All dose/exposure levels reported in studies of
carcinogenic effects of hazardous substances are
presented in the toxicological profiles irrespective of
whether a carcinogenic response was observed. The
lowest dose levels associated with carcinogenic effects
are identified as cancer effect levels (CELs), with the
stipulation that such a designation should not be
construed to imply the existence of a threshold for
carcinogenesis. Also, exposures associated with upper-
bound excess risk estimates over a lifetime of exposure
(i.e., one case of cancer in 10,000 to one case of
cancer in 10,000,000) as developed by EPA are
presented.
C. Exposure Assessment:
Statements regarding the significance of exposures to
carcinogens are based on EPA-derived risk levels (e.g.,
one case of cancer in 1,000,000 in ATSDR public health
assessments), investigations of cancer occurrence, and
biological markers of exposure to carcinogens. The
linkage of exposures to cancer occurrence is
qualitative rather than quantitative. Thus, the
Agency's current use of dose-response relationships in
risk characterization is limited.
Both exposure and toxicity information are necessary to
fully characterize the potential hazard of an agent. ATSDR
considers exposure to an agent to be "an event consisting of
contact at a boundary between a human and the environment at
a specific environmental contaminant concentration for a
specified interval of time; the units to express exposure
are concentration multiplied by time" (NAS 1991).
Furthermore, dose is defined as "the amount of contaminant
that is absorbed or deposited in the body of an exposed
individual over a specified time. Therefore, dose is
different from, and occurs as a result of, an exposure" (NAS
1991).
In assessing exposure to hazardous substances, ATSDR
considers all parameters with potential impact on human
health outcomes including the following:
A. Exposure Duration and Frequency:
A single high-dose exposure to an agent may result in
toxic effects different from those following repeated
lower dose exposures. Therefore, consideration is
given to the duration [acute (ó14 days), intermediate
(15-364 days), and chronic (ò 365 days)], the intensity
(dose rate vs. total dose), and the frequency
(continuous or intermittent) of exposure in evaluating
carcinogenic risk, along with relevant pharmacokinetic
parameters for constituents of concern. With regard to
doses and exposure duration employed in the National
Toxicology Program (NTP) bioassays, ATSDR believes that
caution should be exercised in interpreting the
significance of tumors that are induced only at the
maximum tolerated dose (MTD) of an agent. In such
cases, the Agency will weigh all information relevant
to the particular exposure scenario in developing its
public health assessment.
B. Exposure Routes:
Exposure to hazardous substances is often complex,
entailing exposures via more than one route and/or
media; it may also be "indirect," in which case an
agent is released into one medium (e.g., air) and
subsequently partitioned to other media such as water,
soil, or food. For these reasons, ATSDR considers all
such possible exposure routes in assessing the
carcinogenic risk posed by an agent.
C. Monitoring Studies:
The Agency uses information obtained from assessment of
direct exposure (e.g., drinking contaminated water in
the vicinity of a hazardous waste site) and/or indirect
exposure (e.g., accumulation of contaminants via the
food chain). Ideally, assessment will include
monitored levels of the agent in contaminated
environmental media, and in human tissues and fluids,
and in particular, an estimate of the dose at a
biologic target tissue(s) where an effect(s) may occur.
Such information is necessary to accurately evaluate
the potential health risk of exposed populations.
D. Exposure Modeling:
In the absence of complete monitoring information,
mathematical exposure assessment models may be
employed. These models provide a methodology through
which various factors, such as the temporal/spatial
distribution of an agent emitted from a source, can be
combined to predict levels of human exposure. ATSDR
does not view modeling as a fully satisfactory
substitute for adequate data but rather as a surrogate
to be employed when confronted by compelling needs and
inadequate data. Uncertainty associated with these and
all methods must be articulated to the extent
feasible.
E. Default Assumptions:
In estimating total exposure it is necessary to have
information on inhalation rate, water consumption, food
consumption, life span or body weight, and other
factors depending on the route of exposure. In the
absence of actual values for these parameters, ATSDR
will use default estimates including those described by
EPA (EPA 1986b), recognizing that significant
uncertainty is associated with the use of default
values.
F. Host Factors:
ATSDR considers the influence of behavior, such as the
amount of time spent indoors compared with that spent
outdoors, and its underlying variability in assessing
potential human health effects. Furthermore, ATSDR
recognizes that factors such as nutritional status and
lifestyle variables (e.g.,
tobacco, alcohol, and occupation) may all affect health
risk(s) associated with exposure.
G. Current, Past, and Potential Exposure:
Carcinogenic effects may occur in populations not only
as a result of current exposure to agents but also from
past exposures. Furthermore, based on current
knowledge of the agents, these adverse health effects
might be predicted from potential exposures.
Therefore, ATSDR considers past, current, and potential
exposure to hazardous substances to be of public health
concern.
With respect to ongoing and/or potential exposure,
ATSDR places emphasis on identifying and implementing
strategies to interdict exposures, mitigate toxicity,
and institute other necessary preventive actions.
H. Summary:
ATSDR recognizes that, at present, no single generally
applicable procedure for exposure assessment exists,
and, therefore, exposures to carcinogens must be
assessed on a case-by-case or context-specific basis.
While the need for, and reliance on, models and default
assumptions is acknowledged, ATSDR strongly encourages
the use of applicable empirical data (including ranges)
in exposure assessment.
