UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
EPA-SAB-EHC-,9t-QQ8 OFFICE OF
^jr«. O«.D i^rn_ *« THE ADMINISTRATOR
April 2.9, 1991
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 Interim Methods forDevelopment of Inhalation
Reference Concentrations (EPA/600/8-90/066, August 1990}
Dear Mr. Reilly:
Inhalation Reference Concentrations (RfC) were developed to serve
as a basis for health risk estimates for non-cancer effects (analogous
to the Agency's Reference Dose (RfD) for orally ingested toxicants)
resulting from exposure to airborne pollutants. It is anticipated
that RfCs will be used for Clean Air Act regulatory activities as a
part of the determination of negligible and residual risk for non-
cancer health effects of air toxics.
The methodology to calculate inhalation RfCs follows the oral
Reference Dose paradigm, with an added emphasis on portal-of-entry
considerations of comparative toxicity and inhalation dosimetry for
particles and gases. A draft of the interim methodology was reviewed
at a public peer-review workshop in October, 1987 and the methodology
has since been reviewed and implemented by the Agency's RfD/RfC work
group. It was intended to review and update the methodology as the
state-of-the-art progressed. Now that RfC values are being made
available to the public on the Integrated Risk Information System
(IRIS), and in anticipation of their aforementioned role in regulatory
support, the EPA Office of Research and Development requested an SAB
review in order to incorporate further expert opinion and recommen-
dations on improving the interim methodology.
In response to this request, the SAB Environmental Health
Committee (EHC) met on October 26, 1990 in Arlington, Virginia to
receive briefings on the RfC methodology from Agency staff.
Printed on Recycled Paper
-------
The following issues, comprising the Charge to the Committee,
were discussed and are dealt with fully in the accompanying report:
1. Does the methodology utilize appropriate dosimetric ex-
trapolations for particles and gases, respectively?
The Committee found the extrapolations and other factors used
to be reasonable and well founded. Some specific suggestions for
improvement are provided in the report.
2. Should the same uncertainty factors be used when dosi-
roetric adjustments are incorporated?
Current methods for assessing the Reference Dose (RfD) call
for applying an uncertainty factor of 10 to compensate for extrap-
olation from animal data to human data. The proposed inhalation
Reference Concentration methods are far more detailed in estimating
respiratory exposure and, in fact, adjust for differences in inter-
species dosimetry. The importance and accuracy of that adjustment
is highly variable among compounds and among biological endpoints.
Clearly the use of more precise methods should not be discouraged
by applying the same uncertainty factors that would be applied to
more general methods, but a general statement about the appropriate
uncertainty factor is riot possible, other than to state that this
factor should be smaller with improved data and understanding.
Dealing with this issue could also be aided by a more detailed
articulation of the intent of the various uncertainty factors. An
understanding of the various uncertainties for which a specific
factor is designed to compensate would allow a better evaluation of
the influence of increased information on an uncertainty factor.
3. Are the concepts and applications of the methodology
clearly articulated in its documentation?
The Committee believes that 1PA Staff did an excellent job in
defining and explaining a sophisticated approach to a complex prob-
lem. Specific observations for improving or clarifying the text
have been forwarded to the appropriate EPA staff.
4. Is the research intended to support the methods appro-
priate for improving risk extrapolation procedures?
-------
Suggestions for further research are given throughout the
document. In some cases these are explicitly mentioned; in others
they are inferred. It would be preferable to provide a special
section outlining research needs and suggestions.
Overall, the Committee finds the referenced document to be
useful and comprehensive. It advances considerably the previous
approaches for calculating reference doses for inhaled toxicants.
The Committee is concerned, however, about the emphasis given to
the "No Observed Adverse Effects Level (NQAEL) plus uncertainty
factor" approach, especially in view of the SAB's past urging that
alternative methods, such as the benchmark approach (A statistical
approach for deriving RfC or RfD, based on the entire set of rel-
evant dose-response data,not only the NGAEL/LQAEL points. The low-
er ten percent confidence limit sets the RfC or RfD value,), be
applied to the raw data. The draft document discusses the bench-
mark approach in Appendix A, but refers to this and other methods
as "Novel." We consider these approaches to be alternative, and in
some cases, more desirable, methods.
Also, the Committee wishes to stress that there can be con-
siderable differences in the extent of information available, and
in toxicity mechanisms for various toxicant-endpoint combinations.
