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 ------- 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. ------- 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 ------- United States Environmental Protection Agency Center for Environmental Research Information Cincinnati OH 45268 Postage and Fees Paid Environmental Protection Agency EPA 335 Official Business Penalty for Private Use $300 0000329 ------- |