A. Analysis of Hazard and Risk:
ATSDR recognizes the utility and relevance of the
Office of Science and Technology Policy (OSTP) for
assessing risks from chemicals (OSTP 1985), the
Occupational Safety and Health Administration's
(OSHA) Generic Carcinogen Policy (OSHA 1980), the
Department of Health and Human Services' most
recent Annual Report on Carcinogens (NTP 1991), and
the Report of the Department of Health and Human
Services (DHHS) Committee to Coordinate
Environmental Health and Related Programs
(CCEHRP) on Risk Assessment and Risk Management
of Toxic Substances (CCEHRP 1985). The Agency
embraces these principles along with emerging insights
regarding carcinogenic processes to guide its
evaluation of carcinogenic risks in its public health
assessment efforts. In particular they provide
valuable insights related to the relevance of animal
data to human carcinogenesis, the significance of
nonpositive
study results, and the potential correlation between
benign and malignant tumors.
Cancer assessment by necessity involves a number of
assumptions, all of which reflect scientific and policy
judgments. ATSDR places a premium on such
informed professional judgment and peer review.
The Agency considers that a substance which has
been shown to cause cancer in animals should be
presumed to pose a potential carcinogenic risk to
humans in the absence of data to the contrary. As
more knowledge on particular agents and the
oncogenic process in general is obtained, the Agency's
position on these issues may be subject to change.
ATSDR's positions with regard to these principles are
described below.
- 1. Qualitative Issues:
- a) Weight of Evidence:
ATSDR adopts a weight-of-evidence approach
in evaluating all relevant data, following
the
approach used by the National Toxicology
Program (NTP 1991), the International
Agency for Research on Cancer (IARC 1987),
the Environmental Protection Agency
(EPA 1986a), and the Occupational Safety
and Health Administration (OSHA 1980) (see
Appendix A). Types of evidence that may be
used for qualitatively identifying
carcinogens
include case studies, epidemiologic studies,
long-term animal bioassays, short-term tests,
and structure-activity relationships.
Factors to be evaluated in determining if a substance poses a carcinogenic
risk to humans include, but are not limited to, the quality of the toxicity
studies (choice of appropriate control groups, sufficient number of animals,
administration route, dose selection, tumor types) and the relevance of
animal data to humans. ATSDR places great importance on quality of studies
in evaluating health risks and, therefore, will rely exclusively on peer-
reviewed studies in its assessment of the potential carcinogenic risk. The
Agency endorses the use of a narrative statement incorporating weight-of-evidence
conclusions in lieu of alphanumeric designations alone in conveying qualitative
conclusions regarding carcinogenicity.
- b) Mechanistic Inference and Species Concordance:
Carcinogenesis is generally viewed as a
multistage process, proceeding from
initiation,
through promotion, and progression.
Carcinogens may work through mechanisms
that directly alter the genome (genotoxic),
or
through mechanisms that indirectly involve
the genome (epigenetic). Currently, it is
assumed that many or most carcinogens are
characterized by the absence of a threshold
in
eliciting a tumorigenic response. However,
the presence or absence of a threshold for
one
step in the multistage process of
carcinogenesis does not necessarily imply the
presence or absence of a threshold for other
steps or the entire process. For example,
carcinogenic effects of some agents may
result from nonphysiologic responses to the
agents, such as extensive organ damage or
formation of calculi in the urinary tract.
Under such circumstances, ATSDR evaluates
the relevance of the animal data to humans
on a case-by-case basis with a view towards
extending its assessment effort beyond the
dominant paradigm of carcinogenesis (i.e.,
initiation, promotion, and progression).
- c) Route Specificity:
In the analysis of potential carcinogenic
risk
of agents to humans, it is important to
address
the issue of exposure route specificity. For
some agents, exposure results in adverse
health effects via one route only. For
example, while chronic oral exposures to an
agent may not result in cancer in animals
and/or humans, the same agent may be
carcinogenic via inhalation in the same
species. Accordingly, ATSDR evaluates the
potential health risk of toxic substances
taking into account the relevant route(s) of
exposure. In the absence of data to the
contrary, an agent that is carcinogenic via
one route will be considered to be a
potential
carcinogen via alternate routes.
- d) Role of Epidemiologic Data:
Epidemiologic studies provide direct
information on the carcinogenic risk of
environmental agents to humans. For this
reason, ATSDR assigns a higher weight to
well-designed and well-executed
epidemiologic studies than to animal studies
of comparable quality in evaluating the
potential human cancer risks. However, the
observational nature of such studies, as well
as the use of indirect measures of exposure,
sometimes constrains interpretation of the
data.
Descriptive epidemiologic studies may be
useful in generating/refining hypotheses that
suggest further in-depth studies. These
studies also provide limited information on
causal relationships. Alternatively,
analytical
epidemiologic investigations such as case-
control or cohort studies can provide the
basis for testing causal associations and are
an invaluable resource in public health
decisions. The causal association of toxic
chemical exposure and cancer is greatly
enhanced when studies show: relationships
without significant bias, a temporal sequence
of exposure and response, consistency with
other studies, strength of association, a
dose-
response relationship, and biologic
plausibility.
ATSDR believes that although an agent may
not have been shown to be a carcinogen in a
well-designed epidemiologic study, a
potential association between exposure to the
agent and human cancer cannot be ruled
out. The potential for an association will
remain, particularly if relevant animal data
suggest that a carcinogenic effect exists.
This
premise would also apply in the case of
health effects other than cancer.
- e) Susceptible Populations:
Certain populations may be at high risk of
developing cancer because of several factors,
including exposure to unusually high levels
of
carcinogens, genetic predisposition, age, and
other host factors such as physiological and
nutritional status. ATSDR places great
importance on identifying these susceptible
populations and addressing associated public
health concerns.
- f) Structure-Activity Relationships:
Information on the physical, chemical, and
toxicological characteristics as well as the
environmental fate of many hazardous
substances is available. Thus, some
correlations can be made between the
structures of some hazardous substances and
the properties they exhibit. ATSDR endorses
the use of structure-activity relationships
to
derive preliminary estimates of both the
environmental and toxicological
characteristics of hazardous substances for
which little or no information is available.
