National Academies Press: OpenBook

Drinking Water and Health,: Volume 1 (1977)

Chapter: V INORGANIC SOLUTES

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Suggested Citation:"V INORGANIC SOLUTES." National Research Council. 1977. Drinking Water and Health,: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/1780.
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Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

v INORGANIC S^e ~ ITS. TRACE METALS Trace metals may be present in natural groundwater or surface water. The sources of these trace metals are associated with either natural processes or man's activities. Two important natural processes contribut- ing trace metals to natural water are chemical weathering and soil leaching. The factors affecting the release of trace metals from primary materials and soil and their solution and stability in water are solubility, pH, adsorption characteristics, hydration, coprecipitation, colloidal dispersion, and the formation of complexes. Decaying vegetation can also affect the concentration of trace metals in water. Many plants are known to concentrate various elements selectively. As a result, trace metals may become available during the decay of the plants. Thus, the penetration and movement of rainwater through soil may pick up these available trace metals and affect the groundwater resource. Likewise, runoff resulting from rainfall may transport trace metals to surface-water. Mining and manufacturing are other important sources of trace metals in natural waters. Several operations associated with the mining of coal and mineral ores can lead to the discharge of wastewater contaminated with trace metals or to the accumulation of spoiled material, which may be leached of trace metals by rainfall and reach either surface or groundwater. The discharge of industrial wastewater, such as that generated by plating and metal-finishing operations, may also be the source of trace metals in natural water. 205

206 DRINKING WATER AND H"LTH The treatment of raw surface or groundwater to make it acceptable for public consumption may include the removal of trace metals. However, trace metals may be added to water as a result of the treatment and the subsequent distribution throughout a community. Depending on the quality of the raw water and the quality desired in the finished (treated) water, treatment may involve the use of chemicals, such as alum (aluminum sulfate), lime, and iron salts. The chemicals used are usually of commercial or technical grade with no exact composition, although the American Water Works Association has established standards for most chemicals used in the treatment of water supplies. Because of the possibility of impurities in the chemicals, it is conceivable that trace metals may be added to the water during treatment. A chemical itself, such as alum, may also contribute to the trace metal content of the finished water, depending on its solubility and the characteristics of the water. The occurrence of corrosion in the distribution system may also add trace metals to finished water before it reaches the consumer. Common piping materials used in distribution systems are iron, steel, cement (reinforced concrete), asbestos cement, and plastic. Lead, copper, zinc, aluminum, and such alloys as brass, bronze, and stainless steel may also be used in addition to ferrous metals in pumps, small pipes, valves, and other appurtenances. Trace metals may be contributed to the water through corrosion products or simply by solution of small amounts of metals with which the water comes in contact. 1 0 1 ~ ~ - ~ Trace Metals in Water Samples Collected in the Distribution System or at Household Taps The concentration of trace metals in water collected in the distribution system or at household taps is more relevant with respect to the quality of water being consumed by the public than is the raw water. The data in Table V-1, taken from the community water supply survey involving 969 public water supplies, indicate the levels of several selected elements in water samples collected in distribution systems. Chromium and silver were present in microgram quantities, while cadmium, lead, and barium were found to be in the milligram range (McCabe et al., 1970~. The results of analyzing a number of tap-water samples, collected at homes in Dallas, Texas, for trace metals are given in Table V-2. In the unpublished report from which these data were taken, it was speculated that the high iron concentration was due to the use of steel water mains in the distribution system, whereas the high manganese concentration was the result of accumulation of sandy sediment in the distribution system. The high copper and zinc concentrations in the water samples were

Inorganic Solutes 207 TABLE V-1 Concentrations of Selected Trace Metals in 2,595 Distribution Water Samples Fraction of Maximum Con- Samples Limit,a centration, Exceeding Element mg/liter mg/liter Limit, No Barium 1.0 1.55 <0.1 Cadmium 0.01 3.94 0.1 Chromium (VI) 0.05 0.08 0.2 Lead 0.05 0.64 1.4 Silver 0.05 0.03 0 aUSPHS Dnnking Water Standards of 1962 (From McCabe et al., 1970) believed due to the household plumbing. "Local influences" was the reason cited for the high lead and nickel concentrations in the tap water. Several studies have shown the combined eject of treatment and the distribution system on the trace-metal content of the water reaching consumers. A treatment plant handling 90 million gallons/day (90 mad) and obtaining its raw water from the Allegheny River was studied with respect to barium, copper, and nickel (Shapiro et al., 1960~. This particular plant used sedimentation, slow sand filtration, and chlor~na- tion. Water samples were collected for analysis before and after chlorination and at a consumer's tap at a remote point in the distribution system. Nickel and copper occurred in significantly higher concentrations in the tap water compared with the treatment plant after chlorination TABLE V-2 Concentrations of Selected Trace Metals in Household Tap-Water Samples, Dallas, Texas N Concentration, mg/liter Element Samples Average Median Maximum Minimum Cadmium 43 0.011 0.003 0.056 0.001 Chromium 36 0.004 0.003 0.020 0.001 Copper 43 0.037 0.029 0.164 0.004 Iron 35 0.093 0.088 0.274 0.031 Mercury 43 0.000115 0.000100 0.000885 0 Manganese 43 0.0037 0.004 0.008 0.001 Nickel 36 0.0109 0.010 0.023 0.005 Lead 43 0.0095 0.010 0.027 0 Zinc 43 0.0124 0.011 0.049 0.005

208 DRINKING WATER AND H"LTH TABLE V-3 Comparison of Concentrations of Several Trace Elements in Raw and Tap Water of Three Cities in Sweden Raw-Water Concentration, Element Halites Malmo Concentration Ratio, Tap; Raw Stockholm Goteberg Barium 1-3 6.7 4.0 0.5 Cadmium 0.02~.3 2.5 0.5 1.0 Cobalt 0.1 0.7 1.0 3.0 Copper 2-13 0.5 0.2 0.4 Mercury 0.09~.4 1.1 1.0 1.0 Zinc 8-28 4.5 2.8 1.4 (From Bostrom and Wester, 1967) 100 ,ug/liter vs. 30 ,ug/liter for nickel and 4,000 ,ug/liter vs. 90 ,ug/liter for copper. In the case of barium, the concentration was lower at the tap 40 ,ug/liter vs. 90 ,ug/liter. The concentration of copper in water was higher following chlorination (30 ,ug/liter before and 90 ,ug/liter after). The effect of treatment and the distribution system on the concentra- tion of trace metals was also studied in three cities in Sweden Mahno, Stockholm, and Goteberg (Bostrom and Wester, 1967~. A comparison of the raw and tap water concentration of six trace metals is shown in Table V-3. The change in concentration of several trace metals in raw, finished, and tap water was studied in the Denver municipal system, which draws its raw water from a variety of sources and uses five treatment plants that are interconnected, which makes it impossible to determine the plant from which a tap-water sample is derived (Barrett et al., 1969~. The maximum: minimum ratio for most of the trace metals in the raw water varied from 1.5: 1-6.5: 1; higher ratios were observed for aluminum, iron, molybdenum, and zinc. A comparison of the concentrations of the trace metals in the tap and finished water, based on ratios, shows that there were both reductions and increases in the distribution system. As with the raw waters, the concentrations of trace metals in the tap-water samples showed considerable variation. A distribution system in Seattle, Washington, was studied in an attempt to determine the severity and location of the corrosion that was known to be occurring (Danger, 1975~. The concentrations of several trace metals were determined in the raw water and in two samples collected at household taps. Standing samples were coldected as soon as the tap was turned on; this represented water in contact with the household plumbing at least overnight. Running samples collected after

Inorganic Solutes 209 bleeding the line for 30 s represented water from the distribution main. The corrosiveness of the system was recognized by the low phi and hardness of the water. A comparison of the concentrations of iron, copper, zinc, lead, and cadmium in the raw water with those in the standing water confirmed the corrosiveness of the water. However, after a comparison of the concentrations of the same trace metals in the standing and running samples, it was concluded that most of the metal pickup was occurring in the service lines connecting the distribution main to the buildings and in the inside plumbing. It was also noted that the corrosion products tested the trace metals correlated well with the materials in contact with the water. Trace Metals in Finished Water Supplies A survey of the mineral content of the water served to customers (finished water) in the 100 largest U.S. cities was made in 1962 (Durfor and Becker, 1964~. The highest, median, and lowest concentrations are listed in Table V-4. The raw water used by these cities was either groundwater (wells and infiltration galleries) or surface water (streams, reservoirs, and lakes). The chemical quality of most groundwater supplies is stable, compared with TABLE V-4 Maximum, Minimum, and Median Concentrations of Constituents of Finished Water in Public Water Supplies of 100 Largest Cities in United States Concentration, mg/liter ConstituentHigh Median Low Iron1.3 0.02 0.00 Manganese2.5 0.00 0.00 Magnesium120 6.25 0.00 Silica72 7.1 0.00 ,ug/liter Silver7.0 0.23 ND Aluminum1,500 54 3.3 Barium380 43 1.7 Chromium35 0.43 o 2 Copper250 8.3 <0.61 Molybdenum68 1.4 ND Nickel34 <2.7 ND Lead62 3.7 ND Vanadium70 <4.3 ND ND, not detected. (From Durfor and Becker, 1964)

210 DRINKING WATER AND HEALTH TABLE V-5 Frequency of Detection and Concentrations of Dissolved Trace Metals in 1,577 Raw Surface Waters in the United States (October 1, 1962-September 30, 1967) Frequency of Detection, Concentration, ,ug/liter Element AS MinimumMaximum Mean Zinc 76.5 21,183 64 Cadmium 2.5 1120 9.5 Iron 75.6 14,600 52 Molybdenum 37.7 21,500 68 Manganese 51.4 0.33,230 58 Aluminum 31.2 12,760 74 Beryllium 5.4 0.011.22 0.19 Copper 74.4 1280 15 Silver 6.6 0. 138 2.6 Nickel 16.2 1130 19 Cobalt 2.8 148 17 Lead 19.3 2140 23 Chromium 24.5 1112 9.7 Vanadium 3.4 2300 40 Barium 99.4 2340 43 (From Kopp, 1970) that of streams, whose quality often varies seasonally and during flood periods. The mineral content of impounded water is generally less than that of water in streams. In addition to the quality of the raw water, it is important to recognize that water-treatment practices can affect the concentration of trace metals in finished water. This can be seen from the data in Tables V-5 and V-6. The concentrations of several trace metals in surface water of the United States are summarized in Table V-5. Table V-6 gives values for finished municipal water after treatment. This summary of analyses performed on raw surface water and finished water indicates higher mean concentrations of iron, zinc, lead, copper, and aluminum in finished water. This broad comparison points to the possibility that trace metals are added to water during treatment. Barnett et al. (1969) cited such an instance in which the use of aluminum sulfate at a treatment plant increased the aluminum concentration in the finished water by a factor of 5. Shapiro et al. (1962) observed, in a study of Pittsburgh tap water, a considerable increase in the copper content between samples at the water-treatment plant and those taken in the distribution system. Nickel also showed a tendency to be higher in the distribution water samples than at the treatment plant; however, the opposite was true for barium.

Inorganic Solutes 211 In comparing the concentrations of several trace metals in raw water taken from the Thames River and finished water at two treatment plants using prechlor~nation, flocculation with alum, rapid sand filtration, and postchlorination, it was found that treatment had no eject on the cobalt concentration (Andelman and Shapiro, 1973~. However, as a result of treatment, the concentrations of manganese and nickel in the finished water decreased, whereas those of copper and cadmium increased. In addition, 83 water-supply systems in EPA Region V were examined for various organic and inorganic constituents (USEPA, 1975~. Region V consists of Illinois, Indiana, Michigan, Minnesota, Ohio, and Wisconsin. The water supplies examined were selected jointly by the EPA and the states and consisted of 14 groundwater and 69 surface-water supplies. The concentrations of metals in the raw- and finished-water supplies included in the survey are summarized in Table V-7. Occurrence of Trace Metals in Raw Water Supplies In reporting the results of various water surveys, no attempt has been made to distinguish between different analytical methods used that may well have different sensitivities and precision. TABLE V-6 Frequency of Detection and Concentrations of Trace Metals in 380 Finished Waters in the United States (October 1, 1 962-September 30, 1967) Frequency of Detection. Concentration.,ug/liter Element No MinimumMaximum Mean Zinc 77.0 32.010 79.2 Cadmium 0.2 1212 12 Iron 83.4 21,920 68.9 Manganese 58.7 0.5450 25.5 Copper 65.2 11,060 43 Silver 6.1 0.35 2.2 Lead 18.1 3139 33.9 Chromium 15.2 129 7.5 Barium 99.7 1172 28.6 Molybdenum 29.9 31,024 85.9 Aluminum 47.8 31,600 179.1 Beryllium 1.1 0.020.17 0.1 Nickel 4.6 1490 34.2 Cobalt 0.5 2229 26 Vanadium 3.4 14222 46.1 (From Kopp, 1970)

212 DRINKING WATER AND HEALTH TABLE V-7 Metal Concentration Ranges in Raw- and Finished- Water Supplies of 83 Cities in EPA Region V Concentration, ,ug/liter Element Raw Water Finished Water Silver Arsenic Cadmium Chromium Copper Iron Magnesium Manganese Sodium Lead Selenium Zinc <0.2~.3 ~ 1 .0-10.0 <0.2-12 <5.0-17.0 <5.0-200.0 <20-330 1 ,800~2,000 <5.0-760 1, 100-77,000 <2.0-30.0 <5.0 <5.~210 <0.2~.3 < 1 .0-50.0 <0.2~.4 <5.0~.0 <5.0-200.0 <20-1, 100 800~9,000 <5.0-350 1,000 91,000 <2.0-20.0 cS.O <5.0~60 BARIUM Barium was found in 99.4% of the surfacewater samples examined by Kopp and Kroner (1967~. The range was 2-340 ,ug/liter, and the average was 43,ug/liter. BERYLLIUM The maximum beryllium concentration observed in 1961 by Durum and Haffty was less than 0.22 ,ug/liter in the Atchfalaya River at Krotz Springs, Louisiana. Kopp and Kroner (1967) noted the presence of beryllium in 5.4%of their samples, with concentrations ranging from 0.01 to 1.22,ug/liter and an average of 0.19,ag/liter. CADMIUM Groundwater contamination from electroplating operations has been reported by Lieber (1954) to cause cadmium concentrations of up to 3.2 mg/liter. In Illinois surface waters, 10 of 27 sampling s rations on different watersheds had cadmium concentrations below 10 ,ug/liter; the maxi- mum observed by Ackermann (1971) was 20 ,ug/liter. Of 112 samples of surface and groundwater in Canada examined, only four had detectable

Inorganic Solutes 213 concentrations of cadmium, i.e., 10 ,ug/liter (Procter and Gamble, 1974~. Kopp and Kroner (1967) reported that 2.5% of the surface-water samples examined in their study contained cadmium at 1-120 ,ug/liter, with a mean of 9.5 ,ug/liter. In a comprehensive study of U.S. rivers in 1974 (USGS, 1974), a maximum dissolved concentration of cadmium of 42 ,ug/liter was reported for the Tanana River in Alaska. Durum et al. (1971) reported cadmium concentrations of 1-10 ,ug/liter in 42% of the surface- water samples examined, with only 4% above 10 ,ug/liter; the maximum concentration was 130 ,ug/liter. High concentrations were reported to occur in densely populated areas. Durum (1974) reported a distinct regional pattern: areas with many pollution sources and higher rainfall were higher in cadmium. CHROMIUM Durum and Hasty (1961) reported a range of concentrations for chromium in U.S. rivers of 0.7 to 84 ,ug/liter Kopp and Kroner (1967) detected chromium in 24.5% of the samples examined, with concentra- tions ranging from 1 to 112,ug/liter and averaging 9.7,ug/liter. In a study of surface and groundwater in Canada, all but two of 240 samples examined were below 50 ,ug/liter (Procter & Gamble, 1974~. In 1974, a maximum dissolved chromium concentration of 30,ug/liter was recorded in water from the Pecos River, New Mexico; the Los Angeles River; and the Columbia River, Oregon (USGS, 1974~. In a 1970 survey, 11 of 700 samples had chromium concentrations of 6 to 50 ,ug/liter, with none exceeding 50 ,ug/liter (Durum et al., 1971~. Ackermann (1971) reported chromium concentrations below 5 ,ug/liter for 18 of 27 river stations in Illinois; the maximum was 50,ug/liter. COBALT The limit of solubility of cobalt in normal river water is approximately 5 ,ug/liter, according to Durum et al. (1971), who reported that 37% of the river-water samples examined contained cobalt at 1-5 ,ug/liter, with less than 1% exceeding 5 ,ug/liter. A 1961 study showed a maximum of 5.S ,ug/liter in the Mississippi River at Baton Rouge (Durum, 1961~. A recent survey detected a maximum of 17 ,ug/liter in the Kentucky River at Lockport (USGS, 1974~. Kopp and Kroner (1967) found cobalt in 2.~% of surface-water samples examined; the concentration ranged from 1 to 48 ,ug/liter, with a mean of 17,ug/liter.

214 DRINKING WATER AND HEALTH COPPER Copper has been observed to adsorb to colloidal material at alkaline pH (McKee and Wolf, 1963~. Durum and Hasty (1961) found the maximum copper concentration in the Susquehanna River to be 105,ug/liter. Kopp and Kroner (1967) detected copper in 74.4% of the surface-water samples examined; the concentration ranged from 1 to 280 ,ug/liter, with a mean of 15 ,ug/liter. A recent survey detected a maximum of 40,ug/liter in the North Platte River (USGS, 1974~. Analysis of 13 Canadian surface and groundwaters including wells, rivers, and lakes-showed copper at 20- 860 ,ug/liter, the maximum being recorded in Lake Ontario (Proctor & Gamble, 1974~. Copper in excess of 100 ,ug/liter was reported in 8 of 27 Illinois streams, with a maximum of 260 ,ug/liter (Ackermann, 1971~. LEAD Pickering and Henderson (1966) reported a maximum solubility of lead of 500 ,ug/liter in soft water and 3 Igniter in hard water. Durum and Hasty (1961) reported a maximum lead concentration of 55 ,ug/liter in the St. Lawrence River at Levis, Quebec. In a more recent sampling of 727 U.S. sites, lead was found, at 1-50 ,ug/liter in 63% of the surface- water samples examined (Durum et al., 1971~. However, lead was detected less frequently at U.S. Geological Survey benchmark stations than at locations in more developed areas. In 1974, the Mississippi River at Vicksburg showed a maximum lead concentration of 29 ,ug/liter (USGS, 1974~. Of 52 surface and groundwa- ters examined in Canada, 50 were found to have less than 10,ug/liter; the concentrations in the other two samples were 22 and 25,ug/liter (Procter & Gamble, 1974~. In Illinois surface water, 25 of 27 river stations were found to have lead below 50 ,ug/liter the other two had concentrations greater than 50 ,ug/liter (Ackermann, 1971~. Kopp and Kroner (1967) found lead at 2-140 ,ug/liter, with a mean of 23 ,ug/liter in 19.3%oftheir surface water samples. Durum (1974) reported that the concentration of lead in water, like that of cadmium, can be correlated with urbanization and runoff. MANGANESE Durum and Haffty (1961) observed a maximum manganese concentra- tion of 181-185 Igniter in two different surface waters. The median for all samples was 20 ,ug/liter. Kopp and Kroner (1967) detected manganese in 51.4% of surface-water samples; the concentration ranged from 0.3 to

Inorganic Solutes 215 3,230 ~g/liter, with a mean of 59 ,ug/liter. A maximum of 1,200 ,ug/liter was detected in two different surface waters in 1974 (USGS, 1974~. MERCURY Durum et al. (1971) found dissolved mercury ranging from 0.1 to 4.3 ,ug/liter in 7% of the surface-water samples examined; in some cases, total mercury exceeded 5 ,ug/liter. According to a survey performed by Jenne (1972), only 4% of the surface waters examined showed mercury in excess of 10 ,ug/liter most of these were small lakes and reservoirs. The same study reported that groundwater samples were below the limit of detection for mercury. In 1974, the Rio De La Plata, Puerto Rico, was observed to have a maximum dissolved mercury concentration of 2 g/liter, and the James River in Virginia showed 1.6 ,ug/liter (USGS, 1974~. MOLYBDENUM Durum and Hasty (1961) detected a maximum molybdenum concentra- tion of 6.9 ,ug/liter in the Colorado River, Yuma, Arizona. In a more extensive survey, Kopp and Kroner (1967) found molybdenum in 32.7% of their surface-water samples; the concentration ranged from 2 to 1,500 ,ug/liter, with a mean of 68,ug/liter. NICKEL A maximum nickel concentration of 71 ,ug/liter was observed in the Hudson River at Green Island, New York (Durum and Hasty, 1961~. Kopp and Kroner (1967) found nickel in 16.2% of surface-water samples: the concentration ranged from 1 to 130 ,ug/liter, with a mean of 19 ,ug/liter. In a study of 13 Canadian surface and groundwater resources, only one sample was found to have nickel above the detection limit of 100 ,ug/liter (Procter & Gamble, 1974~. In a study of Illinois surface-waters, 24 river stations had nickel concentrations below 50 ,ug/liter, and 3 had concentrations of 50-530,ug/liter (Ackermann, 1971~. SILVER Samples containing silver at approximately 1 ,ug/liter were noted by Durum and Hasty (1961) in the St. Lawrence River, Levis, Quebec, and in the Colorado River, Yuma, Arizona. Of the surface-water samples examined by Kopp and Kroner (1967), only 6.6% contained detectable

216 DRINKING WATER AND HEALTH amounts of silver; the concentration ranged from 0.1 to 38,~Ag/liter, with an average of 2.6,ug/liter. VANADI~ A high vanadium concentration of 6.7 ,ug/liter has been reported in the Sacramento River, Sacramento, California (Durum and Haffty, 1961~. Kopp and Kroner (1967) observed detectable concentrations in 3.4% of the samples analyzed; the concentration ranged from 2 to 300 ,ug/liter, with an average of 40,ug/liter. ZINC The early studies of Durum and Hasty (1961) showed a maximum zinc concentration of approximately 144 ,ug/liter in the St. Lawrence River, Levis, Quebec. Kopp and Kroner (1967) found zinc in 76.5% of their surface-water samples: the concentration ranged from 2-1,183 ,ug/liter, with an average of 64 ,ug/liter. Durum et al. (1971) reported that zinc concentrations as high as 50 mg/liter could be found in surface water in mining areas, but that most samples had a concentration ranging from 10 to 50 ,ug/liter. Lazarus et al. (1970) reported the average concentration of zinc in rainfall of about 107 ,ug/liter IN 1974, a zinc concentration of 730 ,ug/liter was found in the North Platte River, Lisco, Nebraska (USGS, 1974~. In a variety of surface and groundwater sources in Canada, the zinc concentration was found to be 20-110 ,ug/liter (Procter & Gamble, 1974~. In a study of 27 Illinois surface-water sources, a maximum concentration of 2,000 ,ug/liter was observed (Ackermann, 1971~. Durum (1974) reported that the concentration of zinc in surface water, like those of lead and cadmium, could be correlated with urbanization and runoff. Geographical and Local Factors Durum and Hasty (1961) studied 15 stations on various rivers. Considering 13 of the trace metals pertinent to this review, 3 of the 15 stations had the maximum concentrations of more than 1 element. The St. Lawrence River at Levis, Quebec, had the maximum concentrations of silver, lead, and zinc; the Colorado River at Yuma, Arizona, had the maximum concentrations of silver and molybdenum; and the Mississippi River at Baton Rouge, Louisiana, had the maximum concentrations of cobalt, iron, and manganese. Kopp and Kroner (1967) presented data for 5 years for 16 major river basins in the United States. Table V-8 summarizes the basins in which the

Inorganic Solutes 217 highest and lowest 5-yr means were reported. The variability between the high and low means is shown as a ratio; for example, the ratio for manganese shows more variability than that for any of the other trace metals for which there was a detectable minimal concentration. Table V- 9 shows the highest and lowest observed concentrations of various trace metals in different surface and groundwaters, as reported in the references cited here. The possible frequency of detection is also given. For example, zinc will, in all probability, be found in 75% of all water samples examined for zinc from various locations, and its concentration will range from 2 to 50,000 ,ug/liter. Removal Of Metals By Water-Treatment Processes Beyond health considerations, the necessity of removing metals from drinking water is primarily a function of adequate surveillance and the development of analytical procedures capable of detecting trace concen- trations. The need to remove metals raises the question of how elective the current water processes are in removing metals from a water supply. Most treatment processes in use today were not developed to remove trace concentrations of metal. Chemical coagulation-flocculation, for example, is used primarily to remove turbidity and color from raw water; and any significant removal of lead through coagulation with alum is secondary to the original objective. -Even treatment plant that uses alum coagulation will vary with respect to its potential for removing lead, owing to differences in water characteristics and operating procedures. Table V-10 indicates the potential of several different treatment processes for removing barium, cadmium, chromium, cobalt, copper, lead, magnesium, manganese, mercury, methylmercury, molybdenum, nickel, silver, tin, vanadium, and zinc. The treatment processes consid- ered include chemical coagulation (alum and ferric chloride), lime softening (low lime and excess lime), the application of activated carbon, reverse osmosis, and ion exchange. Removal efficiencies have been rated semiquantitatively as "poor" (<307O removal), "fair" (30-60% removal), "good" (60-90% removal), and "very good" (>90% removal). Unfortu- nately, some studies have been performed whose published reports did not give percentage values for removal efficiencies. In these cases, efficiency was assigned on the basis of the written description. CHEMICAL COAGULATION Salts of trivalent aluminum and iron have long been used to remove color and turbidity from water. Two mechanisms for the removal of trace

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220 DRINKING WATER AND H"LTH TABLE V-9 Overall Minimum and Maximum Metal Concentrations in Groundwater and Surface Water and Probable Frequency of Detection Highest Ob- Lowest Ob served Con- served Con- Probable Frequency centration, centration, of Detection,a ,ug/liter ,ug/liter ~ Barium340 299 + Beryllium1.22 0.0180 Cadmium130 15~0 Chromium112 0.725 66 Cobalt48 15~0 Copper860 175 Lead140 125~6 Manganese3,230 0.350 Mercury10 0.110 Molybdenum1,500 230 Nickel530 125 66 Silver38 0.110 Vanadium300 25 Zinc50,000 275 aEstimated upward from the best values reported in the literature, on basis of current analytical methods. metals by aluminum and ferric salts have been proposed: chemisorption to insoluble A1(OH)3 and Fe(OH)3, and by association with organic matter and clays, which are normally removed in the coagulation- flocculation process (Singer, 1974~. Symons et al. (1975) used jar tests with Cincinnati tap water to which trace amounts of various metals were added and reported very good removal of cadmium with ferric sulfate when the pH of the solution was above 7.5. Removal of cadmium with alum was reported as only poor to fair. Removal of barium was expected because of the formation of insoluble barium sulfate. However, only poor results were achieved with ferric sulfate and alum, presumably because of the supersaturation of barium sulfate. Ferric sulfate and alum concentrations between 20 and 100 mg/liter removed only small amounts of inorganic mercury (II) and methylmercury. Slightly better results were obtained in removing inorganic mercury with ferric sulfate than with alum. Increased removal of inorganic mercury was observed when the suspended solids in the test water were increased. It was speculated that this increase was due to the adsorption of mercury to the particulate matter (Logsdon and Symons, 1973~. Using samples of tap water and wastewater with added doses of

Inorganic Solutes 221 various metals, Nilsson (1975) found that lead and copper were removed very electively by alum doses of 100 mg/liter when the pH was 6.5-7.0. Zinc, nickel, and cobalt were only slightly removed under those conditions. These results were explained by the insolubility of the metals at neutral pH. Lead and copper were suspected to be present as insoluble hydroxides, oxides, and carbonates, which are readily flocculated by alum. Nordell (1961) noted that coagulation of colloidal oxides of iron and manganese with ferric salts may give favorable results. However, the preferred method of removal consists of aeration followed by settling and filtration if reduced species of iron and manganese are present, which is usually the case. Removing dissolved silica by treating surface waters with ferric sulfate may be elective. Aluminum removal to approximately l mg/liter may be achieved by coagulation with alum when the pH of the water is 5.5-6.5. Poor removal of radiosotopes of chromium, molybdenum, and cobalt by chemical coagulation with A1(III) and Fe(III) salts has been reported by Straub (1964~. Coagulant doses of approximately 20-100 mg/liter at neutral pH values were used in jar tests. Increased removal was demonstrated when artificial turbidity was added to the test water, indicating adsorption to the particulate matter. LIME SOFTENING The major objective of lime softening is the removal of hardness from water. Two types of softening processes are used: when the alkalinity of water is sufficiently high, the low-lime process is used, and the pH of the water is raised to approximately 9.5-10.5; when the alkalinity of water is low, excess lime may be used to remove hardness not associated with alkalinity, and the pH of the water may be raised to around 10.5-11.5. Removal of trace metals during either process may be due to precipita- tion as hydroxides at the increased pH or to chemisorption of the metals to calcium carbonate and magnesium hydroxide precipitates. Symons et al. (1975) showed that, although removal of barium by coagulation was poor, good to very good results could be obtained with lime precipition. Cadmium removal with both the low- and excess-lime processes was in excess of 907. The removal of methylmercury was described as poor and the removal of inorganic mercury was fair to good in studies of both lime processes with the jar test procedure. Additional results presented by the authors indicated that significantly better results were obtained for the removal of both methylmercury and inorganic mercury in a pilot-plant operation.

222 /1) ,,, N N ~ _ ~ 8 o o so 8 o 8 o 8 To ~ ~ C) · ~ 4- o. ~ _ ~ 4 ~r ~Or . ~ U. ~o o o V o o o o , o ~;, JO 8 Cal V, Cal o 4- 4 - L4 4 - C. ;^ D Cal - C. o - Ct o So - LU m . ~0 V, a~ .S - ca o ~ _ X ~ =' o - V) 3 c~ o ~ . ~ Ct C) ~ .E ·4O" ~ o: .e V _ ~o o ~_ N C4 O O O O ~) ;> N O _ O _ C) O N - o o - _ ~_ 8 ~ 8 ': 8 - o o 8 o o I ~S -" o o o o ~o o - o o Ct m v - o o N - o o - - · _ 0o ~O - o C ~O ~0, :> ~ 00 - _ cd 0 1 o C: o ~ I ~ I ~ =: ~C ~C~ -~- ~ ~Oo ~C, ~ ~ ~ ~ C) l V V V ~

223 8 g o o-~S ~ ~ ;> - o o 4,,' o ~ C: C. C. o o ~, C1 C: ~° ;> C: ~ ~ ~ - - o ~o o o o o ,= o ~o o po ~C) O L, O l l ', ~ o o o o ~o P" P4 ~ P~ ~P~ _ ~ oa b4 oo o ~ ~ . - - cq e e ~: V) ~ _ ~ ' ~ ~ . c~ ~ _ =- E-_ ~ ~ _ ~ ~- E ~ . a ~e ~ . ~ ~ - ~ ~ ~e ' ~ e P EE a ;= ~ ~ :, ~ 8! . . . _ ~4 ~ _ _ _ . . . . . . . . . _ ~ r-~ ~ ~ \0 ~ X C~ O - C C ~0 o A 11 11 o o 8 ~ C) :> _ _ C ;,. .~ a~ ~ ~ ~ ~L · o o ~ r~ ~ ~ Vo ~ 11 11 E o.- ~ o Ct

224 DRINKING WATER AND H"LTH Lime precipitation of municipal secondary effluent with added trace metals at a pH of 11 was shown to remove silver (50 ,ug/liter) and cadmium (10 ,ug/liter) in excess of 95% (Lindstedt et al., 1971~. Removal of chromium (SO ,ug/liter) was very poor. At a pH of 11, silver and cadmium were found to be present as insoluble hydroxides, and chromium as the soluble chromate, CrO4-2. Nilsson (1971) demonstrated that- although cobalt, nickel, and zinc were poorly removed by chemical coagulation lime precipitation at a pH of 9.S was very elective in removing these metals from samples of tap water and wastewater to which they were added. In a review of the chemistry of lime precipitation, Dye and Tuepker (1971) emphasized that the removal of magnesium was most elective with the excess-lime process. The removal of magnesium by the low-lime process is usually poor, because of the dissociation of magnesium hydroxide [Mg(OH)2] at pH values below 10. Removal of iron by the low- and excess-lime processes and removal of manganese by the excess-lime process were reported to be incidental, because of the high pH associated with each process (Nordell, 1961~. Naylor and Dague (1975) found that the excess-lime process with pH greater than 10.5 was unable to remove lead, either becuase of the physical character of the lead oxides or because of the presence of soluble lead hydroxide Pb(0H)3. Very good removal of lead by the low-lime process was noted. The presence of suspended matter increased the removal of lead with both the low- and excess-lime processes. ACTIVATED CARBON Activated carbon is normally used to remove substances that cause taste, odor, and color in water. The use of activated carbon for removal of organic matter in general has been recognized. The removal of metals by activated carbon may be due to several mechanisms. Impurities in activated carbon, especially oxygen and sulfur, may play a significant role. Also surface oxides may act as weak-acid cation-exchange sites or sulfide groups may interact strongly with some metals resulting in chemisorption. Activated carbon may also act as a nucleation site for the precipitation of metals. On the other hand, trace metals associated with organic matter may be removed by interactions between the activated carbon and the organic matter. Activated carbon can also act as a reducing agent. Reduction of metal oxyanions-e.g., Cr2O7-2 and MnO4-2 to Cr(III) and Mn(II) may result in the precipitation of the reduced species as oxides or hydroxides Cr(OH)3 and MnO2 (Singer, 1974~.

