UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, O.C. 20460
EPA-SAB-EHC-9Q-013
THE ADMINISTRATOR
April 23, 1990
Honorable William K. Reilly
Administrator
U.S. Environmental Protection Agency
401 M Street, s.W.
Washington, D.c. 20460
Subject: Science Advisory Board's review of the Office of Research
and Development document Proposed Amendments_To The Guidelines For
The. Health Assessment Of Suspect Developmental Toxicants. 54 FR
9386-9403
Dear Mr. Reilly:
On March 6, 1989, EPA proposed amendments to the Guidelines
for the Health Assessment of Suspect Developmental Toxicants.
These amendments expanded and clarified points made in the original
guidelines and added new information based on advances in the
field.
The Science Advisory Board (SAB) was asked to focus on the
major proposed amendments to the Guidelines, and to comment on
other aspects of the Guidelines. The charge to the SAB's
Environmental Health Committee contained the following elements:
a. Assess the technical changes to the Guidelines for sound
scientific support.
b. Review the proposal to use broad weight-of-evidence
categories.
c. Review the applicability of the (RfDDT) concept of a reference
dose for developmental toxicity.
d. Review the proposed changes in the relationship between
maternal and developmental toxicity.
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e» Discuss alternative approaches to risk assessment for
developmental toxicity,
The Environmental Health Committee met on October 27, 1989,
in Bethesda, Maryland to receive briefings from Agency officials
involved with the development of the proposed Guidelines revisions,
and to discuss in detail the issues noted above.
With two exceptions, the Committee considers the proposals to
be adequately founded in toxicological and teratological science,
and to reflect the current status in these fields. There are minor
technical points which the Committee believes could be improved or
presented more clearly. Such items need attention, but do not
detract from the overall competency of the proposals.
Consequently, comments on these points have been supplied
separately to the Agency, and are not addressed in the report,
As noted, there are two areas in which the Committee suggests
the need for significant rethinking and revision. First, the
weight-of-evidence classification scheme tends to be confusing vis-
a-vis current Agency and general usage, and still reflects too
strongly its origins in the classification of carcinogenicity as
an unitary endpoint, rather than the multiple possible
developmental outcomes of exposure to developmental toxicants.
Functionally, it does not provide a more powerful conceptual basis
for risk assessment in the developmental area than now exists. A
more powerful system or scheme would provide a biological,
functional basis for assigning priorities to the questions which
arise during an assessment by offering a closer coupling between
dose and the nature of the expected outcome(s).
The possibility of a decision analysis-based approach, as
noted in the report, is attractive, and is offered for
consideration with the understanding that considerable effort would
be required for implementation. The Agency is advised to consider
it, along with any other methodology which could move towards a
more conceptually powerful, yet more economical, biologically-based
approach to developmental risk.
The same rationale underlies the Committee's thoughts on the
subject of the RfDDT and alternative approaches to assessment. The
traditional LQ&EL/NQ&EL process ignores available data, is somewhat
insensitive to trends in the data, and ignores the uncertainty in
the level of risk at the NQAEL. It tends to reward less
statistically precise studies by translating their results into
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higher RfD levels and so provides a disincentive to better science.
The benchmark dose approach discussed in the report avoids these
problems, and is the subject of a growing body of literature
(including some fine contributions by EPA staff scientists), It
seems to be the next logical step towards uniform risk assessment,
and the Agency is urged to begin moving in this direction by
incorporating such an approach in the Guidelines to be used in
conjunction with the current approaches.
The Science Advisory Board is pleased to have had the
opportunity to review the proposed revisions to the Guidelines and
to offer its advice. We would appreciate your response to the
major points we have raised.
