Undid »*f« 0«lc,«
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D,C, 204SO
September 30, 1987
OFFICE OF
TME AOMIN(§
The Honorable Lee M. Thomas
Administrator
U.S. Environmental Protection Agency
401 M Street, S.W.
Washington, DC 20460
Dear Mr. Thomas:
The Clean Air Scientific Advisory Committee (CASAC) has completed
its assessment of research needed to support the development of National
Ambient Air Quality Standards (NAAQS) for Ozone and for Lead. This
report, along with the December 30, 1983 report which outlined research
needs for carbon monoxide, nitrogen oxides, particulate matter, and
sulfur oxides, is in response to the mandate under the Clean A1r Act
Amendments of 1977 to provide you with advice concerning research needs
for ambient pollutants.
Within each of the major research areas identified for ozone and
for lead, we summarize the need for the research and assign priorities.
These priorities represent a continuum since we believe that all of the
research needs that we have identified are of importance to the Agency.
For ozone, we have identified research needs in atmospheric chemistry,
health effects, and agriculture, forests and related ecosystems; for
lead, we have identified research needs in atmospheric processes, ex-
posure, metabolism, and biological and health effects. We have also
provided recommendations on the design of the National Health and Nutri-
tion Evaluation Survey (NHANES III). Clearly, each research program must
be structured so that those studies which can determine the importance
of critical variables and mechanisms are started early and pursued
vigorously. This places additional responsibility on the Agency's re-
search staff to ensuri that timely and appropriate research resource
allocations are made. It is worth emphasizing that the planning of
future studies should be Integrated with the findings from ongoing
research.
The research program which the Committee recommends for ozone can be
pursued and completed within the next five years at a cost which, while
relatively large in relation to the current EPA budget for criteria
pollutant research is relatively modest in relation to the costs of
current monitoring and control efforts. The research results are almost
certain to provide a much better scientific basis for the ozone NAAQS
promulgation in the mid 1990s than that available today.
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Tharik you for the opportunity to present our views on these important
human health and welfare issues. We request that the Agency officially respond
to the scientific advice contained in the attached report.
Sincerely,
Morton Lippmarin
Chairman
Clean Air Scientific
Advisory Committee
cc: A. James Barnes
Vaun Newill
Craig Potter
Terry Yosie
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U.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 a 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 endorse-
ment of recommendation for use.
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TABLE OF CONTENTS
Page
I. EXECUTIVE SUMMARY 1
II. INTRODUCTION 3
HI. RESEARCH NEEDED FOR FUTURE DECISIONS ON NATIONAL AMBIENT 4
AIR QUALITY STANDARDS FOR OZONE
A. Introduction 4
B. Atmospheric Chemistry 4
1. Modeling Program 5
2. Trend Analyses Program 7
3, Predictive A1r Quality Models for Long-Term Ozone 8
Concentration Averaging Tiroes
C, Health Effects 8
1. Chronic Health Effects §
2. Acute Effects 10
3. Mechanistic Studies 11
D. Agriculture, Forests, and Related Ecosystems 13
1* Agriculture 13
2. Forests 16
IV, RESEARCH NEEDED FOR FUTURE DECISIONS ON NATIONAL AMBIENT 19
AIR QUALITY STANDARDS FOR LEAD
A, Introduction 19
B. Atmospheric Processes 20
C. Exposure Considerations 21
D. Lead Metabolism 23
E. Biological and Health Effects 24
1. Developmental Effects 24
2. Cardiovascular Effects 25
3. Other Effects 26
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May 1987
U.S. Environmental Protection Agency
Science Advisory Board
Clean Air Scientific Advisory Committee
Research Needs Subcommittee
Dr. Morton Lippmann, Professor, Institute of Environmental Medicine,
NYU Medical Center, Tuxedo, New York 10987
Members
Dr, James 0, Crapo, Associate Professor of Medicine, Chief, Division of
Allergy, Critical Care and Respiratory Medicine, Box 3177, Duke
University Medical Center, Durham, North Carolina 27710
Or. Robert Frank, Professor of Environmental Health Sciences, Johns Hopkins
School of Hygiene and Public Health, 615 N. Wolfe Street, Baltimore,
Maryland 21205
Dr. Paul B. Hammond, Professor of Environmental Health* University of
Cincinnati College of Medicine, Ketten'ng Laboratory, 3223 Eden
Avenue, Cincinnati, Ohio 45267-0056
Dr. Jay S. Jacobson, Plant Physiologist, Boyce Thompson Institute, .
Tower Road, Ithaca, New York 14853
Dr. Jane Q. Koenig, Research Associate Professor, Department of Environmental
Health, SC-34, University of Washington, Seattle, Washington 98195
Dr. Timothy Larson, Environmental Engineering and Science Program,
Department of Civil Engineering, FX-10, University of Washington,
Seattle, Washington 98195
Dr. D, Warner North, Principal, Decision Focus Inc., Los Altos Office
Center, Suite 200, 4984 El Camlno Real, Los Altos, California 94022
Dr. Gilbert S. Owtnn, Professor and Dean, School of Public Health and
Community Mtd1c1ne, SC-30, University of Washington, Seattle,
Washington 98195
Dr. Michael 8. Rabinowitz, Harvard Medical School, c/o Marine Biological
Laboratory, Woods Hole* Massachusetts 02543
Dr. Robert D. Rowe, Vice President, Environmental and Resource Economics,
Energy and Resource Consultants, Inc., 207 Canyon Boulevard,
Boulder, Colorado 80302
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DP. Ellen K. Sllbergeld, Senior Scientist, Environmental Defense Fund,
1616 P. Street, N.W., Washington, D.C. 20036
Dr, Mark J. Utell, Co-Director, Pulmonary Disease Unit, Associate Professor
of Medicine and Toxicology in Radiation Biology and Biophysics,
University of Rochester Medical Center, Box 692, Rochester, New
York 14642
Dr. James HU Ware, Associate Professor, Harvard School of Public Health,
Department of Biostatisties, 677 Huntington Avenue, Boston,
Massachusetts 0211S
Dr. George T. Wolff, Senior Staff Research Scientist, Seneral Motors
Research Labs, Environmental Science Department, Warren, Michigan 48090
Executive Secretary
Hr. A, Robert Flaak, U.S. Environmental Protection Agency, Science
Advisory Board (A-101F), Washington, D.C. 20460
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September 1987
U.S. Environmental Protection Agency
Science Advisory Board
.P..1 e. Jfl. Ai r Sc 1 ent 1 f i c Adv 1 sory Commi ttee
Chalrman
Dr. Morton Lippmann, Professor, Institute of Environmental Medicine,
NYU Medical Center, Tuxedo, New York 10987
Members
Dr. Robert Frank, Professor of Environmental Health Sciences, Johns
Hopkins School of Hygiene and Public Health, 615 N. Wolfe Street,
Baltimore, Maryland 21205
Dr. Warren B, Johnson, Manager, Research Aviation Facility, National
Center for Atmospheric Research, P.O. Box 3000, Boulder,
Colorado 80307
Dr. Timothy Larson, Research Associate, Environmental Engineering and
Science Program, Department of Civil Engineering FX-10, University
of Washington, Seattle, Washington 98195
Dr. Gilbert S. Oraenn, Professor and Dean, School of Public Health and
Community Medicine, SC-30, University of Washington, Seattle,
Washington 98195
Dr. James H. Mare, Associate Professor, Harvard School of Public Health,
Department of 81ostatisties, 677 Huntington Avenue, Boston,
Massachusetts 021 IS
Or. Jerry Wesolowskl, Chief, Air and Industrial Hygiene Laboratory,
California Department of Health, 2151 Berkeley Way, Berkeley,
California 94704
Executive Secretary
Mr. A. Robert Flaak, U.S. Environmental Protection Agency, Science
Advisory Board (A-101F), Washington, D.C. 20460
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1. EXECUTIVE SUMMARY
This 1s the second in a series of reports prepared by the Clean Air
Scientific Advisory Committee (CASAC) providing recommendations to the U.S.