Inorganic Solutes 225 Logsdon and Symons (1973) and Symons et al. (1975) have reported that trace amounts of inorganic mercury and methy~mercury can be removed effectively by activated carbon. The superior removal of methylmercury, compared with inorganic mercury, was attributed to interactions between the activated carbon and the methyl functional group. Poor removal of barium with activated carbon was reported. Lindstedt et al. (1971) reported removal of silver, cadmium, and chromium (in excess of 95~0) from municipal secondary effluents with activated carbon. The high degree of removal was attributed to a combination of mechanisms. Sigworth and Smith (1972) extrapolated several years of data on removal of several metals from paper mill waste solutions by activated carbon to obtain what they felt to be reasonable removal efficiencies that may be expected in the treatment of drinking water. The data were collected for solutions having very high concentrations of metals and low pH values. The authors concluded that the removal of zinc would be poor under the extrapolated conditions, the removal of vanadium and nickel would probably be fair, and the removal of cobalt, iron, lead, and tin would probably be good. REVERSE OSMOSIS Reverse osmosis is used as a desalination or demineralization process. The ionic strength of water is reduced by forcing it to disuse through a cellulose acetate membrane against the high osmotic pressure caused by ionic imbalance. Furokawa (1973) has reported the rejection (separation) of cadmium, chromium, copper, aluminum, iron, magnesium, nickel, and silver by reverse osmosis to be in excess of 98%. ION EXCHANGE Ion exchange involves the reversible exchange of ions between a solution and an exchange resin. Exchange resins are available to exchange either anions or cations. The for specific ions over other ions, according to the ionic charge, the hydrated ionic radius of the ions, and their concentra- tion in solution. Lindstedt et al. (1971) demonstrated the removal of silver and cadmium from municipal secondary effluents by a cation-exchange bed. Chromium VI was removed effectively by an anion-exchange bed when present as the metal oxyanion HCrO4-. Semmens (1975) has observed very good removal of barium and lead by clinoptilolite, a cation-exchange resin. Very good removal of barium,

226 DRINKING WATER AND H"LTH methylmercury, and inorganic mercury have been reported by Logsdon and Symons (1973~. Bowers (1971) noted the efficient removal of magnesium by ion exchange. Although ion-exchange treatment can be designed for the removal of iron, manganese, and aluminum, the presence of these metals in water may impair the exchange capacity of a resin designed for the removal of other metals. Nordell (1961) stated that some removal of dissolved silica with a strongly basic anion resin is possible. Analysis of Drinking Water for Trace Metals The literature on chemical analyses of trace metals in natural fresh water is voluminous. Only the most pertinent publications will be discussed here. Brown et al. (1970) have prepared a comprehensive manual that contains methods used by the U.S. Geological Survey to collect, preserve, and analyze water samples for dissolved mineral and gas content. Among the topics discussed are the selection of sampling sites, frequency of sampling, sampling equipment, sample preservation, laboratory equip- ment and techniques, accuracy and precision of the analysis, and reporting of results. The methods of analysis are applicable to a wide range of water, from that with trace concentrations of dissolved metals to that with high concentrations. The National Environmental Research Center of the EPA at Cincin- nati, Ohio, has published methods of chemical analysis of water and wastes (USEPA, 1971~. The atomic-absorption method is suggested for the determination of aluminum, cadmium, chromium, copper, lead, magnesium, manganese, silver, and zinc; and the flameless atom~c- absorption method is suggested for mercury. Method selection was based on the following criteria: 1. The method should measure the desired constituent with precision and accuracy sufficient to meet data needs in the presence of the interferences normally encountered in polluted water. 2. The method should utilize the equipment and skills normally available in the typical water-pollution control laboratory. 3. The method should be in use in many laboratories or have been sufficiently tested to establish its validity. 4. The method should be sufficiently rapid to permit routine use for the examination of a large number of samples. Guidelines establishing test procedures for analysis of various pollu

Inorganic Solutes 227 tents in water were published in the Federal Register on October 16, 1973. They included references to 71 test procedures for measurement of pollutants for which limitations were specified under the Federal Water Pollution Control Act Amendments of 1972. Several professional associations have recommended procedures for analysis of water samples for various trace metals. Such publications are Standard Methods for the Examination of Water and Wastewater (Ameri- can Public Health Association, 1976), and Annual Book of ASTM Standards (American Society for Testing Materials, 1970~. In addition, many symposium volumes and handbooks have summa- rized the state of the art for the analysis of trace metals in aqueous solution. Those reviews can be found in Hume (1967), Boettner and Grunder (1968), Hemphill (1973), Cosgrove and Bracco (1973), and others. Recent developments dealing with analytic methods for trace metals in waters are reviewed biannually in Analytical Chemistry and annually in Journal of Water Pollution Control Federation (Minear, 1975~. SAMPLE TREATMENT For the determination of trace metals in fresh water, large volumes of sample are required. Caution must be exercised in the proper collection and treatment of water samples, if the analytic results are to reflect the actual conditions of the water sampled. Water samplers sometimes introduce serious contamination. In selecting sample containers, care must be taken to avoid containers whose interior surfaces contain active metal-binding sites or that may release contaminating metals into the water sample. Inert plastic containers are usually preferred to glass. Polyethylene bottles are generally satisfactory. Ediger (1973) recom- mended a cleaning procedure of soaking containers in a 2% nitric acid solution for 24 h and then rinsing several times with metal-free water. Rapid changes may occur in the chemical composition of water samples during storage, owing either to the introduction of contaminants from the containers or to selective adsorption of metals onto the walls of containers. Trace metals in water are also subject to change because of biologic activity. Water samples are usually stabilized by the addition of dilute acid. The EPA recommends the addition of 3 ml of 50EYO nitric acid to each liter of filtered sample. For unfiltered samples, 5 ml of concentrated nitric acid is recommended. Other preservatives have been recommended for metals known to be unstable in aqueous solution, such as silver (West et al., 1967) and mercury (Oman", 1971~.

228 DRINKING WATER AND H"LTH ANALYSIS A general requirement in analytic chemistry is standardization of methods. Some methods that serve today as the legal standards in drinking-water quality control for trace metals are not sufficiently sensitive and accurate. The establishment of a method, moreover, does not guarantee that it will produce the same results when used by different analysts in different laboratories. A strong effort is required in evaluating and improving the analytic methods used in drinking water quality control. The analysis of trace metals is intimately related to the setting and enforcement of drinking-water standards. The reliability and detectabil- ity of analytic methods may be the limiting factors in defining standards and maintaining surveillance. Methods must be reliable and provide a measurement of the species under consideration. Furthermore, in the case of effective monitoring programs, methods must be rapid and must have a reasonable cost. In any trace analytic method, the first consideration is sensitivity. Because of the very low concentrations of some trace metals in natural water, methods should have sensitivities of a nanogram or less. Such methods may involve concentrating the sample; this should be avoided if possible. The stated sensitivity value for a particular method is generally not an exact figure. "Sensitivity" is sometimes defined as the concentra- tion that yields a reading of 1% of full scale of the instrument; it is used in this manner in atomic absorption. The detection limits are usually defined as twice the background. The specificity of an analytic method indicates the degree to which the method detects one element with no interferences from other elements that are present. Ideally, one would like methods that are specific for each element to be analyzed with few or no interferences. Accuracy and precision of the procedures are important, but results will be less accurate and less precise as concentrations move into the micrograms-per-liter region. Each procedure should be checked for precision on real samples, and the data reported with respect to the standard deviation. In selecting a method of water analysis for trace metals, sensitivity, speed, ease of operation, and relative lack of chemical interferences make the conventional and nameless atomic-absorption spectrophotometers instruments of choice. All analytic procedures recommended by the EPA and the U.S. Geological Survey for determining trace metals in water samples are based on atomic-absorption spectrophotometry. These instruments are generally available in analytic laboratories.

Inorganic Solutes 229 For general information on atomic-absorption analysis, books by Elwell and Gidley (1966), Slavin (1968), Ramirez-Munoz (1968), L'vov (1970), Price (1972), Reynolds and Aldous (1970), Kirkbridge and Sargent (1974), and Robinson (1975) are recommended. Barium OCCURRENCE Barium, one of the alkaline earth metals, occurs naturally in almost all (99.4~O) surface waters examined, in concentrations of 2-340,ug/liter, with an average of 43 ,ug/liter (Kopp and Kroner, 1967~. The drainage basins with low mean concentration of barium (15 ~g/liter) occur in the western Great Lakes, and the highest mean concentration of 90 ,ug/liter is in the southwestern drainage basins of the lower Mississippi Valley. Finished water of public systems frequently (99.7% of supplies examined) contains barium, at 1-172 ,ug/liter, with a mean of 28.6 ,ug/liter. The 100 largest cities (Durfor, 1964) of the United States had a median concentration of 43 ~g/liter, with a maximum of 380 ,ug/liter, but 94% of all determina- tions were less than 100,ug/liter. Drinking water at the tap, as determined in 2,595 samples, had a maximum of 1,550 ,ug/liter; the maximum was found in one of only two samples that exceeded the interim standard of 1,OOO,ug/liter(McCabe, 1970~. CHEMICAL CHARACTERISTICS Barium is slightly rarer than strontium in the earth's crust. It may replace potassium in some of the igneous rock minerals, especially feldspar. Barium sulfate (barite) is a common barium mineral of secondary origin. In stream water and most groundwater, only traces of the element are present. The reason for the small amount of barium in solution is the low solubility of barium sulfate. Because natural water usually contains sulfate, only trace amounts of barium will dissolve. Barium sulfate is soluble in pure water at 20°C barium at 1.6 mg/liter and sulfate at 1.1 mg/liter. The solubility of barium sulfate increases considerably in the presence of chloride and other anions. However, water containing sulfate at more than a few parts per million will not carry barium at more than a few parts per million (USGS, 1959~.

230 DRINKING WATER AND H"LTH METABOLISM The metabolism of barium has been traced by radioisotope techniques and shown to be similar to that of calcium (Seaber, 1933; Bauer et al., 1956~. The digestive system is extremely permeable to barium, allowing for rapid transfer to and from the bloodstream (Batter, 1957~. The metal is transported in the plasma and disappears from the blood completely within 24 h. Excretion of barium is different from that of calcium, in that the rate is greater in feces than in urine. In feces, 20970 of barium is excreted in 24 h compared with 6% of calcium; in urine 7% of barium is excreted in 24 h compared with 0.9% of calcium. HEALTH EFFECTS No vital metabolic function has yet been found for barium, although it is believed to be beneficial for rats and guinea pigs under specific dietary conditions (Underwood, 1971~. Barium is highly toxic when soluble salts are ingested. Fatalities have occurred from mistaken use of barium salt rodenticide. The fatal dose of barium chloride for man has been reported to be about 0.8-0.9 g, or 550- 600 mg of barium (Sollman, 1957~. Industrial exposure to barium oxide and sulfate dusts produces a benign pneumonoconiosis called "baritosis." Although barium poisoning is rare in industry, the potential from the more soluble forms is real. The American Conference of Governmental Industrial Hygienists set an airborn threshold limit value (TLV) for barium of 0.5 mg/m3. The limit was based on several years of observation of workers at Los Alamos exposed to barium nitrate. Acute barium poisoning exerts a strong, prolonged stimulant action on all muscles, including cardiac and smooth muscle of the gastrointestinal tract and bladder. Barium is capable of causing nerve block (deNo, 1946) and in small or moderate doses produces a transient increase in blood pressure by vasoconstriction (Gostev, 1944~. There has been no determination of the chronic ejects of barium administered repeatedly over a long period, either in food or drinking water. ANALYSIS Conventional flame atomization does not have sufficient sensitivity to determine barium in most water samples; however, a barium detection

Inorganic Solutes 231 limit of 10 ,ug/liter can be achieved, if a nitrous oxide flame is used. Renshaw et al. (1973) described a concentration procedure for barium that uses thenoyltrifluoroacetone-methylisobutylketone extraction at a pH of 6-8. With a tantalum liner insert, the barium detection limit of the flameless atomic absorption procedure can be improved to 0.1 ,ug/liter (Renshaw, 1973). CONCLUSIONS AND RECOMMENDATIONS A drinking-water guideline was derived from the 8-h weighted maximum allowable concentration (TLV) in industrial air of 0.5 mg/m3 set by the American Conference of Governmental Industrial Hygienists. It was assumed that, with an 8-h inhalation of 10 me of air, the daily intake would be 5 mg of barium, of which 75% was absorbed in the bloodstream and 90% transferred across the gastrointestinal tract. Based on the above assumptions, it was reasoned that a concentration of about 2 mg/liter of water would be safe for adults. To provide added safety for more susceptible members of the population, such as children, a level of 1 mg/liter was recommended (Stockinger, 1958~. There have been no long- range feeding studies to confirm the safety of this barium intake. The limit set in the USSR is 4 mg/liter of water. International and European standards do not list barium upper limits, because available information is insufficient. It is rare to find sources of water that exceed a barium concentration of 1 mg/liter, although a concentration of 1.55 mg/liter has been recorded in drinking water. The 1975 Analysis of Interstate Carrier Water Supply Systems showed none exceeding the 1 mg/liter standard. Small numbers of people are known to be consuming well waters in Illinois, Kentucky, Pennsylvania, and New Mexico that are at, or exceed by 10 times, the standard for barium. It would be desirable to study any risk that might be associated with this chronic ingestion of barium. Animal studies should be undertaken at least, to determine the toxic effects of long-term ingestion of barium at low concentrations. Beryllium OCCURRENCE A relatively rare element, found chiefly in the mineral beryl (beryllium aluminum silicate), beryllium is not likely to occur in natural water in appreciable concentrations. Although the chloride and nitrate are very

232 DRINKING WATER AND H"LTH soluble and the sulfate moderately so, the carbonate and hydroxide are almost insoluble in cold water (McKee and Wolf, 1963~. Beryllium is used primarily in metallurgy to produce special alloys, in the manufacture of X-ray diffraction tubes and electrodes for neon signs, and in nuclear reactors (Browning, 1961~. It is also used in rockets and in missile fuels. Cralley (1972) presented an extensive discussion of the many modern uses of beryllium metal, be~llium-copper alloys, berylli- um oxide, and minor beryllium compounds. The consumption of beryl increased from 1,200 short tons in 1941 to 8,483 tons in 1969. Using emission spectroscopy, Durum and Haffty (1961) measured beryllium in 59 samples of surface water from 15 rivers in the United States and Canada. The highest concentration observed was less than 0.22 ,ug/liter. Kopp and Kroner (1967) noted the presence of beryllium in 85% of their samples from the 15 major river basins of the conterminous United States; the concentration ranged from 0.01-1.22 ,ug/liter, with an average of 0.19 ,ug/liter. According to Standard Methods (APHA, 1976), beryllium has been reported to occur in U.S. drinking water at 0.01-0.7 ,ug/liter, with a mean of 0.013,ug/liter. In a study of many groundwater samples from the western United States, beryllium was detected in only three highly acid mine waters. Beryllium discharged to ground water will not travel far in neutral solution, because it is rapidly adsorbed by the clay in the soil. In the eastern United States and in Siberia, surface water was reported to contain beryllium at 0.1-0.9 ,ug/liter. Pacific Ocean water contains 2-9 ,ug/liter (Griffitts et al., 1976~. According to the NAS-NAE report on water-quality criteria (NAS, 1973), the concentration of beryllium in seawater is only 6 x 10 4 ,ug/liter. Food does not appear to be a significant source of human exposure to beryllium. According to Griffitts et al. (1976), "there is no evidence at present that beryllium is moving from soils into food or feed plants in the United States in amounts that are detrimental to plants, animals, or people." Furthermore, "the forms of beryllium in plants and their digestibility by animals have not yet been determined." CHEMICAL CHARACTERISTICS Although beryllium is in the same group of elements as the alkaline earth metals, it shares few properties with them. Beryllium replaces silica in the structure of some igneous rock minerals and is present as independent beryllium minerals in pegmatites, the most important of which is beryl. In the weathering process, beryllium (like aluminum) is concentrated in

Inorganic Solutes 233 hydrolysates and does not go into solution to any appreciable degree. Beryllium is not likely to be found in natural water in greater than trace amounts, because of the relative insolubility of beryllium oxides and hydroxides at the normal pH range of such water. The solubility of the oxide is reported as about 2~70 ~g/1 in pure water at about 28°C. The sulfate and chloride of beryllium are very soluble, but would hydrolyze and lower the pH. In the presence of sodium hydroxide (high pH), beryllium hydroxide is soluble, probably because of the formation of anion complexes. The ejects of other ions or cations on the solubility of beryllium are not known (USGS, 1959~. Some data on adsorption of trace quantities of beryllium in water by glass and plastic containers have been reported. At a pH of 3.5, there was no adsorption of beryllium by the container. However, at a pH of 7 and 8, there was considerable adsorption. Adsorption of beryllium by naturally occurring minerals is probably an important cause of the low concentra- tions in water, inasmuch as such adsorption seems to proceed electively at pH values common in natural water. METABOLISM Absorption of beryllium from the digestive tract is slight (about 0.006% of that ingested), and excretion is fairly rapid (Browning, 1961). HEALTH EFFECTS In a comprehensive review, Pomelee (1953) reported that there was no indication that beryllium in any form is harmful when taken orally. Inhalation of particles is by far the major hazard to humans from this metal. Beryllium has been incriminated in pulmonary ailments of workers exposed to beryllium dusts (Browning, 1961). Since the develop- ment, in about 1947, of spectrochemical techniques for detecting beryllium in air, there has been a substantial increase in the number of reported cases of beryllium poisoning. No information was uncovered to indicate that beryllium is a beneficial or necessary component of human nutrition. Rats were healthy after 2 yr on a diet that included beryllium sulfate at about 6.0 mg/day, equivalent to beryllium at 1.0 mg/kg of body weight per day. Four dogs showed no ill ejects after 19 months of daily ingestion of beryllium sulfate at 10 mg/kg of body weight; 1 dog lost weight after 9- months and was killed for examination. No evidence of tissue damage was found (Pomelee, 1953~. When mice were fed beryllium at 5.0 mg/liter

234 DRINKING WATER AND H"LTH in drinking water for life, slight ejects on the body weight of females (but not males) were disclosed, and there were no ejects on the life span and survival of either sex. These studies with mice indicated that beryllium is poorly absorbed through the gut and that ingestion is not a hazard (Schroeder and Mitchener, 1975~. According to Stokinger (1972), the dietary LD50 of beryllium sulfate in rats after 172 days was 2,750 mg/kg of body weight per day. The beryllium metal in beryllium oxide eaten in the diet at 5.0% is so poorly absorbed that no effect on growth occurred over long periods of feeding. Beryllium sulfate did not interfere with growth until a concentration of 1.4% (14,000 mg/kg of diet) was reached. With the data for 10 of the 15 river basins studied by Kopp and Kroner (1967), Berg and Burbank (1972) attempted to establish correlations between carcinogenic trace metals in water supplies and cancer mortali- ty 8 metals compared with 34 types of cancer, for a total of 272 comparisons. At the 0.05 level of significance, they expected about 14 comparisons to show positive correlations. In fact, 28 positive correla- tions were found, 5 of which were associated with beryllium. When they studied these findings in further detail, however, especially with respect to bone cancer, the 5 correlations were not meaningful. Berg and Burbank concluded that the correlations were not consistent with a waterborne pattern and could be explained by other known factors. The inclusion of beryllium in the work of Berg and Burbank (1972) was prompted by the fact that beryllium was the first metal to produce cancers in animals with any substantial frequency away from the site of administration. Stokinger (1972) noted that soluble beryllium sulfate is about equally toxic (in milligrams per kilogram of body weight) to rats, mice, dogs, monkeys, and rabbits, whether administered by inhalation, intratracheally, intravenously, or subcutaneously. When beryllium is transported via the bloodstream from its initial site of deposition, a significant part of the administered dose ends up in the skeleton, irrespective of the mode of administration. In the bones of animals, it has been shown to produce osteosarcoma; but this has been demonstrated only in animals and not yet in humans who have beryllium lung disease from inhaling beryllium dust (IARC, 1973~. According to Sterner and Eisenbud (1951), acute pneumonitis among human beings has been caused by exposures to beryllium in the atmosphere at concentrations of less than 1.0 to over 100 ,ug/m3 of air. The symptoms of beryllosis include skin and lung diseases of variable severity. The reactions of people to a given exposure are said to vary widely, but apparently any person will show a reaction if time and degree of exposure are great enough. It became apparent by 1947 that many cases of what was then thought

Inorganic Solutes 235 to be pulmonary sarcoidosis were appearing among beryllium production workers as a result of inhalation of beryllium compounds and metallic dust. On the recommendations of an ad hoc advisory committee, the Atomic Energy Commission (AEC) established strict in-plant limits for beryllium in the atmosphere and much stricter limits for neighborhoods near AEC plants (Stokinger, 1972~. Apparently, beryllosis is confined to the lungs, and beryllium is not translocated to other parts of the body. Any sputum that might be swallowed would get into the digestive tract, where beryllium has been shown to be relatively harmless. No unusual incidence of lung cancer has yet been found among workers exposed to beryllium, although sizable numbers had exposures more than 20 years ago. This experience indicates that, if beryllium proves to be carcinogenic in humans, it is of low potency (Stokinger, 1972~. ANALYSIS According to Standard Methods (USEPA, 1976), atomic-absorption spectrophotometry and calorimetry are equally suitable for the determi- nation of beryllium. Direct flame atomization offers a detection limit of 2 ,ug/liter. Sachdev and West (1969) have described a concentration procedure that uses solvent extraction with an oxine-acetylacetone- dithizone combination at a pH of 6.0. The detection limit can be lowered to 0.03 ,ug/liter when the graphite furnace is used for atomization. Chapman et al. (1974) have used flameless atomic absorption for beryllium analysis. CONCLUSIONS AND RECOMMENDATIONS Beryllium is relatively harmless when ingested in food and water, except at very large continuing dosages. It is present in natural surface water at concentrations generally less than 1.0 ,ug/liter, with averages of less than 0.2 ,ug/liter; hence, it presents no hazard in drinking water. The USSR has set a limit of 0.2 ,ug/liter, but the World Health Organization has not established any limit (Stoefen, 1973~. The EPA has not promulgated any limit for beryllium in its National Interim Primary Drinking Water Regulations ( 1975~. Beryllium is known to cause cancer in various species of laboratory animals, but to date has not been associated with human cancer. Because of the strong association of beryllium with cancer in animals a continuing effort should be made to study both through epidemiology and chronic low-level feeding studies the toxicology of beryllium.

236 DRINKING WATER AND HEALTH Cadmium The sources, distribution, metabolism, and toxicology of cadmium have been reviewed by Friberg et al. (1971,1974, 1975), Underwood (1971), Nordberg, (1976), and Copenhaver et al. (1973~. OCCURRENCE The principal industrial uses of cadmium are in electroplating, in pigment manufacture, and as a plasticizer, chiefly in polyvinylchioride. Cadmium occurs in zinc ores and is an important by-product in the metallurgy of zinc. Because cadmium is an impurity in zinc, cadmium should possibly receive some consideration when poor grades of zinc are used for galvanizing. The use of cadmium-plated containers in food- and beverage-handling materials is now prohibited by the Food and Drug Administration because acute cadmium poisoning has been recognized in man after consumption of food and particularly acidic beverages stored in cadmium-plated containers. Except where stated, estimates of intake and critical renal concentration are taken from Cadmium in the Environment, II and III (1974, 1975J. In streams and rivers, the concentration of cadmium tends to be higher in sediment than in filtered running water. From studies in Japan (Friberg, 1974) and upstate New York (Kubota et al., 1974; Durum, 1974), it appears that most fresh water contains cadmium at less than 1 ,Ag/liter. The U.S. Geological Survey reported that about 46% of samples contained detectable amounts 1 ,ug/liter or more. Regional differences are noted within the United States, with the higher concentrations found in runoff water in the Northeast, in some urbainzed areas in the South, and in the central states. This distribution pattern suggested to Durum that pollution sources and rainfall may be the major contributors of cadmium in river water. Carbonate content and pH influence the stability and solubility of cadmium in water. It is least soluble at a pH of approximately 8-9 and becomes increasingly soluble as the pH decreases. But, the median concentration in surface water in most areas is less than the detection limit (~1 ,ug/liter of water). Durum used filtered samples and found that 4% of surface waters in the United States exceeded the 1962 USPHS drinking-water standard of 10 ,ug/liter. However, the USPHS National Community Water Supply study indicated that the dnnking-water standard for cadmium was exceeded by only 0.1% of 969 water-supply systems tested, which served an estimated 18 million people. Craun and McCabe (1975) reported data on the interaction between soft water and

Inorganic Solutes 237 accumulation of cadmium in the distribution systems for Boston and Seattle. This survey indicated that 13% of samples obtained in Boston showed a higher concentration at the tap than at the treatment plant. In Seattle, which has more acidic water, 51% of the sample showed an increase. Both running and standing samples were obtained. In Seattle, 7% of the samples exceeded the 10 ~g/liter drinking-water standard; in the Boston area, none exceeded this standard. There is a wide consensus that the cadmium content of food is the major source of cadmium for the general population. Friberg et al. (1974) estimated that the average daily intake for adults is approximately 50 ,ug. If this estimate is adjusted on a caloric basis for children consuming a similar diet, the intake at 2-3 years of age would be about one-third to one-half of the adult intake. There is a rather wide range in the estimates of cadmium intake in food. This may be due largely to difficulties in the measurement of trace amounts of cadmium. Because cadmium is a contaminant of superphosphate fertilizers and because of current plans to use sewage sludge for agricultural purposes, it is the consensus of most experts that the food supply should be carefully monitored for cadmium and other trace metals. Although air cadmium concentrations may be high near lead, zinc, and cadmium smelters and refineries, it is generally about 1 ng/m3 elsewhere. Cigarette tobacco contains cadmium at about 1 ppm. Friberg (1974) has estimated that the smoking of one pack of cigarettes a day can contribute 2-4 ,ug of cadmium a day. The best-described accident related to discharge of cadmium into water is the occurrence of Itai-Itai disease among residents along the Jintsu River in Japan (Friberg et al., 1971~. These residents were apparently exposed not only through the drinking of water, but also through the ingestion of rice grown in the contaminated water. CHEMICAL CHARACTERISTICS Elemental cadmium is present in rocks in much lower quantities than those reported for zinc. Only traces are likely to be found in natural water, but cadmium may be introduced in amounts significant from a health standpoint by solution from containers or tubing or by waste disposal. Cadmium probably could be present only in small amounts in water with the normal alkaline pH, because of the low solubility of the carbonate and hydroxide. Cadmium hydroxide is soluble at about 1 mg/liter at 25°C. Exact data regarding solubility of the carbonate are not

238 DRINKING WATER AND H"LTH available. At a pH below about 4.5, the solubility of cadmium would be controlled by other factors and would probably be greater (USGS, 1959~. METABOLISM The total daily intake of cadmium from air, water, food, and cigarettes is estimated to range between 40 Payday (for nonsmoking rural residents who have negligible air exposure and consume a low-cadmium diet) and 190 ,ug/day (for smokers living in industrialized cities and consuming a high-cadmium diet). Absorption from the digestive tract is thought to average about logo. However, a number of factors, including dietary calcium, protein, and age, may have an important bearing on this. For the digestive-tract route of assimilation the major organs of cadmium storage are the liver and renal cortex. The renal cortex may contain one-third of the total cadmium body burden. The biologic half-life of cadmium in these organs is variously estimated at 13 to 38 yr. Urinary excretion is low, from 1 to 9 ,ug/day. Because cadmium tends to accumulate, a more useful way of looking at the question is to consider the rate of accumulation. The human placenta is apparently highly impermeable to cadmium. The total body burden is estimated at 1 ng at birth and at 15-50 mg at the age of 50 years. This is consistent with an average accumulation of 0.9-1.8 ,ug/day. There is a major need for a more reliable estimate of the rate of cadmium accumulation. The renal cortex is considered to be the critical organ for accumulation of cadmium from low-level dietary exposures, and the critical concentra- tion for renal cortex is approximately 200 ,ug/g of tissue (wet weight) (Friberg et al., 1974; Nordberg, 1976~. At greater concentrations, irreversible renal injury may occur. In the outbreak of Itai-Itai disease on the Jintsu River, renal cortical cadmium concentration was estimated at 600-1,000 ,ug/g of tissue (wet weight) in those most severely (and irreversibly) affected. With an assumed water consumption of 1.5 liters/day, the average cadmium intake from water was estimated at 5 ~g/day, or less than 10% of the total intake. HEALTH EFFECTS In industry, after overexposure to cadmium at high concentrations (50 ,ug/m3) well in excess of that for the general population, bronchitis, emphysema, anemia, and renal stones have been found. Among the general population, gastrointestinal upsets similar to "food poisoning" have been reported in association with consumption of food or beverages

Inorganic Solutes 239 conveyed in cadmium-plated vessels. Sporadic outbreaks of this sort occur when cadmium-plated vessels not intended for food are used to prepare lemonade and other acidic beverages for picnics and similar outings. For the general population, the major route of absorption is through the gastrointestinal tract. The major erects are likely to be on the kidney. There is an extensive literature reviewed by Friberg(1971, 1974, 1975), Nordberg (1976), and Sandstead (1974) on this problem. Experimental data indicate that the zinc: cadmium ratio in the organs is an important determinant of cadmium toxicity (in most foodstuffs, the dietary ratio of cadmium to zinc is 1: 100; it is highest in meat products and lowest in dairy products), and there is some evidence that the intake of sodium may also influence cadmium toxicity. There are no dose-response data. Limited autopsy data suggest that average renal cortical concentrations of cadmium in American and European populations are generally less than 50 ,ug/g of tissue (wet weight) less than the projected critical concentration by a factor of 4 or more. In addition to the suspected interactions between cadmium, zinc, and calcium, recent experimental studies indicate that cadmium at very high doses can interfere with the activation of vitamin D in both liver and kidneys to the final active 1,25-dihydroxycholecalciferol (Nordberg, 1976; Sandstead, 1974~. There is also evidence from animal studies that cadmium is implicated in the etiology of hypertension (Schroeder, 1965~; the thresholds and dose-response relationships are unknown. There is some evidence that cadmium is carcinogenic in the rat, but no substantial evidence to implicate it with human cancer (IARC, 1973~. Cadmium is known to be teratogenic in the rat following rather high (2-13 mg/kg) doses on specific days of gestation (Chernobyl, 1973~. Another erect observed at high doses in rats is ease of producing testicular and ovarian necrosis when cadmium is given by injection. This same effect can be seen in rats (who can not vomit) with high oral doses. There are no identified hypersusceptible segments of the human population. Although victims of Itai-Itai disease were predominantly multigravid, postmenopausal women, this does not mean that these alone are predisposing conditions. It should, however, be noted that, on a body weight basis, infants may have a higher intake of cadmium. If, in fact, calcium intake is an important protective factor, it is well to note that a significant proportion of the population from school age up is lactose- intolerant and may voluntarily reduce milk intake and hence calcium intake on this account. If, as appears likely from experimental studies, zinc is an important protective factor against cadmium toxicity, it is worth noting that preliminary evidence indicates that those with

240 DRINKING WATER AND H"LTH hemoglobin SS or SC have shown signs of zinc deficienyv. Further studies in these groups appear warranted. ANALYSIS o Direct flame atomization has a cadmium detection limit of 2 ,ug/liter. Most reported analyses, however, involve some form of concentration. The U.S. Geological Survey procedure (Brown et al., 1970) recommends extracting the cadmium as an ammonium pyrrolidine dithiocarbamate at a pH of 2.8 with methylisobutylketone. Other concentration procedures have been described for fresh water (USEPA, 1971; Traversy, 1971; Kaminski, 1974; Kinrade and Van Loon, 1974; Kubota et al., 1974; Korkisch and Sorio, 1975; Aldous et al., 1975~. The sampling boat and Delves cup techniques have cadmium detection limits of 0.1 and 0.05 ,ug/liter, respectively. Using the graphite furnace to atomize the sample can improve detection to 0.005 ,ug/liter. Paus (1971) has used the graphite furnace to determine cadmium in lake water at concentrations of 0.5-2.5 ,ug/liter. Other methods have been reported by Dolinsek and Stupar (1973), Surles et al. (1975), and Rattonetti (1974~. Barnard and Fishman (1973) have critically evaluated the use of the graphite furnace for cadmium determinations in fresh water. For all types of biologic samples, the available data indicate that either background correction or extraction is essential when determinations are made by atomic-absorption spectrophotometry, owing to the enhancing eject of sodium on the cadmium signal. Although it has not been fully explored, it appears that electrochemical techniques may be more suitable, although somewhat less sensitive, because such measurements may be influenced, to a lesser degree, by matrix effects. Except on a large- group basis, it appears that the measurement of cadmium in blood and spontaneously voided urine is of relatively little value, because these measurements are not reliable indicators of the concentrations of cadmium in the organs, particularly in the renal cortex. For the reasons stated above, one should scrutinize data carefully. It is likely that data obtained during the early years of atomic-absorption spectrophotometry are not reliable, because the background eject, particularly of sodium, was not appreciated at the time. CONCLUSIONS AND RECOMMENDATIONS There should be a comparison of the intakes of cadmium in various industrial and geographic regions and an attempt to correlate them with specific diseases. These kinds of correlations should also be done on

Inorganic Solutes 241 autopsy samples. There is a need to analyze, particularly in soft-water areas, the accumulation of cadmium in drinking water at the tap. There is also a need for certified reference samples, such as the NBS bovine liver and orchard leaves. Interlaboratory comparisons, exchange of standards, and establishment of a reference method are also warranted. The possible effect of cadmium on vitamin D metabolism needs investigation. The available data do not suggest any need to change the present drinking- water standard of 10 ,ug/liter, although there is a clear need for data on soft, aggressive water areas. Chromium The NAS-NRC has recently (1974) completed an extensive review of the medical and biologic effects of chromium, which has been reviewed and excerpted for this report. Additional material has also been included when necessary. OCCURRENCE Durum and Haffty (1961) reported a range of concentrations for chromium in U.S. rivers of 0.7-84 ~g/liter. Kopp and Kroner (1967) detected chromium in 24.5% of the samples examined, with concentra- tions ranging from 1-112 ~g/liter and averaging 9.7 ~g/liter. In a study of surface and groundwaters in Canada,~all but two of 240 samples examined were below 50 ~g/liter (Procter & Gamble, 1974~. In 1974, a maximum dissolved chromium concentration of 30,ug/liter was recorded in water from the Pecos River, New Mexico; the Los Angeles River; and the Columbia River, Oregon (USGS, 1974~. In a 1970 survey, 11 of 700 samples had chromium concentrations of ~50 ,ug/liter, with none exceeding 50 ,ug/liter (Durum et al., 1971~. Ackermann (1971) reported chromium concentrations below 5 ~g/liter for 18 of 27 river stations in Illinois; the maximum was 50,ug/liter. CHEMICAL CHARACTERISTICS The element chromium is amphoteric and can exist in water in several different states. It is present in minor amounts in igneous rocks and is much more abundant in basic and ultrabasic types than in the more silicic types of rocks. In attack by weathering, chromium in cationic form Cr(III) behaves somewhat like iron and is largely retained in resistates and hydrolysates. Very little chromium goes into solution. Natural water,

242 DRINKING WATER AND H"LTH therefore, would be expected to contain only traces of chromium as a cation, unless the pH were very low. Chromium, under strongly oxidizing conditions, may be converted to the hexavalent state and occur as chromate anions. Natural chromates are rare and, when CrO4-is present in water, it is usually the result of pollution by industrial wastes. Fairly high concentrations of chromate anions are possible in water with normal pH (USGS, 1959~. A study by Schroeder and Lee (1975) indicated that the oxidation state of chromium may be altered in natural water. Because of the possibilities for oxidation of Cr(III) and reduction of Cr(VI), they concluded that water-quality standards should be based on total chromium, rather than on hexavalent chromium. METABOLISM Because of analytic problems related to the determination of chromium, data on the absorption and metabolism of chromium must be interpreted with caution. Trivalent chromium affects glucose metabolism, binds strongly with plasma albumin, and interacts with manganese in glucose metabolism(Hambridge, 1971~. In a study in which rats were administered trivalent chromium for a short time, there was no glucose metabolism erect, whereas administra- tion for 15-120 days markedly affected glucose metabolism. Oversupply is reported to be no problem, and there appears to be a homeostatic mechanism for trivalent chromium involving a hepatic or intestinal transport system that rejects excessive accumulation. Oral ascorbic acid converts hexavalent chromium to trivalent chromi- um, and, when given within an hour or two, reduces gastrointestinal tract injury from hexavalent chromium (Hambidge, 1971~. Glucose tolerance in man declines with age; as many as two-thirds of an elderly population sampled in the United States had an abnormal glucose tolerance test. Tissue chromium in the United States also declines with age (Streeten et al., 1965~. The average daily intake of chromium in the United States varies widely due to diet and geography. Estimates range from 5 to 115 ~g/day with an average of 60~5 ,ug/day (NAS, 1974) to 5-500 ~g/day, with an average of 280,ug/day (Schroeder, 1970~. It has been reported that, regardless of dietary history or amount administered, only 0.5-3% of a given dose of trivalent chromium is available to the organism. The degree of absorption depends on the chemical form of the chromium and ranges from 0.1 to 1.2% of trivalent chromium salts to about 25% of the glucose tolerance factor.

