Handbook of Hazardous Materials

Corn

Ambient Acidic Aerosols

Frederick W. Lipfert,     Environmental Consultant

Ronald E. Wyzga,     Electric Power Research Institute

I. Sources of Atmospheric Acids

II. Transport and Transformations

III. Measurement Methods

IV. Current Ambient Levels

V. Suspected Health Effects

VI. Other Environmental Effects

VII. Control Techniques

VIII. Summary

Glossary

Acid gas Water-soluble gas that yields protons (H+) in solution.

Aerosol Gaseous suspension of solid or liquid particles.

Bronchoconstriction Resistance to breathing caused by narrowing or obstruction of the airways.

Clearance Ability of the cilia to expel foreign particles from the airways.

FEV1 Amount of air expelled from the lungs in the first second of a forced expiratory maneuver.

Strong acid Acid that dissociates completely in water.

Weak acid Acid that dissociates only partially, depending on other substances present.

ACIDIC AEROSOLS are gaseous suspensions of solid or liquid particles that yield electrically charged hydrogen atoms (H+) when dissolved in water. The gas (ambient air) in which the particles are suspended may or may not include acid gases such as hydrochloric (HCl) or nitric (HNO3) acids. Sulfuric acid (H2SO4) and its various ammonium salts [NH4HSO4, (NH4)2SO4, (NH4)3H(SO4)2] are the most commonly found acidic particles, although (NH4)2SO4 is a very weak acid. Some organic acids can exist as particles; these are also weak acids. Because of its low vapor pressure, H2SO4 normally exists in the atmosphere in the particulate phase (as fine droplets). Since most of the extant information on the biologic effects of acid aerosols has been obtained from experiments involving sulfate compounds, this article emphasizes H2SO4 and its ammoniated salts. There are no national ambient air quality standards for acidic aerosols or for suspended sulfates.

I Sources of Atmospheric Acids

A Direct Emissions

Acid gases and particles can be emitted from certain manufacturing processes including the manufacture of H2SO4 and explosives as well as other chemical processes. The physical form of H2SO4 emitted from such processes tends to be as acid mist, characterized by median particle diameters of several micrometers (µm) and larger. In addition, the combustion of sulfur-bearing fuels normally results in the direct emission of a small fraction (<5%) of fuel sulfur in the form of H2SO4 or as metal sulfate salts. These direct stack emissions are referred to as primary sulfates. Another minor source of ambient acids is from oxidation of the sulfur dioxide (SO2) in gasoline (which contains about 0.05% sulfur) as the exhaust gases pass through the catalytic converter. When chloride-containing coal is burned, the Cl− is normally emitted as HCl (gas). Hydrofluoric acid (HF) from industrial sources was one of the agents suspected of contributing to the 1930 air pollution disaster in Meuse Valley, Belgium.

B Secondary Particles

Since most of the sulfur released to the atmosphere from anthropogenic activities is in the form of SO2, the subsequent oxidation of SO2 to H2SO4 is the most important source of acidic aerosols in regions where sulfur-bearing fuels are burned. These particles are hygroscopic and of submicrometer size; as the aerosol travels and ages in the atmosphere, median diameters tend to increase to the order of 0.7–1 μm. Chemical transformations are discussed in Section II.

C Natural Sources of Ambient Acids

Sulfur compounds are emitted from volcanoes, soil, vegetation, and wetlands, and include SO2, hydrogen sulfide (H2S), carbonyl sulfide (COS), and other compounds including sulfates (SO4²−). Their route of removal from the atmosphere is through slow oxidation to water-soluble sulfate particles (some of which may be acidic), which are then scavenged by precipitation. Natural emissions are an important part of the global sulfur cycle because of the large extent of the emitting areas. However, they constitute only a minor part of the total atmospheric sulfur in most urban or industrial regions where the density of sulfur emissions may be several orders of magnitude higher than found in natural areas. (For a ground level source or group of sources, ambient air quality is directly proportional to emissions density.) Although marine aerosols are essentially neutral (NaCl), they can react with strong acids (H2SO4 or HNO3) to release HCl.

II Transport and Transformations

It is commonly assumed that all of the sulfur in fuel is oxidized to SO2 during fuel combustion in modern installations and that, during the combustion process, varying amounts of atmospheric N2 are oxidized to nitric oxide (NO), which is the primary oxide of nitrogen species emitted. As the combustion gas plume travels downwind in the atmosphere, it is subject to various chemical transformations and removal processes which can have important bearings on the nature of any adverse environmental effects. The pollutants that are removed from the air can accumulate in surface deposits, which may have varying effects upon their receptors. This chain of processes is depicted schematically in Figure 1.

Figure 1 Schematic illustrating the main atmospheric processes involved for ambient acidic aerosols. [From Lipfert (1991); courtesy of Springer-Verlag.]

A Transformations

1 Sulfur Compounds

Sulfur dioxide (SO2) can be oxidized to form H2SO4 either in the gas phase through photochemical reactions, or in the aqueous phase in cloud water. When clouds evaporate, sulfate particles are left behind. The photochemical reactions involving ozone (O3) are fairly slow (1–3%/hr) but operate during all daylight hours. Aqueous reactions are faster, but require the presence of clouds; hydrogen peroxide is thought to be the most important aqueous phase oxidant. The relative importance of these two sulfate formation pathways will vary with season and climatic factors.

Secondary sulfate particles are usually associated with ammonium; sulfate particles involving calcium or other crustal elements are also found, but tend to be larger in particle size (>1 μm). The acidity of sulfate particles depends on their source and the extent of contact with ambient ammonia. The high correlation between SO4²− and NH4+ in both aerosol and precipitation may be due in part to the inverse dependencies of their water solubilities on solution pH. Sulfur dioxide dissolves only slightly in water, according to physical (Henry’s Law) solubilities; its solubility is enhanced considerably by dissolution to form bisulfite ion, but this solubility is pH dependent and quite limited for pH <5. As a cloud droplet or surface film acidifies due to the dissolution of SO2, continued SO2 dissolution depends on the oxidation of the SO2 in solution. However, ammonia (NH3) can buffer the solution and NH3 solubility increases as the pH drops. Thus, in the presence of moisture, the two gases have an affinity for each other; sulfate aerosols can be precipitated to the atmosphere as these solutions evaporate.

The low vapor pressure of H2SO4 and ammonium sulfates is an important property, which ensures that they remain as particles under normal atmospheric conditions. In contrast, nitric and hydrochloric acids exist as vapors, and ammonium nitrate tends to be unstable.

