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42 THE RELATION OF SELECTED TRACE ELEMENTS TO HEALTH AND DISEASE Foulks, J., G. Mudge, and A. Gilman. 1952. Renal excretion of cation in the dog during infusion of isotonic solutions of lithium chloride. Am. J . Physiol. 168:642-649. Francis, R.I., and M.A. Trail. 1970. Lithium distribution in the brains of two manic patients. Lancet 2:523-524. Gmelin, Leopold. 1960. Gmelins handbuch der anorganischen chemie. Lithium. System 20 (8th ed.), Verlag Otemie, GMBH, Weinheim, Germany. pp. 64-88. Gutkin, E. S. 1971 . Geochemistry of lithium in bauxites of the north Urals basin. Geochem.1nt. 8(1):37-44. (Trans!. from Geokhimiya (1 ): 72-80.1 Headden, W. P. 1921. Ti, Ba, Sr, and Li in certain plants. Colo. Agric. Exp. Stn. BuU. No. 267. Colorado State University, Fort Collins. 20 pp. Heidel, S. G., and W. W. Frenier. 1965. Otemical quality of water and trace elements in the Patuxent River Basin. Maryland Geo- logical Survey, Baltimore. 40 pp. Hem, J.D. 1959. Study and interpretation of the chemical charac- teristics of natural water. U.S. Geol. Surv. Water Supply Pap. No. 1473. U.S. Government Printing Office, Washington, D.C. 269 pp. Kelley, W. P. 1948. Cation exchange in soils. Reinhold Pub!. Corp., New York. Kent, N. L. 1941. Absorption, translocation, and ultimate fate of lithium in the wheat plant. New Phytol. 40:291-298. Kent, N. L., and R. A. McCance. 1941. The absorption and excre- tion of "minor" elements by man: Silver, gold, lithium, boron, vanadium. Biochem. J . 35:837-844. Kopin,l. J. 1969. How does lithium work? New Engl. J. Med. 280:56o-561. Levy, B. 1968. A practicum for the use of lithium salts in affective psychoses. J. Am. Med. Assoc. 206:1045-1047. Linstow, 0. 1929. Bodenanzeigende Pflanzen (Soil-indicating plants). Preuss. Geol. Landesanst. Abh., n. Set. 114 (2nd ed.). 246 pp. Ljungberg, S., and L. Paalzow. 1969. Some pharmacological prop- erties of lithium. Acta Psychiatr. Scand. Suppl. 207:68-82. Lombardi, 0. W. 1963. Observations on the distribution of chem- ical elements in tJie terrestrial saline deposits of Saline Valley, California. Nav. Ord. Teat Stn. TP 2916.41 pp. Parker, R. L. 1967. Composition of the earth's crust. In Data of geochemistry, M. Fleischer (ed). U.S. Geol. Surv. Prof. Pap. No. 440-D. U.S. Government Printing Office, Washington, D.C. pp. 1-19. Perry, H. M. 1971. Trace elements related to cardiovascular disease. In Environmental geochemistry in health and disease, H. L. Cannon and H. C. Hopps (eds). Geol. Soc. Am. Mem. No. 123. Geological Society of America, Boulder, Colo. pp. 211-219. Puccini, G. 1957. Stimulant action of lithium salts on the flower production of the perpetual carnation of the Riviera. Ann. Sper. Agrar. (Rome) 11:41-63. Ranlcama, K., and T. G. Sahama. 1950. Geochemistry. University of<llicago Press, Oticago. pp. 424428. Robinson, W. 0., L.A. Steinkoenig, and C. F. Miller. 1971. The relation of some of the rarer elements in soils and plants. U.S. Dept. Agric. Bull. No. 600. U.S. Government Printing Office, Washington, D.C. 27 pp. Ronov, A. B., A. A. Migdisov, N. T. Vosltresenslcaya, and G. A. Korzina. 1970. Geochemistry of lithium in the sedimentary cycle. Geochem. Int. (1-2):75-102. (Transl. from Geolthimiya (2):131-161.) Sauer, H. I., and F. R. Brand. 1971. Geographic patterns in the risk of dying. In Environmental geochemistry in health and disease, H. L. Cannon and H. C. Hopps ( eds). Geol. Soc. Am. Mem. No. 123. Geological Society of America, Boulder, Colo. pp. 131-150. Schou, M. 1957. Biology and pharmacology of the lithium ion. Pbarmacol. Rev. 9:17-58. Schou, M., A. Amdisen, and J. Trap-Jensen. 1968. Lithium poison- ing. Am. J. Psychiatr. 125:112-119. Shopsin, B. 1970. Effects of lithium on thyroid function. Dis. Nerv. Syst. 31:237-244. Stewart, F. H. 1963. Marine evaporites. In Data of geochemistry, M. Fleischer (ed). U.S. Geol. Surv. Prof. Pap. No. 440-Y. U.S. Government Printing Office, Washington, D.C. Steinkoenig, L.A. 1915. lithium in soils. J. Ind. Eng. Chern. 7:425426. Strock, L. W. 1936. Zur Geochemie des Lithiums. Nachr. Ges. WISI. Goettingen,IV. N.F. 1(15): 171. Swaine, D. J. 1955. The trace element content of soils. Commonw. Bur. Soil Sci. Tech. Commun. No. 48. Herald Printing Works, York, England. 16 7 pp. Swaine, D. J., and R. L. Mitchell. 1960. Trace-dement distribution in soil profiles. J. Soil Sci. 11(2):347-368. Szabo, K. T. 1970. Teratogenic effect of lithium carbonate in the foetal mouse. Nature 225:73-75. Trautner, E. M., R. Morris, C. H. Noack, and S. Gershon. 1955. The excretion and retention of ingested lithium and its effect on the ionic balance of man. Med. J. Aust. 2:28o-291. Turekian, K. K., and K. H. Wedepohl. 1961. Distnbution of the el~ ments in some major units of the earth's crust. Geol. Soc. Am. Bull. 72:175-191. U.S. Geological Survey. 1972L Geochemical survey of Missouri: plans and progress for fourth six-month period (January-June, 1971). U.S. Geol. Surv. Open-File Rept. U.S. Geological Survey, Denver, Colo. U.S. Geological Survey. 1972b. Southwest energy study, Coal R~ sources Working Group. Appendix J. U.S. Geol. Surv. Open-File Rept. U.S. Geological Survey, Denver, Colo. Vinogradov, A. P. 1952. Pot-culture experiments: Fundamental laws in the distribution of microelements between plants and environment. Acad. Sci. U.S.S.R. Moscow. p. 19. (In Russian.) Vlasiuk, P. A., and M. F. Olthrimenko. 1967. On biological para- doxical phenomena, Vol. I. Lenin AU-Union Acad. Agric. Sci. Rept. 10, UDK 581.1:581.143. Pub!. by Kotas. (English trans!.) Vlasiuk, P. A., and M. F. Olthrimenko. 1969. The effect of lithium on photochromic activity of chloroplasts of tomato and pepper leaves. In Series in geology, geophysics, chemistry and biology. Acad. Sci. Ulcrania RSR (Kiev) No.4, UDK 581.132546. 34. (In Russian.) Voelcker, J. A. 1912. Pot-culture experiments. J. R . .Agric. Soc. (England) 73:314-338. Voors, A. W. 1971. Minerals in the municipal water and athero- sclerotic heart death. Am. J . Epidemiol. 93:259-266. Weischer, M. L. 1969. Ueber die antiaggressive Wirlcung von Lithium. Psychopharmacologia (Berlin) 15:245-254. Wittrig, J., E. J. Anthony, and H. E. Lucamo. 1970. An ashing tech- nique for endogenous lithium in human brain and other biologi- cal tissues. Dis. Nerv. Syst. 31:408411. Wittrig, J., A. E. Woods, and E. J. Anthony. 1970. Mechanisms of lithium action-endogenous tissue levels, excretion in emotional states, and behavioral effects. Dis. Nerv. Syst. 31 :76 7-771.