However, ATSDR recognizes that a great deal
of scientific judgment is required in
interpreting these results since these
methods
need to be refined and validated. Further,
the
Agency recognizes that conclusions derived
by such approaches are, at present,
inadequate
as surrogates for human or other bioassay
data.
- g) Chemical Interactions:
Health evaluations are often complicated by
the fact that multiple hazardous substances
may be of concern at specific waste sites.
The Agency believes that no single approach
is appropriate for all risk assessments of
multiple chemical exposures. Furthermore, at
present, the scientific community has not
reached consensus on the appropriate use of a
particular multiplicative model. Given the
paucity of empirical data and the complexity
of this issue, ATSDR assumes that, in the
absence of information regarding the
interaction of these substances, their
effects
are additive. Such assessments should also
be accompanied by a qualitative weight-of-
evidence-like statement on the potential for
interactive effects, be they potentiating,
additive, antagonistic, and/or synergistic.
Ideally, these conclusions are based on
insights regarding mechanism of action of
individual components as the insights relate
to
the potential for interaction among
components of the mixture.
- 2. Quantitative Issues:
- a) Dose Scaling:
Conversion of exposure levels derived from
experimental animal studies to humans is an
equivocal process because of recognized
differences among species, e.g., life span
and
body size, and pharmacokinetic and genetic
factors, among others. Although a number of
default scaling factors have been proposed,
no
single scaling approach may be universally
appropriate. ATSDR endorses the use of
(mg/kg3/4)/day for dose scaling as a default,
in the absence of empirical data, as
suggested by the Federal Coordinating
Council for Science, Engineering, and
Technology (FCCSET 1992).
The Agency recognizes, however, that the use
of any default approach to scaling is a crude
approximation and that all factors
responsible
for interspecies differences must be
considered in dose/exposure conversions
among species when selecting extrapolation
methods. For these reasons, empirically
derived data relevant to dose scaling are
preferred and should be used preferentially
when they are available. Extrapolation may
not be necessary if epidemiologic data are
used to assess potential carcinogenic risk;
however, differences in individual
sensitivity
must be taken into account.
- b) Pharmacokinetics and Pharmacodynamics:
ATSDR considers it important to conduct
health studies in populations that have been
exposed to carcinogens in the past or that
are
currently exposed to these agents. In
assessing the potential carcinogenic risks of
agents, information on the delivered target
dose rather than the exposure dose may help
in developing a more accurate assessment of
the possible carcinogenicity of an agent.
ATSDR encourages the development and use
of physiologically based pharmacokinetic
models for estimating the magnitude and time
course of exposure to agents at target sites
in
animal models. Once data from the animal
models have been appropriately validated,
they can then be used to estimate
corresponding target tissue doses in humans.
Furthermore, ATSDR recognizes that
estimation of lifetime cancer risks is
further
complicated when available data are derived
from less than lifetime exposures and that
pharmacokinetic insights may be of utility in
addressing this issue.
- c) Mechanistic Considerations and Modeling:
Health assessment for potential carcinogens
must take into consideration dose-response
relationships from all available relevant
studies. In chronic bioassays, animals are
often exposed to levels of the agent that
are,
for practical reasons, far higher than levels
to
which humans are likely to be exposed in the
environment. Therefore, mathematical models
are used to extrapolate from high to low
dose.
The selection of models depends on the
known or presumed mechanism of action of
the agent and on science policy
considerations. In the absence of sufficient
information to choose among several equally
plausible models, preference will be given to
the more conservative (i.e., protective)
model.
The multistage model is widely used for low-
dose extrapolation for genotoxic agents. It
is
based on the premise that a developing tumor
proceeds through several different stages
before it is clinically detectable. In the
low-
dose region, this multistage model is
frequently linear, and it is assumed that a
threshold, below which effects are not
anticipated, does not exist. ATSDR
recognizes that no single mathematical model
is appropriate in all cases and that
incorporation of new information on
mechanism and pharmacokinetics, among
other factors, will increase the usefulness
and
facilitate the selection of the most
appropriate
mathematical model. Existing mathematical
models for low-dose extrapolation may not be
appropriate for nongenotoxic agents. ATSDR
believes that more information on biological
mechanism is needed to determine if there are
threshold exposure levels for nongenotoxic
agents. For these reasons, where feasible,
ATSDR will consider the presentation of a
range of plausible potency estimates in
conveying quantitative conclusions.
- d) Individual vs. Population Risk--The Role of
Molecular Epidemiology:
Recent advances in biomolecular technology
have resulted in the development of highly
sensitive methods for measuring biomarkers
of exposure, effects, and susceptibility
(Shields and Harris 1991; Johnson and Jones
1992). Biomarkers have the potential to
serve
as bridges between experimental and
epidemiologic studies of carcinogens, insofar
as they reflect biochemical or molecular
changes associated with exposure to
carcinogens.
Biomarkers, such as DNA adducts, may be
used as indices of the biologically effective
doses, reflecting the amount of the potential
carcinogen or its metabolite that has
interacted with a cellular macromolecule at
the target site. Furthermore, markers of
early
biologic effect, such as activated oncogenes
and their protein products, and/or loss of
suppressor gene activity, may indicate the
occurrence of possibly irreversible toxic
effects at the target site.
Genetic markers, such as certain aryl
hydrocarbon hydroxylase isozymes, may
suggest the presence of heritable
predispositions or the effects of other host
factors, such as lifestyle or prior disease.
