The Biology of Cadmium

Symposium on Trace Elements

The Biology of Cadmium H. Mitchell Perry, Jr., M.D.,* Gurdarshan S. Thind, M.D.,** and E. F. Perry, A.B. ***

Until recently, relatively little attention was paid to the biologic effects of cadmium. In 1952, Tipton first emphasized the unique tendency for cadmium to concentrate in the human kidney.64 Since then, considerable attention has been given to the environment as a source of the large amounts of cadmium which almost all adults have in their kidneys. The following brief review deals with the demonstrated biologic effects of cadmium in man and in animal, the human body burden of cadmium and its sources, and the data relating renal cadmium to hypertension. Cadmium is a ubiquitous element to which everyone is constantly exposed. As a result, the average American accumulates some 30 mg during his lifetime,13 In the high concentrations involved in heavy industrial exposure, there is no doubt that cadmium is toxic, but no signifjcant biologic effect has been demonstrated for the usually much smaller exposure provided by the ordinary environment. It has recently been suggested, however, that low-level, long-term exposure to cadmium might be associated with essential hypertension, the pathogenesis of which remains unknown despite strenuous efforts to elucidate it. There are data suggesting that renal cadmium concentrations are abnormally high in hypertensive human beings, but the strongest evidence linking cadmium with hypertension comes from animal studies. In rats, chronic ingestion of low doses of cadmium, simulating human exposure, results in mild to moderate elevations in arterial pressure which resemble human essential hypertension in that there are no obvious associated changes. The mechanism by which cadmium raises the arterial pressure of rats remains uncertain; it could involve either sodium retenFrom the Medical Service, Veterans Administration Hospital, and the Hypertension Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 'Professor of Medicine, Washington University **Assistant Professor, Washington University ***Research Assistant in Medicine, Washington University This research was supported by the Veterans Administration. Medical Clinics of North America- V'o!. 60, No. 4, July 1976

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tion by the kidney or a direct effect on vascular smooth muscle, since cadmium has been reported to produce both effects.

DEMONSTRATED BIOLOGIC EFFECTS OF CADMIUM Human toxicity to cadmium, resulting from heavy industrial exposure, was first recognized in 1920.60 Both acute and chronic toxic effects of cadmium in man have recently been reviewed by Friberg and his colleagues;13 Table 1 outlines human toxicity. Acute exposure to cadmium by ingestion can cause severe but temporary gastroenteritis,S and by inhalation, severe and sometimes fatal pulmonary edema. 13 Prolonged inhalation of cadmium oxide can result in pulmonary dysfunction4 and emphysema. 11 Prolonged industrial exposure can produce renal dysfunction, characterized by "tubular" proteinuria, glycosuria, and aminoaciduria;3, 6, 51 however, progression to azotemia and renal failure occurs very rarely. Other less alarming toxic manifestations have included moderate anemia, probably in part hemolytic36 and apparent hepatic dysfunction manifested primarily by hypergammaglobulinemiaY Finally, a peculiar disease called itai-itai, characterized by severe bone pains and osteomalacia and involving parous middle-aged women living in certain parts of Japan where there is a very high environmental exposure to cadmium, has been ascribed to chronic poisoning in combination with a low intake of calcium and vitamin D.1s Animal toxicity from injected cadmium has included the wide range of biologic effects listed in Table 2. Of these, the autoimmune, renal, and cardiovascular effects seem to have the most potential significance in terms of possible relationships between human disease and ordinary environmental exposure to cadmium. The earliest effect on the immune system is stimulation followed by inhibition of antibody formaTable 1.

Effects of Heavy Exposure to Cadmium in Man

TOXIC EFFECT

l. Acute gastroenteritis 2. Acute pulmonary edema and interstitial pneumonitis 3. a. Decreased pulmonary function b. Emphysema 4. a. Proteinuria b. Glucosuria c. Aminoaciduria 5. Moderate anemia 6. Itai-itai disease

7. Increased mortality 8. Possible carcinogenesis

EXPLANATORY COMMENT

REFERENCE

Acid foods in cadmium-plated containers Edema in 24 hours and pneumonitis in 3 to 10 days

Cole 8 Friberg l3

Residual volume increased by 10 per cent after 10 years of inhaling cadmium oxide