This situation gives rise to two additional suggestions:
(1) When the subject interim document is revised, we propose
that its title be changed to identify the approaches set
forth as guidelinesf not fixed "cookbook formulas," thus
retaining flexibility needed to deal with varying toxi-
cants and conditions,
(2) Given the need to accommodate knowledge for specific toxi-
cants, the Committee believes that it would be useful for
the SAB to review some toxicant-specific derivations of
the RfC. This would increase our understanding of the
overall methodology and its data base requirements, and
enhance our ability to review the dosimetric adjustments.
Finally, the Committee would appreciate learning of the
Agency's plans and schedule to revise the current interim document.
We stand ready to review the specific applications noted above, as
well as a future revision of the document itself.
-------
The Science Advisory Board is pleased to have had the
opportunity to review the draft document 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
ENCLOSURE
-------
SEPA
US, Snviromwnttl Washington, DC
protection Agtiwy
REPORT OF THE ENVIRONMENTAL
HEALTH COMMITTEE
REVIEW OF THE OFFICE OF RESEARCH
AND DEVELOPMENT'S DRAFT DOCUMENT
"INTERIM METHODS FOR DEVELOPMENT
OF INHALATION REFERENCE
CONCENTRATIONS"
(EPA/600/8-90/066, AUGUST, 1990)
A SCIENCE ADVISOW BOARD R6PCW Apra- '"1
-------
ABSTRACT
Inhalation Reference Concentrations (RfCs) were developed to
serve as a basis for health risk estimates for non-cancer effects
(analogous to the oral Reference Dose (RfD)) resulting from exposure
to airborne pollutants. On October 26, 1990, the Science Advisory
Board (SAB) reviewed the methodology for development of inhalation Rfc
values (as described in the document "Interim Methods for Development
of Inhalation Reference Concentrations," (EPA/6QQ/8-90/Q66, August
1990), as requested by EPA's Office of Research and Development.
The Committee found the proposed methods for deriving RfCs to be
reasonable, although some specific improvements, such as the use of
the benchmark dose in place of the No Observed Adverse Effects Lev-
el/Lowest Observed Adverse Effects Level (KOAEL/LOAEL), were proposed.
Methods to determine RfCs should retain flexibility to accommodate the
specific information and characteristics of various toxic substances,
and could incorporate a tiered approach in which simpler methods are
applied before the more sophisticated methods defined in the documents
reviewed are used.
Keywords: RfC; Inhalation Reference Concentration; Benchmark dose;
Dosimetry? Methodology.
-------
0. S. 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 products constitute a recommendation for use.
-------
U.S* ENVIRONMENTAL PROTECTION AGENCY
SCIENCE ADVISORY BOARD
ENVIRONMENTAL HEALTH COMMITTEE MEETING
October 26, 1990
ACTING CHAIRMAN
or. Ronald Wyzga
Electric Power Research
Institute
MEMBERS, & CONSULTANTS
Dr. Mel Anderson
Chemical Industry Institute of
Toxicology
Dr. David Gaylor
Department of Health & Human
Services
Food and Drug Administration,
National Center for
lexicological Research
Dr. Marshall Johnson
Professor, Department of Anatomy
Jefferson Medical College
Dr. Fred Miller
Duke University Medical Center
Dr. Richard Monson
Harvard School of Public
Health
Dr. D, Warner North
Principal, Decision Focus
Inc.
Dr. Guenter Oberdoerster
Radiation Biology and
Biophysics Division
University of Rochester
School of Medicine
Dr. Martha Radike
Department of Environmental
Health
Medical Center, University
of Cincinnati
Dr. Bernard Weiss
Professor, Division of
Toxicology
P.O. Box RBB
University of Rochester,
School of Medicine
Mr. Samuel Rondberg
Science Advisory Board
(A101F)
U.S. Environmental
Protection Agency
Washington, D. G. 20460
(202) 382-2552}
FAX-(202) 382-9693
STAFF SECRETARY
Ms. Mary L. Winston
Environmental Protection
Agency
Science Advisory Board
(A101F)
Washington, D,C» 20460
(202) 382-2552
FAX-(202) 382-9693
STAFF PIRECTOR
Dr. Donald G, Barnes
Environmental Protection
Agency
Science Advisory Board
401 M Street S.W., (AlOl)
Washington, D.c. 20460
111
-------
TABLE OF CONTENTS
L.0 Executive Summary .,»,,.... ...... 1
l.Q Introduction ................ . . 3
J, 0 Detailed Charge ...,», 5
1.0 Findings ...... .... ........ 6
4.1 Overall Findings ............. 6
4.2 Appropriateness of dosimetric extrapolations .... 7
4.3 Appropriate uncertainty factors ..... . 8
4.4 Is the document clearly articulated? ... 9
4,5 Appropriateness of suggested research ... 9
5.0 Conclusions and Recommendations 10
-------
1*0 Executive summary
Inhalation Reference Concentrations (RfCs) were developed to
serve as health risk estimates for non-cancer effects (analogous to
the oral Reference Dose (RfD)) resulting from exposure to airborne
pollutants. The RfC is an estimate (with uncertainty spanning
perhaps an order of magnitude) of a daily inhalation exposure to
the human population (including sensitive subgroups) that is lively
to be without an appreciable risk of deleterious non-cancer effects
daring a lifetime,
SAB review of the methodology for development of inhalation
RfC values, as described in the document "Interim Methods for
Development of Inhalation Reference Concentrations," (EPA/600/8-
90/066, August 1989) was requested by EPA's Office of Research and
Development in order to incorporate further expert opinion and rec-
ommendations on the methodology, as well as suggestions for its
improvement.
