645R72002
Health Intelligence
for
Fuel and Fuel Additive Registrations
An EPA Task Force Report
Division of Health Effects Research
National Environmental Research Center
Research Triangle Park, N.C. 27711
March 15, 1972
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I. INTRODUCTION
This task force report resulted from meetings initiated by the
Division of Health Effects Research and held at Research Triangle Park
on February 29, March 1 & 2, 1972. The purpose of the task force was
to develop a systematic plan to provide health intelligence required
under Section 211 ("Regulation of Fuels") of the Clean Air Act of 1970,
as amended. Section 211 gives EPA authority to require the conduct of
tests "to determine potential public health effects" of fuels or fuel
additives designated for registration and to control or prohibit use
of fuels or additives when emission products "will endanger the public
health or welfare". Through this report, the task force has suggested
a program to carry out the above responsibilities.
The members of the task force were as follows:
Office of Fuel and Fuel
Additive Registrations
Division of Chemistry and
Physics
Division of Health Effects
Research
Henry Miller
John Moran
John Finklea (Chairman)
Ferris Benson
Kenneth Bridbord
Kirby Campbell
David Coffin
Anthony Colucci
Marvin Hertz
Wellington Moore
Carl Shy
Wayne Sovocool
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II. RECOMMENDATIONS
1. The Task Force concerned with providing health intelligence for the
Office of Fuels and Fuel Additive Registrations (OFFAR) recommends that
a multidisciplinary committee be formed, composed of personnel from the
Office of Fuel and Fuel Registration, a combustion chemist, an analytical
chemist, a biochemist, a toxicologist, an ecologist, a physician and
others as deemed appropriate. The committee will be concerned with the
systematic assessment of possible hazards to public health and welfare
from fuels and fuel additives submitted for registration.
2. Industry should be responsible for conducting all tests required tp_
characterize exhaust emissions resulting from use of registered fuels or
additives.
3. Standard protocols to assess biological effects of exhaust emissions
resulting from use of registered fuels and fuel additives should be
developed and tested during FY 73.
4. An additive causing significant changes in vehicular emission patterns
or having toxic potential in its emission products should be subjected to
an initial toxicologic (including phytotoxic) screen. Development of the
toxicologic screen should receive high priority early in FY 73.
5. A full toxicological evaluation should be selectively required for
those additives whose initial screening suggests further investigation.
6. Results of toxicological screening and more definitive animal toxico-
logical studies should be selectively evaluated through clinical and epide-
mic! ogical human studies.
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7. New legislative authority should be sought authorizing OFFAR to
obtain quantitative fuel and fuel additive production information and
usage data from manufacturers.
8. Disclosure of information acquired by industry from toxicologic
testing or occupational exposures during the course of manufacture and
distribution of fuels and fuel additives should be required. This dis-
closure could be required through a change in existing regulations
authorized under Section 211 of the Clean Air Act.
9. A tax of 1/100 cents per gallon on retail sales of fuels is recom-
mended to cover the cost of all toxicological testing. This tax would
generate $13,000,000 per year and would provide support to the entire
fuel and fuel additive registrations program. All toxicological testing
should be carried out under EPA, rather than industry, supervision.
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III. NATIONAL SIGNIFICANCE
The 107 million motor vehicles presently registered in the United States
will consume about 130 billion gallons of fuel per year. Gross retail sales
of this volume of motor vehicle fuel amounts to $48 billion annually. Currently,
300 gasoline fuel additives have been registered with the Office of Fuel and
Fuel Additive Registration. In 1969, 870 million pounds of additives were con-
sumed at a gross value of $280 million. Under proposed new regulations requiring
registration of gasoline, diesel fuel, fuel and heating oils, aviation fuels,
crank case lubricants, liquified petroleum gas and additives, a total of 1000
to 1500 additives are likely to be registered. Seventy-seven million tons of
motor vehicle pollutants are emitted annually in the United States. This pol-
lutant mix can be generally characterized as follows:
Emission Rate
Chemical Class (tons/year)
Combustible particulates* 380,000
Carbon monoxide 55,000,000
Hydrocarbons 13,600,000
Polynuclear aromatics 480
Nitrogen oxides 7,600,000
Lead 230,000
Sulfur oxides 280,000
Total 77,090,480
*Includes trace elements
The Environmental Protection Agency has received a mandate from Congress,
expressed in Section 211 of the Clean Air Act of 1970 as amended, to control or
prohibit the manufacture or sale of any fuel or fuel additive when emission pro-
ducts will endanger the public health or welfare or will impair the performance
of any emission control device (Section 211, c.l.). Under this Section of the
Act, EPA may by regulation require registration of any fuel or fuel additive
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prior to sale or introduction into commerce. Registration requires information
on the chemical composition and range of concentration of any additive in fuel.
EPA may also require from manufacturers information "as is reasonable and
necessary to determine the emissions resulting from use of fuels and additives"
and "the extent to which such emissions affect the public health or welfare"
(Section 211, b.2.B.).
The authority and mandate delegated under Section 211 require EPA to evalu-
ate the potential public health effects of registered fuels and fuel additives.
The following problems were identified and considered by the Task Force in
planning to meet this challenge:
1. At present, no EPA person or committee systematically scrutinizes
each registered fuel additive for potential public health effects.
2. EPA lacks a systematic program to evaluate the toxicologic
potential of registered fuels and additives.
3. Prime concern -should not be focused on toxicity of parent com-
pounds registered by the Office of Fuel and Fuel Additive Regis-
tration. The chemical composition of these compounds will undergo
drastic changes in the course of combustion and passage through
advanced emission control systems. The public will be primarily
exposed to these combustion products rather than to parent compounds.
At present, the manufacturer supplies no information on exhaust
products.