Environmental Protection Agency on research needed to develop and support
National Ambient Air Quality Standards (NAAQS). The first report, issued in
December 1983, provided research recommendations on four of the six criteria
pollutants: carbon monoxide, nitrogen oxides, particulate matter, and sulfur
oxides. This present report provides research recommendations for the two
remaining criteria pollutants: ozone and lead.
The research recommendations for ozone are presented in three parts;
1) atmospheric chemistry; 2) health effects; and 3) agriculture, forests and
related ecosystems. Each part is critical to setting an ozone NAAQS, The
litter two areas are critical in establishing exposure-response relationships
for the effects that ambient ozone produces. However, without a better
understanding of exposure profiles, scientists ind regulators cannot accurate-
ly establish the extent of the effects of ambient ozone exposure on public
health and welfare. Furthermore, without a better understanding of atmos-
pheric chemistry, we cannot predict either the frequency of excessive
exposures or the influence of the various sources of the ozone precursors on
the ambient concentrations.
The Committee has the following high priority research recommendations
for ozone:
Atmospheric Chemistry
* The Committee proposes two research programs which will help develop
urban-scale and regional-scale models that can be used for regulatory
purposes, and which will determine existing and future ozone trends to
assess the impact of precursor emissions.
Health Effects
t Research which emphasizes the identification of ozone health effects
related to chronic low-level exposures,
• Population studies linking long-term ozone exposure with development
of chronic respiratory system damage.
t Quantitative animal-to-human extrapolation.
• Interactions of ozone with other air pollutants.
i Influence of ozone on host defenses against infections and
neoplastic diseases,
t Role of inflammation in response to ozone.
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Agrl culture,^Forests, and Rel ated_EcosjfSteins
• Additional exposure statistics research.
• General physiological/biological process models for crops and
trees.
• Comparisons of ozone flux 1n chambers to crop canopies.
* Ozone dosi-response of major tree species and overall forest
productivity analyses.
The research recommendations for lead are presented 1n four parts:
1) atmospheric processes; 2) exposure considerations; 3} lead metabolism;
and 4} biological and health effects. In addition, the Committee has pro-
vided recommendations on the design of the forthcoming National Health
and Nutrition Evaluation Survey (NHANES III).
Atmospheric Processes
t Reassessment of the relative Impact of point sources and gasoline
on ambient air lead.
* Assessment of the impact of air lead on lead in other media to
which man 1s exposed (i.e., food and water)i
* Assessment of factors which determine the transfer of lead from
dump sites to air and water.
Exposure Considerations
* Importance of soil and dust ingestion in children as sources of
lead.
» Bioavailability of lead as a function of particle size and chemical
form.
• Contribution of foods to total lead intake. Including processing
and packaging.
» Contribution of drinking water to total lead intake, including
• water used 1n food and beverage preparation.
Lead Metabolism
» Development of better indices of lead exposure,
• Blokinetic modeling with special emphasis on the fetus and placen-
ta, as well as bone 1n both pregnant women and in the elderly.
» Dietary factors influencing lead absorption.
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Biological Bind Health Effects
• Continued, uninterrupted support for current prospective studies
of neurobehivioral effects of lead In children to school age and
beyond.
In connection with the forthcoming NHANES III study, the Committee
urges EPA to consider questionnaire items to aid in establishing if a
subject's blood lead concentration is representative of long-term duration
of exposure or if it reflects a recent significant incident, and secondly,
to use the best possible methodology for blood lead determinations.
II. INTRODUCTION
A major responsibility of the Clean Air Scientific Advisory Committee
(CASAC), as established 1n the Clean A1r Amendments of 1977, 1s to provide
scientific advice on additional knowledge that is required for evaluating
existing, or setting new or revised National Ambient A1r Quality Standards
(NAAQS). On December 30, 1983, the CASAC issued the first of an eventual
series of reviews intended to evaluate the state of research knowledge
and needs for criteria air pollutants. This first report assessed five
generic research needs for such pollutants that Included: 1) development
of a program in air pollution epidemiology; 2) development of a program
in extrapolation modeling; 3) research relating concentrations at moni-
toring sites to human exposures; 4). research relating exposures to dose;
and 5) responses to multiple pollutant exposures. In addition, the CASAC
identified research directions and needs for four specific pollutants
for which it had reviewed air quality criteria documents: carbon mon-
oxide, nitrogen oxides, particulate matter, and sulfur oxides.
The Committee met on May 21-22, 1987 and July 15, 1987 to discuss and
identify research directions and needs for ozone and for lead. In this
present report, the CASAC has reviewed the research recommendations for
ambient ozone and lead prepared by EPA staff, members of tht public, and
its own members and consultants, and has prepared a set of research
recommendations for each pollutant with a statement of priorities for
the next five years. The priorities are based upon the need to address
scientific issues hiving the greatest potential impact on setting a NAAQS
to protect the public health and welfare*
Research recommendations are Identified as first, second, and third
priorities. It should be noted that the Committee believes that all the
recommendations presented are of great concern to the Agency. The three
priorities should be viewed as a continuum. While the recommendations and
priorities are those of CASAC, we gratefully acknowledge the excellent
preliminary work by EPA staff, and contributions from members of the
public*
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III. RE$EARGtij,MEEDED FOR FUTURE DECISIONS ON NATIONAL AMBIENT AIR
~PAlTfy STANDAROS FOR OZONE ~ ~~ ~™
A,
While research performed since the last ozone NAAQS promulgation in
1979 has greatly increased our knowledge of ozone formation and persis-
tence in the troposphere, its effects on public welfare, and its effects
on human health, major knowledge gaps and areas of uncertainty remain,
These gaps and uncertainties limit the ability of the Administrator to
identify the effects which result from various combinations of concen-
tration, exposure time, and ventilation rate, and the degree to which
some pollutant associated effects are attributable to ozone alone, or
to ozone 1n combination with other airborne pollutants. Thus, while
much is known about ozone exposures and their effects, our current
knowledge of effects remains incomplete, possibly leading to a promul-
gation of a standard which fails to protect against some adverse effects.
On the other hand* the use of an overly conservative margin of safety to
compensate for our incomplete understanding of the effects could lead to
the promulgation of a standard which imposes very large burdens in society,
in terms of unnecessary costs of control and/or restrictions on normal
activities.
CASAC has approached the identification of research needs in a
comprehensive manner, and it does not expect all of the needed research
to be performed or funded by EPA. The Committee recognizes that some of
the ozone research needs are being addressed by other sponsors of research
in the public and private sectors, e.g. National Oceanic and Atmospheric
Administration (NOAA) in atmospheric chemistry, U.S. Department of the
Interior (USDOI) and U.S. Department of Agriculture (USDQA) in welfare
effects, and the Health Effects Institute (HEI) in health related re-
search. While CASAC understands the importance of these other research
programs, it clearly sees EPA playing a lead role, and having the major
responsibility for ensuring that all of the important scientific issues
relevant to standard setting are addressed.
i. Atmospheric Chemistry
Because most of the major metropolitan areas in the United States
still fail to meet the current National Ambient Air Quality Standard
(NAAQS) for ozone, additional controls on emissions of volatile organic
compounds (VOC) and, perhaps, nitrogen oxides (NOX) may be required,
All of the sources that were relatively easy to control are already
subject to some degree of control. Thus, any additional controls will
certainly be more expensive than previous ones, and they will have a
significant economic impact on society. For these reasons, it 1s vital
to know with reasonable certainty the impact that additional controls
will have on ozone air quality. At present, scientists and regulators
do not have that information because existing models have not been vali-
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dated. It 1& also Important to analyze emissions and air quality trends
so to document the Improvements 1n air quality resulting from emissions
controls. At present, the documentation is inadequate.