Dr. Raymond Loehr, Chairman
Science Advisory Board
Dr. Arthur Upton,, Chairman
Environmental Health Committee
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CD A U.S. Environmental Washington, DC
^
Protection Agency 1PA-SAB-EHC-90-013
Report of the Environmental
Health Committee
Review of Proposed Revisions to
the Guidelines for Health Assessment
of Suspect Developmental Toxicants
(54 FR 9386-9403)
A SCIENCE ADVISORY BOARD REPORT April, 1990
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U. 8. ENVIRONMENTAL PROTECTION AGENCY
NOTICE
This report has been written as a part of the activities of
the Science Advisory Board, a public advisory group providing
extramural scientific information and advice to the Administrator
and other officials of the Environmental Protection Agency. The
Board is structured to provide balanced, expert assessment of
scientific matters related to problems facing the Agency, This
report has not been reviewed for approval by the Agency and,
hence, the contents of this report do not necessarily represent
the views and policies of the Environmental Protection Agency,
nor of other agencies in the Executive Branch of the Federal
government, nor does mention of trade names or commercial pro-
ducts constitute a recommendation for use.
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ROSTER
CHAIRMAN
Dr. Arthur Upton
New York University Medical
Center
Institute of Environmental
Medicine
MEMSERS/CQNSUMMTTS
Dr. Gary Carlson
Department of Pharmacology
and Toxicology
School of Pharmacy
Purdue University
Dr. David, G-aylor
National Center for
lexicological Research
Department of Health and Human
Services
Dr. Maureen Hatch
Department of Epidemiology
Columbia University
Dr. Marshall Johnson
Professor, Department
Anatomy
Jefferson Medical College
of
Dr. Nancy Kim
Director, Division of
Environmental Health
New York Department of Health
Dr. Martha Radike
Department of Environmental
Health
Medical Center
University of Cincinnati
Dr. Stephen M. Rappaport
Department of Biomedical and
Environmental Health Sciences
School of Public Health
University of California
Dr. Patricia Rodier
Department of Gbsteterics
1 Gynecology
University of Rochester School
of Medicine
Dr. Bernard Schwetz
National Institute of
Environmental
Health Sciences
Department of Health and Human
Services
Dr. Bernard Weiss
Professor of Toxicology
Environmental Health Sciences
Center
University of Rochester
School of Medicine
Dr. Ronald Wysga
Electric Power Research
Institute
Executive Secretary
Mr* Samuel Rondberg
Environmental Protection Agency
401 M Street, s.w., A-IOIF
Washington, D.c. 20460
Staff Secretary
Ms. Mary Winston
Environmental Protection Agency
401 M Street, S.W., A-101F
Washington, D*C. 20460
Staff Director
Donald G. Barnes
Environmental Protection Agency
401 M Street, S.W., A-1Q1
Washington, B.C. 20460
11
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TABLE OF CONTENTS
1.0 Executive Summary ,,........ i
2+0 Introduction ...... ...... 2
3.0 Detailed Charge ...,.,.. ..... 3
4.0 Detailed Findings .......... 4
4.1 Assessment of Technical Support of Proposed
Changes ...................... 4
4.1.1 Assumptions Regarding Adverse Effects in
Animals . . +,.......„.. 4
4.1.2 Manifestations of Developmental Toxicity . . 4
4.1.3 Animal to Human Correlations ........ 5
4,1.4 Use of the Most Sensitive Species * S
4.1.5 Threshold Assumption . 5
4.2. Weight of Evidence Categories » * * , 6
4.3 Applicability of the RfDDT Concept . 8
4.4 Maternal Toxicity ...,».......»..„. 11
5.0 Conclusions and Recoxtonendations , 11
1X1
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1.0 Executive Summary On March 6, 1989, EPA proposed amendments
to the Guidelines for the Health Assessment of Suspect
Developmental Toxicants (Proposed Amendments To The Guidelines For
The Health Assessment Of Suspect Developmental Toxicants, 54 FR
9336-9403), These amendments expanded and clarified points made
in the original guidelines and added new information based on
advances in the field.
The Science Advisory Board was asked to focus on the major
proposed amendments to the Guidelines, and to comment on other
aspects of the Guidelines. More specifically, the charge to the
Environmental Health Committee contained the following elements:
a. Assess the technical changes to the Guidelines for sound
scientific support.
b. Review the proposal to use broad weight-of-evidence
categories*
c. Review the applicability of the (RfDDT) concept of a
reference dose for developmental toxicity.
d. Review the proposed changes in the relationship between
maternal and developmental toxicity,
e- Discuss alternative approaches to risk assessment for
developmental toxicity.