Buxton4

Following 9 years of inhaling cadmium oxide

Piscator51 BonnelP Clarkson 6 Nicoud36 Hagino 18

Following inhalation of cadmium oxide Osteomalacia in parous women over 40 with other dietary deficiencies Death rate in cadmium workers was higher (p < 0.01) than expected Possibly increased prostatic cancer in workers exposed to cadmium oxide

Friberg 12 Kipling"

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BIOLOGY OF CADMIUM

tion;24 with continued exposure, increased urinary excretion of "light chains" occurs;68 and finally with heavy exposure, there is amyloid deposition. 68 Renal dysfunction, including proteinuria of the "tubular" type,50 glycosuria,! and aminoaciduria,38 has occurred with heavy cadmium exposure; however, as in industrial cadmium poisoning, this dysfunction in animals has not characteristically progressed to renal failure. Increased sodium reabsorption by the proximal tubule suggests a mechanism by which cadmium might induce hypertension;67 however, the acute hypertension induced by single small doses of cadmium seems more likely to result from a direct effect on vascular smooth muscle. Animal toxicity from ingested cadmium can be either obvious and associated with relatively large doses or subtle and associated with smaller doses (Table 3). The smaller doses, which do not produce obvious sickness, seem more likely to be related to effects of ordinary environmental cadmium. Ingestion of 1 to 5 ppm of cadmium in water has produced hypertension in rats. 45 ,54 Cadmium-induced hypertension in Table 2.

Effects of Injected Cadmium in Animals CADMIUM EXPOSURE

EFFECT

1. Hemorrhage in nervous ganglia 2. Congenital malformation 3. Local induction of cancer 4. Reproductive system effects a. Testicular necrosis b. Placental necrosis 5. Anemia 6. Autoimmune effects a. Decrease in antibody b. Urinary light chains c. Amyloidosis Amyloidosis 7. Renal effects a. Proteinuria Proteinuria b. Glycosuria c. Aminoaciduria d. Sodium retention 8. Cardiovascular effects a. Hypertension Hypertension Hypertension Hypertension Hypertension Hypertension

ANIMAL

ROUTE':'

Length of Daily Expo- Total Dose sure Dose (mg/kg) (days) (mg/kg)

Rat Hamster Rat

sc iv sc

8 2 0.2

Rat Rat Rabbit

sc sc sc

4.5 0.3

Rat Rabbit Rabbit Rabbit

sc sc sc sc

0.6 0.3 0.3

Rabbit Rabbit Rabbit Rabbit Dog

sc sc sc sc iv

Dog Rabbit Rat Rat Rat Rat

ip ip ip iv ip ia

Ix':"" Ix Ix

REFERENCE

GabbianF4 8 2 Holmberg 21 0.2 Gunn 15

Ix 4 130

1 18 33

Clegg 7 Parizekl9 Piscator49

22 250 60

10

6 6 63 60

Jones 24 Vigliani 68 Vigliani 68 Baum'

0.3 0.3 0.2 1.5 0.2

130 64 120 45 Ix

33 16 46 68 0.2

Piscator'O Vigliani 68 Axelsson 1 Nomiyama" Vander07

0.3 0.3 2.0 0.8 0.2 0.1

180 50 Ix Ix Ix Ix

50 15 2.0 0.8 0.2 0.1

Thind 61 Thind62 Schroeder58 Perry46 Perry" Perry"

"sc, subcutaneous; iv, intravenous; ip, intraperitoneal; ia, intra-arterial. :"'lx" indicates that cadmium was administered one time.

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Cadmium-Induced Effects in Animals Following Exposure Simulating Human Exposure CADMIUM EXPOSURE

EFFECT

Ingestion of Cadmium 1. Anemia 2. Decreased growth 3. Decreased growth 4. Microscopic lung changes 5. Microscopic kidney changes 6. Hypertension 7. Hypertension Inhalation of Cadmium 1. Pulmonary edema, interstitial pneumonitis and emphysema 2. Emphysema 3. Peribronchial inflammation and emphysema 4. Peribronchial necrosis and emphysema 5. Emphysema and scarring

Intensity

ANIMAL

ppm ppm ppm ppm ppm ppm ppm

in in in in in in in

food water food water water water water

Duration 28 120 163 280 42 120 360

days days days days days days days

REFERENCE

Quail Rat Sheep Rat Rat Rat Rat

77 50 15 17 10 5 1

Rat Rat

33 mg/m' 10 mg/m"