Thus, molecular epidemiology, by combining
experimental models, molecular biology, and
epidemiology, holds promise as a means to
estimate individual cancer risk and to better
define the health implications of hazardous
waste sites for members of exposed
populations (NRC 1991). However, it should
be noted that more research is needed before
biomarkers can be used as prognostic
indicators. ATSDR strongly endorses the
development of such analytical tools to
better
define exposures, effects, and risks,
including individual risk, in the broad
context of risk analysis.
B. Institutional Experience:
A central theme of ATSDR's Cancer Policy
Framework is the development of a construct that will
facilitate optimal decisions in the Agency's human
health assessment programs. Therefore, the Agency's
Cancer Policy Framework places primary emphasis
on the scientific judgment, peer review, and
expertise/knowledge of the scientific community
including ATSDR and other federal agencies, such as
NTP, EPA, OSHA, the National Institute for
Occupational Safety and Health (NIOSH), and the
Food and Drug Administration (FDA), and other
organizations with significant programs in this area,
such as IARC. Although they are useful as adjuncts
to the decision-making process, ATSDR places less
weight on generic, algorithmically derived conclusions
than on biomedical judgment and institutional
experience.
C. The Role of Emerging Scientific Principles and
Techniques:
ATSDR believes that its Cancer Policy Framework is best
viewed as a dynamic and continuously evolving
instrument intended to mirror the scientific
community's new insights into and understanding of
carcinogenicity. Since cancer risk analysis typically
involves significant uncertainty associated with
required extrapolation and assumption, it is
anticipated that as knowledge and understanding of the
carcinogenic process matures, the Agency's Cancer
Policy Framework will have to be modified accordingly.
Additional data on metabolic pathways and
pharmacokinetics, species variability, and mechanistic
insights may better define the relevance of animal data
to humans. Similarly, research findings on biomarkers
(e.g., DNA adducts) may better explain their
significance in relation to carcinogenic risk. Other
areas of research that may reduce uncertainty in risk
analysis include: the development of model systems to
assay compounds that influence the promotion and
progression of initiated cell populations, the study of
factors that influence cell proliferation, and the
development of tests for chromosomal rearrangements and
oncogene and suppressor gene functions. New
information from each of these areas of research will
further understanding of carcinogenesis and thereby
serve to reduce current uncertainties in risk
analysis.
ATSDR views risk analysis as a multidimensional endeavor
encompassing expert judgment, peer review, and risk
assessment (NRC 1983), as well as risk communication and
risk management (CEQ 1989). Of pivotal importance to
credible risk analysis efforts is a systematic
identification of uncertainties attendant to each of the
components and subcomponents of risk analysis. Such
uncertainty is often obscured in the typically linear
progression from the elements of risk assessment as defined
by the National Research Council (NRC 1983) to elements of
risk management and risk communication. As a result,
algorithmically derived numerical risk estimates tend to be
conveyed in an artificially precise manner and sometimes
used inappropriately in decision-making. This artificial
appearance of precision can lead decision makers to rely
heavily on numerical risk estimates. Although ATSDR
recognizes the utility of numerical risk estimates in risk
analysis, the Agency considers these estimates in the
context of the variables and assumptions involved in their
derivation and in the broader context of biomedical opinion,
host factors, and actual exposure conditions. The actual
parameters of environmental exposures must be
given careful consideration in evaluating the assumptions
and variables relating to both toxicity and exposure.
Particular attention must be paid to the differences in
conditions under which empirical data used in the
development of a risk estimate were derived and the actual
environmental exposure conditions being assessed as well as
host factors.
A. Risk Characterization:
In risk characterization, all information derived from
each step of the assessment of carcinogenic risk is
integrated and used to project the frequency and
severity of the adverse health effects in exposed
populations. ATSDR places a premium on a critical
evaluation and presentation of all environmental,
biological, and statistical uncertainties in the final
assessment. Furthermore, the Agency will carefully
reexamine the quality of the studies used to support
all conclusions and compare data across similar studies
that are relevant to specific assessments. When
appropriate, ATSDR will employ plausible ranges
associated with default exposure, toxicological, and
other assumptions/policy positions. These may include
ranges of default values such as the range of pulmonary
ventilation rates (i.e., 8-20 m3/day), human body
weight (i.e., 10-60 or 70 kg), or ranges based on the
use of low-dose extrapolation models (i.e., logit,
probit, multistage, etc.).
B. Risk Communication:
ATSDR recognizes that the needs of the clients of risk
analysis must be well understood by those involved in
the assessment process. There must be feedback and
interaction between practitioners and clients,
including risk analysts, risk managers, risk
communicators, and the public. Furthermore, ATSDR
considers that education and training efforts related
to public health assessment are essential to effective
communication. ATSDR endorses the use of principles of
risk communication as articulated by the National
Research Council (NRC 1989; CCEHRP 1992).
C. Risk Management:
Risk management decisions should be based on a wide
range of issues relevant to risk analysis, including
medical opinion, epidemiology, and professional
judgment, along with socioeconomic factors and
technical feasibility. Although ATSDR does not engage
in risk management per se, the Agency does provide
technical information and professional judgment to be
employed as part of that process. As such the Agency
places a premium on enhancing communication and
feedback among those engaged in the components of risk
analysis and management.
ATSDR. 1989. Statement of organization, functions, and
delegations of authority. Agency for Toxic Substances and
Disease Registry. Federal Register 54:33617.
CCEHRP. 1985. Risk assessment and risk management of toxic
substances. A report to the Secretary, Department of Health and
Human Services (DHHS) from the Executive Committee, Committee to
Coordinate Environmental Health and Related Programs (CCEHRP).
CCEHRP. 1992. Draft Report. Recommendations to improve health
risk communication. Subcommittee on Risk Communication and
Education, Committee to Coordinate Environmental Health and
Related Programs (CCEHRP), Department of Health and Human
Services, Public Health Service.