2 Nitrogen Compounds and Oxidants

Nitric oxide (NO) is nearly insoluble in water and is unreactive in solution; therefore, little is deposited on surfaces or oxidized by reactions in cloud water. Nitric oxide is oxidized to NO2 by reaction with ozone (O3) or other oxidants on a time scale of hours. NO2 is subject to dry deposition and can be further oxidized to form nitric acid by gas phase reaction with the OH− radical. Nitric acid is quite volatile, highly soluble in cloud and rain water, and deposits on virtually all surfaces.

Ozone formation is dependent on both nitrogen oxides and volatile organic compounds (VOCs), which are hydrocarbons emitted from motor vehicles, solvent usage, and natural sources. Ozone and other oxidants participate in complex photochemical cycles, with peak concentrations occurring on summer afternoons.

3 Neutralization of Acids

As discussed further in Section V, the toxicity or irritant potential of an acid aerosol is thought to be due chiefly to its hydrogen ion content (H+). The importance to toxicity of the remainder of the molecule is an open question. In clinical experiments on animals and humans, H2SO4 has been shown to be the most potent sulfate compound; ammonium bisulfate (NH4HSO4) is somewhat less potent (even for the same H+ dose), and ammonium sulfate (NH4)2SO4 is virtually innocuous. The sulfates found in ambient air are not likely to exist as pure compounds per se but, at sufficiently high relative humidity, tend to exist as internal mixtures of H+, SO4²−, and NH4+. These mixtures may reflect the composition of the aerosol when it was first formed, or as modified by contact with other atmospheric compounds during transport. Urban aerosols have been shown to be less acidic than their rural counterparts, for example. Neutralization is also increased near sources of ammonia, which include human and animal wastes, coal combustion, and manufacturing plants. The 1970 British Report on Air Pollution and Health by the Royal College of Physicians recommended placing open bottles of dilute ammonia in the rooms of patients with chronic bronchitis or chronic heart disease to neutralize acid mists.

B Atmospheric Removal Mechanisms

The solubility of SO2 in water is central to its removal from the atmosphere; this removal is responsible for the maintenance of a stable background concentration (rather than a continuous atmospheric build-up in response to continuous emissions). Removal mechanisms are termed wet if associated with hydrometeors; dry, if otherwise. SO2 can readily be removed by dry deposition to vegetation and other moist surfaces, but as discussed earlier, the uptake of SO2 by surface moisture depends on its buffering capacity. Sea water is highly buffered and may be the perfect absorber of SO2. Uptake of SO2 into cloud water or surface moisture layers may be greatly enhanced by aqueous-phase oxidation, especially by hydrogen peroxide (H2O2). In surface moisture, attack of the surface by dissolved SO2 (H2SO3) or H2SO4 can provide buffering.

Removal of airborne sulfate particles is dominated by wet removal processes, mostly by dissolution into cloud water concurrent with cloud formation, followed by deposition in precipitation. Wet removal processes are further controlled by precipitation types and rates. Dry deposition processes on surfaces are affected by atmospheric transport rates that mix fresh pollutant into the surface boundary layers and by the physical properties of particles. Dry deposition of sulfate particles is limited by the low diffusion coefficient of small aerosol particles. Removal of NO2 and ozone is controlled more by chemical reactions than by direct deposition due to their limited solubility in water. For SO2, dry removal processes are generally considered slightly more important than wet, and dry deposition rates of (gaseous) SO2 far exceed those of its sulfate transformation products. This is a result of the characteristic SO4²− particle sizes (typically 0.1–1 µm) being near the minimum for sedimentation and other physical deposition processes. One of the results of this difference in deposition velocities is that sulfur particles will remain airborne and thus travel further from their original sources than SO2.

Fog offers still another opportunity to form or modify atmospheric processes (fog is defined as a cloud in contact with the ground). Since the common sulfate particles are quite hygroscopic, they are readily scavenged by the relatively large (~5–50 μm) fog water droplets, as is nitric acid vapor. In addition, if gaseous SO2 is absorbed into the droplets, it may be oxidized to form H2SO4 by any of several chemical reactions involving either oxidants or catalysts within the droplet. These processes constitute one of the natural sinks for SO2 since the larger fog particles tend to settle gravitationally and deposit at rates much faster than the dry aerosol. After fog water droplets evaporate and the fog clears, sulfate aerosol particles may be left behind; this also happens with clouds. These particles tend to be larger (~0.7 μm) than the aerosol particles formed by condensation of gas phase precursors.

C Atmospheric Transport Processes

If an atmospheric constituent is not removed, it will be transported by the winds, which vary greatly in time and space. The vertical dimension is particularly important, not only because transport speeds increase with height but because the probability of encountering clouds increases with height and the likelihood of being trapped by a ground-based inversion is decreased. Aircraft measurements show that concentrations of water-soluble species decrease much faster with altitude than do insoluble species such as ozone. Electric utilities tend to use tall stacks, up to about 300 m in North America and 200 m in Europe. Many European cities use sulfur-bearing fuels for space heating; these ground-level releases are more likely to be trapped by atmospheric inversions than are emissions from tall stacks.

III Measurement Methods

A Air Sampling and Analysis

Air pollution is traditionally measured in either mass or volumetric units per volume of air; such concentrations are determined using specific reference methods of sample preparation and chemical analysis, as defined by regulatory agencies, for example. Although a reference method has not been defined for acid aerosols, methods of monitoring have evolved over the years into a complex technology. The methodology now in most common use involves the following steps:

• Selecting the desired range of particle sizes

• Capturing a representative sample

• Protecting the collected sample from inadvertent neutralization or other chemical reactions or physical losses during transport to the laboratory or while awaiting analysis

• Preparing an aqueous solution of the collected particles

• Determining the chemical composition of this solution

The difficulties encountered in each of these steps depend on the objectives of the monitoring. For example, characterizing the long-term average properties of the atmosphere is much easier than developing integrated exposure data for free-living populations with representative samples. The latter task requires information on microenvironments for indoors (home, work, transit) as well as outdoors, by time of day and season. In addition, data are required for a range of particle sizes, since different sizes tend to deposit in different regions of the respiratory system and thus may result in different types of health effects.

In most current research programs, acid aerosol monitoring is based on 12–24 hr filter samples of particles smaller than about 2–3 μm. The samples are protected against inadvertent neutralization by ambient ammonia in two ways. First, the sampling apparatus strips the ammonia from the gas stream to prevent a subsequent gas flow from neutralizing previously collected particles on the filter. After removal from the sampler, the filters are further protected against neutralization and loss of acidity by use of a citric acid atmosphere during transit and while in the laboratory. The NH3 removal process has the disadvantage of altering the phase equilibrium of the gas stream and might not be required for shorter sampling times. However, using shorter sampling times and a smaller particle size cut-off (such as one in which most of the acid particles are smaller than 1 μm) would reduce the mass of collected material, which can create analytical difficulties. In addition, shorter sampling times would result in a higher laboratory analysis load.