The Environmental Health Committee met on October 27, 1989,
in Bethesda, Maryland to receive briefings from Agency officials
involved with the development of the proposed Guidelines revisions,
and to discuss in detail the issues noted above.
The Committee supports many of the proposed revisions to the
Guidelines? there are, however/ areas in which improvements could
be made. Detailed comments on specific technical items have been
furnished to the Agency. These items notwithstanding, there was
a consensus that the proposed revisions were adequately founded in
developmental toxicology and represented a step forward for EPA.
The Agency is advised to revisit the weight-of-evidence scheme
proposed, in order to avoid confusion with more commonly applied
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uses of such classifications, and to develop a more powerful
conceptual approach. Further, the Agency should begin to move away
from the current use of the No Observed Adverse Effects/Lowest
Observed Adverse Effects Level (NOAEL/LOAEL) basis for calculating
the Reference Dose, to a benchmark dose/confidence limit approach,
tied to empirical models of dose-response relationships.
2.0 Introduction The U.S. EPA published proposed and final
Guidelines for the Health Assessment of Suspect Developmental
Toxicants in November, 1984 (49 FR 46324} and September, 1986 (51
FR 34028) , respectively. These guidelines represented a consensus
of the scientific community in developmental toxicity on how to
interpret data in this area. However, shortly after the final
guidelines were published, it became apparent that a good deal of
new information had become available that should and could be
incorporated into the Guidelines, Therefore, on March 6, 1989, EPA
proposed amendments to the Guidelines for the Health Assessment of
Suspect Developmental Toxicants (Proposed Amendments To The
Guidelines , For .The Health Assessment 0,£ .Suspect Developmental
Toxicants, 54 FR 9386-9403). These amendments expand and clarify
points made in the original guidelines and add new information
based on advances in the field.
The Science Advisory Board was asked to focus on the major
proposed amendments to the Guidelines, in addition to commenting
on other aspects of the Guidelines. The major changes are
summarized below:
a* The original risk assessment guidance was developed
around several basic assumptions that were implicit but not
stated in the earlier document; in the proposed amendments,
these are clearly stated.
b» Several consensus workshops were held following completion
of the 1986 guidelines and the conclusions of these workshops
have been incorporated as revisions to the guidelines. Areas
affected as a result of these workshops include the
relationship of maternal and developmental toxicity, the
status of the Chernoff/Kavlock assay, and the development of
an approach for a weight-of-evidence classification.
c. A reference dose for developmental toxicity (RfDpT) is
proposed which is based on short-term exposure as is used in
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assessing developmental toxicity potential. This approach is
distinguished from the RfD, which usually applies to chronic
or long-term exposures.
d. The functional developmental toxicity section has been
expanded to reflect the Agency's recent testing guidelines
for assessing potential developmental neurotoxicity.
e. An expanded human studies section now gives more guidance
on the use of human data in risk assessment*
f. A number of other proposed minor changes are discussed in
the Supplementary Information section of the Proposed
Amendments,
3.0 Detailed Charge More specifically, the Environmental Health
Committee was asked.to:
a. Assess the technical changes to the Guidelines for sound
scientific support.
b, Review the proposal to use broad weight-of-evidence
categories,
c. Review the applicability of the RfDDT for developing short-
term reference dose estimates for developmental toxicity.
d. Review proposed changes in the relationship between maternal
and developmental toxicity,
e. Discuss alternative approaches to risK assessment for
developmental toxicity. In particular, address alternatives
to the National Academy of Science/National Research Council
model, as well as more quantitative approaches to risJc
assessment than the RfDOT approach (It was anticipated that
the points in this element of the charge, because of their
nature, could best be addressed in concert with the other
aspects of the charge listed above rather than as a "stand
alone" section, consequently, these issues are addressed as
part of the discussion in section 4.3) .
To carry out the charge, the Environmental Health Committee
met on October 27, 1989, in Bethesda, Maryland to receive briefings
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from Agency officials involved with the development of the proposed
Guidelines revisions, and to discuss in detail the issues noted in
the Charge.