In order to validate the models and document the trends, there is a
need to develop an integrated, targeted research agenda for ozone. Two
ultimate goals of these programs should include: 1) developing an
urban-scale and a regional-scale model which can be used for regulatory
and planning purposes, and 2} determining existing and future ozone
trends to assess the impact of perturbations in precursor emissions.
The CASAC proposes two research programs to achieve these goals, the
elements of which are described below. In addition, a third program
relating to a longer-term NAAQS for ozone is presented.
1. Modeling Program
a) Conduct sensitivity analyses usin^existing models to Identi-
fy and Improve critical model elements^-Existing models have
not been validated, and they can be improved. They can and
should, however, be used to identify the types of ambient
measurements needed for validation purposes and to determine
which assumptions lead to the largest uncertainties. The
models should be exercised to determine the sensitivity of
the results to chemical mechanisms, boundary conditions, VOC
speciatlon, VOC reactivity, aromatic chemistry, number of
monitoring sites and locations, VOC/NOX ratio, upwind and
aloft concentrations of 03, VOC, NOX and carfconyls, grid
size, meteorological parameters and other variables. ..Once
the critical elements have been Identified, programs to
reduce the uncertainty of the model results due to uncertain-
ties in the critical elements should be initiated. Such
programs will undoubtedly include case (field studies), labor-
atory, and smog-chamber studies. In addition, there are
several aspects of the models that are deficient and require
further investigation. These include night time and hetero-
geneous chemistry, reactions involving and/or resulting in
the production of aerosols, H2Q2» HCOOH, PAN, and HN03,
reactions Involving natural hydrocarbons, cloud venting, de-
position velocities as a function of time of day and surface,
nocturnal jets, Inability for the combined use of primitive-
equation model and observations. Methods development for
\\$2 should be a high priority because #2®2 data, would help
test various chemical mechanisms used in modeling. The
models should be used to identify additional high priority
species.
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b) Bevel op ambient data bases for model testIng and model vali-
dation - The first Issue that needs "to" be addressed is the
suitability of existing data bases generated from previous
case studies. If there are any adequate data bases that
exist, then testing should begin. Perhaps data bases gen'
erated from PEPE/NERQS or other studies are adequate. The
regional-scale model, which Incorporates long-range trans-
port, should be applied 1n the Northeast while the urban-
scale model should be applied in Los Angeles and another
city 1n the Northeast, The Southern California A1r Quality
Study (SCAQS), conducted this summer (1987), was designed
to generate a data base that can be used to test and validate
models for ozone and particulate matter (PM-10). This data
base is expected to be ready for use by 1990. Since there
is such a long lead time required to plan and then validate
the data from such studies, planning for additional field
studies should begin as soon as possible.
c) Improve emission Inventories - Present evidence suggests
that the error levelIF the best available estimates of
existing VOC and NOX source strengths is nearly an order
of magnitude larger than the magnitude of emissions re-
ductions contemplated in current control strategies for
03, Consequently, this is a critical element that needs
improvement. Improved regional and urban-scale inventories
for NOX and speciated VOC are needed for the modeling
and trend analyses, and an improved nation-wide inventory
1s need for the trend analysis. The overall emissions
inventory should be examined first and uncertainties assigned
to each category. Subsequent decisions can be made and
priorities established based on which sources can achieve
the greatest reduction in the overall VOC and NO* emissions
uncertainty. Some sources deserving priority attention in-
clude present in-use, on-road and off-road vehicles and
equipment; diurnal, hot-soak and refueling emissions; small
stationary sources; restaurants; end marine-related opera-
tions. Also, an accurate inventory of natural VOC emissions
1s needed because current estimates of the flux of natural
VOC in the northeastern United States are at the same level
as those from anthropogenic sources,
d) Run the validated models to determine optimum control strat-
egies - The models should be exercised for a variety of urban
areas to determine not only the degree of control required
for attainment, but also the effect of nitrogen dioxide re-
ductions on ozone concentrations. Depending on the local
VOC/NOX ratio, reducing NQX could either increase or decrease
ozone.
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2- Trend Analyses Program
Even 1f Models adequately represented real world phenomena, trend anal-
yses are needed because they are the truer measure of progress. In addition,
1t Is vital to know how much of the ozone problem is due to man's activities
and how much Is due to nature.
a) Establish and maintain ambient data bases- EPA needs to Insure
that the stations established for trend analysis ire sited pro-
perly, and not relocated or terminated.
* Metropolitan ozone sites - The existing networks are
probably sufficient.
* Rural ozone sites - A network of rural monitors needs
to be established in both agricultural and remote areas.
The remote sites should be 1n areas away from local
sources so trends 1n the "background" ozone can be es-
tablished.
• VOC and N0? sites - Networks of VOC and NOX monitors
1n metropolitan areas are needed. Many of the VOC and
NOX monitors need to be co-located so that the VQC/NOX
ratio, which 1s a critical input for any model, can be
determined accurately. It is also Important that the
ratio be representative of the area as a whole. In
addition, periodic measurements of individual VOC species
at these sites are needed to determine the trends in VOC
composition,
b) Trend analyses -*The following trends should be examined:
t Trends in the ambient concentrations of ozone, nitrogen
dioxide, and volatile organic compounds by geographic
area,
• Trends in the emissions of volatile organic compounds and
nitrogen dioxide,
• Trends In ozone adjusted to eliminate the influence
of meteorological variations.
c) Background Ozone - Because EPA 1s considering a long-term
ozone standard that is approaching the natural background
range of of 30 - 50 ppbt it Is extremely important that
this range be documented spatially and temporally, and that
the sources of the background be quantified. For this effort,
the following action should be taken:
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* A network should be established to monitor the long-term
trend in background ozone. The siting of these monitors
is critical. It is important that they be upwind of the
synoptic-scale region of interest to assess whether the
regional ozone levels are elevated with respect to the
upwind values,
• The relative magnitude of ozone from stratospheric in-
trusions and 1n-situ photochemical processes in the free
troposphere needs to be determined. This will involve
the monitoring of ozone and several stratospheric tracers,
such as 'beryllium and ^strontium simultaneously, at
different altitudes in the stratosphere and 1n the free
troposphere, as well as on the surface. By examining
the ratios of the tracers to each other and to ozone,
and accounting for their natural decay and deposition
processes, better estimates of these contributions can
be made.
• The importance of natural hydrocarbons needs to be de-
termined. This will Involve improved emission estimates
for not only the natural hydrocarbons but fop the anthro-
pogenic ones as well. In addition, laboratory experiments
to obtain kinetic and mechanistic data for the major
natural hydrocarbons are needed. These data would be
used to develop improved reaction mechanisms which would
be incorporated into photochemical models. The models
would then be tested using appropriate smog chamber
data. In addition* accurate ambient air measurements of
all the hydrocarbons, natural as well as anthropogenic,
will be required,
3. Predictive Air Quality Models forlong-Term Ozone Concentration
'Ave~rag1ng_ Times/ —-—
All the modeling efforts described above are designed to predict a
one day, daytime hourly ozone profile, which could be used to generate an
8-hr or 7-*hr mean 1f such a standard is implemented. However, there is
also some thought being given to longer standards such as a 3-month mean
of the daily 7-hr maximum values. At present, no models exist to address
such a standard. When and if such a standard is implemented, models will be
needed. Therefore, work should begin on the development of such a model if
it appears that such a standard is likely.