CEQ. 1989. Risk analysis: A guide to principles and methods
for analyzing health and environmental risks. Council on
Environmental Quality. Washington, D.C. NTIS: PB89-137772.
EPA. 1986a. Guidelines for carcinogen risk assessment. US Environmental Protection
Agency: Part II. Federal Register 51:33992-34003.
EPA. 1986b. Final draft. Reference values for risk assessment. US Environmental
Protection Agency. Prepared by Environmental Criteria and Assessment Office,
Office of Health and Environmental Assessment. Cincinnati, OH.
FCCSET. 1992. Draft Report. A cross-species scaling factor for
carcinogen risk assessment based on equivalence of
(mg/kg3/4)/day.
Federal Coordinating Council for Science, Engineering, and
Technology. Federal Register 57:24152-24173.
IARC. 1987. IARC monographs on the evaluation of the
carcinogenic risk of chemicals to humans. Overall evaluations of
carcinogenicity: An updating of IARC monographs volumes 1-42,
supplement 7. Lyon, France: International Agency for Research
on Cancer.
Johnson BL, Jones DE. 1992. ATSDR's activities and views on
exposure assessment. Journal of Exposure Analysis and
Environmental Epidemiology, Suppl. 1:1-17.
NAS. 1991. Human exposure assessment for airborne pollutants. National Academy
of Sciences. Washington, DC, p. 3.
NRC. 1983. Risk assessment in the federal government: Managing the process.
National Research Council. National Academy Press, Washington, DC
NRC. 1989. Improving risk communication. National Research Council. National
Academy Press. Washington, DC
NRC. 1991. Environmental epidemiology. Public health and hazardous wastes,
volume I. National Research Council. National Academy Press, Washington, DC
NTP. 1991. Sixth annual report on carcinogens. National Toxicology Program,
US Department of Health and Human Services, Public Health Service.
OSHA. 1980. Identification, classification and regulation of
potential occupational carcinogens. Occupational Safety and
Health Administration, Department of Labor. Code of Federal
Regulations. 29 CFR 1990, Chapter XVII.OSTP. 1985. Chemical carcinogens: A review of the science and
its associated principles. Office of Science and Technology
Policy. Federal Register 50:10372-10442.
Shields PG, Harris CC. 1991. Molecular epidemiology and the
genetics of environmental cancer. JAMA 266:681-687.
Table 1. Classification of carcinogens
--------------------------------------------------------------------------
EPA IARC NTP OSHA
--------------------------------------------------------------------------
(Group A) (Group 1) Human Carcinogen Category I
Human Carcinogen Carcinogenic
to Humans
--------------------------------------------------------------------------
(Group B1, B2) (Group 2A) Reasonably Category II
Probable Human Probably Anticipated to
Carcinogen Carcinogenic be a Carcinogen
to Humans
--------------------------------------------------------------------------
(Group C) (Group 2B)
Possible Human Possibly
Carcinogen Carcinogenic
to Humans
--------------------------------------------------------------------------
(Group D) (Group3)
Not Classifiable Not Classifiable
as to Human as to Human
Carcinogenicity Carcinogenicity
--------------------------------------------------------------------------
(Group E)
Evidence of
Non-Carcinogenicity
for Humans
Identification of Submitters
Submitter #1 is Board of Scientific Counselors, Agency for
Toxic Substances and Disease Registry, Atlanta, Georgia.
Submitter #2 is Richard A. Lemen, Ph.D., National Institute for
Occupational Safety and Health, Centers for Disease Control
and Prevention, Atlanta, Georgia.
Submitter #3 is Richard B. Rothenberg, M.D., National Center
for Chronic Disease Prevention and Health Promotion, Centers
for Disease Control and Prevention, Atlanta, Georgia.
Submitter #4 is Malcolm D. Williams, D.V.M., Ph.D., Division
of Toxicology, Agency for Toxic Substances and Disease
Registry, Atlanta, Georgia.
ATSDR thanks these submitters for their reviews of the
document. The reviews were constructive and provided
valuable perspectives in preparing the ATSDR Cancer Policy
Framework.
General Comments
Submitter #1, Comment 1, believes that the draft document
submitted at the November 6, 1992, meeting reflects
appropriately the recommendations of the Board in April 1992,
and that the revised version of the document need not be
reviewed by the Board. Major revisions, as a result of the
Board's review in April 1992, include (1) addition of a
Foreword to better describe the historical background, the
needs of the Agency, and the intent of the Cancer Policy
Framework, (2) clarification of the intent of the document,
especially in relation to risk assessment activities of the
Environmental Protection Agency and other relevant federal
agencies and organizations, and (3) clarification of the use of
biomarkers, and caution in communicating individual risk.
Response: No response is required.
Submitter #2, Comment 1, states that the document is generally
sound and addresses most of the major issues.
Response: No response is required.
Submitter #2, Comment 2, notes that there is no discussion of
why an additive interactive model was chosen over a
multiplicative model and asks why in all cases an additive
model would be used.
Response: ATSDR believes that no single approach is
appropriate for all risk assessments of multiple chemical
exposures. Furthermore, at present, there is no consensus on
the appropriate use of a particular multiplicative model within
the scientific community. Given the paucity of empirical data
and the complexity of this issue, ATSDR assumes that, in the
absence of information regarding the interactive effects of
hazardous substances, their effects are additive. The rationale
for this position has been further clarified in the document.
Submitter #2, Comment 3, asks how people identified as highly
exposed or at increased risk of cancer will be treated regarding
medical surveillance and follow-up, results notification, risk
communication, and confidentiality of information.
Response: ATSDR believes that the Submitter's comments are
beyond the scope of this document. These topics are more
appropriately discussed in specific health assessment guidelines.