VI Cadmium, Zinc, and Lead HAROLD H. SANDSTEAD, Chairman William H. Allaway, Richard G. Burau, William Fulkerson, Herbert A. Laitinen, Paul M. Newbeme, James 0. Pierce, Bobby G. Wixson CADMIUM Several excellent recent reviews of the toxicology of cad- mium are available. They include those of Schroeder et aL (1967), Nilsson (1970), Flick et aL (1971), Underwood ( 1971 ), and a very comprehensive book by Friberg et aL (1971) and its sequel (Friberg et al., 1973). In addition, a review edited by Fulkerson and Goeller ( 1973) covers properties, the societal flow of cadmium and zinc, abate- ment, ecological cycling and effects, economics, and legal and other aspects of control. There is also a recent anno- tated bibliography on cadmium by Copenhaver et aL (1973). These reviews provide detail considerably beyond the overview possible in this short chapter. Cadmium is toxic to man and to other living things in virtually all of its chemical forms. Threshold doses for long- term toxic effects of cadmium are not known with cer- tainty; however, cadmium tends to accumulate in the body. Consequently, there is concern about the increase in envi- ronmental cadmium that has occurred as a result of its increased industrial use. Cadmium has atomic number 48, an atomic weight of 112.40, and is found in nature in association with zinc, and it is produced commercially as a by-product of the zinc industry. The most important uses of cadmium are in elec- troplating, in pigments, and as stabilizers in plastics. As an impurity in zinc, significant amounts of cadmium are also present in galvanized metals. 43 In 1968 the market value of the cadmium used in the United States was about $35 million compared to $380 million for metallic zinc-a clear indication of its by- product value to the zinc industry. Zinc refming is a major source of cadmium environmental pollution, but more stringent control measures at mines and smelters would be reflected in higher prices for both elements; in addition, the imposition of use restrictions on cadmium would de- press its price, probably increasing the price for zinc. The association of the two metals continues in the most im- portant use of cadmium-electroplating-where zinc is often a successful competitor. Furthermore, because cad- mium is an impurity in zinc, the hazard of cadmium is present to some extent in the use of zinc: The most pro- nounced example occurs in galvanizing where poor grade {high in cadmium) zinc is generally used. The association of cadmium and zinc in geology carries over into biological systems. Zinc is an essential nutrient, but cadmium has no recognized biological function. Cad- mium and zinc appear to compete for certain organic ligands in vivo; this competition is thought to account in part for the toxic effects of cadmium and the ameliorative effects of zinc on cadmium toxicity. For this reason the ratio between these two cations within the cells is thought to be biologically important. Acute cadmium poisoning has occurred in man from food contaminated by cadmium-plated containers (Gleason
44 THE RELATION OF SELECTED TRACE ELEMENTS TO HEALTH AND DISEASE et al., 1969). Use of such containers, and of other packaging or food handling materials containing·cadmium is now pro- hibited by the U.S. Food and Drug Administration and by the U.S. Department of Agriculture. Poisoning has also oc- curred from accidental inhalation of cadmium fumes gener- ated by silver soldering, or the heating of cadmium-plated steel. Poisoning caused by environmental pollution with cad- mium is exemplified by itai-itai disease in people living in the Jintsu River Valley of Japan (Kobayashi, 1971). Chronic kidney damage, with proteinurea, aminoacidurea, hyperphosphaturea and other features of adult Fanconi syndrome occur; other consequences of cadmium pollu- tion include osteomalacia, pathologic fractures, and severe bone pain. These latter effects appear to be due to an in- terference with synthesis of 1-25 dihydroxycholecalciferol. Contamination of the Jintsu River by discharges from zinc and lead mines and smelting plants, resulted in contamina- tion of irrigated crops with zinc, lead, and cadmium (Yama- gata and Shigematsu, 1970). Rice eaten by farmers has been found to have very high levels of cadmium (-1 ppm). In the United States, ill health caused by chronic low- level exposures to cadmium has not been documented in persons living near zinc smelters or other large sources of emissions. On the other hand, cases of industrial poi- soning have been observed. Human Intake, Absorption, and Accumulation Man receives cadmium intake via inhaled air and ingested food and water. The absorption retention and elimination of this material appears to be a function of the intake path- way and of the chemical or physical form of the cadmium. Some knowledge of intake quantities but far less about absorption, retention, and elimination is available. Air Daily inhalation from ambient air may range from nearly zero in many locations to as high as 7.4 p.g/d (cor- responding to a maximum concentration of 0.37 p.g/m3 , reported by the National Air Surveillance Network in Youngstown, Ohio, in 1963). The highest air concentra- tions are found in and around zinc or lead smelters [e.g., 0.69 p.g/m3 in East Helena, Montana (Environmental Pro- tection Agency, 1971)]. In nonurban areas, intakes ap- proach zero; in industrialized urban areas 0.2-0.5 p.g/d might be considered an average figure, corresponding to average concentrations 9f cadmium aerosols in the range O.ot-0.025 p.g/m3 (National Air Pollution Control Ad- ministration, 1968). The limits of atmospheric exposure recommended by the American Conference of Government Industrial Hy- gienists ( 1971) for an 8-h period in an industrial atmosphere is 100 p.g/m3 air of oxidized cadmium. This level is con- siderably in excess of the 8.4 p.g/m3 concentration in air estimated by Friberg et al. (1971) as the minimum value that might cause renal damage after a 25-year period of exposure (8 h/d for 225 d/yr). The Friberg et al. estimate assumes a 25 percent retention of inhaled cadmium. It also assumes that a renal-cortex cadmium concentration of 200 ppm is, on the average, the level at which damage begins to occur. Cigarette tobacco contains about 1 ppm cadmium. Fri- berg et al. (1971) estimate that one pack of cigarettes daily can contribute 2-4 p.g to the intake, making cigarette smoke a potentially important source of exposure to cadmium for some individuals. Water