Assessing health effects of ah pollution The role of controlled studies of human volunteers is examined
complementary relationship of controlled human studies to two other risk-assessment disciplines: animal toxicology and epidemiology. Emphasis is placed upon respiratory irritants common in ambient air, specifically photochemical oxidants and sulfur oxides. A number of other pollutants found in community or occupational environments also may be studied through human exposures, as indicated in Table I .
Jack D.Hackney William S. Linn Edward L. Avo1 Environmental Health Seruice Rancho Los Amigos Hospital School of Medicine Uniuersity of Southern California Downey, Calif. 90242
To set air quality standards adequate to protect public health, regulatory agencies need extensive, reliable scientific data on the health effects of air pollutants. For short-term stan-
dards especially, much of the necessary information is obtained by observing the responses of human volunteers who have been exposed deliberately to pollutants under controlled laboratory conditions. Despite its importance in the regulatory process, the field of controlled human studies remains unfamiliar to many in the environmental protection and health professions. This article describes some current problems in assessing health risks from polluted air, the capabilities and limitations of controlled human studies in solving these problems, and the
What are controlled human studies? Human exposure studies require contributions from the disciplines of atmospheric chemistry, environmental engineering, physiology, and clinical medicine. Scientific investigators must create within the laboratory a polluted air environment that is a reasonably realistic model of the polluted ambient environment of concern. They must then recruit volunteer subjects who are representative of the population at risk in the community. The subjects must be exposed to laboratory polluted air under conditions that are well controlled, well documented, and similar to ambient exposure conditions insofar as possible. Finally, the investigators must employ the most sensitive biomedical tests available to detect subjects’ responses, if any, to the pollutant dose. As in most medical experiments, subjects’ responses to “treatment” must becompared against a controlor placebo. Subjects should be “blind” to the difference between the actual exposure and control conditions, as should the experimenters who are actually measuring the results. Otherwise, the expectations of the people involved, or cxperimental stresses other than the pollutant itself, may provoke responses that could be mistaken for adverse effects of the polluEinviron. Sci. Technol.. Vol. 18, NO.4. 1984
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Table 1
Common ambient air pollutant Substance
NAAOS*
0 14 ppm
None
“Hlph”smb
0 2-0 3 ppm(1 h)io
.A number ofstudies ofS02during the 1960s and 1970s indicated that increased airway resistance and symptoms of irritation couldoccur with exposure, but only at concentrations of I ppm or higher (above the com mon ambient range) . in most subjects. In 1980. however. D. SheoDard and associatcs’of the Universiti’of California at San Francisco reported that asthmatic subjects were consistently a n d markedly more reactive to SO2 than similarly exposed healthy subjects ( 3 / ) . These investigators
subsequently reported finding statistically significant increases in airway resistance in a group of moderately exercising asthmatics who were exposed to as little as 0.25 ppm for 10 min (32). Their reports renewed scientific and regulatory interest in the health effects of SO2 and brought about a number of follow-up investigations, some of which are still in progress. The first SO2 exposures of asthmatics in our laboratory failed to show significant effects at 0.25 or 0.50 ppm (33). This inconsistency with the results of Sheppard et al. most likely related to differences in the mode of breathing during exposure (34, 35). Mouthpiece breathing, as employed originally by Sheppard’s group, typically produces more severe responses than natural unencumbered breathing, which was employed by our group. The difference is at least partly explainable in terms of the high solubility of SO2 in aqueous media. Natural breathing occurs at least partly through the nose, even during heavy exercise. The moist surfaces of the nasal cavity scrub SO2 effectively, reducing the dose to the bronchial passages where constriction occurs. But even natural breathing of SO2 can cause some asthmatics to experience symptoms and increased airway resistance at concentrations at least as low as 0.4 ppm, with sufficiently heavy exercise (36). In some cases, constriction of bronchial passages may perhaps occur as a reflex response to nasal irritation, even if little SO2 penetrates to the lower respiratory tract. The effects develop in less than five minutes, that is, much more quickly than the effects of exposure to 03. Their severity appears to depend on the dose rate of SO2 (concentration times the subjekt’s ventilation rate), rather than on the total dose. In most asthmatic subjects, the effects disappear in less than an hour, with rest, even if SO2 exposure continues (37). Many asthmatics experience symptoms and airway constriction with exercise even in very clean air, so care must be taken to differentiate the effects attributable to exercise from those attributable to S02. Recent controlled SO2 exposure studies leave little doubt that respiratory effects can occur at concentrations within the possible ambient range, in a particular small minority of the population-asthmatics who exercise heavily. Whether these “positive” findings have any connection with earlier positive epidemiologic findings (not related specifically
to exercising asthmatics) is not yet clear. A current concern: “acid fog” Most human exposure studies have been conducted at moderate levels of relative humidity. However, in past episodes of extreme air pollution accompanied by substantially increased death rates, the weather was foggy. In London in December 1952, an episode lasting several days was associated with a t least 3000 premature deaths in people with preexisting respiratory disease (38).Similar though smaller-scale incidents had occurred previously in Donora, Pa., and in the Meuse Valley of Belgium. N o specific pollutant was ever identified as a cause of premature deaths and illnesses. Particulate and SO2 levels are far lower today than they were in these instances and the effects of periods of extreme pollution on illness and death rates are no longer so obvious, although they may not have disappeared entirely. Recent atmospheric studies, however, have redirected attention to possible health risks from fog-associated pollution, presenting a new challenge to the field of controlled human exposure studies. M. R. Hoffmann and coworkers at the California Institute of Technology collected fog water from a number of sites in southern California during winter nights and early mornings (39). They found substantial concentrations of acidic species in some of their samples, with pH values sometimes near 2 (compared with 5 or 6 in water from typical unpolluted fog). Nitrates appeared to be the predominant acidic species in most of these samples, reflecting the relatively high levels of oxides of nitrogen prevalent in urban southern California. In other industrialized urban areas, sulfates might be expected to predominate. The total acidity of water from polluted California fogs may approach that of London’s 1952 incident, although in California such extreme conditions typically persist for only a few minutes rather than for several days. Analysis of fog water by itself does not, of course, provide much information about the dose of potentially toxic pollutants inhaled by people breathing the fog. One still needs to know what the atmospheric concentration of inhalable pollutants is, and in what physical form the pollutants occur. Monitoring foggy atmospheres to obtain such information is difficult, but may be essential to understanding the health implications of acid fog.