No change will be made in the document, although ATSDR
will consider the development of such guidelines in response to
specific programmatic needs, as appropriate.
Submitter #2, Comment 4, suggests that the discussion of
"individual vs. population risk - the role of molecular
epidemiology" should convey more caution about whether
individual risk assessment is warranted and how soon
approaches may be available. Furthermore, the Submitter notes
that there is a danger in basing a prediction of an individual's
risk of cancer on measurements of one or a few markers.
According to the Submitter, such reductionist approaches are
misleading and could both create anxiety and cause
interventions to be targeted too narrowly.
Response: ATSDR concurs with the Submitter's concerns and
has emphasized the sentence, "However, it should be noted that
more research is needed before biomarkers can be used as
prognostic indicators," with italics and bolding in the revised
document. [See Section IV. A. 2. d, third paragraph].
Submitter #3, Comment 1, believes that there is some lack of
clarity in the overall use of language which may result from the
jargon of risk assessment and the area in which ATSDR works.
The Submitter states that a reader who is not familiar with the
issues might benefit from substitution for some of the jargon.
The Submitter cites two examples: 1) "cancer potency factor"
vs. "EPA potency factor" and 2) 10-6 in ATSDR public health
assessments.
Response: ATSDR concurs and has revised the document
accordingly. [See SPECIFIC COMMENTS, ATSDR
response to Submitter #3, Comment 2 (II.B. Quantitative
Practice), and Comment 3 (II.C.-Exposure Assessment),
respectively].
Submitter #3, Comment 2, believes that italics are difficult to
read because they give the sense that everything is special or
everything is emphasized. Furthermore, the Submitter indicates
that when bold is added, it becomes even more difficult to read
and suggests using both forms of emphasis judiciously.
Response: ATSDR concurs and has used italics with bolding
for emphasis only in the revised document.
Submitter #4, Comment 1, believes that overall, the document
is clearly written, concise, and scientifically sound.
Response: No response is required.
Specific Comments
Executive Summary
Background
Submitter #2, Comment 1, asks for clarification of a sentence on page 1, second
paragraph, namely, if the sentence is meant to read "......biomedical judgment
peer review....." or if these are separate items. The Submitter believes that
the latter makes more sense.
Response: ATSDR has revised the sentence to read "Risk analysis is a multidimensional
endeavor encompassing biomedical judgment, peer review, and risk assessment......"
Analysis of Hazard and Risk
(a) Qualitative Issues
Submitter #3, Comment 1, requests clarification of
the sentence "ATSDR believes that although an
agent may not have been demonstrated to be a
carcinogen in a well-designed and well-conducted
epidemiologic study, a potential association
between exposure to the agent and human cancer
cannot be ruled out." The Submitter believes that
the sentence, as currently written, implies that
even if the agent has not been demonstrated to be
a carcinogen in a "good" study, it might still be
one. Furthermore, the Submitter states that this
suggests that ATSDR does not believe in
epidemiologic data.
Response: As stated in the Cancer Policy
Framework, ATSDR believes that epidemiologic
studies are an invaluable resource in public
health
decisions. Therefore, in evaluating the potential
human cancer risks, ATSDR assigns a higher
weight to well-designed and well-executed
epidemiologic studies than to animal studies of
comparable quality. However, ATSDR believes
that a nonpositive study does not necessarily
indicate that the agent may not be shown to be
carcinogenic in future epidemiologic
investigations
or in follow-up studies. No change will be made
in the document.
(b) Quantitative Issues
Submitter #2, Comment 2, asks for clarification of
"cancer potency" vs. "potency factors, developed
by the EPA." (Also, see Section IV.B., first
paragraph).
Response: ATSDR has clarified the issue by
using the term, "cancer potency factors,"
throughout the revised document.
Risk Analysis
Submitter #1, Comment 1, asks for clarification of the
sentence "ATSDR will employ the plausible ranges
associated with default exposure, toxicological, and other
assumptions/policy positions."
Response: ATSDR has clarified this sentence by adding
the following to the revised document, namely, "These
may include ranges of default values such as the range of
human pulmonary ventilation rates (i.e., 8-20 m3/day),
human body weight (i.e., 10-60 or 70 kg), or ranges based
on the use of low-dose extrapolation models (i.e., logit,
probit, multistage, etc.)." Submitter #2, Comment 3, asks for clarification of the
sentence "ATSDR will employ the plausible ranges
associated with default exposure, toxicological, and other
assumptions/policy positions."
Response: See ATSDR response to Submitter #1,
Comment 1 above.
I. Preface
A. Background
Submitter #2, Comment 4, notes two typographical
errors in the first paragraph, and suggests removing
the comma after "Comprehensive" and move
(CERCLA) to after 1980.
Response: ATSDR concurs and has made the
suggested changes.
II. Current Practice within ATSDR
B. Quantitative Practice
Submitter #3, Comment 2, requests clarification of
"cancer potency factors" vs. "EPA potency factors" in
the first two sentences of the first paragraph.
Response: ATSDR has revised the second sentence to
read "In some instances, cancer potency factors,
derived by EPA, are employed....."
C. Exposure Assessment
Submitter #2, Comment 5, asks if ATSDR intends to
adopt EPA risk estimates. Furthermore, the Submitter
indicates that if ATSDR is not going to perform low-
dose modeling then it might also consider alternative
estimates of risk from other federal (e.g., OSHA,
NIOSH, or FDA) and state (e.g., California OSHA)
organizations.
Response: Although ATSDR does not "adopt" risk
estimates used by any particular federal or state
agency, the Agency does "report" risk estimates as
derived by EPA and other relevant agencies and
organizations insofar as they are useful in risk
characterization. No change will be made in the
document.
