&EPA
United States
Environmental Protection
Agency
Office of Environmental Processes and
Effects Research
Washington, D.C. 20460
EPA-600/7-79-121
December 1979
Research and Development
Health Effects
Research Program
Summary Reportfor
Fiscal Years
1974-1978
Federal Interagency
Energy/Environment
R&D Program
Report
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RESEARCH REPORTING SERIES
Research reports of the Office of Research and Development, U.S. Environmental
Protection Agency, have been grouped into nine series. These nine broad cate-
gories were established to facilitate further development and application of en-
vironmental technology. Elimination of traditional grouping was consciously
planned to foster technology transfer and a maximum interface in related fields.
The nine series are:
1. Environmental Health Effects Research
2. Environmental Protection Technology
3. Ecological Research
4. Environmental Monitoring
5. Socioeconomic Environmental Studies
6. Scientific and Technical Assessment Reports (STAR)
7, Interagency Energy-Environment Research and Development
8. "Special" Reports
9. Miscellaneous Reports
This report has been assigned to the INTERAGENCY ENERGY-ENVIRONMENT
RESEARCH AND DEVELOPMENT series. Reports in this series result from the
effort funded under the 17-agency Federal Energy/Environment Research and
Development Program. These studies relate to EPA's mission to protect the public
health and welfare from adverse effects of pollutants associated with energy sys-
tems. The goal of the Program is to assure the rapid development of domestic
energy supplies in an environmentally-compatible manner by providing the nec-
essary environmental data and control technology. Investigations include analy-
ses of the transport of energy-related pollutants and their health and ecological
effects; assessments of, and development of, control technologies for energy
systems; and integrated assessments of a wide range of energy-related environ-
mental issues.
This document is available to the public through the National Technical Informa-
tion Service, Springfield, Virginia 22161.
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EPA 600/7-79-121
DECEMBER 1979
FEDERAL INTERAGENCY ENERGY/ENVIRONMENT
RESEARCH AND DEVELOPMENT PROGRAM
HEALTH EFFECTS RESEARCH PROGRAM
Fiscal Years 1974-1978
Summary
by
Richard D. Thomas
Alexis D. Taylor
Judith G. Gordon
The MITRE Corporation
Metrek Division
McLean, Virginia 22102
Contract No. 68-01-5051
Project Officer
Gerald Rausa
Energy Effects Division
Office of Environmental Processes and Effects Research
OFFICE OF ENVIRONMENTAL PROCESSES AND EFFECTS RESEARCH
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
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DISCLAIMER
This report has been reviewed by the Office of Research and
Development, U.S. Environmental Protection Agency, and approved for
publication. Approval does not signify that the contents necessarily
reflect the views and policies of the U.S. Environmental Protection
Agency, nor does mention of trade names or commercial products consti-
tute endorsement or recommendation for use.
ii
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FOREWORD
The U.S. Environmental Protection Agency (EPA) was established
as a single organizational entity to administer federal environmental
legislation. Such legislation requires EPA to protect and enhance
the nation's environment through control and abatement of environ-
mental pollution.
The Office of Research and Development is the principal scien-
tific component of EPA. Its fundamental role is to produce the
scientific data and technical tools needed to develop a national
policy for effective control of environmental pollution through
development of appropriate guidance or regulation.
This report presents a comprehensive summary to date of the
results of energy-related health research funded by the interagency
energy/environment program which is coordinated by the Energy Effects
Division of the Office of Research and Development.
The objectives of this interagency research program are to pro-
vide the techniques and data necessary to: (1) determine the quali-
tative and quantitative effects of energy-related agents on human
health; (2) assess the human health risks associated with all aspects
of energy production and utilization; (3) provide guidance for energy
systems-related control and abatement programs; and (4) provide reli-
able information requested for the establishment of regulations per-
taining to exposures to energy-related agents.
ill
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ABSTRACT
The Federal Interagency Energy/Environment Research and Develop-
ment Program which is coordinated by the U.S. Environmental Protection
Agency was initiated in the latter half of fiscal year 1974 to ensure
that health and environmental problems related to energy resource de-
velopment would be anticipated and evaluated. This document provides
an overview of the Interagency-supported health effects research
program from an administrative as well as various technical perspec-
tives. In this updated program review, which is based on the indivi-
dual task progress reports available for fiscal years 1974 through
1978, the research projects are reviewed and discussed according to
King-Muir objectives and selected scientific discipline, biological
endpoint, and agent/pollutant categories.
iv
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CONTENTS
Foreword
Abstract
Figures
Acknowledgments
1.0 Summary 1
2.0 Introduction 3
3.0 Summary of Accomplishments of the Health Effects
Research Program 9
3.1 Accomplishments Review from the Perspective of
the King-Muir Objectives 9
3.1.1 King-Muir Objective #1 10
3.1.2 King-Muir Objective #2 11
3.1.3 King-Muir Objective #3 13
3.1.4 King-Muir Objective #4 16
3.1.5 King-Muir Objective #5 18
3.2 Accomplishments Review from the Perspective of
Scientific Disciplines 21
3.2.1 Cellular Toxicology 21
3.2.2 Animal Toxicology 25
3.2.3 Human Health Studies 30
3.2.4 Risk Assessment 33
3.3 Accomplishments Review from the Perspective of
Biological Endpoints 33
3.3.1 Carcinogenesis 34
3.3.2 Mutagenesis 34
3.3.3 Teratogenesis 35
3.3.4 Dysfunction: Physiological Damage 37
3.3.5 Dysfunction: Metabolic Effects 38
3.3.6 Dysfunction: Cytotoxic Response 40
3.3.7 Morbidity/Mortality 41
4.0 Program Review from the Perspective of King-Muir
Objectives 42
4.1 Identification of Hazardous Agents 43
4.2 Dose and Damage Indicators 46
4.3 Metabolism of Hazardous Agents 49
4.4 Evaluation of Hazards 50
4.5 Damage, Repair, and Recovery Mechanisms 53
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CONTENTS (concluded.)
Page
5.0 Program Review from the Perspective of Scientific
Disciplines 56
5.1 Cellular Toxicology 58
5.1.1 Biological Screening 59
5.1.2 Development of Screening Methods 62
5.1.3 Toxicity and Damage Indicators 64
5.1.4 Damage and Repair Mechanisms 66
5.1.5 Metabolism Studies 67
5.2 Animal Toxicology 69
5.2.1 Toxicologic Testing and Screening 70
5.2.2 Development of Testing and Screening
Methods 72
5.2.3 Toxicity and Damage Indicators 74
5.2.4 Damage and Repair Mechanisms 76
5.2.5 Metabolism Studies 77
5.3 Human Health Studies 78
5.3.1 Epidemiological Studies 79
5.3.2 Clinical Studies 80
5.3.3 Toxicologic Studies 81
5.3.4 Support/Other 82
5.4 Risk Assessment 85
5.5 General Support 86
6.0 Program Review from the Perspective of Biological
Endpoints 88
6.1 Carcinogenesis 90
6.2 Mutagenesis 91
6.3 Teratogenesis 92
6.4 Dysfunction 94
6.4.1 Physiological Damage 9Zt
6.4.2 Metabolic Effects 97
6.4.3 Cytotoxic Response 100
6.5 Morbidity/Mortality 101
6.6 Multiple 103
6.7 Not Applicable 104
7.;0 Program Review from the Perspective of Agents/Pollutants 105
7.1 Organic Pollutants 106
7.2 Inorganic Pollutants and Agents 110
7.3 Elemental Pollutants 113
7.4 Physical Agents 114
7.5 Energy-Related Pollutants 116
7.6 Multiple Pollutants 118
7.7 Not Applicable 119
Appendix
List of Projects in the Health Effects Research Program 121
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FIGURES
Number Page
1 Funding of Projects by King-Muir Category 44
2 Funding of Projects by Scientific Discipline Category 57
3 Funding of Projects by Biological Endpoint Category 89
4 Funding of Projects by Agent/Pollutant Category 107
vii
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ACKNOWLEDGMENTS
This overview of the Federal Interagency Energy-Related Health
Effects Research Program is an update of a previous summary review*
that was prepared for the Office of Energy, Minerals and Industry
within the Office of Research and Development of the U.S. Environ-
mental Protection Agency (EPA) under Contract No. 68-01-3539. Some
material from the previous report is incorporated in this document.
The support and helpful comments provided by Gerald Rausa, the
EPA Project Officer, are gratefully acknowledged. The technical
assistance of Rebecca Meadows and Yasuko Anglin and the editorial
assistance of Pamela Miller are appreciated.
*J. Dorigan and H. Mahar. "Health Effects Research Program, Fiscal
Years 1975-1977, Summary." MTR-7630. The MITRE Corporation, Metrek
Division, McLean, Virginia. August 1977.
viii
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SECTION 1
SUMMARY
Under the auspices of the Federal Interagency Energy/Environ-
ment Research and Development (R&D) Program, approximately 58 million
dollars have been funded during the past four and one-half years to
support health research efforts. The purpose of this research is to
ascertain the potential health effects associated with this country's
accelerated energy resource development. This document summarizes
the continuing energy-related health effects R&D effort in a manner
that succinctly conveys the status and direction of the Federal
Interagency Energy-Related Health Effects Research Program to date.
More than 280 energy-related health effects research projects
have been supported by the Federal Interagency Energy/Environment
R&D Program since its inception. All of these research projects are
discussed in this summary which is based on available project docu-
mentation, primarily the three-year summary reports. The accomplish-
ments of the research projects in the program are reviewed from the
perspectives of the King-Muir objectives and selected scientific
discipline and biological endpoint categories. The program is
reviewed from the perspectives of King-Muir objectives and selected
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scientific discipline, biological endpoint, and agent/pollutant
categories.
The projects in the research program are listed in the Appendix.
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SECTION 2
INTRODUCTION
Health and environmental problems arising from intensified
domestic energy development and increased energy use are becoming
increasingly important. As a consequence of the first oil embargo in
1973, the Chairman of the Atomic Energy Commission, Dixie Lee Ray,
organized a committee to survey federal and private energy-related
research activities and to recommend an energy research and develop-
ment (R&D) program for the nation. Specific goals and recommenda-
tions were conveyed in the December 1973 report of the Ray Committee
(The Nation's Energy Future). This report led to a special Congres-
sional appropriation for environmental and health research related to
energy development which ultimately resulted in the establishment of
the Federal Interagency Energy/Environment R&D Program.
Two federal Interagency Working Groups* representing 23
departments and agencies were convened to ensure that major health
and environmental problems related to energy resource development
would be anticipated and evaluated on a schedule compatible with
*The Interagency Working Group on Health and Environmental Effects
of Energy Use and the Interagency Working Group on Environmental
Control Technology for Energy Systems.
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energy technology development and commercialization. These Working
Groups developed the program structure for a federal interagency
research and development effort that would assess potential health
and environmental effects of accelerated energy development and would
perfect pollution-control measures in order to minimize the asso-
ciated environmental impacts. In addition, the Working Groups also
defined specific goals and recommendations for the Federal Inter-
agency Energy/Environment Research and Development Program.
The Federal Interagency Energy/Environment R&D Program is admin-
istered and coordinated by the U.S. Environmental Protection Agency
(EPA). Program monitoring was previously the responsibility of the
Office of Energy, Minerals and Industry (now the Office of Environ-
mental Engineering and Technology) within the Office of Research and
Development, but this responsibility was recently assigned to the
Energy Effects Division in the Office of Energy Processes and Effects
Research (previously the Environmental Effects Division in the Office
of Air, Land and Water Use). In order to maximize useful output, the
program utilizes an extramural implementation approach, with EPA
relying heavily on expertise available within other federal agencies.
Research activities are performed by more than a dozen federal agen-
cies in addition to EPA. The overall effort consists of two major
parts:
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• R&D on effects of pollutants, including health effects,
ecological effects, pollutant characterization and mea-
surement, pollutant transport and fate, and integrated
assessment of all types of effects
• R&D on technological measures for controlling the release
of pollutants to the environment, including changes in the
processes of energy extraction, conversion and utilization
as well as end-of-system pollution-control measures
The R&D program initiates research in order to develop the
health and ecological effects data base that is needed to support
environmental quality standards and source discharge regulations
for energy technologies, many of which will not be commercially
available before 1985 or 1990. The health and environmental effects
component of the Federal Interagency Energy/Environment R&D Program
incorporates an implementation strategy that addresses short-,
intermediate-, and long-term research needs: the short-term need to
support regulatory actions, the intermediate-term need to define the
problem areas, and the long-term need to prevent, rather than merely
to regulate, health and environmental damage. The criteria for de-
termining research priorities include:
• the potential magnitude and importance of the health/
environmental impacts
• the nature and potential utility of the technology
*Described in the Final Report of the Interagency Working Group on
Health and Environmental Effects of Energy Use (King-Muir Report),
prepared for the Office of Management and Budget and the Council
on Environmental Quality, November 1974.
**Described in the Final Report of the Interagency Working Group on
Environmental Control Technology for Energy Systems (Gage Report),
prepared for the Office of Management and Budget and the Council
on Environmental Quality, November 1974.
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• the expected rate of development/utilization of the
technology
Within this framework, the R&D program must provide the clearest
possible statement of the nature and extent of actual and potential
changes in the human environment that will be associated with ongoing
and proposed energy development.
Four federal agencies are participating in the health-effects
component of the Federal Interagency Energy/Environment R&D Program—
EPA, the Department of Energy (DOE), the National Institute of Envi-
ronmental Health Sciences (NIEHS), and the National Institute for
Occupational Safety and Health (NIOSH). The Federal Interagency R&D
Program was designed with the base research program of each partici-
pating agency in mind; and, therefore, the additional funding from
the Interagency Program (often referred to as the "EPA 'Pass-Through1
Program") supports energy-related research that complements the
existing research efforts of each participating agency. Health
effects research areas not only reflect the current priorities
assigned to the various energy technologies but also the perspectives
of the participating agencies as defined by their legislative
mandates.
The Federal Interagency Energy-Related Health Effects Research
Program examines the health problems associated with fossil fuel
combustion (both conventional and advanced), coal conversion, and
energy conservation efforts. Problems associated with alternative
energy sources are also being considered; some of the research effort
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is directed to generally applicable methods development and
fundamental research.
This summary of the Federal Interagency Energy-Related Health
Effects Program was limited by several constraints. The information
used to prepare this document was derived primarily from three-year
project summary reports. Other information sources that were used
when necessary/available include project progress reports and
quarterly, semiannual, annual and three-year project status reports.
The number of reports available for each research project varied
considerably, ranging from a general project description to a full
complement of progress reports accompanied by publication reprints.
These reports were prepared by the principal investigator, the pro-
ject officer, and/or the program coordinator. The perspectives of
the authors differed, and the type of information and the level of
detail provided in the reports differed greatly.
This document provides a general overview of the Federal
Interagency Energy-Related Health Effects Research Program from four
perspectives. The more than 280 individual research projects that
comprise the research program are reviewed and discussed from the
perspectives of the King-Muir objectives and selected scientific
disciplines, biological endpoints, and agents/pollutants.
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This report is an update of and incorporates some material from
a previous summary* that was prepared for the Office of Energy,
Minerals and Industry within the EPA Office of Research and Develop-
ment under Contract No. 68-01-3539.
*J. Dorigan and H. Mahar. "Health Effects Research Program, Fiscal
Years 1975-1977, Summary." MTR-7630. The MITRE Corporation, Metrek
Division, McLean, Virginia. August 1977.
8
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SECTION 3
SUMMARY OF ACCOMPLISHMENTS OF THE
HEALTH EFFECTS RESEARCH PROGRAM
Many of the projects in the Interagency Energy-Related Health
Effects Research Program are long term, and many were funded only
recently. Nevertheless, it is possible to identify accomplishments
that have been made to date. In this section, the accomplishments of
the research program, as determined from the most recent reports
available for the individual projects, are discussed from the per-
spectives of the King-Muir objectives, the scientific disciplines,
and the biological endpoints of the research.
3.1 ACCOMPLISHMENTS REVIEW FROM THE PERSPECTIVE OF THE KING-MUIR
OBJECTIVES
Each research project in the program was reviewed from the per-
spective of the five King-Muir objectives—Identification of Hazard-
ous Agents; Dose and Damage Indicators; Metabolism of Hazardous
Agents; Evaluation of Hazards to Man; and Damage, Repair, and
Recovery Processes. The accomplishments and research findings within
each category are discussed and summarized.
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3.1.1 King-Muir Objective #1
Most of the efforts in this part of the program, the Identifica-
tion of Hazardous Agents, were devoted to: developing new assay sys-
tems, adapting proven assays to specific needs, validating assays,
determining optimum conditions, and establishing protocols for test-
ing/screening samples. Two new mutagenicity/carcinogenicity
screening techniques are adaptations of the Ames testr-one allows
liquid culture and the other is the well test that greatly reduces
sample size. Other mutagenic assay systems that were developed
include a multiple marker assay that uses Chinese hamster ovary (CHO)
cells, an assay in which mutations are produced in mouse germ and
somatic cells, a DNA-repair assay, and a bacteriophage system in
which replication is inhibited. Methods developed for toxicity
assays include the use of cellular ATP level as an early indicator of
particle toxicity to rabbit alveolar macrophages (RAM) and an
automated testing system to detect behavioral changes in monkeys. A
new technique that may be useful in determining reproductive and
teratogenic effects of energy-related substances is the automated,
quantitative measurement of changes in sperm size and shape.
The energy-related products that have been tested include stack
emission condensates from eastern and western coals; crude products
and fractions thereof from coal gasification, coal liquefaction, and
in situ retorting of shale oil; fibrous minerals; and various partic-
ulates. Efforts were devoted to obtaining, characterizing, frac-
tionating, and preparing the test samples. For example, a cyclone
10
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system was developed that produces size-segregated particles, and
methods were devised to prepare and to characterize specific partic-
ulate systems (e.g., metal oxides, pesticides, and fibrous amphibole
minerals).
Samples are tested with the various assay systems in order to
identify the hazards associated with these materials. Stack emis-
sions condensates from combustion of eastern and western coal samples
are being characterized and tested. It was determined that the
different fractions of the various energy products differ in degree
of hazard and that, for example, the basic fraction of Synfuel A-3 is
the most mutagenic fraction. The chlorides and sulfates of various
metals were ranked for toxicity to RAM cells: mercury, cadmium, and
vanadium are most toxic; copper and zinc have moderate toxicity; and
manganese and nickel are least toxic. In a study of the effects of
simultaneous exposures to these compounds, it was found that the less
toxic metals decrease the toxicity of the more toxic by competing for
the same sites.
3.1.2 King-Muir Objective #2
The initial efforts in this part of the program, Dose and Damage
Indicators, were also devoted primarily to developing assay systems
and selecting appropriate test organisms/organs/cells. Some screen-
ing of energy-related substances was accomplished during testing of
the assay systems.
Various assay systems were developed, improved, and/or tested
for use in studies of the different harmful effects (carcinogenicity,
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mutagenicity, teratogenicity, toxicity) that can result from exposure
to the energy-related substances. In work on assay systems pertain-
ing to cell transformation, a bioassay system for transformation of
lymphocytes was established, an improved method of scoring oncogenic
transformations in mouse embryo cells was perfected, and cytochemical
markers for cell transformation were developed. Progress was made in
developing techniques for point mutation assays, multiple loci
screening for mutations, and detection of inversions. Other test
methods that were worked on include measurement of DNA repair,
automatic screening for aberrant sperm, and a sulfite oxidase assay
for detecting presence of sulfite in plasma after exposure to sulfur
dioxide. A computer automated pattern recognition system for
detecting and assessing neurobehavioral changes in monkeys is now
complete and functional.
Other accomplishments are related to development of equipment,
techniques, and test organisms. Some of the test systems required
development of new equipment such as special tanks for long-term
experiments involving exposure of fish to carcinogens. A method of
providing slow release of test substances into experimental animals
was perfected; tracheal implants of beeswax pellets that contain
carbon particles coated with the chemical being tested are suitable
for this purpose. New mouse strains were developed that have
increased sensitivity to induction of point mutations. New cell
lines were established in continuous culture (e.g., two human
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lymphocyte lines and a raurine myeloma line) for use in specific
assays.
Substances that were tested include: the effects of cadmium on
spermatogonia and CHO cells; the effects of trace metals on pulmonary
macromolecular metabolism, particularly with reference to enzyme
inhibition and interference with collagen synthesis; the effects of
lead on cultured liver cells (i.e., the mechanism of inhibition of
heme synthesis) and on cell shape; and the effects of in vivo
exposure of rats to sulfur dioxide on the immunoglobulin fraction of
serum proteins and the amine levels in brain and plasma.
The foundations were laid for establishment of a National Envi-
ronmental Specimen Bank. Material was selected for use in the sample
containers; sample handling and preparation techniques were estab-
lished; and analytical techniques were standardized.
A workshop was held on Screening Systems for Alternate Energy
Effluents.
3.1.3 King-Muir Objective #3
The objective of research projects in this part of the program—
Metabolism of Hazardous Agents—is to elucidate the mechanism of
toxicity by examining routes of exposure to hazardous agents; by
determining how these agents are incorporated, metabolized, and
eliminated in/by various tissues and organs; and by studying the
effects on tissues and organs and their functions. Many of the
projects in this category were funded only recently, and it is
therefore too soon to report on accomplishments.
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In this category as in other parts of the research program, some
of the initial work was devoted to developing and testing equipment
and models that would be used in the research efforts. For example,
equipment was developed and methods perfected for generation of
ultrafine aerosols of ammonium sulfate and sulfuric acid for inhala-
tion studies; metal aerosols were developed for in vivo and in vitro
studies of lung metabolism; and a special aerosol sampling system for
use in inhalation studies was designed, constructed, tested, and
modified as necessary. An NMR spectrometer that has improved capa-
bilities for characterizing bonding modes of organic and inorganic
compounds is now operational. Equipment and techniques that have
been developed for study of respiratory tract deposition include
casts of the upper respiratory system and various aerosol deposition
models. Computer simulation models for predicting body burden were
completed for, e.g., lead. A carbon monoxide metabolism model accu-
rately predicts absorption and elimination.