Inorganic Solutes 243 Chromium is excreted in urine and feces with the urinary pathway accounting for 80%. Nearly all chromium in urine is present in the form of low-molecular-weight complexes: very little protein bound chromium is excreted. Estimates of excretion also vary between wide extremes. Mean 24-h urinary chromium excretion of 20 young adults was 8.4 ,ug with a range of 1.6 - 21,ug (NAS, 1974~. Other estimates have shown an average urinary excretion from 3 to 160, ~g/day with an average of 138 ,ug/day (Schroeder, 1970~. It is possible that pH plays a role in the physiologic distribution of hexavalent and trivalent chromium; the trivalent precipitates at physio- logic pH and forms chromic hydroxide. Trivalent chromium may also precipitate with proteins (IARC, 1973~. According to Schroeder (1974), the background body burden of chromium in Americans is low and declines between the ages of 34 and 44. Body burdens of Africans, New Easterners, and Orientals are much higher. Thais had higher tissue chromium concentrations than any other group. Organ distribution studies have been inconclusive. Results in rats given doses of chromium chloride showed the ovaries and spleen to have the highest uptake and, the kidneys and liver the next highest, with the lungs, heart, pancreas, and brain lower. But when chromium was given in the form of glucose tolerance factor, the results were different; the liver accumulated most, followed by the uterus, kidneys, and bone. In autopsies of humans, the highest accumulation has been in lungs; this suggests that humans are accumulating most chromium from the air, rather than from water or food (NAS, 1974~. HEALTH EFFECTS Acute systemic poisoning from chromium may result from accidental exposures, from therapeutic uses of chromium, and from suicide attempts. Principal damage to the body is tubular necrosis of the kidney. Cats fed 5~1,000 mg/day of chromic phosphate for 80 days were not affected. Rats fed trivalent chromium at 25 ppm for 1 yr or 5 ppm for a lifetime were also not affected (NAS, 1974~. Hexavalent chromium chemicals can be tolerated by animals in low concentra- tions, especially when they are administered in feed or drinking water, in which the degree of absorption is a factor. For example, rats tolerated hexavalent chromium in drinking water at 25 ppm for a year, and dogs showed no eject of chromium as potassium chromate at 0.45-11.2 ppm over a 4year period. Even higher concentrations have been reported by some investigators. However, larger doses of hexavalent chromium are highly toxic and may cause death, especially

244 DRINKING WATER AND H"LTH when injected intravenously, subcutaneously, or intragastncally (NAS, 1974, p. 82~. Chronic toxicity can be observed In several mammalian species with hexava- lent chromium in the drinking water In concentrations of more than 5 mg/liter. At this concentration, the element was found to accumulate In rats, but it caused no changes in growth rate, food intake, or results of blood analysis. Even 25 mg/liter in the drinking water failed to produce changes In these characteristics or in the histologic appearance of the tissues after 6 months. Dogs tolerated Hexavalent chromium In the water at up to 11.2 mg/liter for 4 years without ill effects. The minimal lethal dose in dogs is approximately 75 mg of chromium as sodium chromate, when injected intravenously. The salt causes acute hypertension, hypocholesterolem~a, and hypoglycemia. Growing chickens showed no detnmen- tal symptoms when they were fed 100 ,~g/g In diet (NAS, 1974, p. 29~. Although Hexavalent chromium has long been recognized as a toxic substance, trivalent chromium is considered by most investigators to be relatively innocuous and even (in microgram amounts) essential to human health. Hexavalent chromium produces hemorrhage of the gastrointestinal tract after ingestion. Inhaled chromate may cause cancer of the respiratory tract in occupationally exposed individuals (IARC, 1973~. It also produces ulceration on dermal exposure. The chronic adverse ejects most often considered in chromium toxicity are respiratory and dermatologic. It now appears that investiga- tors agree on several points: 1. People who work with Hexavalent chromium can develop cutaneous and nasal mucous-membrane ulcers, whereas exposure to trivalent chromium does not produce these effects. 2. People who work with Hexavalent chromium compounds can develop contact dermatitis from these agents, and they react to patch and intracutaneous tests with nonirritant concentrations of potassium bichromate. 3. Hexavalent chromium in tissue is reduced to the trivalent form. 4. Hexavalent chromium has greater diffusibility and solubility In tissue than trivalent chromium. 5. Hexavalent chromium can readily penetrate membranes. 6. Trivalent chromium can readily bind with some proteins to form complexes (NAS, 1974, p. 72~. Atherosclerosis in relation to chromium has been of interest. Studies have indicated that atherosclerosis can be induced in animals by chromium-deficient diets (Hambridge, 1971~. With regard to carcinogenicity, intraosseous, Intramuscular, subcuta- neous, intrapleural, and intraperitoneal injections of chromium com- pounds have been reported to cause the development of sarcomas in rabbits, mice, and rats. There is some evidence that calcium chromate in the form of a pellet attached to the bronchial mucosa in rat lung may be .

Inorganic Solutes 245 carcinogenic, but there is no support for the view that it constitutes a carcinogenic hazard in human food (Sunderman, 1971~. An IARC working group (1973) concluded "there is no evidence that non-occupa- tional exposure to chromium constitutes a cancer hazard." ANALYSIS Both hexavalent and total chromium concentrations are commonly determined in water. Direct aspiration of samples into a flame is used to determine the total chromium content with a detection limit of 3 ,ug/liter. The U.S. Geological Survey (Brown et al., 1970) has suggested a procedure for the determination of hexavalent chromium by extraction with ammonium pyrrolidine dithiocarbamate at a pH of 2.8. The same procedure is also used for the determination of total chromium after oxidation of any trivalent chromium present to the hexavalent state with potassium permanganate. Nix and Goodwin (1970) have used diethyldi- thiocarbamate for extraction of chromium. Fernandez and Manning (1971), Barnard and Fishman (1973), and Surles et al. (1975) have used the graphite furnace to increase sample vaporization for the determination of total chromium; the detection limit is 0.1,ug/liter. CONCLUSIONS AND RECOMMENDATIONS The NAS chromium report offered recommendations for research. These were among the most pressing: 1. At present, only two analytic techniques can be successfully used for accurate quantitative determination of chromium at the low concentrations that exist in many environmental media, especially in plant and animal tissue-neutron activation and shielded-arc emission spectrography. Both methods are expensive and time-consuming and require considerable experience and thus are not applicable to large-scale environmental studies. Laboratory research, using the latest analytic instrumentation, is needed for the development of sensitive, accurate, and precise methods for the analysis of chromium that could be used by most laboratory investigators. . . . 2. Accurate background information on normal concentrations of chromium in various media is necessary for predicting trends. 3. The potential toxicity of chromium depends on its valence state. There are no techniques for estimating the concentration of chromium in relation to its valence state, especially in animal and plant tissue. Data of this type also would be extremely useful for understanding the biologic function and availability of chromium. 4. Research is needed to ascertain the relation between exposure to airborne chromium and chromium concentrations in urine, blood, and other biologic

246 DRINKING WATER AND H"LTH media, such as hair. If any relation is demonstrated, biologic standards for exposure may become possible. (WAS, 1974, pp. 112-113~. There is a strong link between airborne chromium and lung cancer, but there is no firm evidence to establish a relationship between non- occupational exposure by any other route. There is also evidence that chromium has an important role in maintaining glucose metabolism and may also be a factor in atherosclerosis. It is therefore possible that with the exception of occupational exposure a deficiency of chromium may be more of a problem. The present interim drinking-water standard of 0.05 mg/liter is less than the no-observed-adverse-health-e~ect level. Consideration should be given to setting the chromium limit in terms of the hexavalent form. Extensive work is urgently needed to establish the role of dietary chromium with regard to atherosclerosis and glucose metabolism as well as its possible carcinogenic ejects at low levels in lifetime feeding studies. Cobalt OCCURRENCE Cobalt and its salts are used for making alloys, in nuclear technology, as pigments in the china and glass industry, and as binders in the tungsten- carbide tool industry. Cobalt may be divalent or trivalent. Solutions containing Cobaltous ions (Co+2) are relatively stable, but cobaltic ions (Cr+3) are powerful oxidizing agents and are thus unstable in natural water. Cobaltous chloride, Cock, is a highly soluble salt that is used in the manufacture of sympathetic ink, barometers, and hydrometers, as well as in galvanoplating, ceramics, and (as a feed supplement) salt licks for ruminant animals. Cobaltous nitrate, Co(NO3~2, is used in the manufacture of cobalt pigments and sympathetic ink and in decorating porcelain. Cobaltous sulfate, CoSO4, a red crystalline substance that is readily soluble in water, is used in decorating and plating and for remedying cobalt deficiencies in cattle and sheep (McKee and Wolf, 1963~. Durum et al. (1971) examined more than 720 river-water samples during low flows in October 1970 in the 50 states and Puerto Rico; 37% contained traces of cobalt, in the range of 1.(~5.0 ,ug/liter; 54% contained cobalt below the detection limit, i.e., less than 1.0 ~g/liter; 21 samples (2.9~o) contained 6-9 ,ug/liter; 20 samples (2.8~o) contained 10-19 g/liter; 17 samples (2.45370) contained 20-39 ,ug/liter; and 6 samples (0.8~o) contained 40-99 ,ug/liter.

Inorganic Solutes 247 In an earlier report, using emission spectroscopy on 59 samples of water from 15 rivers in the United States and Canada, Durum and Hasty (1961) found a maximum cobalt concentration of 5.8 ,ug/liter in the Mississippi River at Baton Rouge, Louisiana. Kopp and Kroner (1967) noted the presence of cobalt in only 2.8% of their samples from the 15 major river basins of the conterm~nous United States, with concentra- tions ranging from 1.0 to 48,ug/liter and a mean of 17,ug/liter. In Russia, Barabannik et al. (1961) measured cobalt in two artesian supplies used for drinking water at Kiev. These wells vary from 89. 261.5 m in depth. In the shallower wells, cobalt concentrations varied from 0.61 to 2.41 ~g/liter, with an average of 1.32 ~g/liter; in the deeper, the range was 0.43-1.4,ug/liter, with an average of 0.94,ug/liter. Green leafy vegetables are the richest and most variable sources of cobalt in human diets; dairy products and refined cereals are among the poorest. Typical concentrations in food are 0.4{).6 mg/kg (dry weight) in spinach, 0.2 in cabbage and lettuce, 0.01 in cornseed, and 0.003 in white flour. These figures indicate that the diet contributes far greater amounts of cobalt than are ever likely to be obtained from water. CHEMICAL CHARACTERISTICS Cobalt and nickel are very similar in chemical behavior. Both are present in igneous rocks in small amounts and are more prevalent in the basic and ultrabasic types than in silicic rocks. In the process of weathering, cobalt may be taken into soluton more readily than nickel, but it is adsorbed to a great extent by the hydrolysate or oxidate sediments. Cobalt may be taken into solution in small amounts through bacteriologi- cal activity similar to that causing solution of manganese. METABOLISM Cobalt is part of the vitamin BE molecule and as such is an essential nutrient. Ruminants can synthesize their own vitamin BE if they are given cobalt orally. A wide margin of safety (well over 100) exists between the required and toxic doses for sheep and cattle (NAS, 1973~. Nonruminants, such as humans, require preformed vitamin Bit, in which the one cobalt atom per molecule accounts for only 4.34% of the total molecular weight of the vitamin. The requirement of humans for cobalt in the form of vitamin BE is about 0.13 ~g/day (USFDA, 1975~.

248 DRINKING WATER AND H"LTH HEALTH EFFECTS According to Underwood (1973), cobalt has a low order of toxicity in ad species studied. Daily doses of 3 mg/kg of body weight (about 1,000 times normal) can be tolerated by sheep for many weeks without harmful effects. Using the data on 10 of the 15 river basins studied by Kopp and Kroner (1967), Berg and Burbank (1972) examined correlations between potentially carcinogenic trace metals in water supplies and cancer mortality among humans. Cobalt showed no correlation with any of the 34 different types of cancer studied. Cobalt has been severely indicted as a toxicant when added to beer to promote the formation of foam (USFDA, 1975~. Clusters of congestive heart failure deaths were observed in Quebec, Canada; Omaha, Nebras- ka; and Leuven, Belgium among heavy beer drinkers about 1965. Cobalt salts had been added to the beer at cobalt concentrations of 1.2-1.5 mg/liter (Underwood, 1973~. At such concentrations, the consumption of 24 pints a day would supply only about 15 mg of cobalt sulfate well below the amount that can be taken with impunity by normal people. In fact, cobalt salts have been used therapeutically at up to 300 mg/day without cardiotoxic effects. The episodes were clearly attributed to the cobalt: the toxicity was no longer observed when the cobalt was removed. Research has since shown that the addition of cobalt to ethanol results in toxicity which is greater than the additive effects of feeding the materials separately (USFDA, 1975b). In an attempt to provide additional evidence to validate the USSR requirement for cobalt in water, Krasovskii and Fri~yand (1971) performed experiments on 380 white mice, albino rats, and guinea pigs, with various oral doses of cobaltous chloride, nitrate, sulfate, and acetate. The LD50 of cobaltous chloride was 80 mg/kg of body weight for albino rats and 55 mg/kg for guinea pigs. Aqueous solutions of cobalt at 2.5, 0.5, and 0.05 mg/kg of body weight were administered orally for 6 days/week for 7 months. Cobalt poisoning at 2.5 mg/kg was manifested in disturbed conditioned reflexes and alterations in hematopoiesis. The effects on other metabolic processes and overall resistance were less pronounced. The animals treated with 0.5 mg/kg exhibited only mild and transient polycythemia and a decrease in phagocytic activity of leukocytes. At 0.05 mg/kg, there were no effects on the characteristics investigated. According to the FDA report (USFDA, 1975), acute cobalt toxicity in some animals has been demonstrated only at very high doses e.g., in chickens at 50 mg/kg of diet per day and in sheep at 6 mg/kg of body weight per day. At doses under 5 mg/kg of diet (or under 2 mg/kg of

Inorganic Solutes 249 body weight) no adverse effects were noted. At higher dosages, a loss of appetite, loss of weight, and debilitation were observed. However, intravenous injection of cobalt (at less than 1.0 mg/kg of body weight) causes death. The mechanisms of cobalt's toxic action are not well understood. Long-term toxicity in humans was observed primarily in children when cobalt was given to correct anemia (USFDA, 1975~. Between 1955 and 1961, more than four incidents involving more than 10 children were reported. Children between the ages of 3 months and 12 years became ill as a result of cobalt administration with iron in a commercial prepara- tion. The most common observations were the development of goiter and decreased thyroid function. Increased cardiac rate, increased respiration rate, skin changes, and blood lipid changes were also noted. All symptoms were reversed when cobalt therapy was discontinued. The dosages at which.these conditions were observed were between 1 and 6 mg/kg of body weight per day. ANALYSIS With detection limits at 10 ,ug/liter, cobalt in fresh water is not normally detectable by direct flame atomization; a concentration step is usually required for cobalt determination in water. The U.S. Geological Survey (Brown et al., 1970) uses the APDC solvent extraction procedure, in which the cobalt-APDC complex is extracted at a pH of 2.8 with methylisobutylketone. Similar procedures with APDC have been report- ed (Brooks et al., 1967; Traversy, 1971; Kinrade and Van Loon, 1974; Aldous et al., 1975~. Extractions with diethyldithiocarbamate (Nix and Goodwin, 1970) and dithizone (Sachdev and West, 1969) have also been described. Paus (1971) has used the graphite furnace to enhance atomization of the cobalt in fresh water; the detection limit is 0.4,ug/liter. CONCLUSIONS AND RECOMMENDATIONS Cobalt in natural and treated water has been observed only in trace concentrations one-hundredth or less of the amounts occurring natural- ly in foods. It is an essential element for ruminants, in that it allows them to take vitamin B12 internally. Apart from its content in vitamin B12, it provides no known nutritional benefit to humans. In doses in excess of 1 mg/kg of body weight it may pose a health hazard to humans, especially children and older people suffering from other ailments. Cobalt acts with alcohol to produce severe cardiac effects at concentrations as low as

250 DRINKING WATER AND H"LTH about 1.2-1.5 mg/liter of beer. The USSR has set a limit of 1.0 mg/liter of water(Stoefen, 1973~. The Interim Primary Drinking Water Regulations do not limit cobalt, nor has the WHO recommended a limit on its International or European Standards. Because the maximum no-adverse-health-e~ect concentration is more than an order of magnitude greater than that found in any natural-water or drinking-water supply, there appears to be no reason at present to regulate the concentration of cobalt in drinking water. Copper OCCURRENCE Copper is frequently found in suface water and some groundwater. Copper was detected in 74.4% of over 1,500 river- and lake-water samples in the United States at concentrations up to 280 ~g/liter (Kopp and Kroner, 1970~. A recent survey detected a maximum of 40,ug/liter in the North Platte River (USGS, 1974~. Analysis of 13 Canadian surface and groundwaters, including wells, showed copper at 20-860 ~g/liter, the maximum in Lake Ontario (Procter & Gamble, 1974~. Copper in excess of 100 ~g/liter was reported in eight of 27 Illinois streams, with a maximum of 260 ~g/liter (Ackerman, 1971~. Where higher concentrations of copper are found in raw water, pollution from industrial sources can be suspected. The effect of treatment and the pipe material in the distribution system can sometimes produce higher concentrations of copper in finished and tap water than found in the raw-water source. For example, copper tends to increase with the chlorination of water (Shapiro et al., 1962~. In Sweden, on the other hand, some water systems actually show a decrease in copper at the tap, compared with raw water (Bostrom and Wester, 1967~. This may be a reflection of corrosion control or of the degree to which corner has replaced galvanized iron nine in household Plumbing in 1 1 1 ~ r r ~ r - - 0 . ~ ~ T · . ~ ~ . . · ~ ~ ~ ~ ~ ~ . ~ ~ ~ ~ , · . · · . ~ the United Imitates since 195(). the survey of the 1W largest cities In the United States showed finished-water copper at less than 0.61-250 g/liter, with a median of 83 ~g/liter. In Denver (Harnett et al., 1969), the metropolitan water system five water plants with varying raw-water sources and treatment processes-showed a relationship between raw- versus finished-water copper concentration, in micrograms per liter, as follows: 25 and 7.6, 67 and 10.6, 4.8 and 4.2, 4.4 and 8.0, and 3.0 and 3.0. The process that almost doubled its copper content consisted of

Inorganic Solutes 251 chlorination only. The copper concentration at the consumer tap averaged ~12 ~g/liter. In Washington County, Maryland, 669 copper determinations at the tap were made for both public and private water systems. Efforts were made to sample running water, rather than standing water in contact with plumbing systems overnight, because the latter has been shown to have greatly increased trace-metal concentrations in systems without corrosion control. The correlation coefficients of copper concentration with pH, with hardness, and with conductivity were 0.369, 0.162, and 0.173, respectively; all were significant to p = 0.01 (Oliver, 1974~. The principal anodic and cathodic reactions involving copper in fresh water are known (Camp, 1974~. The cold-water corrosion rate of copper tubing as a function of pH is also known; corrosion decreases with increasing pH. Copper in brass, pipe, and domestic utensils could provide a source of copper in water. Soft, low-pH water could raise the intake of copper by as much as 1,400 ,ug/day, whereas hard water would reduce the intake (Schroeder et al., 1966~. The copper content of soils varies considerably with the parent rock, weathering, drainage, pH, and organic content. Copper uptake by plants depends on species and is generally quite low in highly organic alkaline soils. The copper concentration in commonly consumed vegetables and leafy plants seldom exceeds 25 ppm and usually is 1~15 ppm. Grains and seeds are good sources of copper, containing about 20~0 ppm. Oysters, clams, crustacea, and the liver and kidneys of animals may contain 20()400 ppm. The human intake of copper in food is estimated to be 2-5 mg/day. CHEMICAL CHARACTERISTICS Copper salts, such as the sulfates and chlorides, are highly soluble in water with a low pH, but hydrolyze and possibly precipitate copper in water of normal alkalinity. In the normal pH range of natural water containing carbon dioxide, copper might be precipitated as carbonate. This copper salt is soluble at 1.5 ppm in the absence of carbon dioxide. Copper hydroxide, Cu(OH)2, is soluble to the extent of copper at about 1.9 ppm at 25°C. Copper is more soluble than ferric iron and more copper should remain in solution than ferric iron during the weathering and disintegration of rocks under oxidizing conditions. Copper, however, is dissolved and transported less readily than ferrous iron (USGS, 1959~.

252 DRINKING WATER AND H"LTH METABOLISM Copper is recognized as an essential element for both plants and animals. It is a component of several enzymes that perform important physiologic functions. These involve the metabolism of iron and the rate of cell synthesis in the bone marrow. Copper deficiency has been observed in both man and other animals. It is characterized by anemia, loss of hair pigment, reduced growth, and loss of arterial elasticity. Copper deficiency is not a problem in the United States. The absorption of copper, like all essential elements, from the gastrointestinal tract is limited. Of a daily intake of 2.5 ma, 32% is absorbed. The net absorption is about 5% after fecal and urine excretion. Storage of copper is highest in the liver, kidneys, and intestines. HEALTH EFFECTS Copper is a gastrointestinal tract irritant and can be highly toxic. There have been reports (Chuttani et al., 1965) of suicide with gram quantities of CuSO4. Less severe acute episodes have been reported from the ingestion of carbonated beverages that had been in contact with copper tubing or vessels (Hopper, 1958; Semple et al., 1960; Wyllie, 1957; Nicholas, 1968~. The doses were 4~50 mg of copper. There is a report of an infant fatality associated with the drinking of water that contained copper at 6.75 mg/liter for 14 months. Whether the child was genetically intolerant to copper is not known (Walker-Smith and Blomfield, 1973~. Copper sulfate has been recommended as an emetic at doses (as CuSO4) of 500 mg for adults and 37-50 mg for children (Karlson and Noren et al., 1965~. If vomiting does not occur, these doses are considered to be toxic in children (Holtzman and Haslam, 1968; Decker et al., 1972~. The available evidence does not support chronic toxicity in normal human beings attributed to long-term intake of low (< 1 ma) concentra- tions of copper by mouth (USFDA, 1975~. Unlike most animals, sheep are especially sensitive to copper, and a chronic dietary intake of 20-80 ppm is known to be fatal (Todd, 1969; Adamson et al., 1969; Doherty et al., 1969~. The hazard to the general population from dietary copper up to 5 mg appears to be small. A few people are adversely affected by even normal amounts of copper in the diet. This disorder of copper metabolism, Wilson's disease, is inherited as an autosomal recessive trait and leads to hepatic cirrhosis and to necrosis and sclerosis of the corpus striatum

Inorganic Solutes 253 (Scheinbert and Sternlieb, 1965~. Wilson's disease, formerly fatal within a few years, now can be arrested with chelating agents. There is some concern that any substantial increase in dietary copper intake will result in the conversion of latent cases to overt disease. In addition, there may be a few people who share with sheep the deficiency of glucose-6- phosphate dehydrogenase that is believed to cause hypersensitivity to copper (Salvido et al., 1963~. The only teratogenic effects that may be attributed to copper in mammals are from a deficiency during pregnancy in sheep. It appears that a deficiency or excess of copper has significant consequences for developing embryos (Ferm, 1972~. The interim copper limit of 1 mg/liter of drinking water is based on consideration of taste, rather than toxicity. Depending on individual acuity, the threshold of taste varies from 1-5 mg/liter (Cohen et al., 1974~. The European standards for drinking-water are also set on the basis of taste and discoloration of fixtures: 0.05 mg/liter at the pumping station and 3 mg/liter after 16 h of contact with plumbing. The international standard sets 0.05 mg/liter as the acceptable limit, with a maximum of 1.5 mg/liter. The USSR also sets 0.05-mg/liter as the acceptable limit. This standard for copper in drinking water is only one-twentieth of the current interim standard. Only 81% of the systems surveyed in the 1975 Interstate Carrier Water Supply System Analysis could have met the 0.05 mg/liter international standard. ANALYSIS Copper content of fresh water can be determined by direct flame atomization, with a detection limit of 2 Mg/liter Copper is extracted with little difficulty by a wide variety of chelate-solvent systems. The U.S. Geological Survey (Brown et al., 1970) uses the APDC-methylisobutylke- tone extraction of copper from samples at a pH of ~.8. Several other concentration procedures for fresh water have been described (USEPA, 1971; Paus, 1971; Traversy, 1971; Ichinose, 1974; Aldous et a/., 1975~. Dethyldithiocarbamate can also be used as a chelating agent (Nix and Goodwin, 1970~. The graphite furnace has been used to increase sample atomization by Fernandez and Manning (1971), Paus (1971), Dolinsek and Stupar (1973), Barnard and Fishman (1973), and Surles et al. (1975) to implement the determination of copper in fresh water, with a detection limit of 0.05,ug/liter.

254 DRINKING WATER AND H"LTH CONCLUSIONS AND RECOMMENDATIONS At the copper levels found in several extensive water surveys, the potential for toxicity is virtually nonexistent for humans. The current recommended secondary interim standard of 1 mg/liter was only exceeded by 1.6% of 2,595 tap water samples taken in the Community Water Supply Study (USEPA, 19701. This value would appear adequate to protect the health of persons from toxicity due to copper in drinking water. Lead OCCURRENCE . The natural lead content of lake and river water worldwide has been estimated at 1-10 ,ug/liter (Livingstone, 1963~. Kubota et al. (1974) studied concentrations of zinc, cadmium, lead, copper, and cobalt in rural streams in upstate New York as a model of their distribution under natural geochemical conditions and soil weathering. For lead, average distributions were as follows: soluble lead, 0.12,ug/liter (range, 0.05-0.93 g/liter); lead in suspended particulate matter, 484 ppm; lead in soil, 7.0 ppm. These and other data suggest that much of the lead in natural water ends up in sedimentary deposits. There is, however, a distinct regional pattern of lead distribution in the United States. A survey of the mineral content of finished water in the 100 largest cities in the United States was made by Shapiro (1962~. For lead, the following values were found: maximum, 62 ~g/liter; median, 3.7 ~g/liter; minimum, not detectable. In another study of raw and finished water in the United States, covering the period 1962~1967, Kopp and Kroner (1967) reported the following data: frequency of detection, 18.1%; minimum, 1 ~g/liter (minimum detectable amount); maximum, 139 g/liter; mean, 33.9 ~g/liter. The corresponding values for raw water were as follows: frequency of detection, 19.32%; minimum, 2 ~g/liter; maximum, 140 ~g/liter; mean, 23 ,ug/liter. The increment in the mean value for finished water suggests that lead is picked up from the plumbing system. Water samples collected at the tap serviced by 969 water systems throughout the United States indicated an average lead concentration of 13.1 ,ug/liter (McCabe, 1970~. Of the 2,595 samples, 1.4% contained more than the 1962 drinking-water standard of 50 ~g/liter, with a maximum of 64 ~g/liter. Important local variations occur, apparently in relation to the use of

Inorganic Solutes 255 soft "aggressive" water of slightly acidic pH and the use of lead pipe in service and domestic water lines. Craun and McCabe (1975) have used data from Seattle and Boston to illustrate the eject of"corrosive" water of slightly acidic pH. Both cities use impounded surface-water. Chlorina- tion is the only treatment. Comparison between finished-water and tap- water samples showed that in Seattle 95% of the tap-water samples had higher concentrations, with 76~o exceeding the limit of 50 ,ug/liter. In Boston, analyses similarly indicated that lead was being "picked up" in the distribution system; 65~o of the tap-water samples exceeded the 5 g/liter limit for lead. Karalekas et al. ( 1975) have made further studies in the metropolitan Boston area by collecting multiple water samples from 383 households in Boston, Cambridge, and Somerville, Massachusetts. These cities were selected for study mainly because of the wide use of lead pipe in service lines. Lead concentrations at the tap ranged from < 13 to 1,510 ~g/liter, with an overall mean of 30 ~g/liter. Of the samples collected, 15.4% exceeded the EPA interim drinking-water standard of 50 g/liter. In all cases, the lead content of drinking water was higher at the tap than at the treatment plant. Highest concentrations were found in early-morning samples, with the lowest mean concentrations in running water and intermediate values in standing water and in composite samples obtained throughout the day. The mean concentration for composite samples was 93 ~g/liter; for this type of sample, 26.7% exceeded the standard of 50 ~g/liter. The percentage of households exceeding the standard was greater in the Boston (25.5~o) and Somerville (30%) areas than in Cambridge (14.5~o). This was attributed to some differences in the overall composition of the different water-supply systems. Available data generally indicate that the addition of lead to drinking water occurs chiefly in the distribution system, including household plumbing, and that this is most likely to occur in areas with soft "aggressive" water. Craun and McCabe (1975) have reported that the average intake of lead from drinking-water by adults may be estimated at 26 ,ug/day, using the following assumptions: the average lead concentration in tap water is 13 ~g/liter and the daily water consumption by adults is 2 liters. In children, water intake is related to caloric requirements, water absorbed from food, and the need to maintain a dilute urine. On the basis of body weight, water requirements are 2-3 times higher in children than in adults. If one assumes a heavy use of dehydrated powdered food and beverages for infant feeding, with reconstitution entirely with tap water, then lead intake from tap water in a 6-month-old infant may be as high as half the adult intake as estimated above, or 13 ,ug/day. Generally, for ~ 7 , .

256 DRINKING WATER AND H"LTH children under 3 yr of age who receive either a mixed diet or concentrated liquid formula, the amount of tap water used may be estimated at up to 500 ml/day, which would provide a lead intake of up to 6 ~g/day, if one uses the average figure of 13 ,Ag/liter of drinking water at the tap. For young children, this is small, in comparison with food lead. For the general adult population, the lead content of foods is the major source of exposure. Kehoe (1961) estimated from fecal lead data in studies carried out primarily in men that daily dietary lead intake is approximately 300 ~g/day. More recently, Tepper and Levin (1975) concluded that in women, 100 ,ug/day is a closer approximation of current dietary intake. For the adult, balance studies have indicated that absorption of dietary lead is approximately 5-10%. Koybye et al. (1974) used "market basket" data and other information available to the FDA and estimated for 2-yr-old children that dietary intake is approximately 100 ,ug/day. Limited balance data (Alexander et al., 1973) indicated an average intake of 9-10 ,ug/kg or 10~150 ,ug/day for 2-3-yr-old children. More important, these balance data in children are consistent with those in young growing animals and indicate that approximately 4~50~o of dietary lead is absorbed and that 2~25% is retained. Although the distribution of retained lead between bone and soft tissue cannot be determined from these balance studies, autopsy data (Barry, 1975) show a steady increase in bone lead throughout the first 15- 20 yr of life. For children, ingestion of soil and exposure to household dust in old houses are important additional sources of lead intake (Ter Haar and Aronow, 1975; Sayre et al., 1974~. Residents near stationary point sources also constitute special lead- exposure groups (Landrigan et al., 1975~. In summary, it appears that, at an average drinking-water-lead concentration of 13 ,ug/liter, lead intake from drinking water constitutes about one-tenth or less of that obtained from an ordinary diet. CHEMICAL CHARACTERISTICS Lead occurs in rocks primarily as the sulfide (galena) and in the form of oxides. It may replace some ions, such as calcium. Lead also occurs in potassium feldspar, where it replaces potassium. Lead carbonate is common in the oxidized zone of lead ores. Lead sulfate is reported to be soluble in water to the extent of 31 ppm at 25°C. In natural water, this concentration is not approached, however, because a pH of less than 4.5 would probably be required to prevent the formation of lead hydroxide and carbonate. In natural water containing bicarbonate and carbonate alkalinity, the concentration of lead is usually

Inorganic Solutes 257 limited by the solubility of lead carbonate. It has been reported that at 13°C water free of carbon dioxide will dissolve the equivalent of lead at 1.4 ppm; the solubility is increased nearly fourfold by the presence of carbon dioxide at 2.8 ppm. The presence of other ions may increase the solubility of lead. It is likely that lead is adsorbed by minerals in sediments and soils, so that the observed concentrations rarely reach the theoretical limit (USGS, 1959~. Lead may be dissolved from water pipes most readily by water that is low in hardness, bicarbonate, and pH and high in dissolved oxygen and nitrate. The chemical forms and physical states in which lead and other trace metals occur in raw water are not well known. Recent reports (Guy and Chakrabarti, 1975a; Ramamoorthy and Kushner, 1975) suggested that the problem is complex and may well vary from one body of water to another. It has been demonstrated that some aquatic organisms can convert inorganic mercury and arsenic to aLkyl compounds. Recent preliminary data (Won" et al., 1975) suggested that under rather unnatural experimental conditions it is possible to alkylate lead. Wood (1976) has summarized basic conditions for the alky~lation and reductive dealkylation of heavy metals in aquatic systems. He noted that the vitamin BE found in microorganisms holds a unique position in aqueous systems for the alkylation of heavy metals. Conversely, cytochromes may be important in the reduction of metal ions to elemental form. These considerations are not cause for alarm, but they do indicate the need for research in this field. Progress may well depend on improved analytic techniques, if the total metal content is to be fractionated into its various constituents. METABOLISM The absorption of dietary lead is 5-10~o in the adult (Kehoe, 1961) and 4~50YO in children 2-3-years old (Alexander et al., 1973~. No data are available for very young infants, but animal data indicate that the percentage absorbed is age-related and may be higher in early infancy (NAS, 1976~. Absorbed lead is excreted through both the kidneys and the intestinal tract. Long-term balance studies by Kehoe (1961) in adults suggested that adults are in balance. However, these data derived front a few people must be weighed against autopsy data, which indicate that, although soft-tissue lead concentrations remain stable in adults, bone lead content may increase with age, at least to the age of 40 or 50 yr (Barry, 1975; Gross et al., 1975~. Bone is the storage site for at least 90~o

258 DRINKING WATER AND H"LTH of the total lead body burden in adults and approximately 70% in growing children. HEALTH EFFECTS No beneficial elects of lead have yet been found. Acute lead poisoning is extremely rare, if it occurs at all in the general population. One child was estimated to have consumed approximately 1 g of lead per day in fruit juice during the 5 weeks immediately before his death (Klein et al., 19704. In one adult, estimated to have consumed approximately 2 mg of lead per day, at least a year and a half elapsed before the onset of acute symptoms of plumbism (Harris and Elsea, 19671. Lead apparently does not cause gastrointestinal symptoms within a few hours, as is the case of acute poisoning due to ingestion of cadmium, iron, or other heavy metals and metalloids (such as arsenic). The induction of renal tumors with lead has been demonstrated in rats but not in other species. Similarly, mutagenic and teratogenic effects have been reported in experimental systems (NAS, 1972~. However, none of these elects have been documented in man. The main chronic adverse effects of lead are those produced in the hematopoietic system, central and peripheral nervous system, and kidneys. Although disturbance in heme synthesis is considered to be the critical or first adverse effect of lead (Nordberg, 1976), measures of comparable sensitivity for the detection of disturbances in nervous system metabolism are not available. Zielhuis (1975a,b) has summarized available data on dose-response relationships for lead in man. Currently, the most sensitive effect is that on heme synthesis. There is a detectable and statistically significant increase in red-cell protoporphyrin in women and children, as blood-lead concentration increases above about 25-30 ~g/dl (Roels, 1975; Zielhuis, 1975a,b). In men, increase in red-cell protoporphyrin apparently does not occur until blood-lead concentration exceeds about 35~0 ~g/dl of whole blood. Zielhuis (1975a,b) and Albert et al. (1974) reviewed clinical data and suggested that the no-e~ect concentration of lead in the developing human nervous system is approximately 55~0 ~g/dl of whole blood as judged by clinical outcome. However, animal data have suggested that this value may be lower (Brown, 1975; Carson et al., 1974~. In addition, Lancranjan et al. (1975) reported evidence of disturbance in reproductive function in occupationally exposed men with blood-lead concentrations in excess of about 50 60 ~g/dl of whole blood. These disturbances included alterations in spermatogenesis (asthenospermia, hypospermia. teratospermia) through a direct toxic effect of lead on the gonads. Comparable data for women are not available.