Using ftltered samples, the U.S. Geological Survey (Durum et al., 1971) recently found that 4 percent of the surface waters measured in the United States were found to have levels of cadmium that exceed the 10 ppb drink- ing-water standard of the U.S. Public Health Service (1962); whereas, for 42 percent the levels measured were between 1 and 10 ppb, and 54 percent were found to contain less than 1 ppb. The U.S. Public Health Service National Community Water Supply Study revealed that the drinking-water stan- dards for cadmium were exceeded by only 0.2 percent of 969 water supply systems tested. These systems serve some 18 million people (McCabe et al., 1970). Plumbing materials containing cadmium, such as galva- nized pipe, may be a source of cadmium contamination of drinking water when the water is soft. Systematic investi- gation of this source is needed. If water consumption is 1.5 1/d the cadmium intake from water may range from less than 1 p.g to 45 p.g, depending on the source of the water. The average intake from water is probably 5 p.g/d (Friberg et al., 1971). Food Reported estimates of cadmium intake from food vary widely. Friberg et al. ( 1971) suggest that the average intake is 50 p.g/d. Rautu and Sporn (1970) calculated a range of dietary intake of Germans to be 38-176 p.g/d with an average of 46 p.g. Murthy et al. (1971) found an average value of 92 p.g/d for institutional diets in the United States. Thus, the total intake from air, water, and food prob- ably ranges from about 40 p.g/d for a nonsmoking rural resident who consumes a low-cadmium diet, to perhaps as much as 190 p.g/d for a smoker living in an industrialized city who consumes a high-cadmium diet. Cadmium levels and the zinc/cadmium ratios of some foods are tabulated in Table 14. The differences between the ratios reported by Schroeder and Balassa ( 1963) and Schroeder et al. ( 196 7) and those reported by Ishizaki et al. ( 1970) need resolution. Tipton and Stewart ( 1970; also, private communication from I. H. Tipton, September 1971) found a ratio of I 00 for mixed diets, which agrees well with the fmdings of Murthy et al. (Table 15), but Friberg
Cadmium, Zinc, and Lead 45 TABLE14 Cadmium Content and Zinc/Cadmium Ratio of Some Foods Cadmium Content by Investigator, ppm (wet wt) Zn/Cd Ratio Food Type a b Vegetables Potatoes 0.03 0.017 Onions O.oi 0.0071 Carrots 0.30 0 Cabbage 0.07 0 Kohlrabi 0.09 Beans, kidney 0.07 Beans, string, fresh 0.01 Tomato, fresh 0.03 0.013 Tomato, canned 0.02 0.044 Greens 0.06 Peas, green, fresh 0.04 Spinach, fresh 0.45 0.064 Beans, string, canned O.o3 0.024 Grains Com (cornmeal) 0.12 0 Wheat 0.15 Bread, white 0.22 0.042 Bread, dark 0.15 0.054 Fruits Tangerine orange 0.02 Apricot, canned 0.01 Banana O.o3 Grapes 0.007 Apples 0.0065 Meats Pork 0.25 0.034 Beef 0.89 0.060 Chicken 1.25 Whale Kidney 0.52 0.43 Dairy Milk, whole 0.12 0 Cheese 0.039 Butter 0.56 Eggs, whole 0.09 0.021 Seafood Oysters, fresh 3.66 Oams,fresh 0.31 Shrimp 0.24 Tuna 0.21 Sardines 0.13 0.066 Salt herring 0 Mackerel Freshwater fish Carp Bass 4 Schroeder et al. (1967). bRautu and Sporn (1970). et aL ( 1971) have criticized these data because of probable sodium interference during atomic absorption analyses. The findings relative to the zinc/cadmium ratio for rice grown in the Jintsu Valley, Japan (Yamagata and Shige· rnatsu, 1970), are instructive (Table 16). Homeostatic mechanisms of the plant apparently keep zinc concentra· c d a c O.o38 290 85 0.012 89 106 0.041 17 67 0.009 0.034 26 201 0.052 25 0.019 12 1120 125 0.032 20 45 6 7 200 0.128 s 71 3 0.033 30 0.025 130 230 0.046 s.s 130 35 0.003 72 250 s 0.011 7 150 0.004 52 0.016 45 1080 0.054 63 1220 0.027 60 600 0.33 31 40 0.015 950 0.62 350 165 0.28 60 67 0.032 62 220 0.066 87 77 0.011 150 770 0.018 530 0.003 0.036 5800 0.037 clshizaki et al. (1970). dFulkerson and Goeller (1973). tions relatively constant even when soil zinc is high, but they do not control the cadmium levels, and cadmium ac- cumulates in the plant. Absorption and Accumulation Tracer studies with animals show that relatively small percentages of orally ingested
46 THE RELATION OF SELECTED TRACE ELEMENTS TO HEALTH AND DISEASE TABLE IS Range and Average Values for Food Consumption and Cadmium and Zinc Content of Institutional Total Diets, Jan.-Dec. 1967a Food Consumption, Cadmium Content, Zinc Content, Zn/Cd Ratio Location kg/d mg/kg mg/kg (average) Juneau, Alaska 2.15-3.10 0.02o-o.033 2.13-3.34 100 (2.55) (0.027) (2.67) Palmer, Alaska 1.22-1.83 0.016-0.062 2.74-4.70 112 (1.59) (0.033) (3.76) Phoenix, Ariz. 1.52-2.21 0.032-0.065 3.13-4.16 80 (1.92) (0.048) (3.85) Uttle Rock, Ark. 1.14-2.12 0.036-0.072 3.41-4.73 86 (1.92) (0.048) (4.15) Los Angeles, Calif. 1.47-2.18 0.022-0.053 2.40-5.90 116 (1.94) (0.033) (3.85) San Francisco, Calif. 1.99-2.88 0.025-0.049 3.02-5.78 120 (2.40) (0.033) (4.00) Denver, Colo. 1.98-2.43 0.028-0.04 7 2.63-5.92 114 (2.28) (0.034) (3.89) Wtlrnington, Del. 2.05-2.38 0.04 7-0.070 4.23-8.91 liS (2.20) (0.055) (6.36) Tampa, Fla. 1.94-2.18 0.048-0.076 4.15-5.89 90 (2.08) (0.060) (5.38) Idaho Falls, Idaho 1.56-2.16 0.035-0.089 s .oo-6. 04 95 (1.97) (0.060) (5.71) Oticago, Ill. 1.30-1.95 0.034-0.082 S.Sl-11.30 123 (1.58) (0.055) (6.80) Louisville, Ky. 1.23-2.28 0.03o-o.079 3.61-5.39 85 (1.67) (0.056) (4.78) New Orleans, La. 1.42-2.26 0.04o-o.070 3.65-5.66 86 (1.84) (0.056) (4.82) Boston, Mass. 1.48-2.08 0.04o-o.089 4.79-9.70 116 (1.68) (0.052) (6.08) Columbia, Miss. 1.79-2.39 0.045-0.071 3.82-6.44 93 (2.17) (0.058) (5.40) St. Louis, Mo. 1.33-2.53 0.049-0.087 5.35-6.21 90 (1.74) (0.064) (5.78) Omaha, Neb. 2.07-2.39 0.037-0.108 5.54-7.73 110 (2.16) (0.061) (6.74) Carson City, Nev. 1.04-1.88 o.o3o-o.06s 3.37-8.74 113 (1.42) (0.045) (5.08) Albuquerque, N.M. 1.44-2.51 0.032-0.062 3.73-6.16 86 (2.32) (0.053) (4.55) aeveland, Ohio 1.17-1.48 0.036-0.069 4.14-5.72 96 (1.35) (0.053) (5.03) Woodburn, Ore. 2.18-2.86 0.024-0.050 2.52-4.21 108 (2.42) (0.032) (3.48) Pittsburgh, Pa. 2.06-2.30 0.039-0.074 4.32-8.23 108 (2.21) (O.CSI) (5.51) Owlcston, S.C. 1.36-2.13 0.034-0.063 3.38-5.77 93 (1.64) (0.048) (4.47) Sioux Falls, S.D. 1.05-1.31 0.028-0.124 3.25-7.75 91 (1.18) (0.058) (5.28) Austin, Tex. 1.53-1.88 o.04o-o.on 2.61-5.42 89 (1.72) (0.054) (4.80) Salt Lake City, Utah 1.57-2.08 0.018-0.040 2.01-5.18 101 (1.91) (0.029) (2.97) Burlington, Vt. 0.92-1.03 0.043-0.091 4.78-7.84 98 (1.30) (0.062) (6.04) Seattle, Wash. 1.59-2.23 0.028-0.04 7 3.16-5.69 123 (1.92) (0.034) (4.18) a Adapted from Murthy etal. (1971).