Extraction of the collected particles from the filter into solution is now a well-developed process with no particular problems. Determination of the concentrations of the major ions in solution is also straightforward, with ion chromatography the preferred technology. However, direct determination of the acidity of the solution has several options. The simplest method uses a pH meter with a glass electrode and measures the free acidity of the solution. This will equal the strong acid content if no buffering agents are present in the sample. Determination of the total acidity requires titration to a specified end point (i.e., total titratable acidity). For example, titration to pH 3 yields strong acidity; to pH 7, strong and weak acidity; to pH 10 will include very weak acids such as ammonium sulfate.

This technology is now in routine use by several research groups but yields no direct information on the chemical species present. To the extent that the effects of, say, H2SO4, differ from those of NH4HSO4 at the same pH, for example, this is an important unfulfilled need. Methods of selectively extracting H2SO4 from filters are not in common use because of uncertainties regarding their efficiency. Methods of determining H2SO4 without using filters were first developed in the 1970s and have been refined since then. The basic method uses the flame-photometric SO2 analyzer, modified to accept small particles. Thermal volatilization is used to separate H2SO4 from the ammonium salts, which unfortunately cannot be further speciated through this technique. If the ionic composition is known and the sulfuric acid content has been determined independently, the split between ammonium bisulfate and ammonium sulfate may be inferred.

Another technology for speciation of ammonium salts is based on differentiating their infrared spectral signatures. This method offers fast response and nondestructive analysis, but thus far its application has been limited to the laboratory where it was developed.

An approximate measure of aerosol acidity levels may be otained from ion charge balances if reliable measures of sulfate, nitrate, and ammonium ion concentrations are available. This method has often been used to check the validity of pH determinations in precipitation samples. While sulfate ion concentrations are usually reliable, there can be problems with both ammonium and nitrate. Ordinary filter sampling will likely capture some gaseous nitric acid on the filter, resulting in an overstatement of particulate nitrate. However, in the eastern United States, particulate nitrate levels are sufficiently low so that this error does not significantly affect the ion balance, especially at high levels of acidity. Ammonium concentrations may be subjected to either positive or negative artifacts. Ambient ammonia may add to the ammonium present in the air sample if allowed to contact acidic particles, as discussed earlier. If ammonium sulfate contacts basic particles (which are usually in the larger size fractions), ammonia gas may be liberated, resulting in a negative artifact. This is more likely to occur in non-size-selective sampling such as high-volume sampling, and is a likely explanation for the inordinately low NH4+ levels typically found in some of the older ambient databases.

B Measures of Dose or Effect

Multiplying concentration by the rate of breathing (typically about 20 cubic meters per day or 14 liters per minute, for quiet breathing) gives the amount of pollutant inspired (i.e., the nominal pollutant dose). This is straightforward for a well-defined stable substance such as carbon monoxide. However, for chemically or physically reacting substances, it is more difficult to predict the effective dose actually received at a specific location or region of the airways.

For example, strong acids are characterized chemically by their pH or by the concentration of hydrogen ions (H+). For fog, concentrations are based on the liquid content; for other aerosols, on the volume of air sampled. The two may be related by the liquid water content (LWC) of the aerosol, which ranges from about 0.01 to 1 g H2O per cubic meter of air for fogs and about four orders of magnitude less for clear air aerosols, depending on the relative humidity. For this reason, the same mass concentrations of acid fog particles and acid aerosol particles represent greatly different ionic strengths and pH values. For example, a fog with a liquid water content of 1 g/m³ and pH of 3.7¹ corresponds to an air concentration of 10 µg/m³ as sulfuric acid. That same concentration in a clear air aerosol could correspond to pH <1. These considerations refer to the particles before they enter the respiratory tract, where dilution will take place through hygroscopic growth.

Both chemical and physical changes take place during breathing. The respiratory tract is characterized by high humidity (~98%) and varying amounts of endogenous ammonia (NH3), which can neutralize acids. More ammonia is found in the mouth, probably because of the bacteria found there. Thus, the amount of aerosol neutralization depends on whether the nose or the mouth is the primary route of entry into the respiratory tract. In addition to being neutralized by ammonia, hygroscopic particles can absorb moisture; this increases their average diameter and reduces the pH (but not the mass of H+). The particle size is very important in determining the specific region of the respiratory tract in which the particles deposit. Water-soluble gases (such as SO2 or HNO3) are scrubbed out by the moist surfaces of the upper respiratory tract, where they may react with some of the NH3. Submicrometer particles may penetrate deeper into the lung and some of them will be exhaled. Larger particles (up to 5 μm) are more likely to deposit higher in the airways, although some of them may also deposit in the pulmonary region. Research is in progress to model these chemical and physical processes to develop a better understanding of the relationships between various measures of ambient concentrations and the actual dosage delivered to various parts of the respiratory system. It is likely that the physical properties of inhaled particles are important in this regard, a phenomenon which may help explain some of the differences in health effects observed between particles of the same H+ concentration but differing composition.

IV Current Ambient Levels

A Methods of Reporting Ambient Data

There are several metrics in common use for reporting ambient acidity data. Mass (µg/m³) or volumetric (ppb) concentrations are used for specific compounds. Acidity may be reported as

• pH (usually only for fog or precipitation)

• Mass units expressed as µg/m³ of H2SO4, as if H2SO4 were the only acidic species and no ammonium were present in the mixture (not to be confused with direct measurements of H2SO4 per se)

• Concentration of chemical (H+) equivalents (equivalent weight = molecular weight/valence)

The last metric is usually expressed as nanoequivalents per cubic meter of air sampled, or neq/m³. H+ concentrations can be converted from neq/m³ to equivalent mass units expressed as H2SO4 in µg/m³ by dividing by 20.4. Chemical equivalents provide a useful means of comparing the acid potency of different compounds.

Measurements of aerosol H2SO4, per se, have been reported in the literature, but if the aerosol is internally mixed, these data must represent a portion of the mixture rather than free sulfuric acid particles.