C. Health Effects
The effects of ozone on human health have received intensive scientific
scrutiny. Recent evidence has shown that inhalation of ozone at concentra-
tions near ambient levels produces acute reversible changes in lung func-
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tion. Yet stprtfleant gaps remain in the health effects data base for ozone:
effects of lowMevel chronic exposure, relationships between acute and chronic
effects, exposure-response relationships, and mechanisms of ozone-induced
injury identify broad areas that are incompletely understood. The research
program developed by the EPA his identified many of these major gaps and
proposed realistic strategies for narrowing the remaining uncertainties.
Given the wide array of research needs, and the limited resources available,
the program has appropriately integrated controlled human clinical studies,
animal toxicology, and/or epidemiology into its research planning.
The CASAC endorses the EPA efforts to advance ozone health research
using a broad-based program including both human and animal studies. Al-
though the CASAC Is cognizant of the multiple approaches for subdividing
the broad research categories, it chose to organize the long-range goals
of the ozone research program into three general areas; a) chronic health
effects, b) acute health effects, and c) mechanistic studies.
1. Chronic HealtJLjffects
a) Objective
The objective of this research is to achieve an Improved understanding
of effects of chronic, low-level ozone exposure on the respiratory tract.
At present, knowledge of acute effects following short-term ozone exposure
is considerably greater than that following long-term, low-level Inhalation.
Several Investigative approaches are identified:
* Chronic low-level animal exposures with endpoints including biochem-
ical alterations, structural changes, alterations in pulmonary func-
tion, or other early Indicators of ozone-induced lung disease.
• Population studies designed to determine whether long-term exposure
is linked to development of chronic respiratory disease,
• Measurements of ozone dose and toxic effect in target tissues of
several species to enhance the possibility of animal-to-man extra-
polatlon.
b) Research Needs
The EPA should give very high priority to those components of Its
research program targeted at identifying ozone health effects related to
chronic low-level exposures, ienerally thest efforts should take advantage
of the findings from recently completely chronic exposure studies before
developing new protocols.
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F1 rst Priority jesearch Needs
t Effects of chronic ozone exposure* A major limitation of the
ozone data-base relates to the 11 suited understanding of chronic
effects resulting from low-level exposure. The CASA6 strongly
supports studies Involving long-term exposure of animals which
are designed to elucidate the structural/functional Implications
of chronic diseases as determined by lung function, morphology,
and biochemistry. Although efforts to develop early indicators
of ozone-Induced chronic lung disease are appropriate, it is not
clear whether useful blomarkers would be developed for use In
clinical epidemic!ogic studies of low-dose oxidant Inhalation.
t The carefully designed epidem1olog1c study remains the ultimate
mechanism for linking long-term ozone exposure with development
of chronic respiratory system damage In humans. Despite the
enthusiasm for such studies, the CASAC acknowledges their com-
plexities. For example, the difficulties related to poor docu-
mentation of exposures, the variety of confounding variables,
and uncertain endpolnts have severely curtailed Interpretation
of such studies to date. Although the CASAC finds the possibili-
ty of using results from autopsies of accident victims interest-
Ing and Imaginative, the problems of obtaining good tissue rapid-
ly from autopsies, and difficulties 1n obtaining accurate expo-
sure histories, somewhat dampened enthusiasm for this approach.
Despite these reservations, the Committee encourages EPA to
support and encourage studies of human populations 1n relation to
chronic lung diseases associated with ozone exposure.
* Quantitative Animal-to-Man Extrapolation, This is an important
research area that presents the opportunity to develop dosimetric
models which allow adequate estimates of dose to specific target
lung tissues across a variety of animal species. Emphasis should
be placed on distinct species-specific as compared to across-
sped es phenomena. Such an approach should enhance application
of the toxicologictl data-base to risk assessment.
2. Acut_e_ Effects
a) Objective
The objective of this research area is to better understand the
acute effects of ozone related to Intermittent or prolonged daily expo-
sures; in addition, it focuses on the potential connection between acyte
cellular damap to the respiratory tract and subsequent development of
chronic disease.
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b) Research Needs
EPA should continue to assign priority to the controlled clinical
studies using the environmental chamber facility at Chapel Hill. The
controlled clinical studies have been remarkably productive over the
past five years in enhancing scientific understanding of acute ozone
effects on healthy populations
First Priority Research Needs
• Health effects of prolonged daily exposures. The CASAC strongly
endorses the concept of prolonged daily studies, with emphasis
on the influence of concentration and duration of exposure.
Such studies should prove instrumental in helping EPA decide
whether a separate standard using a longer averaging time (for
example, eight hours) is warranted for ozone,
• Determination of factors influencing the magnitude of the ozone
response. One of the most interesting findings of the clinical
ozone exposure study is the existence of wide variation in the
magnitude of response in a healthy population. The CASAC sup-
ports further efforts to characterize the variability of response
and to identify factors ranging from genes to cells that may
influence this variability.
• Relationship between effects of acute and chronic ozone exposure.
The Committee supports efforts to obtain a better understanding
of the potential interaction between cellular and molecular
events surrounding damge to the respiratory tissue from acute
oxidant exposure and development of chronic pulmonary disease.
The Committee recognizes the difficulty of undertaking such
studies in the absence of valid markers of early Injury or
disease. However, it encourages in vivo studies at the biochemi-
cal and molecular level aimed atlJiterminlng whether acute ozone
exposed humans respond by producing factors capable of inducing
inflammation, fibrosis, etc.
3. Mfchjnist1c^Studj_es
a) Objective
The objective of such studies is to further elucidate mechanisms
reponsible for tither acute or chronic ozone injury. This goal Is broadly
stated and applies to research recommendations that overlap between acute
and chronic categories. EPA should continue to give very high priority
to mechanistic research with ozone ranging from clinical physiological
studies to the rapidly advancing arena of molecular biology.
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b) Research Needs
First Priority Research Needs
• Interactions of ozone with other air pollutants. There 1s a
need to investigate the potential for ozone to interact with
other co-existing pollutants either in the air or in their
effects after being taken up in the lungs. The real world
ratios of pollutants are likely to be an influencing factor
in provoking a potentiation of airway response. The few studies
conducted fh this area have not been highly rewarding, and this
emphasizes the need for studying exposure-response curves rather
than effects of single pollutant concentrations.
t Influence of ozone on host defenses against Infectious and
neoplastic diseases. Effects of ozone on viral infections are
not well understood and studies of host-defense mechansims in
both animals and humans are needed. There is also a need to
better understand alterations in the immune system following
both acute and chronic ozone exposure. In contrast, the CASAC
has expressed less enthusiasm for studies designed to examine
host defenses against "neoplastic disease". If the relationship
between ozone exposure and neoplasia should be strengthened, then
such studies would warrant a much higher priority.
• Role of inflammation in response to ozone. Inflammatory process-
es have been linked both to development of chronic lung disease
as well as the acute development of airway hyperreactivity. The
use of new clinical tools such as broncho-alveolar lavage in
efforts to evaluate acute responses to ozone is a promising
research opportunity,- Inflammatory events may serve as a poten-
tial link bttwten acute and chronic health effects resulting from
ozone exposure. However* the Committee emphasizes the need for
animal models to validate lavage flndlnp and predictions of
long-term effects.
Second Priority Research Needs
t Ozone molecular mechanisms of action. The Committee encour-
ages studies aimed at elucidating the molecular mechanisms of
ozone tffects. However, it notes that while specific probes
for studying molecular mechanisms are rapidly evolving, their
current applications have yet to be demonstrated.