TABLE 16 Concentration of Cadmium and Zinc in Rice (unpolished) and Soil on Which the Plant Was Growrf Concentration in Concentration in Sample Rice, ppm Soil, ppm Category No. Cadmium Zinc Cadmium Zinc Contaminated SA I.SS 20.8 4.2 1008 area 58 3.87 21.6 3.2 1104 sc 4.17 26.7 2.2 800 7A 3.36 28.4 7.2 1020 78 1.32 35.2 s.o 1224 7C 0.72 27.0 3.2 1042 Control area 2A o.os 20.8 <1.0 92 28 0.11 18.9 <1.0 88 2C 0.11 20.6 1.0 82 4A O.o7 28.2 168 48 0.08 20.8 4C 0.03 26.8 11 Adapted from Y amaaata and Shfaematsu (I 970 ). cadmium are absorbed. For example, Cotzias et aL (1961) found that rats absorbed 0.5-8 percent of orally adminis- tered cadmium chloride e09CdCh) after 4 h. How absorp- tion varies with the chemical form of the cadmium intake has not been established. A much larger percentage of in· haled cadmium from aerosols may be absorbed depending on the chemical composition and the particle sizes involved. Friberg et aL ( 1971) indicate a range of I 0-40 percent re- tention in the lung. Once absorbed, the elimination rate is generally very slow so there is a net accumulation. As the human body contains virtually no cadmium at birth, and the total body burden at middle age is about 15 mg (Smith et aL, 1960) to 38 mg (Schroeder et aL, 1967), the average accumulation rate may be estimated at 0.9-1.8 pg/d. Fur- ther, retention of cadmium in the body may depend on the composition of the diet itself; calcium and protein deficient diets in animal experiments increase cadmium accumulation in the kidney and liver (Friberg et al., 1971 ). Usual urinary excretions of cadmium range from I to 9 p.g/1, or 2-17 percent of ingested cadmium ( 60-70 pg) if the urinary volume is 1.2 I (Friberg et al., 1971 ). Increased con- centrations of urinary cadmium may be found when renal damage is present, particularly in individuals with damage due to cadmium exposure. Distribution Within the body, cadmium is concentrated in the renal cortex, with lesser concentrations in other tissues. According to Schroeder et al. (1967) the distribution is as follows: kidney, 33 percent; liver, 13.8 percent; lung, 23 percent; pancreas, 0.3 percent, and small amounts in other tissues (U.S. Public Health Service, 1962). Smith eta/. (1960) found the average cadmium content of organs from three 50-year-old men who had had no known unusual expo- Cadmium, Zinc, and Lead 4 7 sure to cadmium to be as follows: kidney, 4.1 mg; liver, 3.9 mg; muscle, 3.3 mg; skin, 0.4 mg; stomach and colon, 0.6 mg; lung, 0. 7 mg; bone marrow, 0.5 mg; and other organs, about I mg, for a total of 14.5 mg. Effects on Health The significance of present environmental concentrations of cadmium with respect to health are unknown. According to some authors, environmental cadmium may contribute to the pathogenesis of hypertension in man (Carroll, 1966; Schroeder, 1965; Schroeder and Balassa, 1965). Others dis- pute these conclusions because industrial exposure to cad- mium bas not been found to be associated with these two diseases (Friberg et al., 1971). On the other hand, it is clear that renal tubular damage may occur after sufficient expo- sure to cadmium (Friberg et al., 1971 ). The competitive interaction between zinc and cadmium seems to indicate that the ratio between these cations may be important biologically. In Schroeder and Vinton (1962), Schroeder ( 1964 ), and Schroeder and Balassa ( 1965), a correlation between arteriosclerosis and a decreased zinc/ cadmium ratio in tissues of experimental animals is re- ported. If this apparent relationship between low zinc/ cadmium ratios and hypertension is real, its implications for human health are of obvious importance. Studies by Schroeder ( 1965) and more recently by Voors et al. (1973, 1974) that support the hypothesis indicate the need for additional research on the subject. Voors et aL (1973, 1974) assessed the relationship between atherosclerosis judged at autopsy and the ratio of zinc to cadmium in the renal cortex of individuals from the Pied- mont and Coastal Plain of North Carolina and found a sig· nificant relationship. On the other hand, the relation to hypertension as judged by cardiac weight was not significant at the 95 percent probability level. They found also a posi- tive correlation between concentrations of cadmium in renal cortex and smoking that accounted for 29 percent of the variations observed. V oors and his colleagues suggested that the higher incidence of cardiovascular disease in people living in the Coastal Plain may be related to the geochemical en- vironment of the area. The water in the coastal region tends to be soft and the soil concentration of zinc low (Sauer et aL, 1966). Threshold Levels The threshold at which chronic expo- sure to cadmium will cause disease in man is unknown. However, estimates have been made on the basis of animal studies (Nilsson, 1970). With a safety factor of I 00, it has been suggested that an intake of 170-500 pgjd might cause anemia, hypertension, and reduction of life span. As a comparison, the levels of cadmium intake of individuals with itai-itai disease probably ranged from 600 to I ,000 p.g/d (Yamagata and Shigematsu, 1970). It remains to be
48 THE RELATION OF SELECTED TRACE ELEMENTS TO HEALTH AND DISEASE determined whether the above safety factor is too high. Friberg et a/. ( 1971) suggest that a 50-year cadmium in· gestion of 132 p.gjd could result in kidney damage if 5 per- cent of the cadmium were retained. Exposure to ambient air concentrations of 1.3 p.gjm3 (equivalent to the effect of 7 packs of cigarettes per day) for 50 years would have similar effects if 25 percent of the cadmium were retained. These estimates are consistent with a relatively narrow safety margin for cadmium. If the zinc/cadmium ratio is of health importance as sug- gested previously, then it should also be considered in the estimation of thresholds for cadmium toxicity and permis· sible intakes. Additionally, if the ratio of zinc to cadmium in diets is 100 (Murthy eta/., 1971 ), then a daily intake of 6.5 mg of zinc is equivalent to an intake of 65 p.g of cad- mium, and an intake of 15 mg of zinc is equivalent to ISO p.g of cadmium. This level of cadmium is near the intake level suggested by Friberg et a/. ( 1971) as sufficient to cause renal damage through chronic intake over a period of 50 years. Whether this oversimplified relationship is relevant to human health, remains to be determined. The levels of other essential metals in the diet are probably im· portant factors in the zinc-cadmium equation. Pollution The flow of cadmium in the United States, based on 1968 estimates, is shown in Figure 6 (Fulkerson and Goeller, 1973). The annual demand was about 13 million pounds, and 80-90 percent of this went to dissipative (nonrecyc1a- ble) uses. The majority was used for electroplating, paints, pigments, and for stabilizers in making plastics (especially polyvinylchloride ). AU of the flows in the f~gure are ex- pressed in percentages of the annual demands. Knowledge of the quantities or forms of cadmium pol- lution is incomplete, but some estimates are given (Fig- ure 6). Major sources of air pollution probably rank as follows: smelter > incineration of plastics and cadmium pigments> fossil fuel (including coking)> steel mills> metallurgical. In water pollution, the probable order of sources is mining and beneficiation > electrolytic refm- ing > electroplating > paints, plastics, batteries, metal· lurgical > phosphates from detergents. As regards soil pollution, cadmium associated with superphosphate fertilizer may be of importance to health because of its possible availability to plants. Data on the cadmium uptake by plants from soils treated with phos- phate fertilizers are conflicting (Schroeder and Balassa, 1963; Schroeder eta/., 1967). A number of studies both in this country and abroad (Kobayashi, 1972; Environmental Protection Agency, 1971; Munshower, 1972; Lagerwerff eta/., 1973; Buch- auer, 1973) have shown significant cadmium contamina· tion in soil, plants, and animals in the vicinity of lead and zinc smelting operations. For example, Kobayashi ( 1972) reported cadmium levels ranging from less than I ppm in corn to about 41 ppm in Chinese cabbage raised near a large zinc smelter in Japan. Although some of this con- tamination was undoubtedly from airborne foliar depo- sition, the soil in which these crops were grown contained RECYCLABLE USES METALLURGICAL USES AND ALLOYS 2.,. BATTERIES ).,. OtSSIPATIV[ uSES ELECTROPLATING 45-49 .,_ PAINTS AP\0 PIGMENTS 18-2 1..,. PLASTICS â¢5.,. ME TALLURGIC4L USES Afl{) ALLOYS 2~. F"UNGICI0£5 7 MISCELLANEOUS AND UNACCOUNTED SUPERPHOSPHATE 2·70ppm:d FIGURE 6 Diagram showing the flow of cadmium in the United States in 1968. All flows are given as percentages of the total demand of 13.3 X 106 lb. (Adapted from Fulkerson and Goeller, 1973.)