Inorganic Solutes 259 Preliminary clinical data from soft-water areas in Boston and in Scotland are now available and suggest a relationship between lead in tap water and blood-lead concentration. The consumption of soft water from the acidic moorlands of Scotland and northern England has been associated with clinical cases of lead poisoning (Bacon et al., 1967; Beattie et al., 19721. In these cases, it appears that soft well water or rainwater was not only conveyed in lead pipes, but also stored in lead- lined cisterns. In these clinical cases, the lead concentration in tap water ranged between 570 and 3,136 ~g/liter. Such water had apparently been consumed over a number of years; those involved were adults. This led Moore et al. (1975) to make a more intensive study in Glasgow, Scotland. In a study of 23 Glasgow households, significant associations were found between water-lead content, length of lead piping, and use of a lead-lined storage tank. Studies in Edinburgh, although showing a relationship between blood lead and tap-water lead, did not fully confirm the data from Glasgow. In Edinburgh, households with copper plumbing were compared with households with lead plumbing. The early-morning sample of water was drawn to clear the lines and then discarded, and a sample drawn later in the day was used. Water-lead concentration in homes with copper plumbing was less than that in homes with lead plumbing, and blood-lead content could be correlated with water-lead content. In the Boston area, Craun and McCabe (1975) reported preliminary data indicating that, when household water-lead content in the sample obtained during the day exceeded 100 ,ug/liter and the data were controlled for proximity to traffic density, a significantly increased frequency of blood-lead concentrations in excess of 35 ~g/dl was found. These human studies although they involved a small number of subjects and were not controlled for sex, age, and smoking habits suggested that drinking-water with a lead content greater than lOO,ug/liter may be sufficient to raise and sustain blood-lead concentrations at above 25 ,ug/dl whole blood. This is the blood level that has been shown to be the apparent threshold for the increased red-cell protoporphyrin. In a provocative retrospective study, Beattie et al. (1975) investigated 77 2-5-yr-old mentally retarded children and 77 nonretarded healthy control children, matched for age, sex, and geographic location in the city of Glasgow, Scotland. They did not have blood-lead data obtained at an earlier, more vulnerable period of development. They concluded that a child exposed during gestation and early infancy to a water-lead content greater than 800 Igniter "is at least 1.7 times (and probably a much greater factor) more likely to be mentally defective than a child whose exposure to water-lead is completely unknown."

260 DRINKING WATER AND H"LTH Experimental data strongly indicate that among human populations the fetus and young child, particularly under 3 yr old, are at increased risk of adverse ejects due to lead. This is based on both a higher rate of intestinal absorption and a high rate of brain growth and maturation. Animal data further suggest that absorption and other dietary compo- nents play a very prominent role in this susceptibility (NAS, 1976~. In addition, people with chronic renal insufficiency and metabolic distur- bance in bone homeostasis and possibly those with zinc deficiency may be at increased risk. There are, however, no data on humans to substantiate these latter hypotheses. ANALYSIS The analysis of lead in biologic samples is fraught with difficulties. The great variations in comparisons between and within laboratories are well known (Lauwerys et al., 1975~. The detection limit with direct flame atomization is 10 ~g/liter. As for most trace metals in water, solvent extraction is the method of choice for concentration. The U.S. Geological Survey (Brown et al., 1970) uses APDC-methylisobutylketone extraction at a pH of 2.8, and this proce- dure has been used by other investigators (Brooks et al., 1967; USEPA, 1971; Paus, 1971; Traversy, 1971; APHA, 1971; Everson and Parker, 1974; Kinrade and Van Loon, 1974~. Diethyldithiocarbamate has also been used to extract lead (Nix and Goodwin, 1970~. Specialized aspiration procedures may be used to improve lead detection limits. The sampling boat and Delves cup have a limit of 1 ,ug/liter (they use 1- and 0.1-ml samples, respectively) and have been applied to water analyses by Kerber and Fernandez(1971), Paus (1971), and Mains et al. (19751. The graphite furnace will increase sample atomizaton and can be used to increase detection to as little as 0.05 ,ug/liter and has been used for fresh water analyses by Paus (1971), Fernandez and Manning (1971), Dolinsek and Stupar (1973), Barnard and Fishman (1973), Rattonetti (1974), and Surles et al. (1975~. CONCLUSIONS AND RECOMMENDATIONS If one uses the critical toxic eject approach to preventive medicine, then a water-lead content of 100 ~g/liter at the household tap is probably not acceptable. "The critical toxic effect is defined as the most sensitive and specific biological change which is outside of acceptable physiological variation" (Nordberg, 1976~. Preliminary data suggest that the present

Inorganic Solutes 261 limit of 50 ,ug/liter may not, in view of other sources of environmental exposure, provide a sufficient margin of safety, particularly for fetuses and young growing children. Although further studies will be necessary to arrive at a reasonable limit, it is suggested that the limit be lowered. This recommendation is made with the assumption that analytical methodology will be sufficient to detect this value above background. 1. A further elucidation of the neurochemical disturbance caused by lead is a basic research need, which should be worked out in appropriate animal models and followed with confirmatory clinical and epidemiolog- ic studies, where possible. Much experimental evidence points to significant interactions between lead, copper, zinc, iron, calcium, and magnesium. These interactions are high-priority items, although their significance may pertain more to nutrition and genetic susceptibility than to drinking water itself. 2. Definitive studies in soft-water areas in relation to the influence of lead contents in the distribution system and measures for its control deserve the highest priority, insofar as drinking-water quality is con- cerned. 3. The question of whether or not lead can be alkylated by aquatic organisms in relation to drinking-water deserves high priority. 4. There are no data on illness of human infants between birth and 1 yr of age as related to lead. Dose-response data for this group, as well as for pregnant women, are urgently needed, to provide a base for estimating overall safe levels of lead exposure for these highly susceptible population groups. Dose-response data are also needed throughout the preschool years; there are very few data that satisfy both epidemiologic and toxicologic criteria for dose-response data in this group. 5. The needed data depend heavily on the availability of precise and accurate analytical measurements. Substantial improvements in methods are needed. Electrochemical approaches appear to be the most promising in this regard, including anodic stripping voltammetry and differential pulse polarography. Magnesium OCCURRENCE In view of the geologic abundance, high solubility, and numerous industrial uses of magnesium, it is not surprising that seawater contains about 1,350 mg/liter. The average for natural fresh water is about 4 mg/liter. In a survey of finished water in public supplies of the 100 largest

262 DRINKING WATER AND H"LTH cities in the United States, Durfor and Becker (1964) reported a median concentration of 6.25 mg/liter, a maximum of 120 mg/liter, and a minimum of nil. The USPHS drinking-water standards of 1925 included a maximum recommended magnesium concentration of 100 mg/liter. This limit was raised to 125 mg/liter in the 1942 and 1946 standards, but it was deleted in the 1962 standards. According to Stoefen (1973), the USSR has not set a limit on magnesium; however, the World Health Organization (WHO) has established European and International desirable limits ranging from 30 to 125 mg/liter, depending on the sulfate concentration. If the sulfate exceeds 250 mg/liter, the magnesium is limited to 30 mg/liter. The WHO specifies an absolute maximum of 150 mg/liter for magnesium in drinking water. Several categories of foods are rich in magnesium e.g., nuts, about 1,900 mg/kg; cereals, about 800 mg/kg; seafoods, about 350 mg/kg; meat, about 260 mg/kg; legumes, about 240 mg/kg; vegetables, about 170 mg/kg; and daily products, about 150 mg/kg. Fruits, refined sugars. and fats are low in magnesium (Schroeder et al., 19699. CHEMICAL CHARACTERISTICS _ a ~7 Magnesium is one of the most common elements in ores, minerals, rocks, and soil. It constitutes about 2.1% of the earth's crust and ranks eighth among the elements in order of abundance. Because it is very active chemically, it is not found in the elemental state in nature. Most of its salts are very soluble; even the carbonate will dissolve to tire extent of 100 300 mg/liter at 20°C. On the basis of the solubility product of magnesium hydroxide at 18°C, magnesium ions theoretically can be present in the following amounts: 28,000 g/liter at pH 7, 28.8 mg/liter at a pH of 10, and 0.288 mg/liter at a pH of 11. This solubility phenomenon is useful in treatment processes to remove magnesium from water; but, insofar as natural waters are concerned, it is described here merely to show that at common pH values magnesium ions may be present at concentrations of many grams per liter in dissolved form (McKee and Wolf, 1967~. METABOLISM Magnesium is an essential element in human and animal nutrition and also in plants, where it is a component of all types of chlorophyll. It is the most abundant intracellular divalent cation in both plants and animals. It is an activator of many mammalian enzymes. Magnesium deficiency in

Inorganic Solutes 263 humans and animals depends on many factors. It occurs in alcoholics, persons performing hard labor in hot climates, those with some endocrine disturbances, and patients using potent diuretics. Excessive magnesium in the body (hypermagnesemia) occurs in humans primarily as a result of severe kidney disease. The average adult American ingests between 240-480 mg/day of magnesium in food and water. Magnesium intakes of 3.6 4.2 mg/kg/day are thought to be adequate to maintain magnesium balance in normal adults (Jones et al., 1967~. The recommended dietary allowances for magnesium are 300 mg/day for women, 350 mg/day for men, and 150 mg/day for children (Coussons, 1969~. The nutritional value of magne- sium supplements beyond these levels has not been established. According to Szostak (1961), magnesium is one of the most important electrolytes in the body. In adults, the body content averages about 25 g (or about 350 mg/kg of body weight) and can vary from 21-28 g. The tissues contain 98% of the body content of magnesium, with the other 257O found in extracellular fluids. The concentration of magnesium in plasma averages 21.6-25.2 mg/liter, with a normal range of 16.8-30 mg/liter. The greatest amount of magnesium is found in the skeleton, which contains more than half the magnesium stored in the body. For normal people on regular diets, the average daily absorption of available magnesium from the gastrointestinal tract is about 3()~0%. Aikawa et al. (1958) administered magnesium-28 orally to 26 human subjects. They found that fecal excretion within 120 h accounted for 59- 88% of the administered dose. Less than 10% of the radioactivity was recovered in the urine within 72 h. The low renal excretion was thought to be due to poor gastrointestinal absorption. Normally, the kidney is the major excretory pathway for magnesium, once it is absorbed. Hence, the kidney is the organ primarily responsible for regulating the total human body content of magnesium. According to Consolazio et al. (1963), when men were exposed to desert temperatures for several days, 1~15% of the total output of magnesium occurred in perspiration. Under extreme conditions, sweat can account for 25% of the daily magnesium excretion; this could lead to hypomagnesemia. HEALTH EFFECTS Magnesium salts at levels over 700 mg/liter (especially magnesium sulfate) have a laxative effect, particularly on new users, although the human body can adapt to the elects of magnesium with time (McKee and Wolf, 1963~. The most sensitive people are affected by MgSO~ at

264 DRINKING WATER AND H"LTH about 400 mg/liter, and the average person, at about 1,000 mg/liter (Kehoe, 1953~. Magnesium salts (principally magnesium hydroxide) are used extensively as antacids and laxatives. The usual therapeutic doses are 5-15 ml of a 7-8.5% solution of magnesium hydroxide and at least 250 mg of magnesium oxide (Goodman and Gilman, 1975~. Magnesium in water is not considered a public-health hazard, because the taste becomes quite unpleasant before toxic concentrations are reached (Negus, 1938~. The taste threshold for magnesium has been reported by Lockhard et al. (1955) as 100 mg/liter in sensitive persons and about 500 mg/liter for the average person (Kehoe, 1953~. A thorough discussion of the role of magnesium in the human body is presented by Szostak (1961) but such detail is beyond the scope of this report. It is sufficient to note here that magnesium is an essential element in human nutrition, that most diets contain adequate amounts of magnesium, that hypomagnesemia occurs frequently in ruminant animals and occasionally in humans under stress, and that hypermagnesemia occurs in humans only as a result of kidney malfunction. ANALYSIS According to Standard Methods (APHA, 1971), three methods are used for the determination of magnesium in water. A gravimetric method can be used, but only after the removal of calcium salts. Magnesism in water can also be determined by atomic-absorption spectrophotometry, with a sensitivity of 15 ~g/liter, and by photometry with a sensitivity of 100 ~g/liter. CONCLUSIONS AND RECOMMENDATIONS Magnesium is an essential element in human, animal, and plant nutrition. Excess magnesium in the diet is seldom harmful, for it is generally excreted in the feces. High concentrations of magnesium sulfate in drinking-water may have a cathartic effect on new users, but persons usually adapt to these levels with time. Excessive magnesium in body tissues and extracellular fluids occurs only as a result of severe kidney malfunction. Magnesium deficiency in humans may occur in alcoholics, persons performing hard labor in hot climates (because magnesium is excreted in sweat), those with some endrocrine disturbances, and patients using potent diuretics. Such deficiencies can best be overcome by oral administration of magnesium compounds. The National Interim Primary Drinking Water Regulations contain no limit for magnesium, nor did the 1962 USPHS Drinking-Water Stan

Inorganic Solutes 265 cards. The USSR has set no limit, but the WHO has recommended a maximum of 150 mg/liter. In view of the fact that concentrations of magnesium in drinking water less than that that impart astringent taste pose no health problem and are more likely to be beneficial, no limitation for reasons of health is needed. Manganese The NAS-NRC (1973) has reviewed the medical and biological ejects of manganese; that work has been reviewed and evaluated for this report, and some sections are quoted here. The EPA has also discussed (1975) manganese, and portions of its review are cited. OCCURRENCE Durum and Haffty (1961) observed a maximum manganese concentra- tion of 181-185 ,ug/liter in two different surface waters. The median for all samples was 20,ug/liter. Kopp and Kroner (1967) detected manganese in 51.4% of surface-water samples; the concentration ranged from 0.3- 3230 ,ug/liter, with a mean of 59 ,ug/liter. A maximum of 1,200 ,ug/liter was detected in two different surface waters in 1974 (USGS, 1974~. CHEMICAL CHARACTERISTICS In chemical behavior and occurrence in natural water, manganese resembles iron. However, manganese is much less abundant in rocks. As a result, the concentration of manganese in water generally is less than that of iron. Manganese occurs in more than one oxidation state. The oxidation states of manganese to be expected in water are Mn+2 and Mn+4. Manganese can also occur in more highly oxidized states (such as permanganate, MnO4-), but is not normally encountered in those forms in natural water. Under reducing conditions, manganese goes into solution in water containing carbon dioxide as manganous ion. Manganous ion is more stable in water in the presence of oxygen than is ferrous ion under similar conditions.-~e presence of organic matter in water stabilizes manganous solutions, perhaps owing to formation of complex ions by organic compounds. "Total" and "dissolved" manganese are reported separately in most water analyses. The difference between the two is likely to be less significant for manganese than for iron, but the same problem exists in determining actual conditions in the aquifer on the basis of"dissolved"

266 DRINKING WATER AND H"LTH manganese values. The "total" manganese values are better for determin- ing these conditions, even though the manganese may be partly in the form of colloidal oxide and hydroxide by the time it is determined. Manganese concentrations greater than 1 mg/liter may result where manganese-bearing minerals are attacked by water under reducing conditions or where some types of bacteria are active. METABOL ISM The divalent manganese ion activates many enzyme reactions involved in carbohydrate breakdown and in the metabolism of organic acids, nitrogen, and phosphorus. Manganese metabolism is regulated by the adrenal glands. Ingested manganese is absorbed through the intestine and is concentrated in the liver. Although manganese may be distributed to the tissues, most of the excess is discharged via the bile or by other gastrointestinal routes, thereby keeping the manganese concentration in various tissues relatively stable (USEPA, 1975~. A small percentage of the manganese excreted into the intestines is reabsorbed and transported in the plasma in its trivalent form. Fast and slow components of the manganese disappear- ance curves have been identified that have respective half times of 4 days and 39 days in humans (USEPA, 1975~. Inorganic manganese excretion is almost exclusively fecal. However, the organic form is excreted in both feces and urine (USEPA, 1975~. Manganese is found in minute concentrations in the cells of all living things and has been established as essential to a wide variety of organisms, including bacteria, plants, and mammals. Manganese is widely distributed throughout the body; concentrations are characteristic for the various organs and vary little within or among species. Higher concentrations of manganese are generally associated with pigmented portions of the body including retina, pigmented conjunctive, dark hair, and dark skin. The pituitary gland, pancreas, liver, kidney, and bones normally have higher concentrations of manganese, and skeletal muscle has a very low concentra- tion . . . . The storage capacity of the liver for manganese is limited and offers a contrast in this regard with iron and copper .... Human livers from healthy people of all ages contain manganese at about 6 8 ppm (dry-weight basis). In contrast with many other trace metals, manganese does not accumulate significantly in the lungs with age, averaging about 0.22 ppm in aged man (WAS, 1973, pp. 8~811. In foods consumed by humans, the highest concentrations of manga- nese are found in nuts, tea, and spices (USEPA, 1975~. The average daily

Inorganic Solutes 267 consumption of manganese for man is from 3 to 7 mg (NAS, 1973~. Of the trace metals, manganese is third in the proportion of intake from water as compared to food (Craun and McCabe, 1975~. HEALTH EFFECTS Manganese is an essential trace nutrient for microorganisms, plants, and animals, including all species of mammals and birds that have been investigated. Manganese deficiency has been observed in many mammalian species, both under field conditions and in the laboratory. It is therefore reasonable to conclude that man also has a nutritional requirement for manganese. The incidence of human manganese deficiency has not been investigated, nor has it been determined whether such a deficiency is a health hazard to man. Moreover, minimal human nutritional requirements have not been established. It will be necessary to determine such requirements if desirable limits of exposure to dietary and environmental manganese are to be established (NAS, 1973, p. 91~. Manganese is a coenzyme in many mitochondrial reactions. Examples of non-specific manganese-activated enzymes include hydrolases, kinas- es, decarboxylases, and transferases. Some enzymes such as succinic dehydrogenase have an absolute requirement for manganese (NAS, 1973). Acute manganese poisoning is extremely rare. Chronic exposure is seldom fatal but may result in permanent crippling. Diagnosis is difficult unless a history of exposure of at least three months is present. The symptoms are sleepiness, muscular twitching, leg cramps, increased tendon reflexes, a peculiar character~s- tic spastic gait, emotional disturbances, and a fixed mask-like expression (USEPA, 1975, p. 6 1~. The toxicity of specific manganese compounds appears to depend upon the type of manganese ion present and the oxidation state of the manganese; the divalent manganese cation is reported to be 2~/~3 times more toxic than the trivalent cation (USEPA, 1975, p. ~2~. Manganese has a very low order of acute oral toxicity. When rats are given 2,000 ppm in their diets growth is unaffected, and hens can tolerate 1,000 ppm without ill effects, but 4,800 ppm is toxic to young chickens (NAS, 19731. Chronic manganese poisoning almost always is the result of inhaling high concentrations of manganese dust. The symptoms appear after several months and are often reversible if exposure is terminated. Even with an inhalation exposure there is some evidence that a large amount of manganese enters the body through intestinal absorption (EPA, 1975~. Chronic manganese poisoning is characterized by progressive deteriora- tion of the central nervous system; the effects are not completely reversible.

268 DRINKING WATER AND H"LTH There is currently no evidence that human exposure to manganese at the levels commonly observed in the ambient atmosphere results in adverse health effects. The only human health effects attributable to manganese in ambient air were found in persons living in the immediate vicinity of two major point sources in Norway and Italy. Manganese pollution is presently a local problem, but the widespread use of manganese fuel additives would make man-made emissions more ubiquitous. There is no evidence that predicted manganese concentrations resulting from the use of methylcyclopentadienyl manganese tricarbonyl would result in adverse health effects; however, respiratory irritant elects from long- term or frequent exposure to low concentrations have not been thoroughly investigated. Most effects from manganese in humans appear to result from prolonged inhalation. Manganese pollution of water does not appear to be a problem except possibly in isolated cases of waste disposal. Atmospheric concentrations of manganese observed in urban areas can be attributed primarily to man-made sources. The principal source of atmospheric emissions is metallur- gical processing (USEPA, 1975, p. 2-31. Chronic exposures to high levels of manganese increase hemoglobin values and erythrocyte counts, which indicates that manganese stimulates production of erythrocytes, as does iron-deficiency anemia. Recovery from anemia caused by improper nutrition is much prompter following the administration of ferrous sulfate and manganese chloride than of ferrous sulfate alone, which demonstrates the relationship between the effect of manganese on erythrocyte production and the intestinal absorption of manganese in anemic individuals (USEPA, 1975, p. 6 2~. The necrologic manifestations of manganese poisoning appear to be caused mainly by inhalation of dust or fumes, with ingestion as an additional factor. An acute waterborne epidemic was reported in Japan in 1941. An encephalitis-like disease occurred in six members of a family. All had the same symptoms, including loss of appetite, constipation, and a mask-like facial expression, with running saliva. Tonicity of muscles was decreased; the leg joints were painful and rigid; the arm muscles showed rigidity and tremors; there was temporary double vision; tendon reflexes were increased; and there was some mental disturbances, memory loss, and melancholia . . .. One victim had died, two were hospitalized, and three were up and about. Blood and spinal fluid samples were sterile, with normal cellular counts. Histologic examination of the autopsy material from brain and spinal cord showed no signs of encephali- tis . Symptoms pointed strongly to some form of intoxication . . . . It was learned that the family maintained a bicycle-repair shop and that many old dry cells for bicycle lamps had been buried near a well that supplied water for the family. It was presumed that the intoxication was caused by manganese, which, with zinc, is a principal constitutent of the cells. [Well-water] analysis showed unusually high concentrations of manganese and zinc in the water from this and several other wells. Manganese and zinc were found in large quantities in the viscera of the autopsied victims and in the blood and urine of survivors. Ten more patients were

Inorganic Solutes 269 discovered among the neighbors of the family; all had drunk the contaminated water (WAS, 1974, pp. 109-110~. Both acute and chronic ejects of manganese poisoning are similar to Parkinson's disease. There appear to be some similarities between the clinical features of the extrapyramidal disease of manganism and those of Parkinsonism. There is some indirect evidence that chronic manganism and Parkinsonism may have similar biochemical abnormalities with respect to the extrapyramidal system. It has been shown that levels of dopamine, one of the chemicals that functions in transmission of nervous impulses, are reduced in discrete areas of the brain in Parkinson's disease. Europa, the precursor of dopamine, can cross the blood-brain barrier and be converted to dopamine in the brain. Europa has proved to be quite beneficial in Parkinson's disease. It has has also been successfully used as therapy in persons with chronic manganism, which has been associated with decreased brain dopamine (NAS, 19741. ANALYSIS The manganese detection limit by direct flame atomization is 2 ,ug/liter. However, solvent extraction is used for many determinations. Analytic conditions are more critical for the extraction of manganese than for most other metals, because many manganese-chelate complexes are unstable in solution. With pH control and immediate analysis after extraction, accurate determinations are possible. The U.S. Geological Survey procedure (Brown et al., 1970; Aldous et al., 1975) uses the extraction of the manganese-APDC complex with methylisobutylketone at a pH of 6.0 with immediate aspiration of the extract. Yanagisawa et al. (1969) and Jenne and Ball (1972) have studied the stability of manganese chelates. When the graphite furnace is used to increase sample atom~za- tion, the detection limit is lowered to 0.01 ~g/liter. Fernandez and Manning (1971), Barnard and Fishman (1973), Surles et al. (1975), and Shigematsu et al. (1975) have described its application to freshwater analysis. CONCLUSIONS AND RECOMMENDATIONS Manganese is an essential trace element for man. It plays an important role in many enzyme systems. Manganese toxicity has been associated with airborne exposure, but chronic toxicity from drinking water has not been reported. With surface water averaging less than 0.05 mg/liter in

270 DRINKING WATER AND H"LTH several surveys, the potential for harm from this source is virtually nonexistent. The main problem with manganese in drinking water has to do with undesirable taste and discoloration of the water. The WHO (1970) suggests that such problems may arise at concentrations of manganese greater than 0.05 mg/liter, the same limit recommended by the USPHS (19621. The manganese report from NAS (1973) suggested several research priorities for gaining a better understanding of manganese toxicity. Some of the questions which need answers include the following: 1. Is there individual human susceptibility to excessive or deficient concentra- tions of manganese? If so, how can it be detected, and how can it be predicted? Are the differences due to diet, genetic makeup, concomitant stress, variations In absorpton, disease, or interactions with drugs and chemicals? Are there also group differences? 2. What are the effects on pregnant women and infants of chronic excessive exposure to manganese? Is the fetus at risk? 3. What controls the metabolism and turnover of manganese? 4. What accounts for the time course of the symptoms in manganism? Why do the psychiatric symptoms precede the necrologic? 5. With few exceptions, manganese pollution does not occur in isolation from pollution from other substances. How do these pollutants interact? Are their ejects merely additive, or do some combinations create special hazards to health? 6. Are the so-called lower exudative states more toxic than the higher ones? This has often been reported but has not been proved. Indeed dose-response relations have not been established for any manganese compound. Does the toxicity of manganese depend on its physical form? 7. Further research is needed to determine the clinical value of present tests of blood, urine, and hair as indices of recent absorption of excessive manganese. Does increased manganese content of any of these samples correlate with later features of manganese toxicity? (NAS, 1973, pp. 137-138~. Mercury OCCURRENCE Mercury is one of the least abundant elements in the earth's crust, being seventy-fourth in a list of ninety. Greater than trace amounts are found in at least thirty ores, but in only one, the sulfide cinnabar, does the concentration justify commercial extraction. A major use of mercury has been as a cathode in the electrolytic preparation of chlorine and caustic soda; this accounted for 33% of total demand in the United States in 1968. Electrical apparatus (lamps, arc

Inorganic Solutes 271 rectifiers, and mercury battery cells) accounted for 27%, and industrial and control instruments (switches, thermometers, and barometers) and general laboratory applications accounted for 14% of demand. Use of mercury in antifouling and mildewproofing paints (into) and mercury formulations used to control fungal diseases of seeds, bulbs, plants, and vegetation (by) were other major sources of demand. The remainder (by) was for dental amalgams, catalysts, pulp and paper manufacture, pharmaceuticals, and metallurgy and mining (Wallace et al., 1971~. Because of associated environmental hazards, the EPA in February 1976 canceled registrations for all pesticide products containing mercury used as bactericides and fungicides in paints and coatings, on turf, for seed treatment, and for any other use not specifically permitted (USEPA, 1976). According to data published by the U. S. Geological Survey in 1970 (USGS, 1970), mercury concentrations in broad categories of rocks ranged from 0.01 to 20 ppm. Igneous rocks generally contain less than 0.2 ppm and sedimentary rocks generally average less than 0.10 ppm, except for organic rich shales, which may have concentrations of 10 ppm or more. Seawater contains 0.03-2.0 ,ug/liter, depending on the sampled area, the depth, and the analyst. In a study of Pacific waters, mercury concentrations were found to increase from surface values of near 0.10 ,ug/liter to 0.15-0.27 ,ug/liter at greater depths. In an area seriously affected by pollution (Minamata Bay, Japan), values ranged from 1.~3.6 ,ug/liter. Oceanic mercury is generally present as an anionic complex (HgCl3-), which does not have as pronounced a tendency to bind to particulate substances and then settle out as do mercury compounds found in fresh water (Wallace et al., 1971~. Little attention was paid to mercury in water in the United States before 1970. A 5-yr summary (1962-1967) of trace metals in rivers and lakes of the United States prepared by the U.S. Department of the Interior, Federal Water Pollution Control Administration, did not include mercury among the trace elements reported (Kopp et al., 1967~. The Department of the Interior carried out a nationwide reconnaissance of mercury in U.S. waters in the summer and fall of 1970 (Jenne et al., 19724. Of the samples from the industrial wastewater category, 30% contained mercury at greater than 10,ug/liter; nearly 0.5% of the samples in this group contained more than 1,000 ~g/liter. Only 4% of the surface- water samples contained in excess of 10 ~g/liter. The higher mercury concentrations were generally found in small streams. About half the 43 samples from the Mississippi River contained less than 0.1 ,ug/liter. The

272 DRINKING WATER AND H"LTH mercury content of lakes and reservoirs was between 0.1 and 1.8 ,ug/liter. With few exceptions, the mercury content of groundwater samples was below detection (0.1 ,ug/liter). In a survey done by the EPA Division of Water Hygiene, 273 community, recreational, and federal installation water supplies were examined. Of these 261 or 95.5% showed either no detectable mercury or less than 1.0 ,ug/liter in the raw and finished water. Eleven of the supplies had mercury concentrations of 1.0~.8 ,ug/liter and one supply exceeded 5.0 ,ug/liter. When this one supply was extensively reexamined the mercury concentration was found to be less than 0.8 ,ug/liter (Hammerstrom et al., 19721. The combined ejects of treatment and distribution on trace elements, including mercury, were investigated in the municipal water systems of three cities in Sweden. The concentration range for mercury was 0.09~.4 ,ug/liter in raw water, and it remained unchanged in tap water in the three systems (Andelman, 19741. All vegetable materials naturally contain traces of mercury, the actual amount depending on the locality from which the sample was taken, the species, and other factors. The mercury concentrations in plant materials generally range from 0.10 ppm down to 0.01 ppm or even less; but higher concentrations are found and may be caused by naturally high concen- trations of mercury in the soil. Background concentrations of mercury in animals are difficult to assess, particularly for terrestrial samples, because former agricultural uses of mercury products were so widespread and uncontaminated sources so rare. Data from the literature suggest that normal values for eggs and the flesh of birds and animals are generally less than 0.02 ppm. Marine fish have mercury concentrations usually below 0.10 ppm and nearly always below 0.15 ppm, but this depends very much on species as swordfish may contain more than 1 ppm. Concentrations of 0.20 ppm or less are assumed normal for freshwater fish, but once again this depends on species and region. The higher background concentrations in fish as compared to other animals, fruits, and vegetables are due to the marked ability of fish to accumulate methylmercury ~lallace et al., 1971~. Of particular significance with regard to assessing the potential health hazard of mercury is the fact that the mercury in freshwater fish flesh is predominantly in the form of methylmercury compounds, despite the fact that most mercu~released-into rive - lakes, and oceans is in the form of the inorganic salt or the metallic element (Goldwater and Clarkson, 1972~. Methylmercury becomes available in the fish food chain through the transformation of inorganic mercury into the organic methylmercury form by microorganisms or other biologically derived alkylating systems present in the sediments of lakes, rivers, and estuaries. These systems are

Inorganic Solutes 273 capable of forming methylmercury and dimethylmercury from inorganic mercury, under both aerobic and anaerobic conditions. Although environmental mercury had been a matter of concern and under intensive investigation for many years elsewhere, notably in Sweden and Japan, it was not until 1970 that the problem received noteworthy attention in the United States. In March 1970, a Norwegian investigator working in Canada reported high concentrations of mercury in fish from Lake St. Clair. This triggered extensive investigations of mercury in fish from both Canada and the United States (Goldwater, 19711. The USFDA established a mercury concentration of 0.5 ppm in fish tissue as a guideline for evaluating results of the fish investigations. By September 1970, 18 states had taken specific actions, ranging from general warnings to closure of fishing in designated waters. Attention was focused on mercury-containing waste discharges from chlor-alkali plants. The operators of these plants took prompt action to reduce mercury discharges. The reductions were monitored by the Department of the Interior, which found that the overall extent of mercury emission dropped 86%, from 287 lb/day in July to 40 lb/day in September (Wallace et al., 1971~. CHEMICAL CHARACTERISTICS 0 1 ~- ' Metallic mercury is regarded as virtually insoluble in water. Mercury forms two series of salts, traditionally considered as being univalent and divalent. However, it has been shown that the "univalent" compounds contain the group Hg2+2 (or +Hg=Hg+), with two mercury atoms covalently bound to each other, so this series is actually divalent. Univalent (mercurous) salts are mostly insoluble, and the divalent (mercuric) series is mostly soluble, except the iodide and sulfide. Mercury has a remarkable ability among metals to form compounds with organic radicals, normally linking covalently to a carbon atom. Organic mercury compounds can be conveniently classified into two types, RHgX and R2Hg, where R is an organic radical and X an inorganic (radical) ion. RHgX compounds in general are crystalline solids whose properties depend on the nature of X. When X is chloride, bromide, iodide, cyanide, thiocyanide, or hydroxyl, the compound is a covalent nonpolar substance more soluble in organic liquids than in water. When X is a sulfate, nitrate, phosphate, or perchlorate radical, the substance is saltlike, that is, ionic. R~Hg compounds are nonpolar, volatile, toxic liquids or low-melting- point solids. All are thermally unstable and light sensitive (Wallace et al., 1971).

274 DRINKING WATER AND HEALTH METABOLISM Investigations of the metabolism of mercury and its various compounds, particularly the comprehensive studies in Japan and Sweden, have been reported on extensively. Takeuchi ( 1970) has summarized Japanese investigations of the biologic reactions and pathologic changes in human beings and animals caused by organic mercury contamination. Specific data on human excretion of methylmercuric nitrate were derived from studies with orally administered labeled compound. Three male volunteers were given an oral dose of [203Hg~methylmercuric nitrate. Over 90% was absorbed; maximum blood content was reached 3- 6 h after ingestion. The liver contained 55% of the total radioactivity, with 12970 in the head. The biologic half-life was determined to be 70 74 days (Ekman et al., 1968; Aberg et al., 1969; Falk et al., 1971~. Methylmercury and other short-chain alkylmercury compounds exert their main toxicologic effects on the nervous system. In man, methylmer- cury concentrations in blood cells and hair provide the best index of exposure of the nervous system to methylmercury compounds. If exposure to other mercury compounds is minor, compared with exposure to methylmercury, analysis of total mercury mall be used instead. Blood concentrations of mercury reflect more accurately the intake from recent exposure to methylmercury; hair concentrations reflect the average intake over a long period. The mercury concentrations in successive segments of hair over the period of its formation can indicate the degrees of past absorption of mercury compounds. The factors that determine the biotransformation of mercurials, their passage through barriers in the body, and the ultimate action on cellular mechanisms are only beginning to be understood. The amount of a particular compound present in the body is the result of a balance between intake and excretion. When the same amount is taken in each day, the body content rises progressively to a plateau at which excretion equals intake. The time to reach a steady state in the body is determined by the half-time of excretion. Taking the half-time of excretion in man as 70 days, a steady state in a person will be reached in approximately a year. Once attained, the steady state concentration of mercury is proportional to the daily intake. Studies of methylmercury in humans support this conclusion (Goldwater et al., 1972~. HEALTH EFFECTS Exposure to metallic mercury via routes other than inhalation is infrequent. Oral doses of 100 500 g have been given to man with little

Inorganic Solutes 275 effect, because of poor absorption, although they occasionally resulted in diarrhea. The comparative toxicity of inorganic mercury salts is related to their absorption. Thus, insoluble mercurous salts, such as calomel (mercurous chloride), are relatively nontoxic. In man, some data are available on accidental or intentional overdosage with mercuric chloride. The immediate elects of acute poisoning are due to irritation, coagula- tion, and superficial corrosion of exposed tissues. Chronic effects include kidney damage, as intestinal hemorrhage, and ulceration. Investigation of laboratory technicians subject to inhalation exposure to mercuric chloride (0.2~.3 mg/m3) showed high urinary concentrations of protein, considered suggestive of early renal tubular dysfunction. From these considerations, it appears that metallic mercury and inorganic mercury salts themselves are not significant contributors to the current problem concerning environmental contamination. The problem appears to be related mainly to methylmercury compounds in the environment, particularly in fish, and to accidental ingestion, either of treated seed grain or of meat from animals that had been fed grain treated with alkylmercury compounds (Lu et al., 19721. Two major outbreaks of environmentally related methylmercury intoxication have occurred in recent years in Japan in the Minamata Bay area (1953-1961) and in Niigata (1964 1965~. Of the 121 cases recorded in the Minamata Bay episode, there were 46 deaths. About half the adult victims, one-third of the children, and one-eighth of the fetal victims died. In Niigata, 30 cases, including five deaths, were reported in 1965. Thereafter, 17 cases, including one death and one fetal case, were reported from 1966-1970. In both outbreaks, industrial pollution of waters, with later contamination of fish and shellfish by mercury as methvlmercurv. was shown to be the cause (Beralund. 19711. There was J J. no indication in the report that drinking water was considered as a possible contributor to the outbreaks. There have been many reports of poisoning after accidental ingestion of methylmercury compounds. In Pakistan, in 1961, several families became ill after eating wheat seed treated with phenylmercuric acetate and ethylmercuric chloride, and 5 of 34 hospitalized patients died. A similar episode occurred in Guatemala in 1965, when there were 20 deaths among 45 people who displayed typical symptoms of mercury poisoning after eating wheat seed treated with methylmercury dicyan- diamide. In Iraq, 331 cases of poisoning with 36 fatalities resulted between 1956 and 1960, owing to ingestion of seed treated with ethylmercuric-p-tolylsulfanilide. In Ghana, in 1967, 17 of 65 persons died after ingestion of stolen maize that had been treated with Merkuran, a product containing 2% ethylmercuric chloride (Lu et al., 19721. Members

276 DRINKING WATER AND H"LTH of a family in Alamogordo, New Mexico, were victims of mercury intoxication in 1969 from eating meat from animals that had been fed grain treated with alkylmercury compounds. This episode is particularly significant, because it demonstrated the effects of methylmercury on the fetal nervous system: There was a case of mercury poisoning during a pregnancy. The patient's mother ate mercury-contaminated pork, proba- bly during the second trimester of her pregnancy. The full-te'~' boy who was born had severe tremors at birth, which persisted for several days.- His urinary mercury concentration during the first day of life was 2.7 ,ug/liter, 100 times the quoted normal adult concentration. By 6 weeks of age, the infant was noted to be hypertonic and irritable; mercury could not be detected in his urine. By 8 months of age, he had myochon~c seizures and was hypotonic, irritable, grossly retarded, and probably cortically blind. He had never been breast fed; this fact provided evidence that this was a case of intrauterine poisoning. The mother was asymptomatic, despite having documented increased urinary mercury concentrations during the third trimester of her pregnancy (Scanlon, 1975~. The frequency of occurrence of various symptoms and signs in Minamata disease (methylmercury poisoning) among adults, children, and infants as recorded in the Japanese studies is presented in Table V- 11. The amount of methylmercury needed to produce Minamata disease is TABLE V-l I Frequency of Occurrence of Various Symptoms and Signs In Minamata Disease (~o) Symptoms Infants" ChildrenAdults Mental disturbance 100 10071 Ataxia I 00 10094 Impairment of the gait 100 10082 Disturbance in speech 100 9488 Hearing impairment 4.5 6785 Constriction of visual fields 100?100 Disturbance in chewing and swallowing 100 8994 Brisk and increased tendon reflex 82 7234 Pathological reflex 54 5012 Involuntary movement 73 4027-76 Primitive reflex 73 00 Impairment of superficial sensation ? ?100 Salivation 72 5624 Forced laughing 27 29 (From Takeuchi, 1970) "Exposed in utero.