4. However, occupational exposures to parent compounds do occur
as a result of evaporative losses during manufacture and handling
of fuels and additives. In many cases, manufacturers have large,
excellent occupational health and safety programs, through which
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human exposure data are acquired. This information is often pro-
prietary and is not made available to the Government. Protection
of the health of fuel and additive handlers, including service station
operators and to a lesser extent the general public, could be con-
siderably furthered by requiring transmission of existing occupational
health data to the Government. This effort could be coordinated
through the National Institute of Occupational Safety and Health, DHEW.
5. The following compounds have been identified in motor vehicle
exhausts:
TABLE. Compounds Identified in Motor Vehicle Exhausts
I. Particulate Emissions
A. Lead and Organics B. Other Trace Elements Emitted
in Exhaust Particulates*~
Pb (Cl, Br)2 ~
Pb (NH3)2 & Pb NH3 Cl Fe Mg
PbO-Pb (Cl, Br)2 Ni Mn
PbO-Pb $04 Cu Cr
Pb Cl2 Al Sn
Pb Br2 Ca Zn
Organics (PNA's, etc.) Si Ti
HC1 Sb Mo
Fe2 03
Fe3 04
NH4 Cl
II. Gaseous Emissions (based on 23 minute test cycle)
PNA (polynuclear aromatics)
NO
N02
CO
CO 2
200 Hydrocarbons
Aldehydes and Oxygenates
*List is not exhaustive; other trace elements are being identified.
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Emission controls on 1975 and 1976 vehicles should reduce hydro-
carbon and polynuclear aromatic emissions by a factor of 100 from
1966 levels. These hydrocarbons are likely to be broken down almost
completely to C02 and h^O. Advanced catalytic control systems employing
reducing catalytic reactors are likely to achieve substantial re-
duction of nitrogenous compounds but may result in emissions of
ammonia and organic nitrogen compounds. In addition, trace metals
in fuels and additives and in deterioration products of catalytic
controls will be emitted. The Task Force agreed that the following
pollutants, likely to occur in emission of fuels combusted through
catalytic reactors, have significant toxic potential:
a. Trace metals
b. Ammonia and other nitrogenous compounds
c. Organic particulates and gases
(at 1/100 of 1966 levels)
Of most immediate concern are trace metals in blended or raw motor
vehicle fuels, and known to be present in exhaust particulates. The
Task Force agreed that these trace metals could be ranked from highest
to lowest in terms of potential public health hazard and exposure
levels as follows:
Relative Concentration
Element (% of particulate fraction)
1. Manganese 0.10
2. Nickel 0.02
3. Cobalt 0.02
4. Chromium 0.05
5. Tin 0.02
6. Antimony trace
7. Molybdenum 0.01
8. Titanium 0.02
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These elements possess the potential for accumulating in human
tissues and producing definite systemic toxicity at elevated
tissue levels. Other trace elements of low toxic potential in
fuels and exhaust particulates include iron, calcium, zinc,
silicon, copper and aluminum. Cadmium is reported at trace
amounts in some fuels, but this finding is disputed. Barium,
lithium and boron are fuel additives which are not known to be
in raw fuels. Of these three elements, barium has the highest
toxic potential. In general, systematic studies of these trace
elements have not been conducted, and EPA is not in a position
to take regulatory action based on health intelligence.
6. The Task Force recognized the need to acquire emission pro-
files, chemically characterized, of particulates and gases re-
sulting from combustion of fuels and their passage through
advanced emission control systems. Profiles must be acquired
for reference gasolines to serve as a comparison for changes
caused by use of registered fuel additives. The Task Force
further recognized that these emission profiles would demon-
strate a complex array of chemical constituents. The array
could change markedly with irradiation or with blending of
each new fuel additive. Evaluation of the toxicity of indi-
vidual constituents would be a costly and tedious task, whereas
the toxicity of the complex whole is the single important con-
sideration. Therefore, as a first step, a system is needed to
evaluate comparative toxicologies of reference fuels against
fuels with specific additives at concentrations approximating
anticipated ambient exposures.
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7. An inexpensive rapid toxicologic screening system is needed
to obtain information on potential toxicity of exhaust particulate
profiles for which little or no biological effects data exists.
This screening system must employ standardized protocols using
proven toxicologic methods. Methods to provide exhaust particu-
lates for these tests are also required.
8. Depending on the results of toxicologic screening, more
definite toxicological studies of exhaust particulates resulting
from use of fuel additives should be selectively applied. Protocols
for these evaluations are required and must be standardized as soon
as possible in fiscal year 1973.
9. Trace elements of significant toxic potential in fuels and
additives should be evaluated in elemental or simple form by
inhalation exposures of whole animals. These substances will pass
through advanced emission control systems; hence, their presence
in fuel additives requires assessment both in isolated form and
within the particulate exhaust complex.
10. The Task Force recognized that fuel additive composition may
affect emission rates of carbon monoxide, nitrogen oxides and
precursors of photochemical oxidants. The health effects of these
compounds are presently under intensive study within the Division
of Health Effects Research.
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iv. MEETING: THE CHALLENGE
Registration and testing procedures must minimize the risk of adverse
human health effects that can reasonably be attributed to differences in fuels
or fuel additives. Such effects may be linked to individual additive components,
complete additives, blended fuels or gaseous and particulate emissions .from
mobile and stationary sources. Effects of concern include, but are not limited
to an increased risk of cancer and mutations, impaired reproductive performance,
increased susceptibility to respiratory infection, increased human pollutant
burdens and subtle changes in cellular morphology and enzymatic function. A
schematic overview of the public health impact of fuels and fuel additives may
be visualized in Figure 1. The effect of individual additive components may
be evaluated by reviewing industrial toxicologic screening data compiled during
research and development for new products. Routine occupational health studies
and specialized surveillance of industrial exposures can be utilized to evaluate
the hazards associated with the direct exposure to complete additives and to
blended fuels. Such exposures occur during additive and fuel manufacturing,
during distribution and, to a lesser extent, during consumption. However, the
primary concern of the Task Force was the impact of differences in fuel and fuel
additives upon gaseous and particulate emissions which can affect the general
population, segments of which may be especially susceptible. As previously
discussed, necessary research on the direct effects of carbon monoxide, oxides
of nitrogen and particulates per se have been considered by the Health Planning
Task Force and in other program elements. On the other hand, our Agency has
devoted limited resources to research on the health effects of gaseous and parti-
culate organic compounds, trace elements, ammonia, and other nitrogenous compounds,
These are the pollutants that may be qualitatively and quantitatively altered by
differences in fuels or fuel additives.