20-88 ppm. Normal concentrations of cadmium in soils are usually well below 1 ppm. Similarly, the Helena Valley study (Environmental Protection Agency, 1971) showed that vegetables cultivated within a 4-mile radius of the lead- smelter, slag-fuming, and paint plants in East Helena, Mon- tana, contained 0.05-10 ppm cadmium, and barley, wheat, and oat kernels contained 0.1-1.5 ppm. The top 4 in. of cultivated soil at 1-, 2-, and 4-mi radii from the smelter averaged 21, 9, and 3 ppm cadmium, respectively. Oats grown on contaminated soil obtained near a battery plant (presumably a nickel-cadmium battery plant) showed 16-19 ppm cadmium in the oat shoots when the soil con- centration was 46 ppm, whereas the value was 0.51 to 0.86 ppm for oat shoots grown in soil containing 1.3 ppm cad- mium (John et aL, 1972). These were laboratory experi- ments so that, in this case, the levels in the oats resulted from plant uptake from the soil and not to foliar deposition from the air. Cadmium and Sewage Sludge Because there is concern about the use of sewage sludge for fertilizer, two tables by Regan and Peters ( 1970, 1972) are included. The high levels of trace elements in sewage digestors at the time of a failure of the plant in Lexington, Kentucky (Table 17), are of special interest. The metal content of sludges from 12 recent digestor failures is shown in Table 18. Information on cadmium uptake by plants from soil treated with contaminated sewage sludge is sparse and some- what conflicting. Peterson eta/. ( 1971) did not fmd a sig- nificant increase in the cadmium concentration in corn leaves following applications of over 20 metric tons of sew- age sludge per hectare of soil. The sludge used contained 0.05 kg cadmium per metric ton (50 ppm). (Sludge appli- cation rates and analytical results are reported on a dry weight basis.) The phosphate content of the sludge and the pH of the soil may have been important factors in their study. On the other hand, the U.S. Food and Drug Administration (Jelinek, 1973) measured the cadmium, arsenic, mercury, lead, zinc, and pesticide concentrations TABLE17 Metal Content in Sludge0 Cadmium, Zinc, and Lead 49 in soybeans, and cadmium, zinc, lead, and pesticides in corn grown by the University of Illinois on control and sewage-sludge treated test plots. For soybeans, a significant increase in concentration was observed only for cadmium: 0.038 ppm in control, compared to 1.09-1.80 ppm in beans grown on soil treated over a 3-year period with 152 metric tons of sludge solids per hectare. The cadmium concentra- tion of the sludge was 227 ppm (dry wt). The addition of phosphorus had no important effect on the uptake by plants. Corn grown on soil treated with 56 metric tons of dry sludge per hectare had a cadmium concentration of 0.07 ppm, compared to 0.02 ppm for the control. In this in- stance, the concentration of cadmium in the sludge was about 780 ppm (dry wt). More work on plant uptake is needed to assess the advisability of the large scale chronic treatment of agricultural land with sewage sludge. Recommendations for Research Studies assessing the impact that cadmium may have on human health should be conducted. Some specific studies that may be of value follow: I. comparisons of the intakes of cadmium, zinc, other essential trace metals and macroelements of representative groups of individuals from various geographic and industrial regions around the country, and assessment of these intakes in terms of incidence of various diseases; 2. measurements of the zinc, cadmium, and other trace element concentrations in the urine, hair, and blood (plasma) of people participating in the U.S. National Health Survey and assessment of these measurements in terms of geochemistry, atmospheric and water pollution, diet, and diseases occurring in the people tested; 3. metabolic studies in human volunteers to assess zinc and cadmium uptake, retention, and excretion [should in- clude long-term mass balance measurements, such as those attempted by Tipton and Stewart (1970), and be designed to show how retention is related to important variations Date Concentration by Metal, ppm (dry wt) Sludge Sample (September-1967) Fe Zn Cr Cu Ni Pb Cd Raw primary 13 9,800 4300 2100 1200 790 650 290 14 4300 2200 1200 980 690 290 Digester No. 1 13 10,900 4700 2200 1500 960 810 360 14 5200 2500 1700 1100 900 370 Digester No. 2 13 11,000 7690 3200 2100 1200 1100 440 14 5300 2700 1800 1100 870 400 Drying bed 4900 2300 1700 950 860 520 0 Adapted from Regan and Peten (1970; 1972).