0.25 15 hours

Peterson 40 Snider'"

Rabbit

5 mg/m3

480 hours

Fribergl l

Guinea Pig Dog

0.6mg':' 0.3 mg/m'

X 3" 0.5 hours

Thurlbeck 63 Harrison 19

Fox' o Itokawa 23 Doyle 9 Miller 31 Nishizumi 37 Schroeder54 P erry45

*Thurlbeck and Foley injected 1 ml/kg of a solution containing 0.9 mg cadmium per ml H20 into the trachea; emphysema was observed following 3 or more injections.

animals resembles human essential hypertension in that it is usually mild or moderate and not accompanied by renal dysfunction or other associated changes; however, even the lowest effective animal exposure reported to date45 is about two orders of magnitude above the ordinary human exposure by ingestion which approximates 1 ILg per kg of body weight. Despite this disparity, tissue concentrations in exposed rats are comparable to those in human beings without unusual exposure. Thus, renal cadmium concentration in exposed rats ranges from 5 to 50 ILg per gm,42 while the average American adult has about 30 ILg per gm.47 Animal toxicity from inhaled cadmium is characterized by serial changes in the lung, with the earliest and most acute change being pulmonary edema40 followed by proliferative interstitial pneumonitis,40 including necrosis of the alveolar lining and peribronchial inflammationY The latest and most chronic anatomic change was emphysema with scarring19 (Table 3). In vitro effects of cadmium are presumed to be primarily associated with inhibition of enzymatic activity resulting from mercaptide formation with cysteinyl residues of many enzymes including alcohol dehydrogenase, glutamic dehydrogenase, glutathione reductase, adenylate kinase, and disulfide reductase. Cadmium shares this inhibitory activity with mercury, zinc, silver, copper, and lead. 6G In addition, cadmium, in concentrations of 5 x 106 molar, uncouples phosphorylation from oxidation,23 and at ten times this concentration it has been reported to completely inhibit mitochondrial respiration of pulmonary alveolar microphages by binding to components of the respiratory chain.35

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BIOLOGY OF CADMIUM

HUMAN BODY BURDEN OF CADMIUM AND ITS SOURCES Body burden of the average adult American has been estimated to be about 30 mg of cadmium,13 of which 10 mg are in the kidneys and 5 mg are in the liver. Unlike other "non-essential" trace elements, cadmium has a specific and unique pattern of distribution, with the kidney having about 10 times the concentration of the liver which in turn has about five times the concentration of other organs. 65 There is very little renal cadmium in the newborn infant, and the metal is accumulated throughout life42 (Fig. 1). Moreover, there are wide geographic differences, with some groups of Negroid Africans having significantly less and some groups of Asiatic Mongoloids having significantly more renal cadmium than Caucasoid Americans, Europeans and Indians 42 (Fig. 1). These differences seem likely to be primarily environmental, since in the United States, tissue cadmium concentration is apparently largely independent of race. 65 Any biologic effects of relatively small amounts of cadmium in man would presumably depend on its distribution among the organs and within a critical tissue as well as on the substances to which it is bound and on the concentrations of other metals with which it competes. Thus, 10000 5000 -

2000

-

1000

-

500

-

200

-

100

-

-

..c:

'" cC

E

en

-c u

en

::t

~

GEOGRAPHIC DIFFERENCE AMONG ADULTS

.GE DIFFERENCE AMONG AMERICANS

~

11 Infants

10

24

Children

Adults

42

49

50

Netroids Caucasoids Montoloids

Figure 1. Mean renal cadmium concentrations and their standard deviations for six groups of subjects!' The "Americans" in the first panel were all from the St. Louis area and included 10 infants from 45 to 450 days old. 11 children from 450 to 4500 days old and 24 adults over 45 years of age. Both whites and blacks are included because there is no signifi· cant difference between the two groups. The "adults" in the second panel included six groups of Negroids from Africa, four groups of Caucasoids from the United States, Switzerland and India, and five groups of Mongoloids from the Far East. Although the mean is similar, the standard deviation for the "adult" group from one geographic location (St. Louis) is much less than for the adult "Caucasoids" from three continents. Note that the scale is logarithmic. (Data from Perry, H. M., Jr., Tipton, I. H., Schroeder, H. A., et al.: J. Chron. Dis., 14:259, 1961.)