Inorganic Solutes 277 not known, nor is there a specific biochemical test available as a diagnostic aid in mercury poisoning (Goldwater et al., 1972~. Establish- ment of exact relationships between the dose of a mercurial taken into the body and the health effects expected presents a number of difficulties. The nature of the mercury compound has a marked effect on absorption and metabolism, and therefore on toxicity. Data that refer only to the amount of elemental mercury are not of much help. Methods of analysis have not been very sensitive, so the effects of small doses continued over long periods cannot be followed accurately. In a report issued in 1970, the Swedish Commission on Evaluating the Toxicity of Mercury in Fish set forth its recommendation related to allowable intakes of methylmercury (Berglund, 1971~. It recommended the use of the "allowable daily intake" (ADI) as a method of warning consumers so they could restrict their intake of mercury-contaminated foods. On the basis of available information, they concluded that it appeared "justifiable" to assume that clinically manifest poisoning of adults sensitive to methylmercury may occur with a concentration in whole blood down to 0.2 Agog, which seems to be reached on exposure to about 0.3 mg of mercury (as methylmercury) per day, or about 4 ,ug/kg/day. It was pointed out, however, that concentrations of 0.2 Gag or higher in the blood cells had been measured in some 20 persons and concentrations exceeding 0.4 ,ug/g in four persons without any clinical symptoms of methylmercury poisoning in Sweden and Finland, and even concentrations of 50 ,ug/g or more in the hair of at least 130 persons in Japan who were not considered to be poisoned. They cited a number of elements of uncertainty that must be considered in further evaluation of these conclusions, including the acknowledgment that the data on prenatal poisoning are particularly limited. A safety factor of 10 was applied to the lowest mercury exposure that was assumed to cause the necrologic symptoms of clinically manifest intoxication. It was conclud- ed that the "acceptable daily intake" of methylmercury through fish would correspond to about 0.03 mg of mercury (as methylmercury), or about 0.4 ~g/kg of body weight. ANALYSIS Mercury in fresh water is below the detection limit of 250 ,ug/liter by conventional flame atomization. Issaq and Zielinski (1974) observed a 5~ fold mercury signal enhancement when hydrogen peroxide was added to the aqueous mercury solution. Solvent extraction with APDC or dithizone may be used, but the preferred method of analysis is the cold- vapor technique of Hatch and Ott (1968~. By this procedure, mercury

278 DRINKING WATER AND H"LTH vapor is formed by reduction of mercuric ions in solution by stannous chloride and passed through an absorption cell situated in the light path of a spectrophotometer. Detection limits better than 0.1 ~g/liter are easily obtainable for water samples. Most other published procedures also use stannous chloride as the reducing agent (USEPA, 1 97 1; Omang, 1 97 1; Traversy, 1971; Baltisberger and Knudson, 1974~. Mercury in organic matter can be oxidized by persulfate; the resulting solution is analyzed for mercury by flameless atomic absorption (Alberta et al., 1974; Feldman, 19741. Methylmercury can be extracted with benzene and then subjected to flameless atomic-absorption analysis (Bisogni and Lawrence, 1974~. CONCLUSIONS AND RECOMMENDATIONS The current problems concerning mercury contamination of the environ- ment appear to be related mainly to methylmercury compounds. As far as humans are concerned, the presence of these compounds in foods (principally fish) and the accidental ingestion of treated seed grain or the ingestion of meat from animals that had been fed grain treated with alkylmercury compounds are the major problems. Drastic limitations imposed or being imposed by official agencies on the industrial discharge of mercury-containing wastes that contribute to methylmercury contami- nation of fish, on the allowable mercury content in fish used for human consumption, and on the use of mercurial fungicides should minimize the mercury hazard to man from these sources. There is no indication that mercury compounds in the concentrations and forms found in the ambient atmosphere or in drinking-water supplies contribute significantly to methylmercury intoxication in humans. European drinking-water standards (WHO, 1970) do not contain a standard for mercury. The international standards for drinking water (WHO, 1971) recommend that the tentative upper limit for mercury in drinking-water be I ~g/liter. The USSR has a standard of 5 ~g/liter (inorganic compounds only) (Stofen, 1973~. The EPA-proposed drinking- water standard for mercury is 2 ~g/liter (total mercury). Drinking water containing mercury at this concentration will contribute a total of 4 leg to the daily intake. According to the EPA, only a small fraction of the mercury in drinking water is in alkyl form, and the contribution of methylmercury to the daily intake will be less than 4 ng (0.004 ~g)- approximately 0.01 % of the ADI for methylmercury recommended by the Swedish commission. At this level, the potential hazard to humans from mercury in U.S. water supplies is inconsequential, compared with the contribution from food.

Inorganic Solutes 279 In light of this and the fact that nearly all drinking-water supplies in the United States are already in compliance with the current interim regulation, there is serious question as to whether a standard is needed or serves any useful purpose. There is however, a lack of firm data on the ratio of organic mercury to total mercury in drinking water supplies, although it is Generally accented that mercurY in drinking water is ° °- ~ ~~ ~ -~---r-~ ---I --- ~ me, .~ _ · · .. · · · ~ .. ·. · . · . . . . . . . . .. ~ . principally in 1norgamc form. onto it 1S demonstrated that tills belle! 1S universally applicable to water supplies' it appears desirable to limit the concentration of mercury in drinking water as if it were methylmercur,y. There is a need for specific investigations to validate or modify the prevailing opinion that mercury in drinking water is principally in the . . ,% inorganic form. Molybdenum OCCURRENCE Molybdenum metal and its salts are used primarily in metallurgy and for electric and electronic apparatus. Other uses are in the glass and ceramics industries, for the production of pigments, and as a constituent of fertilizers for leguminous crops (McKee and Wolf, 1963; NAS, 1973; Davis, 1974~. Molybdenum salts can reach surface and groundwater as a result of the mining of molybdenum sulfide. They are also by-products of the mining and milling of uranium. The burning of fossil fuels and natural weathering processes are other sources of molybdenum in the environment. Transport can be by air and water (Chappell, 1973~. Molybdenum is present in surface water and groundwater at very low concentrations. With emission spectroscopy, Durum and Haffty ( 1961 ) measured molybdenum in 59 samples of surface water from 15 rivers in the United States and Canada. The maximum concentration observed was 6.9 ~g/liter, in the Colorado River at Yuma, Arizona. Kopp and Kroner (1967) noted the presence of molybdenum in 32.7% of their surface-water samples from the 15 major river basins of the coterminous United States, with concentrations ranging from 2.0 to 1,500 ~g/liter. The overall mean was 60 ~g/liter, and 26 stations had means greater than 50 g/liter. Of the 4 stations recording the highest values, 3 were in Colorado and I was just across the border on a stream draining from Colorado (Chappell, 1973~. Chappell (1973) reported tap-water concentrations as high as 580 ,ug/liter. In the finished-water supplies of the 100 largest cities in the United States, Durfor and Becker ( 1964) reported the maximum molybdenum concentration as 68 ~g/liter, the median as 1.4 u~/1iter. and 1 ~

280 DRINKING WATER AND H"LTH the minimal as not detectable. In a survey of 380 finished waters in the United States between 1 October 1962 and 30 September 1967, Kopp (1970) reported that 29.9% had measurable concentrations of molybde- num, with a maximum of 1,024 ~g/liter, a minimum of 3 ,ug/liter, and a mean of 85.9 ~g/liter. According to Hadjimarkos (1967), the mean drinking-water concentration was 8 ~g/liter. Kehoe et al. (1944) reported that the concentrations of molybdenum ranged from nil to 270,ug/liter in groundwater and from 0.1 to 0.5 ,ug/liter in seawater. Wells used for watering livestock and irrigated forage at Canon City, Colorado, had up to 25,000,ug/liter and resulted in molybdenosis (Chappell, 1973~. Barnett et al. (1969) studied several trace metals in raw, treated, and tap water for the Denver municipal system. This system draws its supplies from three watersheds (one being Dillon Reservoir) and treats them in four filter plants, one of which is an old, slow sand filter. Distributed water was sampled at four carefully selected locations in residences. On 15 September 1966, water from Dillon Reservoir reached 530,ug/liter of molybdenum, but it was blended with water from the South Platte River before filtration. Unlike copper and manganese, molybdenum is not removed sig- nificantly by treatment processes and not changed by distribution. At one tap, for example, a sample collected in May 1966 (when very little water from Dillon Reservoir was being used) contained 8 ,ug/liter; by 16 September 1966, the concentration in water from this tap was 190 ,ug/liter. Distribution and plumbing have very little, if any, measurable erect on molybdenum concentration. The USSR has established a limit of 0.5 mg/liter for Mo+6 in surface water (Stoefen, 1973~. Konovalov et al. (1966) reported the concentration of suspended and dissolved molybdenum in four major drainage basins of European USSR. In 32 samples, molybdenum was detected in only 4, with a maximum concentration of 14.8,ug/liter and a minimal concentra- tion of 0.1 ~g/liter. High concentrations occurred in rivers draining molybdenum mining and milling operations. The atmospheric transport of molybdenum may be significant, but human ingestion of airborne molybdenum is unlikely to constitute a major pathway of intake. Kaakinen and Jorden (in Chappell, 1973) studied the fate of molybdenum in a coal-fired electric power plant in Colorado. Their results showed that molybdenum from coal is definitely enriched in fly ash leaving a coal-fired power plant in stack gases (even after treatment with electrostatic precipitators and wet scrubbers), but significantly decreased in bottom ash. Enrichment in fly ash appears to be related to the volatility of molybdenum and its adsorption on fine particles. Molybdenum that escapes in particulate matter in stack gases

Inorganic Solutes 281 may be expected to settle to earth and enrich the soil, plants, and water, thereby possibly contributing to molybdenosis of livestock. It is concluded that molybdenum in drinking-water, except possibly from highly contaminated molybdenum-mining wastewater, is not likely to constitute a significant portion of the total human daily intake of molybdenum. For example, according to Hadjimarkos ( 1967), the average drinking water provides only 1.6% of the daily human intake of molybdenum. CHEMICAL CHARACTERISTICS Molybdenum occurs in nature in a IV oxidation state in the sulfide molybdenite (the commercial source) and in a VI oxidation state in molybdate salts. It is uniformly distributed among igneous rocks, with a slight concentration in basaltic rocks. It makes up approximately 2 mg/kg of the continental crust (Davis, 1974~. About 60970 of the molybdenum mined in the United States is taken from the world's largest deposit of molybdenum sulfide, near Climax, Colorado (Chappell, 1973~. According to Asmangulyan (1965), molybdenum sulfide is sparingly soluble in water, but is fairly readily oxidized to form more soluble molydates (salts of molybdic acid), which are stable in water in the absence of a reducing agent. Organoleptic tests showed that ammonium molybdate imparted a slightly astringent taste to water, starting at a molybdenum concentration of 10 mg/liter. A concentration of 100 mg/liter produced a marked inhibitory elect on the biochemical oxygen demand (BOD) of water, but 10 mg/liter had no effect on the total number of bacteria in water. METABOLISM Schroeder et al. (1970) estimated that the daily intake of molybdenum was 390 ,ug. Hadjimarkos ( 1967) estimated the human intake of molybdenum in food at 1,000 ~g/day. On the basis of very limited data, Tipton et al. (1966) calculated the total dietary intake of molybdenum by adults to be approximately I 00 ~g/day. The mean daily dietary intake of molybdenum is so small (about 1 mg/day) and of such minor importance that its role in human nutrition and metabolism has been studied very little (Davis, 1974~. Miller et al. (1959) did balance studies on 24 girls, 7-9 years old, who were fed molybdenum at an average of 75 mg/day; most of this appeared in the urine. The higher the protein intake, the less molybdenum was retained.

282 DRINKING WATER AND H"LTH Molybdenum concentrations are normally very low in animal tissues. Davis (1974) presented the following concentrations for adult man: Tissue Molybdenum Concentration, mg/kg (dry weight) 3.2 1.6 0.20 0.15 0.14 0.14 Liver Kidney Spleen Lung Brain Muscle The molybdenum content of food varies greatly. In general, legumes, cereal grains, leafy vegetables, liver, and kidney are good sources; fruits, root and stem vegetables, muscle meats, and dairy products are among the poorest. Molybdenum is excreted primarily in the urine, probably as molybdate anion (Davis, 1974~. According to Asmangulyan (1965), molybdenum is fairly rapidly eliminated from animals, but it has some slight cumulative properties, especially in the bones, kidneys, and liver. HEALTH EFFECTS Molybdenum is recognized as an essential mineral for both man and other animals. It is an integral part of at least two mammalian enzymes, xanthine oxidase and aldehyde oxidase (USFDA, 19751. In man, molybdenum poisoning has rarely been observed. High intakes in Armenia (USSR) have been associated with high incidences of gout. In India, a bone-crippling disease occurs in areas where sorghum contains high amounts of molybdenum; it has been postulated that molybdenum increases the toxicity of fluoride in producing this disease. Both these human-related incidents are speculative and await more definitive information to establish cause-and-effect relationships (USFDA, 19751. Although it is known that molybdenum is an essential trace element (Browning, 1961), excessive dosages in laboratory animals and in the forage of herbivores, such as cattle, have been deleterious. Molybdenum is picked up by forage crops from the soil moisture and concentrated in the foliage. Water-soluble molybdates in herbage cause cattle to scour severely-i.e., to have diarrhea which sometimes results in death. Soil moisture from pastures in which cattle had scoured contained moly~de

Inorganic Solutes 283 num at 20-100 mg/liter, whereas noninjurious fields contained less than 5 mg/liter. The herbage content of molybdenum varied with plant species on the same soil (McKee and Wolf, 1963, citing several references). Animals vary greatly in their sensitivity to molybdenum. Cattle appear to be the most sensitive, with severe diarrhea occurring at intakes as low as about 20-100 mg/kg of forage. Pigs tolerate 1,000 mg/kg of diet without discernible ill erects. In young chickens, dietary supplements of 200, 2,000, and 4,000 mg/kg of food induced growth suppression and anemia. In rats being fed a copper-deficient diet, molybdenum at 10 mg/kg of food produced a reduction in the rate of weight gain, but if copper at 3 mg/kg of diet was present, no elect was observed when molybdenum was added at 100 mg/kg. High sulfate or sulfate-forming components, such as methionine, exacerbated the molybdenum toxicity (USFDA, 1975~. The toxicity of molybdenum in animals is related to a number of dietaIy factors, including copper, sulfate, endogenous sulfate-producing substances, and other trace metals that affect copper metabolism. The mechanisms by which these components ameliorate or intensify molyb- denum toxicity are largely unknown, owing to the complexity of the interrelationships of these nutrients. Signs of toxicity in most species are similar to those of copper deficiency and often include reduced growth, loss of appetite, anemia, hair loss, bone defects, and loss of hair color (USFDA, 19751. The daily food intake of animals is appreciably lower on molybdenum- containing diets than on control diets. Rejection of the diet may be a conditioned response caused by sensory detection of the presence of molybdate ion or its interaction with unidentified constituents of the diet (Monty, 1960). Rats fed toxic dosages of molybdate showed a reduction in liver sulfide oxidase activity. Significantly, rats were unable to discriminate between the molybdate-containing diet and the control diet for the first 5 days after molybdate was added to the diet. If diets that had been "aged" for at least 5 days were offered to rats, they were able to discriminate against the molybdate-containing diet within 2 days. It has been postulated that molybdate interacts with some dietary constituent over a period of 5 days to produce a change that permits the rats to discriminate (Anon., 1962~. According to Asmangulyan (1965), who introduced various doses of molybdenum into the diets of young rabbits, chronic poisoning by molybdenum gives rise to marked functional changes, including an increase of sulfl,ydryl groups in the serum and liver and a decrease in vitamin C in the liver, at dosages as low as 0.5 mg/kg of diet. The fact that a rise in the content of biologically active sulfLydryl groups has been

284 DRINKING WATER AND H"LTH shown to be caused by molybdenum may assist in elucidating the mechanism of the "molybdenum gout" that is found in Armenia. The inactive dose of molybdenum for rabbits was 0.025 mg/kg of diet (or approximately 0.5 mg/liter in drinking-water). As a result, Asmangulyan recommended a maximum permissible concentration of molybdenum in open bodies of water of 0.5 mg/liter. This recommendation may well have been the evidence on which the USSR limit was based. ANALYSIS With atomic-absorption spectrophotometry, a detection limit of 20 ,ug/liter is attainable by direct aspiration into the flame, necessitating concentration for ordinary determinations. Chau and Lum-Shue-Chan ( 1969) have studied extraction systems for molybdenum and recommend- ed an oxine-methylisobutylketone system, with extraction at a pH of 2- 2.4. When the graphite furnace is used to increase sample atomization the detection limit is lowered to 0.5 ~g/liter. CONCLUSIONS AND RECOMMENDATIONS Soluble molybdate ions are present in trace concentrations in many surface waters, primarily as a result of industrial waste, but also as a product of natural weathering of molybdenum-bearing soils. Both suspended insoluble molybdenum sulfide and soluble molybdates are present in streams that drain areas where molybdenum ore is mined and processed, especially in Colorado and New Mexico. Typical diets contain molybdenum at around 100 1,000 Gay, whereas typical surface water (except that draining mining areas) contains nil to about 100 ,ug/liter, with mean or median of about 10 ,ug/liter. Hence, it is evident that water is a minor factor in the total molybdenum intake in most locations. In humans, molybdenum poisoning has rarely been observed. A1- though it has been implicated in gout in Armenia and in a bone-crippling disease in India, these involvements are speculative and await more definitive information to establish cause-and-effect relationships. Molybdenosis in livestock, however, is a significant toxicologic problem in many areas. Consumption of molybdenum-rich forage by cattle and sheep causes severe diarrhea (scouring) that sometimes results in death. It can be prevented or ameliorated by the administration of copper, but the relationship of molybdenum, copper, and sulfate-forming compounds in animal metabolism needs further study. The USSR has established a molybdenum limit of 0.5 mg/liter in open

Inorganic Solutes 285 water, but the WHO has not yet promulgated a limit (Stoefen, 1973~. The National Primary Drinking Water Regulations USEPA, 1975) do not set any limit for molybdenum. Nickel The National Academy of Sciences has recently completed an extensive review of the medical and biologic enacts of nickel (1975~. This section includes excerpts from that publication, Nickel (with appropriate page numbers shown). OCCURRENCE Kopp and Kroner reported that nickel was found in U.S. waters with a frequency of 16% and at an overall mean concentration of 19 ,ug/liter. The detection limit for nickel in water with total dissolved solids of 400 ~g/liter was 20 ,ug/liter. If the dissolved solids amounted to 200 ,ug/liter, the detection limit would be 10 ,ug/liter (P. 91. The Missouri River and Western Gulf basins had the lowest frequency of nickel detection and among the lowest mean concentrations, at 5 and 3 ,ug/liter, respectively. The highest mean concentration was 130 ~g/liter, in the Cuyahoga River at Cleveland, Ohio (p. 9~. It was concluded that most of the nickel in surface water and groundwater originates from man's activities. This conclusion was strengthened by data on nickel concentrations determined by spectro- graphic analysis of evaporated residue of selected samples taken in 1962 of public water supplies of the 100 largest cities in the United States. On the basis of analyses of nickel concentrations of 969 water supplies in the United States during 1969-1970, . . . the average concentration of nickel in water samples taken at the consumer's tap was 4.8 ,ug/liter. With an estimated daily intake of 2 liters of water, an adult would consume approximately 10 ,ug of nickel per day in drinking water (p. I 1~. Man's exposure to nickel in food derives from the natural occurrence of nickel in food ingredients and from man-made sources, such as alloys, food-processing equipment, and fungicides, which may increase the amount of nickel in food substances beyond that naturally present .... With the exception of some preliminary studies in plants, nothing is known about the chemical form of nickel in foods. Detailed information of this type needs to be developed for consider- ation of possible differences in bioavailability and biotoxicity of nickel in foods. However, the available information indicates that the concentrations of nickel in foods are low and do not pose any toxicity problem (p. 51~. The usual oral intake of nickel by American adults thas been calculated] at 30 600 ,ug/day. Nickel ingestion may vary widely. [It has been calculated] that a

286 DRINKING WATER AND H"LTH person who ingests a 2,300-cal diet containing 100 g of protein, 250 g of carbohydrates, and 100 g of fat and who consumes meat, milk, fruit, refined white bread, wheatena, butter, and corn oil would takein3-lO~gofnickelperday.At the other extreme, a diet that has the same calorie value and the same proportions of protein, carbohydrate, and fat might contain 70~900 leg of nickel per day, if the person consumes oysters, meat, milk, eggs, oats, whole-wheat or rye bread, some vegetables, potatoes, and legumes, with little added fat. 1 he wide range of oral intake of nickel may also result from variable ingestion of beverages such as tea, coffee, beer, and red wine-that contain more than lOO~g of nickel per 100 g (p. 62-631. CHEMICAL CHARACTERISTICS With the exception of carbonates, rocks low in silica are high in nickel, and those high in silica are relatively low in nickel. Farm soils of the world contain nickel at 0.0003-~.1%. The average farm soil in the United States contains nickel at more than 0.003%. Soils with less than 0.0003% are too acidic to support normal plant growth (p. 51. The nickel content of seawater ranges from 0.1{).5 ,ug/liter. In most groundwa- ters, nickel has not been identified; and in instances where it has been detected, analysts theorize that it is probably in colloidal form (p. 8~. It has been determined that, in the rock-weathering process, nickel goes into the insoluble minerals of the hydrolysates. Therefore, any nickel in surface or groundwaters is likely to be in small amounts, unless its presence is due to industrial pollution (p. 8~. METABOLISM Most of the nickel that is ingested in food remains unabsorbed within the gastrointestinal tract and is excreted in the feces . . . . Fecal excretion of nickel by healthy human subjects thas been reported to be] 100 times greater than urinary excretion .... There appears to be a mechanism that limits the intestinal absorption of nickel in mammals, despite the relatively large amount of nickel present in their food (p. 63~. Inhalation from the atmosphere and tobacco smoke provides a mode of entry of nickel into the body: The reported mean nickel content of cigarettes have ranged from 2.(K.2 ,ug/cigarette. Analyses . . . have shown that 1~20~o of the nickel in cigarettes is released into the mainstream smoke. Of that nickel 84% is in the gaseous phase and only 16% in the particulate phase. [There is suggestive evidence] that gaseous nickel in mainstream smoke occurs in the form of nickel carbonyl (pp. 178-179~. 1 [It has been] calculated that a cigarette smoker would inhale a maximum of 14.8 ,ug of nickel per day from 40 cigarettes. [The estimated] actual retention of inhaled

Inorganic Solutes 287 nickel within the body is probably only 75% of the calculated intake . . 63-64). · (PP There is wide variation in the average concentrations of nickel in urban atmospheres. Of urban areas of the United States that were surveyed during 1964 and 1966, the cleanest with respect to atmospheric nickel were Boise, Idaho; Albuquerque, New Mexico; and Moorhead, Minnesota. No nickel was detected in those three areas . ... In comparison, the cities with the highest atmospheric concentrations of nickel were New York City (1966 average, 0.118 ,ug/m3 of air) and East Chicago, Indiana ( 1964 average, 0.69 ,ug/m3) . . . . The daily inhalation of nickel by residents of New York City and East Chicago [was estimated], assuming that 20 m3 calf air (24.1 kid is inhaled daily. . . . at 2.36 u of nickel per day and . respectively] (p. 63~. ~ 0, J ~ O 13.8 leg of nickel per day [for the two cities, The metabolism of nickel that enters the body by the pulmonary route is similar to that of nickel compounds that are adminstered parenterally. Inhaled nickel carbonyl is excreted primarily in the urine and to a minor degree in the feces .... A correlation of atmospheric concentrations of nickel in a nickel smelting plant with the concentrations of nickel in the urine of exposed workmen thas been reported] (pp. 64-65~. It has also been shown that measurements of nickel in serum and urine can serve as biologic indexes of environmental exposure to nickel. HEALTH EFFECTS Man is not naturally exposed to the inhalation of atmospheric nickel, with the possible exception of nickel from volcanic emanations. The available evidence indicates that the natural concentrations of nickel in waters, soils, and foods do not constitute a biologic threat. Indeed, nickel may be an essential trace element for the nutrition of man and animals (p. 191~. Recent evidence suggests that nickel partially satisfies the criteria for essentiality of trace elements as micronutrients: presence of the element in the fetus or newborn, presence of homeostatic regulation of the metabolism of the element, demonstration of a metabolic pool of the element that is specifically influenced by hormonal substances or pathologic processes, demonstration of a metalloenzyme of which the element is an integral part, and demonstration of a deficiency syndrome that can be prevented or cured by trace amounts of the element (p. 89~. Nickel is probably essential for animal nutrition, but there has not yet been unequivocal demonstration that nickel deprivation produces consistent abnormalities in experimental animals that can be prevented or cured by the administration of nickel. Toxicity studies have demonstrated that nickel and nickel salts have relatively low toxicity in various species of animals when administered orally. However, parenteral injections of nickel salts are much more toxic. Major signs of acute

288 DRINKING WATER AND H"LTH nickel toxicity consist of hyperglycemia and gastrointestinal and central nervous system effects. Ingested nickel is excreted primarily in the feces, whereas parenterally administered nickel is excreted mostly In the urine. Little informaion is available on animals relative to the acute ejects of inhaled nickel compounds, except for nickel carbonyl, which is extraordinarily toxic .... Several n~ckel- containing substances including nickel dust, nickel subsulfide, nickel oxide, nickel carbonyl, and nickel biscyclopentadiene have been demonstrated to be carcinogenic in experimental animals after inhalation or parenteral adm~n~s- traion. There is no evidence that nickel compounds are carcinogenic in animals after oral or cutaneous exposure. There is veer little information on the teratogen~city or mutagenicity of nickel compounds in experimental animals (p. 192~. Epidemiologic studies of workmen in nickel smelters and refineries have revealed a significantly increased incidence of cancers of the lungs and nasal cavi- ties .... Respiratory cancers in nickel workers have usually developed after long latent periods, such as are typical of occupational cancers .... There is only scanty evidence of an increased incidence of respiratory cancers among workmen who have other types of occupational exposure to nickel, such as nickel electroplating and grinding. Nickel is a common cause of chronic dermatitis in man, as a result of industrial and other exposures [and] use of n~ckel-conta~n~ng alloys In jewelry, coinage, clothing fasteners, . . . utensils, [and] implanted therapeutic devices and prostheses . . . (p. 193~. Berg and Burbank (1972) found nickel in drinking water to be poorly correlated with mortality from oral or intestinal cancer. There was no correlation between nickel and mortality from nasal or pulmonary cancer, even though these are the types of cancer usually associated with industrial exposure to nickel. ANALYSIS Conventional flame atomization has a nickel detection limit of 2 ~g/liter. Extraction procedures are usually used to concentrate the nickel before analysis. The APJ)C-methylisobutylketone extraction at a pH of 2.8 is used by the U.S. Geological Survey (Brown et al., 1970~. Others have used similar procedures for freshwater analysis (USEPA, 1971; Paus, 1971; Traversy, 1971; Kinrade and Van Loon, 1974; Aldous, 1975~. Jenne and Ball (1972) have studied the stability of the nickel-APDC complex. Diethyldithiocarbamate has also been used as a chelating agent (Joyner et al., 1967; Nix and Goodwin, 1970~. Paus (1971) and Surles et al. (1975) have used the graphite furnace to increase sample atomization for

Inorganic Solutes 289 freshwater analysis; this procedure has a nickel detection limit of I g/liter with direct sampling into the furnace. CONCLUSIONS AND RECOMMENDATIONS Because of the low toxicity of nickel and nickel compounds in food and drinking water, the low concentrations present in drinking water, and the small daily intake of nickel in drinking water (compared with food), there is no present need to establish nationwide limits for nickel in drinking water. The USEPA National Interim Primary Drinking Water Standards and the WHO European standards for drinking water do not include standards for nickel. There is no pressing need for research with regard to nickel in drinking water. In this regard, however, research to clarify the role of nickel in nutrition appears to be desirable, particularly as to its dietary essentiality. Silver OCCURRENCE The intentional addition of silver to drinking water for disinfection is one possible source of silver in public water supplies. The silver ion has bactericidal characteristics at concentrations of 15-50 ,ug/liter (don Nageli, 1893~. As a result the Katadyn process and others have been promoted for treatment of drinking and swimming-pool water. She bactericidal action is slow, especially in cold water, and silver is neither viricidal nor cysticidal in the concentration used (Renn et al., 1955~. Dosages in excess of 150 fig/ I iter have been used in swimming pools, but, because of cost and the opalescence caused by colloidal silver chloride, the method is not practical or recommended for public supplies. Data from 1,577 samples of well and surface water from 130 points in the United States showed detectable concentrations (0.1 ~g/liter or more) of silver in only 104 samples. The concentration ranged from 0.1-38 ,ug/liter, with a median of 2.6 ~g/liter (Kopp, 1969~. The highest concentrations were noted in the St. Lawrence and Colorado Rivers (Durum and Hafty, 1961~. The examination of finished water in public supplies of the 100 largest cities in the United States revealed trace quantities of silver as high as 7 g/liter, with a median of 2.3 ,ug/liter (Durfor and Becker, 1964~. Another survey of finished water found silver in 6.1% of 380 samples, with concentrations of 0.3-5 ,ug/liter (mean, 2.2 ,ug/liter) (Kopp, 1973~.

290 DRINKING WATER AND H"LTH Chemical Analysis of Interstate Carrier Water Supply Systems (USEPA, 1975) reported nondetectable silver (<0.1 ,ug/liter) in 45% of the analyses; 99.5% of all determinations were equal to or less than 50 ,ug/liter, the interim standard. The community water-supply survey (McCabe, 1970) found that none of the 2,595 samples from household taps exceeded the standard. The maximum concentration was 30 ,ug/liter. Unless lime softening in the water-treatment process results in a high pH, very little difference in silver concentration may be expected between raw and finished water. When water containing silver is used for culinary purposes, it is reasonable to assume that vegetables belonging to the family Brassicaceae-such as cabbage, turnips, cauliflower, and onions would combine with the residual silver in the cooking water. The silver content of 2 or 4 liters of water could thus be ingested, but rarely by one person. Soil contains only small amounts, but humus from decaying plants may contain up to 5 ppm. Some foods, such as bran and wheat flour, contain trace quantities (less than 1 ppm), but mushrooms have unusually high concentrations-up to several hundred parts per million (Ramage, 1930~. CHEMICAL CHARACTERISTICS Trace amounts of silver are found in natural and finished water originating from natural sources and from industrial waste. Silver is a rather rare element with a low solubility of 0.1-10 mg/liter, depending on pH and chloride concentration (Hem, 1970~. Water-soluble silver compounds include the acetate, chlorate, nitrate and sulfate. METABOLISM For reasons still unknown, individuals and individual organs absorb silver selectively. Tissues of animals and humans do not often contain silver. About 10% of tissues and samples contain silver, and the concentrations rarely exceed 0.01 ma/ 100 grams (Kehoe et al., 1940~. The cases of generalized argyria prove that silver can be absorbed from the gastrointestional tract, by inhalation of dust, and after medication with silver compounds. Excretion of silver is almost entirely in the feces, with only a trace to be found in the urine. There is little retention of silver in general, but, when it occurs the greatest concentrations are found in the reticuloendothelial organs. After intravenous injection in animals (Gammill, 1950), the order of silver concentration is spleen, liver, bone marrow, lungs, muscle, and

Inorganic Solutes 291 skin. The balance between intake and elimination is inconclusive, but evidence suggests that ingested silver is only slightly stored. HEALTH EFFECTS Large single doses of colloidal silver can be fatal. A dose of 500 mg was lethal in a dog in 12 h (Shouse and Whipple, 1931~; death was due to pulmonary edema and was preceded by anorexia and anemia. In addition to hyperplasia of the bone marrow, repeated injection of silver has caused anemia (Shouse and Whipple, 19311. It was suggested that long-term feeding of animals with silver salts may cause vascular hypertension, hypertrophy of the right ventricle, and thickening of the glomerularmembranes(Olcutt, 1950~. The chronic effects in man usually have taken the form of an unsightly permanent blue-gray discoloration of the skin, mucous membranes, and eyes known as "argyrosis" or "argyria." Although this is considered only a cosmetic defect, with no significant physiologic effect, some observers maintain that deposition in the kidney is associated with arteriosclerotic changes, and deposition in the eye, with poor night vision (Gettler, 1927; Velhagin, 19531. Local and generalized argyria, rarely seen today, has been caused by medical use of silver by ingestion or injection. Topically applied silver ointments have been shown not to pass the dermal barrier; this ensures safety on contact with bathing water treated with silver preparations (Norgaard, 19541. Industrial poisoning is a more likely cause of argyria, which develops slowly after 2-25 yr of exposure. Estimates from industrial exposure show that the gradual accumulation of 1-5 g of silver will lead to generalized argyria (Hill and Pillsbury, 1939~. The exact quantities of silver stored are not known. A safe assumption would be that 50% of the intake is retained in the body. Thus, the interim drinking- water level of 50 ,ug/liter would be equivalent to a retention of 50 fig of silver per day and would result in an accumulation of 1 g in 55 yr, to give a probable borderline argyria. However, the maximum measured silver concentration in drinking water was 30,ug/liter, which would mean 91 yr to retain the quantity believed to produce argyria. The usual silver concentrations in public water supplies are even lower about 2-3 ,ug/liter. Some states have more stringent standards, such as California (10 ~g/liter) and Illinois (0.5 ,ug/liter). The Water Quality Criteria (1972) concluded that, "Because silver in waters is rarely detected at levels above 1 ,ug/liter, a limit is not recommended for public water supply sources." There is no evidence of any beneficial effect to be derived from the ingestion of silver in trace quantities.