50 THE RELATION OF SELECTED TRACE ELEMENTS TO HEALTH AND DISEASE TABLE18 Metal Content in Sludge Samples Where Digestor Failures Occurred4 Concentration by Metal, ppm (dry wt) City Heated Zn Cr A No 2,000 2600 8 Yes 5,100 2700 C-1 Yes 7,400 5250 C-2 Yes 5,100 3600 D-1 Yes 5,000 2350 D-2 Yes 6,000 3000 D-3 Yes 5,600 3300 D-4 Yes 5,900 3200 E Yes 1,300 200 F Yes 13,800 9100 G No 1,400 4000 H No 21,200 1300 a Adapted from Regan and Peters ( 1 972 ). in the diet, such as the quantity and quality of protein, and fiber and phytate content; also, should include studies of the chemical composition and particle size distribution of cadmium aerosols as variables in the metabolism of inhaled cadmium] ; and 4. additional chemical assay of autopsy specimens for cadmium, zinc, and other trace element concentrations and their relation to disease and the geochemical environment. Mechanistic Studies Systematic investigation of the mech- anisms by which cadmium and the zinc/cadmium ratio might be related to hypertension, other cardiovascular dis- eases, and other chronic maladies should be undertaken- including experiments with animals at low-level, long-term exposure under a variety of carefully controlled conditions. These experiments might involve 1. the effects of cadmium on the juxtaglomerular appa- ratus, sodium retention, and aldosterone secretion in the rat, correlated with blood pressure; effects of altered zinc/ cadmium ratio on lipid metabolism in vessel walls and platelet function; and 2. low-level experiments on the effects of altered zinc/ cadmium ratio on survival, response to dietary sodium, di- etary sucrose, dietary saturated fat, and dietary fiber, and to environmental stress in lifetime studies with experimental animals. In addition, the mechanisms of cadmium toxicity at the cellular and molecular levels are not well understood: For example, the nature and function of metallothionein should be much more fully explored. The effects on enzyme sys- tems, and especially cadmium competition with zinc, and the effects of cadmium on calcium and phosphorus me- tabolism should be further investigated. Possible genetic, carcinogenic, and teratogenic effects Cu Ni Pb Cd 400 70 220 <SO 510 190 920 <50 390 1450 890 2850 360 2000 920 970 1,600 1000 860 370 1,900 1200 970 420 1,900 650 980 370 1,900 550 960 370 10,300 130 3500 <50 730 <SO 300 <SO 1,700 550 <SO 500 so <50 should also be investigated. Subcutaneously or intramus- cularly injected cadmium compounds have been shown to induce sarcomata in rats. Apparently, animal experi- ments where cadmium was administered by inhalation have not been done. There is no conclusive evidence that cadmium induces cancer in humans, but considering the amount of cadmium in cigarette smoke, as well as in in- dustrial fumes, it would seem worthwhile to explore the carcinogenic potential of inhaled cadmium. Sublethal injections (2 mg/kg) of cadmium sulfate have been shown to be teratogenic to the golden hamster (Holm- berg and Ferm, 1969). Sodium selenite administered 30 min before or after the cadmium injection was antagonistic. This interaction should be explored further. The zinc/cadmium ratio is, of course, an important vari- able in needed studies, but the mechanisms of other antag- onistic interactions-such as with selenium, cysteine and various chelating agents-should be studied as well. Other Recommendations Much more information about the flow of cadmium in the environment is needed. Mass balances, where these can be obtained, around various types of industrial processes should be measured, or at the very least, the emission char- acteristics should be measured. In addition, the fate of cad- mium in products from use and disposal patterns needs to be more carefully investigated-for example, in galvanized plumbing, incinerators, landftlls, sewage sludge, and phos- phate detergents. We have very limited knowledge of the details of the movement and fate of cadmium in the environment. We need to investigate how cadmium moves from the soil- sediment sinks into the food chain and how the food and water zinc/cadmium ratio is influenced by both natural and man-made variables.
Schroeder et aL (1967) report that refming can decrease the zinc/cadmium ratio in flour, and they cite a study by Moritsugu and Kobayashi ( 1964) that found a similar re- sult in polished rice. Processing effects such as these need to be evaluated carefully. Finally, it should be noted that concentrations of cad- mium in the environment are very low, ranging from 1 ppb in natural waters to 0.5 ppm for soils and sediments, to a few parts per million for certain biological specimens, such as liver and kidney. Corresponding zinc concentrations will generally run from 1 to 3 orders of magnitude higher. Ac- curate cadmium analytical results are extremely difficult to obtain. For this reason, we urge that there be a national program to establish standard reference materials to test ana- lytical results and that these materials include soils, plants, and other biological materials. The National Bureau of Stan- dards orchard leaf and bovine liver reference materials are examples of the standards needed. Further, it is suggested that a certain fraction of specimens from studies of cadmium and other trace elements in the environment and in man be banked in a national environmental specimen bank. This could provide a basis for monitoring changes in concentra- tions over time, for re-evaluation of old data as new ana- lytical methods are perfected, and for retrospective studies of currently unsuspected environmental factors or results. Because zinc and lead are closely associated with cad- mium, the accompanying brief discussions are included in this chapter. ZINC Concern with zinc in the environment and its relationship to health primarily centers around its role as an essential nutrient and those factors that may interfere with its role as a nutrient. Toxicologically, zinc is relatively unim- portant in that there is a wide range between the usual environmental levels and toxic levels. Zinc has atomic number 30, and an atomic weight of 65.37. Environmental and Dietary Sources of Zinc in Man Contamination of the environment around lead smelters or zinc smelters is of concern. Because these environments are also high in lead and cadmium, both of which are much more toxic than zinc, the role of zinc in diseases that may occur in these environments is unclear. Unpublished obser- vations on horses (Lennart Krook, personal communication, 1972) are consistent with there being a zinc-lead toxic in- teraction in horses exposed to high environmental concen- trations of both metals simultaneously. The remodeling of bones by osteoclasts is the abnormality observed. Similar Cadmium, Zinc, and Lead S 1 toxicologic phenomena do not appear to have been ob- served in man. In factories where workers are exposed to zinc fumes or dust, so-called metal fume fever occurs, (Papp, 1968). From a geochemical point of view, this disease is of practically no importance. Man also may be exposed to excessive concentrations of zinc in beverages or foods that have been exposed to gal- vanized metal (Brown et al., 1964 ). This type of exposure is also not in the realm of geochemistry. Zinc in tap water from galvanized pipes may range from 3 to 2,100 p.g/1 with an average of 79.2 p.g/1 (Kopp, 1970). Other sources of zinc in water include the runoff of zinc from fields where zinc containing fertilizers have been spread, certain wells, and industries that dump zinc con- taining materials into streams. The health significance of zinc in concentrations found in drinking water is unknown. Whether it is nutritionally important for some individuals remains to be established. The relationship between zinc in water and cadmium in water to health is also unknown. If it is found that the zinc/cadmium ratio in vivo is a factor in health, then the zinc/cadmium ratio in water may be of importance. Roughly 22,000 tons of zinc are used in fertilizer each year in the United States. The application of zinc to soils does not necessarily imply that the soils are "zinc deficient." In some instances, the available zinc is insufficient for cer- tain plants but adequate for others. In other regions, the available zinc is low for all food plants. Sometimes zinc is applied empirically without relation to a demonstrated decreased productivity. The acreage of tillable soil in the United States which is considered "zinc deficient" is a subject of debate. It is clear, however, that in some regions, the application of zinc to soil contributes significantly to the plant productivity. Zinc in plants is distributed throughout the organism. Application of 65Zn to the leaves is followed by its ap- pearance in remote parts of the plant including the fruit. In an analogous manner, application of an available form of zinc to soil may be followed by entry of the zinc into the plant and in some instances, a significant increase in the zinc content of the plant, including the edible portion. At present it seems unlikely that this phenomenon is of importance as far as human nutrition is concerned. The refming of the edible portions of plants, such as grains, removes a large portion of the zinc. For example, Schroeder reports that whole wheat may contain 31.5 ppm while certain patent flours contain 8.9 ppm zinc. Similarly the 18.9 ppm zinc present in dry corn may be decreased to half that amount in the manufacture of cornmeal (Schroe- der, 1971). It has been suggested, but not established, that removal of zinc from grain products through refming may be of adverse nutritional consequence to individuals who customarily eat small amounts of foods from which zinc