Submitter #2, Comment 6, disagrees with the
sentences, "The linkage of exposures to cancer
occurrence is qualitative rather than quantitative.
Thus, causal inferences in risk characterization are
limited." The Submitter believes that the second
sentence does not seem to be supported by the first
one.
Response: ATSDR concurs with the Submitter, and
has revised the second sentence to read "Thus, the
Agency's current use of dose-response relationships in
risk characterization is limited."
Submitter #3, Comment 3, requests clarification of
"10-6" in ATSDR public health assessment.
Response: ATSDR has revised the sentence to read
"...(e.g., one case of cancer in 1,000,000)...."
III. ATSDR Policy Statement on Exposure to Carcinogens
A. Exposure Duration and Frequency
Submitter #2, Comment 7, notes that the premise that
ATSDR weighs all relevant information on a particular
exposure scenario in developing its public health
assessment is appropriate. However, the Submitter
considers that the term "lower dose exposures" may be
better than "exposure to lower doses." Furthermore,
the Submitter believes that the terms "acute,
intermediate, and chronic exposure" do not equate to
duration alone but to a combination of duration and
intensity. The Submitter suggests rewording.
Response: The term, "lower dose exposures," is used
in the revised document, as suggested by the
Submitter. However, ATSDR defines "acute,
intermediate, and chronic exposure" as durations only,
consistent with usage in the ATSDR toxicological
profiles.
Submitter #4, Comment 1, suggests that it may be
informative to the reader for ATSDR to indicate the
definition of acute, intermediate, and chronic
duration.
Response: ATSDR concurs and has defined acute,
intermediate, and chronic duration as 14 days, 15-
364 days, and 365 days, respectively, in the revised
document. D. Exposure Modeling
Submitter #2, Comment 8, agrees with ATSDR's
position that uncertainty associated with risk
assessment methods should be clearly articulated.
Response: No response is required.
F. Behavior
Submitter #4, Comment 2, suggests that the heading,
"Host Factors" may be more appropriate than
"Behavior" because the multitudinous factors within
the host that may affect the development of cancer
upon exposure are not all related to behavior.
Response: ATSDR concurs and has changed the
heading to "Host Factors" and revised the text
accordingly.
Submitter #4, Comment 3, suggests the word "other"
be deleted from the sentence "...status and other
lifestyle variables...."
Response: ATSDR concurs and has made the
suggested change.
G. Current, Past, and Potential Exposure
Submitter #2, Comment 9, suggests that the sentence
"Carcinogenic effects may result in populations not
only from current exposure to agents but also from
past and/or potential exposures" be rephrased since
potential exposures cannot produce carcinogenic
effects, although such effects can be predicted.
Response: ATSDR concurs and has revised the
sentence to read "Carcinogenic effects may occur in
populations not only as a result of current exposure to
agents but also from past exposures. Furthermore,
based on current knowledge of the agents, these
adverse health effects might be predicted from
potential exposures."
H. Summary
Submitter #2, Comment 10, notes that for most pre-
construction occupational exposure assessment,
modeling is a necessity. The Submitter reasons that
due to high variability in site characterization and
environmental data, there are many cases where
modeling will be a better predictor of exposure than
empirical data. Therefore, the Submitter suggests
rewording the policy statement to end after "exposures
to carcinogens should be treated on a case-by-case
basis" and delete "rather than, hypothetical basis."
Response: ATSDR concurs and has made the
suggested change.
IV. ATSDR Policy Statement on Health Assessment of Carcinogens
A. Analysis of Hazard and Risk
1. Qualitative Issues
b) Mechanistic Inference and Species Concordance
Submitter #1, Comment 2, suggests deleting
the phrase "somatic mutation" from this
section.
Response: ATSDR concurs and has made the
suggested change.
Submitter #2, Comment 11, notes that the
definition of "epigenetic" is at variance
with
the meaning attributed in the document.
Response: ATSDR believes that the
definition of "epigenetic" in the document is
consistent with that in the scientific
literature,
e.g., Cohen SM, Ellwein LB. Genetic Errors,
Cell Proliferation, and Carcinogenesis.
Cancer Research 51:6493-6505, 1991, and
Williams GM, Weisburger JH, Chapter on
Chemical Carcinogens. Casarett and Doull's
Toxicology--The Basic Science of Poisons,
Third Edition. No change will be made in the
document.
Submitter #2, Comment 12, suggests that the
sentence "Carcinogenesis is generally viewed
as a multistage process, proceeding from
somatic mutation, initiation through
promotion, and progression" be rephrased to
either: "Carcinogenesis is generally viewed
as a multistage process, proceeding from
initiation (somatic mutation), through
promotion, and progression" or
"Carcinogenesis is generally viewed as a
multistage process, proceeding from
initiation,
through promotion, and progression."
Response: ATSDR concurs and has revised
the sentence to read "Carcinogenesis is
generally viewed as a multistage process,
proceeding from initiation, through
promotion,
and progression."
Submitter #2, Comment 13, suggests that the
fifth sentence in this paragraph, "For
example,
carcinogenic effects of some agents may
result from nonphysiologic responses such as
extensive organ damage or formation of
calculi," should be rephrased to read "For
example, carcinogenic effects of some agents
may result from nonphysiologic responses
with a threshold such as extensive organ
damage or formation of calculi."
Furthermore, the Submitter suggests including
the reference, Cohen SM, Ellwein LB. Cell
Proliferation in Carcinogenesis. Science
249:
1007-1011, 1990, if needed.
Response: Based on available information, it
is not possible to derive definitive
conclusions
with regard to the issue of threshold for
agents acting via epigenetic mechanisms.
Furthermore, this is supported by the
reference suggested by the Submitter (see
section entitled, "Classification of
Chemicals
for Human Risk Assessment" in the
reference). Therefore, the sentence will not
be revised.