B Ambient Measurements

No routine monitoring databases have been developed for aerosol acidity, but a number of research campaigns have accumulated useful data. As with most other air pollutants, concentrations of acid aerosols vary with time of day and season and are influenced by sampling and averaging times. Current ambient levels in the eastern United States range from about 1–2 µg/m³ (expressed as µg/m³ of equivalent H2SO4) on an annual average basis to about 10–40 µg/m³ on a 24-hr basis. Frequency distributions vary by location and typically consist of periods of low levels or even negative values (i.e., at alkaline pH) punctuated by episodic periods of a few days’ duration (Figure 2). As a result, the frequency distribution of H+ doses over a year or an entire season tends to be dominated by these few episodic values, more so than ozone, SO2, or sulfates, for example. The episodic nature of H+ exposure is shown in Figure 3; in a location near large SO2 sources in the summer (Figure 3a), about 50% of the total H+ exposure occurs in only 20% of the total time, whereas the exposure to ozone is more nearly uniform throughout the time period. At a more remote location and considering the entire year (Figure 3b), H+ exposure is even more episodic: 50% of the exposure occurs in less than 10% of the time. Note that at this location, H+ values are alkaline about 30% of the time. The highest short-term acid peaks tend to occur during summer afternoons, apparently because the higher levels of oxidants outweigh the higher levels of ammonia typically present then.

Figure 2 Time history of aerosol acidity at Whiteface Mountain, New York, based on intermittent sampling. [Modified from Lipfert (1991); courtesy of Springer-Verlag. Data from T. J. Kelly, Trace gas and aerosol measurements at Whiteface Mountain, NY. Brookhaven National Laboratory Reports BNL 37110 (Sept. 1985) and BNL 39464 (Jan. 1987).]

Figure 3 Distributions of cumulative exposures to various pollutants as a function of exposure time. Samples have been ranked according to the H+ dose. (a) Allegheny Mountain, PA, August 1983. (b) Whiteface Mountain, NY, 1984. (a) [Data from W. R. Pierson et al. (1989). Atmospheric acidity measurements on Allegheny Mountain and the origins of ambient acidity in the northeastern United States. Atm. Env. 23, 431–459.] (b) [Data from T. J. Kelly, Trace gas and aerosol measurements at Whiteface Mountain, NY. Brookhaven National Laboratory Reports BNL 37110 (Sept. 1985) and BNL 39464 (Jan. 1987).]

Since routine monitoring of aerosol acidity has not yet begun, data on aerosol acidity are sparse and have been gathered mainly from various research campaigns. Figures 4 and 5 present eastern U.S. annual average and maximum 24-hr levels of aerosol acidity, expressed as μg/m³ of H2SO4. Given the limited data available, the patterns are surprisingly consistent. For both measures, acid concentrations are higher near and east of the Appalachian Mountains. Twenty-four-hour values reach a maximum in southwestern Pennsylvania, whereas the few annual data suggest a peak in the southern Appalachians. To the west, [H+] decreases dramatically; since sulfate levels drop less rapidly, this is apparently due to increased neutralization. Acid levels on the west coast are also quite modest (except perhaps for local areas in the Los Angeles basin). The range in peak acidity values appears to be due more to variability in neutralization than in sulfate concentrations. Data on the values of average molar ratios suggest that compositions close to free sulfuric acid are rarely present in ambient air, and that the average aerosol composition corresponds to a mixture slightly less acidic than ammonium bisulfate. Concentrations of acid gases can be higher than those of acid particles on a molar equivalent basis. Most of the data shown in Figures 4 and 5 were obtained from rural and suburban sites, where the aerosol tends to be less neutralized than in urban locations.

Figure 4 Annual average measured aerosol acidity levels at various locations in the Eastern United States (H+ in µg/m³ as H2SO4). [From Lipfert (1991); courtesy of Springer-Verlag. Data from J. D. Spengler et al. (1989). Exposures to acidic aerosols. Env. Health Perspect. 79, 43–52; and from T. J. Kelly, Trace gas and aerosol measurements at Whiteface Mountain, NY. Brookhaven National Laboratory Reports BNL 37110 (Sept. 1985) and BNL 39464 (Jan. 1987).]

Figure 5 Maximum 12–24 hr average aerosol acidity levels (H+ in µg/m³ as H2SO4). [Data from J. D. Spengler et al. (1990). Acid air and health. Envir. Sci. Tech. 24, 946–956.]

California fog composition data are compared in Figure 6, on the basis of air concentrations (fog water concentrations multiplied by liquid water content). This places the values in the same range as for clear air aerosols in the eastern United States, except for the South Coast Air Basin (SCAB) data. These data are based on the averages of several sampling campaigns. Fog water at locations in the eastern United States and in Europe tends to contain less nitrate than in southern California, but a much higher proportion of nitrate than typically found in aerosol at the same locations because of the absorption of nitric acid vapor.

Figure 6 Acidity and composition of fog in California. [From Lipfert (1991); courtesy of Springer-Verlag. Data from various field measurements (see F. W. Lipfert, An assessment of acid fog. Paper IU-8.09, presented at the 9th World Clean Air Conference, Montreal, Canada, September 1992).]

C Coincidence with Ozone

Figure 7 plots aerosol acidity versus ozone at various diverse sites, with a linear regression line shown for each site. Most of these data fall into a common envelope defined by H+ ≤ 50 µg/m³ (as H2SO4) at an ozone level of 200 μg/m³ (0.1 ppm) (24-hr averages for both parameters), suggesting that the ozone level at a given site has an influence on the maximum aerosol acidity. Note that ozone is reduced in many urban areas because of titration by nitric oxide. The aerosol acidity levels at Allegheny Mountain and Laurel Hill, Pennsylvania, stand out as significantly higher than the other sites (which can also be seen in Figure 5).

Figure 7 Aerosol acidity versus ozone, for various locations and time periods. [From Lipfert (1991); courtesy of Springer-Verlag. Data from J. M. Waldman et al. (1990). Spatial and temporal patterns in summertime sulfate acidity and neutralization within a metropolitan area. Atm. Env. 24B, 115–126; T. J. Kelly, Trace gas and aerosol measurements at Whiteface Mountain, NY. Brookhaven National Laboratory Reports BNL 37110 (Sept. 1985) and BNL 39464 (Jan. 1987); and W. R. Pierson et al. (1989). Atmospheric acidity measurements on Allegheny Mountain and the origins of ambient acidity in the northeastern United States. Atm. Env. 23, 431–459.]

D Indoor Acidity Levels

Indoor levels of aerosol acidity have been found to be much lower than outdoor levels, except in the presence of acid aerosol sources such as unvented kerosene heaters. Indoor sources of ammonia, including cleansers and pets, are thought to be responsible for the reduced levels of indoor acidity.