10
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Figure 1
Overview of Public Health Impact of Fuels and Fuel Additives
Factor Considered
Production and Consumption Stages
Fuel or Fuel Additive
Component
Emissions of
Concern
Research
and
Development
Additive
Components
»
Manufacturing
Additive or
Blended Fuel
1
Distribution
and
Vending
: ^
Evaporative Losses
of Blended Fuel
Consumption
Gaseous and
Parti cul ate
Emissions
from Mobile
and Stationary
Sources
Human Exposures
Workers
Workers
Workers
General
Population
Health Intelligence
Research Approaches
Industrial
Toxicology
Occupational
Health
Occupational
Health
Occupational
Health
Special
Toxicology
Toxicology
Epidemiology
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A systematic effort is required to evaluate the public health risks
which may result from emission changes and to assure human safety through the
registration mechanism. Such a system is schematically presented in Figure 2.
Registration applications containing relevant industrial toxicology and occu-
pational health summaries would be received by the Office of Fuels and Fuel
Additive Registration (OFFAR). These would then be screened by a Review Com-
mittee composed of a representative from OFFAR, an ecologist, a toxicologist,
a biochemist, a representative of the Office of Research and Monitoring, a
representative of the Office of Air Programs, and others as deemed appropriate.
The OFFAR Review Committee would consider each fuel and fuel additive registration
and registration application. Some fuel additives or specific,fuels would be
selected for testing on the basis of widespread usage, predicted survival of a
potentially toxic substance, predicted effects upon gaseous and particulate
emissions, impact on pollution control devices, alteration of atmospheric
reactivity and visibility, and postulated public health and welfare hazards
including damage to plants and wildlife.
In general, the Committee would first require characterization of emissions
according to standard protocols now being developed by the Division of Chemistry
and Physics of the Research Triangle Park National Environmental Research Center.
The results of this testing would be evaluated by the Review Committee and toxi-
cologic screening would be requested when indicated by significant qualitative or
quantitative changes in emissions of gaseous hydrocarbons, trace elements, organic
particulates, ammonia or other nitrogenous compounds. Should toxicologic screening
tests be positive, more definitive investigations could be instituted including
further toxicologic testing, special studies of occupational groups, appropriate
exposure of human volunteers and epidemiologic studies of populations representing
an exposure gradient for the pollutants in question. The results of these tests
12
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Figure 2
Assessment of Public Health Impact
of Fuels and Fuel Additives
Registration /
Application /
Environmental
Information
System
Registration
Register
without
Testing
OFFAR
Review
-~s\ Commi ttee
/ i .—
Review
Report
Use
Restricted
or
Emissions
Characterization
T
Register
with
Testing
, Prohibited.-
Toxicology
Screening
Definitive
Toxicology
Clinical
Studies
I , :Epidemiclogic
I Studies
J F
*0fftce of Fuel and Fuel Additive Registrations
**Phytotoxtc screening could most easily be performed concurrent with
emissions characterization
13
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would be reported to the Review Committee which would make recommendations on
the use of a particular fuel additive or fuel. On occasion the Review Committee
might simultaneously initiate tests involving emissions characterization, toxi-
cologic screening and even more definitive toxicologic and human studies. The
Review Committee would utilize inputs from an environmental information system
and submit reports to such a system.
A more detailed overview of the proposed toxicologic screening system, shown
in Figure 3, reveals four levels of complexity. A rough index of toxicity will
first be established by comparing the response of tissue culture cell lines ex-
posed to suspended particulate matter collected from reference fuels and similar
fractions collected during emissions characterization testing. Both morphologic
and biochemical endpoints would be utilized. When such screens indicate signi-
ficant increase in toxicity, or when the Review Committee deems appropriate,
more specific screening at two levels of complexity may be initiated with endpoints
involving susceptibility to infection, carcinogenesis, mutagenesis, and reproductive
\
efficiency. In vitro enzymology profiles would then be obtained on those materials
which had caused significant adverse effects. Enzymology profiles will help
elucidate mechanisms of action and will provide crosswalks to relate more definitive
toxicologic testing and human studies to the toxicologic screening tests.
Toxicologic testing of appropriate compounds of trace elements would involve
the steps shown in Figure 4. Trace element aerosols of interest would be generated
by the same propane-combustion system that is currently utilized in human exposure
studies of lead. One or more species of animals would be exposed. Routine tests
would involve metabolism and tissue burdens, biochemical and pathological changes,
and assessment of physiologic function. Special toxicologic testing would also
be instituted where appropriate. Definitive toxicologic testing of the carcinogenic,
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Figure 3.
Toxicologic Screening of Fuels and Fuel Additives
Emissions
/ Characterization /
Request from •
OFFAR Review f
Commi ttee /
7
/ Environmental
Information
Toxicology
Screening
Report
Toxicologic
Screening
Toxicity to
Pulmonary
Alveolar
Macrophages
Carcinogenesis
in Newborn
Mice
Mutagenesis i
Screen
Positive
Screen
Positiv
Intratracheal
Test in
Dominant
Lethal Test
in Mice
Animal
Infectivity
Studies
Negative
\Screen
Negative
Screen
Negative
Screen,
Screen
os i ti ve
Screen
crsitive
\Positive
In Vitro Enzymology Screen
Toxicology Screening
Report
15
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FIGURE 4. Definitive Toxlcologic Testing of Trace Elements Found
in Fuels and Fuel Additives
OFFAR
Review Committee
I Definitive
>\ Toxicology
i Testing
; Toxicology
----j Screening
j Report
Chemical and Physical
Characterization
of Emissions
: Generation and j
.' Animal Exposures j
of Trace Element |
Aerosols !