52 THE RELATION OF SELECTED TRACE ELEMENTS TO HEALTH AND DISEASE is more available, such as meat. For example, beef steak contains nearly 60 ppm while pork and eggs may contain roughly 20 ppm. Animal studies suggest that the availability for absorp- tion of "plant zinc" compared to "animal zinc" is less. A number of factors in foods of plant origin appear to be re- sponsible. The most extensively studied of these factors is phytate (inositol hexaphosphate) (Likuski and Forbes, 1964). In the intestinal environment, phytate forms insolu- ble complexes with zinc and calcium, which are lost in the stool (O'Dell and Savage, 1960). Other constituents of the plant which conceivably may bind zinc and form insoluble complexes include fiber, certain hemicelluloses, and amino acid carbohydrate complexes. The greater availability of "animal zinc" for absorption may not be simply due to the relatively greater digestibility of animal products compared to vegetable materials. Zinc may complex with certain amino acids such as histidine in the intestinal milieu to form soluble chelates, which are then actively absorbed by the mucosal cells. This hypoth- esis is currently being evaluated (Evans et aL, 1974). The health significance of the contrasting availabilities of plant and animal zinc for intestinal absorption is a sub- ject for conjecture as far as man is concerned. At the present time, it seems likely that individuals who subsist primarily on vegetable products, and especially on products that are high in phytate and fiber, are at risk as far as developing a marginal zinc nutriture. Under conditions of increased physiological stress, or increased anabolism and growth, such individuals may develop clinical evidence consistent with zinc deficiency. Pathologic Conditions in Man Associated with an Inadequate Zinc Nutriture Zinc Responsive Growth Failure and Sexual Infantilism This syndrome has been studied in detail in Egypt (Prasad et aL, 1963; Sandstead eta/., 1967) and in Iran (Halstad eta/., 1972). The major constituent of the diet of such individuals is an unleavened bread prepared from wheat. Other factors which contribute to the disease include blood loss due to hookworm and schistosomiasis (Egypt), geophagia (Iran) and possibly sweat loss due to high ambient temperature. A similar syndrome in patients with intestinal malab- sorption has been observed in the United States. The first reported patient had congenital hypogammaglobulinemia and parasitism (Caggiano eta/., 1969). Two other indi- vidual cases have been studied at Vanderbilt University School of Medicine, Nashville (Sandstead, 1973; H. H. Sandstead, personal observation, 1972). One of these pa- tients, a 20-year-old man with severe regional enteritis, responded to zinc therapy with growth and sexual matura· tion. The fmding of zinc responsive growth failure and hypo- geusia in young children from middle class families (Ham- bidge et aL, 1972) indicates that some children, who are "poor eaters" and consume relatively little animal protein other than milk, may become zinc deficient. This report suggests that zinc deficiency may be responsible for the impaired Qrowth of some children who fall in the classifi· cation of failure to thrive. Impaired Wound Healing Delayed wound healing has been found responsive to zinc in some patients (Pories et aL, 1967). Although these observations have been met with some skepticism, the requirement of zinc for wound heal- ing has been established in experimental animals (Sandstead eta/., 1970). In addition, biochemical studies have shown zinc essential for the synthesis of DNA (Sandstead and Rinaldi, 1969), RNA (Terhune and Sandstead, 1972), and protein (Hsu eta/., 1969) and in particular collagen (McClain et aL, 1973). From the clinical studies reported, the pathogenesis of the impaired healing is unclear. Factors such as the propor- tion of the patient's diet which is vegetable, versus the pro- portion which is animal, require investigation. On the basis of the foregoing information regarding the availability of zinc from foods, it seems possible that the patients with zinc-responsive delayed wound healing may have been sub- sisting on diets that were marginal in available zinc. Loss of Taste and Smell {ideopathic hypogeusia and hypos- mia) A syndrome of impaired taste and smell, which is responsive to therapy with zinc, has been reported (Henkin et al., 1971; Henkin, 1971 ). The relationship of this illness to zinc nutriture is as yet incompletely understood. Because it appears in some instances to be associated with increased physiological stress, it is reasonable to suggest that an al- teration in zinc homeostasis, with or without a decreased dietary intake of available zinc, may be responsible. Some patients with this syndrome lose their appetite to a significant degree and experience severe weight loss (H. H. Sandstead, personal observation, 1972; C. E. Butterworth, personal communication, 1972). Administration of zinc to these patients is followed by improved taste and a return of appetite. The self-perpetuating aspects of the syndrome are obvious. Recommendations The following studies are recommended: 1. assessment of the availability of zinc in food to man; 2. determination of the human zinc requirements in re- lationship to age and physiologic state; 3. evaluation of the possible implications of the zinc/ cadmium ratio for health;
4. detennination of the zinc status of various well-defined populations and relation of these fmdings to other parame- ters of nutritional status; and 5. assessment of the effect of zinc supplementation and/or enrichment on the health status of well-defined populations. LEAD Health problems related to lead are with few exceptions the result of man-induced environmental contamination. There· fore, in the usual sense, the effects of lead on health are not geochemical in origin. Lead has atomic number 82 and an atomic weight of207.19. Sources of Lead in Man Atmospheric Lead The major source of lead in the atmo- sphere is combustion of lead<ontaining fuel. In the United States, roughly 180,000 tons of lead are released into the environment from this source each year. This is said to con· tribute 98 percent of all listed lead emissions (Committee on Biologic Effects of Atmospheric Pollutants, 1972, p. 12). Much of this lead falls on or near roadways. That which is ·in the fonn of very small particles may be more widely dis- persed by the wind. An estimated 120,000 tons of such aero- sols were disseminated in the Northern Hemisphere in 1966 (Committee on Biologic Effects of Atmospheric Pollutants, 1972, p. 14). Lead is removed from the atmosphere by rain· fall and by aggregation. Thus, lead is spread on soils and enters water supplies. It has been estimated that 1.2 J,tg of lead per year falls per square centimeter of earth (Commit· tee on Biologic Effects of Atmospheric Pollutants, 1972, p. 27). This fallout is against a natural lead burden of 2- 200 J,tg. Assays of the lead in surface soils reveal significantly higher amounts than in deep soils. In some areas of Scot- land, the surface horizon has been found to contain I Q. times as much lead as lower levels (Committee on Biologic Effects of Atmospheric Pollutants, 1972, p. 28). Greatest concentrations are found in the organically rich unculti- vated horizons. In Illinois it has been found that lead in fann soil has increased from 12 J,tg/g to 25 J,tg/g in ap- proximately the last 40 years (Snyder et al., 1971). A similar increase in lead concentration has been noted in the ice cap of Greenland (Murozumi et al .