V Suspected Health Effects

A Grounds for Health Concerns

The best evidence that air pollution can seriously affect health comes from the historical air pollution disasters of the Meuse Valley (1930), Donora, Pennsylvania (1948), and London (1952), in which the increases in rates of mortality and morbidity were incontrovertible. Air pollution measurements were sparse during these episodes but airborne acids were implicated indirectly in all of them. Direct emissions sources of H2SO4 were present in the Meuse Valley and Donora (with acid gases also likely), and it was later hypothesized that the foggy conditions in London, together with soot and metal catalysts, could have oxidized a substantial portion of SO2 to H2SO4.

Concerns about airborne acids have been exemplified in recent years by the debate on the effects of acidic precipitation. Recently, this issue has broadened to include the direct health effects of breathing acidic pollutants, especially fine particles. In 1989, the Environmental Protection Agency (EPA) began the process leading to the listing of acid aerosols as a criteria air pollutant, with specific reference to acidic particulates. The first steps in that process include establishing a reference measurement method and assessing ambient concentration levels of acid aerosols.

The literature on respiratory effects of H2SO4 is extensive and includes animal toxicology, chamber experiments on human volunteers, and studies of occupational exposures. Studies of mixed sulfate aerosols typical of actual ambient exposures are scarce, however.

B Experimental Evidence

1 Animal Iexicological Studies

Animal studies have found several endpoints responsive to acid aerosol exposure, ranging from changes in lung clearance rates to changes in lung morphology and rates of cell turnover. Guinea pigs appear to be the most sensitive species, with pulmonary function changes for exposures as low as 1 hr at 100 µg/m³. Larger particles can be more lethal, however; an 8-hr exposure to 2.7-µm particles at 27 mg/m³ killed half of the test animals, while 60 mg/m³ was required to achieve this response with 0.8-µm particles. Studies of bronchial clearance rates in various animals have shown increased clearance at low doses (similar to or higher than present ambient levels) and decreased clearance at higher doses; evidently, acid aerosols stimulate clearance defenses at low doses but inhibit them at the higher exposure levels.

2 Human Clinical Studies

Experimental exposures of human volunteers have emphasized transient lung function and clearance effects in response to sulfuric acid at concentrations greater than current ambient levels. Early studies on normal subjects found responses only after exposure to very high levels (often in excess of 1000 µg/m³) of H2SO4. More recent work has reported transitory responses by asthmatic subjects at lower levels (68–100 µg/m³), lasting only a few minutes. These experiments have also shown that the pulmonary response to H2SO4 is enhanced if the subjects take steps to reduce their oral ammonia levels immediately before the test, which supports the hypothesis that the active agent is the H+ content of the aerosol. Exposure times for the reported laboratory studies vary from single doses of less than an hour to repeated doses of a few hours per day. The magnitude of the inspired dose also depends on the breathing rate, which can be elevated by exercise.

C Unresolved Issues for Experimental Studies

1 Effects of Specific Sulfate Mixtures

Monitoring data show that the average composition of the mixed sulfate aerosol typically found in the eastern United States is approximately that of ammonium bisulfate; sulfuric acid is not the major acid constituent in the ambient environment. It has generally been assumed that H+ is the agent of principal concern and that biological responses to other acidic species may be estimated by using the H+ contribution as a measure of relative potency, based on responses to H2SO4. Some experimental evidence is consistent with this hypothesis; however, there have also been contradictions: NH4HSO4 exposures to rabbits had significantly less effect on alveolar clearance than did equivalent concentrations of H+ delivered as H2SO4. These findings were confirmed by comparisons of phagocytic activity of alveolar macrophages in rabbits. Thus the question of predicting human response to identical H+ loads delivered by means of differing aerosol compositions remains an important subject for research. The extant body of experimental research on acid aerosol health effects deals almost entirely with sulfuric acid exposures.

2 Effects at Realistic Doses

The disparity between experimental exposures and current ambient levels is illustrated in Figure 8, which plots aerosol composition (ratio of NH4+ to SO4²−, or the degree of neutralization, where a value of 2.0 represents complete neutralization and 0.0 represents sulfuric acid) against sulfate concentration level. The plot shows little overlap between the exposure levels used for experimental human clinical studies (right-hand portion of the figure, which features H2SO4 at high concentrations) and the ambient exposure levels (left-hand portion of the figure, with highly neutralized sulfate at much lower concentrations).

Figure 8 ). [Ambient data from F. W. Lipfert (1988). Exposure to acidic sulfates in the atmosphere. EPRI EA-6150, Electric Power Research Institute, Palo Alto, CA.]

3 Separate Effects of Concentration and Exposure Time on Effective Dose

Results from animal studies have been used to support the hypothesis that the total integrated exposure or dose (concentration × time [C × T]) may be the most appropriate acid aerosol dose measure. For effects on lung clearance, there are limited supporting data; however, these data are also consistent with an effect due to variations in concentration alone, since concentration and integrated exposure were highly correlated in these experiments. More recent results that examined responses of rabbits exposed to the same total dose (C × T) of H2SO4, but with varying concentrations (C) and exposure times (T), suggest that there may be a threshold concentration below which acute responses are not observed.

Figure 9 contrasts recent U.S. ambient data with concentrations and exposure times for clinical exposures of asthmatic subjects. Note that acidity concentrations do not continue to rise with shorter averaging times (shown by the circles and the best-fit curvilinear regression line). The clinical exposures (triangles) are characterized by high concentrations and short times; the two regimes do not overlap. The solid triangles in the figure represent conditions under which a statistically significant (reversible) lung function change was observed; the lowest of these is somewhat problematic since subsequent experiments have failed to replicate this outcome and the responses typically lasted only a few minutes. The open triangles represent clinical exposures to asthmatics that did not produce significant responses. By following the diagonal lines of constant C × T in the figure, it appears that exposure times of 12 hr or more at the maximum observed ambient concentration levels (about 30–40 µg/m³) would be needed to inspire a total acidity dose similar to those reliably inducing lung function changes.

Figure 9 , maximum observed ambient. [Data from J. Koenig, An assessment of pulmonary function changes and oral ammonia levels after exposure of adolescent asthmatic subjects to sulfuric or nitric acid. Paper 89–92.4, presented at the 82nd Annual Meeting of the Air and Waste Management Association, Anaheim, CA, June 1989; Linn et al. (1989). Effect of droplet size on respiratory responses to inhaled sulfuric acid in normal and asthmatic volunteers. Am. Rev. Respir. Dis. 140, 161–166; and Linn et al. (1990). Respiratory response of young asthmatics to sulfuric acid aerosol (abstract). Am. Rev. Respir. Dis. 141, A74.]