Metabolism
and
I Tissue Burdens
] Studies
i
j
! Uptake
Distribution
i Excretion
iBiotransformation
Routine
Biochemical
and
Pathological
Tests
Assessment
Physiological
Function
Cardiac,
Respiratory,
Renal,
Neurologic
Reproductive
Hematopoietic
Special
Tests
Dependent on
Compounds under
Study
Toxicology
Test
Report
16
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mutagenic and teratogenic hazards associated with specific organic fractions or
compounds could be requested from the National Center for Toxicologic Research
or performed by other EPA toxicology groups utilizing protocols recommended by
the National Academy of Sciences.
Epidemiologic studies, investigations involving accidental or occupational
exposures and controlled exposures of human volunteers would be most appropriate
when evaluating the potential hazards attributable to toxic trace metals and
hazards associated with evaporative losses or occupational exposures.
Task statements found in the Appendix detail the necessary steps and
resources for the described OFFAR activities to meet the scientific challenge
of fuel and fuel additives.
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V. BUDGET IMPACT
At present only $225,000 is budgeted from the Fuel and Fuel Additive
Registration program element for health effects research. Two other component
tasks of the proposed system, Effect on Emission Products (Task 2) and Determi-
nation of Fuel and Fuel Additive Usage Patterns, (Task 3), are scheduled to re-
ceive $885,000 from the same program element. Another system component,
Toxicologic Testing of Trace Elements (Task 7} will receive limited support
from the Biomedical Research program element.
The present budget will allow design and testing of one fuel additive in
part of the proposed toxicologic screen. The present budget will not support
establishment of a biochemical effects screen or any human studies. A minimally
adequate budget for health effects studies of fuels and fuel additives would
total $1,115,000 and an optimal budget would amount to $2,925,000. At the
minimally adequate level, the toxicologic and biochemical screening systems
would be established in FY 73 and 10 fuel additives would be screened. At the
optimal level, 20 fuel additives would be screened and needed human studies of
trace elements completed.
The man-years of effort and dollar resources required to support the
health intelligence program at three levels of funding are given in the
following Table. Specific objectives, milestone dates and number of additives
tested are listed in the tast statements of the Appendix.
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Table
Task Description
1. Review Committee
2. Effect on Emissions
3. Usage Patterns
4. Collect Exhaust Participates
5. Toxicologic Screening System
6. Biochemical Screening System
7. Trace Element Toxicology
8. Controlled Human Exposures
9. Epidemiclogic Studies
Total
(Intramural)
(Extramural)
Dollars ($1000)/Man-Years of Effort (MY)
Present Minimally Adequate Optimal
25/1 60/3 240/7
—Non-health, considered elsewhere—
—Non-health, considered elsewhere—
None 45/2.0 45/2
200/4.1 610/6.5 1260/11
None 250/5 750/10
—Biomedical Research Program Element—
None 100/1.7 430/6.7
None 50/0.2 . 200/0.4
225/5.1
(135/5.1)
(110/0)
1115/18.4
(394/18.4)
(721/0)
2925/37.1
(863/37.1)
(2062/0)
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VI. POTENTIAL PROBLEMS
The proposed system for evaluating the health risks of specific fuels
and fuel additives represents the most practical, presently feasible approach,
but it is still beset by a number of perplexing problems. These belong to three
broad groupings: scope of the system, relevancy of the biological test pro-
cedures and economics of testing.
The scope of the proposed system will not initially include lubricating
oils, aviation fuels, diesel oil, kerosene and fuel oils or their additives
even though these products are also subject to the registration procedure.
Separate but analogous emissions characterization systems must be established
to evaluate these products. The biological testing systems proposed by the
Task Force would, however, be applicable to such products. An unanswered, but
important problem, is the relative health risk resulting from trace element and
organic particulate emissions from fuels and fuel additives when compared to
coal-fueled stationary sources not subject to registration. Will expensive
motor vehicle fuel controls be acceptable if quantitatively more important sta-
tionary sources are not controlled? Another problem with the proposed system
is the use of test methods, based upon a single additive and a standard reference
fuel. In practice, more than one additive might be present in any single
marketed fuel blend and any single additive could be utilized with a number of
different fuels. The picture is even further complicated by seasonal shifts in
fuel composition, by seasonal shifts in additive use and by frequent variations
in the crude oil precursors of a single market fuel. A third problem with the
proposed emissions test system relates to the use of standard, carefully maintained
combustion and exhaust control systems coupled to artifical irradiation chambers.
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Significant variations from this system would certainly be found if studies
focused upon operating vehicles. The Task Force recognized the need to
quantitate these sources of variation, but held firm in its conviction that
the proposed emissions and biological test systems should be developed as
soon as possible and modified as needed later.
Many questions can be raised about the relevancy of the proposed biological
test systems. First, there are questions regarding pollutant exposure. Should
test systems not be exposed simultaneously to gaseous and particulate emissions?
The Task Force felt that such interaction studies might be desirable, but were
not feasible for toxicologic screening. We could not justify at this time the
substantial additional investment in facilities and personnel or the increase
in logistical complexity that would result. Should test systems not utilize
single compound exposures instead of the complex particulate mixture or trace
element exposures now planned? Again the Task Force felt that the very large
number of organic compounds precluded the single compound approach in the
screening process. Should potential exposures from partially combusted fuel
additives and evaporative losses receive greater emphasis? The Task Force
thought not in view of rapid changes in evaporative and exhaust controls and
the elapsed time which will occur before testing systems can become functional.
The relevance of the toxicologic screening tests can also be questioned.
Effects on cell cultures, increased susceptibility to respiratory infection,
mutagenesis, carcinogenesis, impaired enzymatic function and trace element
toxicity are the most significant, but not the only adverse health effects of
fuels and fuel additives. Other health indicators could be added if experience
indicates additional significant health risks or if additional resources become
available. Tfie proposed screening tests provide feasible indices of suspicion,
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but are neither perfectly sensitive nor perfectly specific. As new knowledge
develops, other screening procedures can be substituted. The lack of perfect
screening test is not a legitimate excuse to delay biologic testing.
