Environmental Health PerspectivesVol. 12,pp. 149-170, 1975

Health Effects of Fossil FuelCombustion Products: Report of aWorkshop*

by Co L. Comart and Norton NelsontJudgmental positions are presented on research priorities in regard to the health

effects from stationary sources of fossil fuel combustion products. Hopefully, they can pro-vide guidance for efforts to ensure that national energy needs are met with minimum en-vironmental and economic burdens on the public. The major areas include epidemiologicalstudies, controlled biological studies, mutagenesis and carcinogenesis, trace elements,monitoring and analysis.

INTRODUCTION AND SUMMARY OF RESEARCH PRIORITIES **

A series of developments has brought the UnitedStates to a point where serious decisions have to bemade as to energy sources and energy conservation.The elements involved have been diverse: escalatingenergy usage, intensely heightened apprehensionsabout the environmental and health costs, and un-certainties as to the extent of and access to fuelreserves. The concerns have been communicated inmany studies, including a report to the President ofthe United States, by Dr. Dixy Lee Ray, Chairmanof the Atomic Energy Commission (1), a Ford Foun-dation study (2), and National Academy of Sciences-National Research Council studies and reports.

Clearly, some very difficult decisions will need tobe made over the next decade in regard to energyresearch priorities, energy strategies, the planningand design of facilities, and regulatory policies. Oneof the largest gaps in the understanding required forsuch decision making is due to lack of knowledge

*Sponsored by the Cornell Energy Project and ElectricPower Research Institute, Indian Wells, California, November11-13, 1974.

tScientific Editor and Workshop Coordinator, Environmen-tal Assessment Department, Electric Power Research Institute,P. 0. Box 10412, Palo Alto, Calif. 94303.

tinstitute of Environmental Medicine New York UniversityMedical Center, New York, New York 10016.

**Norton Nelson (General Chairman) and C. L. Comar(Scientific Editor and Workshop Coordinator).

about the direct effects of the fossil fuel combustionproducts on human health and well-being, sincemuch of our additional electricity and most of ourother midterm needs for energy will come fromcombustion of coal and oil. Indeed, this is of suchgrave concern that it will be urgent that an appropri-ate and substantial part of the national budgetarycommitment to Project Independence be devoted tothe resolution of such health effects. Since many ofthe studies required to answer these questions have along lead time, the planning to guide such investiga-tion will, in many cases, need to be started im-mediately. For this effort a set of directions andpriorities is required.

It was toward this end that the present exercisewas undertaken. The Workshop on Health Effects ofFossil Fuel Combustion Products was sponsored bythe Cornell Energy Project and the Electric PowerResearch Institute (EPRI) as the first of a series ofspecialized meetings to provide considered andauthoritative guidance for the research needed on anational basis and by the utility industry to assurethat energy needs are met with a minimum environ-mental cost.

Present technology assessment in the UnitedStates is recognized as having two important compo-nents: the scientific-technological base and publicperception. The emphasis of this workshop was en-tirely on the scientific basis for decision making rel-

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Table 1. High priority research studies.

Epidemiological StudiesDetermination and quantification of health effects resulting from exposure to low levels of pollutants and to changes of levels of

exposureDetermination of exposure/effects relationships in special risk groupsEvaluation and surveillance of new, potentially harmful pollutantsDevelopment of further international comparisons and cooperation

Controlled Biological StudiesHuman studies

Tests of airway narrowingSynergistic effects of gas- aerosol mixturesForm in which sulfur oxides are most damagingObservations and dose response for gas-gas interactions

Animal and in vitro studiesAerosol parameters likely to influence toxicity or irritancyEffects in disease statesChemical changes in the mucus and effects on mucociliary transport mechanismsEffects on alveolar macrophage functionEffects on structural elements of the lung

Pollutant interactions: effects, in humans and animals, of pollutant mixtures similar to those existing in air and quantitativelyand qualitatively identified; role of temperature and humidity in modifying such effects

Mutagenesis and CarcinogenesisChromosomal aberrations in populations occupationally exposed to high levels of potential mutagensBirth defects and other anomalies among populations exposed to high levels of oxidants (e.g., ozone)Mechanisms of interactions of potential mutagens and carcinogens with informational macromoleculesStudy of populations occupationally or otherwise exposed to point sources of known or suspected carcinogens

Trace ElementsCharacterization of trace element emissions from fossil fuel plantsDetermination of concentration, translocation, uptake, and conversions of elements such as lead, arsenic, selenium, and merc-

ury in components of the biosphereStudy of metabolism and toxicity, in human beings, of selected trace elements such as lead, arsenic, selenium, and nickelEvaluation of the role of trace elements in catalysis of atmospheric reactions of gaseous pollutants, especially SO2 and NO2

Monitoring and AnalysisCharacterization of trace element emissions (as above)Sampling and analytical methods for selenium, mercury, arsenic, and berylliumBetter methods for NO2; monitoring of peroxyacetyl nitrate (PAN)More definitive methods for particulates, and evaluation of emissions from fly ash dumps and coal pilesComplete characterization of physical and chemical pathways and factors affecting the sulfur compounds that enter the at-

mosphereCharacterization of acid-sulfate aerosols and personal monitoring for the sulfur oxidesImproved air monitoring for sulfur oxides to permit trend monitoring, compliance, and more reliable retrospective and

prospective assessment of health effects

ated to health effects. The intention was not,however, to carry through to ultimate decisions ex-pressed in terms of standards or guidelines, since thisis the responsibility of others and, in addition to ascientific and technical data base, requires con-siderations of a complex economic and sociologicalnature. Nevertheless, the need for public under-standing and the needs of those who must makepublic policy were kept in mind.

The report is by design concise: it restricts itselfprimarily to brief judgmental positions on the stateof knowledge relating air pollution to health. Thekey questions are: If our present information is in-adequate yet important to the development of na-tional policy, what needs to be done to sharpen the

information, and how should the nation go aboutfilling these gaps? There have been many good re-cent reviews on the relationship of air pollution tohealth. It was felt that rereviews at this time wouldbe far less useful than an analysis of research needs,with suggestions on how these needs might be filled.It is hoped that the thoughtful advice of the work-shop participants, as set forth on the followingpages, can provide substantive guidance for na-tional efforts to ensure that national energy needsfare met in ways which do not pose unacceptablehealth or economic burdens on the public.

The report represents an attempt to defineresearch directions aimed at filling energy needssafely. Ionizing radiation and nuclear power were

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deliberately not examined, and coverage ofautomobile exhausts was not meant to be definitive.The report is especially aimed at the problems of thenext decade, before major new types of nuclear,solar, or geothermal energy can become available. Itis hoped that it will provide a helpful planning basisfor those national groups on whom will fall theburden of developing the needed information. Thesegroups include both industry and the research agen-cies of the federal government. However, there isalso an important role to be played by local agen-cies, the scientific community generally, andresearch foundations. Moreover, it seems probablethat the major inputs to the field discussed here willcome from the academic community, where thelargest resources in health research are to be found.

The various sections of the report represent theproducts of the working groups as identified in therespective footnote. Each section was examined inplenary sessions involving all members of theworkshop leading to agreement with the generalthrust of the report although not necessarily withevery detail. A list of proposed studies developed inthe workshop is given in Table 1. All are consideredto be of very high priority; no attempt was made atpriority ranking, either among or within the groupareas. This list should be regarded only as an iden-tification of the general area of research. The in-dividual sections of the report should be consultedfor further details.

'EPID'EMIOLOGICAL"'STUDIES*

IntroductionEpidemiological studies are useful in identifying

the factors involved in the development of diseaseand disability, and then are essential in quantifyingthe impact of such factors. Such studies become in-creasingly critical as the risk attributable to a factorbecomes smaller and as the time needed for the fac-tor to act becomes greater. The major episodes of airpollution (Meuse, Donora, London, New York City)clearly showed that pollution, when sufficientlysevere, could cause illness and death. During the1950's and 1960's, research was mainly directedtoward answering the question: Does pollution atconcentrations which are normally encountered inindustrial cities cause adverse effects on people'shealth? During the later 1960's, perhaps stimulatedby the preparation of the Air Quality Criteria Docu-ments, interest became more focused on quantifyingpollution in relation to the effects it may produce.Now, in the 1970's, with the recognition that fossilfuel supplies with low sulfur content are limited andthat consequently it may be necessary to use crudergrades of fuel, quantification of the effects of varyinglevels of exposure becomes increasingly urgent.Thus while exposure-effects relationships are stillthe central interest, emphasis has now shifted tothe effects of low levels of pollution and the effectsof pollutant interactions.

In this section we first consider the measurementof exposure and its effects on man, then indicatesome of the difficulties encountered in allowing for

*Ian Higgins (Chairman), Robert E. Carroll, C. L. Comar,Charles Florey, John R. Goldsmith, Lester B. Lave, David P.Rall, Frank E. Speizer.

confounding variables, and go on to touch lightly onanalytical methods which permit sound conclusions.Finally, we turn to promising areas of research andoutline a number of studies that we believe shouldhave high priority.

ExposureIdeally, in quantifying a person's exposure one

would like full information on present and past ex-posures to the relevant gases and to particulate mat-ter carefully specified as to kind and size. Needlessto say, even the most admirably designed andbrilliantly executed surveys will not provide suchfull information, and the analysis of available obser-vations must rest upon data which are far from ideal.The following attributes of exposure should be con-sidered by anyone launching an epidemiologicalsurvey.

