x-xEPA
United States
Environmental Protection
Agency
Health Effects Research
Laboratory
Research Triangle Park NC 27711
Research and Development
EPA-600/S2-81-235 Feb. 1962
Project SulJimary
Possible Approaches to the
Health Effects Testing of Fuels
and Fuel Additives
Emily M. Cause, Martin L. Meltz, and Nathan D. Greene
This document describes possible
approaches to the testing of fuels and
fuel additives for potential health
effects. Such health effects testing is
required of the manufacturer of a fuel
or fuel additive. The health effects
tests must include but are not limited
to carcinogenic, teratogenic, or mu-
tagenic effects. In order to determine
the appropriate protocol for health
effects testing, the following areas
were discussed:
(1) test materials,
(2) relationship of physical and
chemical properties of test ma-
terials to physiological distri-
bution and biological activity,
(3) weighting factors involved in
determining an approach to appro-
priate health effects testing, and
(4) route and mode of exposure.
The possible health effects tests
described are organized into the fol-
lowing areas:
(1) toxicity (with an emphasis on
pulmonary effects),
(2) mutagenesis,
(3) carcinogenesis, and
(4) teratogenesis and reproductive
performance.
The final chapter describes two pos-
sible approaches to testing. This report
is a technical background document
and is not intended to serve as a health
effects testing protocol for fuels and
fuel additives.
This Project Summary was developed
by EPA's Health Effects Research
Laboratory, Research Triangle Park,
NC. to announce key findings of the
research project that is fully documented
in a separate report of the same title
(see Project Report ordering informa-
tion at back).
Introduction
The Environmental Protection Agency
(EPA) is responsible for the regulation of
fuel and fuel additives, according to
Section 211 of the Clean Air Act (1970)
and Section 222 (1977). Registration is
required by the Agency of Fuels and
Fuel Additives prior to sale or intro-
duction into commerce. The EPA shall
promulgate regulations to implement
the authority to require the manufac-
turer of a fuel or fuel additive:
(1) ta conduct tests to determine
potential public health effects of
such fuel or additives (including,
but not limited to, carcinogenic,
teratogenic, or mutagenic effects);
and
(2) to furnish...such other information
as is reasonable and necessary to
determine...the extent to which
emissions affect the public health
or welfare; with respect to each
fuel or fuel additive which is
registered on the date of promulga-
tion of such regulations and with
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respect to each fuel or fuel additive
for which an application for regis-
tration is filed thereafter.
In addition/ all such manufacturers
would be required to furnish summa-
ries of information in their possession
about mechanisms of action of addi-
tives, reactions between fuels and their
additives, on emissions, identification
and measurement of emission products,
and effects of the emission products on
heajth, welfare, and emission control
devices.
This document addresses itself to the
acquisition of health effects testing data
necessary for determination b/the EPA
as to whether or not an increased health
risk would exist should the fuel or fuel
additive in question become a product
of commerce.
Test Materials
Since human exposure to fuels and
fuel additives may occur from both the
initial chemical forms and the combus-
tion products, and since both states of
matter may or may not be subjected to
irradiation in the environment, the poten-
tial health effects of all forms of these
substances must be considered for their
most likely routes-of exposure. There-
fore, testing for specific health effects of
any or all of the forms of registered
fuels, fuel additives, or fuel/fuel addi-
tive combinations may be required.
The whole exhaust effluent, irradiated
or non-irradiated, represents the most
relevant test material for study of effects
of alterations in fuel composition upon
health effects associated with motor
vehicle emissions. However, for many
of the accepted screening tests for bio-
logical activity, it will not be practical to
employ whole exhaust, but components;
i.e., particulates and isolated fractions
can be tested. To some extent, the
actual form of test material employed
may be dictated by requirements and
limitations of the test selected. There-
fore, to attempt to correlate biological
effect with additive presence, it will be
necessary to determine the fate of the
additive upon combustion; specifically,
with what physical phase(s) or piyc-
essed fraction(s) of the emissions is
either the unreacted additive, its com-
bustion products, or both associated.