The proposed testing system is not inexpensive. Industry should pay for
emissions characterization and the collection of exhaust particulates before
and after irradiation for use in biological testing. If possible, it would
be best for the Federal Government to sponsor the necessary biological testing
utilizing an extremely small portion of the Federal tax on fuels. This dual
strategy would result in the least economic dislocation to industry, which
already utilizes test procedures closely akin to those now visualized for
emissions characterization. Industry has little or no experience with the
proposed toxicologic screening system and this system will likely further
evolve during the next few years. Industry might, however, be required to
support and perform additional standard toxicologic testing of additive com-
ponents and surveillance of occupational groups exposed during manufacturing
and distribution.
The Federal Government should support the infrequent, but necessary, tests
involving human volunteers and any epidemiologic investigations. The proposed
tax of .01<£ per gallon of gas would amply support the establishment and improve-
ment of the biologic testing system. When compared to the economic importance
of fuels and fuel additives, the proposed testing costs are more than reasonable.
Remember, the health insurance purchased by the recommended program benefits the
entire population of our nation.
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APPENDIX
Task Statements Relating to
Health Intelligence for Fuel and
Fuel Additive Registration
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Task 1. Establish Fuel and Fuel Additive Review and Recommendation
Committee.
A. Task Objective Statements:
1. To identify fuels and fuel additives which require further
health and impact evaluation before registration is permitted.
2. To identify relevant health and environmental impact testing
systems for fuels and fuel additives.
3. To constantly re-evaluate currently registered additives.
B. Approach:
Representatives from the following EPA groups should participate
in this committee:
Office of Fuel and Additive Registration
Division of Health Effects Research
Division of Chemistry and Physics
Division of Ecology
Office of Research and Monitoring
Office of Air Programs
Consider each registered fuel or additive and select some for further
testing, based on predicted effects on emissions or control devices,
extent of use, and postulated public health and welfare hazards.
C. Required Resources- for Each Objective:
FY 73 Resource Estimate: $1000/MY
Present Minimally Adequate Optimal
1. Review of fuels and
additives submitted
for registration 9/0.4 30/1.5 60/3.0
2. Identify testing
systems 8/0.3 10/0.5 120/1.0
3. Re-evaluate registered
additives 8/0.3 20/1.0 60/3.0
25/1.0 60/3.0 240/7.0
Allocation of
Resources
In-House
Contracts
$25,000
0
$60,000
0
$140,000
$100,000
A 1
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D. Milestone Events/Target Dates for each Objective:
Target Dates at 3 Funding Levels
Present Minimally Adequate Optimal
1. Review present registered
additives 1/73 10/72 10/72
2. Develop and approve
testing systems:
- existing protocols 2/73 10/72 10/72
- new protocols - - 1/73
3. Begin evaluating new
additives 6/73 4/73 1/73
A 2
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TASK 2. "identify Effects of Additives on Emission Products
A. Objective:
The Division of Chemistry and Physics has program responsibility
to determine the effects of fuels and fuel additives on emission
products. Specific task objectives which will result in test
protocols are:
1. Determine the effect of fuel and fuel additives on
exhaust particulate emissions.
2. Determine the effect of fuel and fuel additives on exhaust
gas emissions.
3. Determine the effect of fuel and fuel additives on the
performance of emissions control devices.
4. Determine the effect of fuel and fuel additives on
ratmospheric visibility.
5. Develop a predictive emissions model which allows an
assessment of fuel and fuel additive effects on exhaust
products by analysis of intermediary combustion products.
B. Approach:
Effects research" efforts by DCP are aimed at developing protocols
utilizing specified base fuels and additives, automotive engines,
engine operation procedures, and gaseous and particulate collection
procedures to allow the assessment of the effects of fuels and fuel
additives on gaseous and particulate emissions, performance of
control devices, and atmospheric visibility (secondary particulates),
An additional approach is aimed toward the development of a
relatively fast screening method to determine potential exhaust
species and the effect of fuels and additives thereon by analysis
of combustion intermediate species thus allowing rapid and
economical assessment of potential toxic emission products.
The approach would involve collection and analysis of gaseous
emission products. Additionally, it would involve collection
and analysis for total mass emitted, trace metals, and organic
fractions of both fresh and irradiated exhaust particulate.
Collected particulate materials would be available for subsequent
toxicological screening.
C. Resources: (Outside of Funds for Health Intelligence)
FY '73 In-house manpower $200,000
Equipment 225,000
Contract program 350,000
Total $775,000
A 3
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D. Milestone Events/Target Dates:
FY 73 A functioning emissions characterization system which will
allow collection of fresh and irradiated exhaust particulates.
A 4
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Task 3. Fuel and Additive Usage Data
A. Task Objective Statement:
To obtain information on the use of individual fuels and fuel
additives, in order to determine magnitude of impact of harmful
emissions on the environment.
B. Approach:
The direct approach, recommended by this Task Force, is to request
legislation to provide the authority to obtain from fuel additive
manufacturers their production of each additive and from fuel manu-
facturers their use of each additive in, and their production of,
each designated fuel.
Lacking such legislative authority, preliminary contact has been
made with the Air Quality Management Branch, OAP, to develop fuel
usage by manufacturer for combination with fuel and additive
registration data to provide total usage of a fuel, an additive,
or a chemical compound.
C. Required Resources: (outside of funds for Health Intelligence)
In House Contract Total
FY 1973 1/2 man-year 10,000 90,000 100,000
D. Milestone Events/Target Dates:
9/1/72 Contract awarded.
3/1/73 Arrangements for receipt of State data completed.
7/1/73 Usable data on fuel usage available.