Particulate Matter and Gases

Particles should be characterized both physicallyand chemically. Particular attention should be givento their surface absorptive characteristics, hy-groscopicity, and size distribution. Althoughemphasis should be on particles within the respirato-ry size range, large particles should not be ignored.Within the respiratory size range, a case can be madefor differentiating between particles above andbelow 1 Am. Chemical characteristics of interest in-clude pH, oxidation state, and reactive attributes.Particulates include trace metals and potential car-cinogens; however, sulfuric acid and acid sulfatesare the particle phase pollutants of greatest interest

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at this time. Sulfur dioxide is, of course, the gas ofmajor interest, but ozone and oxidants, carbonmoRoxide,and -o-xides of nitrogen are- also o,f con-cern.

Existing Monitoring Networks

In the United States, selected pollutants havebeen monitored for a number of years. The NationalAir Sampling Network (NASN) has information onvariations in particulate pollution and specific com-ponents of it at several stations in an increasinglylarge number of metropolitan areas and otherplaces. The Continuous Air Monitoring Program(CAMP) has provided data on gaseous componentsfor eight cities for over a dozen years. Thesemonitoring systems were designed to evaluate airquality in the regions in which they were placed.They have been useful in combination with emissiondata for determining and predicting departure fromacceptable standards.

As originally planned, the systems were notdesigned for measurement of exposure inepidemiological surveys. Many of the sites chosenfor monitoring have little relevance to particular ex-posure of study populations. With careful selectionof certain sites, however, some of the data have beenuseful for defining exposure in populations under in-vestigation. In other studies, the degree to whichthese data reflect actual exposure or dose to the in-habitants is uncertain.

In the United Kingdom, the National Air Sam-pling Network, coordinated at Warren SpringLaboratories, has provided extensive informationfor many years on smoke and S02 concentrations.Relatively little study, however, has been carriedout on other pollutants. Sites are classified as havingbeen chosen for their relevance to industrial pollu-tion sources or to general environmental exposure,and data which are relevant to population exposurehave sometimes been correlated with health func-tions.

The pollutants being monitored may be measuredand reported with averaging times from 5 min to oneyear. The choice of averaging time needs to be ap-propriate to the type of epidemiological study beingconducted. Even with a fairly extensive network ofstations in a city, the levels of pollution to which aperson is exposed can only be imperfectly estimated.Sampling in or near subjects' homes, indoor and out-door comparisons, and the use of personal monitorsto assess current ambient exposures are desirable.

Biological estimation of exposure has certain ad-vantages when feasible. Examples are the use ofblood or expired air samples for carboxy-

hemoglobin as a measure of carbon monoxide ex-posure (3) and hair samples as an indicator of ex-posure -to-lead or-mercury.

EffectsSeveral health indices are available: (1) mortality

(all causes of death): causes which might be expectedto be related to air pollution, such as respiratory dis-eases, cardiac diseases, and influenza; and, for com-parison within the same population, causes of deathwhich might not be expected to be related to pollu-tion, such as strokes, diabetes, and cirrhosis;(2) morbidity (all causes): disease-specific (as formortality) but including diseases which may be un-common causes of death, such as arthritis andrheumatism; (3) symptoms: especially of respiratorysymptoms, such as cough, sputum, wheezing,breathlessness, and chest illnesses, usually recordedby means of standardized questionnaires;(4) impairment of lung function, especially impair-ment measured by simple spirometry;(5)impairment of other functions or performance:work capacity, athletic, CNS (central nervoussystem) functions, or indirect evidence of impair-ment as implied by accidents or alterations in men-tal acuity; (6) eye irritation; (7) annoyance andpsychological effects of reduced visibility; (8) ac-cumulation of a potentially harmful pollutantwithin the body.

One evaluation of pollution abatement is pro-vided through cost/benefit analysis, which is difficultbut increasingly necessary. The technologicalpossibility of reducing pollution and the cost ofdoing so are of great relevance to the rationale forepidemiological investigation. It is desirable,wherever possible, to include indices of effects ofpollution on health that can be translated intocost/benefit ratios. Examples of such indices are lostworking time, premature disability, sickness, ab-sence, days in bed, and days in hospital.

Exposure-Effects RelationshipsThe health indices of effects of exposure to pollu-

tants of concern, which were summarized above, areinfluenced by many factors other than pollution.These factors confound the interpretation of anyassociations which may be demonstrated betweenexposure and response. Apart from the demographiccharacteristics of age, sex, race, and socioeconomicstatus, the most important confounding variables aretobacco smoking and occupational exposures.Wherever possible, consideration should be given to

Environmental Health Perspectives

these variables in the design of any studies. Where tribution of pollution at present levels to mortality issuch considerations have been inadequate or over- uncertain. In the New York City metropolitan area,1ooked,.Aue-attenti@nvust begiveto thes likelihod _Bueehleyandhis cuHea4)estimatedo11-ution-of such factors having influenced the conclusions in caused mortality to be about 2 or 3% of total dailythe analysis. mortality, comparing pollution at the lowest and

Strategies already exist or can be developed for highest levels for the period 1962-1966. On thedealing with the multivariate systems required in other hand, Schimmel and Greenburg (5) andepidemiological studies. Examples include path, Schimmel et al. (6), using the same data, estimatedcomponent, and canonical analyses. These analyses that pollution was immediately responsible for 14%require the combined efforts of mathematical of all deaths. This is a considerable discrepancy thatstatisticians, epidemiologists, and data systems ex- needs to be resolved. Buechley has analyses fromperts. While such strategies may ultimately be based Philadelphia and Chicago which have not beenon multiple regression and correlation procedures, published. The studies of Hexter and Goldsmith (7)uncritical applications of multiple linear regression for Los Angeles for 1962-1964 could be extendedcomputer programs are not likely to provide con- to include additional confounding variables andvincing evidence of exposure/effects relationships. It other urban areas.is important to emphasize that relevant variables More recent analyses of daily mortality in Lon-must be included, that variables must be in an ap- don, England, and in Tokyo and Osaka, Japan,propriate form, that nonlinear relationships be ex- would be useful. In London two additional pointsplored, and that appropriate statistical criteria must might be made: (1) it would be interesting to explorebe used. the trends in daily deaths and pollution between

1958 and 1974, and (2) daily morbidity could beused as well as mortality.

Interactions To date, with the exception of London, noanalyses have been made of deaths by cause,Although possible interactions should be con- stratified by age and sex. Such analyses are desira-

sidered in any statement of exposure-effects rela- ble. It seems clear that studies of daily mortality intionships, they perhaps deserve to be categorized relation to pollution levels should have someseparately as an area of great interest about which priority, as they may shed light on both the ex-far too little is known. There are several types of in- posure/effects relationships and on the overall effectteractions: (1) interaction of one pollutant or of change over time.category of pollutants (particulates) with others to An extension of the effects of daily mortality inproduce a more harmful exposure, e.g., particulates relation to daily pollution levels might be anand SO2, SO2 and ozone, and particulates and NO2; analysis of the distribution of deaths throughout the(2) interaction of pollutants with meteorologic or year (annual cycle). If, as the daily mortality studiesclimatic factors such as temperature, humidity, and suggest, pollution causes immediate deaths and if, aspossibly barometric pressure to produce a more in London and New York City, pollution is worse inserious effect (3) interaction of pollutants with the winter than in the summer, with the reduction inother personal or environmental variables, such as pollution which has been achieved in London and iscigarette smoking and occupational or socio- being achieved in New York City there should be aeconomic factors (4) interaction of pollutants with reduction in the winter/summer differences in mor-infection, particularly with influenza and other tality commensurate with the reduction in pollution.recurrent respiratory infections. Interactions at the Trends in mortality in different cities (Standardphysiological level are discussed in the section on Metropolitan Statistical Areas, SMSA) and otherbiological studies. areas during the past 10-15 yr deserve more atten-

tion than they have yet received. In some areaspollution has declined, in others it has remained thesame, and still in others it has risen. Age- and cause-

Methods specific mortality rates have not been compared inrelation to these environmental changes.

Mortality In no city has reduction in pollution been moredramatic than in London. Yet there has been

Daily deaths in relation to pollution levels and peculiarly little interest in relating changes in age-other factors have provided useful information on specific mortality to this decline. The statistics areone type of exposure/effects relationships. The con- for the most part readily available.

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Morbidity

In Britain, records of morbidity of the wholeworking population of the country were introducedin 1948. Changes in morbidity should be related tochanges in pollution between 1948 and the present.The main aims of such a study would be to relate in-cidence of bronchitis incapacity to levels of pollu-tion around 100 ug/m3 instead of around 300,ug/m3, as was the situation at the time of the surveycarried out by the Ministry of Health. In the UnitedStates, long-term morbidity trends are not availablefor any substantial segment of the working popula-tion. Data collected- in the National, Health Surveycan, however, be categorized by SMSA and may beuseful in making comparisons of morbidity rates atvarying levels of exposure.

Surveys to Monitor Pollution andHealth Effects

General Community: Surveys of the typerecommended by Rall (8) should be made. Thus,representative samples of the community living indifferent areas should be compared. The areasshould be chosen on the basis of levels and type ofpollution and of expectation of change.Longitudinal observations should be made tomeasure change in lung function, respiratorysymptoms, disease incidence, and mortality and torelate these to levels and changes in pollution.

Children must be included not only becausecohorts of children will provide information onsecular changes in pollution but also because the useof children eliminates the confounding effects ofsmoking and occupational exposures.