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it may be significant that there are marked differences in the ratio of renal to hepatic cadmium; for instance, the average ratios for the groups of subjects included in Figure 1 ranged from 7 to 25. 42 Cadmium is bound to metallothionein, an unusual protein of small molecular weight and very high sulfur content which binds zinc as well, but less tightly.52 The ratio of renal cadmium concentration to renal zinc concentration also varies, with the average ratios for the groups of subjects included in Figure 1 ranging from 0.25 to 1.0.42 Ingested cadmium is probably the major source of accumulated cadmium in man. According to Friberg et al. the usual total daily amount ingested approximates 50 ILg with a range from 25 to 75 ILg. The concentration of cadmium in most foods is less than 0.05 ILg per gm; but certain foods, such as shellfish and mammalian liver, may contain more than 100 ILg per gm. Moreover, when large amounts of cadmium are present in the soil or water, as much as 1 ILg per gm may accumulate in some plants, including certain staple grains; such concentrations occur in rice from some regions of JapanP Cadmium concentration in water is usually less than 1 ILg per liter;17 however, soft (acidic) water may contain more than 15ILg per liter,52 apparently because it tends to dissolve any available cadmium, particularly from galvanized surfaces. Drinking water that has less than 5 ILg per lit er is unlikely to contribute significantly to the total intake of cadmium, but water with much higher concentrations such as observed by Schroeder when he first turned on the tap in the morning55 might be significant if regularly used. Absorption of ingested cadmium usually approximates 3 to 8 per cent,13 but it may rise to 10 per cent or more when the diet is deficient in calcium or protein. 27 The biological half-life of cadmium in man following nontoxic doses has been estimated to be 20 to 40 years, with a daily urinary excretion of 0.004 to 0.015 per cent of the body burden. 13 Inhaled cadmium is usually responsible for relatively little of the body burden of cadmium, except in smokers. Absorption of cadmium from the lungs ranges from 25 to 50 per cent and thus is more complete than it is from the ga.strointestinal tract. The usual cadmium content of air in the United States varied from less than 0.001 to as much as 0.05 ILg per cubic meter. Therefore the average amount of air breathed per day, some 20 liters, usually contributes less than 1 ILg to the daily intake of cadmium. Air concentrations as high as 5 ILg per cubic meter, however, have occurred in areas around cadmium-emitting factories. 3 In such areas, 100 ILg per day would be inhaled and 25 to 50 ILg absorbed. A cigarette contains about 2 ILg of cadmium, of which 5 to 10 per cent is inhaled. Thus, "pack-a-day smokers" may inhale from 2 to 4 ILg of cadmium per day, or from 0.25 to 0.5 mg of cadmium per "pack-year."3o

RENAL CADMIUM AND HYPERTENSION In addition to the unequivocal toxic effects of industrial exposure to cadmium in man and the various reported effects of cadmium in animals, it has been suggested that the life-long exposure to ordinary envi-

765

BIOLOGY OF CADMIUM

ronmental cadmium which leads to a body burden of some 30 mg may be a factor in the pathogenesis of some segment of human essential hypertension. With the variability in the human body burden of cadmium clearly in mind, several studies can be mentioned which suggest that hypertensive subjects have significantly more renal cadmium than otherwise similar but normotensive subjects. These data have been summarized in Table 4. Schroeder compared 117 normotensive Americans who died sudden accidental deaths with 17 hypertensive Americans who died similarly. The normotensive group had an average of 2940 ILg cadmium per gm of kidney ash, whereas the hypertensive group had 4220 ILg. The difference was highly significant (p <0.005).53 Despite a wider range of renal cadmium concentrations, a similar trend was observed in a heterogeneous group of subjects from various parts of the world. 53 In Czechoslovakia, Lener and Bibr found a similar difference with small numbers of patients.33 Morgan, in contrast, did not find any significant difference in the mean renal cadmium concentrations of hypertensive versus normal subjects, although she did observe that the hypertensive group had a median concentration which was 20 per cent above that of the normotensive group.28 Thus, her data were not inconsistent with hypertension being associated with an elevated renal cadmium. As indicated in Table 3, hypertension has been induced in rats by long-term, low-level cadmium feeding. Since these feeding experiments simulate human exposure, they deserve further consideration here. In 1962, Schroeder and Vinton first reported that, under standard conditions, including a standard diet relatively high in zinc, feeding rats 5 ppm of cadmium in drinking water for a year from the time of weaning resulted in significant hypertension;57 Schroeder measured systolic Table 4.