A 5
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TASK 4. Extracts of Emissions Resulting from Use of Selected
Fuel Additives for Toxicologic Screening
A. Task Objective Statement:
Collect and provide for use in toxicologic screen
test systems exhaust particulars associated with
the use of selected fuel additives.
B. Approach:
Using a standard fuel engine atmosphere generation
system, produce successive test atmospheres (irradiated
and non-irradiated) by combustion of reference fuel
with and without single selected fuel additive products
(NCT, etc.), followed by extracting particulate
material and forwarding for testing in a rapid
toxicologic screening system (Task 5 ).
C. Required Resources:
FY 73 Resource Estimate ($1000/MY)
Present Minimally Adequate Optimal
Allocation: In-house 0/0 $45/2 45/2
Contract -
D. Milestone Events/Target Dates:
Present Adequate Optimal
Initial extracts for reference
fuel alone and with MCT - 7/72 7/72
Remaining extracts corresponding
to 4 or 5 additional selected
additives . - 9/72 9/72
(Note: On line toxicologic testing in laboratory animals of emission
atmospheres from above generation system is proposed under
Biomedical program element support for FY 73.)
A 6
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TASK 5. Toxicologic Evaluation of the Contribution of Fuel Additives
to Vehicular Exhaust
Objective:
To detect biological effects of exhaust particulates by a
sequential application of a variety of biological models. The source
of particulates for biological exposure is to consist of an engine
dyanometer reaction chamber, designed and built, or adapted to collect
particulate emissions and operated according to a standard protocol.
SUBTASK 1.
A. Task Objective Statement:
Screen particulates derived from the above source in tissue culture.
B. Approach:
Determine comparative toxicity by means of selected biological
and biochemical parameters on material collected from combustion
of a referenced gasoline, alone and after addition of the fuel
additive, and before and after reaction in the irradiation chamber.
C. Required Resources for Each Objective:
Resource Estimate: $1000/MY
Present (FY '73) Minimally Adequate Optimal
$ 50/1.0 $ 100/1.0 $ 350/2.0
Allocation of - In-House $25 $25 $ 50
Resources - Contract 25 75 300
D. Milestone Events/Target Dates for Each Objective:
Target Dates at 3 Funding Levels
Objective Milestone Present Minimally Adequate Optimal
Screen in Exploratory work 10/72 10/72 10/72
tissue culture Design protocol 1/73 1/73 1/73
Negotiate contract 3/73 3/73 3/73
Data collection & report
1 additive 12/73 10/73 8/73
5 additives - 8/74 6/74
15 additives . - - 12/74
A 7
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Subtask 2. Determination of the Effect of Fuel Additives, Selected on Basis
of Reaction in Subtask 1 Above, Stepwise in a Number of Definitive
Systems to Further Delineated the Toxicology and Validate Results
in Subtask 1.
A. TASK OBJECTIVE STATEMENTS:
1. Test the effect of fuel additives on pulmonary alveolar macrophages.
2. Test the effect of additives on a in vitro mutagenic model.
3. Test the effect of fuel additives on a carcinogenesis model in
newborn mice.
4. Test, etc, on enhancement of pulmonary infection.
5. Test, etc, on production of dominant lethal mutations in mice.
6. Test, etc, on production of pulmonary tumors by intratracheal
instillation in hamsters.
B. APPROACH:
Y.Material would be placed in surviving cultures of pulmonary alveolar
macrophage and effect would be noted on selected biological and
biochemical parameters.
{ • ''.
2. Material would be studied for its property to induce mutagenesis in
yeast or mold cultures.
3. Material would be injected subcutaneously in newborn mice which
would be sacrificed and studied pathologically after an appropriate
latency period.
4. Material would be introduced into the lungs of mice to be proceeded
or followed by infectious organism. Parameters of clearance, bacterial
growth and mortality would be observed.
5. Material would be injected into male mice which would then be bred,
and females examined by standard procedure to detect presence of
dominant lethal genes in mice.
6. Material would be injected into tracheal of hamsters lone, with inert .
particles and with known carcinogens. Animals would be sacrificed
and examined for tumors after period of latency.
C. REQUIRED RESOURCES FOR EACH OBJECTIVE:
Resource Estimate: $1000/MY
Objectives Present Minimally Adequate Optimal
T.Toxicology in P.A.M. $20/1.0 $80/1.0$150/2.0
Allocation of - In-House $20 $20 $40
Resources - Contract $60 $110
2. Mutagenesis in vitro $20/0.2 $40/0.5 $100/1.0
Allocation of - In-House $5 $10 $20
Resources - $15 $30
A 8
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Objectives Present
3. Carcinogenesis in $50/0.5
newborn mice
Allocation of - In-House $10
Resources - Contract $40
4. Infectivity studies $20/1.0
Allocation of - In-House $20
Resources - Contract 0
5. Dominant lethal $20/0.2
in mice
Allocation of - In-House $5
Resources - Contract $15
6. Intratracheal $20/0.2
Allocation of - In-House $5
Resources - Contract $15
D. MILESTONE EVENTS/TARGET DATES FOR
Minimally Adequate Optimal
$120/1.0
$30
$90
$80/1.0
$20
$60
$120/1.0
$20
$100
$70/1.0
$20
$50
EACH OBJECTIVE:
$150/1.0
$30
$120
$160/2.0
$40
$120
$230/2.0
$40
$190
. $120/1.0
$20
$100
Target Dates at 3 Funding Levels
Objective Milestone Present Minimal
1. Toxicity Design protocol
in PAM Negotiate contract
Data collection
& report:
1 additive
10 additives
20 additives
2. Mutagensis Design protocol
in vitro Negotiate contract
Data collection
& report:
2 additives
10 additives
20 additives
12/72
3/73
12/73
12/72
3/73
12/73
ly Adequate
12/72
3/73
12/73
12/74
12/72
3/73
12/73
12/74
Optimal
12/72
3/73
12/73
6/74
12/74
12/72
3/73
12/73
6/74
12/74
A 9
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Objective
Milestone
Target Dates at 3 Funding Levels
Preseirt Minimally Adequate Optimal
3. Carcinogenesis
in newborn
mice
4. Infectivity
studies
Dominant
lethal test
in mice
Intratracheal
innoculation
of hamsters
Feasibility
studies 12/72 12/72
Design protocol 2/73 2/73
Negotiate contract 3/73 3/73
Data collection
& report:
1 additive 6/74 6/74
10 additives — 10/74
20 additives
Design protocol 10/72 10/72
Negotiated contract 3/73 3/73
Data collection
& report:
1 additive 12/73 12/73
5 additives -- 6/74
15 additives —
Design protocol 12/72 12/72
Negotiated contract 3/73 3/73
Data collection
& report:
1 additive 12/73 10/73
6 additives — 8/74
12 additives
Design protocol 6/73 6/73
Negotiate contract 12/73 12/73
Data collection
& report:
1 additive 12/75 12/74
5 additives — 12/75
12 additives
12/72
2/73
3/73
6/74
10/74
6/75
10/72
3/73
12/73
6/74
12/74
12/72
3/73
8/73
6/74
12/74
6/73
12/73
12/74
6/75
12/75
A 10
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TASK 6.., Use of Selected In Vitro Enzyme Assays as Indicators of Auto
Exhaust Toxicity.