These test materials are discussed in
more detail in the research report as
well as the relationship of physical and
chemical properties of test materials to
physiological distribution and biological
activity.
Weighting Factors Involved in
Determining an Approach to
Appropriate Health Effects
Testing
. For a given fuel or fuel additive, the
factors outlined in this section should
be taken into consideration in the selec-
tion of both test material and test
approach.
• Amount of Raw Material Produced
• Amount of Potentially Toxic
Material Emitted
• Persistence and Chemical Form
• Evaluation of Existing Health Data
Health Related Tests
The following health related tests are
discussed and references provided for
consideration in developing a testing
program for fuels and fuel additives.
1. Toxicity
a. General
b. Pulmonary
c. ' Central Nervous System/
Behavior
2. Mutagenesis
a. Gene Mutations
b. DNA Damage and Repair
c. Chromosomal Effects
3. Carcinogenesis
a. Selected Mutagenesis Tests
b. Mammalian Cell Neoplastic
(Oncogenic) Transformation
c. Rodent Tests
d. Cocarcinogenesis and Tumor
Promotion
4. Teratogenesis and Reproductive
Performance
a. Reproductive Performance
b. Teratogenesis
Possible Testing Approaches
The following two approaches to
testing are discussed:
(1) a matrix (battery) approach
(2) a hierarchical (tier) approach
Either of these approaches could be
implemented with a fixed set of tests or
could employ a flexible set of tests
which would be selected'based on the
chemical structure of the test material,
preexisting data base and other
weighting factors discussed in other
sections of the report.
The final determination of which
specific tests and approach to testing
will be implemented would take into
account many of the following factors:
(1) The purpose of such tests (e.g., to
detect potential biological activity
versus making regulatory decisions).
(2) The weighting factors discussed
in one section.
(3) Consultation by scientific experts
as to which tests are most appro-
priate.
(4) Desirability for uniform health
effects testing requirements within
EPA and across several regulatory
agencies.
(5) The number of fuels and fuel
additives or test materials derived
from them that would require
. testing.
(6) The cost/benefit considerations
for including specific tests.
Matrix Approach
The matrix approach to health effects
testing which, for example, is utilized in
the registration of pesticides, involves
the employment of a prescribed battery
of tests which may be sufficient for
human risk assessment. Under these
guidelines all tests are completed prior
to decision making. Generally acute
tests are utilized in this approach to
^determine exposure conditions for the^
chronic studies. The matrix of tests*
employed can be flexible. Alternately,
the entire matrix could be fixed such
that a specified number of tests would
be required for registration of the sub-
stance.
Hierarchical Approach
The hierarchical approach to health
effects testing-has been recommended
as an approach to testing large numbers
of compounds. A tiered battery of tests
is employed in a step-wise fashion with
results from each of the first tier of
screening tests determining whether
further tests should be used. In this
approach, after prioritizing chemicals
based on chemical structure (Tier 0), a
large number of chemicals would be
screened in rapid, sensitive in vitro or
acute in vivo tests. The first tier or level
of tests detects biological activity in the
areas of toxicity, mutagenicity, carci-
nogenicity, and teratogenicity. The sec-
ond tier of testing employes confirma-
tory or subchronic tests while the third
tier of tests involves chronic whole animal
exposures which should allow risk
assessment.
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Emily M. Cause. Martin L Meltz, and Nathan D. Greene are with the
Department of Behavioral and Environmental Sciences, Southwest Founda-
tion for Research and Education, San Antonio, TX 78284.
J. L. Huisingh is the EPA Project Officer (see below).
The complete report, entitled "Possible Approaches to the Health Effects Testing
of Fuels and Fuel Additives, "(Order No. PB 82-132 002; Cost: $18.00, subject
to change) will be available only from:
National Technical Information Service
5285 Port Royal Road
Springfield, VA 22161
Telephone: 703-487-4650
The EPA Project Officer can be contacted at:
Health Effects Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
U S GOVERNMENT PRINTING OFFICE, 1982 - 559-017/7446
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United States
Environmental Protection
Agency
Center for Environmental Research
Information
Cincinnati OH 45268
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