4 • .Q_._Detailed Findings
4.1 Assessment .of Technical Support Of Proposed Changes It was
the consensus of the Committee that the changes generally had
adequate rationale and support. It was felt that the changes were
not only proper, but that they moved the Guidelines forward in
terms of current thinking. Specific comments were addressed to
five basic assumptions underlying the proposed revisions,
4.1.1 Assumptions Regarding- Adverse Effects in Animals The
revisions state that, "An agent that produces an adverse
developmental effect in experimental animal studies is assumed to
pose a potential hazard to humans following exposure during
development." This is a proper, conservative stance. The
assumption is consistent with our knowledge of biology,
toxicology, and clinical experience to date. If there are
exceptions, they do not provide a basis for ruling out this
position based on chemical structure of a specific agent under
consideration, or the type of response observed in a specific
instance.
4.1.2 Manifestations of Developmental Toxicity It is posited that
all four manifestations of developmental toxicity (death,
structural abnormalities, growth alterations, and functional
deficits) are of concern. Although the relative importance of the
four manifestations is not well established, there is general
agreement that the assumption is sound.
More specifically, the importance of structural variations is
not agreed upon by developmental toxicologists. Some workers feel
that variations are as important as malformations or fetal deaths?
others regard variation as less predictive of adverse effect in
humans than more serious manifestations of developmental toxicity.
In addition, we have less experience in detecting functional
alterations, as well as less experience in looking at their
correlates in the human. Further, the importance of variations
is confounded by their common occurrence in the presence of
maternal toxicity. Many developmental toxicologists consider that
a significant increase in structural variations noted only in the
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presence of significant maternal toxicity is a weaker signal than
the presence of major mal format ions or fetal deaths in the absence
of maternal toxicity. Thus the assumption stated in the proposed,
revisions is a generally accepted one, albeit a point of
disagreement in the field as to the relative importance of the
various subsets of variation or adverse effects noted within these
four major manifestations of developmental toxicity.
4.1.3 Animal tp__Roman.. Correlations The proposed revisions assume
that "..the types of developmental effects seen in animal studies
are not necessarily the same as those that may be produced in
humans." This is generally accepted by toxicologists, although the
supporting data base is not strong. Further examination of this
issue is needed, including the generation of proper data to permit
a thorough analysis. -
4.1.4 use of the Most Sensitive Species The revised guidelines
call for using the most sensitive experimental species to estimate
human risk. This is an appropriate default position when more
relevant data are not available, but the basic position should be
to use the most relevant data to estimate human risk. We would
like to see the Guidelines pushing the field in the direction of
trying to develop the most relevant data, rather than routinely
developing data in rats and rabbits without serious concern about
the relevancy to man or the use of other species.
4_._1_._5_ T_hreshoia__Assumption The Guidelines assume a threshold in
the dose-response function for most developmental toxicants. There
is general agreement that this assumption is reasonable, but there
is a lack of consensus as to the importance of this assumption in
the risk assessment process. For instances in which developmental
toxicity is already observed in untreated control animals,
endogenous or exogenous factors may be sufficient to produce the
developmental toxicity. The addition of substances which augment
these factors may produce additional developmental toxicity. For
those effects which are caused by non-mutational events, and
perhaps even for those caused by mutations, it is important to
develop more comprehensive approaches to risk assessment which use
the total data available, not just the LOAEL or NOAEL (Lowest
Observed Adverse Effects Level or No observed Adverse Effects
Level) . This concern is relevant not only to the Developmental
Guidelines, but to most of EPA's endeavors in risk assessment, and
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has been a continuing concern of the SAB1 - It is also addressed
below (see section 4.3). Risk assessment procedures for
developmental effects should be based on our knowledge of the
biology of development. The assessment of carcinogenic risk is
still usually done with methods based on assumptions for the
mechanism of action that have been in use for decades; in
developmental toxicology, where we know very little about
mechanisms of action, we should be careful not to tie ourselves
to mechanistic-based risk assessment procedures where potential
errors could be quite significant.