* Methodology development. There is a need for further method
development, including physiological techniques to asstss small
airway function, monitoring of individual exposures, and statis-
tical design and analysis. However, in some circumstances, such
development would best be undertaken by other agencies with even-
tual application in EPA laboratories.
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* Influence of ozone exposure on inhaled particle dosi«etry.
Alttl'ltlons of dosiraetry Induced by ozone Inhalation should
prove-useful in the extrapolation modeling process.
* Studies on the attenuation of ozone effects. Further evaluation
of the biochemical. Inflammatory, and morphologic changes asso-
ciated with the well recognized phenomena of adaptation has
merit. The influence of pharmocologic agents on the phenomena
of ozone adaption warrants investigation.
• Responses of human bronchial and alveolar epithelium to ozone*
Permeability of the pulmonary epithelial barrier is increased
after ozone exposure. Further studies of changes In permeability
from the nose to the alveolar level are encouraged in both
laboratory animals and humans.
ThirdPriority Research Needs
• Identification of groups potentially at risk from ozone exposure.
This 1$ of obvious Importance in protecting populations from
ozone exposure but can best be investigated by studying factors
influencing the magnitude of response.
• Genotoxic, carcinogenic, and co-carcinogenic effects of ozone.
Although the influence of pollutant exposure on the development
of cancer is of concern, it is not currently an area that warrants
a higher priority because of the present lack of data on associa-
tions between ozone and cancer.
• Extrapulmonary effects. The Committee is not convinced that
ozone studies targeted to effects beyond the respiratory tract
should represent a major focus of the research program,
0. Agriculture, Forests, and Related Ecosystems
1. Agriculture
a) Objectives
The objective of research on the effects of ozone on agriculture is to
improve the tff1c1ent evaluation of alternative secondary ozone ambient
air quality standards. Broadly speaking, this requires:
• Accurate Information as to the form of the standard that will
best characterize the relationship between ozone and relevant
measures of damage to crops and other important vegetation.
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* Accurate and comprehensive information as to the physical,
ecotMjMftc and social Importance of ozone impacts on vegetation.
What crops are affected; how much physical damage occurs; what
1s the economic and soda! Importance of this damage and to
whom, where, and when; and what is to be considered "adverse"?
• Provide generalizable understanding and modeling of the ozone-
crop-welfare impacts' relationships that will provide the basis
for updating the evaluation of the standard and stimulating
methods to prevent and mitigate damage.
* Providing information in the most cost effective manner.
b) Research Needs
The National Crop Loss Assessment Network (NCLAN) has been an
intensive, coordinated research effort sponsored by EPA and is now
nearing completion. This program has developed a wealth of data. EPA
should give first priority to a complete evaluation of the results of
this research and related efforts supported by U.S. Department of
Agriculture (USDA). The new information obtained and the remaining gaps
in knowledge should be Identified. Given the knowledge provided by
NCLAN, EPA should identify the additional information needed to evaluate
the current standard and support recommendations for modifications,
where appropriate.
First Priority Research Needs
• Additional Exposure Statistics Work. In order to set efficient
but not overly complicated standards, two lines of research ire
needed;
(1) Examine alternative characterizations of exposure to ambient
ozone and their effects upon crop yield. NCLAN focused upon 7-
hour ind 12-hour average exposures, but peak concentrations may
be of more concern. Additional investigations should consider
exposure characteristics in terms of duration, frequency, peak
concentration, and maturity of plants.
(2) Explore the relationship between patterns of ozone exposure
and climate In different geographic regions and the response of
vegetation. Different dose characteristics may best represent
the scientific relationship between ambient ozone and crop
yield for different regions, but they may be overly complex for
standard setting. Therefore, generalized ozone dose-response
relationships satisfactory for a range of environmental condi-
tions should be developed for the most susceptible crop plants.
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As r natural consequence of addressing alternative exposure
measures 1n the dose-response relationship, the functional form
of th« relationship must be simultaneously addressed* although
emphasis on this 1s In the second priority of research pursuits.
This 1s because once general functional forms for the dose-res-
ponse relationship are determined, refinements tend to have only
a small impact on the physical and economic assessments.
t General physiological/biological process models. Seneral process
models are required concerning susceptibility and resistance to
ozone. This provides explanations for dose-response relation-
ships found and a basis for development of genetic lines of
plants that can maintain satisfactory yield and quality at
ambient levels of ozone, as it may be well Into the next century
before ambient levels decrease. This will reduce the need to
repeat exposure studies for each new variety of crop.
§ Accurate exposure data. Accurate monitoring Information 1s
needed on the concentrations of ozone and their variation with
time 1n agricultural regions. Very limited ozone data is avail-
able for major agricultural regions. Often this data is the
estimated growing season average based upon distant monitors.
Improved data bases of multiple characteristics of exposure
conditions throughout the growing season are needed to improve
the application of dose response functions to better estimate
yield losses and their resultant economic Impacts on a more
site specific basis.
t Flux comparisons. Compare flux of ozone to crop canopies in the
field and 1n chambers used in the NCLAN program. The specific
objective would be to determine whether fluxes in chambers,
given the patterns and rates of air movements there* are similar
or different than fluxes of ozone In the field, given the patterns
and rates of air movements found in the regions where crops are
grown. This effort would have to be undertaken for three seasons
to encompass different climatic conditions and should be perform-
ed for those crops previously studied by NCLAN.
Second Priority Research Needs
• Additional dose-response studies on selected key high-valued
crops 1n selected regions. The NCLAN program analyses are most
applicable to major crops and growing conditions in the mid west
and selected other locations. Additional dose-response analyses
for the same crops in other regions and for key regional crops
are needed to broaden the basis for evaluating the current
secondary standard.
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* Analysis of mitigation effectiveness, costs and Implementation.
chemical protectants and mitigation behavior, In terms of develo-
ping and producing resistant crop varieties, may potentially
reduce ozone induced crop yield losses at low cost. Additional
studies on the costs and effectiveness of these actions are
merited to reduce the burden of ozone impacts and ozone control,
• Improved economic assessment. The NCLAN program, and other work
at EPA's Office of Air Quality Planning and Standards (QAQPS)
and the California Air Resources Board (CARI), have signif-
icantly Increased the reliability of national and regional
economic assessments. However, the models are still sensitive
to many key Inputs and assumptions which can be readily address-
ed. Model refinements important to pursue Include:
- Adding more crops, especially regional crops,.
- Sensitivity of results to omitted crops assumptions.
- Rerunning dose-response and economic model with improved
rural ozone data.
- Additional model development to deal with government
subsidy issues, international trade, sensitivity analy-
sis on economic inputs and assumptions on demand elasti-
cities, substitution activities* etc.
- Expansion of the issue of what is an "adverse" impact.
t Urban ornamentals. Urban ornamentals are exposed to significant
ozone levels and may be associated with significant welfare
loss. Initial assessments of damage magnitudes are warranted
for grasses, bushes, and trees. If damages are potentially
large, then longer-term research should be planned.
*
Thjrd Priority Research Needs
• Genetic control of pollutant susceptibility. NCLAN and other
research efforts have generally addressed ozone Impacts with the
most intensively-used cultivars of key crops. Breeding for Im-
proved yield and harvesting characteristics continually produces
new cultlvars with unknown pollutant susceptibility. Better un-
derstanding of how susceptibility to injury and yield reduction
by exposure to ozone is inherited would enable the inclusion of
pollutant susceptibility in the list of desirable characteristics
used In breeding new crop cultlvars,
2. Forests
a) Objectives
Currently, there is a substantial research program supported by EPA,
the U.S. Forest Service (USFS), the Electric Power Research Institute
(EPRI), and the National Council on Air and Stream Improvement (NCASI)
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concerning tree response to acid rain ind related pollutants Including
ozone. This program 1s coordinated under the National Add Precipitation
Assessment Program (NAPAP), which is required to provide an overall
assessment by the year 1990.