The Committee finds the proposed methods for deriving RfCs to
be reasonable, although some specific improvements, such as the use
of the benchmark dose in place of the No Observed Adverse Effects
Level/Lowest Observed Adverse Effects Level (NOAIL/LOHEL) , are pro-
posed* Methods to determine RfCs should retain flexibility to
accommodate the specific information and characteristics of various
toxic substances, and could incorporate a tiered approach in which
simpler methods are applied before the more sophisticated methods
defined in the documents reviewed are employed.
The Committee recommends review of RfC derivations for several
specific chemicals that illustrate each of the dosimetric adjust-
ments, demonstrate inadequate data bases for derivation ("not veri-
fiable" status) or represent difficult scientific issues (e.g.,
sensitizing agents like toluene diisocyanate)."
The Committee also notes that:
l. The magnitude of uncertainty factors used for a spe-
cific agent should decrease as more data are incor-
porated into a given RfC assessment.
-------
2. A clear articulation of the definition and intent of
the various uncertainty factors is needed.
3. Research needs are not clearly described. A special
section or report should be drafted to detail these
needs.
-------
2.0
The Clean Air Act Amendments (CAAA) recently passed by the
Congress identifies 189 substances and classes of chemicals, which,
if emitted at specified quantities (10 or more tons of a specific
substance, or 25 or more tons of of several chemicals) , are sub-
jected to Maximum Achievable Control Technology (MACT) * Additional
chemicals may be listed, and listed chemicals may be delisted, de-
pending on health risks. In addition, the CAAA require emitting
sources to demonstrate that, based on health risk estimates, only
negligible risks (and no residual risk) exist after implementation
of control technology. Inhalation Reference Concentrations (RfCs)
have been developed to serve as base-line health risk estimates
for non-cancer effects (analogous to the Agency's Reference Dose
(RfO) for orally ingested toxicants) resulting from exposure to
airborne pollutants. The RfC is an estimate (with uncertainty
spanning perhaps an order of magnitude) of a daily inhalation
exposure in the human population (including sensitive subgroups)
that is likely to be without an appreciable risk of deleterious
non-cancer effects during a lifetime. It is anticipated that RfCs
will be used for CAAA regulatory activities as a part of the
determination of list ing/del ist ing decisions, lesser quantity
cutoffs, and residual risk for non-cancer health effects of air
toxics. Additionally, regional, state and local air pollution
control offices have begun to utilize RfC values in risk management
programs .
The inhalation RfC methodology follows the oral Reference
Dose (RfD) paradigm with an added emphasis on portal-of-entry
considerations of comparative toxicity and inhalation dosimetry for
particles and gases. Extrapolation modeling has been used to
derive factors that have been incorporated in the methodology to
adjust exposure concentrations for dosimetric differences between
experimental animal species and humans. A draft of the interim
methodology was reviewed at a public peer-review workshop in
October, 198? and has since been reviewed and implemented by the
Agency's RfD/RfC work group. The methodology was interim and
intended to be reviewed and updated as the state-of-the-art
progressed. Since the RfC values are now being made available to
the public on the Integrated Risk Information System (IRIS) , and
anticipating their aforementioned role in regulatory support, the
EPA Office of Research and Development requested an SAB review to
-------
-------
receive further expert opinion and recommendations on improving the
methodology.