The effects of fly ash from coal combustion and coal gasifica-
tion processes have been studied in ingestion as well as inhalation
experiments. It was demonstrated that fly ash in the diet does not
affect the metabolism and toxicity of cadmium, manganese, or mercury
in rats. Loss in body weight that occurs when the diet contains 10
percent ash is greater in male than in female rats. Toxicity of fly
ash particles on RAM cells in tissue culture is a function of par-
ticle size as well as composition (toxicity ranking in decreasing
order is lead, nickel, manganese).
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Respiratory tract deposition models have demonstrated that the
primary mechanism of deposition is particle inertia in the nasal
chamber. Use of casts of the upper respiratory system revealed a
close correlation between aerosol deposition sites in specific airway
branches and the observed sites of primary bronchial cancer.
The specific effects of some hazardous agents have been eluci-
dated. Findings include, for example, that exposure to acid
atmospheres in vivo decreases the rate of ciliary beating and alters
the morphology of the tracheal epithelium. Selenium accumulates in
liver, kidney, lung, gastrointestinal tract, blood, and bone and is
cleared from internal organs in 10 to 35 days (half-time). Vanadium
inhibits biosynthesis of unsaturated phosphatidyl choline and
therefore would interfere with phagocytosis, the primary defense
mechanism of the lung. Cadmium absorption is affected by the amounts
of calcium and phosphorus present in the diet, and the rate of
gastrointestinal absorption is age-related (greater in young than in
old rats and guinea pigs). Exposure to microwave radiation for three
months causes significant differences in serum electrolytes and rat
behavior, differences that disappear after a one-month recovery
period.
An Environmental Teratology Information Center was established.
This data bank now includes 14,000 references and 3000 chemical
agents that are listed by CAS number, molecular formula, synonyms,
trade names, and generic name.
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3,1,4 King-Muir Objective I'M
In accordance with King-Muir Objective #4, Evaluation of Hazards
to Man, most of the projects in this part of the research program are
exploring the health effects of exposures to combinations of pollu-
tants from energy-related processes and activities. The techniques
used include in vivo and in vitro animal studies as well as epidemio-
logical studies of exposed human populations.
Many of the studies examined the effects of various air pollu-
tants, alone and in combination. These pollutants include particu-
lates (fly ash, carbon particles, and metals), gases (sulfur and
nitrogen oxides and ozone), and aerosols (acid mists).
It was found, for example, that inhalation of fly ash produces
an immunosuppression response in the mouse and reduced lung and body
weights in the guinea pig. Inhalation of a mixture of respirable
carbon particles and acid mists causes greater adverse effects in the
hamster than either of the individual pollutants, and exposure to the
mixture reduces the ability of both hamsters and mice to resist res-
piratory infections.
Various epidemiological studies were initiated, and they are now
in different stages of completion ranging from selection of subjects
and design of questionnaires to data analysis. Several studies
involve the general population, e.g., people exposed to air pol-
lution in Chicago, to pollution from coal combustion in Cleveland,
and to pollution from fossil fuel power generation in selected U.S.
counties. Other epidemiological studies are examining health data on
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workers in various industries for correlation with industrial hygiene
practices and occupational exposure to various pollutants that are
energy-related.
In some of the projects, especially those that were funded more
recently, accomplishments to date are primarily in the realm of ini-
tial preparatory work for the experiments. Different types of equip-
ment (e.g., exposure chambers, aerosol analyzers, particulate
monitors) were developed, calibrated, and/or evaluated. Some new
experimental methods were developed and tested, e.g., a more
sensitive method of determining mucopolysaccharide histochemically, a
quantitative assay of monamine oxidase types A and B, the use of pica
as a quantifiable behavioral assay of toxicosis, and a system for
detecting inactive enzyme mutations and electrophoretic mobility
mutations in the same loci. Statistical techniques were developed
for low-dose extrapolation and for analysis of dose-response data.
Two air quality monitoring systems are now in operation after
the component parts were evaluated, selected, and calibrated, and
operation and maintenance procedures were established. The CHAMP
system now includes mobile as well as stationary units, and data on
air quality are being collected. A survey was conducted of the
CLEANS/CLEVER system to develop a quality assurance system.
Various support projects are now in operation or in the final
planning stages. The Chemical Repository for Alternate Energy Source
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Material received 108 samples from five coal liquefaction or purifi-
cation processes, two coal gasification processes, three shale oil
recovery processes, and four coal combustion sources. The Repository
then distributed 110 samples to 22 investigators for use in their
research projects. Methodology was established for use by the
National Environmental Specimen Bank in analysis of tissues and other
samples. The Environmental Mutagen Information Center had 22,100
bibliographic entries in its information system as of March 1978 and
21,000 of these had been cross-indexed for rapid identification of
the chemicals by GAS number, formula, generic and trade names, etc.
3.1.5 King-Muir Objective #5
King-Muir Objective #5—Damage, Repair, and Recovery Processes—
is the determination of the damage, repair, and recovery processes in
biological systems exposed to hazardous agents associated with energy
technologies. With many of the projects in this part of the research
program, initial efforts were devoted to preliminary work such as
determining baseline data and developing equipment and assay systems.
Various hazardous agents have been tested in animal systems (in vivo
%i}d in vitro) to ascertain the damage, repair, and recovery
processes. In other projects, the emphasis was on immediate
practical application of the findings through the development of
health and safety guidelines for particular energy-related
occupations and industries.
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Determination of baseline data is essential so that adverse
effects of hazardous agents can be recognized and quantified. Among
the data ascertained so far are the normal values for immunochemistry
in rats and hamsters, various baseline data for mouse lung tissue,
and data on the histopathology, cell cycle kinetics, and ultra-
structure of the hamster lung.
Special equipment, techniques, and assays were developed,
tested, and/or calibrated or validated for use in some of the proj-
ects. Types of equipment include an ozone reaction chamber and a
cell sorter for separating cell types involved in immune response.
Among the specialized techniques developed in these projects are
those for flow analysis, aerosol generation, in vitro stimulation of
blastogenesis in hamster lymphocytes, preparation of nanogram samples
of DNA by quantitative precipitation, and quantitative measurement of
lead distribution in tissues by X-ray spectrometry. The assay
systems that were developed or validated include an assay for
immunologic competence, an enzyme activity test in pulmonary tissue,
and the use of ethane and pentane as an index of lipid peroxidative
lung damage.
The studies of the damage and repair processes induced by vari-
ous hazardous agents are on-going, but some definitive findings have
been reported. For example, during exposure to sulfur dioxide,
ATPase activity in RAM cells is increased and the levels of
intracellular and secreted lysozyme are reduced. Exposure of
hamsters to nitrogen dioxide causes lesions in the terminal
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bronchiole area; multiple exposures induce fewer lesions than a
single exposure, which may indicate an adaptive process. The fate of
injected lead in mice depends on the compound (i.e., lead acetate or
lead citrate); at physiological pH, lead citrate remains soluble in
tissues whereas lead acetate is hydrolyzed and then taken up by
reticuloendothelial tissues. Studies with marmosets demonstrated
that polychlorinated biphenyls (PCBs) and dimethylhydrazine (DMH)
affect the platelet-forming system; DMH causes thrombocytopenia
whereas PCB causes thrombocytosis and anemia. The presence or lack of
Vitamin E in the diet has no effect on the phoapholipid or fatty acid
composition of mouse lung tissue, but high levels of dietary vitamin
E reduce the ozone-induced changes in lung fatty acids. Dietary
vitamin A is important in the repair of respiratory tract injury
induced by nitrogen dioxide. The thiol compound WR-2721 provides
protection against the adverse effects of cadmium, decreasing the
mortality rate in rats exposed to cadmium oxide by inhalation (if it
is administered just prior to the inhalation exposure) and reducing
hemolysis of rat erythrocytes in saline containing cadmium oxide.
Two sets of health and safety guidelines that have been pub-
lished are "Recommended Health and Safety Guidelines for Coal Gasifi-
cation Plants" and "National Plan for the Safety and Health of Divers
in Their Quest for Subsea Energy." A seminar was held on recircula-
tion of industrial exhaust air; the objective of studies on this
subject is the development of guidelines for exhaust air
recirculation.
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3.2 ACCOMPLISHMENTS REVIEW FROM THE PERSPECTIVE OF SCIENTIFIC
DISCIPLINES
In the review of the Interagency Energy-Related Health Effects
Research Program, the individual research projects were examined from
the perspective of various scientific disciplines. This summary of
program accomplishments is presented from the perspective of four
scientific disciplines—Cellular Toxicology, Animal Toxicology, Human
Health Studies, and Risk Assessment.
3.2.1 Cellular Toxicology
Research projects that involve study of the adverse effects of
pollutants at the organ, tissue, cellular, and subcellular levels are
classified under the scientific discipline of Cellular Toxicology.
Many of the projects involve the respiratory system whereas others
examine the effects of pollutants on the immune system and the
reproductive system. Other projects are concerned with the subcellu-
lar level of activity (i.e., cell transformations and mutations).
Studies of the respiratory system use tissue cultures of lung
and tracheae as well as alveolar macrophages to ascertain the effects
of exposure by inhalation. In experiments using lung organ cultures,
it was determined that many trace metals affect enzyme systems; for
example, the synthesis of collagen is reduced as the result of enzyme
inhibition by cadmium, copper, mercury, nickel, ruthenium, and zinc.
The rate of ciliary activity in epithelial cells of tracheal
rings is not affected by carbon particulates but ia decreased by
exposure to sulfuric acid mist and to sulfuric acid mist combined
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with carbon particles. A tracheal implant system was developed that
provides a useful technique for screening agents; it was found that
both benzo(a)pyrene (BaP) and dimethylbenzanthracene (DMBA) induce
hyperplasia in the epithelium and marked changes in the submucosa.
Cultures of RAM cells are being used to assess the toxicity of,
for example, fly ash particles and various metals. It was found that
particle size is an important factor in the toxicity of fly ash
particles; the composition of the particle is also important with the
toxicity of metals being (in decreasing order): lead, nickel,
molybdenum. The RAM system was also used to determine the relative
toxicities of various metal sulfates; they are (in order of
decreasing toxicity): mercury, cadmium, vanadium, copper, zinc,
manganese, nickel, sodium.
Most of the studies involving the immune system reported prelim-
inary accomplishments. These include the establishment of lympho-
cyte cell lines from various mammalian species in continuous culture,
development of techniques for reproducible cloning and stimulation of
in vitro blastogenesis, and development of an assay for immunologic
competence.
In studies of the effects of agents on the reproductive system,
it was found, for example, that CHO cells concentrate cadmium which
stimulates the production of M-RNA polysotne (whereas it is decreased
by exposure to X-ray). A multiple marker assay for mutagens that
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uses CHO cells has been developed. Tissue cultures of endometrial
cells are being used to explore the effects of hormones on chemical
carcinogenesis; it was found that progesterone conveys protection
when it is added to the culture medium simultaneously with DMBA, but
the cytotoxic effect is increased when progesterone is added first.
A variety of cell lines and tissue cultures are used in other
studies. For example, cultured brain cells were used to ascertain
the effects of lead on the offspring of pregnant rats administered
lead in drinking water; the level of glycerol phosphate dehydrogenase
was suppressed in pup brain cells. Rat liver cell lines were
developed for use in the study of induction of metallothionein by
heavy metals. Lead-resistant and cadmium-resistant rat cell lines
(e.g., liver, glial cells) were isolated that will be valuable for
the study of metal toxicity. It was confirmed that the 7,8-dihydro
diol 9,10-epoxide of BaP, a mutagen, is a major metabolite of BaP in
a variety of cells and tissues.
Achievements relating to carcinogenesis have been primarily in
the realm of technique and assay development and validation. Tech-
niques that were developed include an improved method of scoring
oncogenic transformations in mouse embryo cells, plating techniques
for transformed cells, a microfluorophotometry method for analyzing
single cells and a flow cytometry technique to distinguish between
normal and transformed cells. It was found that when suspended rat
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hepatocytes are treated in vitro with carcinogens, the number of
binucleate cells decreases while there is an increase in the number
of mononucleate cells.
Much of the progress in the work on mutagenesis is also related
to the development of techniques and assay systems. The Ames test
has been modified in various ways to meet particular needs (e.g., a
"well test" that greatly reduces sample size and a liquid culture
method that was used to analyze mutagenic urinary metabolites of
carcinogens). Conditions were established for a liver cell mutagen-
esis assay in continuous rat liver cell lines. The sensitivity of a
multiple loci screen for mutations in mammalian cells was validated
by examining clones exposed to ultraviolet light. An assay system
was developed which is based on the induction of inactive enzyme
mutations and electrophoretic mobility changes in the same loci in
two inbred mouse strains. New mouse strains were developed for use
in studies of induction of point mutations. Air samples from various
sites were tested for mutagenicity. In tests of specific substances,
it was found that six synthetic fuel oil samples had no significant
mutdgenic activity; cyclophosphamide increases the rate of chromosome
aberrations in six human lymphoid cell lines; and the mutagenicity of
fluorene compounds is inhibited by other fluorene compounds.
Some of the research projects pertain to DNA damage and repair.
The induction of unscheduled DNA synthesis in mouse germ cells pro-
vides an in vivo assay for DNA repair. DHBA does not induce
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unscheduled DNA synthesis in males; furthermore, BaP binds to sperm
heads and to liver DNA. Of 15 carcinogens tested, 3 induce
unscheduled DNA synthesis directly and 8 require prior metabolic
activation. Lead and mercury induce base error into DNA.
Ultraviolet and near-ultraviolet light differ in their effects on DNA
damage and repair. A method of quantitatively preparing small
samples of DNA was developed that should be able to provide material
for direct studies of DNA.
In some of the projects, special equipment, techniques, and
assays were developed. For example, a cyclone system for producing
large quantities of size-segregated particles was calibrated.
Automated flow systems were adapted to provide single-cell
suspensions from hamster lung epithelium by lavage. An ozone
reaction chamber for cultured cells was constructed and tested.
Methods involving assays of enzyme activity and electron microscope
examination were developed for assessing toxicity in cultured RAM
cells. An RAM assay system was developed that is based on the
cellular ATP level as the earliest indicator of particle toxicity.
3.2.2 Animal Toxicology
In animal toxicology studies, animals are exposed in vivo to
hazardous agents in order to ascertain the effects of the exposure.
The test animals are usually mammals although bacteria, insects, and
fish are also used. In most of these research projects, the route of
exposure was inhalation, the principal means by which man is exposed
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to energy-related agents, while in other projects the route of
exposure was ingestion or injection. In some studies, exposure was
to physical agents such as radiation.
Inhalation studies include exposures to fly ash and other par-
ticulates and to various gases and mists. It was demonstrated that
fly ash inhalation increases lysozymic and protease activity in
guinea pigs, causes an immunosuppression response in mice, and re-
sults in deposits of granular dust in the alveoli, subpleural and
peribronchiolar lung areas in hamsters. In studies of inhalation of
metal aerosols, it was found that: the moat common atmospheric forms
of selenium are readily soluble in biological fluids, and selenium
accumulates in liver, kidney, lung, gastrointestinal tract, blood,
and bone; vanadium inhibits the biosynthesis of unsaturated phospha-
tidyl choline and therefore would interfere with phagocytosis, the
lung cells' primary defense mechanism; and cadmium chloride causes
severe damage to lung tissue and enzymatic responses in the airways.
When mice and hamsters were exposed to respirable carbon particles
and/or acid mists and infectious agents, it was found that the
pollutant mixture had a greater effect than either of the individual
pollutants and that exposure to the mixture decreased resistance to
respiratory infection.
Inhalation of sulfur dioxides causes, a temporary increase in
ATPase activity, alters the immunoglobulin function of serum
proteins, changes araine levels in brain and plasma, and decreases the
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rate of ciliary beating. Both sulfates and sulfites are cleared
rapidly from the respiratory system, with the clearance rate for
sulfates being greater; prior inhalation of ferric oxide retards
bronchial clearance initially and then accelerates it. Inhalation of
sulfur dioxide or crude air particulate changes the rate at which BaP
is metabolized in the lung. Inhalation of nitrogen dioxide increases
the rate of mitosis in alveolar raacrophages, the surfactant level in
the lung, and the level of pulmonary phosphatidyl choline. Dietary
vitamin A is important in the repair of respiratory tract injury
induced by nitrogen dioxide inhalation. Inhalation of ozone causes
lung damage, the extent of which is age-related (older rats, for
example, are more susceptible) and also enhanced by lack of dietary
vitamin E; another effect of ozone is decreased rate of bacterial
ingestion by alveolar macrophages. Many of the effects of inhaled
nitrogen dioxide and ozone are similar; for example, both cause a
temporary increase in metabolic activity that disappears after a
recovery period. After rats were exposed to aerosolized lead
nitrate, distribution studies determined that lead is absorbed very
rapidly from the lung—about 65 percent of the lead is located in the
gastrointestinal tract within 6 hours after exposure and is then
excreted in the feces within 24 hours; lead is cleared rapidly from
soft tissues but accumulates in bone.
In most of the studies of metal toxicity, the substances were
administered by ingestion or injection. The function of metallo-
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thionein in heavy metal metabolism is being investigated, and the
time course for induction of metallothionein and chelation in rat
liver in vivo was studied for cadmium, copper, and zinc. In studies
of cadmium toxicity, it was determined that the rate of absorption
depends on the levels of calcium and phosphorus in the diet and also
on the age of the animal (being greater in the young); cadmium
stimulates the movement of iron into serosal fluid; and cadmium is
bound by serum proteins. The age factor in susceptibility was
elucidated in various experiments with lead. Lead injected into
pregnant rats is maternal- and embryotoxic, causing hemorrhage in the
central nervous system and the fetoplacental unit and teratogenesis.
Lead acetate fed to rat pups from birth induces lead encephalopathy
whereas lead carbonate fed to 18-day-old rats causes toxic,effects
but no encephalopathy.
Various organic compounds were also administered by ingestion or
injection in order to ascertain their effects. It was found, for
example, that when BaP is administered at the maximum tolerated dose,
it reduces the mating ability of male mice and causes females to
produce fewer litters with fewer mice per litter. Dose-dependent
vertebral abnormalities and reduced birth weight in mice are also
effects of BaP. The effects of PCBs were studied in different
animals. The ability to metabolize PCBs varies with the animal
species (it is greater in the dog than the monkey or rat) and the
molecular structure of the compound. Tetrachlorobiphenyl is
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fetotoxic, teratogenic, and neurotoxic in mice. Marmosets are
particularly sensitive to PCBs and DMH, both of which affect the
platelet-forming system, the former inducing thrombocytosis and
anemia and the latter thrombocytopenia. Other organic compounds were
also studied. Hexabromobiphenyl adversely affects mice and rats,
depressing body weight, open field activity, forelimb grip strength,
and reflexes. Dipterex has teratogenic effects, the severity of
which varies with the species (rat > hamster > mouse). Synfuel and
its fractions cause dominant-lethal mutations in mouse oocytes and
spermatozoa.
The effects of electric fields were studied in different
species. A DC electric field induces a sex-linked lethal mutation in
male Drosophila and frameshift mutation in Salmonella TA-98, and
confers upon Photobacterium fisheri the ability to grow in the
presence of normally inhibitory concentrations of tetracycline.
Sixty-hertz electric fields have little effect on rats, but sinusoi-
dal electric fields decrease calcium efflux from cerebral tissue.
Exposure to microwave radiation (918 MHz) induces biochemical and
behavioral changes in rats that disappear after one month of
recovery.
Many of the projects in this category, as in the other cate-
gories, required preliminary work. Exposure chambers and techniques
for generating and characterizing aerosols were developed for the
inhalation experiments. A computer-automated pattern recognition
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system for detecting and assessing behavioral changes in monkeys was
completed and is now functional. New and improved assay methods that
were developed include quantitative determination of monamine oxidase
Types A and B, histochemical determination of mucopolysaccharide with
increased sensitivity, automated quantitative determination of aber-
rant sperm cells, and a mouse oocyte system that is a good monitor of
chemical toxicity because it is a highly sensitive in vivo system.
3.2.3 Human Health Studies
The projects in the Human Health Studies category are all
directly related to the effects on human health of energy-related
agents. Most of the projects involve epidemiological studies of
general populations exposed to air pollutants or of workers exposed
occupationally to energy-related agents. Some of the projects
pertain to industrial hygiene studies and the development of safety
and health guidelines for various energy-related industries. Other
projects are more general in nature, being concerned with model
development and the establishment of national information centers.
One experiment with human subjects was a study of the effects of
exposure to nitrogen dioxide at rest and during moderate exercise.
There were no physiologically significant changes in cardiovascular,
metabolic, or pulmonary function that were attributable to nitrogen
dioxide exposure.
Epidemiological studies of general populations exposed to air
pollution from fossil fuel power generation are in progress in
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Chicago, Cleveland, and selected U.S. counties. Air monitoring
stations are in operation, the subjects are undergoing medical tests,
and health and emissions data are being collected and analyzed. The
CHAMP air quality monitoring system was developed and placed in
operation. The CLEANS/CLEVER system is also operating, and a survey
of the quality assurance system was conducted.
Various epidemiological studies have been started of workers
occupationally exposed to energy-related agents. These include
studies of workers at TVA coal-fired power plants and oil shale
workers as well as workers in nonenergy industries who were exposed
to nitrogen oxides, sulfuric acid, ozone, and various mineral fibers
(e.g., mineral wool, clay fiber, attapulgite clay, and fibrous
glass). Study groups have been selected, medical examinations
administered, and data collected; these efforts as well as data
analysis are continuing.
Several of the research projects are concerned with the working
environment and industrial hygiene at different energy-related facil-
ities. Information on coal gasification and liquefaction facilities
and on other energy technologies (oil shale, tar sands, geothennal,
solar, nuclear, and electric power transmission) was collected by
literature searches and site visits. Medical and operating standards
for divers were published, and work practices were recommended to
protect Alaskan pipeline workers from cold stress and to provide for
the occupational safety and health of workers in coal gasification
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pilot plants. In work on the recirculation of industrial exhaust air
feasibility studies were completed, a seminar was held, guidelines
are being developed, and in-plant evaluation has begun.