Vulnerable Groups: Douglas and Waller (9)showed that following a cohort of children frombirth to age 15 provided valuable information on theeffects on infants and children of air pollution inBritain. No such study has been attempted in thiscountry. A nationwide cohort such as was used inBritain is probably neither practicable nor desirable.Instead, cohorts of newborn in different cities shouldbe chosen and followed for comparisons ofrespiratory indices such as those used by Douglasand Waller. At the same time, appropriate airmonitoring should be carried out. Such a studymight show not only the effects of pollution on earlydevelopment but also the impact of changes in pollu-tion.

Lawther and Waller's studies (10) of chronicbronchitic patients were prototypes of investigationsof patients with chronic lung and/or cardiac dis-

ease. More could and should be extracted fromsuch surveillance than was possible in the 1950'sand 1960's. Emerson (11) has shown the value ofincorporating simple lung function studies intostudies of this kind. The possibility of using thisgroup of patients for much more precise measure-ments of exposure/effects relationships needs to beexplored. Home measurement of pollution, per-sonal monitoring, and consideration of multiplepollutants would add appreciably to the value ofsuch studies. Cardiac patients or persons withasthma could similarly be monitored.

For many of the pollutants of interest, occupa-tional exposures occur at. higher levels than do ex-posures in the general community. Such occupa-tional exposures are often quite well defined.Among other occupations to be given considerationare those internal to the power generation and dis-tribution industry and those exposed to combustionproducts (firemen, metal workers, automobile andtraffic workers).

The record-keeping system in industry now beingrequired by the Occupational Safety and Health Ad-ministration (OSHA) should be explored both as asource of exposure/effects relationships and as anapproach to one of the major confounding effects inother community studies. This is particularly truefor conditions such as cancer which develop after aprolonged latent period.

European Studies

Studies at present being conducted in Europe aredesigned to identify the effects on health of exposureto individual pollutants, to establish ex-posure/effects relationships, and to determine theeffect of reduction in air pollution. Two studies areinternational in scope, one under the auspices of theWorld Health Organization (WHO) (12) and theother under the Commission of the European Com-munities (CEC). A third study, in the UnitedKingdom, is investigating the effects of change inpollution (13). All the studies are concerned withchildren as indicator populations because of theirfreedom from the confounding exposures ofcigarette smoking and occupational pollution. Ap-proximately 1500-2000 children aged 6-10 arechosen in areas defined by high (>100 ,ug/m3) orlow (< 50 ,ug/m3) levels of smoke or SO2. At presentother pollutants are not being considered, as theyare so rarely measured routinely. Physical measure-ments (height, weight, and peak expiratory flowrate) and a symptom questionnaire are completed.Both the WHO and CEC studies are cross-sectional,but their design permits conversion to longitudinal

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studies if appropriate. The U.K. survey islongitudinal and is planned to last 4 yr. Countriesinvolved in the WHO study are Poland,Czechoslovakia, Yugoslavia, Denmark, the Nether-lands, Spain, and possibly Greece; those in the CECstudy are Belgium, France, West German FederalRepublic, Ireland, Italy, and the U.K. Uniform pro-tocols prepared by a panel of experts are being used.Although these cooperative studies are in their in-fancy, European epidemiologists feel strongly thatstudies using common protocols will advance under-standing much more rapidly than those in which,without such standardization, the data are not com-parable.

The need for improving comparability inepidemiological studies of chronic respiratory dis-ease in the U.S. has been recognized by the NationalHeart and Lung Institute and the AmericanThoracic Society. A committee of the AmericanThoracic Society on standardization ofepidemiological procedures, with subcommittees onquestionnaires, lung function procedures, and chestx-rays, has recently been established. Plans arebeing formulated with the National Heart and LungInstitute (NHLI) to assess the methods and pro-cedures now in use and to develop ways of improv-ing them.A number of studies of children, with varying

levels of monitoring of environmental exposure,some of them similar to the European studies, arebeing conducted in this country. For example, onegroup of investigators has embarked on a prospec-tive study of children in several cities with varyinglevels of exposure, using a common protocol. In ad-dition, other groups are engaged in studies ofchildren, with varying levels of monitoring of en-vironmental exposure. The desirability of com-parability not only between these studies but also,wherever possible, with those being conducted inEurope is clear. We strongly urge that high prioritybe given to increasing cooperation and communica-tion among the various international groups so thatcommon protocols and measurement techniques canbe developed to enhance the comparability of the in-vestigations.Many of the concepts underlying the Environ-

mental Protection Agencfy's Community Health andEnvironmental Surveillance Studies (CHESS) (14)are similar to those specified above. Some of theearlier CHESS studies indicated all too clearly theproblems involved in carrying out adequateepidemiological investigation. In fact, there are fewcenters with the experience and resources requiredto conduct such taxing studies in a satisfactory man-ner. In part, this is due to the lack of adequate finan-cial support.

Support of EpidemiologicalResearch

Epidemiological research, as is clear from thepoints already mentioned, is becoming ever more

urgently needed for the planning and control oftechnological development. A major problem hasbeen that such research has not been adequatelysupported either in level or in duration. Federaland industrial support, whether or not in academiccenters, has tended to be short-term, volatile, andoften inadequately planned-and hence incapableof useful interpretation. This difficulty is also facedby other types of research, but chronic diseaseepidemiology is particularly sensitive to the needfor critical levels and duration of effort to avoiduseless or, even worse, misleading results. In viewof the critical need for institutional supportstrategies, the following suggestions are offered.

There should be encouragement, motivation,and support for the National Center of HealthStatistics to become more sensitive to and more in-volved in epidemiological and epidemiologicallydirected research. This, in combination with otherongoing activities, would provide a much more

useful data base than is now available. Examplesof such opportunities in the U.S. can be seen in thereports on occupational mortality (15) and on oc-

cupational and environmental factors in disable-ment (16). An outstanding example of the use ofthese kinds of data is the British Registrar-General's Decennial Reports on social and occupa-tional factors in mortality (1 7).

There are a few centers in the U.S. that have thecompetence and facilities for the long-term studiesrequired for successful epidemiological research.Urgent epidemiological studies should be en-

couraged and initiated in selected centers by com-

mitment of long-term personnel and operating sup-

port. This is being done in some of the MedicalResearch Council units in the U.K. but not signifi-cantly in the various U.S. national laboratories.

Long-term studies of a number of communitiesin the U.S. have of course been conducted for manyyears, e.g., at Framingham (18), Tecumseh (19),and Hagerstown (20), as have some cohort studiesof occupational groups (rubber, steel, and mineworkers) (21).

In some instances where there is no predefinedpopulation of special interest, it is possible to gainimportant data from cooperative community-sam-ple studies involving cohorts based on a probabilitysample which has appropriate attributes and isavailable for periodic follow-up examination, datainterpretation, and analysis. Examples include the

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Ferris-Speizer project, the American CancerSociety longitudinal study (22), the WHO and CECstudies of children, and the Douglas-Waller cohortstudy (9). Adequate support for such studies shouldbe maintained.

It is suggested that a task group be establishedto maintain support among epidemiologists andtheir funding sources to assure appropriate finan-cial and institutional commitment. Such a groupmight include representation from professionalbodies, e.g., the American Thoracic Society, theSociety for Epidemiological Research, and the In-ternational Epidemiological Association.

Research PrioritiesThe areas of research considered to have the

highest priority are presented in four categories.1. Determination and quantification of health

effects resulting from exposure to low levels ofpollutants and to changes of levels of exposure: Ofparticular importance are the combined effects ofS02 and particulates. Also important are effects ofinteractions and changes of different classes ofpollutants in the atmosphere, such as the formationof sulfates or acid droplets.

High priority should be given to detailed studyof existing data in areas where change is known to

have occurred. In addition, studies of short- andlong-term effects of anticipated change in airquality should be made.

2. Determination of exposure-effects relation-ships in special risk groups: Of particular interestare groups that may be unusually sensitive topollutants, e.g., asthmatics, chronically disabledpersons, persons with added burdens of exposurefrom other sources such as occupational or per-sonal pollution (smoking), and infants andchildren.

3. Evaluation and surveillance of new, poten-tially harmful pollutants: Better communicationamong chemists, toxicologists, and epidemiologiststo anticipate potentially toxic new substances ornew processes can lead to earlier identification andcontrol. This requires research collaborationamong several disciplines and must involvegovernmental, academic, and industrial organiza-tions. In addition, a further search must be madefor more subtle effects of existing pollutants, e.g.,performance in a physical and psychological sense.

4. Development of further international com-parisons and cooperation: Pollution and healtheffects vary from country to country; however,studies in other countries can have great impor-tance to the U.S. Utilization of data would beenhanced by improved comparability, and everyeffort should be made to standardize methods.

CONTROLLED BIOLOGICALSTUDIES*

IntroductionA full understanding of the role of environmen-

tal factors affecting health depends critically on theinterplay of epidemiological, animal, and humanlaboratory studies. Epidemiological studies are im-portant in uncovering possible associations whichcan then be tested under controlled laboratory con-

ditions; they are also important in the evaluationof human risks suggested by laboratory experi-ments. As in other fields of biological research,animal studies are extremely important. They can

often determine efficiently the sites of effects,mechanisms, and exposure/effects relationships,and they lend themselves more easily to chronic

*Jay Nadel (Chairman, Human Studies), Robert Frank(Chairman, Animal and in Vitro Studies), David V. Bates(Chairman, Interaction of Agents), William Coate, John F.Finklea, Charles Florey, Bernard D. Goldstein, Elliot Golds-tein, Steven M. Horvath, Sidney Marks, Byron Mechalas, DavidP. Rall, Frank E. Speizer.

studies than does human research. However,because of species differences, human laboratorystudies are still needed to establish the presenceand importance of specific responses and to deter-mine the influence of altered human states (e.g.,disease) on these effects.