Renal Cadmium in Hypertensiont ILg/gm

NO. OF PATIENTS

TISSUE

Mean

ILg/lO mg ASH Median Mean

SIGNIFICANCE AND AUTHOR

Hypertensive Normotensive

17 117

37* 29"

42 29

P < 0.005 Schroeder- V.S."

Hypertensive Normotensive

17 23

49* 27':'

51 32

P < 0.025 Schroeder - foreign"

Hypertensive Normotensive

12 25

27 22

25 25

Not significant Morgan-Albama"

Hypertensive Normotensive

12 10

36 27

P < 0.005 Lener- Czechoslovakia33

"Values for renal cadmium in hypertensive and normotensive subjects. Note that to make the values for ash and wet weight roughly comparable, the values for the latter are expressed in the unusual units of "ILg Cd per 10 mg ash". (Tipton's figures indicate that the mean renal ash weight is 1.1 % of wet weight: Tipton, I. H. 1960. In: Metal-Binding in Medicine. Marvin D. Seven, Ed., page 27. Lippincott. Philadelphia, Pennsylvania). tPersonal communication.

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Control 5 ppm Cd

110 100

90 80 ............................Schroeder and Buckman

Perry and Erlanger

Figure 2. Mean systolic pressures for typical groups of female Long-Evans rats reported by Schroeder and Buckman5• or by Perry and Erlanger.4' Animals in both laboratories were handled similarly: From the time of weaning, they were exposed to either 5 ppm cadmium in drinking water or else to no added cadmium. Although the hypertensive effect associated with cadmium was considerably larger in Schroeder's laboratory, it was highly significant in both laboratories.

pressure indirectly in order to avoid surgical insertion of the cannula needed for direct measurements (Fig. 2).56 Using conditions very similar to Schroeder's, Perry and Erlanger found that 1,2.5, and 5 mg cadmium per liter of drinking water reproducibly induced an elevation in systolic pressure of 14 to 19 mm Hg after 1 year (Fig. 2). Although the magnitude of the mean increase in systolic pressure may seem unimpressive, 25 per cent of the exposed rat colony had pressures which were 2 standard deviations or almost 30 mm Hg above the control mean. 43 In this context, it is noteworthy that the majority of the approximately 25 million Americans currently estimated to have hypertension41 have only borderline or mild hypertension;43 yet among this mildly hypertensive group there is a very marked increase in the risk of myocardial infarction and apoplectic stroke.16 • 25

CADMIUM AND EMPHYSEMA Sufficient industrial exposure to inhaled cadmium has been recognized as a possible but very rare cause of emphysema. In 1969 Lewis and his co-workers raised the possibility that cadmium was much more generally involved in the pathogenesis of emphysema when they observed that, even without any specific exposure to cadmium, the cadmium concentration in water-soluble protein extracts from livers of patients dying with emphysema and/or chronic bronchitis was

767

BIOLOGY OF CADMIUM

significantly higher than the cadmium concentration from comparable extracts of normal subjects. 29 At about the same time, Morgan observed an increase in the cadmium content of the kidneys and livers from patients with bronchogenic carcinoma,32 and subsequently she noted similar increases in the renal and hepatic cadmium of patients with emphysema, either alone or coexisting with bronchogenic carcinoma. 34 Hirst et al. found a similar increase in pulmonary and hepatic, but not renal, cadmium in emphysematous subjects when they were compared with subjects with normal lungs who were matched for age, race, and sex.20

SUMMARY Industrial exposure to large amounts of cadmium is known to be toxic to man; however, the low levels of cadmium in water, food, and air to which everyone is continually exposed have no obvious effects. During childhood and adolescence, ingestion and inhalation of cadmium are responsible for the average American accumulating about 30 mg of cadmium in his body, with the highest concentration being in the kidney. It has been suggested on the basis of two observations that elevated renal cadmium might be associated with essential hypertension: (1) Hypertensives have been reported to have higher renal cadmium concentrations than normotensives. (2) Long-term exposure to low levels of cadmium has reproducibly caused mild hypertension in animals. Finally, increased levels of cadmium have been found in lungs and other tissues of emphysematous subjects.