Progress was made in developing a method of using teeth as indi-
cators of human exposure to toxic elements. More than 1500 teeth
have been collected and analyzed and correlation analysis of environ-
mental data, case histories, and chemical analysis data was started.
Various models have been developed that are now in different
stages of testing and validation. These include respiratory tract
deposition models, the trumpet model of aerosol deposition, and casts
of the upper tracheobronchial tree. These models have demonstrated
that the primary mechanism of aerosol deposition is particle inertia
in the nasal chamber, that air mixing can occur in the deep lung,
that aerosol concentrations in the airway and alveoli differ, that
electrostatic charge enhances the deposition of smaller particles,
and that there is a close correlation between deposition sites in
specific airway branches and the observed locations of primary
bronchial cancer. Some computer simulation models for body burden
have been completed, including those for lead and the alkaline earth
metals. A carbon monoxide metabolism model accurately predicts
absorption and elimination.
The Environmental Teratology Information Center was established;
as of February 1979, the system contained 14,000 references and
listed 3000 chemical agents. The Environmental Mutagen Information
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Center contained 22,100 bibliographic entries as of March 1978. In
both information systems, chemicals are listed by CAS number,
molecular formula, generic name, synonyms, and trade names.
3.2.4 Risk Assessment
The projects in the Risk Assessment category involve statistical
and modeling techniques that are used in the estimation of risks
associated with energy processes and energy-related agents, individu-
ally and in combination. Progress was made in developing and testing
these methodologies.
Statistical methodology based on the Armitage-Do11 multistage
model for carcinogens was developed. When this methodology was used
to analyze dose-response data from animal experiments, it was found
that the response curves for most carcinogens are essentially linear
at low dose levels.
Other efforts were devoted to the development of statistical and
modeling techniques for estimation of the public health hazards
associated with energy technologies. These techniques can also be
used to evaluate alternative approaches to the question of competing
risks.
3.3 ACCOMPLISHMENTS REVIEW FROM THE PERSPECTIVE OF BIOLOGICAL
ENDPOINTS
Each research project in the Interagency Energy-Related Health
Effects Research Program was reviewed from the perspective of the
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biological endpoint. The research findings are summarized below for
each of the following endpoints: Carcinogenesis, Mutagenesis, Tera-
togenesis, Dysfunction: Physiological Damage, Dysfunction:
Metabolic Effects, Dysfunction: Cytotoxic Response, and Morbidity/
Mortality.
3.3.1 Care inogenes is
Much of the effort in carcinogenesis research has involved the
identification of morphological, cytological, and biochemical changes
that lead to neoplastic cell transformations. Morphological trans-
formations which lead to tumorigenic response have been identified
for a number of mammalian cell lines. For example, research has
identified the histological changes in lung tissue that lead to an
increased incidence of tumors following multiple exposures to car-
cinogens combined with irritating mists and gases. The morphological
transformations are being correlated with alterations in cell bio-
chemical pathways.
The tumorigenic potential of many energy-related substances has
been determined. For many substances, testing required the develop-
ment of new techniques, laboratory equipment, and model testing
systems. The new testing systems developed have specific genetic
characteristics that are ideally suited for carcinogenicity
screening.
3.3.2 Mutagenesis
There is considerable overlap in the research efforts on car-
cinogenesis and mutagenesis. As in carcinogenesis, much of the work
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in mutagenests has led to the development of new model test systems.
Current test systems have been validated, and multiple loci test
systems have been developed. A major problem in testing industrial
products and wastes is their complexity. Through newly developed
fractionation procedures, crude industrial samples can now be
screened for mutagenic potential with reliability. The components of
many complex mixtures have been chemically identified. The mutagenic
activity of many crude mixtures has been found to correlate with the
mutagenic potential of individual components. Mutagenic synergism
has been recognized for a few complex mixtures, though for most
mixtures the subtraction activity is approximately additively equal
to the total activity for the whole mixture.
Baseline data have been established for cytogenic aberrations
(e.g.» translocation, deletion, inversion, sister exchange) in a
number of cell lines (e.g., human lyphoid, Escherichia coli, CHO,
Syrian hamster embryo, rat hepatocyte). Validation of these cell
lines for selective mutagens has been completed. A few testing
techniques (e.g., heritable translocation test and the Ames test)
have been integrated to provide for more efficient testing
procedures.
3.3.3 Teratogenesis
Baseline information is being collected concerning the types of
damage observed during periods of differentiation in developing
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embryos that are caused by exposure to energy-related agents. As
with other types of toxic effects, some animal species are more
sensitive to teratogenic damage than others. For example, sensitiv-
ity to the teratogenic potential of dipterex decreases in the follow-
ing order: rat, hamster, mouse. In addition to pronounced and
distinct abnormalities in the newborn, other features such as sternal
variation, reduction in birth weight, and mortality in newborn are
being correlated with exposure. The factors influencing cross-
placental transfer of such agents as metallic pollutants are being
determined. The distribution of lead over time in the fetus and the
placenta of laboratory animals has been determined.
Chromosomal aberrations in mouse germ cells induced by coal
conversion products have been determined. Some carcinogenic agents
are toxic to oocytes. 3-Methylcholanthrene is a powerful mouse
oocyte toxin. A number of agents have been tested for mouse oocyte
killing activity. The mouse oocyte system is highly sensitive to
toxic substances, and it can now be used for comparison with other,
in vitro test systems for screening toxic substances.
Another new test examines sperm for shape abnormalities. Many
energy-related agents have been tested in hamsters, mice, and rabbits
by screening for abnormal sperm shape. New automatic quantitative
techniques have been developed for measuring these abnormalities.
The ability to measure sperm size has greatly improved the sensitiv-
ity of the sperm assay. Changes in size are found at concentrations
well below those that would induce shape abnormality.
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3.3.4 Dysfunction; Physiological Damage
Since the lung is a major route of exposure to toxic chemical
agents, much research has focused on lung damage mechanisms. New
test systems have been developed to screen toxic materials for lung
damage potential. An in vitro model uses tracheal rings to measure
the effect of agents on ciliary escalator action, an important upper
respiratory tract clearance mechanism. Molybdenum, barium, and lead,
and chromium sulfate do not affect this clearance mechanism; however,
mercury, zinc, nickel, manganese, and cadmium cause considerable
damage to the ciliary function.
An infectivity test uses mice and hamsters to screen toxic
agents for their potential to hinder resistance to disease. Sulfuric
acid mist and carbon particulates both reduce the animals' ability to
resist respiratory infection.
Work has been completed on theoretical computerized models to
predict aerosol depositions in various parts of the lung. The models
are able to predict particle deposition efficiencies and patterns in
the human nasal passages, tracheobronchial tree, and alveoli. There
is a close correlation between aerosol deposition sites in specific
airways and the observed locations of primary bronchial cancer.
In testing the neuro- and behavioral toxicity of energy-related
agents, an automated behavioral testing system for monkeys has been
developed. It is a computerized, automated pattern recognition
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system using television cameras* The "seeing computer" is more
reliable than trained observers in scoring behavior after agent
exposure.
3.3.5 Dysfunction; Metabolic Effects
Extensive metabolic studies are being conducted on the effects
of trace metals including their effects on the biosynthesis of
pulmonary connective tissue. A number of metals inhibit enzymes,
thereby causing severe toxic effects. For example, lead is strongly
toxic in the lung because it inhibits creatine phosphokinase by
irreversibly binding to the enzyme. The structure of the enzyme is'
then drastically altered. This type of biochemical reaction, which
interferes with collagen synthesis in lung organ cultures, provides a
new sensitive biochemical tool for the in vitro evaluation of the
toxicity of pollutants by monitoring collagen levels in organ
cultures.
The metabolism of a number of energy-related agents in various
laboratory animals has been determined. Their metabolism in some
animals differs from that in others. The rate of metabolism can also
differ among species. For example, the dog metabolizes PCBs better
than either the monkey or the rat. This has important implications
with respect to the monkey's susceptibility to cancer.
In the in vitro test systems, care must be taken to ensure
formation of the proper metabolites of the agents being tested.
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In many instances, the metabolites are carcinogenic and the original
test material is not. A principal carcinogenic metabolite of BaP was
isolated from Syrian hamster embryo cells, in vitro bovine and human
tnucosa incubations, mouse 10T 1/2 cells, and in vivo human skin. New
in vitro cell lines were developed that have the ability to metabo-
lize potential carcinogens to active metabolites.
Age plays an important role in metabolism. The ability of
younger animals to metabolize toxic substances is quite different
from that of older animals. Younger animals absorb much larger
amounts of many substances from the gastrointestinal tract than older
animals. There are also differences in the metabolism of various
chemical forms of a substance. When both lead acetate and lead
citrate were injected into mouse tissues, there were considerable
differences in the deposition rates of the two compounds.
The metabolism of cadmium chloride, chromium, selenium, and
vanadium in the lung was determined. At the same time, mechanisms of
toxicity have been clarified. Vanadium inhibits the biosynthesis of
unsaturated phosphatidyl choline; this interferes with phagocytosis,
hindering the lung cells' primary defense mechanisms. Cadmium
chloride causes acute inflammation and severe damage to lung tissue,
disrupting enzymatic mechanisms in the lung airways. The competing
nutritional factors affecting cadmium uptake were determined. The
rate of gastrointestinal absorption of cadmium in the rat and guinea
pig is age-related. Transport studies of cadmium and lead show that
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lead intoxication disrupts the transport of calcium at the
blood-brain tissue barrier (choroid plexus). Calcium is necessary
for proper nerve function.
3.3.6 Dysfunction: Cytotoxic Response
The cellular toxicity of metallic sulfates was determined using
RAM cells and human lung fibroblasts. The most toxic metals—as
determined by these two in vitro models—are mercury, cadmium, and
vanadium. Copper and zinc have moderate toxicity, and manganese and
nickel have low toxicity. Many metals seem to compete for the same
sites of toxic action. Modifications in toxicity were observed when
combinations of metals were added to cell cultures. For example,
vanadium toxicity is reduced when copper sulfate is added. Zinc
sulfate reduces cadmium sulfate toxicity, and sodium selenite
protects against the toxicity of both cadmium sulfate and mercury
sulfate. Some metals also increase fibrous collagen in human lung
fibroblasts while others produce severe morphological changes in the
macrophages.
The effects of cadmium on the karyotype stability of CHO cells
is being investigated. CHO cells exposed to nontoxic levels of cad-
mium seem to become more resistant to its toxicity. Some metal salts
and oxides are more soluble than others and therefore can be more
toxic; however, some are not toxic because they are not soluble in
the culture media or are not able to penetrate the cell wall.
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In cytogenetic studies of lung cells, the epithelial cells
lining small airways and alveoli showed greater susceptibility to
nitrogen dioxide injury than cells lining bronchi or tracheae.
Nitrogen dioxide stimulates lung cell and alveolar macrophage
division in hamsters; however, no chromosome aberrations were induced
at the levels used for exposure.
3.3.7 Morbidity/Mortality
Many of the studies examining morbidity and mortality as an end-
point are new research projects that have not yet produced results.
Those projects that have been active for a longer period have identi-
fied and assembled the necessary personal health and medical records
and have identified the cohort populations to be examined in the
studies. In a few, data analysis is currently being completed and
results should be reported soon.
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SECTION 4
PROGRAM REVIEW FROM THE PERSPECTIVE OF KING-MUIR OBJECTIVES
The Federal Interagency Energy/Environment R&D Program was
originally established to address the objectives defined in the
King-Muir Report. The health effects research program component of
the total R&D program is reviewed in this section from the perspec-
tive of the five King-Muir categories. These correspond to the five
objectives defined in the King-Muir Report, namely:
Objective #1: Identification of hazardous agents—to utilize
simple, inexpensive and reliable biological assay
systems to detect the presence of toxic, carcino-
genic, mutagenic, and/or teratogenic agents
associated with energy-related activities.
Objective #2: Dose and damage indicators—to develop more
rapid and sensitive biological methods to detect
and quantify early, sublethal, reparable changes
in various target organs or systems.
Objective #3: Metabolism of hazardous agents—to define the
routes and rates of incorporation, metabolism,
deposition and elimination of hazardous agents
in order to specify tissues, organs, and func-
tions at risk.
Objective #4: Evaluation of hazards to man—to quantitatively
evaluate short- and long-term hazards to man
(normal, susceptible and stressed populations)
through simultaneous exposures to combinations
of stresses associated with energy activities.
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Objective #5: Damage, repair, and recovery processes—to deter-
mine the processes of damage, repair, recovery,
protection, and amelioration in biological sys-
tems exposed to hazardous agents associated with
energy technologies.
The funding provided each King-Muir category through fiscal year 1978
is indicated in Figure 1.
4.1 IDENTIFICATION OF HAZARDOUS AGENTS
Research that is being performed for King-Muir Objective #1,
Identification of Hazardous Agents, involves the use of existing and
new biological screening and testing systems to determine the pre-
sence of carcinogenic, mutagenic, teratogenic, and physiologically or
metabolically toxic agents associated with energy technologies.
Research projects in this category are concerned with identifying the
specific fractions or subfractions of energy-related products,
aqueous effluents, and atmospheric emissions that are responsible for
toxicologic effects.
The various biological screening and testing systems that are
used include microbial assays (e.g., Ames test), in vitro studies
using specific cell lines (e.g., Chinese hamster ovary cells) or
tissue cultures (e.g., rat hepatocytes), and in vivo studies (e.g.,
rat intratracheal studies and golden hamster inhalation studies).
The purpose of these studies is to detect biochemical alterations,
metabolic changes, cellular toxicity, carcinogenesis, mutagenesis,
teratogenesis, system dysfunction (e.g., pulmonary effects), and/or
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Identification of
Hazardous Agents
Dose and Damage
Indicators
Metabolism of
Hazardous Agents
Evaluation cf
Hazards to Man
Damage, Repair,
and Recovery
Processes
(15%)'
(13%)
(11%)
(9%)
(52%)
I I I I I I I I I A I I I I I I
1 3 5 7 9 V 27 29 31
Millions of Dollars
Percentages indicate portion of total effort.
FIGURE 1
FUNDING OF PROJECTS BY KING-MUIR CATEGORY
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whole animal effects (e.g., behavioral effects in primates and so-
matic mutations in mice).
Objectives of these research projects include determination of
the effects of airborne respirable particulates on the phagocytic
activity of rabbit alveolar macrophages and investigation of hormo-
nal regulation of the effects of chemical carcinogens on endometrial
cells.
Different agents or pollutants associated with various energy
technologies are being subjected to biological screening and test-
ing systems. These include crude effluents from alternate energy
sources, coal conversion by-products, emission condensates, fractions
and subfractions of complex mixtures from energy-related technologies
(e.g., Synthoil, Synthane), airborne respirable particles and gases,
fibrous minerals associated with the extraction of ores, trace ele-
ments (e.g., thallium), and particulates (e.g., metal-coated fly ash
particles from coal combustion, fluidized bed combustion, and coal
gasification). Some of the projects involve separation, classifica-
tion, and characterization of the samples prior to testing. Emis-
sions from combustion of eastern and western coals are being
characterized, and their toxicologic effects are being compared.
Research projects pertaining to King-Muir Objective #1 were
funded at approximately $8.5 million through fiscal year 1978, or
about 15 percent of the total expenditures for the Health Effects
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Research Program. Allocations for individual research projects in
this category ranged from $64,000 to $530,000.
4.2 DOSE AND DAMAGE INDICATORS
King-Muir Objective #2, Dose and Damage Indicators, entails the
development of the techniques needed for evaluation of the conse-
quences of human exposure to energy-related toxic substances. The
research projects in this category are concerned with improving ana-
lytical indicators of exposure, developing techniques for estimating
damage, or developing more rapid and more sensitive techniques for
determining adverse biological activity. Biological activity can be
determined by examining subtle metabolic and biochemical changes in
cells, tissues, or whole animals.
In some cellular studies, rabbit alveolar macrophage cells
are being used to examine the toxic properties of trace metals and
particulate material. Response indices include cell viability, ATP
content, functional integrity, and various metabolic enzyme changes.
Heavy metals (e.g., lead and cadmium) are applied to cell
cultures derived from nerve, liver, muscle, and lung tissue. The
effects of metals on general growth, DNA and protein synthesis,
metabolism, and expression of differentiated functions such as re-
production are being examined in cells from various animal species.
Some metals seem to interfere with the synthesis of important macro-
molecules like collagen, a component of the connective tissue. The
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lack of proper synthesis of collagen could explain the damage some
metals cause to tissue structure. The ability to measure biochemical
changes such as the level of collagen synthesis in the human body may
aid in quantifying the levels of specific metal pollutants to which
the person had been exposed and the subsequent damage.
Bioindicators of exposure to sulfur and nitrogen oxides, ozone
and hydrocarbons are being sought. Selected mammalian cell lines
(e.g., Chinese hamster ovary, Syrian hamster embryo, and mammalian
lymphoid cells) as well as human fibroblast and lymphocyte cells are
used to detect mutation and other biological changes. Some of the
changes being examined as possible bioindicators include synthesis
and repair of DNA, alterations related to mutagenesis, carcinogene-
sis and teratogenesis, and reproductive effects. Newly developed
bioindicators will aid in determining the genotoxic nature of energy~
related pollutants.
A variety of epithelial cell lines from various animal species
are being tested to determine the neoplastic transformation potential
of specific pollutants. Because most human tumors are derived from
epithelial tissues, epithelial cell lines are highly relevant as bio-
logical screening tools.
A number of new cell lines that possess particular sensitivity
for certain types of agents are being developed for use in mutagene-
sis screening. The new cell lines will be used as cellular models.
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They should provide estimates of exposure and the relative toxicities
of a variety of agents.
The toxicity of energy-related compounds to spermatogonia and
other germ cells is being investigated in mice. Mutations in sperm
cells of mouse and man that are caused by toxic agents constitute an
important indicator of human susceptibility. New computerized scan-
ning procedures are being developed to detect aberrant sperm cells.
These new procedures should improve the accuracy in detecting aber-
rant cells and should decrease the counting time so that more test
samples can be examined.
Techniques are being developed for examining behavioral changes
in rats and monkeys following exposure to sulfur dioxide, sulfuric
acid, auto exhaust particulates, and coal conversion pollutants.
Behavioral changes could become important new indicators of the
consequences of exposure to pollutants. However, the ability to
estimate damage and toxicity from behavioral changes is very limited
at present.
Research projects for King-Muir Objective #2 received approxi-
mately 7.6 million dollars in funding through fiscal year 1978. This
sum amounts to 13 percent of the total expenditures for the Health
Effects Research Program. Allocations for individual projects ranged
from $25,000 to $730,000.
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4.3 METABOLISM OF HAZARDOUS AGENTS
In the research projects funded under King-Muir Objective #3,
Metabolism of Hazardous Agents, the metabolism of energy-related
toxic substances is being studied. The mechanisms and kinetics of
uptake, distribution, and excretion of toxic agents are being exam-
ined as well as the relationship between metabolism and toxicity.
Knowledge of the mechanisms for metabolizing and detoxifying toxic
pollutants is probably the single most important piece of information
necessary for an understanding of the toxicity of substances.
Methods are being developed to determine the concentrations of
toxic agents and their metabolites in various body tissues and or-
gans. The uptake and accumulation of lead in brain tissue is being
investigated to determine the effect of lead on calcium transport at
the blood brain barrier. The mechanisms of toxicity and detoxifica-
tion of heavy metals such as lead are being determined. The effect
of heavy metals on the detoxification of sulfide by sulfide oxidase
in tissues is under investigation. New techniques being developed
for determining the concentrations of toxic substances in tissues
and body fluids include innovative uses of radioactively labeled
compounds and new spectrographic procedures.
Much of the research effort on the toxicology of energy-related
agents focuses on the pulmonary system because most pollutants will
enter the body through the lungs. New techniques are being used to
examine the physical and deposition characteristics of pollutants
49
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such as fly ash in the lung. These characteristics are then associ-
ated with morphological changes and damage in the lungs. Topics of
investigation include the biochemical mechanisms of toxicity for
pollutants such as sulfur and nitrogen oxides. The effects of pol-
lutants on the uptake of antioxidants (e.g., vitamin E) and on blood
and liver enzymes are also under study. The effect of toxic agents
on the alveolar macrophage metabolism of carcinogens is being cor-
related with lung cancer induction. Various biochemical mechanisms
that relate lung disease to chemical exposure are being investigated.
Mathematical, physical, and animal models are being developed to
predict the levels and rates of deposition of particulates in various
regions of the lung. These models will be used to correlate the
deposition of particulates in specific regions of the lung with the
sites at which cancer and other diseases are initiated. Compartmen-
tal models are also being developed for use in predicting total body
burdens of various energy-related pollutants.
Approximately $6.4 million was obligated through fiscal year
1978 to the research projects funded under King-Muir Objective #3.
This funding constitutes 11 percent of the total expenditures for the
Health Effects Research Program. Funding for individual projects in
this category ranged from $20,000 to $610,000.
4.4 EVALUATION OF HAZARDS TO MAN
Research projects funded under King-Muir Objective #4, Eval-
uation of Hazards to Man, are concerned with the development of
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techniques for correlating animal study findings with human diseases.
Epidemiological and clinical studies of selected human populations
are used to determine the frequency of various disease states in man.
These studies may also indicate the potential causes of some of the
diseases, even though their etiology is not clear and the mechanisms
of disease production are unknown. Selected cellular and animal
models can assist in determining the mechanisms and etiology of
disease and, finally, acceptable human exposure levels.
The effects of energy-related agents on human respiratory func-
tion are receiving considerable attention. The effects on the lung
of acid sulfates, sulfates, nitrogen dioxide, nitric acid, nitrates,
ozone, carbon monoxide, hydrogen sulfide and various carcinogens such
as 1,2-benzanthracene are being determined. The deposition of these
agents in the lung and their metobolism are being examined. Clear-
ance, defense, damage, and repair mechanisms in the lung are being
studied. The interaction of two or more agents is being investi-
gated; for example, the interactions of diesel exhaust and coal dust
are being examined in laboratory animals.
The effects of pollutants on other organs are also under study.