A. TASK OBJECTIVE STATEMENTS:
The object of this task is to develop a series of twenty-five in vitro
enzyme assays which can be used to study auto exhaust' component toxicity.
The enzymes chosen will constitute a spectrum that focuses on many
aspects of general metaboltsm or serve as points of metabolic control
In critical pathways. Thts assay protocol will be used as a back-up
to the whole cell system task and wtlI serve to evaluate selected
examples prior to their study in whole animal specific models. Findings
in these enzyme systems wfll serve as more specific indicators and
quantifiers of component toxicfty and thus, will provide a more com-
prehensive definition of component toxicity in all test systems.
B. APPROACH:
The approach will Involve the development of a series of in vitro
enzyme assays to serve as test systems in the specific evaluation
of auto exhaust component toxicity.
These assays will serve as a furtner refinement of the systems out-
Tfnecf in Task S^and wilj^ be applied only to samples shown to have
toxicity in the£e~preTimi7)ary ToxfcdTdgicaTllssay systems. It may
not be necessary" in every case to use the entire spectrum of enzyme"
assays, "but IT heeded "they can be applied,
Components wiN be added in graded doses to the suFtable enzyme
preparation and the IC50 and IC90 (50$ and 90% inhibition concentration)
will be determined. If a component is shown to have significant
toxicity for a specific enzyme or class of enzymes studies of its
inhibitory kinetic profile will be made. In this case components will
be classed as competitive or non-competitive and attempts will be made
to define the molecular basis of competition.
The enzymes selected for use in this system appear below:
Enzyme Class MetaIs Cofactors
Acetyl Choline Esterase Hydrolase
Pancreatic Lipase Hydrolase Ca
Ribonuclease Nucleotfdyl Transferase
Phosphorylase b Hexosyl Transferase PLP
Amylase Glucoside Hydrolase Ca
Leucine Aminopeptidase Aminopeptide aminoacid Zn
hydrolase
Carboxvpeptidase.A .. ,. Carboxypeptide Aminoacid Zn
hydrolase
A 11
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Alcohol Dehydrogenase
Lactic Dehydrogenase
Gl ucose-6-Phos.' Dehydrogenase
Cytochrome Oxidase
Xanthlne Oxidase
Tyrosfnase
Carbonic anhydrase
Glucose Phosphate Isomerase
PhosphogIucomutase
Superoxide Dismutase
Alkaline Phosphatase
Hexoki nase
Creattne phophokFnase
Phosphofructoklnase
Aspartate Aminotransferase
Alanine Aminotransferase
Phosphor IbosyI Transferase
Dihydrofolate Dehydrogenase
Oxldoreductase
Oxtdoreductase
Dehydrogenase
Oxfdase
Oxidase
Oxidoreductase
Hydro-lyase
Isomerase
Phosphotransferase
Dismutase
PhosphohydroIase
Phosphotransferase
PhospKotransferase
Phosphotransferase
Ami.no Transf erase
Amino Transferase
Transferase
Oxtdoreductase
Zn
Zn
Fe, Cu
Mo, Fe
Cu
Zn
NAD
NAD
NADP
Mg
Zn, Cu
Zn
Mg
Mg
Mg .
HDP
ATP
ATP
ATP
PLP
PLP
C. REQUIRED RESOURCES FOR EACH OBJECTIVE:
NADP
Resource Estimate: $IOOO/MY
Objectives
Al 1 Enzyme
Assays
Tota 1 s
Present
0/0
0/0
Minimally Adequate*
250/5.0
250/5.0
Optimal*
750/10.0
750/10.0
AI location of
Resources
In-House 100/5.0
Contract 150/0
300/10.0
450/0
*This resource figure includes only the funds needed to set-up and refine
all assay systems _ _
**The cost per unit sample carried through the entire assay protocol
is calculated to be $2000/sample.
A 12
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D. MILESTONE EVENTS/TARGET DATES FOR EACH OBJECTIVE:
Milestone Events Target Dates at 2 Resource Levels
Minimally Adequate Optima I
Negotiate contract 12/72 12/72
Develop Assays In-House 3/73 3/73
A 13
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TASK 7. Trace Element Inhalation Toxicology of Combustion
Products from Fuel Additives
A. Task Objective Statements
1. Modify existing aerosol generation system for the
combustion of fuel additives.
2. Characterize and define exposure chamber atmospheres.
3. Quantitate in laboratory animals the imoact of trace
elements (initially Mn) present in the additives upon
normal body burdens. Determine the uptake, excretion
and tissue levels of the trace metals.
4. Evaluate specific physiologic functions as indicated
based on anticipated biological effects of the
combustion products. For example, behavioral
changes and neurological should be evaluated
following exposure to additives containing Mn.