REFERENCES 1. Axelsson, B., and Piscator, M.: Renal damage after prolonged exposure to cadmium. An experimental study. Arch. Environ. Health,12:360, 1966. 2. Baum, J., and Worthen, H. G.: Induction of amyloidosis by cadmium. Nature, 213:1040, 1967. 3. Bonnell, J. A., Kazantzis, G., and King, E.: A follow-up study of men exposed to cadmium oxide fume. Brit. J. Ind. Med., 16:135, 1959. 4. Buxton, R. St. J.: Respiratory function in men casting cadmium alloys. 11. Brit. J. Ind. Med., 13:36,1956. 5. Carroll, R. E.: The relationship of cadmium in the air to cardiovascular disease death rates. J.A.M.A., 198:267, 1966. 6. Clarkson, T. W., and Kench, J. E.: Urinary excretion of amino acids by men absorbing heavy metals. Biochem. J., 62:361,1956. 7. Clegg, E. J., and Carr, I.: Changes in the blood vessels of the rat testis and epididymis produced by cadmium chloride. J. Pathol. Bacteriol., 94:317, 1967. 8. Cole, G. M., and Bair, L. S.: "Food Poisoning" from cadmium. U.S. Nav. Med. Bull., 43:398, 1944. 9. Doyle, J. J., Pfander, W. H., Grebing, S. E., et al.: Effect of dietary cadmium on growth, cadmium absorption and cadmium tissue levels in growing lambs. J. Nutr., 104:160, 1974. 10. Fox, M. R., Fry, B. E. G.: Cadmium toxicity increased by dietary ascorbic acid supplements. Science, 169:989, 1970. 11. Friberg, L.: Health hazards in the manufacture of alkaline accumulators with special reference to chronic cadmium poisoning. Acta Med. Scand:, 138: (Suppl. 240) 1950. 12. Friberg, L., and Kjellstrom, T.: Unpublished data. In Friberg, L., Piscator, M., Nordberg, G., et al., Cadmium in the Environment, Cleveland, Ohio, CRC Press, 1974. 13. Friberg, L., Piscator, M., Nordberg, G. F., et al.: Cadmium in the environment. Cleveland, Ohio, CRC Press, Inc., 1974. 14. Gabbiani, G.: Action of cadmium chloride on sensory ganglia. Experientia, 22:261,1966.