These studies include the effects of nitrogen dioxide and ozone on
cardiac, pulmonary and peripheral circulatory function in adult men
who are experiencing heat stress at various activity levels. The
long-term effects of acute and chronic exposures to pollutants and
radiation on the development of the rat brain and nervous systems are
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being studied in a project that examines rat offspring for a number
of generationso Prenatal exposure to microwaves, electric fields,
and metallic pollutants is being used to determine the effects of
such exposures on the developing nervous system and the development
of latent behavioral changes0 The neurochemical effects of these
exposures are also being examined°
The genetic effects of energy-related agents are being investi-
gated, and selective teratogenic test systems are being developed.
Mutagenic, carcinogenic, and reproductive effects are being studied
in laboratory animals and cellular test models„ Species-to-species
carcinogenesis extrapolation techniques are being developed for the
comparison of data on various animals and mane Risk assessment
methods involving more complex factors are being developed,. The
development of statistical methodology using computer techniques for
low dose extrapolation from the high doses used in laboratory testing
should provide better correlation among cellular models, animal mod-
els, and maiio
Epidemiclogical studies of the effects of pollutants on selected
human populations are in progress0 Occupational exposures to acid
sulfates, sulfur dioxide, sulfates, nitric acid, nitrogen dioxide and
nitrates are being studied„ Epidemiological studies can be made of
people living near fossil fuel-fired power plants0 With continuous
air quality monitoring, the deterioration in air quality that is
caused by these plants can be determined and correlated with the
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health effects data. People are being examined for adverse health
effects attributable to water supplies that originate in coal extrac-
tion areas. Workers in the shale oil, coal gasification, coal lique-
faction, mineral wool fiber, and insulation industries are being
studied for occupational diseases.
A chemical repository for alternate source materials and a
national environmental specimen bank are being organized. Establish-
ment of these repositories necessitates development of sampling,
storage, chemical analysis, and standardization methods.
The sum of approximately $30.3 million constitutes the Inter-
agency funding through fiscal year 1978 for the research projects
designed to meet King-Muir Objective #4. This level of funding
amounts to 52 percent of the total expenditures for the Health
Effects Research Program. Allocations for individual research
projects in this category ranged from $8000 to about $1.6 million.
4.5 DAMAGE, REPAIR, AND RECOVERY PROCESSES
King-Muir Objective #5—Damage, Repair, and Recovery Processes—
concerns the determination of these processes in biological systems
that are exposed to hazardous agents associated with energy technolo-
gies. Many research projects in this category involve establishing
quantitative methodologies that relate mechanisms of toxicity to
agent exposure. Cell models used in studying the damage, repair, and
recovery mechanisms include blood platelets; cultured nerve, heart
muscle, and endometrial cells; and lung fibroblasts and tnacrophages.
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Methods of evaluation include examining the changes that occur in the
viability, morphology, plasma and organelle membrane characteristics,
locomotion, and biochemical constituents of the eelIs„
The cellular regulatory processes involved in the metabolism
of polycyclic aromatic hydrocarbons (PAH) are under study,, The role
of free radical intermediates formed during PAH metabolism is being
investigated by electron spin resonance spectroscopyo In vivo DMA
repair assays are being conducted in mice; the germ cells are
examined to determine the ability of PAH to induce unscheduled DNA
synthesiso In addition, the mechanism by which light (ultraviolet
and visible) synergizes the tumorigenicity of PAH on skin is being
investigated.
The effects of metals (e.go, selenium, beryllium, and iron)
on regulatory processes in damaged cells, specifically their ability
to inhibit induction by hormonal regulators, are being studied0 The
interaction of heavy metal ions found in the effluents from oil shale
processing (e<>go, copper and cobalt) with human plasma and tissue
proteins is being investigatedo The uptake of cadmium by pulmonary
alveolar macrophages, the intracellular distribution of cadmium,
and alterations in macrophage function caused by cadmium are being
studied in rabbits,,
.Research is being conducted on the effects of atmospheric pol-
lutants (e0g0, sulfur and nitrogen dioxides) on alveolar macrophages.
Studies in progress are attempting to demonstrate that the toxicities
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of ozone and nitrogen dioxide are related to the ability of these
compounds to initiate peroxidation of unsaturated fatty acids; and
that vitamin E as an antioxidant can minimize lung damage. The role
of vitamin A in cell cycle kinetics of the hamster respiratory tract
resulting from exposure to nitrogen dioxide is being investigated;
dietary vitamin A appears to be an important nutritional factor in
the repair of nitrogen-dioxide-gas-induced injury of the respiratory
tract.
Research projects funded under King-Muir Objective #5 received
approximately $5.6 million through fiscal year 1978. This allocation
represents 9.5 percent of the total expenditures for the Health
Effects Research Program. Funding for individual research projects
in this category ranged from about $9000 to $920,000.
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SECTION 5
PROGRAM REVIEW FROM THE PERSPECTIVE OF
SCIENTIFIC DISCIPLINES
In this section, the Health Effects Research Program in the
Federal Interagency Energy/Environment R&D Program is reviewed from
the perspective of the scientific discipline of research emphasis.
For the purpose of this review, the following scientific discipline
categories were selected: Cellular Toxicology, Animal Toxicology,
Human Health Studies, Risk Assessment, and General Support. The
funding through fiscal year 1978 in each scientific discipline
category is indicated in Figure 2.
The Health Effects Research Program component of the Federal
Interagency Energy/Environment R&D Program is designed to examine the
potential for adverse impacts on human health of energy-related
agents and pollutants. The cellular toxicology discipline involves
the use of cell and tissue cultures as screening models for the eval-
uation of the potential toxicity of various pollutants. When adverse
effects are observed in cellular systems, more complex tissue, organ,
and whole animal systems can be used to determine more definitively
the types of toxic effects that might occur in humans.
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Cellular
Toxicology
Animal Toxicology
Human Health
Studies
Risk Assessment
(33%)'
(32%)
(27%)
(1%)
General Support
(7%)
I I I I I I I I I I I I I I I 1 1 I I I
1 3 57 9 11 13 15
Millions of Dollars
t'ercentages indicate portion of total effort.
17 19 21
FIGURE 2
FUNDING OF PROJECTS BY SCIENTIFIC DISCIPLINE CATEGORY
57
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Human health studies are a pivotal part of the program. The
data obtained from environmental, occupational, and experimental
exposures of humans to energy-related pollutants and agents are
compared with data from the cellular and animal toxicology studies.
From these comparisons, the risks to human health from exposure to
various energy-related agents can be asessed.
5.1 CELLULAR TOXICOLOGY
The Cellular Toxicology discipline involves the development and
use of cell and tissue cultures as screening tools for the evaluation
of potentially toxic agents. Toxicity and damage indicators are mon-
itored in various cultures to evaluate the biological effects of spe-
cific types of toxic agents on cellular structure and function. The
ability of a damaged cell to repair itself and metabolize and detoxi-
fy an invading agent is essential to the cell's continued survival
and its ability to deal with the insult of a toxic agent. For these
reasons, the damage and repair mechanisms in cells are under study,
and the metabolism of toxic agents in cellular systems is being
investigated.
Research in the Cellular Toxicology discipline is of five major
types: Biological Screening, Development of Screening Methods,
Toxicity and Damage Indicators, Damage and Repair Mechanisms, and
Metabolism Studies. Cellular methods alone cannot definitively
assess the effects that toxic agents will have on man; however,
they do provide an indication of potential toxicity and help
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determine the relative toxicities of various energy-related agents.
The cellular toxicology discipline, therefore, complements the animal
toxicology efforts and the human health studies.
Funding for research in the Cellular Toxicology discipline was
about $19.1 million through fiscal year 1978. This sum represents 33
percent of total expenditures for the Health Effects Research Pro-
gram. Funding for individual research projects in this category
ranged from $20,000 to $1.5 million during this period.
5.1.1 Biological Screening
The research projects that pertain to biological screening are
designed to provide qualitative and semiquantitative information on
the adverse health impacts of energy-related activities. In the
bioscreening program, cell and tissue cultures are used as rapid,
accurate, and inexpensive biological assay systems to examine large
numbers of energy-related materials in order to identify potentially
toxic agents and to estimate relative toxicities. Crude complex
pollutant mixtures, isolated fractions, and purified substances are
screened. The crude mixtures are identified chemically and physi-
cally before testing, although the components are not necessarily
separated and purified.
The bioscreening program uses several response indices to assess
the biological activity of a particular substance—the substance's
carcinogenic, mutagenic, teratogenic, and toxic properties, and its
effects on reproduction. The biological activity of a substance is
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sometimes implied indirectly (e.g., rautagenic screening is used to
identify potential carcinogenicity).
A variety of energy-related air pollutants is being tested for
carcinogenic potential using the CH3/10T 1/2 and BALB/c 3T3 neoplas-
tic transformation bioassays. The sensitivity of the assay systems
is improved by the introduction of metabolic activation preparations
to activate materials being tested. Morphological transformations
and biochemical changes are being monitored as indicators of neoplas-
tic cellular changes. The neoplastic transformation potential of
specific agents on epithelial cell lines of hamsters, rats and mice
is being determined. Since most human tumors are derived from epi-
thelial tissues, these cell lines are highly relevant as screening
tools.
Agents obtained from coal and oil shale processes are being
screened for their ability to enhance carcinogenesis (i.e., as co-
carcinogens) and to induce other adverse biological activity. The
use of rodent cell lines in bioassay systems provided indications
that induction of some DNA lesions occurs differently in rodent and
human cell lines. These findings demonstrate the need for caution in
extrapolating research results from animal to human cell lines.
Agents from low-BTU industrial gasifiers and coal liquefaction
operations are being examined to determine their potential for in-
ducing DNA lesions or changes such as chromosome breaks, chromatid
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exchanges and nondisjunctions in DNA repair synthesis in polymorpho-
nuclear leukocytes (PMN).
The mutagenic potential of numerous energy-related pollutants is
being determined using several microbial test systems (e.g.,
Salmonella typhimurium histidine-deficient strains). Because the
mutagenic agents are in many cases the metabolites of the test agents
rather than the test agents themselves, metabolic activation prepara-
tions are added to the test systems along with the agent that is
being tested. Structure-activity relationships are being sought and
have been demonstrated for some chemical categories of pollutants.
Selected mammalian cell lines (e.g., Chinese hamster ovary
[CHO], Syrian hamster embryo [SHE] , and mammalian lymphoid cells) are
being used to detect point mutations that are caused by exposure to
selected energy-related pollutants. Mutagenic screening involving
multiple loci tests uses electrophoretic methods to determine loci
changes. The multiple loci systems are used to test crude and
fractionated hydrocarbon samples and heavy metals generated in coal
conversion and oil shale processes.
Some cellular toxicity screening studies use rabbit alveolar
macrophages (RAM) for testing the effects of metallic-oxide-coated
and uncoated fly ash and selected metal ions. The response indices
used in these studies include cell viability, ATP content, functional
integrity, and various enzyme activities.
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5.1.2 Development of Screening Methods
A number of research projects in the Cellular Toxicology dis-
cipline were designed for the development of screening methods.
Screening methods are needed that will provide accurate and reliable
data for estimating the hazards of toxic agents. Many techniques
that are used at present require standardization and additional
development. New screening methods are needed to investigate a wide
variety of biological indicators and to screen specific classes of
agents that cannot be screened by methods now available. There are
many new types of crude mixtures and individual substances that must
be screened for biological activity, and current screening methods
will need modification before they can be used effectively with many
of these substances. Furthermore, the practical application of
cellular screening methods necessitates the development of new
equipment and instrumentation.
Microbial screening systems that are under development (e.g.,
Escherichia coli K12 and Coliphage T4) will introduce new types of
biological response indicators in addition to those found in the
present testing systems. The microbial screening systems now in use
(e.g., Salmonella typhimurium and Saccharomyces cerevisiae) are being
modified to screen selected air pollutants as either complex mixtures
or individual components. Multiple-marker assays are being developed
to measure the frequency of induced forward mutation. Some systems
are being modified to test human urine for carcinogenic metabolites
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that may have originated from alternative energy sources. Various
synthetic fuel oil samples are being screened in specially modified
microbial systems.
Screening methods that use mammalian somatic cell lines (e.g.,
CHO, SHE, mouse embryo [C34/10T 1/2], and V-79CH lung cells) are
being developed. Neoplastic transformation response is being deter-
mined by identifying morphological, biochemical, and growth changes
that occur after the cells are exposed to carcinogenic agents.
Improved methods are being developed for determining cell transforma-
tions; these include detection of cytochemical markers by microfluor-
ometry, and flow system analysis. Improved methods of sorting normal
and transformed cells will increase the number of cells that can be
handled and will improve sorting accuracy. Multiple site screening
methods for mutations are being developed for use with somatic cells
when electrophoretic shifts are examined.
Rabbit alveolar macrophage cells are being examined as sensitive
indicators of the toxic effects of airborne particulate materials.
It was found that ATP content is an especially sensitive indicator of
phagocytosis and particle toxicity. Selected air pollutants are
being examined for genotoxic effects using cultured liver cells
(hepatocytes) from mice.
Epithelial cell lines are being developed for screening pur-
poses. Cultured human lymphocytes and hamster lymphocytes are being
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used in modified host-mediated assay systems and a variety of other
mutagenesis testing systems. Alterations in metabolic, enzymatic,
and growth properties, rates of chromosome exchange, and other char-
acteristics are being determined. The effects of chemical exposure
on the cellular immune system of hamster lymphocytes are under
study. Quantification of immune system inhibition by toxic agents
would be an important screening tool. Enzyme profile changes in
mouse embryo and human lung fibroblasts caused by exposure to toxic
agents are being determined. Flow cytometry can now discriminate
between normal and transformed human lung fibroblasts.
5.1.3 Toxicity and Damage Indicators
In the Cellular Toxicology research projects that pertain to tox-
icity and damage indicators, the respiratory tract and skin receive
major consideration because these are generally the principal routes
by which man is exposed to energy-related pollutants. Indicators of
respiratory tract damage focus on the alveolar macrophage because it
represents the primary means of defense against inhaled materials
and on the lung epithelium because of its rapid mitotic rate and
proclivity to develop cancer.
Developments in the macrophage system include the addition of
enzymatic, morphological, and functional indices of damage to the
existing cell viability measurements. The ability to monitor the
functional integrity of the alveolar macrophage is important because
of its involvement in lung clearance mechanisms.
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Much effort is being expended to determine the mechanisms in-
volved in damage and preneoplastic changes after chemical insult.
Studies use various epithelial lesions to determine potential markers
for preneoplasia. Lung epithelial cells demonstrate increased cell
turnover in response to irritation, and studies are now underway to
determine whether the turnover rate can be used as an indication of
early damage and progression to latent disease including cancer.
The biochemical mechanisms of pulmonary injury and the biochem-
ical response to energy-related pollutants are being investigated.
The effect of agents on antiviral mechanisms are being correlated
with the general immunological competence of lung cells so that de-
creases in cell viability can be correlated with chemical insult as
indicators of potential damage.
Research is being done on the mechanisms involved in skin tumor
induction by chemical carcinogens. Skin and liver cell cultures are
used in attempts to detect cytological and biochemical changes that
correlate in time with the promotion and progression of cancer.
At the molecular level, molecular damage to DNA and various
proteins caused by metals, metal ions, and organic compounds asso-
ciated with fuel and energy production is being investigated. For
example, it was found that lead and mercury inhibit DNA synthesis
and induce base error in DNA. The mechanisms involved in muta-
tions are being determined. The control of frame shift mutation can
be achieved by using a competitive agent that competes for the same
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site as the agent that causes mutation. Emphasis is being placed on
the DNA damage that results from simultaneous exposure to chemicals
and physical agents.
5.1.4 Damage and Repair Mechanisms
Another aspect of the Cellular Toxicology discipline category is
the study of damage and repair mechanisms. Substantial effort is
being directed toward evaluating the basic mechanisms of pollutant
interaction at the cellular and subcellular levels. At the molecular
level, the mechanisms of damage may transcend mammalian species dif-
ferences and thereby aid in extrapolating information from experi-
mental animals to man. Recent studies with carcinogenic polynuclear
hydrocarbons indicate that exposure to these chemicals in the acti-
vated state results in DNA binding according to first order kinetics.
Similar kinetics have been demonstrated for gene mutations and the
initiation phase of carcinogenesis caused by several of the same
hydrocarbons. Studies are being made of the mechanisms involved in
DNA damage and repair in various germ cell stages of mammals. Exci-
sion repair and unscheduled DNA synthesis are two repair mechanisms
that are receiving considerable attention.
Pulmonary epithelial cell biology is being examined in order
to attain a more thorough understanding of repair, replication, and
other mechanisms. The effect of toxic agents on the enzyme synthesis
necessary for cell recovery after damage is being studied. All regu-
latory processes in damaged cells are important to the cell's ability
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to recover from chemical insult and to remain viable. The interac-
tions between damage and repair mechanisms also provide a better
understanding of neoplastic cell transformations.
Because of their sensitivity and proliferative activity, stem
cells tend to magnify injuries. Consequently, the immune and
hematopoietic systems, both of which contain stem cells, have been
suggested as good indices of pollutant toxicity. Humoral and cell-
mediated immunity are being examined in rabbits exposed to poly-
nuclear hydrocarbons that were derived from coal gasification and oil
shale processes.
Although some progress has been made in studies of repair in
prokaryotic organisms, there is a need for more work with mammalian
cells, especially human cells. Such work is just beginning and is
hampered by the lack of repair-deficient mutants, except for cells
obtained from people with xeroderma pigmentosum. Efforts are
underway to develop such mutants.
5.1.5 Metabolism Studies
The last subcategory of research projects in the Cellular
Toxicology discipline consists of metabolism studies. The bio-
chemical and metabolic functions of a cell are basic in determining
the effects that toxic agents will have on cellular integrity.
The metabolic alterations of energy-related substances can lead to
either detoxification or increased toxicity. Many substances are
not in themselves carcinogenic although their metabolites can be
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carcinogenic. The carcinogenic potential of a pollutant may very well
depend on the ability of the exposed organism to metabolize the pollu-
tant into a carcinogenic metabolite(s). An understanding of the
biochemical changes that occur in cells following insult by a toxic
substance is critical to understanding neoplastic changes in cells,
tumorigenesis in organs and tissues, and other pathological changes.
Biochemical changes that occur in the lung are receiving consid-
erable attention because of the importance of the lung in pollutant
exposure. The reactions of atmospheric contaminants with receptors in
lung tissue are being studied. The effects of pollutants on pul-
monary function are being determined. Of particular interest are the
molecular interactions of pollutants (e.g., organometallic compounds)
with membrane constituents and the subsequent effects on membrane
properties. Free radical formation during lung metabolism that leads
to superoxide formation and auto-oxidation of lipids and lung surfac-
tants is being studied. The interactions of metal ions such as cad-
mium with pulmonary alveolar macrophages are under study. It was
determined that serum proteins play an important role in the uptake
and binding of cadmium by macrophages.
Toxic agent metabolism in cultured cells is being correlated
with metabolism in animals so that more metabolically effective cell
lines can be used in screening systems. Some cellular screening
systems totally lack the ability to metabolize pollutants and, there-
fore, metabolic activation preparations must be added to the cellular
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systems. The improvement of metabolic activation preparations for
cellular testing is vitally important to the success and worth of the
systems in predicting adverse human health effects.
5.2 ANIMAL TOXICOLOGY
Animal toxicologic studies use animal test systems for screening
pollutants for possible toxic effects and for estimating dose-
response relationships. Animal studies are short term (e.g., screen-
ing tests and acute exposure studies) or mid-to-long term (e.g.,
metabolism, chronic exposure, and carcinogenesis studies). Some
chronic exposure studies last the lifetime of the laboratory animal.
Animal studies provide important information for assessing the
potential short- and long-term hazards to man of energy-related
substances.
Although a major disadvantage of whole animal testing is the
difficulty in extrapolating findings from animals to man, those tests
provide many advantages over human health studies. Ethical considera-
tions restrict the testing of hazardous substances in people. Animal
tests are quicker and less expensive than human toxicologic studies.
Human subjects are highly variable and are difficult to control under
test protocols, whereas animal environments and experimental condi-
tions can be tightly controlled and test protocols judiciously fol-
lowed in experimental studies. Specific animal species with unique
characteristics are used to provide particular types of information
for predicting human effects. New strains of laboratory animals have
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been developed for examining specific types of toxic actions or
specific classes of substances. Metabolism studies in whole animals
provide important clues as to why certain substances react as they do
in man to produce toxic effects and diseases.
Research projects in the Animal Toxicology discipline category
were divided into five groups: Toxicologic Testing and Screening,
Development of Testing and Screening Methods, Toxicity and Damage
Indicators, Damage and Repair Mechanisms, and Metabolism Studies.
Review of this scientific discipline is presented below in terms of
these five subcategories.
Funding through fiscal year 1978 for the research projects in the
animal toxicology discipline category amounted to approximately $18.8
million. This sum constitutes about 32 percent of the total funding
for the Health Effects Research Program. Individual research projects
in this category received allocations that ranged from $29,000 to
$921,000.
5.2.1 Toxicologic Testing and Screening
Some of the research projects in the Animal Toxicology category
involve toxicologic testing and screening using whole animals. In
most of these studies, pollutant exposure is by inhalation.
The inhalation studies include detailed studies of the struc-
tural, biochemical, and functional changes in the lung that result
from pollutant exposures. Pollutants under consideration include
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sulfur-containing compounds, nitrogen oxides, oxidants, metals, and
selected hydrocarbons.
Biochemical indicators of damage and adverse effects in animal
systems are being used as endpoints in the screening protocols. The
various laboratory methods used to monitor these indicators include
flow system analysis, cell separation, spin-labeling, spectroscopic,
and mass balance techniques. Tissue samples are examined for physio-
logical, structural, biochemical, and immunological changes. Early
deviations in one or more of these or other factors can be used as
indicators of toxicity. Many of these indicators can be related
directly to the development of damage and disease caused by toxic
agents.