Submitter #4, Comment 4, requests
clarification of the sentence, "For example,
carcinogenic effects of some agents may
result from nonphysiologic responses such as
extensive organ damage or formation of
calculi in the urinary tract." The Submitter
suggests replacing the above sentence with
"For example, carcinogenic effects of some
agents may be associated with predisposing
pathologic factors such as extensive organ
damage...."
Response: The examples quoted, such as
extensive organ damage, are results of
exposure to agents and are not preexisting
pathological factors. The document has been
revised to read "For example, carcinogenic
effects of some agents may result from
nonphysiologic responses to the agents such
as extensive organ damage or formation of
calculi in the urinary tract."
d) Role of Epidemiologic Data
Submitter #2, Comment 14, suggests that the
sentence in the first line of the third
paragraph should read, "....an agent may not
have been shown [to] be..."
Response: ATSDR concurs and has made the
suggested change.
Submitter #2, Comment 15, suggests the
paragraph break between the first and second
paragraph be changed for better presentation
of the information, namely, the first
paragraph
will address epidemiology in general and the
second paragraph will address both
descriptive and analytical epidemiologic
studies.
Response: ATSDR concurs and has made the
suggested change.
Submitter #2, Comment 16, asks for
clarification of the sentence in the first
paragraph, i.e., "ATSDR assigns a higher
weight to well-designed and well-executed
epidemiologic studies."
Response: ATSDR has revised the sentence
to read "ATSDR assigns a higher weight to
well-designed and well-executed
epidemiologic studies than to animal studies
of comparable quality."
g) Chemical Interaction
Submitter #2, Comment 17, suggests that
additive may be the default position between
synergism and antagonism and, thus, might
very well be the best factor.
Response: ATSDR concurs with the
Submitter. No change is required in the
document. (Also, see ATSDR response to
Submitter #2, Comment 2, in section on
General Comments).
2. Quantitative Issues
a) Dose Scaling
Submitter #2, Comment 18, suggests revising
the second sentence of the second paragraph,
by replacing the phrase "empirically derived
data" with "scientifically calculated
values."
Response: ATSDR believes it to be most
relevant to use data which are derived from
experiments and observations (as opposed to
technically supported calculations), whenever
such data are available. Therefore, the
phrase, "empirically derived data," will not
be
changed in the document.
d) Individual vs. Population Risk--The Role of Epidemiology
Submitter #2, Comment 19, notes that in the
second sentence of the second paragraph,
"oncogenies" should be "oncogenes."
Response: ATSDR concurs and has made the
suggested change.
Submitter #2, Comment 20, suggests that the
first sentence of the third paragraph,
"Genetic
markers, such as aryl hydrocarbon
hydrolase..." should read "Genetic markers,
such as certain aryl hydrocarbon hydrolase
isozymes..."
Response: ATSDR concurs and has made the
suggested change.
B. Institutional Experience
Submitter #2, Comment 21, suggests that ATSDR
mention NIOSH in this Section.
Response: ATSDR concurs and has made the
suggested change.
V. Analysis of Carcinogenic Risk
Submitter #2, Comment 22, considers some language to be
confusing and presents a revision of the paragraph in this
section, starting with the sentence, " As a result...." In
addition, the Submitter states that some words are too
complex (e.g., "probity" in Section I.C. Scope and
"moieties" in Section IV. C. The Role of Emerging
Scientific Principles and Techniques.
Response: ATSDR has adopted the revised version of the
paragraph for Section V., as suggested by the Submitter,
with the exception of the first revised sentence.
Furthermore, ATSDR has replaced "probity" with "value,"
and the phrase "...the significance of such moieties...."
has
been changed to "...their significance..."
Submitter #2, Comment 23, suggests revising the sentence
next to the last sentence of the first paragraph, by
replacing
the phrase "empirically derived data" with "scientifically
calculated values."
Response: ATSDR believes the phrase, "empirically
derived data" (revised as "empirical data" per Submitter #2,
Comment 22) to be appropriate in the context of the
paragraph; therefore, no change will be made. (Also, see
ATSDR response to Submitter #2, Comment 18, in Section
IV.A.2.a) Dose Scaling.
A. Risk Characterization
Submitter #2, Comment 24, asks for clarification of
the sentence "ATSDR will employ the plausible ranges
associated with default exposure, toxicological, and
other assumptions/policy positions."
Response: ATSDR has clarified this sentence by
adding the following to the revised document, namely,
"These may include ranges of default values such as
the range of human pulmonary ventilation rates (i.e.,
8-20 m3/day), human body weight (i.e., 10-60 or 70
kg), or ranges based on the use of low-dose
extrapolation models (i.e., logit, probit, multistage,
etc.)."
B. Risk Communication
Submitter #2, Comment 25, suggests replacing the
word "clients" with "users" in the first two sentences
because the identity of the "clients" is not clear to
the
Submitter.
Response: ATSDR believes that the word "clients" is
appropriately used in the context of this Section. No
change will be made.
Appendix
Submitter #2, Comment 26, notes that the OSHA
classification of carcinogens is listed incorrectly. The
OSHA carcinogen standard (29 CFR 1990) lists two
categories (I and II) of carcinogens. The four categories
that are listed by ATSDR in the Appendix were proposed
by OSHA in 1977, but the final standard reduced these
cancer categories to two. Furthermore, the Submitter
indicates that ATSDR should mention the OSHA cancer
policy under "Qualitative Practice" in Section II.A. and
Section IV.A.1.a.
Response: ATSDR concurs and has made the suggested
changes.
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This page last updated on June 25, 2001
Joanne Cox / vzc6@cdc.gov
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