Current short-term research efforts of NAPAP will provide a basis
for a first-order evaluation of tree response to pollutants. Given the
perennial nature and longevity of trees, their close association with
climatic factors, and the likelihood that emissions of precursors of
ozone and add rain will continue into the next century, we recommend
that EPA focus upon developing a long-term program of research on forest
response to pollutants, including ozone.
The aim of the EPA long-term program should be to extend the initial
efforts of NAPAP and provide a more thorough and extensive evaluation
than can be obtained from a short-term research program. The EPA research
plan should provide for interim changes in emphasis because the assessment
to be completed in 1990 will undoubtedly provide important guidelines
for future research. The plan should provide for a coordinated program
of research on effects of ozone and other long-range transported pollu-
tants on forests to Insure continuity of effort over a period of at least
ten years.
b) Research Needs
The needs specifically Identified in this section are long-term
research directives.
First Priority Research Needs
• Exposure statistics* 61ven the perennial habit of trees and
their close dependence on edaphie and climatic conditions,
quite different exposure statistics may be required to protect
forests against injurious effects of ozone and other pollutants.
This work will take a long time period to resolve because it
must take Into account cumulative effects and the capacity of
trees to recover from stress.
• Ozone dose-response of major tree species and overall forest pro-
ductivity analyses. Dose-response relationships between ozone
and other long-range transported pollutants and trees need to
be developed using field chambers on whole trees and/or on
branches of mature trees. These, too, will have to be long-term
studies because the effects of competition, and different edtphic
and climatic conditions on growth, development, competition,
and reproductive success need to be established. These long-
term studies also need to address the effects of air pollution
impacts on trees upon the entire forest ecosystem in a unified
approach.
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t ienerilizible tree physiological models. Physiological models
have greatest potential for prediction of effects over long
time periods. To be of greatest value, they should be linked
to models of climate change and geochemical cycling of elements.
Model development is a difficult undertaking and requires a
substantial multldlsciplinary effort. Therefore, this research
requires secure funding over a substantial period of time.
Second Priority Research Needs
t Economic model development. This includes considerations of
forest productivity and succession, aesthetics and non-timber
service flows from forest ecosystems. In the long-term, this
analysis requires a comprehensive and integrated forest ecosystem
valuation framework. Work should also extend and integrate
available regional timber models, account for different timber
quality and design sensitivity analyses of the economic models.
This research must be closely linked to the other research
efforts because it Is dependent on them for accurate Inputs.
c) Short-Term Research Initiatives
While the most important focus should be upon long-term initiatives,
several short-term initiatives already underway or planned that CASAC
supports. These include, but are not limited to:
• Characterization of the resource at risk. Mapping of forest
resources against ozone levels and current information/hypo-
theses about tree species sensitivity to assess the resource at
risk are used as a tool that can be updated and Improved as the
science developes. These efforts are underway it 1PA, the
California Air Resources 8oard» the National Park Service and
elsewhere.
• Retrospective study. A resurvey of the San Bernardino National
Forest to validate projected impacts, trace long-term tree
impacts and succession, validate or reject hypotheses and review
other forest ecosystem Impacts would provide substantial insight
in developing long term direction.
• Preliminary economic studies. These studies are underway under
the NAPAP program and will provide useful information upon
which to develop long-term analyses.
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IV. RESEARCH HEEDED FOR FUTURE DECISIONS ON NATIONAL AMBIENT AIR
QUALITY STANDARDS FOR LEAD
A. Introduction
Since 1977 there has occurred a steady downward trend in atmospheric
lead concentrations along with a similar downward trend in the lead
burden of adults and children. Although both of these trends are impres-
sive, concerns about the impact of lead on human health remain a valid
scientific and public policy Issue, This is mainly because of recent
epidemiological evidence that adverse effects occur at levels of exposure
previously thought to be safe. In short, lead exposure 1s declining
while perceptions and evidence of what constitutes a safe level of ex-
posure are also shifting downward. The implications of this development
for future directions of research are substantial. For exposure issues,
the current major contributions to total lead Intake are quite different
than previous data indicated, at least as applies to the general popula-
tion. Since scientists and regulators have indentifled blomedically
adverse effects within the usual range of human exposure, EPA needs
better information on which media and sources to target for further
reduction in human exposure.
Further lead exposure reduction may not prove to be equally fea-
sible or sufficient to prevent harm to certain populations at risk,
notably the fetus. Information, therefore, 1s needed concerning the
circumstances {apart from high lead exposure) which result in adverse
effects 1n certain individuals but not in others, e.g. unusual patterns
of lead absorption and deposition.
The Committee discusses these and other issues 1n approximate order
of their urgency and importance, bearing in mind the regulatory role of
EPA. It strives to make research recommendations to better Inform the
Apncy's decisions on whether to take further regulatory actions to
minimize the risk of adverse health effects due to lead.
Finally, EPA staff requested the Committee to present recommenda-
tions concerning the design of the forthcoming National Health and Nutri-
tion Evaluation Survey (HHANES III). The earlier NHANES II survey,
completed 1n 1980, proved to be a valuable resource for identifying
health effects of lead in the general population that were not widely
understood at that time. In developing its recommendations, CASAC recog-
nizes that any broad-based survey e.g. NHANES, has competing scientific
needs and priorities to reconcile. The Committee has relied heavily upon
the OAQPS staff paper and the EPA Air Quality Criteria Document for Lead
as source documents for this activity.
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B. AtnKtspheH c Proces ses
The phasedown 1n the sale of leaded gasoline has probably been the
major contributor to the accompanying reduction in ambient air levels of
lead. The specific extent to which this is true has some remaining
uncertainties since other regulatory actions hive been in effect during
the same general time period, Basically, this has been a matter of
enforcing regulations which limit the emission of lead from point sources
to achieve and maintain ambient air quality levels at or below 1.5 ug
lead/it^, fhe Committee urges EPA to reassess the relative impact of
various point sources and of leaded gasoline on general ambient air lead
concentrations. As one means of Implementing this recommendation, EPA
should consider the use of existing, or the development of new, tracer
techniques.
IPA's regulation of ambient lead has exclusively focused on inorganic
lead, although it is known that alkyl species of lead exist 1n the environ-
ment. Alky! lead Is released from sources such as the use of tetra-ethyl
lead (TEL) 1n mobile sources. Inorganic lead can be alkylated 1n the
environment. Little is known of the distribution of alky! lead, its
concentrations 1n ambient air, or the processes of bioalkylation. Because
of the substantial toxldty of alkyl lead compounds, additional research
on these topics 1s useful.
Sampling sites should Include areas in the Immediate vicinity of
major stationary sources such as primary and secondary lead smelters,
battery plants, and other sources such as municipal waste incinerators.
Such sites should be distributed around the country to capture different
climatic and geographic conditions.
The above recommendations have high priority, but the impact of lead
emissions on total lead concentrations in various media is an equally
important issue. Current estimates relating air lead concentrations to
surface soil and dust lead levels are derived mostly from older studies
with no site-specific indication of whether the trends are upward or
downward, A series of measurements are needed, over time, in various
locations to assess the impact of changes in lead air quality and particle
size on soil and dust lead pools and other sources (e.g., snow) of depo-
sited lead accessible to children, and the turnover rate of lead in
these media. Sites selected for study should Include areas where the
total lead concentration is both high and low. This 1s necessary in
order to identify the role of atmospheric contributions and compare it
with other pathways.