4.2. weight of Evidence Categories The Committee believes that the
revised guidelines reflect a commendable attempt to structure and
conceptualize risk assessments for developmental toxicants so that
they fit neatly into a regulatory framework. They represent the
thoughtful application of toxicological principles and insights to
a set of difficult, even volatile, issues.
The Committee sees two significant problems, however, one
rooted in current usage within the Agency, and the other rooted in
the conceptual approach employed in weight-of-evidence (WOE)
schemes ger se.
Assessing the completeness and quality of the data base for
a specific agent is an important part of the risk assessment
process. The term "weight-of-evidence" as used in the proposed
Guidelines nay be inappropriate, since many in the field tend to
think of the WOE as the total composite of the information that is
available on which to make a judgement about risk, rather than to
assess the quality of the data base. Within the Guidelines
themselves, and as evidenced by the comments submitted by the
public, there is confusion about the term WOE as applied to the
data base, compared to the application to a specific chemical
agent.
In terms of the underlying conceptual structure, this proposed
WOE scheme (like others), is encumbered by ambiguities. Recall,
for example, the repeated discussions within the Agency about the
proper labelling of carcinogens, and how to differentiate, say,
1See the recent SAB Environmental Health Committee letter
report on modifying and uncertainty factors in RfD calculations
(EPA-SAB-EHC-90-005).
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categories B2 and C. Those discussions, moreover, are circum-
scribed by their focus on a single endpoint—carcinogenicity—•
albeit an endpoint manifested in many ways.
The proposal is sensitive to the web of complexities
surrounding the WOE classification scheme, and takes care to
recognize its multiple facets. Following a fundamental tenet of
toxicology, it stresses the need to incorporate dose into the
scheme. The exposition stops short, however, of offering guidance
on how to do so. Further, it fails to provide guidance on how to
evaluate the contribution of maternal toxicity? on how to define
the dimensions of "adequate evidence?" or how to construct a
coherent model of functional endpoints. The exposition fails to
provide guidance on how to structure an inquiry about developmental
toxicity that does not extend over the entire realm of
possibilities—with the concomitant potential to consmne enormous
resources-«in the application of the WOE classification scheme.
Each of these questions suggests many others,* we note them
here out of the disquiet that WOE designs arouse. This particular
WOE approach seems tightly bound to its origins in cancer. We
urge EPA to develop an approach suited to developmental toxicity
that can be implemented with available resources,
Given the above comments, we should at least touch on some
other approaches or schemes. If one considers the major difference
between developmental and carcinogenic risk assessment, the
significant factor is that in dealing with the developmental area,
many different outcomes, as opposed to one, are possible. For
example, the guidelines distinguish the four major manifestations
noted above: death, malformations, growth alteration, and
functional deficits. Is there some way in which these are linked?
Does embryolethality imply the other possibilities at lower doses
or at other exposure times? Do malformations imply growth
alterations at lower doses? Is there an element of intransitivity
or a directional bias in these mutual relationships? As noted
above, are they all considered to be of equal importance? If not,
how should the relative importance of these endpoints be evaluated?
An approach borrowed from decision analysis may clarify this
dilemma. if one considers each of the major manifestations
described in the guidelines as a primary category, each primary
category would encompass a set of associated aspects. Death, for
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example, might include embryolethality, stillbirths, reduced litter
size, early neonatal mortality, and even premature death after
maturity. Malformations would include all of the indices described
in the guidelines. Functional deficits, although spanning an
almost infinite number of measures, could be assigned to a much
smaller number of primary categories. Even growth alterations may
be expressed in many ways? for example, prenatal methylmercury
exposure revealed an influence on growth in monkeys only when they
approached sexual maturity*
One could then conceptualize the relationships between the
major categories in terms of an estimate of the dose ratio
required to evoke such an effect. The same scheme may be
extended to elements within each of four major outcomes, and to the
influence of maternal toxicity as well. Is it reasonable to try
to guess the extent to which some functional measure, based on
preweaning tests in rats, might portend the value of another
functional measure based on adult performance?