A series of studies on the effects of synfuels and specific coal
conversion products on the mouse reproductive system are underway to
identify chemically induced chromosomal aberrations in germ cells and
to detect cell death in mouse oocytes. The tests used include domi-
nant lethal and heritable translocation tests. The mouse specific-
locus method is used to quantify chemically induced gene mutations
that are caused by exposure to energy-related substances.
The neurotoxicity and potential for behavioral modification in
monkeys of sulfur-containing compounds, hexabrominated biphenyls, and
other hydrocarbon pollutants are being determined. The behavioral
effects of radiation from microwaves, electrical fields, and triti-
ated water are being studied in monkeys, rats, and other laboratory
animals. In addition to nervous system effects, the effects on
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reproduction, organ function and structure, and biochemistry are being
monitored.
Fruit flies (Drosophila) and fish (Poecilia formosa) are used in
nonmammalian animal screening systems. Drosophila are used to screen
a number of environmental pollutants for genotoxicity which is
manifested, for example, by chromosomal aberrations that can block
inheritance of specific traits by offspring flies. Fish are used for
quantitative evaluation of the carcinogenicity of coal conversion
products.
5.2.2 Development of Testing and Screening Methods
The development of testing and screening methods is an important
subcategory of the Animal Toxicology scientific discipline. New tests
and screening methods are needed that can be performed quickly and
relatively inexpensively using laboratory animals. The variations in
response induced in different animal species by the same pollutant is
a complexity of animal testing that requires further investigation.
Application of the findings from whole animal testing to the estima-
tion of human risk from toxic agents has many uncertainties that need
clarification. Proper modification of animal testing protocols fol-
lowing the development of new methods will increase the usefulness of
animal test data in predicting human risk from energy-related agents.
Much of the emphasis in developing new techniques and testing
systems centers on the lungs. Indicators of biochemical and immuno-
logical changes in various types of lung cells after animals are
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exposed to sulfur and nitrogen dioxide and specific hydrocarbons are
being investigated. Dose-response curves based on the exposure levels
to specific agents and the resultant biochemical changes could contri-
bute much to the understanding of pulmonary toxicity that results from
pollutant inhalation. Methods using tracheal transplants and grafts
for examining neoplastic cell transformations are being developed:
the trachea is removed from a rat or hamster, pellets containing toxic
substances are placed in the trachea which is transplanted into
another animal of the same species, and changes in the transplanted
tracheal epithelium are then monitored. New methods are being devel-
oped to produce aerosols from substances such as fly ash so that more
effective inhalation studies can be performed with particulate pollu-
tants.
Another area receiving considerable attention is neurotoxicity
and behavioral changes that are induced by toxic agents. Automated
computer pattern recognition systems using closed-circuit television
are being developed for use in the study of primate behavior. After
baseline data on normal primate behavior are compiled, monkeys will be
exposed to pollutants and the "seeing computer" will be used to
monitor changes in pattern recognition, spontaneous behavior, learning
and memory abilities, and stimulus response. Monkeys will be exposed
to thallium, methyl mercury, and hydrocarbons from coal conversion and
synfuel production.
New strains of mice that have marked chromosomal inversions are
being developed for use in studying the effects of chemically induced
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point mutations on the offspring of exposed animals. The development
of electrophoretic methods to detect enzyme variants in new mouse
strains should maximize the sensitivity of the point mutation assay.
The effects of point mutations on offspring are being investigated in
a number of animal species (e.g., dogs, rats, and mice). An under-
standing of the mutagenic effects on offspring of known mutagens will
help in the development of new screening methods.
Reproductive studies are examining the effects of pollutants on
mouse oocyte death and sperm morphology. Sperm shape variation as an
indication of sperm damage is being investigated in hamsters, rabbits,
and other animals including man. These studies should lead to faster,
more efficient, and less costly methods of determining the reproduc-
tive effects of energy-related agents.
5.2.3 Toxicity and Damage Indicators
Much of the effort in the research projects that pertain to
toxicity and damage indicators is directed toward investigation of
indicators of lung disease. Many energy-related pollutants cause lung
damage that can lead to lung disease. Early indicators of potential
damage are being detected in current studies; these might help to
avoid the damage resulting from pollutant exposures that could lead
eventually to lung disease in man.
The early indicators of damage resulting from the inhalation of
sulfur acids, nitric acids in aerosols, and particulates that contain
metals (e.g., cadmium) and oxides of metals (e.g., lead, mercury, and
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cadmium) are being determined. Alveolar and bronchial clearance
mechanisms are being studied to determine their ability to protect the
lung against foreign agents. Biochemical, morphological, and
physiological indicators of lung damage are being correlated with
agent exposure.
Of special importance are the lung's defense mechanisms against
infectious invasion. The effects of coal gasification products on the
pulmonary defense mechanisms are being determined. Pulmonary
bactericidal responses, cell population changes, and the role of
alveolar macrophages in the lung defense mechanisms are being
examined. Substances that might offer protection against damage from
exposure to toxic agents are being studied. The interactions of known
pulmonary carcinogens with lung-irritating pollutants are being
determined in inhalation studies with pollutant and carcinogen mix-
tures. These studies should lead to better understanding of the early
mechanisms that are involved in the induction of lung disease by toxic
agents.
The effects of sulfur dioxide and carbon monoxide-sulfur dioxide
mixtures on the development of the conceptus during gestation are
being determined in mice and rabbits. The offspring are examined for
external and internal alterations just before birth. Factors that
affect the cross-placental transfer and teratogenicity of various
metallic pollutants are being sought. For example, the kinetics of
lead distribution are being studied. The effects of cadmium on the
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ultrastructure of mouse spermatogonia are being determined as well as
the effects of environmental pollutants on specific reproductive tract
functions.
5.2.4 Damage and Repair Mechanisms
Another aspect of the Animal Toxicology discipline is the study
of damage and repair mechanisms. Of particular concern are the damage
and repair mechanisms of the lung because most animal testing entails
inhalation studies. Once the lung is injured, its ability to repair
itself is of considerable importance if the lung is to remain viable.
If, for some reason, the lung is not able to repair itself properly
and to a sufficient extent, then pulmonary disease is likely to
develop. For this reason, the mechanisms involved in lung repair are
being investigated.
Laboratory animals are exposed to specific pollutants that cause
different degrees of lung damage and the immune and repair systems are
then examined. The effectiveness of substances such as vitamin E in
preventing oxidative damage and the effects of vitamin A on cell cycle
kinetics are being determined. For example, vitamin A deprivation in
animals causes a lack of cell reproduction so that damaged cells are
not replaced and the necessary adaption of the lung to air pollution
does not proceed correctly.
The immune system is also monitored during the development of
respiratory carcinogenesis. Studies of toxic trace metals require
the development of new methods of tissue analysis. Therapeutic
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procedures are being developed that can be used to reduce metal
concentrations in tissues effectively.
5.2.5 Metabolism Studies
An understanding of the metabolism of toxic agents in animals
will help explain the deleterious effects that many pollutants have in
man. With many pollutants, it is not the substance itself but rather
its metabolites that are toxic. If the formation of toxic metabolites
can be prevented and/or if levels of toxic agents in the tissues can
be effectively reduced, the deleterious effects of many pollutants
could be prevented. Metabolism studies involve measuring concentra-
tions of pollutants in animal/human tissues and fluids and determining
uptake, distribution, excretion, and the various metabolic pathways of
energy-related agents in laboratory animals and man. Once these
metabolic data are obtained, the toxic action of pollutants can be
better understood and possibly prevented.
Methods are being developed to use gas chromatographic-mass
spectrographic systems to determine the levels of specific energy-
related substances in human tissue, blood, and various body fluid
samples from adults and children. The metabolism of inhaled trace
metal emissions from combustion processes is being investigated.
Levels of trace metals in biological fluids, vital organs, and bone
are being determined. The metabolism and mode of action of nitrogen
dioxide and hydrocarbon solvents in the lung are being studied. Lead
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metabolism in the immature brain of young rats is being investigated
in order to better understand the mechanisms involved in lead toxicitv
to the brain. The effects of competing agents on the metabolism of
the host animals are being determined; for example, the effects of
endogenous antioxidants on the metabolism and toxicity of nitrogen
dioxide in the lung are being studied in hamsters. Pollutant-caused
immunological changes that might hinder defense mechanisms against
chemical insult are receiving considerable attention.
Using metabolic data, pharmacokinetic models are being devel-
oped that will predict distribution, tissue concentrations, and
excretion rates of specific pollutants. Special emphasis is being
placed on species sensitivity to the bioaccumulation of energy-
related compounds such as polychlorinated biphenyls (PCBs).
5.3 HUMAN HEALTH STUDIES
The research projects pertaining to Human Health Studies were
grouped in four subcategories—Epidemiological Studies, Clinical
Studies, Toxicologic Studies, and Support/Other—for the purposes of
this program review.
The Human Health Studies discipline category received approxi-
mately $15.3 million in funding through fiscal year 1978, about 27
percent of the total expenditures for the Health Effects Research
Program. Allocations during this period to individual research
projects in this category ranged from $8000 to about $1.6 million.
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5.3.1 Epidemiological Studies
Research involving epidemiological studies includes investi-
gation of the occurrence and effects of occupational exposure to
various agents, the morbidity/mortality that results from energy-
related work environments, and the industrial hygiene practices at
various energy-related facilities. Research projects include such
diverse studies as determining the adverse health effects caused by
drinking water contaminated with by-products of energy production, and
assessing the effects of inhaling insulation material substances.
With regard to the energy-related work environment, health
effects studies are being conducted on workers in oil shale, coal
gasification and liquefaction, solar energy, coal-fired power,
coal-cleaning, and petroleum product facilities. In other occupa-
tional health studies, miners and deep-sea divers are being examined.
For example, as part of the oil shale worker study, oil shale workers
at the Anvil Points facility were identified, death certificates of
former employees were reviewed, and oil shale workers and control
subjects were given medical examinations.
Pollutant-specific research is being conducted on workers ex-
posed to sufuric acid, sulfur dioxide, sulfates, nitric acid, nitro-
gen dioxide, nitrates, ozone, and insulation materials (e.g., clay,
small glass, and mineral wool fibers). In one study, 300 salt miners
who worked in five mines, all of whom had been exposed to nitrogen-
containing gases from diesel fumes, were examined by chest X-rays and
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pulmonary function tests and were surveyed by questionnaires on
respiratory dysfunction. In addition, research is being conducted to
detect chromosomal abnonnalties in the peripheral blood lymphocytes of
welder trainees who are occupationally exposed to ozone.
Other studies involve determining acute and chronic oral toxi-
cities from exposure to coal gasification emissions and emission
fractions. The levels of toxic elements in various organs of the
workers in coal gasification plants are being measured. Human teeth
are being analyzed by atomic absorption spectrophotometry to deter-
mine the exposure histories of people who live near energy-related
facilities.
5.3.2 Clinical Studies
Clinical human health studies usually involve the direct obser-
vation of patients in clinical situations. Other research projects in
this group involve teeth analysis and method development.
The effects of nitrogen dioxide on pulmonary function in pa-
tients with asthma and chronic bronchitis are being investigated by
studying physiological changes in cardiorespiratory parameters.
Similar research is in progress to determine human biochemical and
physiological responses to acute photochemical air pollution expo-
sures; the short-term effects of photochemical oxidants on asthmatics,
chronic bronchitics, athletes and outdoor workers are being measured.
The childhood health effects of infant exposure to polychlori-
nated biphenyls (PCBs) are being investigated. The extent to which
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residues of persistent, fat-soluble PCBs, and chlorinated hydrocarbon
pesticides are present in mothers' breast milk is being determined.
Cohorts of breast- and formula-fed children are being established for
follow-up studies.
The objective of one on-going research project is to develop a
simple, rapid, and inexpensive method of determining trace concentra-
tions of toxic energy-related elements in the human body. In another
study, more than 1000 teeth from several hundred donors and deceased
individuals (including Egyptian mummies) were analyzed for trace and
heavy metals; the data are being analyzed statistically for correla-
tions and trends.
5.3.3 Toxicologic Studies
Human toxicologic studies usually involve determining the effects
of energy-related pollutants on people under controlled laboratory
conditions. Effects on the human pulmonary and nervous systems are
currently being investigated.
The effects of various pollutants on human respiratory function
are being determined in subjects who are exposed to the pollutants in
exposure chambers. After exposure, the subjects are tested for
pulmonary function (e.g., spirometry, plethysmographic determination
of specific airway conductance, and functional residual capacity),
cardiac function, and peripheral circulatory function. The pollu-
tants used in these experiments are sulfuric acid aerosols, respir-
able sulfates, and low levels of nitrogen dioxide and ozone. In some
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experiments, factors that might affect toxicity (e.g., temperature,
humidity, duration of exposure) are varied for comparison. In other
studies, subjects are exposed to trace elements by aerosol inhalation.
The pharmacokinetics of pulmonary uptake, deposition, and metabolism
of these elements are then studied.
The effects of microwave radiation on neural response and the
central nervous system are being studied. Research efforts involve
identifying peripheral and central receptor mechanisms that mediate
the effects of microwave radiation on brain (e.g. , auditory nerve)
activity. Electrophysiological and neurochemical methods are being
used in this study.
5.3.4 Support/Other
The subcategory of the Human Health Studies discipline that is
designated as Support/Other consists of projects that support human
health research (i.e., the epidemiological, clinical, and toxicologic
studies). Included in this group are projects that entail information
gathering, establishment of computerized data bases, development of
predictive models, and establishment and maintenance of air-monitoring
systems.
The air quality monitoring systems (e.g., CHESS, CHAMP) that were
set up under the program are being maintained. These systems support
community human health studies by collecting air samples. They are
also important in providing the opportunity to evaluate various
pollutant monitors and analyzers. In the CLEANS/CLEVER program,
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stationary and mobile facilities are maintained for the development of
a physiological data acquisition system to study the effects of
environmental contaminants on human health.
Other support projects involve development of indicators, recom-
mendations, standards, and safety plans. For example, there is
research to develop reliable biological indices (e.g., sulfate oxi-
dase enzyme measurement) for use in epidemiological studies. Work is
in progress to develop appropriate health-monitoring and testing pro-
cedures for personnel in energy-related industries. Other on-going
projects should result in recommendations for work practices to pro-
tect Alaskan pipeline workers from cold stress, medical and operat-
ing safety standards for divers in offshore oil exploration, and
occupational exposure to microwave and radio frequency radiation.
Other studies involve establishing computerized data bases,
collecting published information (e.g., by literature searches),
assessing work practice procedures, and developing programs and
models. The Environmental Teratology Information Center (ETIC)
maintains a computerized data base that contains more than 14,000
reprints pertinent to the teratogenic potential of environmental
agents or contaminants. Work is continuing on the Environmental
Mutagen Information Center (EMIC), another computerized data base.
EMIC contains more than 22,000 bibliographic entries on the mutagenic
effects of energy-related pollutants and 21,000 abstracts that are
indexed by agent, organism, and Chemical Abstract Service Registry
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(CAS) number. Literature searches are being conducted for various
programs in order to: (1) enumerate energy-related occupational
health problems; (2) assess energy-related occupational safety and
health problems; (3) identify the major health effects, pollutants,
and risks from oil shale, tar sands, and geothermal, solar, nuclear,
and electric power transmission processes; (4) characterize the indus-
trial hygiene of coal-gasification pilot plants; (5) assess safety in
fossil fuel-fired electric power-generating stations (particularly
relevant to fire and explosions); and (6) determine the health effects
of increased indoor air pollution resulting from energy conservation
strategies.
Other support studies involve the development of models. Models
now under development include:
• respiratory tract models for determining regional deposition
of inhaled particles in smokers, patients with obstructive
pulmonary diseases, and various animal species
• physiological kinetic models (compartmental) for carbon mon-
oxide, the lead-calcium system, and the cadmium-zinc system
that use nonlinear regression techniques for experiments on
uptake and elimination
• stochastic models for external dosage of carbon monoxide and
lead and for prediction of body-burden estimates for lead
and the alkaline earth metals
• models for assessing the general population health effects
that would result from a change in air pollution caused by
changing energy requirements so that changes in acute and
chronic health conditions can be predicted and correlated
with changes in air pollution.
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5.4 RISK ASSESSMENT
The scientific discipline of Risk Assessment includes risk
assessment research such as identifying problems associated with risk
assessment methodologies, performing species-to-species comparisons,
and developing low-dose extrapolation techniques.
Research is being conducted to identify the probabilistic and
mathematical-statistical problems encountered in the estimation of
public health hazards associated with nuclear generator construction,
synergistic effects with binary response variables, and competing
risks. Studies on species-to-species extrapolation of carcinogenic
risk entail quantifying species differences in relation to exposure to
particular carcinogenic agents (e.g., dimethylnitrosamine and vinyl
chloride). Development of low-dose extrapolation methodology—i.e.,
estimation of low-dose toxic effects from high-dose experimental
data—is based on the Armitage-Doll multistage model for carcino-
genesis. This model is being used to analyze dose-response data from
experiments in which animals are exposed to various chemical
compounds.
The Federal Interagency Energy/Environment R&D Program provided
about $750,000 in funds through fiscal year 1978 to the research pro-
jects that are included in the scientific discipline of Risk Assess-
ment. This sum constitutes 1.3 percent of the total expenditures
during this period for the Health Effects Research Program. Funding
for individual research projects in this category ranged from $17,000
to $234,000.
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5.5 GENERAL SUPPORT
The General Support category consists of projects that provide
support for the research endeavor in the various scientific dis-
ciplines. Typical support projects include the collection and
preparation of environmental samples for toxicologic testing, the
development of an environmental specimen bank, and scientific workshop
meetings.
Several projects involve the procurement (e.g., CHAMP air moni-
toring stations) and preparation of energy-related agents. Other
studies are conducted primarily to characterize samples prior to
testing (e.g. , determination of the nucleation properties of respir-
able coal dust, development of nuclear magnetic resonance spectro-
scopic methods for characterizing specific bonding modes of organic
and inorganic compounds, and study of photodegradation of absorbed
polycyclic arenes).
Projects pertaining to establishment of a National Environmental
Specimen Bank include researching analytical methodologies and evalu-
ating methods of sampling, preparing, transporting, and storing bio-
logical specimens which might reflect contamination from developing
energy technologies. Plans are underway for a chemical repository to
store source material from oil shale and coal gasification and lique-
faction facilities and particulate effluents from power stations for
future chemical analysis. These materials will be available in the
future to researchers for use in comparative studies.
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Various energy-related workshops have been conducted. Workshop
topics include discussion and evaluation of aneuploidy assay systems,
screening systems for alternate energy aqueous effluents, and health
problems related to recirculation of industrial process exhaust air.
Funding for General Support research projects totaled approxi-
mately $3.8 million through fiscal year 1978. This sum constitutes
about 7 percent of the total funding for the Health Effects Research
Program that was provided during this period by the Federal Inter-
agency Energy/Environment R&D Program. Individual research projects
in this category received allocations ranging from $4500 to $627,000.
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SECTION 6
PROGRAM REVIEW FROM THE PERSPECTIVE OF
BIOLOGICAL ENDPOINTS
Review of the Health Effects Research Program from the
perspective of the biological endpoints of the research projects
provides a different view of this component of the Federal Inter-
agency Energy/Environment R&D Program. Each research project was
assigned to one of the following Biological Endpoint categories:
Carcinogenesis, Mutagenesis, Teratogenesis, Dysfunction, Morbidity/
Mortality, Multiple, and Not Applicable. Figure 3 depicts the level
of funding and the related level of effort provided each Biological
Endpoint category.
Some research projects are designed specifically to examine the
types of changes that lead to specific biological endpoints (e.g.,
carcinogenesis). This is also true of those projects that pertain
to biological screening methods, including the development of new
screening methods. Other research seeks to correlate disease states
and various types of dysfunction with agent exposure so that the
factors leading to dysfunction and disease can be determined and
preventive measures can be taken to avoid the adverse biological
effects of energy-related agents.
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Care inogene sis
Mutagenesis
(5%)'
Teratogenesis
Dysfunction
Morbidity/
Mortality
Multiple
Not Applicable
(16%)
(3%)
(39%)
(12%)
(2%)
(23%)
I I I I I I I I I 1 I I I I I I II I I I I I I
1 3 5 7 9 11 13 15 17 19 21 23 25
Millions of Dollars
Percentages indicate portion of total effort.
FIGURE3
FUNDING OF PROJECTS BY BIOLOGICAL ENDPOINT CATEGORY
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6.1 CARCINOGENESIS
The research projects in the Carcinogenesis category use cells,
organs, and whole animals to investigate the morphological, cytolog-
ical, and biochemical changes that lead to neoplastic transforma-
tions. Many of the carcinogenesis screening tests use mutagenesis
cellular screening techniques (see Section 6.2 on Mutagenesis).
Much effort is devoted to identifying markers and indicators of
preneoplastic transformations. For example, markers of preneoplasia
in the respiratory epithelium are being identified, and antigenic
responses to squamous carcinomas are being determined.
The mechanisms of tumor production are being investigated, spe-
cifically the mechanisms involved in the induction and production of
skin tumors by weak and strong carcinogens. The initiation of car-
cinogenesis by specific energy-related compounds such as benzo(a)-
pyrene (BaP) is being investigated. The role of irritant gases in
organ susceptibility to tumor production (e.g., in the lung) and in
initiation of carcinogenesis is being studied.
The tumorigenic potential of a number of energy-related sub-
stances is being determined. New systems are being developed for
determining the transforming activity of pollutants. Cloned fish of
the species Poecilia formosa (Amazon molly) are being developed for
use as screening models. Development of rodent cell lines for use in
screening to determine the neoplastic potential of energy-related
substances is continuing.
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The Carcinogenesis biological endpoint category received about
$3.1 million in funding through fiscal year 1978, or about 5 percent
of the total expenditure for the Health Effects Research Program.
Funding for individual research projects in this category ranged from
$85,000 to $524,000 during this period.
6.2 MUTAGENESIS
Mutagenesis is the biological endpoint of many of the research
projects funded by this Federal Interagency Energy/Environment R&D
Program. Energy-related agents are being screened by a variety of
test systems (e.g., Trandescantia, CHO cells, mouse specific-locus)
to detect mutations. In addition, mutagenesis screening techniques
are often used to screen substances for potential carcinogenicity
because mutagenic alterations in DNA are considered precursors of
neoplastic cell transformations.