In response to this request, the SAB Environmental Health
Committee (EHC) met on October 26, 1990 in Arlington Virginia to
receive briefings on the RfC methodology from Agency staff, discuss
the issues devolving from the Charge to the Committee (see follow-
ing) , and to initiate development of a report responding to these
issues. Dr. Ronald Wyzga served as Chair, in the absence of Dr,
Arthur Upton,
-------
-------
3.0
The SAB was requested to review the methodology for develop-
ment of inhalation Rfc estimates, as described in the document
"Interim Methods for Development of Inhalation Reference Con-
centrations," (EPA/6QQ/8-90/Q66, August 1990) and its associated
documentation, Appendix B to the IRIS (essentially an executive
summary to the methodology which also serves as a quick reference
for the calculations) . Key issues for the review were:
1* Does the methodology utilize appropriate dosimetric ex-
trapolations for particles and gases, respectively?
2. Should the same uncertainty factors be used when dosi-
metric adjustments are incorporated?
3. Are the concepts and applications of the methodology
clearly articulated in its documentation?
4, Is the intended research to support the methods appropri-
ate to improving risk extrapolation procedures?
-------
4.0 Findings
4.1 Overall Findings The document is useful and comprehensive,
and it advances considerably the previous approaches for deriving
reference concentrations for inhaled toxicants. The proposed
dosimetric adjustment factors are relatively sophisticated, how-
ever, and require the development and consideration of significant
quantities of detailed information; often information at this level
of detail may be incongruent with some of the cruder aspects of the
methodology, e.g., the application of roughly defined uncertainty
factors to numbers of several significant digits. The Agency
should give consideration to the development of an iterative ap-
proach, in which simpler methods are first applied? only when human
exposures appear to be significant, given these initial results,
would more detailed methods then be considered. The Committee is
also concerned about the emphasis given to the "NOAEL plus un-
certainty factor" technique, despite the SAB's past urging that
alternative approaches, such as the benchmark method1, be applied
to the raw data2. The draft Document discusses the bench-mark
method in Appendix A, but refers to this and other approaches as
"Novel," We believe these approaches to be alternative, and in
some cases, more desirable, methods.
The proposed methods emphasize the importance of the effect of
cumulative dose (concentration x time) on response. Although this
emphasis may be reasonable for many toxicant-endpoint combinations,
the Committee cautions that there are many known examples in the
literature when this assumption is not correct and urges flexi-
bility in utilizing alternatives to the cumulative dose concept.
The methods should recognize that there can be considerable
differences in the extent of information available, and in toxicity
mechanisms for various toxicant-endpoint combinations. This re-
quires flexibility in the methods. Given the need to accommodate
knowledge for specific toxicants, the Committee believes it would
1 A statistical approach for deriving Rfc or RfD, based on the
entire set of relevant dose-response data,not only the NQAEL/LQAEL
points. The lower ten percent confidence limit sets the RfC or RfD
value.
2 SAB Report "Comments on The Use of Uncertainty and Modifying
Factors in Establishing Reference Dose Levels," EPA-SAB-EC-005,
January 17, 1990
-------
be useful for the SAB to review some toxicant-specific derivations
of the RfC. This would increase our understanding of the overall
methodology and its data base retirements and enhance our ability
to review the dosimetric adjustments.
The methods should also more explicitly communicate the degree
of uncertainty associated with the derivations of the various RfCs.
Factors which could be so addressed might include issues such as
the validity of the RfG to particles of different sizes, changes in
assumptions about breathing mode, applicability of results for
children, differences in alternative lung deposition models, and
whether deposited dose should be normalized on the basis of lung
surface area or per graw of lung tissue. It would be desirable to
use 95% confidence intervals for deposition of particles to derive
a similar 95% confidence interval for RfCs. In addition, several
sizes of particles could be grouped together rather than being
detailed so specifically as in the draft document* For example,
particle sizes could be categorized in a number of appropriate
ranges, based on their aerodynamic size. Finally, the role of, and
assumptions about, clearance should also be discussed in more
detail.
4«2 appropriateness of dosimetric extrapolations Overall, we find
the methodology to be reasonable. There are some areas, however,
where improvements can be made. For example, it is assumed that
there are linear relationships between breathing parameters used to
derive the Regional Retained Dose Ratios (RDDR) and other sets of
breathing parameters. The proposed method also assumes that all of
a gas inspired goes to the region of concern. This simplification
could be improved by having available two uptake values for the
gas, one where only physical absorption is assumed, and another
where instantaneous chemical reactions are assumed. These two
values would then define bounds for the deposition of the gas.
The methodology might also take note of the fact that there is
a close continuum between ultrafine particles and gases. This
"continuity" may suggest ways to modify the gas approaches in order
to address ultrafine particles.
In the case of the many inhaled chemicals which impact organs
other than the lung, toxicity is sometimes related to metabolites
of the chemicals, rather than the inhaled chemicals themselves.