One advantage of such an approach might be that it helps us
to "map" the location of important gaps in knowledge. Such a map
might enable us to apply a probability value to an un-evaluated
outcome, which despite its grossness, might be better than no
information at all.
A basis for assigning priorities to questions will be required
if regulations and resources are to enjoy even modest
compatibility. The volume of data implied as necessary by the
guidelines is so overwhelming that it is likely to arouse fierce
resistance or, worse, evasion. The decision analysis approach
involves new concepts, and would require further development. Care
is needed so that this approach also does not require an
unreasonable amount of data and analysis. However, the type of
scheme outlined above may offer a closer coupling between dose and
the nature of the expected outcome(s), which, after all, is the
aim of risk assessment.
4_._3 applicability of the RfDDT_pj>_o_cjq3j: The proposed Guidelines
substitute the use of an RfDDT (Reference Dose for Developmental
Toxicity), based on the use of short-term or acute developmental
toxicity data, for the RfD, which is usually based on chronic data.
This substitution is appropriate, given the endpoints considered,
but the use of the RfD concept has weaknesses that are recognized
8
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in the Guidelines? specifically, the value of the RfD can be
influenced by the characteristics of the experimental design used
to generate the toxicity data. Hence, an RfD based upon a study
with low statistical power may be (inappropriately) considerably
greater than one based upon a study with greater power. For that
reason/ RfDs based upon very limited studies may not be
sufficiently protective. In addition, the current procedure makes
no explicit use of any trend in response to dose.
Alternatives to this approach require some assumption about
an underlying dose-response model. Not enough is known about the
biology of a specific case to know which model(s) properly
represents that case. This is particularly problematic if there
is need to extrapolate response to a level of risk much lower than
that observed in the experiments used to generate the data.
Moreover, it is often supposed that developmental toxicity is
associated with a threshold phenomenon, yet there are no clear-cut
models which can be used in a risk assessment.
Both the choice of models and the existence of threshold doses
need to be addressed in the generation of developmental toxicity
guidelines. The latter are discussed and used to justify the use
of the RfDDT. Some of its weaknesses are acknowledged and there is
some indication that the weaknesses are factored into the RfD
estimate (although no specifics or examples are given). It
generally is not recognized that the incidence of developmental
toxicity at the NOAEL, which is the starting point for calculation
of the RfD, may be as high as 6%2. Hence, at the RfD, there exists
a non-zero baseline risk, which is independent of exposure*
An alternative which may overcome some of the difficulties
with the RfD applications of the above approaches has been
presented. A recent paper by Kiramel and Gaylor3 suggests the use
of a benchmark dose associated with a response level of 10 percent.
The benchmark dose, defined by the lower confidence level for the
ED10 (the dose level at which a 10 percent risk is associated), is
estimated through use of an empirical model that makes use of all
dose-response data. If we choose the lower confidence limit to the
2Gaylor, D.W,, Environmental Health Perspectives 79:243-246,
1989
3
Risk Analysis, 8(1), 15-20, 1988
9
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ED10, denoted by LED10, then studies with higher statistical
precision generally will yield larger values for the LED10 and
larger RfDs than studies with lower precision. Hence, the greater
uncertainty associated with limited data (and thus lower
statistical precision) is factored into the benchmark dose.
The model used to estimate the ED10 is less critical than when
extensive extrapolation is required because the ten percent
response is likely to be in the range of dose levels used to
generate the toxicity data. Thus, any empirical model which fits
the data well is likely to provide a reasonable estimate of the
ED10; in fact, several models could be applied to suggest how
robust the estimates of the SD10 actually are. It is realized that
the nature of developmental toxicity data presents specific model
problems; e.g., individual data derived from a given litter are not
independent. Suitable models are available to account for this
lack of independence, and they should be applied. Since the model
is only used to extrapolate (or interpolate) to the £D10, no
assumptions about the existence (or non-existence) of a threshold
are needed.