Mammalian cell mutagenesis assays are used to screen in situ
coal gasification effluents and fractionated coal-conversion by-
products. The effects of coal and oil shale conversion products on
CHO cell cycle kinetics and chromatin structure are being investi-
gated. Research is also being conducted to detect chromosomal aber-
rations that can be correlated with exposure to photochemical air
pollutants and ozone.
Other research projects involve attempts to modify or to develop
methodologies for mutagenesis screening and research. Screening
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methods under development include a polygenic assay for point muta-
tions in mice and methods to detect lethal mutations in mice, to
validate short-term mutagenicity tests as predictors of carcinogenic
activity, and to modify the host-mediated assay system by using human
lymphoid cells.
Mutagenesis studies in the Health Effects Research Program
received approximately $9.4 million in funding through fiscal year
1978 from the Federal Interagency Energy/Environment R&D Program.
This sum constitutes about 16 percent of the total expenditure for
health effects research that was funded by this interagency pro-
gram. Allocations to individual research projects in this category
ranged from $25,000 to $1.5 million.
6.3 TERATOGENESIS
Teratogenesis is the biological endpoint of some of the research
projects in the Health Effects Research Program. These projects
pertain to the screening of energy-related substances for teratogenic
effects.
The distribution of various pollutants in the mother and the
fetus and the subsequent effects on mother and fetus are being deter-
mined in mice, rats, and hamsters. The factors that affect cross-
placental transfer of metallic pollutants and other agents in rats
are being determined. The effects of gestational exposure to pollu-
tants on the development of the conceptus are being studied in mice
and rabbits by examining structural abnormalities in offspring just
before birth.
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New screening systems being developed will make it possible to
predict the teratogenic potential of various pollutants from altera-
tions in the reproductive process. One of the most sensitive is the
mouse oocyte system which is very sensitive to chemical toxicity.
The DNA damage and repair in specific germ cell stages of mam-
mals is being studied. Chemical induction of chromosomal aberrations
in mouse germ cells by coal-conversion products is being investi-
gated. Spermatogonia and related cells from the basement membrane of
the testes are very sensitive to toxic substances. Changes in the
ultrastructure of mouse spermatogonia following pollutant exposure is
being correlated with the teratogenic potential of these substances.
Abnormalities in sperm shape induced by energy-related hydrocarbons
are being studied in laboratory animals as well as man. Defective or
abnormal morphology of sperm cells can be linked to specific terato-
logical changes in offspring.
Teratogenesis studies received $2 million through fiscal year
1978 in funding provided by the Federal Interagency Energy/Environ-
ment R&D Program. This sum represents about 3 percent of the total
funding of the Health Effects Research Program component of the
interagency program. Allocations for individual research projects in
this category ranged from $25,000 to $340,000 through fiscal year
1978.
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6.4 DYSFUNCTION
The Dysfunction category consists of those research projects
that pertain to pollutant-caused dysfunction in an organism. The
subcategories of Physiological Damage, Metabolic Effects, and Cyto-
toxic Response reflect the different levels at which dysfunction is
manifested.
The sum of $22.6 million was expended through fiscal year 1978
in support of energy-related health effects research projects in the
Dysfunction biological endpoint category. This level of funding
constitutes 39 percent of the total expenditure for the Health
Effects Research Program. Allocations for individual research
projects in this category ranged from $20,000 to $921,000 through
fiscal year 1978.
6.4.1 Physiological Damage
Damage to an organism that hinders its vital functions or the
function of a vital organ is termed physiological damage. The damage
that leads to dysfunction is usually related directly to cellular
damage in the affected organ. The research projects grouped in this
subcategory deal specifically with organ dysfunction and the changes
in the vital functions of people and laboratory animals that are
caused by exposure to toxic agents.
Most of the research on physiological damage is concerned with
developing methods of detecting the types of changes that might be
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preliminary indicators of chemically induced physiological change/
damage. The types of damage indicators being examined include
behavioral, structural, biochemical, and immunological.
Many of the research projects in the physiological damage sub-
category pertain to the pulmonary system. The effects of air pollu-
tants on lung structure are being determined by scanning electron
microscopic (SEM) examination. Pulmonary tissues are also examined
by histopathological methods. Regional deposition of inhaled parti-
cles in the human lung is being determined, and predictive models
that use the patterns of the human tracheobronchial tree are under
development. Functional changes in the lung are being correlated
with the onset of chronic diseases such as asthma and bronchitis.
Upper respiratory tract clearance mechanisms are being examined
in hamster tracheal rings exposed to metallic dusts; from the data,
mathematical models to predict lung function changes are being
developed. The effects of coal-gasification products, especially
particulates, on the defense systems of lungs are being investigated.
For example, the ability of the lung clearance mechanisms to remove
metal particulates is being related to the lung's susceptibility to
bacterial and viral infectious diseases; the objectives are to
correlate pneumonia-induced mortality with specific forms of air
pollution and diseases in general with environmental conditions.
Mathematical models are under development that will predict changes
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in acute and chronic health conditions on the basis of changes in air
pollution using various health and environmental data. Changes in
health conditions would be predicted not only for the pulmonary
system but also for other vital systems.
The interactions of specific pollutants are being studied to
determine additive or synergistic effects. Interactions of vital
systems such as the cardiac and pulmonary systems following agent
insult at various levels are being analyzed. The effects on the
cardiac and pulmonary systems, with special emphasis on the
peripheral circulatory function in adults, are being determined for
exposures to nitrogen dioxide and ozone at low concentrations. The
acute and chronic effects of the inhalation of fly ash and mixtures
of carbon monoxide and sulfur and nitrogen dioxides are being
determined.
The effects on mammalian brain development of generations of
exposure to low-level radiation are being ascertained. Postnatal
development and function of the central nervous system in monkeys
after their exposure to tritiated water during the period from
conception to birth and weaning are being assessed.
Neurotoxicology is a rapidly developing field that needs new
testing and screening methods. One new method uses "seeing
computers"—i.e., computer-based on-line closed circuit television
monitors that feed behavioral response patterns in experimental
animals into a computer for analysis and comparison with baseline
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response data from control animals. Studies are being made of be-
havioral changes that result from exposure to metal dusts, coal con-
version products, hydrocarbons and other pollutants. With such
automated systems, behavioral testing is less time-consuming and more
reliable. Behavioral testing and other neurotoxicologic studies of
the effects of exposure to chemical agents, electrical fields, and
microwave radiation are being conducted. For example, the behavioral
effects of prenatal exposure to microwaves and the effects of micro-
wave radiation on brain activity involving the peripheral and central
receptor mechanisms are being investigated.
6.4.2 Metabolic Effects
All the research projects that involve metabolism studies are
grouped into the metabolic effects subcategory. The functions of
cells, organs, and living organisms all depend on chemical reactions,
i.e., metabolism. These chemical reactions allow cells to perform
life-sustaining functions such as reproducing, obtaining nourishment,
growing, expressing genetic characteristics, and providing defense.
This is true for all living things including man; the only difference
is that usually the more complex the organism, the more complex the
chemical reactions involved. Many substances occur naturally in
living organisms and are necessary for the organism to remain viable.
However, energy-related technology introduces substances into the
environment that affect the chemical reactions necessary for life.
Changes in metabolic reactions caused by environmental agents are
receiving considerable attention.
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The biochemical effects on the macromolecular metabolism of the
lung of trace metals such as cadmium, nickel, lead, and arsenic are
being investigated. The effects of metals on membrane constituents
of the lung and other organs are of special interest. Also being
studied are the effects of hydrocarbons, sulfur dioxide, and related
fossil fuel pollutants on lung membranes, particularly during devel-
opment from birth to adulthood. The metabolism and accumulation of
hazardous agents in lung tissues explains the level of damage seen in
lungs following exposure and often also the degree of toxicity of the
agent. The molecular mechanisms involved in the initiation of cancer
and other diseases by specific energy-related pollutants are being
investigated. Repair and recovery mechanisms are also being studied;
if these mechanisms remain active and viable after chemical insult,
the organ may recover and may construct defense mechanisms against
future pollutant insult.
Methods are being developed to quantify the levels of various
pollutants in tissues, fluids, fat, and other biological samples.
These data provide information that is necessary for determining
metabolic pathways. Factors such as diet that affect metabolic
pathways in various organs are being assessed; diet might affect the
gastrointestinal absorption of cadmium, for example. Sites that
store chemical agents are being analyzed so that storage information
can be used in determining exposure histories. In one study, teeth
are being analyzed for lead to determine the history of lead exposure
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levels in the community. Radioactively labeled compounds are being
synthesized for use in animal metabolism studies so that concentra-
tions of these compounds in body tissues and fluids can be determined
accurately and body clearance rates can be estimated.
Metabolic activation of specific classes of substances is being
studied because many agents require metabolic activation before they
can exhibit toxicity. The enzymatic characteristics of the process
of metabolic activation of carcinogens and subsequent DNA binding are
being investigated. The relationship between the metabolism of car-
cinogens in alveolar macrophages and the induction of lung cancer is
being determined. The potential synergism of two pollutants such as
nitrogen dioxide and ozone are being investigated so that the mode of
toxic action of nitrogen dioxide can better be understood.
Receiving special consideration are the metabolic pathways of
metals, their sites of localization, and transfer mechanisms. For
example, the biochemistry of methyl mercury and its ability to bind
to DNA are being investigated. The neurotoxicity of metals is being
studied from the aspect of their metabolism and their effects on
brain biochemistry. The metabolism of metals and other pollutants in
various cell lines is being investigated. New epithelial cell lines
are being developed; these cell lines have special characteristics
and can activate specific classes of energy-related agents and thus
should prove useful in future screening programs.
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6.4.3 Cytotoxic Response
The research projects that are grouped in the cytotoxic response
subcategory deal with cellular toxicity (cytotoxicity). Cells repro-
duce, grow, and die, and during their lifespan they may undergo gene-
tic alterations that affect the function of the metabolic, damage,
and repair mechanisms. These mechanisms and other cellular reactions
can be monitored for evidence of cytotoxic response to exposure to
toxic substances.
Cellular systems provide an important screening tool for deter-
mining the relative toxicities of pollutants because they are less
complex than whole animal models. Many studies are directed toward
developing new cell lines and cellular systems for screening. Others
are improving present screening procedures and developing new method-
ologies that will improve their efficiency and reliability. Auto-
mated flow systems are being developed to perform chromosomal analy-
sis, to check for karyotype stability in cell lines, to profile
cytochemical markers, and to detect other early cell changes. These
new techniques will shorten analysis time in screening procedures.
Scanning electron microscopic (SEM) procedures are being developed to
examine alveolar macrophage cultures for cytological changes that
constitute the effects of air pollutants on the pulmonary system.
Hyperplastic, metaplastic, and neoplastic changes in epithelial cell
lines caused by toxic chemicals can be detected by microscopic exami-
nation. These cytotoxic responses are important for determining the
hazards of specific environmental agents.
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The effect of toxic agents on the regulatory macromolecules of
mammalian cells is of special interest. Molecular damage to DNA,
auto-oxidation of lipids in biomembranes, the effects of enzyme al-
terations and inhibitions on the synthesis of protein, phagocytic
activity, and collagen synthesis are all being studied. Efforts are
being made to determine the ability of cells to metabolize foreign
agents such as metals and to estimate the agents' rates of binding to
various cell components. Specifically, the cofactors involved in the
conjugation of carcinogens with DNA and other regulatory macromole-
cules are being determined. The effects on the cell of combinations
of agents such as ultraviolet light and polycyclic aromatic hydrocar-
bons are being studied. The effects of toxic agents on neuronal com-
munication in the central nervous system are being investigated by
studying neurons in tissue culture. The promoting role of estrogens
in the hormonal regulation of chemical carcinogenesis is being inves-
tigated so that the induction of endometrial adenocarinoma by estro-
gens can be better understood.
6.5 MORBIDITY/MORTALITY
The Morbidity/Mortality biological endpoint category contains
research projects that are concerned with human morbidity and mortal-
ity related to the energy industries. Many of these studies pertain
to occupational safety and health.
The subjects of occupational health studies include oil shale
workers; deep-sea divers; Alaskan pipeline workers; petroleum
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production workers; miners; coaL-cLeaning workers; solar energy
workers; Tennessee Valley Authority employees; and workers in the
sulfuric acid, sulfate, nitrate, clay fibers, fibrous glass, mineral
wool, and coal liquefaction and gasification industries.
In these studies of workers in energy-related fields, the
workers' occupational histories are recorded, physical examinations
are conducted on a routine basis, and death certificates are
examined. More specifically, petroleum production workers, miners,
and coal-cleaning workers are being examined for evidence of physical
and chemical skin irritation. Workers exposed to insulation
materials (e.g., clay, glass, and mineral wool fibers) are being
studied for lung dysfunction and disease. Alaskan pipeline workers
are being examined to determine the health effects of cold stress.
In addition, acute and chronic toxicities to humans and the safe
exposure levels of several energy-related hazardous materials are
being estimated.
Epidemiological studies include studies of the health effects
resulting from the deterioration in air quality that is attributable
to fossil fuel power generation, the health effects of increased
indoor air pollution, and the childhood health effects' of infant
exposure to PCBs in mothers' milk. A survey of people using water
\
supplies that originate in areas used for coal extraction is in
progress.
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Morbidity/Mortality studies received approximately $6.8 million
in funding through fiscal year 1978, or about 12 percent of the fund-
ing for the energy-related health effects research that was provided
by the Federal Interagency Energy/Environment R&D Program. Alloca-
tions through fiscal year 1978 for individual research projects in
this category ranged from $8000 to nearly $1 million.
6.6 MULTIPLE
A few research projects have been grouped in the Multiple bio-
logical endpoint category. Each of these projects examines various
effects of given energy-related pollutants and, therefore, deals with
more than one biological endpoint.
These projects include studies of the hematologic and mutagenic
effects of arsine, the teratogenic and mutagenic effects of trace
metals, and the mutagenic and carcinogenic effects of hydrocarbons on
cultured mammalian cells. In other studies, the chemistry, cytotoxic-
ity, mutagenicity, and pulmonary effects of stack emission condcn-
sate samples are being determined.
Funding for the Multiple biological endpoint category amounted
to about $1 million through fiscal year 1978. This level of funding
constitutes about 2 percent of the total expenditure for the Health
Effects Research Program. Individual research projects in this
\
category received allocations that ranged from $36,000 to $475,000.
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6.7 NOT APPLICABLE
Those health effects research projects that do not involve
specific biological endpoints are grouped in the Not Applicable
category. These projects are usually supportive in nature. Some
entail information gathering, establishing computerized data bases,
or developing predictive models.
The objectives of other projects in this category are to estab-
lish a national environmental specimen bank, organize workshops,
develop risk assessment methodologies and safety recommendations, and
prepare environmental samples for testing. Some projects involve
maintaining air quality monitoring stations (e.g., CHESS and CHAMP)
in support of human health studies and maintaining stationary and
mobile facilities (e.g., CLEANS/CLEVER) for developing a physio-
logical data acquisition system.
The Not Applicable category of research projects received
approximately $13.1 million through fiscal year 1978, a level of
funding that represents about 23 percent of the total support for
the Health Effects Research Program. Expenditures for individual
research projects in this category ranged from $4500 to about $1.6
million.
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SECTION 7
PROGRAM REVIEW FROM THE PERSPECTIVE OF AGENTS/POLLUTANTS
In this section, the Health Effects Research Program component
of the Federal Interagency Energy/Environment R&D Program is reviewed
in terms of the agents and pollutants that derive from the various
energy technology processes. For the purposes of this review, seven
agent/pollutant categories were selected:
• Organic—includes substances such as hydrocarbons, sodium
acetate, and methyl mercury
• Inorganic—includes inorganic compounds and substances such
as fly ash, particulates, fibers, and asbestos
• Elemental—includes elements such as metals (e.g., iron,
lead, and molybdenum) and oxygen (i.e., ozone)
• Physical—includes physical agents such as radiation (e.g.,
ultraviolet, microwave, and radio frequency) and temperature
• Energy-related—includes nonspecified substances derived
from energy technologies
• Multiple—includes substances such as mixed carcinogens and
photochemical air pollutants
• Not Applicable—for those research projects that are not
concerned with any specific agent or pollutant as a test
substance (e.g., occupational safety studies, workshops,
data bases, and specimen banks).
Each research project was assigned to the appropriate agent/pollutant
category.
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The funding provided each agent/pollutant category through
fiscal year 1978 and the relative levels of effort are indicated in
Figure 4.
7.1 ORGANIC POLLUTANTS
Organic substances are classically defined as those that contain
carbon. For the purposes of this discussion, all carbon-containing
substances including organometallic compounds are classified as
organic pollutants. Many of the products and by-products of energy-
related technology processes are organic in nature, and they are
used/tested in many of the health effects research projects. These
studies involve developing testing methods, screening suspected toxic
substances, determining relationships between agents, and determining
the mode of toxication.
Polycyclic aromatic hydrocarbons (PAH) are derived from several
energy technologies, and many are carcinogenic. These compounds are
being subjected to a variety of tests. Research is in progress to
develop screening systems suitable for PAH. These include a tracheal
graft model system and a bacteriophage system for evaluating the
toxicity and carcinogenicity of PAH. In other PAH research projects,
the investigators are trying to identify the susceptible positions on
PAH substrates that react with nucleic acids, to determine the damage
i
and repair mechanisms for DNA in specific germ cell stages of mammals
following _in vivo exposure to PAH, and to determine other biological
damage mechanisms of PAH. The carcinogenicity of PAH and the
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Organic
Inorganic
Elemental
Physical
Energy-
Related
Multiple
Not Applicable
(15%)'
(21%)
(4%)
(10%)
(19%)
(27%)
LL1 I I 1 I 1 1 I I r I I I
13 5 7 9 11 13 15
Millions of Dollars
17 19
Percentages indicate portion of total effort.
FIGURE4
FUNDING OF PROJECTS BY AGENT/POLLUTANT CATEGORY
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regulatory role of estrogens and other hormones in the induction of
carcinogenesis are being studied.
Several studies pertain to halogenated hydrocarbons. Research
on PCBs involves examination of mother's milk for PCBs, determination
of the childhood health effects of PCB exposure in infancy, and study
of the pharmacodynamics of PCBs. Studies of hexabrominated biphenyls
involve determination of their neurotoxicity to mice and rats.
Benzo(a)pyrene (BaP) is being studied in several research proj-
ects. One involves research on carcinogenesis initiation and its
analogy to other biological responses such as mutations. A pulmonary
carcinogenicity testing system is being used to ascertain whether
there is a correlation between cell proliferation and lung tumor
susceptibility and whether susceptibility to BaP is age dependent in
mice. The metabolic capability of in vitro test systems to produce
the same metabolically active carcinogenic metabolites of BaP as are
formed in vivo is being examined. The structure of BaP metabolites
bound to DNA of Salmonella is being determined.
Polycyclic arenes are under study, specifically their photo-
degradation. The effects of carbon monoxide on neurons in tissue
culture are being studied. Research projects dealing with organo-
metallic compounds include studies of the effects of cadmium acetate
on the ultrastructure of type A spermatogonia and the binding of
methyl mercury with DNA.
A number of organic substances and mixtures are being subjected
to toxicologic screening. For example, potential air pollutants are
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being screened for carcinogenicity with the BALB/C3T3 and C3H/10T 1/2
bioassay systems, for gene mutations in mouse germ cells (in vitro),
and for carcinogenesis and virus activation (in vitro). Organic
products and by-products of coal and oil utilization are being
studied to determine the functional and quantitative changes that
they induce in immunocompetent cells. Environmental chemicals are
being tested to detect their genotoxic effects on cultured liver
cells.
Other research projects on nonspecified organic substances
involve the development of testing methodologies and the determina-
tion of response relationships. These studies include development of
a modified host-mediated assay using human lymphoid cells, develop-
ment of a DNA repair system for monitoring human health effects, and
determination of the relationship between carcinogen metabolism in
the alveolar macrophage and the induction of lung cancer. Coal
conversion and utilization products are being tested in monkeys; an
automated behavioral testing system is being developed for evaluation
of the toxicity of these products on the central nervous system.
Environmental mutagenic agents are being screened by both in vitro
and in vivo testing methods. The study of environmental carcinogens
will be aided by the development of permanent epithelial cell lines
i
for use in determining toxic/carcinogenic effects.
Some research projects are concerned with the combined effects
of both organic and nonorganic substances. Those that combine
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organic and inorganic substances include the following studies:
determination of the effects of whole animal exposure to acid mists
on pulmonary metabolism of BaP in isolated perfused rabbit lung;
development of faster, more efficient, and less costly methods of
determining teratogenic changes that result from exposure to dipterex
and asbestos; determination of the role of irritant gases on the
susceptibility of respiratory tract epithelium to tumor induction;
and assessment of the effects of mixed pollutants (e.g., sulfur and
nitrogen dioxides and formaldehyde) on alveolar macrophages by bio-
physical and biochemical techniques. The chemical toxicity of PAH,
chloroform, sodium sulfite, lead and platinum is being monitored by
the mouse oocyte system. One research project is screening organic
substances and physical agents by teratology test systems. A study
of metal-binding components of emissions from mobile and stationary
energy sources is characterizing them chemically and determining
their toxicity.
The Organic pollutants category received approximately $8.7
million through fiscal year 1978, or 15 percent of the funding for
the Health Effects Research Program. Expenditures for individual
research projects in this category ranged from $25 ,006 to $719,000.
7.2 INORGANIC POLLUTANTS AND AGENTS
i
For the purposes of this review, the Inorganic pollutants and
agents category includes agents such as fly ash, particulates, and
fibers in addition to inorganic compounds.
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Various inorganic sulfur compounds are being studied. One re-
search project is a study of the effects of respirable sulfates and
sulfuric acid mists on the respiratory function of normal human sub-
jects. Occupational exposures to sulfuric acid and sulfur dioxide
are being examined in epidemiological studies. The effects of hydro-
gen sulfide on neurons in tissue culture are being examined in
another study.