The validity of the C × T hypothesis needs to be investigated more systematically, especially at lower concentrations and longer exposure times, conditions for which thresholds due to neutralization by endogenous ammonia may be important. Note that elevated breathing rates induced by exercise are unlikely to be sustained long enough to substantially influence doses greater than a few hours.

4 Ammonia Neutralization

Most clinical experiments have only considered concentration levels substantially higher than ambient. It is not clear how to extrapolate responses observed under these conditions to more realistic (lower) ambient conditions. Such an extrapolation may be particularly confounded by endogenous (breath) ammonia, since experiments have determined that artificial depletion of oral NH3 (by dental brushing or ingesting acids) can enhance the lung function responses obtained at a given sulfuric acid dose level:

• The responses of exercising asthmatics increased about 150% when they gargled with lemon concentrate before exposure to 350 µg/m³ H2SO4.

• Lung function responses of adolescent exercising asthmatics to about 70 µg/m³ H2SO4 were statistically significant only when the subjects drank lemonade before exposure.

The ability to predict responses to current ambient acid levels requires further understanding of the role of endogenous ammonia and the extent to which it may offer some protection from breathing acids. Also, exercise will complicate the neutralization process, by changing the breathing mode, breathing rate, and the residence times of particles.

5 Effects of Other Acidic Species

Although the emphasis has been on acid sulfate particles, it is possible that gaseous acids (HNO3, organic acids) might be important. Significant lung function decrements in adolescent asthmatics exposed to 0.05 ppm 3 have been reported, and a significant synergistic biological response was associated with joint exposures to ozone and NO2, which in combination will yield HNO3 and HNO2. Finally, acid gases may react with endogenous ammonia that would otherwise be available to neutralize acid particles.

Mixtures may be important since acidic ambient aerosols do not occur in isolation and peak levels may coincide with those of other pollutants. Animal studies have suggested that synergism can occur between high doses of acid aerosols and other pollutants, such as ozone.

6 Effects of Particle Size

The effects of particle size are not well defined. Those epidemiological studies that can reasonably be interpreted as showing acid aerosol health effects all involve larger particles (fog and mist). Large particles have also been shown to exacerbate symptomatic responses at high concentrations, but asthmatics seem to respond more to submicron aerosols.

7 Clarification of Adverse Health Effects

The medical significance of the different symptomatic and biological responses observed in health studies is not always clear and may differ according to the subject’s health status. Examples include small transitory decrements in lung function and small transient increases and decreases in lung clearance rates, which are difficult to interpret. Research to achieve a better understanding of biological mechanisms of action and their relationships to clearly adverse responses in humans would be one way to clarify significance. Long-term studies of animals may be useful in this regard.

D Epidemiology

Definitive (positive) associations of ambient acidic aerosols with adverse human health responses by the general population have yet to be demonstrated in any epidemiological studies completed. In the past, this outcome was partially due to the lack of appropriate exposure measurements. However, a more recent time-series study of daily mortality in several U.S. cities found consistent linear dose–response relationships for PM10, but not for H+ concentrations. Several previous observational studies have linked sulfates with excess mortality and with hospital admissions, but these studies could not rule out other pollutants as causal factors. In addition, the relationship between SO4²− and H+ can be quite variable, so that it is problematic to assume that H+ was the causal factor on the basis of the sulfate relationships in these studies.

E Occupational Studies

It has been estimated that over 800,000 workers in the United States have some potential occupational exposure to H2SO4. These exposures tend to involve concentrations much higher than ambient (the occupational health standard for H2SO4 is 1 mg/m³), and median particle sizes are larger than typically found in community air. However, the range in particle sizes in industrial exposures is large (geometric standard deviations from 2 to 7), so that small particles are likely to be found in these exposures as well. Occupational studies necessarily deal with a selected subset of the population from which susceptible individuals are likely to have been removed through self-selection.

Lead-acid battery workers exposed to H2SO4 concentrations from 80 to 350 μg/m³ were found to have no acute lung function changes associated with daily exposures. The prevalences of various acute respiratory symptoms related to work were less than 7% for both high and low exposure groups; cough, eye irritation, wheeze, chest pains, and nausea were more frequent in the high exposure group; nasal congestion and headache were more frequent in the low exposure group. The upper range of H2SO4 exposures was about 1 mg/m³ and particulate lead concentrations ranged up to about 600 µg/m³. Median acid particle sizes were around 5 µm, but at two of the five plants studied, about 20% of the acid particles were of submicrometer size. A similar study in a British battery factory also failed to find significant decrements in lung function over the course of an 8-hr shift that could be attributed to acid exposure. These data sets extend the range of human exposure (C × T) data to about 8–11 mg/m³ hr.

Chronic effects were examined in a companion study, which found no changes in symptoms and only slightly reduced (around 5%) lung function parameters in the high exposure (210 µg/m³) compared to a low exposure group (100 µg/m³). There may have been particle size differences between these two groups as well. Smoking and age differences were controlled in these studies; the lung function decrements due to acid exposure were slightly less than those due to smoking. The most obvious chronic health effects associated with acid exposure were tooth etching and erosion. It is particularly interesting that no upper respiratory effects were noted in these studies, which involved particles large enough to affect these regions.

A mortality study of steel workers exposed to pickling acids showed a significant excess in lung cancer deaths, beyond what could reasonably be expected due to higher than average rates of smoking. Excesses were shown for exposure to both sulfuric acid mist and to other acids (mainly hydrochloric acid vapors). Exposures to other air pollutants were not taken into account, which could include high concentrations of metals. Deaths due to other respiratory diseases and to circulatory causes were within expected limits. Although some of the sulfuric acid particles involved in these exposures could be expected to penetrate to the pulmonary region, where clearance could be affected, this is less likely for the acid vapors. When the mortality comparison was based on the experience of all steel workers in the county rather than on the general U.S. population, only the other acid group showed a significant excess in lung cancer.

VI Other Environmental Effects

A Atmospheric Visibility

Atmospheric visibility, the ability to see distant objects clearly, depends on the transmission of light and the ability of the observer to distinguish an object from its background. The contrast with background depends on scattering and absorption of light by the atmosphere. Both particles and gases in the atmosphere can scatter and absorb light. The scattering and absorption of light by aerosols depends on their size distribution, refractive index, and shape, as well as the relative humidity. For visible light, particle diameters in the range 0.1–1.0 µm are effective light scatterers. Thus, sulfate aerosols have been associated with visibility reductions, in both the eastern and western United States. This property is essentially independent of particle chemistry (except for hygroscopic properties and size changes in response to relative humidity).