B. Approach:
1. A simple combustion system such as a jet flame will
be incorporated into our existing inhalation exposure
system.
2. The atmospheres will be characterized as to the gaseous
components such as CO and hydrocarbons, particulate
mass and size; and quantisation of the trace metal of
concern.
3. Following exposure of the animals, trace metal
determinations will be made on a selected group
of tissues along with determination of the amounts in
the diet, feces and urine. The tissue values will be
compared with those obtained from control animals
exposed to ambient levels.
4. As indicated by the compound under study, certain
other physiological parameters will be evaluated
so as to determine the effects of increased levels
of exposure.
C. Required Resources for each Objective:
Funded under the Biomedical Research Program Element.
A 14
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D. Milestone Events/Target Dates of Each Objective:
1. Modification of Equipment 9/72
2. Testing and Atmospheric Characterization of the System 11/72
3. Exposures and data collection 12/72-3/73
4. Analysis and report 4/73
A 15
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TASK 8. Controlled Human Exposures to Components of Auto Exhausts
A. TASK OBJECTIVE STATEMENTS:
T!Test the eye irritation potential of auto exhaust components
resulting from use of new fuels or additives registered with
the Office of Fuels and Fuel Additive Registrations.
2. Quantitate in humans uptake, excretion and tissue levels of
trace elements present in fuels and additives and emitted
from advanced control systems.
3. Test in humans adverse effects of controlled exposure to auto
exhaust components upon resistance to infectious challenge,
after demonstration of such effects in animal model systems.
B. APPROACH:
1. Eye irritation studies: graded doses of exhaust components
will be tested against tear lysozyme levels and subjective
sensation of eye irritation at exposures bracketing ambient
levels resulting from projected use of new fuels or additives.
2. Trace element studies: careful measurement of trace element
in food will be coupled to controlled inhalation after vaporization
of the element in jet flame. Amounts taken in, excreted in feces
and urine, and concentrations in blood and hair will be quantified.
Potential for increased body burdens from ambient levels produced
by exhaust emissions will be defined. Effects on activity of
selected enzymes in blood will be determined.
3. Infectivtty studies: respiratory challenge with common benign
respiratory viruses and bacteria will follow carefully dosimetered
exposure to auto exhaust components found to adversely affect
animal resistance to infectious challenge.
C. REQUIRED RESOURCES FOR EACH OBJECTIVE:
FY 73 Resource Estimate: $1000/MY
Objectives
1. Eye i rri tati on
2. Trace elements 0/0
3. Infectivity
Totals
Allocation of
Resources
Present
0/0
0/0
0/0
0/0
-
Minimally Adequate
$20/0.4
80/1.3
0/0
$100/1.7
In-House $40
Contract $60
Optimal
$50/1 .0
250/4.0
100/1.7
$400/6.7
$100
$300
A 16
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D. MILESTONE EVENTS/TARGET DATES FOR EACH OBJECTIVE:
1. Eye irritation
Target Dates at 2 Resource Levels
Milestone Events Minimally Adequate Optimal
Negotiate contract 12/72 12/72
Data collection - one additive 3/73 3/73
-second additive — 4/73
-third additive — 5/73
Analysis and report 5/73 5 to 7/73
2. Trace element studies
Target Dates at 2 Resource Levels
Milestone Events Minimally Adequate" Optimal
Negotiate contract 10/72 10/72
Data collection - one element 2/73 2/73
-second element 4/73 2/73
-third element — . 4/73
-fourth element ~ 4/73
-fifth element — 6/73
-sixth element — 6/73
Analysis and report 6/73 6 to 9/73
3. Infectivity studies
Target Dates at 2 Resource Levels
Milestone Events Minimally Adequate" Optimal
Negotiate contract ~ 1/73
Data collection - one element — 3/73
-second element ~ 5/73
Analysis and report ~ 7/73
A 17
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TASK 9. Epidemiologic Studies Necessary to Predict the Health Impact
of Fuels and Fuel Additives
A. TASK OBJECTIVE STATEMENTS:
TiTo elucidate changes in human pollutant burdens which might
result from use of specific fuels and fuel additives.
2. To link changes in human pollutant burdens to alterations in
physiology and increased risk of acute or chronic diseases.
B. APPROACH:
T!Changes in human pollutant burdens might be predicted by special
study of populations already representing an exposure gradient
for the pollutants in question-- This approach would be most
appropriate for trace element exposures,! the most important of
which are manganese, nickel and chromium. Tissues and body
fluids would be collected from volunteers and at necropsy.
The levels of selected trace metals would then be assayed by
appropriate techniques. Information from these studies would
be interfaced.
2. -Human pollutant burden levels in selected cases could be
linked to changes in metalloenzyme activity, to appropriate
indices of erythrocyte metabolism, to changes in neurophysiology,
alterations in performance testing, and to cytogenetic abnor-
malities in circulating lymphocytes and respiratory epithelium.
C. REQUIRED RESOURCES FOR EACH OBJECTIVE:
FY73 Resource Estimate: $1000/MY
Objectives Present Minimally Adequate Optimal
1. Human pollutant burden 0/0 $50/0.2 $100/0.2
2. Pathophysiologic studies 0/0 0/0 100/0.2
Total 0/0 $50/0.2 $200/0.4
Allocation of - In-House -4- -8-
Resources - Contract $46 $192
D. MILESTONE EVENTS/TARGET DATES FOR EACH OBJECTIVE:
1. Human pollutant burden
Target Dates at 2 Resource Levels
Milestone Events Minimally Adequate Optimal
Negotiate contract 12/72 12/72
Data collection: one trace element 6/73 6/73
two trace elements -- 6/73
Analysis and report 12/73 12/73
A 18
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Pathophysiologic studies
Target Dates at 2 Resource Levels
Milestone Events Minimally Adequate Optimal
Negotiate contract ~ 12/72
Data collection: one trace element -- 12/73
two trace elements
Analysis and report ~ 3/74
A 19
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