Human Studies

General

In the design of human studies, ethical con-siderations are imperative. Because it is desirableto limit their total number, human studies shouldbe designed carefully on the basis of informationobtained from appropriate animal and epi-demiological studies. As an illustration, a largenumber of experiments can be performed inanimals to determine the sulfur-containing com-pounds that are most potent in narrowing airways,

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impairing mucociliary clearance, or increasingsusceptibility to infection. From the results of theseexperiments, a few critical studies in humans canbe designed. Information on the acute effects of airpollutants on humans is woefully sparse, and morestudies are urgently needed. Fortunately, informa-tion from animal and epidemiological studies hasidentified areas where human studies are likely tobe profitable.

Features of Experimentation

Human exposures should generally be limited to"realistic" concentrations ofpollutants which haveoccurred in some ambient atmospheres. Charac-teristics of the individuals studied (e.g., age, en-vironmental exposure, place of residence, cigarettesmoking and disease history) must be consideredand described in detail. Generally, healthy subjectsshould be studied first. In order to discoverwhether responses are changed as a result of en-vironment, acute effects of pollutant exposureshould be studied in individuals exposedchronically to the pollutant either in the ambientatmosphere or at work and the responses should becompared with those of matched groups notchronically exposed. Subjects can also be studiedearly and late in the "smog season" to determinewhether adaptation occurs. Present evidence sug-gests that some patients with lung disease may bemost susceptible; studies are badly needed toestablish this. Among groups which may provideuseful information are young asthmatics, youngsymptomatic smokers, individuals with a history offrequent respiratory infections, and healthy sub-jects during and following respiratory viral infec-tions (responses may be increased during viral in-fections, so the healthy subject serves as his owncontrol). It must be emphasized that animals canprovide much valuable information which can beuseful in designing studies in potentially suscepti-ble populations of humans. For example, healthyunanesthetized dogs can be utilized for studies atrest and during exercise. In these animals experi-mental asthma can be produced which is similarimmunologically to the human disease. Resultsfrom such experiments will be useful in designingcritical human studies.

Performance

Performance in humans can be defined as"physical" and "mental," and both kinds havebeen shown to be influenced to some extent by thepresence of atmospheric pollutants. Physical per-

formance requiring 50-100% aerobic capacity hasbeen voluntarily terminated by individuals of allages when certain levels of air pollutants have oc-curred in the free atmosphere. The factor or factorsresponsible have not been identified completely,and studies to eliminate the reasons for and theeffects of various pollutant combinations in termsof physiological and biochemical alternations inthe organism need to be performed. Examination ofthe possible interaction of ambient temperatures,vapor pressure, and pollutant levels is essential insuch studies.

Another investigative tool is sustained physicaleffort at levels such as 35% of maximum aerobiccapacity, which has been shown to represent thelevel of activity at which man can continue to per-form for 8-hr days over several years. The effect ofpollutants on such performance may be partly re-l;ated to the changes in mass delivery of pollutants,but it may also involve other physiological systemsbesides the lung (e.g., heart rates increase fasterduring 4 hr of 35% work in polluted environmentsthan in filtered air). In subjects exposed to pollu-tants, more striking physiological changes in lungfunction have been shown to occur during modestbouts of exercise than under conditions of rest. It isconceivable that effects on or within otherphysiological systems will be induced when activityof this level is utilized as part of the experimentalsystem.

Mental, or more precisely "behavioral," altera-tions representing subtle changes in CNS (centralnervous system) function have been shown to occurconsequent to exposure to some pollutants. Themost precisely evaluated system-changes invigilance-has shown decrements of as much as50%. Similar studies on this and other dynamicCNS functions are indicated, not solely becausethey have already been implicated but also becausethey may represent the "other" effects of contami-nants. Sociological behavior patterns may also be areflection of the peculiar ambient conditions whichfavor high pollutant levels. More subtle"behavioral malfunctions" have been suggested tooccur as a consequence.

Exercise is a unique physiological tool in thatalmost every function of the organism is enhancedor altered to meet the various levels of activity. It isalso a function which all organisms undergo andwithout which survival may be difficult. The in-terplay of multiple systems provides for stress-strain relationships which may be induced tobreakdown points if a further stress, such as apollutant, is superimposed. To many investigatorsthe best experimental tool is the utilization of

December 1975 157

multiple stresses to an organism as a means of pro-viding more effective insight into the functioningcapabilities and adaptive potential of the organism.The combination of exercise and pollutant ex-posure fits into this concept.

Research Priorities

In evaluating responses, tests of airway narrow-ing still appear to be the simplest and most useful,and they are presently given the highest priority.However, evidence suggests that, especially insusceptible individuals, morbidity and mortalitymay be related to effects on mucociliary transportand/or susceptibility to infection. It is suggestedthat these systems be given careful scrutiny inanimal experiments and, if important clues aredeveloped, that they then be tested in humans. Pa-tients with cardiovascular disease also appear to bemore susceptible to the effects of air pollutants. Itis possible that inhaled pollutants have effects onthe cardiovascular and other systems (e.g., bloodand central nervous system) either reflexly or bycirculating in the blood. While these areas mayprove very important, present information does notsuggest specific studies in humans that are likely tobe fruitful at this time.

Results from previous epidemiological, animal,human, and meterologic studies suggest that fourgroups of experiments need to be performed inhuman subjects. These should be performed firstwith the subjects at rest. However, since exercise in-creases ventilation (and therefore increases ex-posure to atmospheric pollutants), critical observa-tions need to be repeated following exposure duringexercise. The four groups are as follows:

Synergistic Effects of Gas-Aerosol Mixtures:Studies originally performed in guinea pigsdemonstrated increased effects of irritant gases onairflow resistance in the presence of aerosols, butthese results could not be confirmed subsequentlyin cats or humans. A recent study suggests that ele-vated relative humidity enhances the interactionbetween S02 and certain aerosols and thus in-creases gas-aerosol synergism. These studies mustbe repeated in healthy and then in susceptiblehumans, using lower ranges of S02 gas concentra-tions and small aerosol particles (0.1-1.0 am),with careful control of particle size, relativehumidity, and temperature, The effect of changingthe concentration of aerosol, temperature, andrelative humidity should be evaluated.

Form in Which S02 Is Most Damaging: Re-cent evidence for the presence of sulfur-containingsubmicronic particles in the ambient atmosphererequires further evaluation of their effects. Theeffects of various sulfur-containing aerosols ofknown particle size (in the submicronic range) andconcentration should be studied to identify themost irritant compounds.

It is emphasized that the planning of suchhuman studies depends critically on concomitantanimal and "bench" experimentation. For exam-ple, animal studies can narrow the range of sulfur-containing aerosols that need to be tested inhumans. Rates of growth of soluble aerosols can betested in humans as well as in controlled at-mospheres, in lung models, and in animals. Animalstudies can also be utilized to determine whetherthese pollutants have effects on other systems(besides bronchomotor).

Gas-Gas Interactions: The recent observa-tion that low concentrations of ozone in combina-tion with S02 have greater bronchoconstrictoreffects than either pollutant alone requires furtherevaluation. Studies need to be performed to con-firm and extend this observation and to determinethe mechanism of the response. Dose-responsecurves are necessary to determine whether poten-tiation is occurring.

Central Nervous System Function andBehavioral Patterns: A number of subtle but im-portant changes may be induced in other than therespiratory system, e.g., changes in red cellmorphology, shifts in activity levels in enzymesystems, and alterations in CNS function andbehavioral patterns. Behavioral modification andCNS dysfunction may well be the most importantof all effects. The marked decrement in "vigilance"reported for at least one pollutant has significancebeyond its simple effect in that performance is con-siderably influenced by this loss of vigilance. Othercomplex CNS functions and behavioral modifica-tions have not been studied to any great extent.Animal work suggests that some striking shifts andinvestigations on humans may now be warranted.Cross-pollutant effects have not been studied. Norhave any "age"-related studies been undertaken-an area of extreme concern, with the knownchanges in CNS function already present conse-quent to aging. More exploration of all CNS func-tions seems highly desirable (animal and humanstudies).

Environmental Health Perspectives158

There remain a number of unexplainable andunverified secondary effects in other systems re-lated to pollutant exposure. These effects need tobe clarified, as does their potential impact on thefunctioning of the total system.

More information is needed on the question of"adaptation to pollutants." We have little infor-mation on this possibility. Even the simple questionof adaptation to CO has never been resolved. Arethere physiological changes in humans or animalsconsequent to prolonged or even intermittent ex-posures over years?

Animal and in Vitro StudiesGeneral

Among the advantages of animal experimentswhich have proven valuable for study of thebiological effects of air pollution, the following maybe cited: (1) they are ideal for determining mecha-nisms of effects; (2) they permit assessment ofstructural and biochemical responses which,because of ethical and legal constraints, often can-not be done in man; (3) they can be used to sort outand test hypotheses as a preamble to clinical in-vestigation and as an aid in the design ofepidemiological studies; (4) they are appropriatefor chronic exposures in which the endpoint may in-volve irreversible or serious damage to the targetorgan or changes in the rate of development oraging of the entire organism, or of a specific organ;there is no other acceptable means of obtainingsuch information.