B Damage to Materials

In theory, deposition of acidic aerosols can add to the rate of atmospheric corrosion of certain susceptible materials, including carbonate stone, galvanized steel, and paints containing acid-soluble compounds. However, rates of deposition of submicrometer aerosols tend to be much lower than those of acid gases (SO2 and HNO3), both because the particle (dry) deposition velocities are about an order of magnitude lower and because air concentrations of acid aerosols are usually lower than SO2. Thus, in practice, the contributions of acidic aerosols to atmospheric corrosion can usually be neglected.

C Ecological Acidification

Since acidic aerosols tend to be distributed over large regions, including natural areas, and their main sink is deposition to the surface, they can cause acidification of poorly buffered natural areas. Because of its reactions in soil, NH+4 is also acidifying, so that the chemical composition of the aerosol does not play a major role in such acidification. However, scavenging of aerosol particles is one of the pathways for acidifying precipitation, and wet deposition at sufficiently low pH can cause direct damage to some species of vegetation. The possibility of acidification of drinking water supplies in remote areas also exists, which can cause indirect adverse health effects by leaching toxic substances out of the water delivery systems if the pH is not controlled.

VII Control Techniques

A Additional Neutralization

Figure 1 suggests several possibilities for controlling atmospheric acidity. The most direct method would be to increase ambient levels of neutralizing substances. For example, it has been suspected that one of the reasons for higher precipitation pH levels in the 1950s was higher ambient levels of alkaline dust from unpaved roads. While it is feasible to increase indoor ammonia levels by various means, our environmental ethics generally do not permit adding to the (outdoor) ambient pollutant burden as a means of controlling its chemistry.

B Reduced Oxidation

The fraction of SO2 oxidized to sulfate depends on the operative mechanism and the supply of reagents. For example, in winter, the process may be limited by the supply of oxidants, because of reduced photochemical activity. The summer of 1988 was hotter and dryer than normal, for example, and both ozone and sulfate levels increased slightly. Control of oxidants by reductions in emissions of precursors (NOx and VOCs) thus may provide some additional benefits by also reducing sulfate levels.

C Reduced Direct and Precursor Emissions

Controlling direct emissions of acids from manufacturing processes requires only the use of appropriate collection devices and should be encouraged. Reductions in primary sulfate from fuel oil combustion (for a given sulfur content) can be achieved by reducing the amount of excess combustion air; the limit to this process is the creation of excess smoke and CO emissions.

Reducing the atmospheric sulfur burden by cutting back on SO2 emissions should also have a nearly direct benefit on ambient sulfate levels. This is the stated intention of the acid deposition provisions of the 1990 Clean Air Act Amendments. However, the effects of oxidant limitations may change the spatial distribution of sulfates and acidic aerosols. For example, SO2 emissions in the United States increased from 1950 to the mid-1970s, after which they decreased slightly. Ambient SO2 levels have tended to follow suit, except that reductions in cities using sulfur-bearing fuels for space heating have generally been larger. Ambient sulfate levels have changed very little over this time period, however, especially if one considers the likelihood that the earlier levels were biased high because of the types of collection filters used. Thus, the implication is that in more recent years, a higher fraction of the emitted SO2 has been oxidized to sulfate. If sulfate levels are controlled by the available oxidant supply, one would expect little change in sulfate levels near the SO2 sources, but larger changes further away.

VIII Summary

Acidic aerosols are found in industrial atmospheres and in both rural and urban areas in the eastern United States. Average concentrations in community air are about two orders of magnitude lower than in industrial exposures. Much remains to be done to characterize the extent of population exposures and their potential health significance. It appears that the major gaps in ambient exposure characterization include detailed particle size resolution and speciation for periods less than 24 hours, sampling in major eastern population centers, and indoor sampling.

The major health effects question is: What are the dose–response relationships at conditions similar to current actual population exposures? The fact that only minor chronic respiratory effects have been found for industrial exposures suggests that effects in healthy, nonsensitive individuals exposed to community air are likely to be minor. This conclusion is supported by the results of lung function tests of normal subjects at high acidity concentrations. For asthmatics and other sensitive groups, further experiments are needed at longer exposure times involving realistic ambient mixtures and appropriate concentration levels before adequate judgments can be made about their health risks.

Related Articles: MONITORING INDICATORS OF PLANTS AND HUMAN HEALTH FOR AIR POLLUTION; NITRIC OXIDE AND NITROGEN DIOXIDE, TOXICOLOGY; OXIDES OF NITROGEN; PLANTS AS DETECTORS OF ATMOSPHERIC MUTAGENS.

Bibliography

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Acid Aerosols, special issue of Environmental Health Perspectives. 79, 3–205 (1989).

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Lipfert, F.W. Acid aerosols. In: Longhurst J.W.S., ed. Acid Deposition, Origins, Impacts, and Abatement Strategies. Berlin: Springer-Verlag, 1991.

Lipfert, F.W., Morris, S.C., Wyzga, R.E. Acid aerosols: The next criteria pollutant. Env. Sci. Tech. 1989; 23:1316–1322.

Morris, S. C., and Lipfert, F. W. (1989). Health Effects of Acid Aerosols and Their Precursors. Brookhaven National Laboratory Report to the U.S. Department of Energy. Brookhaven National Laboratory, Upton, New York.

National Acid Precipitation Assessment Program (1990). State of Science and Technology Reports, Washington, D.C.

National Research Council of Canada (1982). Effects of Aerosols on Atmospheric Processes. NRCC No. 18473. Ottawa, Canada.

Tanner, R.L. The measurement of strong acid in atmospheric samples. In Lodge J.P., ed.: Methods of Air Sampling and Analysis, 3rd ed., Chelsea, Michigan: Lewis Publishers, 1989.

U.S. Environmental Protection Agency (1988). Acid Aerosols Issue Paper. EPA-600–8-88–005a. Washington, D.C.

¹At a pH of 3.7, the concentration of H+ = 10(6–pH) = 10².³ = 200 μeq/liter of water. Since there is 1 g of water per cubic meter of air, it requires 1000 m³ of air to supply 1 liter of fog water. Thus the H+ concentration on an air basis is 200 neq/m³. Expressed in mass units of H2So4, this corresponds to 9.8 µg/m³.