The choice of uncertainty factors applied to the LED10 could
be similar to those applied to a LOAEL. If the data are adequate
to estimate the EDQ1, which is closer to a threshold dose if one
exists, the choice of uncertainty factors applied to the I£D01 could
be similar to those applied to a NOAEL. Another advantage of the
benchmark dose over the current approach is that benchmark doses
likely allow upper bound health risk estimates. As Gaylor4 has
argued, since dose-response relationships are often sub-linear in
the low dose range, decreasing the dose by an uncertainty factor
will generally lead to a proportionately greater reduction in risk.
Thus, if a maximum risk is indicated, a dose level can be estimated
through the benchmark/uncertainty factor procedure such that the
dose level is a lower bound for dose levels associated with the
risk.
The above approach is not entirely new (in 1984, Crump
suggested replacing the NOAEL with a benchmark dose5), but it
4JOurnal of Toxicology and Environmental Health, 11, 329-336,
1983
5Crump, K.S. Fundamental Appl. Toxicology, 4:854-871, 1984.
10
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offers some advantages over the NQAEL/LQAEL approach. We recommend
that it be considered for incorporation into the health assessment
guidelines for developmental toxicants, to be used in conjunction
with other currently "standard" techniques. This will facilitate
understanding of both approaches and allow them to be compared.
4.4 Maternal JCgxioity One of the major points of uncertainty in
developmental toxicology today is the relationship between maternal
and developmental toxicity. With the exception of some specific,
minor technical points (which have been separately transmitted to
the Agency), the Committee endorses the proposed revisions, and
considers them to be a good explication of the basic tenets of the
teratological literature.
The proposed revisions do not (and probably cannot) "solve"
the question of the relative weight or significance to be placed
on the manifestation of developmental toxicity in the presence of
observed maternal toxicity. This subject elicited considerable
comment from the public, and was the source of considerable
discussion by the committee. We suggest that the Agency retain the
current statement in the proposal, i.e., "..when adverse
developmental effects are produced only at maternally toxic doses,
they are still considered to represent developmental toxicity and
should not be discounted as being secondary to maternal toxicity,"
making only those modifications which do not weaken the thrust and
basic sense of the proposal.
5.Q Conclusions and Recommendations On the whole, the proposals
are adequately founded in toxicological and teratological science,
and reflect the current status in these fields. There are numerous
minor technical points, ranging from considerations of utilizing
human epidemiological data, to the use of in vitro testing (perhaps
the technically weakest element of the proposals) which the
Committee feels could be improved or whose presentation could be
clarified. Such items need attention, but do not detract from the
overall competency of the proposals. Consequently, comments on
these points have been supplied separately to the Agency, and are
considered beyond the scope and purpose of this report.
There are two areas in which the Committee suggests the need
for significant rethinking and revision. First, the weight-of-
evidence classification scheme tends to be confusing vis-a-vis
11
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current Agency and general usage, and still reflects too strongly
its origins in the classification of unitary endpoint carcinogen
effects, rather than the manifold possible outcomes of exposure to
developmental toxicants. Functionally, it does not provide a more
powerful conceptual basis for risk assessment in the developmental
area than now exists, A more powerful system or scheme would
provide a biological, functional basis for assigning priorities to
the questions which arise during an assessment by offering a closer
coupling between dose and the nature of the expected outcome(s),
The possibility of a decision analysis-based approach as
discussed above is attractive, and is offered for consideration
with the understanding that considerable effort would be required
for implementation. The Agency is advised to consider it, along
with any other methodology which could move towards a more
conceptually powerful, yet more economical, biologically-based
approach to developmental risk.
The same rationale underlies the Committee's thoughts on the
subject of the RfDDT and alternative approaches to assessment. "The
traditional LQAEL/NQAEL process ignores available data, is somewhat
insensitive to trends in the data, and ignores the uncertainty in
the level of risk at the NQAEL. It tends to reward less
statistically precise studies by yielding higher RfD levels and
provides a disincentive to better science. The benchmark dose
approach discussed above avoids these problems, and is the subject
of a growing body of literature (including some fine contributions
by EPA staff scientists). It seems to be the next logical step in
assessing risk, and the Agency is urged to begin moving in this
direction by incorporating such an approach in the Guidelines to
be used in conjunction with current methods.
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