Species differ in their susceptibility to pollu-tants, a factor that must be weighed in the design ofexperiments and evaluation of results. Thus, dogsare tenfold more resistant to injury from nitrogendioxide than are rodents. Among rodents, mice andrats appear to be more susceptible to injury fromoxidants than do rabbits or guinea pigs. The use ofsubhuman primates in acute and chronic studies isto be encouraged. Finally, in vitro studies in whichcellular or subcellular components are exposed to apollutant are of value in suggesting mechanisms oftoxicity and in indicating parameters suitable foruse in dose-response experiments with the wholeanimal.

Physicochemical Systems

There is considerable interest in the effects thatindividual pollutant gases, gas-gas interactions,gas-aerosol interactions, and specific ambient

aerosols may have on the respiratory and circula-tory systems. It is important to emphasize that thechemistry and aerosol physics involved in suchresearch are exceedingly complex and that col-laboration is essential between physical andbiological scientists.

Atmospheric aerosols appear to be essentiallybimodal in size distribution (23?). The smaller moderanges from about 0.02 to 2,m in diameter, thelarger mode extends up to about 100 ,um indiameter. Chemical transformations in the at-mosphere involving S02 and photochemical oxi-dants contribute to the formation of the sub-micronic particles (24-26). These particles arelargely soluble (by contrast, the supramicronic par-ticles tend to be insoluble) and contain most of thesulfates, nitrates, and trace metals present inpolluted air (27). Since the submicronic mode isprobably more hazardous to health, it shouldreceive major emphasis in laboratory research.

Experiments utilizing soluble and, in particular,hygroscopic aerosols should control and monitorrelative humidity. Sulfuric acid serves to illustratethe importance of relative humidity and at thesame time the complexity of such systems. There isan intimate relation between the pH of the H2SO4aerosol and the ambient relative humidity. Thisrelation determines the size of the particle atequilibrium. In turn, the size of the particle prior toinhalation will determine the rate at which it growsto a new state of equilibrium within the airways.This rate of growth (hydration) may be expected toinfluence not only where the particle is depositedand how much is deposited, but also its pH at theinstant of deposition. All of these factors are likelyto influence the nature and magnitude of thebiological response. To illustrate even further thecomplexity of the system, it should be noted thatammonia, a common contaminant of laboratoryenvironments, may in concentrations as low asseveral parts per billion by volume alter the pH ofH2SO4 and other aerosols. Ordinarily, the problemof understanding and controlling these critical fac-tors is beyond the competence of biologists.

Biological Measurements

There are a number of conventional physiologi-cal, biochemical, and structural (light and electronmicroscopy) measurements that have proven usefulin toxicological research. Familiarity with thesetechniques and the fact that some of them,especially the physiological measurements, areused routinely in human studies add to their value.Most of these functional measurements can be

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made repeatedly and safely in animals, althoughanesthesia and tracheal intubation may be re-quired in some instances. These measurements mayinclude flow resistance, compliance, andflow-volume curves. They are appropriate forstudying the evolution of changes during chronicexposure to pollutants. The development and useof models which mimic abnormal human statessuch as asthma, acute and chronic infections, anddegenerative diseases are of value for assessingchanges in susceptibility to pollutants.

Epidemiological studies suggest that infants andchildren may be especially vulnerable to air pollu-tion. It is possible that pollution experienced earlyin life and even in the prenatal period may haveeffects that are either unusually persistent or slowto manifest themselves. These questions warrantstudy with animal models.

Air pollution may increase human susceptibilityto infection. Animal models can be useful in deter-mining the mechanisms by which resistance to in-fection is impaired. Injuries to the mucociliary andmacrophage systems are considered to be impor-tant factors. The effect of pollutants on the abilityof pulmonary macrophages to inactivate inhaledbacteria has been tested in rodents. Dose-responserelations for individual pollutants (e.g., ozone andnitrogen dioxide) and for the same pollutants incombination have been established, but little workhas been done thus far with realistic concentrationsof irritant aerosols. Exposures to the latter shouldbe combined with other forms of stress that appearto have significance epidemiologically, i.e., cold,malnutrition, and underlying injury or disease ofthe respiratory system. Exercise or hyperventila-tion (produced, for example, by adding carbondioxide to inspired air) may be expected to increasethe magnitude of the animal's exposure to thepollutant and thereby alter the effect. It should benoted, however, that the effects associated with ex-ercise and hyperventilation might be quitedifferent, despite similar increases in ventilationfor the two circumstances.A large body of biochemical data indicates that

pollutants, especially oxidants, are capable ofaltering specific enzymatic systems. Some of thesechanges have implications for aging, for suscep-tibility to infection, and for the development ofpulmonary fibrosis and degenerative disease. Thepotential importance of these findings warrantscontinuing research. Caution is necessary in design-ing and evaluation such experiments, owing to thecomplexity of the biochemical systems. The techni-ques for isolating and studying individual types ofcells, especially of the respiratory system, are stillin need of refinement.

Research Priorities

Physicochemical Systems: High priorityshould be given to the study of aerosol parameterswhich are likely to influence toxicity or irritancy.For soluble aerosols, these parameters include: am-bient relative humidity and temperature, pH, parti-cle growth, relative toxicity, and site of reactions.

Ambient relative humidity and temperature areespecially important if the aerosol is mixed withsoluble gases such as SO2, NO2, and 03.

Chemical transformations in the atmosphere in-volving these same gaseous pollutants produceacids such as H2SO4 and acid salts such as(NH4)2SO4. It would be useful to know how impor-tant the hydrogen ion concentration of the aerosolis in determining toxicity.

The influence that particle growth within theairways, during hydration, may have on the rateand site of deposition of the particles, and conse-quently on the biological response, may be signifi-cant. To date, the bulk of our information on parti-cle behavior within the respiratory system has beenobtained using hydrophobic particles. As notedearlier, the soluble, hydrated aerosols are probablyof greater significance for health.

The relative toxicity of specific sulfate and ni-trate aerosols that are indigenous to polluted at-mospheres needs investigation. It is common torefer to the toxicity of "sulfate aerosols" as agroup, as if sulfate itself were responsible. There isno evidence that this is so. Certainly, differences intoxicity have been found in aerosols among suchspecies as ZnNH4SO4, ZnSO4, and (NH4)2SO4.Further, it is not known whether bisulfate (HSO3-)and sulfite (SO3=), two ions that are formed whenS04 dissolves in water, may contribute to toxicity;it is known, however, that sulfite ion does enter thebloodstream where it is reversibly bound.

In experiments combining gases and aerosols, ortwo or more gases, the site of interaction should bedetermined. The reaction may occur in the ambientair (reaction chamber), in the air stream within therespiratory system, or at the tissue level, especiallyin the mucus layer. In the past, inferences unsup-ported by physicochemical measurements or bytheory have been drawn with regard to where reac-tions occurred.

The results of such research should contribute tothe design and interpretation of epidemiological in-vestigations, and possibly both to the setting ofmore explicit ambient air quality standards and todecisions on the control of emissions. It would seemappropriate to carry out such studies on animals, atleast initially. The results could then be used to

10Environmental Health-Peeropeotives.160

design more selective clinical studies. Most ofthesestudies could be accomplished within 3- 5 yr.

Bilogical Systems: High priority should begiven to experiments involving chronic exposures ofanimals, preferably those which utilize (realistic)irritant aerosols, alone or in combination withreactive gases, and which take into account en-vironmental and biological factors that arethought to interact with pollutants, i.e., tem-perature, humidity, age, and nutritional state.There is strong epidemiological evidence for theeffects of air pollution on children which should beexamined experimentally in newborn and younganimals. In assessing the effects of pollutants, theuse of animal models that are analogues ofasthma,bronchitis, and perhaps alveolar injury is of poten-tial value.

More data are required on the chemical, physi-cal, and rheological changes in mucus that may oc-cur following the uptake of gases and particles. Lit-tle is known about the buffering capacity ofmucus.Such factors have implications for mucociliaryclearance and resistance to infection. Indeed, theprogressive thi of the mucus layer which oc-curs in small peripheral airways may be responsi-ble in part for the apparent vulnerability of theseairways to pollutants. Changes in mucus chemirymay indicate changes in the bronchomotor toneeither by stimulating sensory (reflex) receptors orby direction action on the smooth muscle.

Since pollutants are known to alter airwayclearance, studies are needed to define effects onclearance efficiency of pollutants and the impor-tance of such changes for increased susceptibility toother agents.

Studies of the relations between pollutant ex-posures and the function of alveolar macrophageare needed. It is suggested that they focus on theadverse effects of pollutants on the biochemicaland histochemical system for killing infectiousorganisms within the cell. Such efforts should bedirected at determining dose-response relation-ships at low levels of the pollutants.

Studies which delineate the effects of pollutantson the structural elements of the lung should be un-dertaken. Damage to these elements has implica-tions for elastic behavior (and morphometry), rateof aging, and predisposition of the lung todegenerative disease.

Pollutant InteractionsIt has long been recognized that the effects of air

pollutants on humans may be additive to or syn-

ergistic with other environmental factors, mostparticularly cigarette smoking, occupational ex-posures, and the stress of unusually h or lowtemperatures. In this section, attention will bedrawn to interactions of pollutants with each otherand to the possible influence of other environmen-tal factors on the effects of pollutants on therespiratory system.