Aquatic Toxicology, Analysis of Combination Effects

Rolf Altenburger, Wolfgang Boedeker, Michael Faust and L. Horst Grimme,     University of Bremen, Germany

I. Introduction and Scope

II. Terminology and Concepts

III. Experimental Design

IV. Models for Assessment

V. Choosing a Model

VI. Survey of Reported Effects

Glossary

Additivity Combined effect of agents expected from the effects of the individual substances. Expected effects are calculated using biometrical models based on either the concept of effect summation, effect multiplication or concentration addition.

Concentration addition A concept for combination effects based on the assumption that any constituent of a mixture can be replaced totally or in part by the equieffective amount of another while the effect of the mixture remains constant.

Effect multiplication (independence) A concept for combination effects based on the assumption that the effect of a mixture equals the product of the effects of the components applied singly.

Effect summation A concept for combination effects based on the simple idea that the effect of a mixture equals the sum of the effects provoked by the individual constituents.

Synergism/antagonism Terms denoting effects of mixtures which are greater or less than expected on the basis of one of the concepts mentioned above.

THE ANALYSIS of combination effects in aquatic toxicology is focused on the efforts to predict the effects of chemical mixtures from the effects of single substances. With this scope, terms of widespread use like synergism, potentiation, antagonism, and additivity are explained on the basis of underlying concepts. The necessity to provide a reasonable reference for judgments on combined effects is shown in order to avoid confusion of terminology. The requirements for experimental studies concerning the amount, type, and quality of data needed to allow for meaningful statements are considered. Biometrical models for the assessment of combined effects are discussed and recommendations concerning their use are given. Finally, an overview is supplied on combination effect studies of aquatic pollutants.

I Introduction and Scope

Simultaneous or sequential exposure of organisms to two or more chemicals may alter biological responses in qualitative and quantitative ways relative to that for single compounds. The analysis of combination effects resulting from an exposure to mixtures of chemicals has therefore been the subject of numerous studies in pharmacology, toxicology, and biometrics. These long-lasting efforts led to various procedures for hazard management (see Table I). The main focus of those regulatory activities has been human toxicology. In contrast, although surface waters are subject to pollution with numerous chemicals, water quality standards are commonly based on risk extrapolations from studies with single substances.

Table I

Examples of Regulations and Recommendations on Chemical Mixtures

Experimental studies dealing with the aquatic toxicity of mixtures may be differentiated according to their scope:

1. The toxicity of a specific complex mixture, whose components are often not precisely known, is assessed in much the same way as for single toxicants. Examples might be a specific industrial waste, a sewage plant effluent, or a typical composition of pollutants found in a specific surface water. As far as the results are compared with the effects of individual chemicals, the aim is to identify constituents which dominate the overall toxicity of the mixture.

2. The modification of the toxicity of a single compound by the presence of other substances or a change in environmental conditions is functionally analyzed. Typical examples are alterations of a biological response by water quality characteristics like pH, hardness, salinity, temperature, and nutrients. The aim is to determine the variation of toxicity under realistic environmental conditions and to identify major toxicity-modifying factors.

3. The effects of definite combinations of substances are set in relation to the effects of the individual compounds. An expected effect, formulated or calculated on the basis of single toxicity data, serves as a criterion for the assessment of the observed mixture toxicity. The aim is to identify types of combination effects, to improve the pharmacological understanding of such effects, and to develop tools for reliable prediction of the toxicity of mixtures of pollutants.

With the focus on the effort to predict the effect of combined substances on the basis of the effects of the single substances, the main task is to decide whether the magnitude of the observed effect of a mixture of agents is smaller, equal to, or even greater than expected from the concentration effect relationships of the individual agents. The assessment cannot be done without making use of some kind of mathematical model developed to calculate expected responses from toxicity data of single substances. The validity of results obtained from the use of any mathematical model depends on reasonable assumptions about expected effects. Therefore, knowledge of the inherent features of the different models is necessary in order to make a rational choice. The purpose of this article is to give a comprehensive and structured survey of mathematical modeling of combination effects with special emphasis on applications in aquatic toxicology.

II Terminology and Concepts

There are different terms used to label possible types of combination effects, but these terms are used inconsistently. Despite the efforts of several authors, a standardization in terminology is not in sight. Table II gives a survey of frequently found terms used to classify combination effects.

Table II

Classification Terms for Combination Effects

First of all, it should become apparent that any statement on the type of combination effect observed requires an answer to the question: What is the expected response? It is now generally held that any combination of substances is expected to be more active than any of the substances alone. Denotation of this situation, however, is difficult. Nevertheless, additivity is the most frequently used term of reference. On the one hand, the usage of the term additivity might be confusing because it is sometimes taken to mean that the effects of such combinations may be obtained by adding the effects of their constituents. On the other hand, combined effects termed independence, indifference, or noninteraction will be easily misinterpreted as (eco-) toxicologically irrelevant, since sometimes they are used with the meaning that the effect of a combination is equal to the effect of the most active component alone. Much confusion also exists concerning the understanding of antagonism and synergism. Furthermore, there is no proper differentiation between synergism and potentiation. Sometimes potentiation is used synonymously with synergism, while commonly the former is used for a characterization of an effect stronger than synergistic.

Second, the question of how to calculate expected additive effects arises. To meet this challenge, various mathematical methods and models have been invented more or less implicitly based on three different concepts and understandings of additivity.

The concept of effect summation has greatly influenced and confused the discussion about the assessment of combination effects. However, consensus seems to be achieved that additive effects do not simply equal the sum of the single effects. Effect summation seems to lack a pharmacological apprehension of additivity; therefore, there is no clear reference for the determination of combination effects.

The concept of effect multiplication, which is sometimes called response addition or independence, is based on the assumption that the toxicants of a mixture act on different biological subsystems within the same organism (e.g., have different sites and modes of actions). However, it should be noted that the concept of effect multiplication originally was brought forward by biometricians and that, despite its convincing mathematical features, the pharmacological inference for a nonreceptor level is far from being clear.

Finally, the concept of concentration addition should be mentioned. This concept gained widespread acceptance because of its plausible pharmacological understanding. Concentration addition in the most simple case is said to occur when one substance acts like a dilution of another, so any effect can be obtained by replacing one substance totally or in part by the equi-effective amount of another. There is widespread belief that mixtures obeying this concept show similar action (e.g., by a common molecular target site). There is still no agreement whether concentration addition is a suitable concept even in cases of pharmacologically dissimilar behavior of substances.

Generally, we recommend labeling of different types of combination effects only when making clear reference to a defined and pharmacologically plausible concept. In order to avoid further confusion and misunderstanding, enhanced or weakened effects should be named super- or subadditive, respectively, whenever additivity is