292 DRINKING WATER AND H"LTH ANAI Y,SIS Silver ions in solution are unstable under many conditions, but the addition of ethylenediaminetetraacetic acid to collected natural-water samples has been found to be an adequate preservative (West et al., 19671. Nitric acid is used by the USEPA ( 1971 J for stabilization. With direct flame atomization, the detection limit for silver is 2 ~g/liter. At the silver concentrations normally found in fresh water, some form of concentration is required for conventional atomization. An APDC- methylisobutylketone extraction at a phi of 2.8 is used by the U.S. Geological Survey (Brown et al., 1970~; similar procedures have been reported by others (Chao et al., 1969; USEPA, 1971; Traversy, 1971; Kinrade and Van Loon, 1974~. When a graphite furnace is used to increase sample atomization the silver detection limit is lowered to 0.005 /liter with direct sampling. Rattonetti (1974) determined silver in fresh water with flameless atomic absorption. The sampling boat and Delves cup methods over detection limits of 0.2 and 1 ~g/liter, respectively. CONCLUSIONS AND RECOMMENDATIONS There seem to be no pressing research needs with regard to silver in drinking water. There seems to be little possibility that the addition of oligodynamic silver will have any place in public water supplies, and natural concentrations are so low that consideration should be given to taking silver on the list of substances included in primary drinking-water standards. Tin OCCURRENCE Tin is seldom measured in natural water, in treated-water supplies, or at the tap. It is not indexed or mentioned in the NAS report on water- quality criteria in 1972 (USEPA, 1973), nor was it included by Durum et al. (1971) in their reconnaissance of selected minor elements in Up. surface waters. It is not listed in the National Interim Primary Drinking Water Regulations (USEPA, 1975), nor in the USSR, European, or international drinking-water standards (Stoefen, 1973~. Indeed, there are serious reservations about its valid determination, as noted below, and it is not included in Standard Methods (USEPA, 1976~.

Inorganic Solutes 293 According to Beeson et al. (1976) public water supplies in 42 U.S. cities contained tin at 1.1-2.2 ~g/liter, and water from 175 natural sources in west-central Arizona contained 0.8-30 ~g/liter. Seawater contains 0.2~.3 g/liter. With emission spectrography, Durum and Hasty (1961) analyzed 59 samples of water from 15 rivers in the United States and Canada, of which 56 values were reported as zero, i.e., below the detection limit. The other three values were 1.3, 1.4, and 2.1 ,ug/liter. Although tin is present in natural water only in traces, it may occur in industrial waste when water is stored for any length of time in tin-coated metal containers. Stannic and stannous chlorides are used as mordants for reviving colors and dyeing of fabrics, weighting of silk, and tinning of vessels. Stannic chromate is used in decorating porcelain. Stannic oxide is used in glassworks, in dye houses, and for fingernail polishes. Stannic sulfide is used in some lacquers and varnishes. Tin compounds are also used in fungicides, insecticides, and anthelmintics (McKee and Wolf, 19631. Finally, it should be noted that stannous fluoride is used in many toothpastes and consequently reaches municipal sewers. From various industrial processes and from municipal sewage, tin salts are bound to reach surface water or groundwater; but, because many of the salts are insoluble in water, it is unlikely that much of the tin will remain in solution or suspension. The major source of human intake of tin is canned foods and beverages. It is usually present in canned foods and drinks at levels less than 100 mg/kg, but much higher concentrations (greater than 1,000 mg/kg) may be present in some products after prolonged storage in closed nonlacquered cans or after some days of storage in open cans (Monier-Williams, 1949~. Schroeder et al. (1964) reported that natural foods, many from garden soils, contained tin ranging from zero to 8.5 mg/kg on a fresh-weight basis or up to 40 mg/kg in dry material. These values are considerably lower than those observed for canned food and beverages, but both sets are three or more orders of magnitude greater than the concentrations in water. Very little information is available on airborne tin, but there may be danger to industrial and agricultural workers from the inhalation of atmospheric organic tin compounds, e.g., triphenyltin acetate, used in fungicides and insecticides (Klimmer, 19681. Needless to say, the use of such pesticides increases the potential for intake of tin by ingestion of the pertinent crops as food. Dust sediments from industrial regions of Europe were reported by Morik and Morlin (1959) to contain tin at 1~10,000 mg/kg of dust.

294 DRINKING WATER AND H"LTH CHEMICAL CHARACTERISTICS In nature, tin is a decidedly minor rock component; it would not be expected to be found in natural water, except in very minor traces. Stannous hydroxide, Sn(OH)2 is soluble in water at 25°C at about 1.6 ppm. At a pH considerably below that normally found in natural water, a much nigher concentration may be possible; at a high pH, above the normal for natural water, tin may be part of an anion complex and dissolve in greater concentrations (USGS, 1959~. . . ~ , 1_ 1 · ~ . . METABOLISM According to the FDA (USFDA, 1975), "tin is poorly absorbed from the alimentary tract and most ingested tin is excreted via the feces. The tin that is absorbed is found mainly in the liver and lung with small traces in other tissues." In contrast, Kent and McCance (1941) found that at least half the dietary tin was excreted in urine. With a tin intake of 14.4 mg/day for 7 days, their subject excreted 7.2 mg/day in urine and 6.6 mg/day in feces. Hence, almost all the ingested tin was excreted. It has been reported that the average human diet contains tin at 17.14 mg/day and that people can apparently tolerate 850-1000 mg/day (McKee and Wolf, 1963~. In contrast, Schroeder et al. (1964) stated that the daily oral intake of tin by a man in the United States is between 1 and 30 mg/day, with typical intakes near 3 4 mg/day. Even the highest value (30 mg/day) is considerably lower than the 5-7 mg/kg of body weight at which toxic symptoms may appear (WHO, 1973~. Tipton et al. (1969) reported that the daily intake of tin in the United States ranged from 0.1~100 ma, with an average of 5.8 ma. Again, such values are below those that might cause toxicity. Higher concentrations of tin are found in tissue from people in wealthier countries, probably as a result of greater use of canned foods (Schroeder et al., 1964~. HEALTH EFFECTS There is no conclusive evidence that tin plays an essential biologic role in human nutrition (Browning, 1961~. However, in rats maintained on purified amino-acid diets in trace elements, Schwarz et al. (197(~) found that trimethyltinhydroxide, dibutyltinmaleate, stannic sulfate, and potas- sium stannate enhanced growth at tin dosages of 0.5-2.0 mg/kg of diet. Although the use of animal data to determine optimal intakes for people is subject to many possible errors, one might calculate that a 70-kg person

Inorganic Solutes 295 would require tin at about 7.0 mg/day. Before tin can be conclusively considered as an essential trace element, ejects should be demonstrated in several generations of various animals. inorganic tin is relatively nontoxic. DeGroot et al. (1973) fed inorganic tin compounds to rats for 13 weeks and found no toxic effects at tin concentrations of 450-650 mg/kg of diet. Indeed, some inorganic tin compounds had no effect on rats at three times that concentration. Organic tin compounds, however, have demonstrated toxicities and have been used as fungicides, bactericides, insecticides, and anthelmintics (i.e., against intestinal worms). These compounds are generally of the type R3snx' where R is an alkyl group (especially ethyl or propyl) and X is an anion, such as chloride. The toxicities of organotin compounds have been reviewed by Barnes and Stoner ( 1 959) and Poller (19701. According to the FDA (USFDA), the "symptoms of acute tin toxicity" (to humans) "are nausea, abdominal cramping, diarrhea, and vomiting." These symptoms have often followed consumption of canned fruit juices containing 1,400 ppm tin, canned salmon containing 650 ppm tin, and vodka punch containing 2,000 ppm tin. The latter had been held in a tin can. Due to low intestinal absorption of tin, the acute toxic symptoms are probably due primarily to local irritation of the gastrointestinal tract. "One hundred deaths in France resulted from capsules known as 'Stalinon,' used for treatment of staphylococcal skin infections. The capsules contained diethyltindiiodide (15 mg/capsule) and linoleic acid and were contaminated with mono- and triethyl tin." (USFDA, 1975) ANALYSIS Beeson et al. (1976) expressed serious reservations about the analytic determination of tin, especially at low concentrations. Many foreign substances in a sample interfere with the determination of tin by atomic absorption. Dry ashing is also subject to several errors, especially for most organotin compounds. As a result, many, or all, of the data reported on tin in water, food, and air can be accepted only with some reservations. Direct flame atomization offers a tin detection limit of 10 ~g/liter; however, tin can be determined to quite low concentrations by special- ized atomization devices. With sodium borohydride as a reductant, Fernandez (1973) detected tin at 0.2 ~g/liter in 20-ml sample. The acidity of the solution is critical and appears to be optimal near 0.2 N in hydrochloric acid. When the graphite furnace is used to increase sample atomization a detection limit of 0.1 ~g/liter is possible (Everett et al., 19741.

296 DRINKING WATER AND H"LTH CONCLUSIONS AND RECOMMENDATIONS inorganic tin is relatively nontoxic, but organotin compounds can be toxic at very high concentrations. Indeed, they are used as fungicides, insecticides, and anthelm~ntics. Tin has seldom been determined in natural or municipally treated water. The few available data generally show concentrations about 1 or 2 ,ug/liter. In contrast, tin is present in most natural foods, and especially in canned products, up to 30 mg/day. This is three or more orders of magnitude higher than the probable amount in a liter of tap water. The EPA has not set a maximum containment level for tin in its National Interim Primary Drinking Water Regulations. No maximum containment level is recommended or needed. Perhaps the foremost research need with respect to tin is the development of a rapid accurate method of determination at the low concentrations expected in drinking water. Until such a method is available, reliable data for natural or treated water cannot be expected. Vanadium The NAS has recently (1974) completed an extensive review on the medical and biologic ejects of vanadium, which has been used in preparing this report. OCCURRENCE A high vanadium concentration of 6.7 ,ug/liter has been reported in the Sacramento River, Sacramento, California (Durum and Hasty, 1961~. Kopp and Kroner (1967) observed detectable concentrations in 3.4% of the samples analyzed; the concentration ranged from 2 to 300 ~g/liter, with an average of 40 ~g/liter. One kind of pollution from vanadium must be noted when considering water. Residues from the milling and mining of vanadium are often heaped on the ground or used as landfills, thus being exposed to rainfall and groundwater drainage, which could result in water pollution for many miles around. CHEMICAL CHARACTERISTICS Vanadium does not occur naturally in highly concentrated forms. This is true despite the fact that it is as abundant in the earth's crust as zinc and nickel and occurs in at least 50 different mineral species. It usually occurs in some oxidized form usually as a metal vanadate. Vanadium

Inorganic Solutes 297 can also be found in trace amounts in fossil fuels. The solubility in water of vanadium pentoxide and sodium metavanadate are 0.07 and 21.1 gilOO ml, respectively. Vanadium can also form covalent bonds with organic molecules to yield organometallic compounds (NAS, 1974~. METABOLISM It has been reported that absorption of vanadium through the skin occurs from an approximately saturated (kilo) solution of sodium metavana- date. Even with exposure to vanadium particles, the skin absorption appears to be of minor importance (NAS, 19744. In an experimental study in which humans were exposed to vanadium oxide dust - with tests being run, before, during, and after exposure the greatest amount of vanadium was found in the urine 3 days after exposure; none was detectable after a week. Fecal vanadium was at a maximum of 0.003 mg/g; none was detected after 2 weeks. All reactions to the exposure were respiratory. Coughing, mucus formation, rates, and expiratory wheezes were present, but did not last (NAS, 1974~. Vanadium concentrations in human tissues have been found to be less than 1 ~g/g of ash, except in the lungs, where up to 108 mg/g (ashed material) has been reported after extremely high exposure. Vanadium pentoxide is readily absorbed from the lungs into the bloodstream (USEPA, 1975~. It would have to be concluded that absorption in the human body is extremely low; and it must be kept in mind that vanadium has not been proved to be essential to humans (Shakman, 1974~. Evidence seems to indicate that the excretion pathway of vanadium is through the kidney, regardless of the form administered. Rats, rabbits, and man all excrete sodium metavanadate via the urinary pathway. Man also excretes ammonium vanadyl tartrate in the urine (USEPA, 1975~. HEALTH ASPECTS A relatively large amount of vanadium (some 30,000 metric tons/yr) enters the environment from man's activities, but no widespread detrimental ejects have been identified. Presumably, man and other animals do not store or accumulate vanadium in hazardous amounts. The degree of vanadium toxicity depends largely on the dispersion and solubility of vanadium aerosols in biologic media. Toxicity also depends on the valence; i.e., it increases with increasing valence, with pentavalent vanadium being most toxic. In addition, vanadium is toxic both as a cation and as an anion.

298 DRINKING WATER AND H"LTH The oral LD50 of vanadium trioxide for albino mice is 130 mg/kg, while the LD50 for vanadium pentoxide and vanadium bichloride is 23 mg/kg (Roshchin et al., 19659. The major signs and symptoms of acute vanadium toxicity in man are primarily respiratory. Aside from its acute inflammatory eject on the · . . . . . lungs, it appears to act mainly on various enzyme systems. Chronic respiratory exposure to vanadium may decrease cholesterol synthesis, uncouple oxidative phosphorylation in liver mitochondria, and decrease urinary excretion of 5-hydroxyindoleacetic acid, with transient bilirubinemia and albuminuria. Another symptom is the appearance of scattered allergylike eczema- tous skin lesions. These are found, for the most part, on exposed skin. This allergic syndrome has been seen in workers and experimental animals. A persistent complication is a slight to moderate change in the mucous membranes of the upper respiratory tract, particularly the pharnyx; but no chronic bronchitis or changes in the lung have been reported. Permanent damage to the target organs, including the lungs, has never been conclusively established. There is no evidence of chronic oral toxicity (NAS, 1974~. ANALYSIS With a vanadium detection limit of 40 ,ug/liter, conventional flame atomization lacks sensitivity for direct determination in most samples. Crump-Wiesner and Purdy (1969) have studied various extraction systems and found that both vanadium (IV) and vanadium ~ are extracted from an aqueous solution at a pH of 3.8 with a cupferron- methylisobutylketone system. With direct sampling, the graphite furnace can be used to increase sample atomization with a detection limit of 5 g/liter. CONCLUSIONS AND RECOMMENDATIONS A limit of 0.1 mg/liter has been suggested in the USSR as a maximum permissible limit for water basins (USEPA, 1975~. The lack of data on acute or chronic oral toxicity is not surprising because of the extremely low absorption of vanadium from the gastrointestinal tract. Inhaled vanadium can produce adverse health ejects, but the available evidence does not indicate that vanadium in drinking water is a problem.

Inorganic Solutes 299 Zinc Zinc is considered an essential trace element in human and animal nutrition. This topic has been recently reviewed in Clinical Chemistry (1975) in a special issue on trace elements, by Sandstead (1974), by Underwood (1971), and in Toxicants Occurring Naturally in Foods ~AS, 1972~. The recommended daily dietary allowances for zinc recently recommended by the NAS (1974) are as follows: adults, 15 mg/day; growing children over a year old, 10 mg/day; and additional supplements during pregnancy and lactation. As far as human health in the general population is concerned, the major concern is not with toxicity, but rather with marginal or deficient zinc intake. The available data indicate that the contribution of drinking water to the daily nutritional requirement for zinc is negligible under most circumstances. OCCURRENCE In general, in streams and rivers, zinc is concentrated in sediments, but concentrations are quite low in running filtered water. It is reported that approximately 22,000 tons of zinc are used in fertilizers each year in the United States. The extent to which this may run on into rivers and streams is not known. Likewise, no significant body of data relative to the runoff into streams from dumps and metallurgic wastes has been found. Craun and McCabe's (1975) recent summary indicates that concentra- tions of zinc in finished water at the treatment plant are well below the 1962 drinking-water standard of 5 mg/liter. However, in areas of soft acidic water in Seattle, Washington, and Boston, Massachusetts pickup in the distribution system was noted in comparing water samples from the treatment plant with samples at the tap. In the Boston study, 35% of 108 samples showed pickup, but both mean and maximum concentrations in running water were well within the current limit (mean, 223 ,ug/liter; maximum, 1,625 ~g/liter). In the more acidic water in Seattle, pickup of zinc was noted in 95% of samples, and 10% were in excess of the standard of 5 mg/liter. The maximum concentration found in the study was 5.46 mg/liter. In rocks, zinc is most commonly present in the form of the sulfide sphalerite, which is the most important zinc ore. Zinc may replace iron or magnesium in certain minerals. It may be present in carbonate sediments. In the weathering process, soluble compounds of zinc are formed and the presence of at least traces of zinc in water probably is common. Concentrations of 40 ppm impart a strong astringent taste to water. Food is the major source of zinc. This topic has been reviewed

300 DRINKING WATER AND H"LTH elsewhere (Sandstead, 1974; Underwood, 1971~. Regarding industrial exposures, the acute metal fume fever generally attributed to zinc is a brief self-limited disease and is well known. In other types of industrial smelting operations, zinc, lead, and cadmium frequently occur together; the latter two are much more toxic than zinc. Where accidental discharge in water has been identified, it has been related to smelting and refining operations and has involved combined exposures to zinc, cadmium, and lead (Friberg et al., 1974~. Airborne zinc is generally not considered significant, as far as the general population is concerned. CHEMICAL CHARACTERISTICS Zinc chloride and sulfate are very soluble in water, but hydrolyze in solution and reduce the pH. If the pH is maintained by the presence of an excess of bicarbonates and other anions normally present in natural water, the solubility of zinc is likely to be controlled by the solubility of its carbonate and hydroxide. Zinc carbonate is soluble in pure water at 25°C to the extent of zinc at 107 mg/liter. The hydroxide is soluble only to the extent of zinc at 0.2 mg/liter. The pH at which zinc might precipitate as hydroxide is probably not reached in the presence of excess carbon dioxide in solution. At a very high pH, zinc may form anion complexes, but such conditions are not likely in natural water (USGS, 1959) METABOLISM An earlier NAS committee (Sandstead, 1974) identified zinc balance data in humans as an area needing much more research. In general, animal studies indicate that, although zinc is distributed throughout the body, including bone, there is a small labile pool with a rather rapid turnover. The urinary excretion of zinc is generally less than 1 mg/day. HEALTH EFFECTS Diets grossly deficient in zinc have been found in Iran and Egypt. These have been associated with growth failure, loss of taste, and, in the postpubertal male, hypogonadism and decreased fertility. It is likely that factors in addition to zinc may also be involved. With the exceptions of diminution of taste discrimination and appetite, such conditions have not been identified in the United States, although there is a suspicion that some segments of the population are marginally zinc-deficient. Of interest is the recent finding that patients with sickle-cell disease may be zinc- deficient, owing at least in part to an increased loss of zinc in the urine.

Inorganic Solutes 301 Acute adverse ejects of zinc include acute metal fume fever by the inhalation of fumes. There appears, on the basis of animal studies, to be a rather wide margin of safety between tap-water zinc content and oral doses that will produce toxicity (NAS, 1973~. There have been reports of human cases of zinc poisoning associated with the prolonged consump- tion of water from galvanized pipes. In two adults, irritability, muscular stiffness and pain, loss of appetite, and nausea were reported when the water contained zinc in a concentration of 40 mg/liter, which is well above the current secondary drinking-water standard of 5 mg/liter. There is no evidence that zinc in excess is carcinogenic, mutagenic, or teratogenic. Zinc interacts with other trace metals (Sandstead, 1974, 1976~. It clearly has a protective action against cadmium and lead. Animal data suggest that the zinc: copper ratio in the diet may be important. As noted above, there may be an interaction between zinc and iron. If these experimental observations are, in fact, important for human health, then it is possible that the ratio of zinc to these other metals in drinking water may be of some importance. This problem has not been explored. ANALYSIS Most freshwater analyses may be made by using atomic-absorption spectrophotometry with direct aspiration, with a zinc detection limit of 1 ,ug/liter. She EPA (1971) and the U.S. Geological Survey (Brown et al., 1970) procedures are typical. For low concentrations in fresh water, solvent extraction may be used. Mulford (1966), Paus (1971), Kinrade and -Van Loon (1974), and Aldous et al. (1975) have found that the APDC-methylisobutylketone system extracts zinc at a pH of 2.6. Diethyldithiocarbamate (Joyner et al., 1967; Nix and Goodwin, 1970), dithizone (Sachdev and West, 1969), and dibenzyldithiocarbamate (Ichinose, 1974) are among other chelating agents used for concentrating zinc. The Delves cup and sampling boat (Paus, 1971) have been used for zinc analysis, with detection limits of 50 and 30 ,ug/liter, respectively. Fernandez and Manning (1971) and Surles et al. (1975) have demon- strated the use of the graphite furnace to increase sample atomization for fresh-water analysis, with a zinc detection limit of 0.001 ,ug/liter. Background correction appears to be essential in atomic-absorption spectrophotomet~y. In recent years, since the introduction of background correction, normal plasma zinc concentrations have consistently de- creased.

302 DRINKING WATER AND H"LTH CONCLUSIONS AND RECOMMENDATIONS Research needs have been proposed previously by an NAS committee (Sandstead, 19741. These are related primarily to the zinc content of foods, the need to determine whether a significant proportion of American diets are either deficient or marginal in zinc, and whether specific segments of the population are genetically susceptible to zinc deficiency. The recommendations include: 1. Assessment of the availability of zinc in food to man. 2. Determination of human zinc requirements in relation to age and physiologic state. 3. Evaluation of the possible implications of the zinc: cadmium ratio for health. 4. Determination of the zinc status of various well-defined populations and relation of these findings to other measures of nutritional status. 5. Assessment of the eject of zinc supplementation and enrichment on the health status of well-defined populations. In addition, animal data suggest that zinc is also protective against lead toxicity. This possibly significant interaction needs further investigation. As far as drinking water is concerned, the present drinking-water standard, assuming an adult water consumption of 2 liters/day, would permit the intake from drinking water of up to 10 mg/day, which is less than the estimated adult dietary requirement for zinc. The available data on drinking water, however, suggest that the amounts in drinking water are far lower than this. Another area requiring further investigation is related to the zinc content in the presence of soft water and the use of galvanized pipes. The present recommended primary interim drinking- water standard of 5 mg/liter appears adequate for acceptable taste and appearance of drinking water. Summary-Trace Metals The Interim Primary Drinking Water Regulations list maximum allow- able concentrations for six metallic elements barium, cadmium, chro- mium, lead, mercury, and silver. Ten additional metals were reviewed in this study-beryllium, cobalt, copper, magnesium, manganese, molybde- num, nickel, tin, vanadium, and zinc. Sodium, which is also a metallic constituent, is considered in a separate section because the problems it poses are quite distinct from those associated with the other metallic substances.

Inorganic Solutes 303 Eight of these selected metals are known to be essential to human nutrition: chromium, cobalt, copper, magnesium, manganese, molybde- num, tin, and zinc. Nickel and vanadium probably are essential also, and it is possible that barium can be beneficial under certain conditions. The toxic metals, lead, mercury, and cadmium are believed not to be essential to humans. Beryllium and silver also are not known to be essential. Elements that are beneficial in small quantities very often exhibit toxic properties when ingested in excessive amounts or concentrations. In assessment of the adverse health effects of such materials it is important not to overlook the deficiency problems that might be enountered if the substances were to be completely eliminated from water supplies. Trace metals, usually in the form of ions, occur in water both as a result of natural processes and as a consequence of man's activities. Groundwa- ters, because of long contact with rocks and mineralized soils, usually contain greater concentrations of trace metals than surface waters. There is considerable temporal and spatial variation in concentrations of trace metals in surface waters. Generally, the trace metal concentrations of rivers tend to increase from source to mouth and to vary inversely with discharge, which dilutes the natural and industrial contaminations. Of the 16 metals studied the relative contribution of man's activities to the concentrations found in water supplies can be rated roughly as follows: very great cadmium, chromium, copper, mercury, lead, and zinc; high silver, barium, molybdenum, tin; moderate beryllium, cobalt, manganese, nickel, and vanadium; low magnesium. Other important sources of trace metals in drinking water are water treatment processes and pickup of metallic ions during storage and distribution. Although a large fraction of the United States continues to receive water from ground sources or from impounded upland sources without treatment other than disinfection, most large surface supplies are subjected to treatment that includes coagulation, sedimentation, filtra- tion, and disinfection. Should trace metals occur in the raw-water supply, these normal water-treatment processes have either no eject or an uncertain one on removing the usual low level concentrations of these metals. Moreover, probable trace metal impurities in the technical-grade chemicals used may introduce additional concentrations into the treated water. Control of the corrosive properties of the finished water is important to prevent increase in trace metal concentrations during storage and distribution. A wide variety of materials, including several metals, alloys, cements, plastics, and organic compounds, are used in the pumps, pipes, fittings, and reservoirs of distribution systems and home plumbing. Reactions, particularly of soft, low-pH waters, with materials of the

304 DRINKING WATER AND HEALTH distribution system very often have produced concentrations of iron, copper, zinc, lead, and cadmium at the tap much greater than those in the raw or treated waters at the plant. The positive correlations between "hard" water supplies and reduced cardiovascular disease is discussed in detail elsewhere in this report. Adverse health effects associated with trace metals depend upon the total intake from all sources water, air, and food. As a general rule concentrations of trace metals in foodstuffs greatly exceed those found in drinking waters. Because the diet of most of the U.S. population is increasingly varied and comes from diverse geographical sources as a result of modern food distribution practices that counterbalance local excesses or deficiencies, the dietary intake of trace metals exhibits relatively small variation throughout the United States. This factor is helpful in evaluation of maximum no-adverse-health-e~ect concentra- tions for drinking water. Airborne exposure to trace metals is largely occupational through the inhalation of industrial dusts or fumes, except for lead, to which there is more general exposure from motor exhaust fumes. Most evidence for acute and chronic health ejects is derived from data on occupational exposures; caution must be observed in extrapolation of these data to the general public. All of the trace metals studied' are letdown to exhibit toxic effects at some level of intake. Many of these, however, are at levels greater than the maximum concentrations found in drinking water. To include such materials in primary drinking-water standards with a requirement for mandatory surveillance does not confer any health benefit. Adverse health ejects from trace metals that are not found in excessive concentration in delivered water supplies can be avoided most readily by preventing the discharge of such contaminants into water in quantities that might increase concentrations to the maximum no-observed-ad- verse-health-effect level. The following sections summarize the findings on individual trace metals. Barium It is rare to find barium in drinking water at a concentration in excess of 1 mg/liter because of the low solubility of barium sulfate. Natural and treated waters usually contain sufficient sulfate so that more than 1 to 1.5 mg/liter of barium cannot be maintained in solution. Acid-soluble barium salts are very toxic, whereas insoluble compounds are benign. There has been no determination of the chronic effects of low

Inorganic Solutes 3~)5 levels of barium ingested over a long period of time. The chronic phase of poisoning is an occupational disability following prolonged exposure to barium dust. It is recommended that animal studies involving long-term low-level ingestion of barium salts in water be carried out to determine possible health ejects. The Interim Primary Standard of 1 mg/liter for barium has been based on extrapolation from ejects of industrial exposure to dusts of soluble barium salts. Insufficient data are available to estimate maximum no- adverse-health-e~ect levels on the basis of water intake. The limit of 4 mg/liter of the USSR is based on organoleptic factors. International and European standards of the World Health Organization do not list barium. Beryllium Beryllium is not likely to be found in natural waters in greater than trace amounts because of the relative insolubility of beryllium oxides and hydroxides in the usua! pH range of drinking waters. The sulfate and chloride are very soluble, but they hydrolyze quickly to the insoluble hydroxide. Beryllium produces acute or chronic toxicity in animals when ingested continuously as beryllium sulfate in food or water only at 1~. els in excess of 1~20 n~g/kg of body weight per day or at concentrations greater than 5 mg/liter. Soluble beryllium has been shown to be transported in the bloodstream to bone where it has been found to induce bone cancer in animals, but the data are insufficient to allow estimation of risk. Prolonged inhalation of dusts containing beryllium is known to produce findings similar to pulmonary sarcoidosis. However, increased incidence of lung cancer among workers exposed to beryllium-containing dusts has not been found. No maximal allowable concentration for beryllium has been listed in the Interim Primary Drinking Water Regulations, nor has the WHO recommended a maximum limit. The USSR, however, has set a limit of 0.2 ~g/liter. Until now the maximum concentration of beryllium found in U.S. surface waters has been 1.2 ~g/liter and in finished U.S. drinking waters has been 0.17 ~g/liter. Only 1.7% of drinking-water supplies examined have been found to contain any detectable beryllium. Additional studies of the frequency of occurrence and concentration levels of beryllium in natural waters are needed to determine the extent to which it presents a hazard to health.

306 DRINKING WATER AND H"LTH Cadmium Cadmium is not known to be an essential or beneficial element. It has been found in 2-3% of U.S. surface waters, generally in concentrations not exceeding a few milligrams per liter due to the low solubilities of cadmium carbonate and hydroxide at pH greater than 6. Only 0.2% of the supplies in the Community Water Supply Survey showed cadmium in excess of 0.01 mg/liter. In addition to its geological sources, cadmium enters water from the discharge of plating wastes and by the action of corrosive waters on distribution piping and home plumbing. Food is the primary source of cadmium intake. Total daily intake from air, water, food, and tobacco ranges from 40 ,llg/day for the rural nonsmoker on a low cadimum diet to 190 ~g/day for the urban smoker on a high cadmium diet. Drinking water conributes only a small fraction (<5~O) to this total intake. Chronic ingestion of cadmium at levels greater than 600 ~g/day in combination with several other necessary predisposing factors was found to be responsible for the onset of Itai-Itai disease in Japan. Dietary intake of amounts in excess of a milligram per day is needed for appearance of acute toxicity. Major toxic ejects are on the kidney; data indicate that the toxicity of cadmium is related to the zinc: cadmium ratio within the organs. Both zinc and calcium may be protective against cadmium toxicity. Persons deficient-in these elements, and especially lactose- intolerant persons who are likely to be calcium-deficient, may constitute a high risk group toward cadmium. There have been some indications of carcinogenic and teratogenic ejects of cadmium in animal studies, but dose-response relationships are unknown. Cadmium has also been implicated as a factor in hypertension. Insufficient data are available for establishment of a maximum no- observed-adverse-health-e~ect value. It may be noted, however, that at a concentration level of 10 ,ug/liter in water, cadmium contributes only about 20% of the normal total daily adult intake with water consumption at 2 liters/day. Both the WHO and the USSR have set the maximum allowable limit for cadmium at 10 ~g/liter. Chromium Microgram amounts of chromium, derived primarily from food, are essential for maintenance of normal glucose metabolism. Chromium (VI) is known to be toxic, principally on the basis of information from respiratory occupational exposures. Increased risk of lung cancer among

Inorganic Solutes 307 those exposed occupationally to chromium (VI) has been established. Although inhaled hexavalent chromium may cause cancer of the respiratory tract, the IARC working group concluded "there is no evidence that non-occupational exposure to chromium constitutes a cancer hazard." Concentrations of chromium found in natural waters are limited by the low solubility of chromium (III) oxides. A study of more than 1,500 surface waters showed a maximum chromium content of 0.1 1 mg/liter, with a mean of 0.01 mg/liter. Little information is available on average total daily intake of chromium in the United States, although it appears to be in the range of 6(}280 ,ug/day. It has been suggested that diets containing mostly processed foods may be chromium-deficient. Tissue chromium in U.S. adults has been shown to decline with age. In addition to the beneficial eject of chromium on glucose metabolism, there have been indications from animal studies that chromium deficiency may induce atherosclerosis. Toxicity of chromium depends on the valence. No toxic ejects were observed in rats when drinking water contained 25 mg/liter of trivalent chromium for a year or 5 mg/liter for life. Acutely toxic doses of trivalent chromium fall in the range of grams per kilogram of body weight. nexava~ent chromium was also tolerated at the 25 mg/liter level for a year by rats. Dogs showed no effects with 11 mg/liter over a 4-yr period. Higher doses are toxic, however, producing erosion of the gastrointestinal tract and kidney lesions. The maximum limit of the Interim Primary Drinking Water Standards, 0.05 mg/liter, is only one-hundredth of the maximum no-observed- adverse-health effect concentration. The European standards of the WHO and Japanese standards give the same acceptable limit, but set it in terms of hexavalent chromium only. The USSR has limits of 0.1 mg/liter chromium (VI) and 0.5 mg/liter total chromium, based on organoleptic factors. More information is needed on the carcinogenic potential of ingested chromium (VI) and chromium (III). If it becomes clear that highly toxic or carcinogenic ejects occur only with chromium (VI) and a suitably sensitive analytical technique is available, then the standard might be set for chromium (VI) alone. In view of the U.S. trend toward dietary chromium deficiency and the suggestion that chromium protects against atherosclerosis, it seems advisable to investigate whether greater allowed concentrations are without adverse health ejects, as some animal experiments suggest. ,, ~. ~

308 DRINKING WATER AND H"LTH Cobalt Cobalt is an essential element as a component of vitamin Bin. This is its only known nutritional function. Excessive intake of cobalt may be toxic with the most notable instance being the association of congestive heart failure with the consumption of beer containing about 1.5 mg/liter of cobalt. Cobalt has been observed in natural waters only in trace amounts. Most waters have no detectable cobalt and values greater than 10 ~g/liter are rare. The maximum recorded value in any of several broad studies was 99 ~g/liter. The major source of cobalt is food; concentration in green, leafy vegetables may be as great as 0.5 mg/kg dry weight. Normally, less than 1% of total intake of cobalt is derived front aqueous sources. Acute toxic ejects in animals have been observed only with daily cobalt doses greater than several mg/kg of body weight. Chronic cobalt toxicity has been observed in children taking cobalt preparations to correct anemia at daily doses of 1 6 mg/kg body weight. T he Interim Primary Drinking Water Standards do not list cobalt, nor has the WHO recommended a limit in its International or European standards. The USSR has set a limit of 1.0 mg/liter. Because the maximum no-observed-adverse-health-effect level is more than an order of magnitude greater than the concentration found in any natural-water or drinking-water supply, there appears to be no reason at present to regulate the concentration of cobalt in drinking water. Copper Copper is an essential element for both plants and animals; it is a component of several enzymes that perform important physiological ~ . {unctions. Copper is a minor constituent of natural waters, the concentration ranging from 1 to 280 ~g/liter in a survey of 1,600 surface waters of the United States. Concentrations may be increased in drinking waters to several mg/liter by corrosion of copper piping in distribution systems, particularly with soft, nonalkalinc waters. Copper may also be released into water in industrial discharges and has been used for algal control in reservoirs at concentrations of a few tenths of a milligram per liter. Average total intake of copper is about 2.5 mg/day, so that when water contains more than 1 mg/liter of copper, the intake from water may equal or exceed that from food. The general health hazard from excess copper intake at a level of a few

Inorganic Solutes 309 milligrams per liter appears to be small, but few people are adversely affected by ingestion of even trace amounts of copper. This disorder of copper metabolism, called Wilson's disease, can be arrested by the use of chelating agents. Individuals with deficiency of glucose-6-phosphate dehydrogenase may be sensitive to copper. The USPHS Drinking Water Standards (1962) recommended a limit for copper of 1 mg/liter based on organoleptic rather than health effects. Because no general adverse-health-e~ects have been observed at the organoleptic limit and because the few individuals with metabolic deficiency are at the mercy of total copper intake rather than copper in water, there is no hygienic reason to impose a limit lower than the presently accepted secondary standard. Lead No beneficial ejects of lead on human or animal development have yet been found. Although acute lead poisoning is rare, chronic lead toxicity is severe and occurs even with low daily intake of lead (~1 ma) because of its accumulation in bone and tissue. The natural lead content of surface waters is generally small. In a survey of nearly 1,600 raw surface waters 20~o were found to contain detectable concentrations of lead and these had a mean concentration equal to 0.023 mg/liter. The lead concentration in municipal supplies at the tap may be much greater, however, for soft, low pH (agressive) waters will dissolve lead from service connections, lead-lined household piping or soldered joints. Lead concentrations in excess of the interim standard of 0.05 mg/liter were found in 1.4% of the water systems tested in the Community Water Supply Survey. The maximum value was 0.64 mg/liter. The mean concentration of lead in U.S. drinking waters has been estimated to be 0.013 mg/liter. Consumption of 2 liters/day per capita gives a mean daily intake of 26 fig. Lead intake from food varies greatly with mean daily values estimated at 100 300 leg per capita for adults. Average water intake is considerably less than that from food, but when the concentration in water is close to or exceeds the interim standard of 0.05 mg/liter, water intake approaches that from food. Absorption of lead from dietary sources, either food or water, is estimated to be about logo for adults. Daily lead absorption from food is, then, 1~30 ,ug, while absorption from water ranges from an average of 3 ,ug to 10 fig or more, when water having a lead concentration of 0.05 mg/liter or greater is ingested at 2 liters/day.