It is possible to define at least four possible waysin which one pollutant may modify the effect ofanother: (1 by one pollutant affecting the site ofdeposition of another-as, for example, the deposi-tion of a soluble gas within the airway beingaffected by its adsorption onto a submicronic parti-cle; (2) by one pollutant interacting within the lungin combination with another to produce an aero-sol-the lun may accelerate aerosol formation byfunctioning as a mixing and reaction chamber inawhich gas is heated, humidified, and exposed to alarge surface; (3) by one pollutant affecting a 1'imechanism so that the clearance of another is ad-versely affected, as might occur if one pollutantaffected mucociliary clearance or the alveolarmacrophage; and (4) by one pollutant producing an,effect on the lung which makes it more vulnerableto another-as, for example, an effect on lungelasticity compromising airway clearance mecha-nism.

The principal ambient factors which influencedroplet size, aerosol formation, and the acidity ofan aerosol are relative humidity and temperature.The study and understanding of these interactionsare in a very preliminary stage. A high priorityshould be accorded human and animal exposuresin which the aerometric conditions of mixtures ofpollutants are precisely measured and in whichtechniques are used in animals to identify sites ofdeposition and mechanisms of action. This work ismade urgent by the changing nature and increasingcomplexity of the pollutant mixtures to which peo-ple are being exposed, and it is essential if answersto questions of comparative hazards of compoundsformed from sulfur, oxides of nitrogen, and oxi-dants are to rest on a solid foundation.A second concern is to characterize more pre-

cisely the influence of temperature and relativehumidity in modifying the effects of similar con-centrations of pollutants. Such measurementsshould be made not only in animal experiments butalso in humans during different kinds of physicalactivity.

It may be true to say that the complexity of theenvironments to which children and adults are nowbeing exposed has far outdistanced the laboratory

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potential to study, on a short-term basis, the possi- complexity consists in problems of pollutant in-ble consequences of such exposures. Much of the teraction.

MUTAGENESIS AND CARCINOGENESIS*

IntroductionThe quantitative relationship of fossil fuel com-

bustion products to mutagenesis and car-

cinogenesis in man requires a closer definition thanpresent data permit. Verification of a mutagenic or

carcinogenic hazard for man from an environmen-tal source must include: (1) identification of thechemical or physical agent (a single agent need notbe identified for preventive purposes) and the pro-

duction of mutation or cancer in an appropriatebiological system, and (2) demonstration of an in-creased risk of mutation or cancer in an exposedpopulation. While the first criterion has been metby several fossil fuel combustion products formutagenesis and carcinogensis, for the second cri-terion, despite suggestive data for a relationship ofpollution to cancer, there is no general agreementon the increased risk of mutation or cancer in manfrom exposure to air pollution. This is not to say

that such risks do not occur but that the methodshitherto used to study those relationships haveyielded inconsistent results.

MutagenesisThe potential mutagenic agents produced by

fossil fuel combustion include, as shown bylaboratory experiments, sulfate and nitrite in thechemical transformation of S02 and NO2, benzo-[a] pyrene (BAP), and trace metals (e.g., arsenic,chromium usually present in particulate, ra-

dionuclides, and oxidants (e.g., ozone). Thesemutagens are present in low concentrations and ex-

cept for ozone, which has produced chromatic-typeaberrations in human lymphocytes (28), there havebeen no demonstrated mutational effects on man.

CarcinogenesisThe classes of carcinogenic agents identified as

present in small amounts in fossil fuel combustionproducts are: polycyclic and other aromatic hy-drocarbons; trace metals; and radionuclides. Par-

*Leonard Hamilton (Chairman), Robert E. Carroll, C. L.Comar, John R. Goldsmith, Ian Higgins, Lester B. Lave, SidneyMarks.

ticulates may contain potential carcinogens such astrace metals and hydrocarbons. In addition, thereis evidence that in experimental animals SO, po-tentiates the carcinogenic activity of BAP. Becauseof the known mutagenic activity of oxidants, oneshould keep in mind their possible carcinogenic ac-tivity, although there has been no substantial evi-dence of their carcinogenicity to date.

These carcinogenic agents or their reaction pro-ducts are present in only small amounts in -fossilfuel combustion products compared with levelsthat might be expected to produce detectableeffects. There thus exists considerable uncertaintyas to their actual impact on man.

Uncertainties in Epidemiology ofPollution-Induced Cancer

Lung cancer has been more studied byepidemiologists than any other cancers that mightbe associated with air pollution. The principalarguments that air pollution is a causal factor inlung cancer in urban areas are: polluted at-mospheres contain known potent carcinogens; lungcancer in urban areas and in some internationalmigrant groups can be associated statistically withurban residence and by inference with urban pollu-tion; workmen occupationally exposed to benzo [a]pyrene, asbestos, and other materials present aspollutants have excess cancer; and cigarette smok-ing causes bronchitis, emphysema, and lung cancer(29). Urban pollution contains ingredients similarto those in cigarette smoke.

The arguments against air pollution being acausal factor in urban area excess of lung cancerare as follows. The differential excess due to the ur-ban factor should be detected as a relative or ab-solute excess in those states and countries wherethere is the greatest urban pollution. It is not. If ex-posure to urban pollution increases lung cancer,then rates should be higher in lifetime urban resi-dents than in migrants to urban areas. They arenot. Correlations of lung cancer rates withmeasured pollution should be found in the U.K.studies where lung caricer rates are high and pollu-tion has been great. The positive correlation is withpopulation density, not with pollution. If the urbanfactor were community air pollution, it shouldaffect women as much as men. It does not appear to

Environmental Health Perspectives162

do so. If urban pollution by benzo [a] pyrene makesan important contribution to the urban excess, lungcancer in locations most polluted by this agentshould be highest; when the agent decreases, lungcancer should do so as well. This has not yet beenfound.

There may be explanations other than air pollu-tion for the urban factor (greater smoking,domestic exposures, occupational exposure,population density, infectious agents). The evi-dence presently available does not support the con-clusion that air pollution per se is the factor; norcan this possibility be rejected.

Even though air pollution has not yet decisivelybeen shown to be the causal agent of lung cancer inurban areas, there are important practical con-siderations. Control of soot, suspended particularmatter, and products of incomplete combustion isappropriately among the highest and most urgentgoals of air pollution control. This is because of theevidence on the the induction of chronic bronchitisand because of other undesirable features of suchpollution. Reducing this type of pollution will paripassu decrease pollution by benzo[a]pyrene andother possible carcinogens.

Research PrioritiesMutagenesis

Because of the need to establish whether any ofthese previously mentioned potential mutagens areindeed mutagenic in man, the following studies

should be undertaken in humans: a search for ele-vated prevalence of chromosomal aberrations inpopulations occupationally exposed to high levelsof oxidants (e.g., ozone); correlations between birthdefects, spontaneous abortion and miscarriagerates, etc., and air pollution; and the mechanism ofthe action of these agents on the informationalmacromolecules, including their transport to sensi-tive sites. The problem of environmental mutagenichazards, with emphasis on screening, has recentlybeen reviewed (30). One can assume that the pro-ducts of fossil fuel combustion would be ap-propriately included.

Carcinogenesis

Occupational exposures to carcinogenic agentsare likely to be higher than exposures of the generalpopulation, and with better characterization ofdose and possibly, therefore, of response. Popula-tions exposed near point sources of known andsuspected carcinogens can and should also bestudied. We propose that priority be given to thestudy of persons occupationally exposed to knownor suspected carcinogens and to the study of otherpopulation groups who are exposed to point sourcesand whose health may be followed in a cohortstudy, with morbidity data and mortality databeing analyzed and periodically reported. It is im-portant to compare cancer rates in areas wherepollution differs and also in areas where pollutionhas changed over time. As for mutagens, the in-teraction of carcinogens and informationalmacromolecules needs further study.

TRACE ELEMENTS*

IntroductionTrace elements of particular importance from

fossil fuel combustion are considered to be lead,mercury, arsenic, vanadium, selenium, nickel, someheavy radionuclides, and possibly cadmium andfluoride. This selection is based on probable emis-sion rates, likelihood of uptake from air, accumula-tion in food and water, and the known toxicity ofsome of the chemical forms of the trace elements.The anthropogenic contribution to the environ-ment from fossil fuel combustion has been esti-

*Edward P. Radford (Chairman), A. H. Colton, MortonCorn, James R. Fancher, Bernard D. Goldstein, ElliotGoldstein, Steven M. Horvath, Harry A. Kornberg, ByronMechalas.

mated as up to 50% or more for selenium,vanadium, and chromium and as not more than20% for mercury. Even so, the health significanceof these emissions remains uncertain. The emissionof trace elements from the combustion of fossilfuels at stationary plants has not as yet been shownto have health significance for population.Nevertheless, areas around such power plantswould be of importance for future studies. As newfuels and new technologies are developed, thekinds, forms, and levels of trace elements in the en-vironment around power plants may change andresearch strategy should be adjusted accordingly.As a result of activity in different disciplines, itshould be possible to maintain an ongoing reviewof trace elements in regard to sources, combustionchemistry, atmospheric interactions, and possible

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health effects. Some general references are cited toprovide guidance in this area (31-,37).

Emission CharacteristicsThe emission of trace elements from stationary

sources of fossil fuel combustion products has notbeen characterized to the extent necessary to deter-mine the health significance of these materials.Although there is considerable knowledge aboutfuel constituents, the extent to which the trace ele-ment component escapes into the environment ispoorly understood and the chemical nature of thetrace effluents is not known.