Nitrogen compounds—nitrogen dioxide in particular—are being
examined in various research projects. Epidemiological studies are
in progress of persons who are/were occupationally exposed to nitric
acid and to nitrogen dioxide from fossil fuel sources. The effects
of nitrogen dioxide on the lung are being examined in several re-
search projects; these include studies of the auto-oxidation of lung
biomembrane lipids and surfactants that is initiated by nitrogen
dioxide and its inhibition by antioxidants, the effects of vitamin A
on lung cell kinetics, and the alteration of nitrogen dioxide toxic-
ity by vitamin E and lipids. The effects of nitrogen oxides on
membranes (e.g., liposomes, lecithin multilayers, and bioraembranes)
are being determined by electron spin resource spectrometry.
A few of the health effects research projects pertain to inor-
<•
ganic metal compounds. The cytotoxicity of selected metallic
sulfates is being assessed. Metal oxides tare present in emissions
from fossil fuel combustion, and the role of alveolar macrophages in
the distribution of inhaled metal oxides is being studied. The
hematologic and tnutagenic effects of arsine are being determined,
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Several research projects pertain to airborne particulate
matter. Particulate samples are being procured, prepared, and
characterized for toxicologic testing. Particulate material is
screened for potential hazard by an alveolar macrophage test system.
Models are being developed to predict the deposition of inhaled
particles in regions of the human lung. The effects of prolonged
inhalation of nickle-enriched fly ash are being investigated in
Syrian golden hamsters.
Mineral wool fibers, small fibrous glass fibers, and clay fibers
in insulating materials are the agents under study in several proj-
ects. Occupational exposure, mortality, and industrial hygiene
studies are being conducted of workers in these industries.
Some of the research projects are examining the effects of
simultaneous exposure to pollutants/agents from more than one cate-
gory. Those that involve inorganic and organic pollutants were
discussed under Organic pollutants (Section 7.1). Two other projects
involve one other category in addition to Inorganic pollutants. In
one of these, the effects of nitrogen dioxide and environmental trace
metals (i.e., elemental pollutants) on lung metabolism are being
investigated. In the other, the effects of nitrogen dioxide during
<•
heat stress (a Physical agent) are being assessed by monitoring the
cardiac, pulmonary, and peripheral circulatory functions in adult
male volunteers.
Funding for research projects in the Inorganic pollutants and
agents category was approximately $12.2 million through fiscal year
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1978. This sum constitutes 21 percent of the total funding for the
Health Effects Research Program that was provided by the Federal In-
teragency Energy/Environment R&D Program. The level of funding for
individual research projects in this category ranged from $35,000 to
$692,000.
7.3 ELEMENTAL POLLUTANTS
For the purpose of this review, unconjugated metals and elemen-
tal compounds such as ozone are grouped in the Elemental pollutants
category.
Several research projects pertain to lead. Among these are
studies of the concentration of lead in the teeth of children and the
interaction of lead with body tissues and fluids. Lead is usually
included when a group of metals is under study (see below). The com-
bined toxic effect of lead and platinum with several compounds is
being studied (see discussion under Organic pollutants, Section 7.1).
Cadmium is the object of study in several research projects.
These include determination of the effects of cadmium on karyotype
stability in CHO cells and on growth and metabolism of CHO cells
exposed to low levels of cadmium. The interactions of cadmium with
pulmonary alveolar macrophages are being studied.
Some projects involve screening or testing various metals. For
example, methods are being developed for the use of teeth as indica-
tors of the tissue dose of various metals. Cadmium, mercury, nickel,
arsenic, lead, and platinum are being studied to determine their bio-
chemical effects on pulmonary macromolecular metabolism.
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Ozone is the subject of several health effects studies. One, a
study of occupational exposure of welder trainees to ozone, entails
examination of peripheral blood lymphocytes for chromosomal aberra-
tions. In a study of ozone toxicity to lung lipids, the effects of
vitamin E on this toxicity are being examined. The combined effect
of ozone and trace metals on lung metabolism is the subject of
another study. One research project pertains to the effects on adult
males of exposure to ozone during heat stress, as monitored by
changes in their cardiac, pulmonary, and peripheral circulatory
functions.
Funding for the research projects that are grouped in the
Elemental pollutants category amounted to approximately $2.3 million
through fiscal year 1978. This sum constitutes 4 percent of the
total funding for the Health Effects Research Program. Expenditures
for individual research projects in this category ranged from $35,000
to $921,000.
7.4 PHYSICAL AGENTS
The Physical agents that are being studied in the Health Effects
Research Program are radiation and temperature. Several types of
radiation—microwave, electrical field, radio frequency, light, and
radioisotope—are being studied. Temperature studies include the
effects of both cold and heat stress.
Several research projects pertain to microwave radiation and its
effect on the central nervous system. Investigators are examining
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the effect of microwave radiation on neural response; its effects on
the behavior and reproduction of monkeys, rats, and other animals;
and the peripheral and central receptor mechanisms that mediate the
effects of microwave radiation on brain activity. A criteria docu-
ment for occupational exposure to microwave and radio-frequency
radiation was developed; it presents recommendations on the control
of hazards associated with these exposures.
Research on the effects of electrical field radiation includes
behavioral testing, neurotoxicologic studies, and monitoring of
reproductive and biochemical effects. In addition, the genetic
effects of electrical field radiation are being studied by assessing
the frequency of chromosomal aberrations in offspring of exposed
Drosophila.
Research on light involves both visible and ultraviolet light.
The role of visible and ultraviolet light in synergism with PAH is
under study. In particular, the mechanisms of skin tumor initiation
are being investigated.
Radioisotope studies use tritiated water to expose monkeys to
radiation during the period from conception to birth and weaning.
Postnatal development and function of the central ner\jous system are
monitored in the offspring.
The effects of temperature extremes are being studied in two
research projects. One, involving cold stress, is an industrial
hygiene study that was designed to determine the work practices
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needed to protect Alaskan pipeline workers. The other is a study of
heat stress; specifically, the effects on adult males of exposure to
nitrogen dioxide, ozone, and ambient air during heat stress. The
cardiac, pulmonary, and peripheral circulatory functions of the
subjects are being monitored.
Expenditures for the research projects that involve Physical
agents amounted to $2.1 million through fiscal year 1978. This sum
represents about 4 percent of the total funding for the Health
Effects Research Program. The level of funding for individual
research projects in this category ranged from $9000 to $891,000.
7.5 ENERGY-RELATED POLLUTANTS
The general, undefined pollutants that are derived from energy-
related sources are included in this category. Although a few are
nonspecific, some are defined as the by-products present in the
emissions and effluents from alternate energy technology processes.
Crude material from nonspecified alternate energy sources will
be screened for potential carcinogenesis using bacterial mutagenesis
testing methods that are now under development. The effects of coal
and oil shale conversion products on cell cycle kinetics and chroma-
tin structure are being determined. Several research projects in-
volve testing effluents and emissions from alternate energy techno-
logy processes. For example, studies are being conducted with
products released from coal conversion (e.g., gasification and lique-
faction) processes in order to determine mammalian cell mutagene-
sis, evaluate dose-response relationships for immune system enzyme
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levels, determine molecular damage to DNA and proteins, assay the
mutagenicity of fractionated coal conversion products, and develop a
nonmammalian (fish) model for quantitative evaluation of carcino-
genicity.
Cocarcinogenic agents produced during coal and oil shale pro-
cessing and from low-Btu gasifiers are being screened by in vitro
methods. The effects of chemical toxicants associated with the pro-
duction and consumption of fuel on the physiology and pathophysiology
of phagocytic cells are being determined. Undefined pollutants from
various energy technology processes are being subjected to quantita-
tive mutagenesis testing in mammalian cellular systems. The inter-
actions of various undefined pollutants and their relationship to the
causation of pulmonary disease are being investigated.
Several projects involve energy-related air pollutants. The
effects of exposure to photochemical air pollutants are being studied
by examining the resultant chromosomal aberrations in peripheral
lymphocytes of man. In vitro screening of selected air pollutants
for potential carcinogenicity uses microbial systems. Individual
pollutant particles in lung tissue are being analyzed by multimode
scanning electron microscopy. Emissions from power plants that burn
eastern and western coals are being characterized, evaluated toxico-
logically, and compared.
Projects in the category of Energy-Related pollutants received
approximately $6.1 million in funds through fiscal year 1978. This
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sum constitutes about 10 percent of the total funding provided for
the Health Effects Research Program. The level of funding for
individual research projects in this category ranged from $30,000 to
$530,000.
7.6 MULTIPLE POLLUTANTS
The Multiple pollutants category consists of nonspecific
pollutants (e.g., environmental mutagens) and mixtures of pollutants
(e.g., air pollutants).
The effects of environmental mutagens on the genotypes of higher
animals are being monitored. The tumor response evoked by exposure
to mixed carcinogens is being studied to determine the synergistic
action of these substances. DNA is being exposed to chemical
carcinogens and radiation for study of synergistic effects and the
DNA repair mechanisms.
Pollutants present in drinking water are being studied. Areas
where drinking water supplies are contaminated with energy produc-
tion by-products are being identified, an epidetniological study of
the people using these water supplies is in progress, and morbidity/
mortality information and water quality data are being correlated to
identify any adverse health effects that are attributable to the
energy-related pollutants.
Various research projects pertain to air pollutants. The pul-
monary effects of exposure to toxic gases and particulates are being
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investigated through studies of the biochemical mechanisms of pulmon-
ary injury and the biology and pathobiology of pulmonary epithelial
cells. The effects of acute exposure to petrochemical air pollutants
on biochemical and physiological responses in man are being deter-
mined by investigating the interaction of atmospheric contaminants
with respiratory system components and receptors at both the bio-
chemical and functional levels. Changes in air pollution that will
result from changing energy requirements are being determined, and
models are being developed for use in predicting the health effects
that such changes in air pollution will produce in the general popu-
lation. The effects of increased indoor air pollution on human
health are being studied; these changes in air pollution levels are
attributable to energy conservation measures. The effects of ambient
air (compared with exposures to nitrogen dioxide and ozone) during
heat stress are being studied in adult volunteers.
Approximately $10.9 million was funded to research projects in
the Multiple pollutants category through fiscal year 1978. This
level of funding constitutes about 19 percent of the total funding
for the Health Effects Research Program. Expenditures for individual
research projects in this category ranged from $8000 £o $1.5 million.
7.7 NOT APPLICABLE
The Not Applicable category consists'of those health effects
research projects in which no specific agent or pollutant is being
tested or studied. Many of these projects involve information-
gathering tasks that include the establishment of computerized data
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bases, establishment and maintenance of air quality monitoring sta-
tions, and maintenance of data acquisition systems.
Other projects provide different types of support for the Health
Effects Research Program. Some of these involve the continued de-
velopment of risk assessment methodologies and mathematical models.
Other projects entail the development and/or improvement of labora-
tory techniques for use in research; among these techniques are iden-
tification of markers for preneoplasia in respiratory epithelium,
detection of point mutations in somatic cells, scoring of chemical
transformation in C3H/10T 1/2 cells, and detection of early changes
in lung cell cytology by flow-systems analysis.
Funding for research projects in the Not Applicable category
amounted to approximately $15.6 million through fiscal year 1978,
which is 27 percent of the total funding for the Health Effects
Research Program. The level of funding for individual research
projects in this category ranged from $4500 to $2.6 million.
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APPENDIX
LIST OF PROJECTS IN THE HEALTH EFFECTS RESEARCH PROGRAM
K1NC-MUIR CATEGORY #1
Chemical Characterization and Toxicity of Metal-
Binding Components of Emissions from Mobile and
Stationary Energy Sources
from Power Plants Using Eaatern vs. Western Coals
Determination of the Influence of Materials Concerned
with the Extraction of Ores
Wentif y Hazardous Agents Associated with Nonnuclear
Energy Technologies Using New and Available Biologi-
cal Screening and Test Systems
Cellular Toxicity of Selected Metallic Sulfates:
Studies on the Rabbit Alveolar Macrophages In Vitro
Implementation of Screening Tests for Potentially
Hazardous Airborne Participate Materials Using
Alveolar Macrophage Test System
Calibrate Cyclone Used to Obtain Large Quantities of
Size-Segregated Particulate
Field Testing—Application of Improved Combustion
Technology to Power Generation Combustion Systems
Comparison of Pulmonary Carcinogenic!ty of Known
Carcinogens with and without Added HjSQi, Mists,
Airborne Respirable Particles and Gases
Development of Methods for Determination of Carcino-
genesis by Bacterial Mutagenesis Employing Crude
Material from Alternate Energy Sources
Studies to Improve the Reliability and Sensitivity
of Bacterial Mutageneaia as a Screen for Environ-
mental Carcinogens
Development of Automated Behavioral Testing Method-
ologies for Study of Effects of Coal Conversion and
Utilization Products
PRINCIPAL
INVESTIGATOR
Palekar/Carter
Campbell
Manny
Laskin/Sellakumar
Commoner
University of Cincinnati
University of Cincinnati
Northrop Services
Northrop Services/Oak Ridge
Northrop Services
Northrop Services
Southern Research Institute
Exxon R & E
New York University
Washington University
Washington University
Iowa State University
121
-------
K1NC-MUIK CATtXUIKY *l (Continued)
PRINCIPAL
PKOJtlCT INVESTIGATOR
!.»(.• Kiwiroim.-nt.il Contaminants for Biological
Experimental ion
Chemical Char--u:U>ri*at um and Specinu-o Preparation Walia/Yamante
Airborm1 Part i dilates
Chemicals in Cultured Liver Cells
The Need for Combined In Vitro and In Vivo System* in Legator
Carcinogens
Teat System
In Vivo Methods for Assessing Neurotoxicity Borachein
Determine the Relative Cellular Toxicity of Selected
Compounds Including Xetallic CMorid.es, Sutfates,
Samples Obtained from Stationary Sources and
Ambient Air
Systems
Gasification Effluents
Hydrocarbons and Indus tr ial Chemicals
AFFILIATION
IIT Research Institute
Brookhaven National
Laboratories
University of Cincinnati
Northrop Services
Lawrence l.ivemore
Laboratory
Lawrence Live more
Laboratory
Laboratory
A Bacceriophage System for Screening of Carcinogenic
Polycyclic Aromatic Hydrocarbons
Effects of En^rgy-Related Pollutants on Careinogenesis
or Assessment of Carcinogenic Risk from Energy-Related
Environmental Pollutants--Rodent Model
Development of in VJUo Screening Assay for Cocarcino-
gt'nic Agents Produced during Co.it and Oil Shale
Detect ion of Early Chanjje.s in
Flow-Systems Analysis Techni
-------
KIKG-MUIK CATEGORY fl (Concluded)
PRINCIPAL
PROJECT INVESTIGATOR
Products
Polycyclic Aromatic Hydrocarbons
in Mouse Germ Cells by Coal Conversion Produces
Biological Screening Study of Low BTU Industrial
Gas i tiers
Biological Screening Study of H-Coal Liquefaction
AFFILIATION
Laboratory
Laboratory
Laboratory
Nuclear Medicine and
Radiation Biology
Laboratory
Department of Energy
Department of Energy
123
-------
KINOMUIH CATEGORY »2
PROJtXT
Spermatogoni.i
Development .it Lt-lUUr Motto 1 System to Determine
l)i'vt>l»pmt>nt ul Birtindicatorfl ot S02 and NC-2 Exposure
y
Workshop on "Screening Systems for Alternate Energy
Effluents11
and Heopiaatic Transforraat ion--Improved Scoring ot
Chemical Transformation ot C3H/IOT' Cells
Development of Methods for Determination of Potential
Employing Crude Material from Alternate Energy Sources
PRINCIPAL
INVESTIGATOR
Bhatnag.-r
Bower a
Bol linger^Ce I ler
Rajagopalan
Ueinstein
Lloyd
Aldridge
Schrechtman
Cooper
AEM: IATION
University of California
Rockefeller University
Duke University
Co t umb ia University
Kappa System, Inc.
California
Microbiological Associates
University of Cini_innati
During Long-Term Continuous Exposure to S02 and Particu-
late Matter
Chronosomal Aberrations in Peripheral Lymphocytes of Man
as a Function of Exposure to Photochemical Air Pollutants
ChromoBomal Abnormalities Araonjj Welder Trainees
To Evaluate- Existing and Improved Methods for Sanpting.
Transport, Storage, and Analysis of Biological Specimens
Which Might Serve as Indicators of Contamination by
Eifluents from Energy Technologies
Development of CytachemLcaL Markers for Cell Transforma-
tion and Carcinogenesis
EHecCs of Products of Coal and Oil Shale Conversion on
Cell Cycle Kinetics and Oiromatin Structure
Development and Use of Diffe
Developtnent ot Permanent KpithelUl Cfll Line for Study-
ing Toxic/Carcinogenic Effect! of tnvi rorawntal Carcino-
gens
Hayall
Tobey
CerflchensoTi
SeUirk/Kenney
university of Utah
Columbia University
Standards
Lawrence Livermore
Laboratory
Los Alamos Scientific
Laboratory
Development of Method for Utilizing Tteth
ot Tissue Dose tor Trace and Heavy Metals
UCLA Laboratory of Nucl,
Medicine and Radiation
Biology
Oak Ridge National
Laboratory
Brookhaven National
Laboratory
124
-------
KINC-MUIR CATEGORY »2 (Concluded)
PROJECT
Development of Nonmammalian (Fish) Model for Quantitative
Germinal Cells
Mice
Development of a New Mouse Strain to Maximize the Sensi-
tivity of a Point Mutation Assay
Amplification of Point Mutation System: Characterization
of Mouse Esterases by Isoelectric Focusing
Development of a Polygenic Assay for Point Mutations in
Mice
Detection of Point Mutations in Somatic Cells
Development of Faster, More Efficient and Leas Costly
Methods for Determining Teratogenic Changes
Mutageaesia in Cultured Lymphocytes
Development of DNA Repair for Monitoring Human Health
A Modified Host-Mediated Assay Using Human Cells
Developmental Toxicology Indicators
Carcinogenesis of Fossil Fuel Related Combustion
PRINCIPAL
INVESTIGATOR
Set low
Creisemer/Pal
Mailing
Roderick
Roderick
Mien
Crenshaw
Nute
Johnson
Bloom
Siciliano
Mitchell
Huang
Dixon
Nettesheim
AFFILIATION
Brookhaven National
Laboratory
Oak Ridge National
Laboratory
NI&HS
The Jackson Laboratory
Medical University of South
Carolina
Technology
University of Washington
Research Triangle Institute
Columbia University
University of Texas Cancer
Center
New York State Department
of Health
NIEHS
NIEHS
Products
Validation of Short-Term Tests for Mutagenicity as
Predictors of Potential Carcinogenic Activity
DNA Repair Capacity and the Mutagenic and Carcinogenic
Effects of Chemicals in Eukaryotes
Mutagenic Mechanisms
Aneuploidy Workshop
Drake
de Serres
125
-------
KING-MUIR CATEGORY »3
PRINCIPAL
INVESTIGATOR
AFFILIATION
fctfects of fcnvi ronmental Pollutants in R.-lation to Agi
Toxicity of Compounds Emitted fro* Coal Gasification
Scanning Electron Microscopic Examination ol the tffe
of Air Pollutants an Pulmonary Systems
Studies on the Relationship between Carcinogen Metabo
lism in the Alveolar Macrophage
Investigation of Effects of Prolonged Inhalation of
Nickel-Enriched Fly Ash in Syrian Golden Hamsters
lament ot Fly
The Effects of HO2 Exposure »n the Disposition and
Metabolism ol Certain Endogenous Antioxidants of
the Mammalian System
Interactions uf Various Pollutants on Causation of
Pulmonary Disease
effects of Alternate Energy Material on Whole Animal
Lunan/Brandt
Fenters/Ehrlich
Institute tor Mvdi.:-tl
Research and Occupational
Health,
Zagreb, Yugoslavia
IIT Research Institute
Northrop Services
Battelte, Pacific Horthwest
Laboratories
Huntington Research
Corporation
Stanford Research Institute
1IT Research Institute
Effect of Trace Elements and Heavy Metal on the Detoxi
fieat ion of Sulfite by SuLfite Oxidase
Deposition, Retention and Dosiraetry of Inhaled Reactio
Products Which May Result from SC^ Particle Reactions
Metabolism of Inhaled Trace Metal Effluents from Corn-
Influence of Diet on the Gastrointestinal Absorption
of Cadmium
Synthesis of Labeled Organic and Organometallie Com-
pounds for Use in Metabolism and Catabolisn Studies
Metabolism and Disposition of Selected Radio-labelled
Hydrocarbon* and Some of Thevt ChemicalLy Reactive
Epoxides by the Isolated, Perfused Rabbit Lung and by
Soiubilized, Reconstituted Pulmonary Biotransformat ion
System
Environmental Teratology Information Center (ETIC)
Regulation of Neural Distribution of Lead
Function of Metaltothionein in Heavy Meta 1 Metabo
Mechanisms ot Heavy Metal Toxicity
Effects of Microwave Radiation on the Nervous Sy»
Snipes
Cuddihy
Ualburg
Wolf
Was8OB
O'Tauaa
Brady
Woods
Lovely
Duke University
Lovelace Foundation
Lov
University of Tennessee
Brookhaven National
Laboratory
Oak Ridge Hat {.ana I
Laboratory
University of Worth Carolina
University of South Dakota
NLEHS
University of Washington
126
-------
KING-MUIK CATEGORY »3 (Concluded)
PROJECT
PRINCIPAL
INVESTIGATOR
AFFILIATION
Biological Effects of 60-Hertz Electric Fields
Respiratory Tract Deposition Models
Respiratory Tract Deposition of Inhaled Aerosols
Factors Affecting Irritant Potency of Gases and Aerosols
departmental Models for Body Burden of Pollutant*
Trace Element Deposition in Ambient Aerosol Inhalation
Development of NHR Spectroscopic Method* for Character-
izing Specific Bonding (Electronic and Covalent Bond-
ing} Modes of Organica and Inorganics Associated with
Nonnuclear Energy Technologiea
Development of the Probability Matched Gas Chromato-
graphic Mass Spectrographic Systea to Screen Biological
Tissue from Mothers and Newborn Infanta for Energy-
Related Chemicals in the Environment
Biochemical Mechanisms of Pulmonary Injury
The Interaction of Lead with Body Tissues and Fluids
Photodegradation of Absorbed Polycyclic Arenea
Interaction between Light and Environmental Agents
Lung Cell Conversion of PAH
Pharmacology of PCBs
Phimacokinetics of Pulmonary Uptake and Metabolism
Relationship of Metabolism, Fate, and Toxicology of
Participates and Organic Compounds
Nucleation Properties of Reapirable Coal Dust
Cellular Response to Coal Iti Vitro
V/Q in Occupational Lung Disease—Basic Development
Marino
Rasbe
Yu
Asrtur
Marcus
Winchester
Lipf»un
McKinney
Hook/El ing
McKinney
Daisey
Bend
Matthew
Wilson
Bruckner
Schoengerdt
Christian
Massaro
Research Foundation of SUNY
State University of New
York *t Buffalo
Harvard School of Public
Health
University of Maryland
Florida State University
New York University MediciI
Center
M10SH
Colorado School of Mines
University of Cincinnati
University of Wisconsin
127
-------
PRINCIPAL
INVF.SriCATOK
AFFILIATION
K-i feet ,)t Res pi r able SuI fates and HoSO-,
tory Funftion in Normal Human Subjects
Energy Sources on Upper Respiratory Trace Clearance
Mt>t ham smi
i>f Ambient Air Pollution
Us inn Cellular Model Systems
Trachea 1 Organ Culture as Air Pollution Damage Indicator
Effect of Material t
Animal [>ef*na« Syste
K Meet a of Convent iunal and Advanced Coat Conversion j
Etfeets n f Chronic or Intermittent Exposuru to Ruapirable
('articles and Mists in Moust- Pulmonary Infpctivity Model
Evaluation of Ni'onate Siiuirrcl Monkeys Receiving Triti-
atoil Water t h rough nut Cestat ion
Inventvfcalion n( the Neoplaatic and Life Space Effects of
Potentially Sensitive Populatinna ^f Rats Chronically
Exposed to Tritiateil Water
mental Trace Metals on Lung Metabolism
Study of Metabolic and Physiologic Measurements in Popu-
lations with Long-Term Exposure to Pollution from Coal
Combustion
Hion and Utilization t,> Whu'h Han is Exposed Orally and
by Inhalation
Study of People Using Water Supplies Or
Hoschandreas
Schiif/Ehrlich
Cause
Aranyi
Ehr I ich/flradof/Fenter
Janes
University of CaLiforni
University of Maryland
Univ
Ball State University
Oak Ridge National
Laboratory
University of Illinois
Pennsylvania State
University
Southwest Research
foundation
IIT Research Institute
IIT Research Institute
Stanford Research Institute
Dawson Research
Corporation
UCLA School of Medicine
University of Akron
Litton fiionetics
128
-------
KINC-HUtk CATEGORY #4 (Continued)
PRINCIPAL
INVESTIGATOR
AFFILIATION
Evaluate Che Influence of Inhalation of Ac U Aerosols,
H2S04, 503, HNOj and Participates on Production of
Chronic Lung Disease in Rats, Guinea Pigs and Primates
Effects of SOX Pollutants on Respiratory Function, Par-
ticle Deposition and Bronchial Clearance
CLEANS/CLEVER:
Operation and Maintenance
Quality Control for Assessment of Hunan Exposure
AeroaoL Addition to CLEANS
Stationary and Mobile Facilities for Study of Health
Effecta of Environmental Contaminants (CLEANS/CLEVER)
Tyler
Lippoun
Vilcn
University of California
Mew York University
Rockwell International
Northtop Service*
Environments! Research and
Technology
Computer Science Corporation
Continuous Air Quality Monitorinj for Community Raphael
Health Studies
Addition of Mobile Air Monitoring Field Stations Raphael
and Portable Air Pollution Monitors to CHAMP System
Operation, Calibration and Maintenance of Total Raphael
CHAMP System
Operation and Maintenance of the Community Health Sullivan
Air Monitoring Program
The Effect of Whole Animal Exposure to Acid Miata on Warshavsky
Pulmonary Metabolism of BenEo(a)pyrene in the Isolated
Perfused Lung Model
An Environmental Health Study of Lead in Teeth Wilkinson
Maintain CHESS Stations and Collect Data in Chattanooga Decker
Area
Human Biochemical and Physiologic Response to Acute Pho- Pleah
toehemical Air Pollution Exposures
The Effects of Low Levels of NOj, 03, and Ambient Air
Separately and in Combination on Cardiac, Pulmonary, and
Peripheral Circulatory Function in Adult Males in Response
to Heat Stress at Rest and During Moderate Exercise
Feaaibility Study on the Mortality Effects of Deteriora- Shy
tion in Air Quality Due to Fossil Fuel Power Generation
Evaluation and Research of Methodology for National Envi- LaPleur/Rook
ronmental Specimen Rank
HematoLojic and Mutagenic Effects of Arsine
Rockwell International
Rockwell International
Rockwell International
Xonicet Inc.