310 DRINKING WATER AND HEALTH The daily intake from air also ranges widely, and is greatest among city dwellers. For a daily inspiration volume of 20 ma for adults and a lead concentration of 3 ~g/m:` in urban air, the per capita daily intake is 60 fig. The absorption percentage from air is about 40~, however, so that the daily quantity absorbed is 24 fig, a value comparable with the dietary absorption. The sum of the estimated adsorptions from the various routes, 5~60 g/day, is already at the maximum no-observed-adverse-health-e~ect values of 50-60 ~g/day. Children, and especially inner-city urban children, are a special risk group with regard to lead toxicity. A primary reason is that absorption of lead from food and water is 4~50% for 2-3-yr-old children, rather than the 5 to low characteristic of adults. Also, water intake per kilogram of body weight is considerably greater for young children than for adults. Moreover, lead concentrations in urban air increase with proximity to the ground, so that urban children tend to have increased intake from this source. Young children also have the added risk of ingestion of flaking lead-based paints especially in depressed, older, urban areas. Dietary lead intake for a 2-yr-old child (12 kg) has been estimated to be 100 ~g/day (8.3 ~g/kg/day); with water at the present 0.05 mg/liter limit and a consumption of 1.4 liter/day' and with air intake about 18 ~g/day, the estimated total intake for a 2-yr-old would be close to 190 ~g/day, not including other possible sources. If the water contains 0.1 mg/liter of lead, the present allowable limits of the WHO European standards and of the USSR, then an intake of nearly 260 leg lead/day for a 2-yr-old child can be estimated. With this intake an overall absorption close to 100 ,ug/day can be estimated, a value suggesting that the allowable concentra- tions of the WHO European standards and the USSR may fail to provide adequate protection for children. Major chronic adverse effects of lead are produced in the hematopoiet- ic system, central and peripheral nervous systems, and kidneys. Distur- bance in heme synthesis is considered to be the most sensitive eject. There is a detectable increase in red-cell protoporphyrin in women and children with blood lead concentrations greater than about 25-30 ~g/dl. For men occupationally exposed, the maximum no-observed-adverse- health-effect level appears to be somewhat greater at 50 60 ~g/dl. Results of studies in the Boston area indicate that increased blood levels of lead will occur in children when the water supply contains 0.05- 0.1 mg/liter of lead. Thus, the interim limit of 0.05 mg/liter may not provide the margin of safety to safeguard the high-risk population in urban areas. Although satisfactory for a 70-kg adult, the WHO recommendation of 5 fig of lead per kg/day as a safe total daily intake

Inorganic Solutes 311 cannot be met for a 12-kg child when the water supply contains as much as 0.05 mg/liter. It is concluded that the no-observed-adverse-health- e~ect level cannot be set with assurance at any value greater than 0.025 mg/liter. Magnesium Magnesium is an essential element in human, animal, and plant nutrition. It is geologically ubiquitous and the industrial uses of its salts are legion. The average U.S. adult ingests between 240 and 480 mg of magnesium per day. Magnesium intake from 3.6~.2 mg/kg of body weight are believed to be adequate to maintain magnesium balance, which is closely regulated by normal kidneys. The median concentration of magnesium in the water of the 100 largest U.S. cities was reported at 6.26 mg/liter with a maximum of 120 mg/liter. It can be higher, especially in arid western states. An excess of magnesium in the diet is seldom harmful, for it is generally excreted promptly in feces. High concentrations of magnesium sulfate in drinking water have a cathartic effect on new users, but a tolerance is soon acquired. Excessive magnesium in body tissues and extracellular fluids occurs only as a result of severe kidney malfunction. Magnesium deficiency in humans may occur in alcoholics, persons performing hard labor in hot climates (because magnesium is excreted in perspiration), those with certain endrocrine disturbances, and patients using potent diuretics. Such deficiencies can best be overcome by oral administration of magnesium compounds. The National Interim Primary Drinking Water Regulations do not contain a limit for magnesium, nor did the 1962 USPHS drinking water standards. The USSR has set no limit, but the WHO has recommended a maximum of 150 mg/liter. In view of the fact that concentrations of magnesium in drinking water less than those that impart astringent taste pose no health problem and are more likely to be beneficial, no limitation for reasons of health appears needed. Manganese Manganese resembles iron in its chemical behavior and occurrence in natural waters, but is found less frequently and usually at lower concentrations than iron. Manganese, like iron, is an essential trace nutrient for plants and animals. It is not known whether human manganese deficiency occurs in the United States. The solubility of the several oxidation states of manganese (II, III, and IV) depends upon the

312 DRINKING WATER AND HEALTH pH, dissolved oxygen, and presence of complexing agents. Occasionally, deep lakes or impounding reservoirs that contain organic sediments under anerobic reducing conditions can distribute several mg/liter of Mn+2 throughout the water body during "turnover" mixing. Normally, however, manganese in natural surface waters is less than 20 ~g/liter. Manganese can be absorbed by inhalation, ingestion, and through the skin; the consequences of this have been recently reviewed in depth by the National Academy of Sciences. It has been known that the occupational inhalation of manganese dusts results in a disease of the central nervous system resembling Parkinsonism and a fount of pneumo- nia. Ingestion of manganese in moderate excess of the normal dietary level of 3-7 mg/day is not considered harmful. A reported outbreak of manganism in Japan was attributed to drinking well water containing about 14 mg/liter of manganese. The maximum concentration of manganese found in the 1975 Survey of Interstate Water Supply Systems was 0.4 mg/liter except for samples from two Alaskan airports which showed 1.0 and 1.1 mg/liter. A total of 669 supplies were examined. Similarly the maximum concentration found in the 1969 Community Water Supply Survey was 1.3 mg/liter from 969 supplies. Both these maximum concentrations are an order of magnitude less than minimum concentrations at which adverse health effects are observed. Moreover, even with manganese at 0.4 mg/liter the intake of manganese from water would be only about 15% of the normal total dietary intake of manganese. Because concentrations of manganese found in water supplies are much less than those at which adverse health effects have been observed and because the regulation of manganese for esthetic and economic reasons is also far more stringent than would be required for reasons of health, there seems little need to establish a maximum no-observed- adverse-health-effect value. Mercury Mercury is a comparatively rare element. It is relatively insoluble in the inorganic form and can exist only in extremely small quantities under natural conditions. Recent measurements show that only 4% of water supplies contain mercury at concentrations greater than 1 ~g/liter. Industrial use has resulted in increased environmental contamination. The health effects of populations occupationally exposed to mercury and mercury compounds has long been recognized, but the problem of contamination of the general environment is of recent origin.

Inorganic Solutes 313 Inorganic mercury in bottom sediments can be transformed biochemi- cally to injurious methylmercury or other organic mercurial compounds. The organic form readily enters the food chain with concentration factors as great as 3,000 in fish. Several investigators have estimated the blood levels of mercury at which the identifiable symptoms of mercury intoxication occur. These levels may be obtained with a steady mercury intake of from 4 14 g/kg/day. This would be 24~840 ~/dav for adults and 8C~280 u~/dav . .. . . ~ , . ~ , tor children. it Is estimated that the normal diet will contribute about 10 g/day of mercury. With daily intake of 10 lag from food and 4 lag from water it appears that there is considerable margin of safety. However, those individuals regularly consuming fish from contaminated areas may exceed the normal intake by a factor of three or more and thus constitute a high-risk population. There is no indication that concentrations of mercury in drinking water or air have contributed in any significant way to methylmercu~y intoxication of the general population. The interim standard limits the daily intake to 3 - ~,/day. Nearly all public water supplies in the United States contain less than 2 ~g/liter of mercury. The WHO has set no limit and the USSR has a maximum permissible concentration of 5 ~g/liter. Molybdenum Soluble molybdate ions are present in trace concentrations in many surface waters, primarily as a result of discharge of industrial wastes but also as a product of natural weathering of molybdenum-bearing soils. Both suspended ir~soluble molybdenum disulfide and soluble molybdates are present in streams draining areas where molybdenum ore is mined and processed, especially in Colorado and New Mexico. Typical diets contain on the order of 100 1,000 ,ug/kg, whereas typical surface waters (except those draining mining areas) contain less than 100 g/liter, with median values about 10 ~g/liter. Hence, water is a minor factor in the total molybdenum intake in most locations. Since some finished waters have been reported to contain as much as 1 mg/liter, some water intake may provide as much as 2,000 ~g/day of molybdenum. More information is needed about adverse ejects of molybdenum at these levels to deal properly with such supplies. Molybdenum poisoning has rarely been observed in humans. Although it has been implicated for gout in Armenia and for a bone-crippling disease in India, more information is needed to establish cause-and-e~ect relationships. Molybdenosis in livestock is a significant toxicological problem in

314 DRINKING WATER AND HEALTH many areas of the world. Consumption of molybdenum-rich forage by cattle and sheep causes severe diarrhea (scouring) that sometimes results in death. It can be prevented or ameliorated by the administration of copper, but the relationship of molybdenum, copper, and sulfate-forming compounds in animal metabolism needs further study. The USSR has established a limit for molybdenum of 0.5 mg/liter in open waters, but the WHO has not promulgated a limit. Nickel Nickel may occur in water from trace amounts of a few micrograms per liter to a maximum of 100 ~g/liter. At these levels the daily intake of nickel from water ranges from less than 10 ~g/day to a maximum of 200 g/day, as compared to a normal food intake of 30{~600 ~g/day. Available information indicates that nickel does not pose a toxicity problem because the absorption from food or water is low. The principle reason for considering nickel stems from epidem~ological evidence that occupational exposure to nickel compounds through the respiratory tract increases the risk of lung cancer and nasal-cavity cancer. There is difficulty in separating the eject of nickel from the simultaneous inhalation of other carcinogens including arsenic and chromium. Because of the generally low concentration of nickel in drinking water and its reported low oral toxicity, there is no present need to set primary health effect limits for nickel in water. WHO and the USSR have set no standards for nickel in drinking water. Silver Trace amounts of silver are found in some natural waters and in a few community water supplies. It has not been detected at levels exceeding the interim standard of 50 ~g/liter. Colloidal siver consumed in large doses several hundred mg/kg of body weight-can cause anemia and possibly death. The main chronic eject in man is "argyria." Argyria is a cosmetic defect once caused through medical or occupational exposure to silver preparations. It is rarely encountered now. Dosages of from 1 to 5 g of silver are sufficient to produce this syndrome. On the assumption of 50% absorption of silver, consumption of 2 liters/day of water containing 0.005 mg/liter of silver would result in an accumulation of I g of silver over 55 yr. Since silver ion has not been detected in water supplies in concentra

Inorganic Solutes 315 lions greater than half the no-observed-adverse-health-effect level, regulation of its concentration as a primary standard would appear to be unnecessary. T. In There is some indication that tin may be a beneficial micronutrient, although it has not been conclusively demonstrated that tin is an essential trace element in human nutrition. Inorganic tin is relatively nontoxic, but organotin compounds can be toxic at high concentrations. Indeed, they are used an fungicides, insecticides, and antihelminthics. Tin has seldom been determined in natural or municipally treated water. The few available data generally show concentrations of the order of one or two ~g/liter. In contrast, tin is present in most natural foods, and especially in canned products, to the extent that the normal human ingestion varies from 1-30 mg/day, which is three or more orders of magnitude higher than the probable concentration in a liter of tap water. EPA has not set a limit for tin in its National Interim Primary Drinking Water Regulations. In view of the foregoing considerations, no regulation seems necessary. Vanadium Vanadium is a trace metal that has been introduced into the environment in large quantities. Fresh surface waters show concentrations in the 2-300 g/liter range, but with low frequency of detection. The data are limited on levels in finished drinking waters, but vanadium concentrations up to 19 ~g/liter have been reported. Occupational exposure to pentoxides and trioxides of vanadium leads to ear, nose and throat irritation and generally impaired health. The consequences of exposure to vanadium in air, water and food have been reviewed recently. There is no evidence of chronic oral toxicity. Vanadium is considered a beneficial nutrient at ~g/liter levels, having been suggested as protective against atherosclerosis. zinc Concentrations of zinc in surface water are correlated with man's activities and with urban and industrial runoff. The solubility of zinc is variable, depending upon the pH of the water. In the same manner as

316 DRINKING WATER AND FILTH lead and cadmium, zinc is dissolved in concentrations as great as several mg/liter from galvanized pipes and tanks in soft-water systems. Concen- trations ranging from 2-1,200 ~g/liter were detected in 77~O of 1,577 surface water samples and 3-2,000 ~g/liter in 380 drinking waters. Zinc is relatively nontoxic and is an essential trace element with recommended minimum intake levels of 15 mg/day for adults and 10 mg/day for children over 1 yr of age. A wide margin of safety exists between normal intake from the diet and those likely to cause oral toxicity. Concentrations of 30 mg/liter or more impart a strong astringent taste and milky appearance to water. Some acute adverse ejects have been reported from consumption of water containing zinc at 4~50 ,ug/liter. There are no known chronic adverse ejects of low-level zinc intake in diet, but human zinc deficiency has been identified. The presently established standard (USPHS) for zinc in drinking water is a "recommended" or secondary standard based on the threshold of the metallic taste at about 5 mg/liter. The WHO recommends the same limit; however, the USSR has established a limit for zinc at 1 mg/liter for other than health reasons. OTHER INORGANIC CONSTITUENTS Arsenic OCCURRENCE Arsenic is widely distributed in low concentrations in the waters of the United States (Durum, 19744. In one study of selected minor elements in TABLE V-12 Regional Summary of Arsenic in U.S. Surface Waters Region Proportion, Proportion, Maximum Minimum. Median, < 10 ,ug/liter, > 10 ,ug/liter, ,ug/liter ,ug/liter ,ug/liter ~ New England and Northeast60 <10 <10 80 20 SoutheastI .1 10 < 10 < 10 70 30 Central140 < 10 < 10 75 25 Southwest10 < 10 < 10 87 13 Northwest30 < 10 < 10 86 14 (From Durum et al. . 197 1 )

Inorganic Solutes 317 728 samples of U.S. surface waters, the concentration of arsenic ranged from less than 10 to 1,100 ~g/liter (10-1,100 ppb). A study by the U.S. Geological Survey (USGS, 1970) of river waters revealed that the median concentration of arsenic was less than 10 ,ug/liter, the lower limit of detection, but 22% of the samples had concentrations of 1~20 ~g/liter (Table V-12~. In this survey, except for local anomalies where arsenic concentrations could be traced to urban waters or to industrial sources, no major regional differences could be detected in average values or in percentage of contaminated samples. The distribution of arsenic in waters and sediments of the Puget Sound region (Washington) has been studied by Crecelius and Carpenter (1974~. A large copper smelter in the area releases about 300 tons of arsenic per year into the atmosphere in stack dust and about the same amount in liquid effluent directly into Puget Sound. The concentrations of arsenic in Puget Sound waters are 1.5-2.0 ~g/liter, except for surface waters within a few miles of the smelter, where they may reach 1,000 ,ug/liter. Away from the immediate smelter area, the concentrations of arsenic in the Sound are not likely to rise above 1-2 g/liter because of the 1/2-yr replacement time for waters in Puget Sound. There have been a number of reports of isolated instances of higher than usual concentrations of arsenic in well waters. Lassen County, California (Goldsmith et al., 1972), was one such. area. It was examined because of arsenic in well water ranging from 0.1 mg/liter or less to 1.4 mg/liter well above maximal allowable standards. This compares with the 0.05 mg/liter recommenced by the U.S. Public Health Service as well as the WHO in its International and European drinking-water standards. The Lassen County study indicated that when the arsenic concentration in water was above 0.05 mg/liter, storage in hair increased, but there was no evidence of specific illness associated with concentrations up to 1.4 mg/liter. In Perham, Minnesota, a newly bored well was associated with illness in 13 people whose hair samples contained arsenic at37-1,680,ug/g. The well water serving these patients contained arsenic from 1 1,800 to 21,000 ,ug/liter; this was later determined to come from ground contamination by residual arsenical grasshopper bait (Feinglass, 1973). Antofagasta, a city of 130,000 in Chile, had a water supply containing high quantities of arsenic (800 ppb) between 1958 and 1970. The source of the high arsenic content was the Toconce River, whose waters come from the Andes Mountains at an altitude of 3,000 m and were brought 300 km to Antofagasta (Borgono and Greiber, 1972~. At the begining of

318 DRINKING WATER AND HEALTH the 1960's, the first cutaneous manifestations were noted in children. There were several severe cases, including a few fatal ones, of arsenism at the Calve Mackenna Hospital in Santiago. The principal finagling was the close relation between the prevalence elf cutaneous lesions (over 30 of the population) and the exposure to drinking water with a high arsenic content. The arsenic content of the hair and water supplies decreased markedly after action was initiated to clean up the water supply by opening a new water-treatment plant. Natural sources, including the erosion of surface rocks, probably account for a significant portion of arsenic found in surface water and groundwater. Fleisher (1973) noted that fumarolic gases associated with volcanism have been reported to contain arsenic at up to 700 ppb, and waters of hot springs contain up to 13,700 ppb. Otherwise, scattered data for arsenic in groundwater indicate low concentrations, often below the limit of detection and perhaps averaging around 1 ~g/liter (1 ppb). Isolated instances of arsenic in such concentrations which warrant surveillance have been reported. Arsenic is found in many foods; it occurs naturally in some and is introduced into others by way of feeds and pesticides. Crustaceans and other shellfish may contain up to 170 ppm (Frost, 1967~. Apples that have been sprayed with lead arsenate to control coaling moths might contain as much as 2 mg of residue. Wine and cider may contain arsenic, but it is usually removed during processing. Wine yeasts have been shown to contain arsenic in amounts up to 180 ppm, and baker's yeast up to 17 ppm. Meat may contain traces of arsanilic acid that has been used as a growth additive in cattle and poultry feeds. Theoretically, these additives are discontinued several days before marketing, and, in fact, the FDA allows an animal tissue arsenic content of 2.65 ~g/g. There has been considerable speculation about the addition of any arsenic to the diet of animals. Arsenic was found in 3.27 of samples of food items examined in the United States during a market-basket survey; residues ranged between 0.1 and 4.7 mg/kg (Cummings, 19661. The daily intake in the United States is calculated to be 0. 137~.330 mg (Duggan and Lipscomb, 1969). Arsenic occurs in the earth's crust in concentrations averaging 2 ppm (Fleischer, 19734. It is concentrated in shales, clays, phosphorites, coals, sedimentary iron ore, and manganese ores. In the United States, arsenic is produced (and distributed into the environment) largely as a result of smelting nonferrous-metal ores, particularly copper. Recent analyses of petroleum show a median arsenic concentration of 90 ppb, but there are few data. Superphosphate fertilizer made by treatment of phosphorite with sulfuric acid has been reported to contain as much as 0.1% arsenic.

Inorganic Solutes 319 IdETABOL ISM The metabolism of arsenicals by mammalian systems has been reviewed in detail by Frost (1967), Lisella et al. ~1972), Harvey (1975), and others. The present discussion summarizes the available information. Absorption Water-soluble arsenicals are readily absorbed through the gastrointesti- nal tract, lungs, and skin; some nonpolar organic forms are also absorbed from the intestine and skin (Hwang and Schanker, 1973; Tarrant and Allard, 19721. Arsenic trioxide is only slightly soluble in water and is not well absorbed. Pentavalent arsenic, Ast + V), whether inorganic or organic, is better absorbed than the trivalent form, because As(+V) is less reactive with membranes of the gastrointestinal tract. Arsenites are generally better absorbed through skin than arsenates, and absorption depends heavily on lipid solubility of the compound. Some of the selective toxicity of arsenic is explained by arsenates penetration of insect cuticle more rapidly than of human skin. Arsenite is more toxic to humans than arsenate and is more readily absorbed through human skin (Harvey, 19751. Distribution Arsenic is distributed primarily to the liver, kidneys, intestinal wall, spleen and lungs. The extent to which arsenic is taken up by these tissues depends on the rate of exposure and the chemical form. In guinea pigs, rabbits, apes, and humans, radioarsenite (74As) injected subcutaneously was distributed to muscles and other tissues (Hunter et al., 19424. Sodium arsenite (76As) that was injected intramuscularly to rabbits was found mainly in liver, kidneys, and lungs (Ducoff et al., 19484. Arsenic is immobilized by binding to sulftydryl groups in the keratin of hair and nails. Deposition begins within 2 weeks after administration, and the arsenic deposited may remain for the lifetime of the hair or nail. In this way deposition also serves as an excretory mechanism. Excretion There is a great deal of confusion in the literature regarding accumulation of arsenic. Rats (and possibly cats) appear unique, for they accumulate arsenic in the blood, bound to hemoglobin, whereas in other species there is no accumulation (Lanz et al., 1950; Hove et al., 1938; Peoples, 19644.

320 DRINKING WATER AND H"LTH Arsenate is rapidly excreted in the urine (Lanz et al., 1950; Ginsburg, 1965~. Arsenate, however, can be reabsorbed by the proximal tubule in the dog kidney and re-excreted as arsenite (Ginsburg, 1965~. Arsenite is excreted slowly in the urine, and it can take up to 10 days to completely excrete a single dose of parenterally administered trivalent arsenic (Hunter et al., 19421. It appears that arsenite is slowly oxidized to arsenate in the body and filtered into the urine in the pentavalent form. Mealy et al. (1959) suggested that arsenite is excreted by humans in three phases. More than 99% of radioactive sodium arsenite (74As) injected intravenously into five human volunteers was excreted in the first 15 h after administration, most of the balance was excreted at a constant low rate over the next 155 h, and the remainder was excreted at an even lower rate.- An alternative explanation for this observation is that the three phases are artifacts of the sampling time. Administration of arsenic to cows does not appear to influence arsenic concentrations in milk, although tissue concentrations increased (Peo- ples, 19641. Arsenic acid (Peoples, 1964), lead arsenate (Marshall et al., 1963), and arsenic trioxide (Fitch et al., 1939) given to cows are readily excreted as pentavalent arsenic in the urine. Transformation Little is known about the biotransformation of arsenic in man in spite of the long use of arsenicals as pharmaceuticals and pesticides. Arsenic inhibits the activity of many enzymes by reacting with sulfhydryl groups. In most cases the arsenical is converted to the trivalent form as an arsenite or arsenoxide (R - As = 0~. This active form of arsenic then combines with two sulfhydryl groups (often from two protein molecules) to form such products as R - As - (S-protein)c (Harvey, 1975~. Intramolecular reactions also occur when arsenic combines with both sulfhydryl groups of c~-lipoic (thioctic) acid to form a six-membered ring compound. Such reactions are considered responsible for much of the toxic action of arsenicals. HEALTH EFFECTS The toxicity of various arsenic compounds is extremely variable and depends on the species exposed, the formulation of the arsenical, the route of exposure, and the rate and duration of exposure. An assumption that all arsenic compounds are equally toxic is incorrect. Although man and other animals are susceptible to arsenic poisoning, there is a wide variation among species in susceptibility to a specific arsenic compound.

Inorganic Solutes 321 Similarly, there is a wide variation in toxicity of the various arsenical forrrlulations to a given species. Because of the many factors influencing the toxicity of arsenic, there is little point in attempting to state its toxicity in terms of milligrams per kilogram of body weight. It may be said, however, that the lethal oral dose of the more toxic arsenic compounds in most species appears to be 1-25 m~,/kg of body weight, whereas the lethal dose for the less toxic compounds may range from 10 400 times this amount (Buck et al., 1973; Penrose, 1974~. Groups of arsenic compounds can be listed as follows in decreasing order of toxicity (Penrose, 1974~: Arsines (trivalent, inorganic or organic) Arsenite (inorganic) Arsenoxides (trivalent with too bonds to oxygen) Arsenate (inorganic) Pentavalent arsenicals, such as arsonic acids Arsonium compounds (four organic groups with a positive charge on arsenic) Metallic arsenic Arsine gas is an indirect hemolytic agent due to its inhibition of red-cell catalase, which leads to accumulation of hydrogen peroxide which in turn destroys the red-cell membrane (Moeschlin, 1965~. Inorganic arsenite or its anhydride, arsenous oxide, are the most common commercial forms of arsenic. Their acute toxic ejects follow a short latent period and include rapid collapse, shock, and death. Arsenoxides and inorganic pentavalent arsenicals vary considerably in their toxicity. Although they are usually less toxic than the arsenites, their effects on biologic systems appear to be the same. In general, the phenylarsonic compounds are less hazardous for mammals than other arsenical compounds. The toxic effects of these compounds are manifested by incoordination, inability to control body and limb movements, and ataxia resulting from demyelination of the peripheral nerves (Ledet, 1973~. Arsonium compounds and metallic arsenic are quite stable and have relatively low toxicity (Schroeder and Balassa, 1966; Penrose, 1974~. Toxic Effects In Humans Human exposure to arsenic sufficient to cause severe toxicosis usually occurs through ingestion of contaminated food or drink. The signs and symptoms are variable in degree and timing and depend on the form and

322 DRINKING WATER AND H"LTH amount of arsenic, the age of the patient, and other factors (Willcox, 1922~. The major characteristics of acute arsenic poisoning are profound gastrointestinal damage and cardiac abnormalities. Symptoms may appear within 8 men if the arsenic is in solution, but may be delayed up to 10 h if it is solid and taken with a reseal. The signs include excruciating abdominal pain, forceful vomiting, cramps in the legs, restlessness, and spasms. "A feeble, frequent, and irregular pulse ushers in the other symptoms of collapse, the livid and anxious face, sunken eyes, cold and clammy skin. . . . A small proportion of the cases are classed as nervous or cerebral because . . . the . . . conspic- uous . . . phenomena are . . . prostration, stupor, convulsions, para- lysis, collapse, and death in coma" (Holland, 1904~. Only a small fraction of patients will develop any kind of skin reaction secondary to acute arsenic poisoning. Presumably, the arsenic is absorbed from the damaged gut and finds its way to the skin. The usual reaction in these circumstanc- es is acute exfoliative erythroderma, probably reflecting the fact that arsenic is a capillary poison (Harvey, 19651. Exposure to amounts of arsenic sufficient to cause symptoms is probably more common than that sufficient to produce systemic collapse. The patient may go for weeks with gradually increasing or variable signs and symptoms related to several organ systems and with the appearance of a progressive chronic disease. If death occurs, it may appear to have been the consequence of an obscure "natural" disease. Skin manifesta- tions of such victims are particularly prominent. In 1901, over 500 beer-drinkers afflicted with an unusual poisoning attributed to arsenic in one of the ingredients were studied by Reynolds (1901~. The symptoms appeared after many months of drinking 2-16 pints per day of beer which contained a fraction of"the quantity of arsenic which (would be prescribed for) an epileptic." Although Frost (1970) has refuted his conclusions and provided evidence that selenium may have been the contaminant, the clinical manifestations described were compatible with those produced by arsenic. The first symptoms to appear were digestive, especially vomiting and diarrhea. Within a few weeks, catarrhal symptoms appeared such as conjunctivitis, rhinitis, laryngitis, bronchitis as well as various skin eruptions. Hoarseness due to thickening of the vocal chords and hemoptysis were also mentioned. Insidious development of necrologic signs and symptoms began before the appearance of the classical skin lesions, but sometimes were so vague as to go undiagnosed for many weeks. Involvement of the nervous system began with sensory changes, including paresthesias, hyperesthesias, and neuralgias. There was marked muscle tenderness: motor weakness of all degrees (including paralysis with muscle atrophy, progressing from distal

Inorganic Solutes 323 to proximal groups) was a frequent observation. Left-side heart failure with severe peripheral edema was observed in one-fourth of the patients, and the 13 deaths in this series were all due to congestive heart failure. Reynolds also described the nail changes of subacute arsenic poisoning, observable some weeks after the intake of the poison was stopped. When normal nail grew out, it revealed "transverse white ridge across the nail; proximal to this the nail is normal, but distal to it the nail is whiter, cracked, thin, and towards the tip also papery and much flattened. In some cases there have been a series of parallel transverse ridges on the nail almost suggesting a series of weekend drinking bouts." This feature of arsenic exposure, commonly called "Mees lines" on the basis of a later description, has also been described by Aldrich ( 19041. Mitzuta et al. (1956) reported on 220 patients of all ages who had been poisoned by contaminated soy sauce, with an average estimated ingestion of roughly 3 mg of arsenic (probably as calcium arsenate) daily for 2-3 weeks. In this group, 85% had facial edema and anorexia; fewer than logo had exanthemata, desquamation, and hyperpigmentation; and about 20% had peripheral neuropathy. Except for headaches and fever, the findings in these patients appeared to be very similar to those reported by Reynolds (19011. The Japanese report offered additional information based upon modern diagnostic techniques. Although the majority of patients' livers were enlarged, relatively few abnormalities were found in liver-function tests; and the histopathologic description of five liver biopsies did not reveal severe degenerative changes. There were no findings suggestive of congestive failure, but electrocardiograms were abnormal in 16 of 20 patients, and this confirmed the reports of Josephson et al. (1951) and Nagai et al. (1956~. The Japanese patients' symptoms tended to diminish after 5 or 6 days, despite continued intake of arsenic, and necrologic symptoms became prominent as much as 2 weeks after arsenic ingestion was discontinued, at which time urinary arsenic content remained high. Hair was found to contain arsenic at 2.8- 13.0 ppm near the root, compared with 0-1.5 ppm near the end and 0. 2.8 ppm in hair from control patients. In the early 1960's, physicians in Antofagasta, Chile, noted dermato- logic manifestations and some deaths, particularly among children, that were traced to a water supply containing arsenic at 800 ppb. This water supply had been in operation only since 1958. In 1971, Borgono and Greiber (1972) reported on a series of studies of the inhabitants of this city. They compared 180 inhabitants of Antofasgasta with 98 people who lived in a city (Iquique) with a normal water supply. Most of the people studied were less than 10 yr old. Among the residents of Antofagasta the Primary symptoms reported were abnormal skin pigmentation (804370);

324 DRINKING WATER AND HEALTH chronic coryza (60cr%.,); hyperkeratosis (36%~; various cardiovascular manifestations, i.e., Raynaud's syndrome (alto); acrocyanosis (27S7~; abdominal pain (39!YO); chronic diarrhea (TWO); and lip herpes (into). The incidence of these symptoms in the control population was substantially lower or nonexistent. Two additional reports on the Antofagasta studies are worthy of note. Zaldivar (1974) further described a study on a total of 457 patients (208 males, 249 females) bearing cutaneous lesions (leukoderma, melanoder- ma, hyperkeratosis, squamous-cell carcinoma). Children (~15 yr of age) accounted for 69. z% of male cases, and for 77.5% of female cases. These patients exhibited high arsenic content in the hair. The mean concentra- tion of arsenic in drinking water in the period 1968-1969 was 580 ppb versus 80 ppb in 1971, differing by a factor of 7.2. Such difference was attributed to a new filter plant, which started operation in May 1970. The average incidence rates per 100,000 population for cases with cutaneous lesions in 1968-1969 were 145.5 for males and 168.0 for females. The incidence rates decreased in 1971 to 9.1 for males and 10.0 for females. Among the 337 registered children, 5 died showing thrombosis of brain arteries, thrombosis of mesenteric artery, restriction of lumen of coronary arteries, and/or myorcardial infarction. Of the 64 registered adult males, 2 developed multiple skin carcinomata with lymph node metastases. A number of questions are raised regarding this report. For example, the decrease in cutaneous lesions seemed to be too rapid, following installation of the water-treatment plant, suggesting other factors were involved. Protection of the 8-10-yr-old age group showed up in three years and adults exposed for more than 15 yr also had a decrease in incidence rate of cutaneous lesions. In a follow-up study, Borgono et al. (1976) investigated clinical and epidemiologic aspects of the cases first reported in 1971. The study was carried out through the examination of arsenic content in hair and nail clipping samples of the inhabitants of Antofagasta and the determination of this element in cultivated vegetables and carbonated beverages. Also a clinical study was made in school children, looking for cutaneous lesions attributed to arsenicism. Six years after the water treatment plant started to operate the problem had diminished considerably. Arsenic determina- tion of hair and nails of children 6 yr of age or less, born since the water treatment plant went into operation, indicated no cutaneous lesions in this age group. However, those over 6 yr of age still had significant arsenic residues in hair and nails. Although the clinical manifestations have improved, arsenic content of water, soft drinks, and in some foods are still considerably above safe levels and require additional sanitary . . . engineering Improvements.

Inorganic Solutes 325 The Raynaud's phenomenon and acrocyanosis in this population are reminiscent of the report from Taiwan by Tseng et al. (1968), suggesting that chronic arsenism affects the vasculature in a way similar to the more acute phenomena described by Reynolds and others as erythromelalgia and acrocyanosis. Tseng et al. surveyed a group of 40,421 (from a population "at risk" of 103,154) and found hyperpigmentation in 18.4%, keratotic lesions in 7.1%, and blackfoot disease (apparently secondary to arterial spasm in the legs) in 0.9%. All these phenomena were shown to increase with increasing arsenic concentration in the well water of the 37 villages studied. They also increased with age, but the earliest ages noted for specific findings were 3 yr for the characteristic hyperpigmentation and 4 yr for keratoses. The concentration of arsenic in the wells ranged from 17 to 1097 ppb. No cases of melanosis or keratosis were found in a group of 2,552 people living in an area where the wells contained almost no arsenic. Feinglass (1973) reported on 13 persons exposed for 2.5 months to well water contaminated with buried arsenical insecticide. Most patients were seen only once, and the most prominent features were intermittent gastrointestinal symptoms related to water ingestion. Two of the 13 had nail changes, and 6 to 8 had increased arsenic content of the scalp hair. The author did not mention edema, exanthema, hyperpigmentation, or hyperkeratosis. There are many scattered case reports of subacute to chronic arsenic poisoning in the literature. Silver and Wainman (1952) described a patient who ingested approximately 8.8 mg of arsenic trioxide as Fowler's solution daily for a total period of 28 months, as a remedy for asthma. Signs of arsenic poisoning, manifested as increased freckling and as darkening of the nipples, first appeared in association with gastrointesti- nal symptoms after 13 months; redness and puffiness about the eyes and hyperkeratoses developed at approximately 1.5 yr. Neurologic symptoms in the form of paresthesias and weakness were the last to be noted, occurring after 2 yr. When the arsenic intake was stopped, the pigmentation lightened, but the hyperkeratoses remained, and the asthma became more difficult to control. Perry et al. (1948) noted that all of a group of chemical workers handling inorganic arsenic compounds had pigmentary charlges and that one-third of them had "warts," although these were not well described. They reported that the cutaneous "changes were so evident that ithe examiner] could readily tell whether the man . . . was a chemical worker." All these workers had increased urinary arsenic compatible in degree with the extent of exposure; this indicates system~c absorption of the arsenic from dust, probably through the lungs and skin.