In general, a wide range of trace elements isfound in coal, some of the more important beinglead, chromium, manganese, arsenic, fluoride,nickel, cadmium, zinc, and copper. Mercury andantimony are generally in low concentration butmay be important nevertheless. In oil the trace con-stituents are less well defined, but cadmium andvanadium are of particular importance. Nickel,manganese, selenium, and mercury may be signifi-cant in oil from some sources.

Further characterization of the emissions oftrace elements from fossil fuel plants needs to bedone. This is obviously closely related to monitor-ing of fossil fuel plants, which is discussedseparately later. Here we emphasize that deter-mining the chemical form of trace elements in theeffluent and in the environment has a high priority.Detailed emission inventories need to be done onlyin a few prototype plants.

The characterization of trace element content infuel ash is relatively simple and may serve severalpurposes. First, it aids in establishing a massbalance for a plant (if the fuel is also analyzed forthe elements of interest). Second, the ash itselfrepresents a pathway for possible concentration ofelements and for possible reintroduction into thebiosphere. Although we do not recommend suchstudies as being of high priority, they may be ofvalue for analysis of exposure related to particularclasses of plants and fuels.

The effects of various kinds of control equipmentupon emission of individual trace elements, by par-ticle size and species, are not well known andshould be studied for the elements of primary in-terest. As control technology becomes more widelyapplied, its impact on the trace constituents ofplumes is an important consideration; for example,enrichment of some volatile elements in small par-ticles escaping an electrostatic precipitator maylead to greater dispersal of these elements thanwould be expected.

Environmental AssessmentIn order to relate possible health effects with the

emission data on the trace elements of interest, it isnecessary to know what is actually found in the en-

vironment. This involves identifying the elementsin air and in the plant surroundings, with emphasison those which may accumulate in soil or sedi-ments and ultimately reach man. We consider it ofgreat importance that research be done to deter-mine the concentration, translocation, and uptakeinto components of the biosphere of elements suchas lead, arsenic, selenium, and mercury.

Trace elements deposited on the land may

follow several pathways. Depending on soil andelemental characteristics, the materials may pass

on through the soil column, may be trapped withinthe soil column, or may accumulate on the soil sur-

face. Important factors are soil alkalinity, amountof rainfall, and acidity of rainfall. It is expected, forexample, that highly alkaline western desert soilsin areas of sparse rainfall would show a differentaccumulation pattern than would eastern acid soilsreceiving heavy rainfall. Thus the accumulation oftrace elements in soils is a function of the source offuel, the soil type, the amount of rainfall, and thepH of the rain.

Trace elements may pass through the soil col-umn to the groundwater or be washed off the sur-

face of soil by rain runoff, eventually ending up inthe various surface waters-lakes, streams, oceans.

These products may also enter bodies of waterdirectly as fallout from the atmosphere. In thereceiving waters many of the same chemical in-teractions that take place on land may occur.

Solubility changes and chemical transformationmay occur, controlled by such factors as salinity,presence of other reactive elements, and pH. Even-tually many of these materials enter the bottomsediments, where they may undergo furtherchanges or remain buried.A controlling force that can modify the form and

mode of transport of trace elements through thephysical environment is the interaction with thebiota. Some of the trace element fallout may coatout on the surface of vegetation where it may bedirectly ingested by animals, especially in areas oflow rainfall. In many other cases plants may ac-

tively take up certain elements, accumulating themin their tissues. Again these materials may enteranimals that ingest the plants. An important pointhere is that not only may a material be passed fromone living form to another but that at each stepthere may be an accumulation which could mag-

nify the exposure of the ultimate consumer in thefood chain.

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In the aquatic environment, processes similar tothose on land may occur. In addition, the sedi-ments are a biologically rich zone in which manychemical transformations take place, mediated inpart by a rich microbial flora. Here elements mayundergo changes to more soluble forms or even tomore biologically active compounds, an examplebeing the conversion of inorganic mercury to thehighly toxic forms of alkyl mercury.A special issue related to airborne trace ele-

ments is their use as markers of power plantsources of suspended particulates in urban at-mospheres. If one or more elements can be shownto be characteristic of effluents from a power plantin a particular region, then determination of theseelements in urban air may provide a useful esti-mate of the contribution of the plant to the urbanair mass. This aspect of trace element researchcould be of considerable interest.

Health AspectsUptake, excretion, and accumulation of trace

elements in human subjects exposed to these ele-ments from power plant emissions constitute animportant area for future research. Current data onemissions have not included detailed evaluation ofthe chemical form that is inhaled by human sub-jects or is taken up by components of the biosphere.It is known that the absorption, excretion, and in-deed the toxic effect ofmany elements of toxicologi-cal importance depend on the chemical form, in-cluding the valence of the element. For this reason,one cannot state with confidence the extent towhich fixed sources of fossil fuel effluents are con-tributing to the body burden of these elements, incomparison with other sources such as food.

Lead and arsenic are likely to be importantquantitatively as effluents from power plants burn-ing coal; these could be of toxicological significancebecause of relatively slow excretion, with a poten-tial for accumulation. Cadmium may also be sig-nificant for this reason, but it is a relatively minorconstituent of fuels and in many would only be ofsignificance via food sources contaminated withairborne particulates. It appears unlikely that thisroute of exposure is important as a source of cad-mium in food.

It is most important to have knowledge of themetabolism of many elements arising from fossilfuel combustion. Much is already known aboutmany of the elements of concern; however, moreresearch is needed for others such as arsenic andselenium.

In addition to emission, distribution in the en-vironment, and metabolism, it is most important tostudy the toxicity of the trace elements of concern,taking into account the route of exposure. In par-ticular, toxicity studies of selenium and nickel maybe needed and the problem of arsenic as a potentialcarcinogen will have to be investigated. In addi-tion, other elements that we believe may be impor-tant as possible health problems from fossil fuelplants are mercury and perhaps also vanadium andsome of the heavy radioelements, especiallylead-210. Obviously the study of toxicity at lowlevels has inherent difficulties and requires large-scale, long-term commitments.

Atmospheric oxidation products of SO2, andperhaps also of oxides of nitrogen, may be impor-tant factors in community health effects associatedwith stationary source combustion of fossil fuel.Trace elements emitted with SO2 and NO. fromsuch sources may act as catalysts of these reactions.In the case of SO2, the reactions are highly complexand are governed by a number of independent andinterdependent variables, including temperature,relative humidity, and particle size, as well as traceelement composition. As a simplification, at-mospheric SO2 oxidation may be envisioned as twosequential steps: the formation of S03 (H2S04),followed by its conversion to metallic or am-monium sulfates. Based on the sketchy evidenceavailable at present, it would appear that the reac-tion rates for both these processes are governed bythe exact chemical composition of the trace ele-ment constituents, including the valence and theassociated anionic component. However, muchmore information is greatly needed, particularly inview of the potential importance of this conversionprocess to human health.Smog chamber studies of the reaction rates and

kinetics of SO2 oxidation should focus on mimick-ing ambient conditions, using realistic pollutantand trace element compositions as well as ap-propriate temperature and humidity. Reactionrates with the different trace elements should bedetermined with the hope that such informationmight be useful in eventual control measures.Studies of the process should also be performed inpower plant plumes and in the general atmosphere,partly with a view toward ascertaining to what ex-tent trace elements emitted from point sources areresponsible for atmospheric oxidation.

Less information is available concerning possi-ble interactions of trace elements with gaseouspollutants other than S02. However, there is someindication that potentially toxic agents might alsobe derived from nitrogen dioxide through the

-Deembeari -1075- - n.-

catalytic action of trace elements. Further study ofthis area would also appear indicated, although thepriority is not as great as with sulfur oxides.

Research PrioritiesResearch needs have been discussed in the body

of this chapter. Subject areas considered to be ofhighest priority are: characterization of trace ele-

ment emissions from fossil fuel plants; determina-tion of concentration, translocation, uptake, andconversions of elements such as lead, arsenic,selenium, and mercury in components of thebiosphere; study of metabolism and toxicity, inhuman beings, of selected trace elements such aslead, arsenic, selenium, and nickel; evaluation ofthe role of trace elements in catalysis of at-mospheric reactions of gaseous pollutants,especially SO2 and NO2.

MONITORING AND ANALYSIS*

IntroductionThe capability for adequate monitoring and

analysis of air pollutants is essential for assessmentof exposure/effects relationships in epidemiologicalstudies, for establishment of air quality criteria, formaintenance of compliance, and for design and ex-

ecution of controlled experiments. In this discus-sion, emphasis is given to the trace elements, oxidesof nitrogen, particulates, and sulfur oxides. Atten-tion is directed to the following sorts of questions:What is the relationship between the personal ex-

posure to pollutants experienced by individuals intheir day-to-day activities and the exposure pre-dicted by samplers operating at fixed locations in a

network? How dense must the sampling grid be indifferent topographical settings in order to providea valid estimate of personal exposure? To what ex-

tent can biological monitoring be used to evaluatedosages received by subjects exposed to pollutants?