Application of physiological-biological and pharamacokinetic models
-------
in these cases will require detailed information on the nature of
the mechanisms of action for the specific chemical of concern.
Methods should be sufficiently flexible to allow more sophisticated
pharmacokinetic modeling to be incorporated when required.
The Committee also notes that a new set of physiological
parameters (e.g., lung volumes and breathing rates) is to be
published in the International Committee for Radiological
Protection Reference Manual. These up-dated values should be
incorporated into the methodology.
<«3 Appropriate uncertainty factors The oral Reference Dose (RfD)
paradigm, on which this proposed methodology is based, applies
(generally) ten-fold uncertainty factors to account for uncertain-
ties engendered by the various extrapolations performed to arrive
at daily human exposure estimates from the available experimental
data. The proposed Inhalation Reference Concentration methods are
far more detailed in estimating respiratory exposure and, in fact,
adjust for differences in inter-species dosimetry as far as dep-
osition is concerned. The importance and accuracy of that ad-
justment is highly variable among compounds and among biological
endpoints. Clearly the use of more precise methods should not be
penalized by applying the same uncertainty factors that would be
applied to more general methods, but a general statement about the
appropriate uncertainty factor is not possible, other than to
expect that improved data and understanding of uptake, as opposed
to intake, should lead to smaller uncertainty factors. In general,
there will be less uncertainty associated with the dose to the
respiratory region than to organs outside the respiratory tract;
for that reason, the uncertainty factors associated with respira-
tory effects would in general be smaller than those associated with
effects in the more distal organs.
Dealing with this issue could also be aided by a more detailed
articulation of the intent of the various uncertainty factors. An
understanding of the various uncertainties for which a specific
factor is designed to compensate would allow a better evaluation of
the influence of increased information on an uncertainty factor.
An alternative scheme that does not require uncertainty factors
might use the benchmark dose variant to calculate risk
specifically.
8
-------
4.4 Is the damim^ttt; clearly articulated? The Committee believes
that EPA Staff did an excellent job in defining and explaining a
sophisticated approach to a coaplex problem. Many specific de~
tailed observations for improving or clarifying the text were made
by Committee members; these have been forwarded to the appropriate
EPA Staff. Other considerations are addressed above.
4*5 Appropriateness of suggested research Suggestions for further
research are given throughout the document. In some cases these
are explicitly mentioned; in others they are inferred. It would be
preferable to provide a special section outlining research needs
and suggestions. The research suggested should include ways to
address many of the uncertainties raised by the Committee, The
Committee does, however, wish to indicate that in some cases re-
quired research will be compound-specific; the report should ack-
nowledge the need for this research as well for more generic
methods research.
-------
The proposed methods to derive Inhalation Reference Con-
centrations are reasonable, although some specific improvements,
such as the use of the benchmark dose (or other alternative ap-
proach) in place of the NQAEL/LOA1L, have been proposed. It is
important that the methods to determine RfCs retain flexibility to
accommodate the specific information and characteristics of various
toxic substances (in light of this, future iterations of the inter-
im methods document could be entitled as "Guidelines" to reinforce
the idea that the methods are not "cookbook formulas"). The meth-
ods could also incorporate a tiered approach in which simpler meth-
ods are applied before the more sophisticated methods defined in
the documents reviewed are utilized. Also, a review of the appli-
cations of the proposed RfC methods for several specific chemicals
would facilitate the evaluation of these methods, and the Committee
would be pleased to assist in such reviews.
The Committee also notes that?
1. In general, as the amount of scientific information in-
corporated into RfC determination increases, the magni-
tude of the overall uncertainty factor, applied in the
RfC derivation, should decrease.
2. A clear articulation of the definition and intent of the
various uncertainty factors is needed. This would help
define the correct uncertainty factors to be used for
RfCs. A review of RfC estimates that illustrate the dif-
ferent dosimetric adjustments and that illustrate the use
of different uncertainty factors (e.g., laboratory animal
to human, subchronic to chronic, LQAEL to NOAEL, etc.)
would aid in the formulation of any recommendations con-
cerning the uncertainty factors.
3. The methodology is reasonably well described. The in-
clusion of case studies for specific toxicants, as noted
above, would improve this description.
4. Research needs are not clearly described. A special
section or report should be drafted to detail these
needs.
10
-------
The detailed RDDR tables in Appendix M of the draft doc-
ument provide an inappropriate sense of precision by dis-
playing four significant figures after the decimal point.
The tables should be revised to display less detailed da-
ta, perhaps giving ranges of particle sizes and RDDRs
generated with other deposition models.
11
------- |