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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