Because of their relevance to deposition processes, more attention
should be given to the measurement and characterization of lead particle
size distributions. It is also important to determine the chemical
compostion of both the lead-bearing particulates and the chemical form of
the lead in the matrices. Such investigations would provide a basis for
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tracing the source(s) of lead in the air using fingerprinting techniques
and would assist biologists researching the bioavailability of lead as
it relates to chemical composition*
EPA already is confronted with the need to make decisions concerning
the disposal of lead-contaminated soil and refuse. There is a pressing
need for more information about the transfer of lead to the general
environment from dump sites via ground water and air. Such information
would greatly aid in establishing criteria for identifying those dump
sites having minimal Input on human exposure to lead.
First Priority Research Needs
The following recommendations are assigned approximately equal,
first priority. To the extent that is necessary to implement these
recommendations, EPA should consider developing new tracer methodologies.
* Reassessment of the relative impact of point sources and
gasoline on ambient air lead.
• Assessment of the impact of air lead on lead in various media
to which man 1s exposed, with special emphasis on food and
water.
• Assessment of factors which determine the transfer of lead
from dump sites to air and water,
Second Pripnty_Research Need
• Studies concerning the concentration, speciation and sources
of alky! lead in ambient air.
C. Exposure Considerations
It is especially important to quantify the amount of dust and soil
that young children ingest through hand-to-mouth activities in various
settings and to examine 1n detail the factors that Influence lead exposure
through this route (e.g.* household dust lead levels, parental occupa-
tions, housekeeping practices, thumb-sucking, finger licking and nail
biting tendencies, and child-rearing practices.)
Bioavailability of ingested lead (and of inhaled lead) is another
issue urgently 1n need of intensive investigation. Estimates of the
impact of soil lead concentrations on the blood lead of young children
have varied widely from one study to another. Essentially nothing is
known, however, about the reasons for these discrepancies. In the absence
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of more specific Information it is difficult, if not impossible, to make
rational site-specific decisions as to maximum safe limits of lead 1n
soil or dust. The influence of chemical and physical characteristics of
lead 1n soil and dust on bioavallability, therefore, needs to be thoroughly
investigated.
Given the growing data base identifying lead-contaminated soil, and
both interior and outdoor dust, as major remaining exposure sources for
children (especially in older urban areas), it is increasingly important
to determine the most effective soil-lead abatement protocols. These
abatement protocols should Include evaluation of removal of leid-bised
paint and lead-contaminated street and house dusts, as well as lead-
contaminated soil.
Although a great deal of Information Is available concerning human
exposure to lead from multiple sources, much of it may no longer be
valid, particularly if gathered a decade ago or more. Changing technology
(e.g. food packaging), eating habits, and reduction of lead emissions
may have substantially altered the relative Importance of the various
sources, as well as the level of total intake. A reassessment of exposure
needs to be undertaken in order to properly Identify the most promising
strategies aimed at further reduction In human exposure.
Because harmful effects from lead exposure have been observed at
relatively low levels, particularly to the fetus, the relative contribu-
tions of various sources, under normal conditions of intake must not be
overlooked, EPA should work with the Food and Drug Administration to
evaluate the means by which lead significantly enters the classes of
foods which contribute most to total dietary intake, beginning with the
raw products and ending with the fully processed and packaged products.
Studies are also needed to determine how much lead derived from tap
water is consumed by various segments of the population (e.g. children
and pregnant women). This effort should take into account the use of
water for food and beverage preparation, in addition to water which has
remained overnight 1n plumbing. Such water contains considerably more
lead than water drawn after the plumbing has been flushed.
In connection with the forthcoming NHANES III study the CASAC urges
EPA to consider questionnaire items to aid in establishing whether
the subject's blood lead concentration is representative of a fairly
constant long-tern exposure history or whether some recent significant
change in exposure is to be considered in interpretation of the data, e.g.
recent interior renovation of an old residence which had been grossly
contaminated with lead-base paint* Second, NHANES planners should consid-
er the importance of using the best possible methodology for blood lead
determinations, given the low concentrations and relatively narrow range
which will likely be encountered.
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First Priori tyjtesearch Needs
All of these are assigned first priority, although EPA's responsi-
bility is uncertain In some cases.
* Determination of the importance of soil and dust ingestion
as sources of lead exposure in young children, taking Into
account social and other factors that Influence such inges-
tion.
• Bloavaliability of lead, particularly in soils and dusts
as a function of particle sizes and chemical form.
• Reassessment of the contribution of foods to total lead
intake, including the contributions attributable to food
processing and packaging.
t More detailed determination of the contribution of drinking
water to total lead intake, including water used in food and
beverage preparation.
D) Lead Metabolism
Past studies of the relationships between dose and effects of lead
in roan have relied almost exclusively on whole blood lead as the index of
dose. Scientists now recognize that this index has shortcomings. It
reflects only recent exposure, and it does not bear a linear relationship
to concentrations in tissues or at receptors, e»g. ALAD. Thus, develop-
ment of better biomarkers of human lead exposure and techniques for
measuring lead concentrations In biological media are needed. X-ray
fluorescence instrumentation for jjn vjvo measurement of lead in mineral-
ized tissue appears promising and ought to be further explored. This
should include investigations of novel biomarkers of dose. As an example,
kidney and brain tissue contain a unique lead-binding protein which may
be of diagnostic interest to assess toxic manifestations of lead exposure.
Development of a radiolmmunoassay for detection of this protein in bio-
logical fluid specimens such as urine is underway. This 1s particularly
important since current blomarkers are either inadequately sensitive
(e.g. erythrocytlc protoporphyrin) or are not readily amenable to field
investigations (e.g. ALAD).
There is also a need to develop better methods for monitoring
fetal lead exposure across the full period of gestation. This Is a
challenging problem requiring some innovative Ideas and the use of more
appropriate animal models of human pregnancy than rodent species e.g.
perhaps sheep and subhuman primates.
Better understanding also is needed of the impact of bone resorption
in old age on the concentration of lead in blood and, more importantly,
at lead-sensitive sites. Thus, blakinetic modeling of lead metabolism
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must Include detailed attention to the significance of bone stores of
lead, particularly In situations where calcium mobilization occurs, i.e.
pregnancy, lactation and old age.
The question of how various dietary constituents affect lead absorp-
tion and tissue distribution In man Is very poorly understood, not only
in the general population, but in special risk-associated groups (e.g.,
children; pregnant, lactating» or postmenopausal women). Specif1cally»
the effects of varying levels of calcium, iron and, perhaps, of high
sulfur in the diet may be of particular relevance.
First Priority Research Needs
t Development of better indices of lead exposure, notably
lead in hard tissues and circulating lead-binding proteins.
• Biokinetic modeling with special emphasis on the fetus
and placenta, as well as bone in both pregnant women and in
the elderly,
• Dietary factors influencing lead absorption.
E. Biological and Health Effects
1, Developmental Effects
Recent epidemiological evidence reinforces and extends the conclusion
that the early stage of human development is an especially critical period
for deleterious effects of low-level lead exposure* Findings from
prospective studies in Boston, Cincinnati, Port Pirie (Australia), and
Cleveland indicate that disturbances in fetal development, as well as
postnatal neurobehavioral development, may occur at lead exposure levels
well below those previously considered "safe" or even "normal11. The most
clearly identified effect thus far has been lower scores on the Hental
Development Index of the Bayley Scales of Infant Development, a well-
standardized test of infant intelligence. Other developmental endpoints
such as shorter gestational age and lower birth weight have also been asso-
ciated with prenatal lead exposure in many of these studies.