Trace ElementsSufficient data are available to conclude that

trace elements in outdoor air are primarily associ-ated with particulate matter (38). The emissions in-ventory of trace elements from power plant emis-sions-indeed, from all source emissions-is inade-quate, as mentioned above. One needs to know notonly elemental composition of emissions but alsothe chemical species and properties. The capacity ofinhaled particulate matter to evoke responses inman depends on particle size, which determines thesite of particle deposition in the human respiratorytract. Therefore, source emissions from fossil fuelcombustion products should be assessed for trace

*Morton Corn (Chairman), A. H. Colton, James R. Fancher,John F. Finklea, Leonard Hamilton, Harry A. Kornberg, Ed-ward P. Radford.

element composition as a function of particle size.This should minimally include analysis of respira-ble and nonrespirable portions of suspended par-ticulate matter in effluents. More complete size-composition analysis, such as that derived fromcascade impactor analysis, would be desirable.Methods to obtain these data are available, but im-provements are required (39, 40). The solubility ofrespirable and nonrespirable particulates will alsoinfluence their potential to evoke responses andmust therefore be evaluated (41). Because chemicalreaction occurs in plumes, data on particle size,composition, and solubility should be obtained formaterial in plumes as well as in stack emissions(42). To evaluate exposure to individuals at groundlevel, the same data must be collected at siteswhere human subjects may be exposed. The rela-tionship between volatile trace elements in thevapor stage in stack emissions should be studiedbecause those elements may subsequently condenseon nuclei or particulates during or following emis-sion.

The above factors should be studied for typicalpower plants using fuels which can be consideredrepresentative of current or future industry prac-tice, including new fuels (i.e., reused oil, solidwaste).

Depending upon local topographical andmeteorological factors, monitoring at ground levelmust be considered for distances up to, and possiblyexceeding, 25 km from point sources.

It is recommended that more satisfactory sam-pling and analytical capability be developed for theelements Se, Hg, As, and Be. Again, knowledge ofthe combined forms of these elements is essentialfor evaluating their hazard potential; elementalanalysis is helpful but not sufficient.

Because selected trace elements have beenshown to participate, as catalysts or reactants inconversion of gas phase components of power plantplumes (e.g., iron, manganese, and vanadium),

Environmental Health Perspectives166

laboratory studies should be performed to identifythose trace elements and the chemical forms whichare associated with-accelerzation or deceleration ofgas phase reactions in power plant plumes. In-vestigations with this scope are beginning (43).

Oxides of Nitrogen

Oxides of nitrogen emissions from power plantsare almost entirely in the form of NO. The inven-tory for annual emissions of nitrogen oxides is wellestablished, but establishing inventories overshorter time periods presents some difficulties.Methodology for monitoring NO2 in air now ap-pears adequate for measuring the ambient con-centrations usually encountered, but developmen-tal effort is desirable, particularly for short-termsampling.

The occurrence and transformation ofNO2 in airare widespread and must be evaluated on an areabasis, rather than stressing plume studies.However, there is need for further delineating thereactions and reaction rates, including the in-fluence of type of combustion process, fuel, andmeteorology. These investigations could profitablybe included in other plume studies.

There is a substantial base for retrospective datafrom the National Air Sampling Network for NH4 +and NO3- in air (44). These data should be ex-amined for their possible utilization in evaluationof past exposures of inhabitants of areasmonitored. Selective limited studies of NO2 in airindoors (from gas combustion) suggest potentiallyhigh intermittent peak exposures to nitrogen pollu-tants (45). The extent and effects of indoor ex-posure should be carefully investigated.

The capability for monitoring more complexnitrogen compounds in air is severely limited in thelaboratory and in the field because the methods aredifficult and complicated. Despite this limitation, itis recommended that investigations be performedof peroxyacetylnitrate (PAN) in air in both thewestern and eastern United States.

Monitoring of nitric acid will require develop-ment of satisfactory analytical methods for thiscompound.

Research on NO. and its mechanisms of transfor-mation in air can be advantageously pursued inlaboratory chamber-type research. We recommendthat such studies be performed in conjunction withfield studies.

ParticulatesThis section is concerned only with problems

being experienced in monitoring for particulates.Fugitive emissions from power plant fly ash dumpsand coal piles appear to have been largelyneglected, and a further problem arises from wet-ting these dumps. These conditions require evalua-tion. Improvements for measurement and analysisof total suspended particulate matter in ambientair are possible along several fronts: particle sizecuts, analysis for metals, and anions. When studiesrelated to health effects of pollutants are under-taken, values from routine monitoring at networkstations should be augmented with measurementsof particle size and chemical composition.However, it should be recognized that networkcapabilities may be modified with time and thatongoing investigations may require rebuilding andimproving the capacity of existing stations.

Sulfur OxidesSulfur oxides include anthropogenic sulfur diox-

ide, sulfonates, sulfuric acid, ammonium sulfate,ammonium acid sulfate, and other sulfate salts.Acid-sulfate aerosols (sulfuric acid, ammoniumsulfate, and ammonium acid sulfate) can be formedin the atmosphere by conversion of sulfur com-

pounds emitted from combustion processes (46).Being hygroscopic, sulfur trioxide combines withwater to form sulfuric acid. Any research whichwould further clarify the pathways of primary andintermediate sulfur compounds entering into, re-

maining in, or leaving the atmosphere is of highestpriority. Studies of plume chemistry and mesoscalestudies of transport and transformation are re-

quired. The influence of humidity, hydrocarbons,trace elements, oxides of nitrogen, and other at-mospheric constituents must be sorted out andquantified. The effect of cooling towers on plumechemistry should be ascertained. Both chamberand field studies will be required to elucidatetransformation mechanisms. Dispersion modelsapplicable to complex terrain are generally lackingbut obviously needed.

Present measurement methods allow routinemonitoring of sulfur dioxide in emissions and am-

bient air. Acid-sulfate aerosols can be differenti-ated by size and chemical species, using specialresearch techniques that are not yet applicable toroutine monitoring. However, water-soluble sus-

pended sulfate extracted from high-volume filters

December 1975 167

is a useful method to estimate total acid-sulfate ex-posures which can be used in community studies.For exposure studies involving laboratory animalsor human volunteers it is most desirable to charac-terize exposures, using measurements that applyprecise particle sizing to aerosols of known chemi-cal composition.

Personal monitors for sulfur dioxide and foracid-sulfate aerosols or their proxies are in a rudi-mentary, generally unsatisfactory stage of develop-ment. It is recommended that improved measure-ment methods be developed to characterize the sizedistribution and chemical composition of acid-sul-fate aerosols and that personal monitoring techni-ques be developed for sulfur oxides.

Annual emissions inventories for sulfur oxideswere tabulated for each air quality control regionas a part of the state impletnentation plarfs re-quired by the Clean Air Act. Except for a few cities,it is difficult to ascertain how emissions havechanged during past decades or to obtain thedegree of temporal resolution needed to improvemodels of the source-receptor relationship.Therefore, to support health effects studies andstudies of atmospheric transport and transforma-tion it may be necessary to reconstruct emissionsinventories as a means of achieving the necessarydegree of temporal resolution.Human exposure to sulfur oxides may be esti-

mated from sulfur dioxide and water-soluble sul-fate measurements available from sampling sta-tions in commercial, residential, or industrialareas.

Both 24-hr and annual average exposures are ofinterest. Selection of populations for health studiesis best restricted to those who live within a 2- to 3-km radius of an appropriately sited monitoring sta-tion. Indoor monitoring of sulfur oxides is urgentlyrequired. Until personal exposure meters areavailable, it would seem appropriate to study in-dividual activity patterns and to estimate time-weighted exposures. Therefore, it is recommendedthat air monitoring stations be appropriately sitedand that indoor and outdoor monitoring be utilizedto estimate time-weighted exposures.

Air monitoring stations established for trendmonitoring or assessment of compliance with airpollution controls may provide useful informationonce quality assurance problems are surmounted.For example, measurement of sulfur dioxide andtotal suspended particulate matter in suspected im-pact areas around power plants may be used inhealth studies, together with meteorologic data to

improve or validate existing models of short-termexposures. Modest augmentation of these monitor-ing efforts by analyzing high-volume filters for sul-fate, nitrate, ammonium, and selected trace ele-ments would greatly enhance the utility of theseotherwise routine measurements. Instrumentationof existing stations can be further augmented by in-stalling suitable particle sizing devices for specialstudies (47). Studies of exposures lasting less than24 hr require more expensive instrumentation andsophisticated data acquisition systems. It is recom-mended that health studies employ existingmonitoring networks whenever possible, providedthese network-waugment-their particulate analyse,use federal reference methods of their equivalent,and participate in a recognized quality assuranceprogram.

Research PrioritiesThe main features of the research needs are as

follows:(1) There should be more complete studies of

trace element emissions to include elemental com-position and size-composition analysis, with databeing obtained for the plume, for stack emissions,and at ground level.

(2) Better sampling and analytical capabilitiesare needed for Se, Hg, As, and Be.

(3) Better methods are needed for sampling ofNO2 with special attention to occurrence andtransformations on an area basis. Levels of peroxy-acetylnitrate (PAN) in air should be monitored.

(4) Emissions of particulate from fly ash dumpsand coal piles should be evaluated. Particulatemeasurements should be improved to provide dataon particle size, metal contents, and possiblyanions.

(5) For sulfur compounds that enter the at-mosphere, the complete physical and chemicalpathways which are active and serve to transformthe emissions during transport should be clarified,together with the factors that govern them.

(6) Improved measurements are needed for sizecharacterization and analyses of acid-sulfate aero-sols and for personal monitoring of exposures tothe sulfur oxides.

(7) Air monitoring for sulfur oxides should bestudied and improved so that data are as useful aspossible for retrospective and prospective assess-ment of health effects, trend monitoring, and com-pliance.

Environmental Health Perspectives168

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