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15. Gunn, S. A., Gould, T. C., and Anderson, E. A. D.: Cadmium-induced interstitial cell tumors in rats and mice and their prevention by zinc. J. Natl. Cancer Inst., 31 :745, 1963. 16. Health Examination Survey, Health Statistics, U.S. PHS Publication 1000, Series 1, No. 4. Washington, D.C., U.S. Government Printing Office, 1966. 17. Hem, J. D.: Chemistry and occurrence of cadmium and zinc in surface water and ground water. Water Resources Research, 8:3,1972. 18. Hagino, N.: Itai-itai disease and vitamin D. Dig. Sci. Labour, 28:32, 1973 [in Japanese]. 19. Harrison, H. E., Bunting, H., Ordway, N .. et al.: The effects and treatment of inhalation of cadmium chloride in the dog. J. Ind. Hyg. Toxicol., 29:302,1947. 20. Hirst, R N., Jr., Perry, H. M., Jr., Cruz, M. G., et al.: Elevated cadmium concentration in emphysematous lungs. Amer. Rev. Resp. Dis., 108:30,1973. 21. Holmberg, R E., and Ferm, V. H.: Interrelationships of selenium, cadmium and arsenic in mammalian teratogenesis. Arch. Environ. Health, 18:873,1969. 22. Itokawa, Y., Abe, To, Tabu, R, et al.: Renal and skeletal lesions in experimental cadmium poisoning. Arch. Environ. Health, 23:93,1971. 23. Jacobs, E. E., Jacob, M., Sanadi, D. R, et al.: Uncoupling of oxidative phosphorylation by cadmium ion. J. BioI. Chem., 223:157,1956. 24. Jones, RH., Williams, R L., and Jones, A. M.: Effects of heavy metal on the immune response. Preliminary findings for cadmium in rats. Proc. Soc. Exper. BioI. Med., 137:1321,1971. 25. Kannel, W. B., Schwartz, M. J., and McNamara, P. M.: Blood pressure and risk of coronary heart disease: Framingham Study. Dis. Chest, 56:43, 1969. 26. Kipling, M. D., and Waterhouse, J. A. H.: Cadmium and prostatic carcinoma. Lancet, 1 :730, 1967. 27. Larsson. S. E., and Piscator, M.: Effect of cadmium on skeletal tissue in normal and calcium-deficient rats. Isr. J. Med. Sci., 7:495,1971. 28. Lener, J., and Bibr, R: Cadmium and hypertension. Lancet, 1 :970,1971. 29. Lewis, G. P., Lyle, and Miller, S.: Association between elevated hepatic water soluble protein bound cadmium levels and chronic bronchitis and/or emphysema. Lancet, 2:1330, 1969. 30. Lewis, G. P., Jusko, W. J., Caughlin, L. L., et al.: Contribution of cigarette smoking to cadmium accumulation in man. Lancet, 1 :291, 1972. 31. Miller, M. L., Murthy, L., and Sorenson, J. R: Fine structure of connective tissue after ingestion of cadmium. Arch. Path., 98:286, 1974. 32. Morgan, J. M.: Cadmium and zinc abnormalities in bronchogenic carcinoma. Cancer, 25:1394,1970. 33. Morgan, J. M.: Tissue cadmium concentration in man. Arch. Intern. Med., 123:404,1969. 34. Morgan, J. M.: Tissue cadmium and zinc content in emphysema and bronchogenic carcinoma. J. Chron. Dis., 24:107,1971. 35. Mustafa, M. G., Cross, C. E., and Tyler, W. S.: Interference of cadmium ion with oxidative metabolism of alveolar macrophages. Arch. Intern. Med., 127:1050,1971. 36. Nicaud, P., Lafitte, A., and Gros, A.: Les troubles de l'intoxication chronique par le cadmium. Arch. Mal. Prof. Med. Trav. Secur. Soc., 4:192,1942. 37. Nishizumi, M.: Electron microscopic study of cadmium nephrotoxicity in the rat. Arch. Environ. Health, 24:215, 1972. 38. Nomiyama, K., Sato, C., and Yamamoto, A.: Early signs of cadmium intoxication in rabbits. Toxicol. Appl. Pharmacol., 24:625, 1973. 39. Parizek, J.: Vascular changes at sites of oestrogen biosynthesis produced by parenteral injection of cadmium salts. The destruction of placenta by cadmium salts. J. Reprod. Fertil., 7:263,1964. 40. Paterson, J. R: Studies on the toxicity of inhaled cadmium, Ill. The pathology of cadmium smoke poisoning in man and in experimental animals. J. Ind. Hyg. Toxicol., 29:294, 1947. 41. Perry, H. M., Jr.: Chairman, Task Force I: Data Base, Report to National High Blood Pressure Education Advisory Committee, 1973, HEW Pub Number (NIH) 74-593. 42. Perry, H. M., Jr.: Review of hypertension induced by chronic ingestion of cadmium: Trace Elements in Human Health and Disease, Vol. 2, 1975, in press. 43. Perry, H. M., Jr., and Erlanger, M.: Cadmium-induced hypertension following chronic feeding of low doses of cadmium and mercury. J. Lab. Clin. Med., 83:541, 1974. 44. Perry, H. M., Jr., and Erlanger, M.: Hypertension and tissue metal levels after intraperitoneal cadmium, mercury and zinc. Amer. J. Physiol., 220:808, 1971. 45. Perry, H. M., Jr., and Erlanger, M. W.: Metal-induced hypertension following chronic feeding of low doses of cadmium and mercury. J. Lab. Clin. Med., 83 :541, 1974. 46. Perry, H. M., Jr., Erlanger, M., Yunice, A .. et al.: Hypertension and tissue metal levels following intravenous cadmium, mercury and zinc. Amer. J. Physiol., 219:755, 1970. 47. Perry, H. M., Jr., Tipton, I. H., Schroeder, H. A., et al.: Variation in the concentration of

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