326 DRINKING WATER AND H"LTH Some clinical and experimental evidence suggests that arsenic has the capacity to suppress the immune response selectively. For many medical conditions for which arsenic was most popular, steroid drugs are now the treatment of choice. The high incidence of herpes zoster and herpes simplex in cases of subacute arsenic poisoning is reminiscent of patients who were deliberately immunosuF'~ressed to receive kidney transplants. Recurrent pulmonary infections in children in the Antofagasta episode is reminiscent of children with congenital immunodeficiency syndromes. Arsenic is reputed to reduce the lymphocyte count in leukemia which may reflect a selective sensitivity of this cell type, which again is analogous to the ejects of steroids (Borgono and Greiber, 19721. ~arcinogenicit:' A number of studies in man have linked the appearance of cancer to exposure to inorganic arsenic compounds. Evidence has come from the use of arsenicals as drugs. from geographic areas with high concentrations of arsenic in drinking water, and from arsenic-exposed industrial groups, such as miners and smelters, workers in factories manufacturing arsenic-containing pesticides, and vineyard workers. However, the association of cancer with a history of exposure to arsenic in one form or another must be carefully evaluated before arsenic is incriminated as the causative agent (NAS, 1976~. Evidence of the carcinogenicity of arsenic in man is based almost entirely on descriptive, retrospective, epidemiologic studies. Thus, a change in the rate for cancer in various population groups has been identified, suggesting the influence of carcinogens in the environment of . ~ A ~ . ~ ~ tne groups. Though case histories of persons in the afflicted groups have shown exposure to an arsenical, the many variables to which man is subject cannot be controlled in retrospective studies. In none of the human studies was there satisfactory control of exposure to known carcinogens (including cigarette smoke, asbestos, ionizing radiation, polycyclic hydrocarbons, pesticides, and ultraviolet light) or other unknown carcinogens in the environment. The clinical association of skin cancer with the therapeutic administra- tion of arsenic compounds began with a report by Hutchinson ( 1888~. Six patients in whom skin cancer occurred had suffered for very long periods from diseases of the skin (five with psoriasis, one with pemphigus). In five of the cases, arsenic was known to have been used for a long time. Neubauer (1947) summarized 143 published cases of therapeutic arseni- cal epitheliomas. Only a small, but undetermined, proportion of people treated with arsenicals developed cancers. Of the 143 patients, about 70% received arsenicals for skin disease; of these, half had psoriasis. Nearly all the 143 patients received arsenic in the inorganic trivalent form, the most

Inorganic Solutes 327 common drug being potassium arsenite as Fowler's solution. Multiple horn keratoses, especially of the punctate or warty form on the palms and soles, were commonly reported in patients who had received Fowler's solution. Keratoses occurred in about 90370 of the cases of cancer ascribed to treatment with Fowler's solution, about half the skin cancers were - squamous carcinomas arising in keratotic areas of the hands, heels, and toes. The rest were multiple superficial epitheliomas of the basal-cell variety localized on the trunk and proximal parts of the extremities. Only a few of the 143 cases arose in psoriatic patches. There was a substantial frequency of mixed types of epitheliomas. Of the 143 patients, 70970 had multiple lesions, with an average of two per case. The elapsed time from the beginning of administration of the arsenical drug to the beginning of the epitheliomatous growth was variable, but averaged 18 yr, regardless of the type of lesion. The latent period for the onset of keratosis was about 9 yr. In spite of the long latent period, skin cancers started when the patients were relatively young, 3C)% when they were 40 or younger and 70% when they were 50 or younger. There have been numerous reports of arsenic-related occupational cancer, such as those of lung-cancer mortality among Southern Rhode- sian gold miners (Osburn, 1957) and of concurrent lung and liver cancer and clinical arsenism among German vineyard workers exposed to lead arsenate dust (Braun, 1958; Roth, 19571. The association of cancer with arsenic has sometimes been based on the existence of palmer or planter keratoses (Sommers and McManus, 1953~. However, because of the increased concentration of arsenic in the lesions of Bowen's disease, arsenic has been considered as a possible cause of the disease and accompanying visceral tumors, without prior exposure to arsenicals (Graham en al., 19611. Hill and Faning (1948) compared the death records of workers in a British sheep-dip factory with those of other workers in the same district. Of the 75 factory-workers deaths, 22 (29%) were due to cancer; of the 1,216 other deaths, 157 ( 1 Who) were due to cancer. The sites of cancer were primarily the respiratory system and the skin in the factory workers, and there was a considerable incidence of cancer of digestive and abdominal organs in both factory workers and other occupational groups. The median air arsenic content for the chemical workers at the various operations ranged from 254 to 696 ~g/m3. As an upper limit, this represented inhalation of about 1 g of arsenic per year. The excretion of arsenic in the urine of 127 current employees was determined and varied widely. Some exposed workers excreted from 1 to nearly 2 mg/day, whereas many excreted less than 0.1 mg/day. A few of the persons in the control group had very high excretion rates, for no explained reason. It is

328 DRINKING WATER AND HEALTH important to note that 20 of 31 current factory workers had been exposed to airborne sodium arsenite for more than 10 yr, and 5 of them for 4~50 yr. Furthermore, the median age of the 31 exposed workers was 5' yr. None of these mends lungs had pathologic signs attributable to their exposure to sodium arsenite (radiographs, vital capacity, and exercise capacity were studied). The authors concluded that the study of factory workers had produced no concrete evidence to confirm the association of arsenic exposure to death from cancer. Lee and Fraumerli (1969) compared the mortality experience of 8,(~47 white male smelter workers exposed to arsenic trioxide and sulfur dioxide during 1938-1963 with that of the white population in the same state. There was a threefold greater total mortality from respiratory cancer In smelter workers, many of whom were also exposed to silica, ferromanga- nese dust, and and other fumes. Snegire~ and Lombard (1951! made a substantial study of cancer mortality in a metallurgic plant in which arsenic was handled and in a control plant in which "working conditions appro.mmate those of Plant A except that no arsenic is handled." We authors stated that total cancer mortality in the two plants was not significantly different from the figures for the state as a whole, and they concluded that handling of arsenic trioxide did not cause a significant change in cancer mortality. Their data demonstrated, however, evidence of a respiratory system carcinogen among workers of both plants, but arsenic may not have been involved. A study at the Dow Chemical Company was carried out to examine the incidence of respiratory cancer among 173 workers who were exposed primarily to lead arsenate and calcium arsenate and 1,890 workers who worked in the same plant but were not exposed to arsenic (Ott et al., 1974~. Data were presented on the relationship between cumulative arsenic exposure and the ratio of observed to expected deaths from lung cancer. The average exposure of each worker was calculated on the basis of records of job assignments and data on the arsenic content of the air in various parts of the plant. Deaths Mom respiratory malignancy were ~7 times greater than expected for total inhaled quantities of 10.3 mg and 2- 4 times greater for 4.84-8.1? ma. There was no association between the extent of exposure and the time from beginning of exposure to death; most of the respiratory cancers occurred 2~0 yr after initial exposure, regardless of total exposure. In contrast with the Dow Chemical Company workers, orchard workers who used lead arsenate had no evidence of increased cancer (Nelson et al., 19731. A mortality study involving a cohort of 1,231 workers in Wenatchee, Washington, who had participated in a 1938 morbidity survey of the ejects of exposure to lead arsenate insecticide

Inorganic Solutes 329 - spray was conducted in 1968-1969. Air concentrat.ions of arsenic during spraying averaged 0.14 mg/m3. She workers were grouped in three categories according to exposure and compared in terms calf standardized mortality ratios with the mortality experience of the State of Washington. There was no evidence of increased rr~ortality front cancer. heart disease, or vascular leslor!s. High incidences of skin cancer have been reported in several groups exposed to high concentrations of arsenic in drinking water, including people in the district of P~eiche-nstein in Silesia (Geyer, 1898), Cordoba Province in Argentina (Bergoglio, 1964), and Taiwan (Tseng et al., 1968~ The existence of arsenic in waters in an eastern area of the province of Cordoba, Argentina, has been known for many decades; it has been associated with tile occurrence of hyperpigmentation, keratosis, and skin cancer. A study Glade in 1949-1959 indicated a higher proportion of deaths from cancer in the arsenical region thank in the rest of the province 23.87 vs. 1 5.37 (Bergoglio, 19641. The excess was due mainly to cancer of the respiratory and digestive tracts in both men and women and was unrelated to socioeconomic differences. A study by Tseng et al. (1968) was done on the southwest coast of Taiwan, where there were artesian wells that had been used for mo e than 45 yr with high concentrations of arsenic. Most of the well water in the endemic area had an arsenic content of around 0.5 ppm. The total population of 'he area was approximately 100,000, and the survey encompassed the 40,421 inhabitants of 37 villages. The overall prevalence rates for skin cancer, hyperpigmentation, and keratosis were 10.~/1,000, 183.5/1,OOQ, and 71.0/1,0()0. respectively. The mare: female ratios were 2.9: I for skin cancer and 1.1: 1 for hyperpigmentation and keratosis. The prevalence of each of the three conditions increased steadily with age, although there was a decline for cancer and hyperpigmentation in women above 69. The prevalence rate for each condition varied directly with the arsenic content of the cell water. In a continuing survey and follow-up in, some villages of Taiwan, Tseng (1976) confirmed that the prevalence rates for skin cancer and blackfoot disease showed an ascending gradient according to the arsenic content of well water, i.e., the higher the arsenic content, the more patients with skin cancer and blackfoot disease. A dose-response relationship between blackfoot disease and the duration of water intake was also noted. Furthermore, the degree of permanent impairment of a patient was noted to be directly related to duration of intake of arsenical water and alternatively to duration of such intake at the time of onset. The most common cause of death in the patients with skin cancer and blackfoot disease was carcinoma of various sites. The S-yr survival rate after /

330 DRINKING WATER AND H"LTH blackfoot onset was 76.3%; 1()-yr survival rate, 63.3%; and 15-yr survival rate, 52.2%. The 50% survival point was 16 yr after onset of the disease. The more recent observations from Chile and from Taiwan emphasize the public health problems associated with arsenic in specific geographic areas. Recent reports from Sweden (Pershagen et al., 1976) are of interest. The study concerns mortality in an area surrounding an arsenic emitting plant. A metallurgic plant, founded in 1928, processed mainly nonferrous metals. Since the starting of operations it has been using ore with a high arsenic content that has resulted in environmental pollution of air and water with arsenic, as well as other metals and sulphur dioxide. The causes of death for the population of two parishes in the vicinity of the plant were listed from the National Swedish Register on Death Causes. A reference area in the same part of Sweden with similar degree of urbanization, occupational profile, and age distribution was chosen. The causes of death for the two populations were followed during a period of 14 yr. A markedly higher mortality rate for lung cancer was noted in men in the exposed area. Also when the occupationally exposed were excluded there remained indications of an increased mortality in men due to primary respiratory cancer. A continuation of this investigation in the form of a cohort study will consider both the mortality and cancer incidence. Tsuchiya (1976) has recently reported from Japan a number of incidents of arsenic poisoning associated with a variety of vehicles including powdered milk, soy sauce, well water, mines, and smelters. Ejects varied according to the dose, duration. and route of exposure. In the milk incident, infants were exposed to relatively high doses of arsenic in powdered milk and the victims developed acute symptoms of the gastrointestinal tract; in some cases, symptoms of the central nervous system, anemia, neuropathy, cardiovascular and skin changes, but no neoplasms. It is not clear whether the symptoms of the central nervous system were due to the stimulation of the cerebral membrane or to organic changes of the cerebral parenchyma. It is important to note that the development of some possible changes of the brain as indicated by BEG and possibly by the higher incidence of epilepsy occurred at a later stage as late as 15 yr after clinical changes had disappeared. No other study has reported the development of chronic encephalopathy among heavily exposed children or adults. Another important question after having reviewed these episodes is whether arsenic is related to the production of liver cirrhosis. In incidents reported in Japan, there is no increased prevalence of liver cirrhosis among those exposed to arsenic. In the well water incident, the married

Inorganic Solutes 331 couple who had been drinking water containing 0.125 ppm arsenic showed liver cirrhosis (the husband) and Banti syndrome (the wife). However, since no cases of either disease have been observed among those who suffered heavier exposure, the relationship between these diseases and arsenic is still open to question. In the soy sauce incident, it was noted that the symptoms improved even while the ingestion of the contaminated soy sauce was still in progress. The mechanism of this phenomenon should be further investigated. The report on the increased prevalence of abnormal EMG findings is also of interest since prolongation of electric conduction velocity has been reported in persons whose blood lead level was lower than 70 ,ug/100 ml. . Since there have been no other reports on the increased risk of lung cancer due to arsenic among occupationally exposed workers in Japan, and also since the induction of lung cancer by arsenic in animal experiments has not been successful, the direct relationship between arsenic and lung cancer is still open to question. In the Saganoseki copper smelter incident, attention was drawn to the fact that smelter workers had also been exposed rather heavily to substances other than arsenic, including polynuclear organic substances, sulfur dioxide and possibly to other chemical substances. Mutagenicity Petres and Berger (1972) and Petres and Hundeiker (1968) have reported chromosomal breakage in human leukocyte cultures after short-term in vitro exposure to sodium arsenate and in cultures obtained after long-term exposure to arsenical compounds in viva. The cytotoxic and mutagenic ejects of sodium arsenate were tested in vitro on phytohemagglutinin-stimulated lymphocyte cultures in concentrations of 0.05-30 ,ug/ml of culture medium. It was reported that 33% of metaphase plates were disrupted at 0.1 ~g/ml and 8~10047o at 2 ~g/ml or greater. The "mitosis index" and the "OH) thymidine labeling index" were decreased. Petres et al. (1976) did chromosome analyses of lymphocytes from patients who had been exposed to arsenic. They showed frequent structural and numerical aberrations even following an interval of decades since the last exposure. The in vitro addition of sodium arsenate induced the Dante chromosome changes in lymphocyte cultures from healthy subjects. Radioactive incorporation studies showed that arsenate was able to inhibit dose- dependently the incorporation of radioactively-labeled nucleotide in

332 DRINKING WATER AND H"LTH RNA and ONA. Beyond that, arsenic blocked the cells in the S- and G- phase. A general explanation for the inhibitory eject of inorganic arsenic on cell metabolism Is the known strong affinity of arsenic to enzymes, especially to those containing sulfhydryl groups. These studies require attention and further investigation. - The overall significance of these chromosomal studies is difficult to assess, because many unrelated compounds may cause similar ejects. The fact that arsenic compounds have caused chromosomal damage in a number of biologic systems, however, should alert toxicologists to a possible role of arsenic in chemically induced mutagenesis. In vivo studies were made on 34 patients at the University of Freiburg skin clinic (Petres et al., 19701. Thirteen of these patients had had intensive arsenic therapy for psoriasis, some more than 20 yr before the experiment. The control group (21 patients) consisted of 14 psoriasis patients and 7 with eczema, none of whom had had arsenic treatment. Phytohemagglutinin-stimulated lymphocyte cultures were prepared from each patient for evaluation of chromosomal aberrations. The incidence of aberrations was remarkably greater in the cultures of patients who had been treated with arsenic. Paton and Allison (1972) investigated the effect of sodium arsenate, sodium arsenite, and acetylarsan on chromosomes in cultures of human leukocytes and diploid fibroblasts. Sublethal doses of the arsenicals were added to leukocyte and fibroblast cultures at varous times between 2 and 48 h before fixation. In leukocyte cultures treated with sodium arsenite at 0.29-1.8 x 10-8 M for the last 48 h of the culture period, 60% of 148 metaphases examined were found to have chromatic breaks. No significant number of breaks were found in cultures treated with sodium arsenate at 0.58 x 10--8 M, the highest nontoxic concentration. Chromo- somal damage was observed in diploid fibroblasts to which sodium arsenite was added to the medium for the last 24 h of culture; chromatic breaks were found in 20% of 459 metaphases examined. However, treatment with acetylarsan at 6.0 x 10-8 M resulted in to chromatic breaks in 50 metaphases examined. Environmental exposure to arsenicals has been correlated with a high skin cancer risk among populations exposed to sunlight. These observa- tions suggest that arsenic might interfere with the repair of damage to DNA (mostly thymine dimers) resulting from the ultraviolet rays in sunlight. To test this hypothesis Rossman et al. (1976) have used strains of E. colt, differing from each other only in one or more repair Suctions, to study the interactions. Cultures of E. cold were exposed to UV light and then plated in the presence or absence of sodium arsenite. Survival after

Inorganic Solutes 333 irradiation of wild-type E. cold ~P) was significantly decreased by 0.5 mM arsenite. This eject was also seen in strains unable to carry out excision repair, suggesting that arsenite inhibits one or more steps in the postreplication repair pathways. This was confirmed by the finding that arsenite has no eject on the postirradiation survival of a recA mutant, which does not carry out postreplication repair. Mutagenesis after W-irradiation depends on the recA +and lex+genes. Arsenite decreases mutagenesis in strains containing these genes. In order to determine its mechanism of action, Rossman et al. studied dose- response relationships of arsenite on a number of cellular functions. The most sensitive cellular functions found were the induction of ,B-galacto- sidase and the synthesis of RNA. Since error-prone repair in E. cold is an inducible process, the inhibition of mutagenesis after W irradiation may be the result of inhibition of messenger RNA. Since arsenite inhibits DNA repair in E. colt, specifically post- replication repair, this may be a possible mechanism through which it influences the induction of cancer. Toxic Effects in Animals Arsenic appears to be second only to lead in importance as a toxicant in farm and household animals (Buck et al., 1973; Hatch and Funnell, 1969~. Some of the more common sources of arsenic poisoning include grass clippings from lawns that have been treated with arsenical crabgrass control preparations; grass, weeds, shrubbery, and other foliage that have been sprayed with arsenical herbicides (Buck, 1969~; dipping of animals in vats that even years before had been charged with arsenic trioxide; and soils heavily contaminated with arsenic, either from the burning of arsenic formulations in rubbage piles or through the application of arsenical pesticides to orchards and truck gardens (Clarke and Clarke, 1967; Radele~, 1970~. Arsenical compounds dissolved in water are much more readily absorbed, and thus more toxic than when incorporated into feed (Buck et al. 1973~. In practice, the most dangerous arsenical preparations are dips, herbicides, and defoliants, in which the arsenic is in a highly soluble trivalent form, usually arsenite. Animals often seek out and eat such materials as insulation, rodent bait, and dirt and foliage that have been contaminated with arsenic (Buck, et al., 1973~. Animals that are weak, debilitated, and dehydrated are much more susceptible to arsenic poisoning than normal animals, probably because renal excretion is reduced. Arsenic poisoning in most animals is usually manifested by an acute or

334 DRINKING WATER AND H"LTH subacute syndrome. Arsenic affects tissues that are rich in oxidative systems, primarily the alimentary tract, kidneys, liver, lungs, and skin. It is a potent capillary poison; although all capillary beds may be involved, the splanchnic area is most commonly affected. Capillary damage and dilatation result from transudation of plasma into the intestinal tract and from sharply reduced blood volume. The capillary transudation of plasma results in the formation of vesicles and edema of the gastrointesti- nal mucosa, which eventually lead to epithelial sloughing and discharge of the plasma into the gastrointestinal tract. (Radele~, 1970~. Blood pressure usually falls to the point of shock, and cardiac muscle becomes weakened; these ejects contribute to circulatory failure. Toxic arsenic nephrosis is more commonly seen in small animals and man than in farm animals. Glomerular capillaries dilate, allowing the escape of plasma; this results from the loss of fluid through other capillary beds, and the low blood pressure contributes to the oliguria that is characteristic of arsenic poisoning. The urine usually contains protein, red blood cells, and casts (Buck et al., 1973~. After percutaneous exposure, capillary dilatation and degeneration may result in blistering and edema, after which the skin may become dry and papery. The skin may then crack and bleed, providing a choice site for secondary bacterial invaders (Radeleff, 1970~. In subacute arsenic poisoning, animals may live for several days and show depression, anorexia, watery diarrhea, and increased urination followed by anuria, dehydration, thirst, partial paralysis of the rear limbs, trembling, stupor, coldness of extremities, and subnormal temperature. The stools may contain shreds of intestinal mucosa and blood. Characteristic gross effects associated with inorganic, aliphatic, and aromatic trivalent arsenic poisoning include localized or general redden- ing of the gastric mucosa, reddening of the small-intestinal mucosa (especially the first few feet of the duodenum), fluid and often foul- smelling gastrointestinal contents, a soft yellow liver, and red edematous lungs. Occasionally, in acute poisoning, no gross changes are noted post mortem. The inflammation is usually followed by edema, rupture of the blood vessels, and necrosis of the mucosa and submucosa. This necrosis sometimes progresses to perforation of the stomach or intestine. The gastrointestinal contents may include blood and shreds of mucosa. There may occasionally be hemorrhages on all surfaces of the heart and on the peritoneum (Clarke and Clarke, 19674. Histopathologic changes include edema of the gastrointestinal mucosa and submucosa, necrosis and sloughing of mucosal epithelium, renal tubular degeneration, hepatic fatty changes and necrosis, and capillary

Inorganic Solutes 335 degeneration in vascular beds of the gastrointestinal tract, skin, and other organs (Buck e! al., 1 973; Radeleff, 1 9701. The work of Schroeder et al. (1968) and Peoples (1964) indicates that the rat may be unique in its susceptibility to and metabolism of arsenic compounds. Schroeder et al. noted that, although rats consuming water containing arsenite at 5 ppm accumulated arsenic at 27-47 ppm in their body tissues, they developed no signs of toxicosis and survived a normal 3.5-yr life span. Peoples showed that the rat is unique in its low rate of excretion of arsenic. Both reported that the blood of rats tended to accumulate high concentrations (10~300 ppm) of arsenic. This is not observed in humans. The low rate of arsenic excretion by the rat is probably due to fixation of 8(}90~o in the hemoglobin, which must break down before arsenic is released. These experiments are sufficient to cast doubt on the extrapolation of data from arsenic experiments involving rats to man. Several phenylarsonic formulations have been used as feed additives for disease control and improvement of weight gain in swine and poultry since the mid-1940's. These phenylarsonic acids and their salts include arsanilic acid, 3-nitro-4-hydroxyphenylarsonic acid, 4-nitro-phenylarson- ic acid, and 4-ureido- 1 -phenylarsonic acid. There remains considerable controversy regarding the mode of action of the phenylarsonic compounds. However, they seem to have an action different from that of inorganic, aliphatic, and aromatic trivalent arsenic compounds. The arsenic incorporated in the feed additives is in the pentavalent form, and it is likely that the phenylarsonic compounds have their primary action as pentavalent arsenicals; this may account for their distinctive ejects in birds and animals. Some workers have suggested that both the toxicity and the efficiency of these compounds are due to their degradation and reduction to inorganic trivalent forms (Eagle and Doak, 1951; Harvey, 1965; and Voegtlin and Thompson, 1923~. Others have clearly established that these compounds are excreted unchanged by chickens and that there is no evidence that they are converted to inorganic arsenic (Moody and Williams, 1964a; Moody and Williams, 1964b; Overby and Fredrickson, 1963, 1965; and Overby and Straube, 1965~. Similar experiments by other workers with rats, rabbits, and swine indicate that the phenylarsonic compounds are for the most part excreted unchanged by the kidneys, although some apparently undergo a limited biotransformation (Moody and Williams, 1964b). Because pentavalent arsenic compounds do not readily react with sulf~ydryl groups and because the phenylarsonic acids are apparently excreted unchanged, one must conclude that the mechanism of their

336 DRINKING WATER AND H"LTH action is something other than interaction with sulfhyd~yl containing enzymes and proteins. Clinical signs of phenylarsonic toxicosis in swine and poultry include incoordination, inability to control body and limb movements, and ataxia. After a few days, swine and poultry may become paralyzed, but will continue to eat and drink. Arsanilic acid and its sodium salt may produce blindness but this is rarely seen when it is used as one of the most common feed additives. Erythema of the skin, especially in white animals, and sensitivity to sunlight may be present. The clinical signs are reversible up to a coins. Removing the excess arsenical will result in recovery within a few days, unless the clinical signs nave progressed to partial or complete paralysis due to irreversible peripheral nerve degeneration (Buck, 1969b; Oliver and Roe, 1957~. Chronic arsenic toxicosis has not been encountered significantly in animals. Gainer and Pry (1972) reported that virus-infected mice treated subcutaneously with large doses of arsenicals had higher mortality rates than unexposed controls. Viral diseases so affected by arsenic were pseudorabies, encephalomyocarditis, and St. Louis encephalitis. The elects were similar when 3-nitro-4-hydroxyphenylarsonic salt (75-100 ppm) was added to drinking water. Gainer (1972) reported that sodium arsenite inhibited the induction of interferon in rabbit kidney cell cultures. It was found, however, that, although high concentrations of arsenite inhibited the action of exogenous mouse interferon added to cultures of mouse embryo cells, low concentrations of arsenate increased the antiviral activity of low concentrations of interferon. Carcinogenicity Animal studies have not demonstrated carcinogenicity of arsenic compounds even when administered at near the maximal tolerated dosage for long periods. There are two exceptions, however. Halver (1962) reported the occurrence of hepatomas in trout fed a synthetic diet containing carbarsone at 480 mg/100 g of diet. The data were reviewed by Kraybill and Shimkin (19641. Of 50 trout exposed to carbarsone, 5 developed hepatomas. There were no hepatomas in a large control group fed the synthetic diet without carbarsone. Osswald and Goerttler (1971) reported that subcutaneous injections of sodium arsenate in pregnant Swiss mice caused a considerable increase in the incidence of leukemia in both the mothers and their offspring. A 0.005% aqueous sodium arsenate solution was injected daily during pregnancy for a total of 20 injections, each containing arsenic at 0.5 mg/kg of body weight. Some groups of offspring from the arsenic-treated females were given an additional 20 subcutaneous injections of sodium arsenate

Inorganic Solutes 337 (arsenic equivalent 0.5 mg/kg) at weekly intervals. Leukemia occurred in I I of 24 mothers (auto), 7 of 34 male offspring (214Yo), and 6 of 37 female offspring (ammo). In the offspring given the additional 20 injections, 17 of 41 males (41%) and 24 of 50 females (alto) developed leukemia. Leukemia developed in only three of 35 male (9~O) and in none of 20 female offspring of untreated control mice. Furthermore, 11 of 19 mice (58%) developed lymphoma after 20 weekly intravenous injections, each containing 0.5 mg/kg of arsenic as sodium arsenate. ~ ong-term studies of elects of arsanilic acid on chickens, pigs, and rats were reported by Frost et al. (1967~. No adverse effects were seen in the chickens and pigs after 4 yr of feeding, nor in pigs fed 0.01% arsanilic acid in their diets for three generations. Male and female weanling rats from the Fit generation of a six-generation breeding studio in which 0.0137 and 0.05% arsanilic acid was fed were held on the 0.01% arsanilic acid diet or on the control diet for 1 16 weeks. The overall tumor incidence was the same in all groups and resembled the historical incidence of tumors in the colony, 35 45%. Boutwell (1963) used female mice known to be highly susceptible to skin tumors in a test for cocarcinogenicity of potassium arsenite. It was tested as an initiator, both orally by stomach tube (a total of 2.4 mg in 5 days) and dermally (a total of 1.2 mg in eight applications during 5 days). The initiating exposure was followed by topical application of croton oil twice a week for 18 weeks. He also tested potassium arsenite as a promoter by daily applications (a total of 2.3 mg/week) after a single 75- ~g dose of dimethylbenzanthracene (DMBA). The prolonged skin applications of potassium arsenite were hyperkeratotic and ulcerogenic. Other experiments were done to determine whether arsenic would increase the yield of skin cancers caused by a suboptimal regimen of DMBA plus croton oil given either at the time of DMBA initiation or during the 24-week period of croton oil promotion. Under the latter condition, the mice were fed potassium arsenite at 169 mg/kg offood. In no case was there an effect of arsenite on skin carcinogenesis in these experiments. Many tumors developed in the positive control mice, beginning as early as 6 weeks after treatment began. Baroni et al. (1963) conducted similar studies with male and female Swiss mice, testing the oral elects of potassium arsenite (100 ppm in drinking water) as an initiator with croton oil promotion and as a promoter for DMBA and urethane initiation. Local skin applications of sodium arsenate were tested as a promoter after initiation with DMBA or urethane. The arsenicals had no elect on carcinogenesis, and only a very slight degree of keratosis was observed. Milner (1969) used three strains of mice that differed in susceptibility

338 DRINKING WATER AND H"LTH to the induction of skin tumors with the application of methycholan- threne-impregnated paraffin disks to the skin for 2-3 weeks. The treated site was transplanted syngeneically and observed for 8 weeks for tumor formation. Arsenic trioxide (100 ppm in drinking water) was adminis- tered either during methylcholanthrene exposure, after transplantation, or both. Arsenic exposure was associated with a small increase in papillomas in the low-susceptibi~ity strain, a small decrease in the high- susceptibility strain, and no eject in the intermediate-susceptibility strain. Byron et al. (1967) fed sodium arsenite at 15-250 ppm and sodium arsenate at 3~00 ppm to Osborne-Mendel rats in a 2-yr study. No carcinogenic activity of either material was found. These investigators also did a 2-yr arsenic feeding experiment on dogs, with negative results. This length of time, however, is not adequate for studying carcinogenesis in dogs. Hueper and Payne (1962) incorporated arsenic trioxide in the drinking water (either plain or with 12~o ethanol) of rats and mice. The initial concentration of 4 mg/liter was increased by 2 mg/liter each month, to a maximum of 34 mg/liter at 15 months. Thus, the daily intake of arsenic trioxide ranged from 0.1~.8 me. The administration of arsenic trioxide c, - O . - ~ ~ ~ ~ .1 _ T · .1 , ~ . .1 · 1 1 1 was continued tor Hi months. welder the rats nor Ine mice Developed any cancers in suspected target organs skin, lungs, and liver. Kanisawa and Schroeder (1967) and Schroeder et al. (1968) found no carcinogenic ejects of potassium arsenite at 5 ppm in drinking water in mice or rats exposed from weaning to senescence. Kroes et al. (1974) studied the carcinogenicity of lead arsenate and sodium arsenate with SPF-Wistar-derived male and female rats. In addition, some groups were intubated with a subcarcinogenic dose of diethylnitrosamine to determine synergistic action leading to lung tumors. Food intake and body weights were recorded, and complete gross and microscopic examinations were made on all animals. Lead arsenate that was incorporated in the diet at 1,850 ppm was toxic and caused increased mortality; one adenoma of the renal cortex and one bile duct carcinoma were found in this group. No carcinogenicity was associated with the feeding of lead arsenate at 463 ppm or sodium arsenate at 416 ppm. No synergism with the nitrosamine was observed. In summary, there is epidemiologic evidence of the carcinogenic action of arsenic on the skin and lungs of humans, on the basis of experience with the medicinal use of inorganic trivalent; arsenic, occupational groups exposed to inorganic trivalent or pentavalent arsenic dusts, and popula- tions exposed to high concentrations of arsenic in drinking water. In most instances, however, the exposures to arsenic have been concurrent with J ~

Inorganic Solutes 339 exposures to other agents, and the available data do not exclude the possibility that cofactors are important in the carcinogenic response to arsenic. Differences in the type and distribution of tumors, attributed to the ingestion of arsenic, raise serious questions with respect to a simple etiologic relation of arsenic to the various findings. There is no established procedure to demonstrate carcinogenicity of arsenic in experimental animals. This phenomenon remains an enigma. One must conclude either that arsenic is not a carcinogen for animals or that circumstances not yet understood are essential to demonstrate a role for . . . . . arsenic In exper~menta carc~nogenes~s. Mutagenicity Most of the research on mutagenesis of arsenic has centered on chromosomal reactions to sodium arsenate. There are no data based on the host-mediated assay or the dominant-lethal technique. Levan (1945) treated root meristem cultures of Allium cepa for 4 h with an unspecified arsenic salt at 10 concentrations, from lethal to no-e~ect. Chromosomal changes were observed, including spindle disturbances and metaphase arrests. Similar elects were observed after treatment with salts of 24 other metals. Arsenate has also been found to increase the total frequency of exchanged chromosomes in Drosophila melanogaster treated with seleno- cystine (Walker and Bradly, 1969), and several organic arsenicals have a synergistic elect on the number of abnormalities in barley chromosomes caused by ethylmethane sulfonate (Moutschen and Degraeve, 19654. Teratogenicity Franke et al. (1936) performed what might be called the first teratogenic study of an arsenic compound, when they tested the effect of sodium arsenite on the development of chick embryos. Injection of sublethal concentrations of arsenic into the eggs produced ectopic conditions, but no monstrosities, as are produced by selenium. Ridgway and Karnofsky (1952) found that injection of sodium arsenate into embryonate chicken eggs at 4 days in doses of 0.20 mg/egg caused no specific gross abnormalities in the resulting embryos 14 days later. Growth retardation, impaired feather growth, and abdominal swelling were noted. Recent studies have demonstrated teratogenic effects of intravenous administration of sodium arsenate in mice and hamsters (Ferm and Carpenter, 1968; Ferm et al., 1971~. Single doses (15-20 mg/kg) were administered on the eighth day of gestation, and the results were observed on the fifteenth day: there was a high incidence of anencephaly and other defects. Up to 80% of the embryos had anencephaly; up to 65%, rib malformations; up to 30%, exencephaly; and approximately

340 DRINKING WATER AND H"LTH 20%, genitourinary malformations. Incidences of renal agenesis and cleft lip and palate were lower. Further analysis of the teratogenic conse- quences of sodium arsenate by Holmberg and Ferm (1969) showed that sodium selenite injected at 2 mg/kg simultaneously with a teratogenic dose of sodium arsenate decreased the number of fetal resorptions and congenital malformations caused by the arsenical. in mouse studies, Hood and Bishop (1972) administered a single dose of sodium arsenate or arsenite by intraperitoneal injection on a specific day from the sixth to the twelfth day of gestation and observed the results on the eighteenth day. The injections given on the ninth day were most teratogenic; 60~ of 96 implantations were resorbed or dead, and 63% were grossly malformed. The defects included exencephaly, micrognat- hia, protruding tongue, agnathia, open eye, cleft lip, fused vertebrae, and forked ribs. Mice that received injections of distilled water served as controls. Although teratogenic erects were seen at 45 mg/kg, 25 mg/kg was without effect. Sodium arsenite was more elective, which indicated that the extent of fetal anomalies caused by sodium arsenite at 10 mg/kg was comparable with that caused by sodium arsenate at 45 mg/kg. Hood and Pike (1972) reported that BAL, when administered to mice at 50 mg/kg by intraperitoneal injection within 4 h of sodium arsenate at 40 mg/kg, prevented the arsenic-induced teratogenesis. Potassium arsenate was fed to four pregnant ewes at 0.5 mg/kg during most of pregnancy without elect (James et al. 1966~. Interactions Moxon (1938) first reported the protective effect of arsenic against selenium poisoning when he found that sodium arsenite (5 ppm) in drinking water reduced liver damage in rats on a diet containing selenium at 15 ppm in seleniferous wheat. Moxon and DuBois (1939) demonstrated that arsenic was unique in its ability to prevent selenium toxicity. The protective elect of arsenic against dietary selenium was not seen when the arsenic was added to the diet, instead of the drinking water (Ganther and Bau