Results of these studies to date suggest that adverse effects
resulting from prenatal exposure may be largely irreversible, at least
within the first Z years of life. Ongoing prospective studies, therefore,
should be continued without interruption, at least to the age at which
school performance can be properly evaluated, and even on to puberty.
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Additional prospective studies of the effects of lead on pregnancy
outcomes also are needed, focusing on such unresolved issues as whether
fetal exposures at maternal blood lead concentrations higher than in
current studies result in correspondingly greater adverse cognitive
outcomes, or whether different (or additional) adverse effects emerge.
Although of -considerable interest, such studies would be of lesser
importance than additional studies at current general lead exposure
levels, examining the impact of lead exposure when combined with other
factors known to carry a risk for adverse., f etaj -/ojitcomes »
Because so little is known regarding the Mechanism whereby lead acts
to compromise fetal development, the Committee_is uncertain a$ to what
specific measurements should be recommended for inclusion InlfHANES III
that would add to current knowledge regarding the effects of lead on
pregnancy outcome* It urges that those designing the study consult with
qualified reproductive endocrinologists and reproductive lexicologists
to develop recommendations concerning possible neuroendocrine measurements
that would be useful in assessing adverse influences on fetal development.
Also, developmental psychologists currently studying the effects of lead
on postnatal neurobehavioral development should be asked to review any
currently proposed battery of psychological and neurophysiologlcal tests
for the purpose of recommending additions or raodifi cations that would
enhance their utility in furthering knowledge regarding adverse effects
of lead exposure.
Numerous animal studies currently in progress are aimed at gaining
a better understanding of meehanismsrfcf * wh4cft " T.ea'*'"*'"« M *jto'.'"a * "™ ""
There are large information gaps regarding the dose- response rela-
tionships of chronic alky! lead exposure in the general population
(particularly pregnant women and infants), US|R§_ measures- ..af ^.subtle
neurobehavioral or other effects. Although it slews unlikely thai alkyl
lead is harmful at the concentrations likely to occur in general ambient
air, this judgment is based on occupational exposure rather than on
exposure of fetuses and infants or animal models thereof . Appropriate
animal studies should be undertaken to establish the relative potency
of chronic alkyl lead vis a vis Inorganic lead using sensitive indices of
effects.
2. Cardiovascular Effects
As discussed in the recent addendum to the EPA Air Quality Criteria
Document for Lead (1986), a growing body of literature suggests that low
level lead exposure has both direct and indirect effects on end-arteriolar
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smooth muscle contract!!1ty and cardiac function, and thus essential
hypertension may be causally related to chronic low-level lead exposure*
though this is far from certain given the small effect reported (approxi-
mately 2-7 iron Hg per 15 ug Pb/dl in blood). Nonetheless, a better under-
standing of the health implications of lead effects on the cardiovascular
system is needed since a large number of people are potentially at risk.
Prospective human studies would be desirable in principle, but the power
of such studies would need to be carefully evaluated. Although a study
of the morbidity and mortality Implications of the hypertensive effects
of lead also would be desirable, the feasibility of obtaining useful
studies is questionable.
Studies in experimental animals and studies conducted 1n occupa-
tional exposed workers strongly suggest that the blood pressure effect
occurs only within a rather narrow range and that, in fact, lead may
have a hypotensive effect at exposure levels somewhat above the range in
the general population. It 1s» therefore, important that future epiderolo-
logical studies should be designed to include a wide range of lead
exposures. Future animal studies should be directed toward gaining a
better understanding of the mechanism(s) underlying the hypertensive
effect of lead, particularly in regard to the effects of lead on the
second messenger functions of calcium.
The Committee is pleased to note that the forthcoming NHANES III
study will include a determination of cadmium concentrations along with
lead since the vasopressor effects of lead ind cadmium may be additive.
It is the Committee's impression, however, that blood cadmium has never
been shown to correlate well with toxic effects. Perhaps cadmium metallo-
thionein (CdMt) in seruro would be better than elemental Cd concentrations
as a biomarker. It is our understanding that a sensitive radioimmunoassay
for CdMt has been developed; Cadmium experts should be consulted.
3. Other Effects
The two most currently significant health effect issues are those
relating to growth and development in children, and to hypertension in
adults. These appear to be critical effects, using the term "critical"
to denote "most lead-sensitive". If this belief is correct, further
reductions in lead exposure should serve to decrease the risk of other
adverse effects to which man way be less or equally sensitive. Here
information is needed regarding the significance of other effects* parti-
cularly in subpopulations other than those already identified as being
most sensitive to neurobehavloral and cardiovascular effects. As an
example, old people are a separate subgroup peculiarly sensitive to
factors which contribute to the development of osteoporosis. The impact
of lead on the incidence and severity of osteoporosis needs more attention.
Again, some valuable information in this regard may emerge from the
NHANES III study, particularly if cadmium exposure can also be effective-
ly assessed. Cadmium has been shown to induce bone resorption and
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osteoporosis In postmenopausal women, particularly in conjunction with
Vitamin D deficiency. A major contributing factor may be the fact that
cadmium accumulates in the body with age to an even greater degree than
lead. Further, there is evidence that lead also has toxic effects on
bone development. Admittedly, the evidence is very limited and has
focussed mainly on young children and young experimental animals. Pos-
sible additive effects involving lead and cadmium should be investigated*
This should include studies of the toxicokinetics of skeletal lead,
including the influence of age (See discussion under Lead Metabolism).
In this context, NHANES III should consider including a sufficient number
of old people to establish whether a significant lead problem exists. A
meaningful measure of vitamin D status Is also important, serum 1,25
dihydroxycholecalciferol in particular.
Numerous studies have reported effects of lead on the immune system,
and a small number of studies report an association between lead and can-
cer. No convincing evidence has surfaced, however, suggesting that lead
is a human carcinogen or that it has any role 1n the etiology of other
diseases involving the Immune system. EPA should consider convening a
small group of immunotoxicologists and experts in oncogenic toxicology
to jointly examine whether current information identifies any particular
sub-population in which a special risk may exist Involving the effects
of lead on the immunologlcal system and the sometimes-related cancer
endpoint.
Although the scientific literature identifies other potential toxic
effects of lead, there is no current basis for believing that current
standards do not adequately protect against known or potential effects.
First Priority Research Need
The Committee recommends the following issue as a first priority
research need:
• Continued, uninterrupted support for current prospective
studies of neurobehavioral effects of lead in children to
school age and beyond.
Second Priority Research Needs
Other recommendations are made as only somewhat lesser second
priority research needs:
• Additional prospective studies examining fetal and early
postnatal development examining a wider range of fetal lead
exposures, and with additional risk factors, e.g. diabetes
and toxic substances other than lead.
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• Continued support for investigations concerning the mechan-
isms whereby lead adversely affects neurobehavior with
greater emphasis on neuroendocrinological Influences on
brain development,
t Initiation of prospective studies of the relationship of the
lead exposure to blood pressure, as well as consideration of
the consequences with respect to the incidence of hyperten-
sion. Although this is an important objective, the sub-
committee recognizes that it may not be feasible.
• Initiation of studies regarding the role of lead exposure
In osteoporosis. This should include epidemiologies!
approaches and investigation of meehansims using animal
models.
• Studies of toxic effects of alkyl lead compounds most
prevalent 1n the environment,, with emphasis on subtle
chronic effects in developing animal systems and potency
relatle to inorganic lead.
Finally, the Committee recommends (with moderate enthusiasm) that
the EPA convene a meeting of immunotoxicologists and oncogenic toxicolo-
gists to assess further research needs relating to the possible role of
lead in cancer and other diseases involving the immune system.
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