University of California
Delaware State College
Research Triangle Institute
Copley Internal tonal
University of California
University of North Carolina
National Bureau of Standards
New York Univertity Medical
Canter
129
-------
HkOJECT
c i , st r , c n F u i h i c
Related Industry
ti>gt>nicity ol Metallic Pollutants
Lfv.'l .il Drosop^iU
Usi> ot the Muuat- Spec 1 1 i L--LOLUS Method to yuantity the
Levels ot Such Agents
The Mouse Oocyte System as a Monitor ot Chemical
J'oxu-ity
and Carcinogenic Hydrocarbons on Cultured Mammalian
Cells
Evaluate the ttt'eft ot Low Level Chronic Radiation on
N02, S02. an.i Fly Aah
Bioc hem i at ry
Effect of Acid SuHate particles and S02 on the Bac-
tn the Lung
Cardiopulmonary Injury and Repair after Inhaled Acid
Sulfate Aerosols
Effects ol Carbon Monoxide, Hydrogen Suit ide and Other
Knergy Products on Neurons vn Tisaue Culture
Functional Level »
Temporal Aspecta of Tumor Response to Individual
and Mixed Carcinogen Exposure
The Role of Irritant Gases on the Susceptibility
In Vivo to Polycyclic Hydrocarbons
PRINCIPAL
INVESTIGATOR
Brooks
Hackett
Humgate
Russel 1
Hsie
8u*sel i
Dot? s on
de Veil i«
Zaeenhof
Craig
Loscutof f
Hahn
Mauderly
Tobias
Morrow
Albert
Marchok
AFF 11.1 AT ION
Lovelace Fcuidati „
Laboratory
Laboratory
Oak Ridge Nat ional
Laboratory
Oak Ridge Nat ional
Laboratory
Oak Ridge National
Laboratory
t
t
Laboratory
UCLA Laboratory of Nuclear
Medicine and Radiat ion
Biology
UCLA Laboratory of Nuclear
Medicine and Radiat ion
Biology
Battelle, Pacific Northwest
Laboratory
Battelle, Pacific Northwest
Laboratory
Lovelace Foundation
Lawrence Live more
Laboratory
University of Rochester
Medical School
New York University
Oak Ridge National
Laboratory
Oak Ridge National
Laboratory
130
-------
KING-MUIR CATEGORY #4 (Continued)
The Influence of Irritant Gases on Lung Tumor Induction
in Mice Exposed to Uruthan«
Multi-Mode Scanning Electron Microscopic Analysis of
Individual Pol lutant Part ides in Lung
The Role o£ 1,2-Benzanthracene in Enhancing Hepatic Tumor
Development in Katfi
Animal Toxicology Studies of Effluent from Low BTU Gasi-
f iers
Animal Toxicology Studies of H-Coal Liquefaction Opera-
PR1NCIPAL
INVESTIGATOR
Jones/White
Hayes
Peraino
Lawrence Livenoore
Laboratory
Lawrence Liversiore
Laboratory
Effects of Environmental Agents on Male and Female Repro-
ductive Tract function
Effects of 60-Hz Fields on the Mammalian Central Nervous
System
Respiratory and Cardiovascular Functions in Pollutant-
Exposed Animals
Ettecta ot Cestat tonal Exposure
Arsine Toxicity: A Potential Environmental Hazard
Lead Toxicity and Energy Metabolism in Immature Brain
Binding ol Methyl Mercury, an Environmental Hazard, with
DNA
Neurochemical Correlates of Behavioral Toxicology
Nt'urotoxicological Effects of Hexabrominated Biphenyls
The EC lotogy of Pica in the Rat
Chemical and Environmental Mutagen Studies Utilizing
the Tradescantia Test System
Compilation and Tabular Abstraction of Literature on
Mutageruc Effects of Energy-Related Pollutant! (EMIC)
Electrophoresis of Mouse Tissue: Testing of Offspring
after Parental Treatment with Energy-Related Pollutants;
Electrophortitic Mobility Hutation AnaLysia in Mam-
male
Chemically Induced Mutations at Biochemical Loci
in Mice
Monitoring Mutagens (ClastogensJ with Mammalian Chromo-
somes
Risk Assessment tor Environmental Carcinogena
Development of Statistical Methodology for Low Dose
Davis
Adey
Vans tee
Staples
Goldstein
Wilson
Ti l«on
Mitchell
Van't Hof/ Sparrow
Wasaam
Endocrine Labs of Madison
UCLA
NIEHS
NIEHS
Hew York University Kedical
Center
Stanford University
University of California at
Davis
NIEHS
NIEHS
NIEHS
frrookhaven National
Laboratory
Oak Ridge National
Laboratory
Research Triangle Institute
Hoel
Hoe W Crump
University of Texa* Cancer
Center
NIEHS
HIEHS
131
-------
KINC-HUIK CATEGORY ff4 {Continued?
CRUJtC'l
Statistical Studios ,11 problems of Health and Biology
Extrapolation of Holychlormated Biphenyl Deposition
Statistical Development of Multistage Carcinogenesis
Modi-18
Low Diisi' Toxicologies! Estimation
Hie Effects of Heavy Metals on Neurolransaitter Trans-
location
Lifelong Asse
nt of the Behavioral Effect* of Prena-
eavy Metals
I'dthugcn IL Mechanism* in the Development of Emphyiesu
and Pnt'iimaconios ia
Biology and fathobiology of Pulmonary Epithelial Cell!
Effects tit Exposure to Se lee ted Industrial Hydrocarbon
Solvents on PolycycLic Hydrocarbon Metaboli»» and Toxi-
city in Lungs
Childhood Health ttfecta of PCBs
ot t,n.TKy Oi;.:updt itin4l Safety and Health
Frobl
Man
He a 1th Laboratory
Enumurat ion of Energy Occupat tonal Hea 1th Prob-
Qiiifk Response Evaluation of Energy-Related Occu
pational Safety and Health Problem*
Conduct Oil Shale Worker Studies:
Hortality and Morbidity among Oil Shale Workers
Study ol Health Effects ot Oil ShaU Workers
Hfdith Eft>cta--Oil Shale Work»>rs--Epideaiology
Health Eftccta--0il Shale Workers—Industrial
PHI NCI PAL
INVESTICATOR
Uil 1 ia«
Neynan
Siple
Hoe I
Bondy
Brody/Plopper
Wu/DiAugustine
Bend
Rogan/McKinney/Mat thews
Re»*n/Cost*Uo/ Jones
Coatello
Jo Ties
AFFILIATION
American Health Foundation
University of California
University of Arizona
NIEHS
NIEHS
MIOSH
University of Utah Research
Institute
NIOSH
Stanford Research Inatttute
NIOSH
NIOSH
University Of Utah Research
Institute
NIOSH
HIOSH
132
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K1NG-MUIK CATEGORY *4 (Continued)
PRINCIPAL
INVESTIGATOR
AFFILIATION
Studi<
Knowles/Hearl/Selevan
Gasification Pilot Plants
Coal Liquefaction and Gasification Mortality
Study
Conduct Coal Liquefaction and Gasification
Worker Health Effects Conference
Conduct Studies of Occupational Exposures to
Insulation Materials;
Industrial Hygiene Studies of Mineral Wool
Exposures
Mineral Wool and Clay Fiber Hortality Study
Mineral Wool fibers — Medical Aspects
Mortality and Industrial Hygiene Study of
Mineral Wool Workers
Mortality Study of Small Fibrous Glass
Workers
Mortality and Industrial Hygiene Study of
Clay Fibers Workers
Conduct Studies of Occupational Exposure to Sul-
fur ic Acid, Sulfur Dioxide , Sulf at e» , Nitric Acid ,
Nitrogen Dioxide, and Nitrates;
Occupational Exposure to Sulfuric Acid and
Su If ates— Environmental
Occupational Exposure to H2S04 and Sulfatea —
Mortality
Study of S0x/N0x--Epidemiology
Study of SOx/NOy — Industrial Hygiene
Mortality and Industrial Hygiene Study of
and Sulfate Workers
Conduct a Safety Study of Energy Industries:
Assessing Safety in Fossil Fuel Electric
Power Generating Plant
Conduct Studies of TVA Workers:
Memorandum of Understanding Between NIOSH and
TVA
Epidemic-logical Mortality Study ot TVA
Employees
Industrial Hygiene Studies of TVA Workers
in Coal-Fired Power Plant
Denent/Bayless/Palmer
flayless
Palmer
Zunwalde
ftayless
Ness/Zuawalde
Cassady
Selevan
Gamble
Jones
Cassady
OrtBeyer
NIOSH
The Bend in Corporation
NIOSH
Office of Naval Research
NIOSH
Stanford Research Institute
NIOSH
NIOSH
NIOSH
NIOSH
NIOSH
NIOSH
NIOSH
NIOSH
The Bendix Corporation
The Bendix Corporation
TVA
TVA
133
-------
KINC-MUIR CATEGORY *4 (.Concluded)
PRINCIPAL
INVESTIGATOR
Mt^Ju-al Study ut Divers (Morbidity
Hortdl ityj
l(,'s,n ratory Ktl.-tts o! Insulation Materials--
Inhdlution ttfects
Oit-si- I Kxliaiist and Coat thist Interaction (Diesel
134
-------
KING-MUIR CATEGORY *5
PRINCIPAL
PROJECT INVESTIGATOR AFFILIATION
Chemical and Molecular Interactions of Pollutants Danyluk Argonne National Laboratory
with Key Biological Molecules
Molecular Damage to DNA and Protein* Caused by Haz- Ward UCLA Laboratory of Nuclear
ardoufl Metals, Metal lona, and Organic Compounds Medicine and Radiation
Associated with Coal and Oil Shale Technologies Biology
The Study of Autoxidation of Lipida of Biomembranea Head UCLA Laboratory of Nuclear
and of Lung Surfactants Initiated by Oxidative Medicine and Radiation
Pollutants and Its Inhibition by AntioxidantB Biology
Effect of Hydrocarbons, S02, and Related Fossil Snyder Oak Ridge Associated
Fuel Pollutants on the Biochemical Properties of Universities
Lung Membranes during Development
Effects of Hazardous Agents Associated with Coal and Enger Los Alamos Scientific
Oil Shale Technologies on Informational and Regula- Laboratory
tory Macromolecules of Mammalian Cells
Damage to DNA Synthesis by Trace Metals and Popenoe Brookhaven National
Hydrocarbons Laboratory
Molecular Mechanisms of Chemical Carcinogeneais Calvin Lawrence Livermore
Laboratory
Characterization and Control of Frameshift Tinoco Lawrence Livemore
Mutation Laboratory
Characterization of Damage to DNA Caused by Chemical R«hn Oak Ridge National
Agents: Emphasis on Synergistic Effects in Combi- Laboratory
nation with Sunlight
Regulatory Processes in Damaged Cells
Damage and Repair to DNA in Specific Germ Cell Stages
ot Mammal* Following 1^\ Vivo Expomr* to Product*
Associated with Coal Conversion and Utilization
Interactions between Damage (and Repair to Damage)
Resulting from Hazardous Agents Associated with
Coal and Oil Shale Technologies and Ultraviolet
Damage
Damage-Repair Studies Related to Cell Function and
Molecular Processes
Repair of DNA Treated with Irradiation and Chemical
Carcinogens
Biological Damage Processes of Hydrocarbons:
Molecular Activation and Binding Evaluated by EPR
Reparative and Adaptive Mechanisms in Respiratory
System" of Rodents and Monkeys Exposed to Sulfur
Compound* and Particulatee
Kenney
Sega
Set low
Elkind
Goldthwait
Borg
Goldman
Oak Ridge National
Laboratory
Oak Ridge National
Laboratory
Brookhaven National
Laboratory
Argonne National
Laboratory
Case Western Reserve
Institute
Brookhaven National
Laboratory
University of California,
Davit
135
-------
KINC-ML'IH CATEGORY »5 (Continued)
PRINCIPAL
1 KOJti, 1 I
Alveolar Clearance ot Inhaled Mrtal Oxide Sanders
Production and Consumption ot Ku,- I on th«- Physiol-
Kvaluat son ol tit..- Meohaiusras at Energy- He Laud Steinkarap
Fuju1 1 lonal and Quant i t-H i vt Changes in Immunocompe- Jaros low
tent Cells, Indi.c.'d by j Carcinogen Product .»f Coal
;ind Oi 1 lit i 1 izat i»n
Pr imat i-
io Determine the Processes by Which Laboratory Sfflith
Distillation with traphasis on the Sequence of
Lvaludijun of the Dos.--Et tec t Relationships tor Cram
Immune Response to Biologically Active Afctnts Asao-
AfTILIATION
Lovelace Foundation
Laboratory
University of Chicago
Los Alamos Scientific
Laboratory
Oak Ridge Associated
Un wecsit i«»
Los Alamos Scientific
Laboratory
Los Alamos Scientific
Laboratory
Argonne National Laboratory
Southwest Foundation for
Can Vitamin H or Lipid Alt*r N02 or Oj Toxicity
Lung.'
Luns Cd 1 t Kinetics alter N02
Thi- Int^iaction ot Cadmium with the Pulmonary
Mveolar Macrophagc
Pulmonary Eti*;cts «f Environmental Oxidant
Pollutants
Shale with Biological System
U-enzeL
Chignell
Duke University Medical
Center
Michigan State University
University of Vermont
University of California,
Davis
University of Kansas
N1EHS
pirdtory Epithelium
136
-------
KING-MUIB CATEGORY #5 (Concluded)
PRINCIPAL
INVESTIGATOR
Identification of Peripheral and Central Receptor
MechanUu Mediating the Effect! of Microwave
Radiation on Brain Activity
Effect* of Microwave Radiation on Neural Reeponee
and the Central Narvoui Sy'tea
RecoBMnded Standard* Cor Coal Caaification and
Liquefaction Plant!
Develop Medical Protocol! for Energy Industrie!
Conduct Study of Becirculation of Exhaust Air:
Development of Criteria for the Recirculetion
of Industrial Exhaust Air
Eecirculating Bxhauet Air Bympofiim
Validation of Criteria for Recirculetion
Validation of Criteria for Recirculation
Develop a Criterie Document for Occupational
Exposure to Microwave and RF Radiation
Stud; Work. Practice Deeded to Protect ALeakaa
Pipeline Worker* from Cold Street
Develop Count erneajurei to Protect Divera Involved
in Offehore Oil Ezploratioo:
DevelopMnt of a National Plan for tha Safety
and Health of Divera in the Queet for Sub-See
Energy
Develop Recaesaeoded Medical aad Operating
Standards for Divera
Jeneen
Pairchild
Shelling
Hamilton
Enviro Control. Inc.
Arthur D. Little, Inc.
Research TrUngle Institute
Envirex
Arthur D. Little, Inc.
HIOSH
N108H
Dndereee Medical Society
Tarry town La.be, Ltd.
•Not identified
137
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TECHNICAL REPORT DATA
(Please read Instructions on the reverse before completing)
REPORT NO.
EPA 600/7-79-121
2.
3. RECIPIENT'S ACCESSION NO.
TITLE AND SUBTITLE
Health Effects Research Program—Summary Report For
Fiscal Years 1974-1978
5. REPORT DATE
riecember 1979
6. PERFORMING ORGANIZATION CODE
. AUTHOR(S)
8. PERFORMING ORGANIZATION REPORT NO.
Richard D. Thomas, Alexis D. Taylor, Judith G. Gordon
MTR 79W00100
PERFORMING ORGANIZATION NAME AND ADDRESS
The MITRE Corporation
Metrek Division
McLean, VA 22102
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
68-01-5051
2. SPONSORING AGENCY NAME AND ADDRESS
U.S. Environmental Protection Agency
Office of Environmental Processes and Effects Research
Office of Research & Development
Washington, D.C. 20460
13. TYPE OF REPORT AND PERIOD COVERED
Executive Summary 74-78
14. SPONSORING AGENCY CODE
EPA/600/7
15. SUPPLEMENTARY NOTES
This project is part of the EPA-planned and coordinated Federal Interagency
Energy/Environment R&D Program.
16. ABSTRACT
The Federal Interagency Energy/Environment Research and Development Program which
is coordinated by the U.S. Environmental Protection Agency was initiated in the latter
half of fiscal year 1974 to ensure that health and environmental problems related to
energy resource development would be anticipated and evaluated. This document provides
an overview of the Interagency-supported health effects research program from an admin-
istrative as well as various technical perspectives. In this updated program review,
which is based on the individual task progress reports available for fiscal years 1974
through 1978, the research projects are reviewed and discussed according to King-Muir
objectives and selected scientific discipline, biological endpoint, and agent/pollutant
categories.
KEY WORDS AND DOCUMENT ANALYSIS
a.
DESCRIPTORS
b.lDENTIFIERS/OPEN ENDED TERMS
COS AT I Field/Group
Ecology
Environments
Ecological Effects
Health Effects
Energy Resource Development
97G
18. DISTRIBUTION STATEMENT
Release to Public
19. SECURITY CLASS (ThisReport)
Unclassified
20. SECURITY CLASS (Thispage)
Unclassified
21. NO. OF PAGES
145
22. PRICE
EPA Form 2220-1 (9-73)
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