⢠1969). In contrast to the lead levels in rural soils, the levels in soils from 77 midwestern cities, where populations range from 100,000 to 1,000,000 and auto density is high, are much greater. Residential areas have been found to have an average con- centration of I ,636 J,tg/g while commercial areas have an average concentration of 2,413 J,tg/g (Committee on Bio- logic Effects of Atmospheric Pollutants, 1972, p. 30). As noted below, these very high levels may have health sig· nificance for young children in the inner city. Cadmium, Zinc, and Lead 53 The potential movement of lead in soils into plants is of concern. Fortunately studies using 210Pb indicate that lead in soil is relatively unavailable to many plants (0.003- 0.005 percent) (Committee on Biologic Effects of Atmo- spheric Pollutants, 1972, p. 30). Whether alterations in the characteristics of the soil will increase the uptake of lead by plants is an important question. Fallout also results in lead on the leaves of plants. It appears that deposition of this lead throughout the plant is quite limited. Some is finnly bound to ligands in the surface of the leaf and therefore cannot be washed off. For certain leafy foods, this may be of concern if the foods are grown near high- ways. Lead entering waters from fallout is largely insoluble and apparently is removed by sedimentation. Some is. taken up by aquatic organisms. The health significance of lead in the atmosphere has been the subject of some controversy. On the one hand, the National Academy of Sciences (N AS) committee con- cerned with airborne lead interpreted the published data available in 1970 as showing that the average lead content of the air over most cities had not changed greatly since 1955. This was surprising in view of the fact that the use of lead alkyls in gasoline had increased many times. The high degree of dispersal of burned lead alkyls was felt to be responsible for the fmding. The N AS committee did note that the air concentration of lead over the largest cities was 20-times that over sparsely populated areas (Committee on Biologic Effects of Atmospheric Pol- lutants, 1972, p. 205). The committee felt, on the basis of available data, that it was unlikely that lead in the atmosphere would have significant effects on biologic sys- tems in the years to come. It expressed concern that the fate of lead entering the environment from nonlead alkyl sources is largely unknown. The lead from paint pigments and metallic products is 2-3-times that released into the atmosphere by internal combustion. Its potential impor- tance as far as health is concerned is unknown. Somewhat at odds with the N AS interpretation is the 1971 report by the Institute for Environmental Quality of the State of Illinois (Snyder et al .⢠1971 ). On the basis of preliminary fmdings by Tepper ( 1971 ), the authors express concern about the upward trends in atmospheric lead over certain large cities. For example, atmospheric lead over Los Angeles increased from 1.49-2.80 J,tg/m3 during the period of 1961-1962 to 3.06-4.55 J,tg/m3 during the period of 1968-1969. Less striking but similar increases have occurred over Cincinnati and Philadelphia. Whether other large cities have experienced a similar increase in atmospheric lead is unknown, as is the significance for health of the observed increases. While limited observations on policemen and garage mechanics suggest that their health has not been impaired by the higher levels of atmospheric lead to which they are exposed, many questions regarding their health are
54 THE RELATION OF SELECTED TRACE ELEMENTS TO HEALTH AND DISEASE unresolved. A detailed metabolic study of such individuals with regards to lead would be of value. Lead also enters the atmosphere from such industrial sources as smelters. Very high concentrations may occur in these environments with the inevitable result-fallout on plants and soil. Such environmental contamination may conceivably have adverse effects on health of people living in the immediate vicinity. Data supporting or refuting this hypothesis are not available to us. A population within the city that may be adversely af- fected by lead fallout is that of children who eat dirt. Sur- face soil from a city park in Los Angeles has been shown to contain 3,357 JJg of lead per gram. Depending on the availability of lead in soil for intestinal absorption, children consuming such dirt may be adversely affected. A more common cause of lead poisoning in small children is con- sumption of lead-containing paints. Lead in Plants As noted above, the uptake and transloca- tion of lead into plants is minimal under usual circum- stances. Factors that influence its movement include soil characteristics, and the presence of ligands that complex with it and prevent its movement across cell walls and throughout the plant. Lead that falls on the leaf may be bound by local ligands and, therefore, attempts to remove it by washing will be unsuccessful. While high concentrations of lead may be taken up by forage and thus be hazardous to livestock under special circumstances, the presence of lead in forage is of no demonstrated consequence to human health. Lead in Animals Lead in livestock is, under usual circum- stances, largely sequestered in bone. It thus is removed from the human food cycle and is of no importance. Lead in aquatic animals is likewise of no documented importance to human health. Estimate of Lead Intake by Man and Safety Factors According to the NAS report, the American diet contains an intake of roughly 300 JJg/d of lead. Of this about I 0 percent, or 30 J.Lg, is absorbed. It is also estimated that a suburbanite male who works in a large city inhales roughly 30 JJg/d of lead. Similarly a man who both works and resides in the city might inhale 50 to 60 J.Lg/d. Roughly 30-40 per- cent of inhaled lead is retained, depending on particle size. Thus the suburban commuter might assimilate 40 JJg/d of lead while the man living in the city might retain 50 J.Lg. Using this information and available information on the relationship between blood lead and assimilated lead per day, it is possible to suggest what the safety factor may be between (I) current lead intakes and (2) indicators of ex- cess body burdens of the cation (Committee on Biologic Effects of Atmospheric Pollutants, 1972, p. 66). Roughly 100 JJg of lead musLbe assimilated daily for the blood lead concentrations to exceed 40 J.Lg/ I 00 g of blood. In some individuals, an increase in blood lead to levels between 40 JJg and 60 J.Lg is associated with increased ex- cretion of aminolevulinic acid (ALA), an intermediate metabolic product in the synthesis of porphyrin. This phe- nomenon is consistent with an adverse metabolic effect of lead. However, data obtained on children and adolescents by Chisholm ( 1965) and on adults by Selander and Cramer (1970) indicate that, when the blood lead concentration is less than 40JJg, the excretion of ALA is not increased. On the basis of these data, a blood lead of 40 JJg/ I 00 g has been suggested to indicate the threshold at which the body bur- den of lead exceeds the homeostatic mechanisms and ad- verse effects become evident. Based on this reasoning, the safety factor for the suburban male doing office work is roughly 2.5, while it is about 2.0 for the office worker who lives in the city. From these gross extrapolations, it may be concluded that the tolerance limits for lead are narrow-a fact that has long been recognized by clinical toxicologists. Because limits of tolerance are narrow, increases in such readily assimilable forms of lead as atmospheric lead should be prevented. Prospective monitoring of exposed populations should be carried out to determine whether lead burdens are increasing and whether adverse metabolic effects are related to this phenomenon. The clinical effects of lead intoxication are well-known and need not be discussed. Less is known about the effects of lower levels of exposure with blood concentrations rang- ing from 40 to 60 J.Lg/100 g. Investigation should be done on such individuals. The biochemical effects of lead have been elucidated for relatively high concentrations of the metal. Its effects at more physiological concentrations are less well understood. At these lower levels, lead has been shown to inhibit the dithiol enzyme, lipoarnidehydrogenase. The significance of this observation for in vivo oxidative decarboxylation is unknown (Committee on Biologic Effects of Atmo- spheric Pollutants, 1972, p. 165). The metal is also known to inhibit the enzyme aminolevulinic acid dehy- drase. The activity of this enzyme has been measured in erythrocytes in vitro and found to be related to the con- centration of lead bound to the erythrocytes as indicated by the whole blood lead content. The significance of this observation for health is as yet ill-defmed because the en- zyme is inhibited by "normal" concentrations of blood lead (Committee on Biologic Effects of Atmospheric Pol- lutants, 1972, p. I 06). Recommendations The following steps are recommended: 1. definition of the threshold at which adverse effects occur;
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