The size of the water droplets in polluted fog may strongly affect the fog’s respiratory toxicity. In theory, respirable droplets (a few micrometers or smaller in diameter) may concentrate soluble toxic gas or aerosol species, and when inhaled, may deposit preferentially at certain sites in the respiratory tract (40). Such hot spots of deposition might then receive far higher local doses of toxic agents than they would in the absence of water droplets. On the other hand, many fog droplets are too large to be in the respirable range. Any pollutants dissolved in these large droplets should be prevented from reaching the lower respiratory tract, in which case the fog might have a mitigating effect on the risk to health. Nitrate and sulfate concentrations during pollution episodes in Los Angeles typically are on the order of tens of pg/m3. Controlled exposures to sulfuric acid aerosol-presumably the most irritating sulfate-have shown little effect even at concentrations somewhat higher than this (414 3 ) .Ammonium nitrate has shown no meaningful effect at 200 pg/m3 ( 4 4 , but nitric acid has not been studied. None of the aforementioned studies included fog, and most of them did not investigate a range of high-risk subject groups, such as heavily exercising asthmatics. Thus, neither the available evidence suggesting a health risk from acid fog nor the available contrary evidence is definitive. New investigations will be needed either to confirm or to allay present concerns. Such experimental work is now being considered by several regulatory agencies and industry-sponsored research organizations. The biomedical aspects of acid fog exposure studies can be similar to previous studies of other pollutants, but the atmospheric aspects will be more complex. More extensive ambient air monitoring studies will be needed to provide more complete understanding of the physical and chemical properties of polluted fogs. In addition, techniques will have to be developed to generate and monitor polluted fogs in the laboratory.
Summary Controlled exposure of human volunteers to air pollutants can provide the definitive scientific evidence of health risks that is essential to support air quality regulatory policy decisions. However, controlled studies are applicable only to short-term exposures with mild, temporary effects. Longer term exposures and effects Environ. Sci. Technol., Vol. 18, No. 4, 1984
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must be investigated through animal toxicology and epidemiology. To maximize overall understanding of air pollution hazards, links should be established between short- and longterm biological effects, and between different fields of investigation. Among the numerous pollutants that have been studied in controlled exposures, only 0, and SO2 have shown clear untoward effects on the respiratory system at concentrations likely to be attained in polluted ambient air. The most obvious effect of 0, is irritation of the lower respiratory tract, which develops and resolves slowly. This response is more or less proportional to the total 0, dose: People who exercise heavily, and thus breathe heavily, for prolonged periods seem most susceptible. The typical effect of S02-constriction of the bronchial passages-has been observed at ambientlike exposure concentrations only in exercising asthmatics. This effect develops quickly and usually resolves quickly with rest. Its intensity seems to be proportionate to the dose rate, rather than the total dose, of Sol. Acid fog has provoked concern recently over its possible effects on health. Controlled h u m a n studies provide a way toaddress thisconcern, but should be preceded by atmospheric monitoring studiesand thedevelopment of new exposure methodology. Acknowledgment T h e authors’ recent work mentioned
here has been supported by the Electric Power Research Institute. Southern California Edison co., the U.S. EPA, and Coordinating Research Council. Before publication, this article was reviewed a n d commented on for suitability as an ES& T feature by Dr. Robert G. Tardiff, Life Systems. Inc., Arlington, Va. 22202; Dr. Julian B. Andelman. Dep a r t m e n t of Industrial Environmental H e a l t h Sciences, G r a d u a t e School of Public Health, University of Pittsburgh, Pittsburgh, Pa. 15261; and Dr. Richard G. Cuddihy, Inhalation Toxicology Res e a r c h Institute, Lovelace Biomedical a n d Research Institute, Albuquerque. N.M.
87185.
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