Environmental exposure to cadmium and factors affecting trace-element metabolism and metal toxicity.

9 1986 by The Humana Press Inc. All rights of any nature whatsoever reserved. 0163--4984/86/1003-0243504.00

REVIEW Environmental Exposure to Cadmium and Factors Affecting Trace-Element Metabolism and Metal Toxicity JADWIGA CHMIELNICKA~ AND M. G E O R G E CHERIAN*

Department of Pathology, University of Western Ontario, Health Sciences Centre, London, Ontario, Canada, N6A 5C1 Received November 25, 1985; Accepted December 9, 1985

ABSTRACT In the general population, food constitutes the major environmental source of cadmium (Cd) in nonsmokers. It is established that leafy vegetables, roots, and grains (wheat or rice) can accumulate relatively high amounts of Cd from the soil. Beef liver and kidney and shellfish are also major dietary sources of Cd. The daily intake of Cd in various parts of the world is different and depends on both the dietary habits and concentration of Cd in foodstuffs. Because of the long biological half-life of Cd in humans and absence of any specific indicators of its toxicity, the environmental exposure of Cd should be monitored in various countries. Although environmental Cd poisoning is rare, there are isolated reports on excessive exposure to Cd in Japan and Shipham, a zinc-mining town in England. The body retention and toxicity of Cd depends on various factors, such as daily intake, the form of Cd in food, its interactions with essential elements, and nutritional status of the population. Since kidney is considered a *Author to whom all correspondence and reprint requests should be addressed. *On study leave from Medical Academy in Lodz; Institute of Environmental Research and Bioanalysis, Lodz, Poland. Biological Trace Element Research

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critical organ in Cd toxicity, the indicators of renal dysfunction have been widely used for evaluation of Cd poisoning in occupationally exposed people. It is unclear whether similar indicators can be used for monitoring environmental Cd exposure. Index Entries: Cadmium, in diet; foodstuffs, high cadmium content of; metals, nutritional deficiencies and gastrointestinal absorption of; metals and nutrients, interaction of; renal dysfunction and monitoring of environmental cadmium exposure, indicators of.

INTRODUCTION C a d m i u m (Cd) is an ubiquitous element that is found in close association with zinc (Zn) in the earth's crust. Mining and industrial activities have probably increased its a b u n d a n c e in the biosphere during the last several decades. The world production of Cd has increased markedly because of its increasing use in C d - N i batteries, pigments, metal finishing, and plastic stabilizers. The use of sewage sludge and phosphate fertilizers may also increase the Cd content of plants. Thus, there is a general concern that the environmental exposure to Cd has been continuously increasing since the end of the 19th century (1). In order to evaluate the extent to which Cd represents a threat to the e n v i r o n m e n t in general and to h u m a n health in particular, a n u m b e r of factors should be considered. Some of these factors involve the content and form of Cd in food, its absorption from the gastrointestinal (GI) tract, tissue distribution and retention, and, also, interaction with other metals and nutrients. Since very little Cd is excreted from the body during continuous lowlevel exposure, both tissue m e a s u r e m e n t s and mathematical models favor a long biological half-life of about 10-30 yr for Cd in h u m a n s (2). In addition, unlike other metals, there are no specific indicators of exposure to or toxicity of Cd. Therefore, it is important to study the environmental exposure to Cd in various countries and factors affecting the toxicity of low-level, long-term exposure. In this article we will review various exposure levels of Cd in different countries, the interactions b e t w e e n essential a n d nonessential metals, and the indicators of excessive environmental Cd exposure. We will provide relevant h u m a n and experimental animal data w h e n e v e r available. However, such data are scarce, and, in certain cases, experimental results from studies that may not be directly related to environmental exposure to Cd may be cited.

SOURCES OF ENVIRONMENTAL EXPOSURE TO Cd The major source of intake of Cd in the general population is food, with little contribution from water (2). Normally, the Cd content of air in unpolluted areas is negligible and does not contribute to the daily intake. Biological Trace Element Research

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However, the atmosphere may play a significant role in the dispersal of Cd within the environment, and this has been recently reviewed (3). In certain industrial countries the emission of Cd from the coal-combustion and metal industries may increase the environmental levels of Cd. For example, a report suggests that about 480 t Cd/yr may reach the environment in West Germany (4). Since the retention time for Cd compounds in soil is assumed to be several decades or centuries, excess Cd discharge may lead to accumulation in the soil, which may serve as a major source in transfer of Cd to the food chain. The input of Cd into the soil takes place mainly by dust deposition and the use of sewage sludge and phosphate fertilizers in agriculture. The wide use of Cd-Ni batteries and their disposal may also contribute to increased Cd soil levels, unless a standard recycling procedure is enforced. The concentration of Cd in food is dependent on its level in the soil, its availability for plants, and the type of food. In general, fruits, leafy vegetables, cereals, and liver and kidney from animal sources contain more than 80% of the daily intake of Cd. The level of Cd that can be absorbed by plants is considerably higher than lead or mercury. Apart from soil content of Cd, other factors, such as low pH value, can also increase the uptake of Cd by plants. This is of particular interest to a number of Western and developing countries because of relatively high levels of sulfur dioxide emissions that can lead to acid rain. The various factors that may influence the changes in Cd levels in foodstuffs are reviewed in detail elsewhere (5). Other dietary sources of Cd are shellfish and other marine organisms. High concentrations of Cd have been reported in oysters in New Zealand (6), lobsters and salmon in Canada (7), and crabs in certain areas in the USA (8). Cadmium bioaccumulation by marine organisms has been the subject of considerable interest in recent years because of serious concern that high levels of Cd may have detrimental effects on the marine organisms and may also create problems in relation to their suitability as food for humans (9). Since Cd is not uniformly distributed in the body of fish, but is selectively accumulated in certain specific organs, like liver, kidney, and gills, it may not contribute significantly to the dietary human intake. In addition to dietary intake, cigaret smoking is another source of Cd intake. Samples of tobacco leaves from various parts of the world contain varying amounts of Cd, and the body burden of Cd in smokers has been shown to be much higher than nonsmokers (10,11). Although the environmental source of Cd is increasing, it may not be a major concern in the general population in most countries because of the low average daily intake of Cd, a level far below that estimated by the World Health Organization (WHO) as the maximum tolerable daily intake. However, there are isolated reports on adverse health effects resulting from excessive Cd exposure in certain parts of Japan (12) and Shipham, England (13). The nutritional status and age of the exposed Biological Trace Element Research

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population should also be taken into account in evaluating the risk factors involved in environmental exposure to Cd.

Cd LEVELS IN FOOD IN VARIOUS COUNTRIES As described in the previous section, it is generally accepted that food constitutes the principal environmental source of Cd for humans. Thus, the analysis of foodstuffs for Cd may provide some information pertaining to the environmental exposure levels in various countries. The concentration of Cd in plants depends on its availability in the soil. Plants usually show a higher tolerance to Cd than mammals, and this fact may contribute to the increased accumulation of Cd in the food chain (14,15). All plants contain detectable amounts of Cd, and the background levels in crops grown in soils without any known source of Cd is in the range of 0.1-1.0 mg Cd/kg dry matter. The Cd concentration in plants is increased by the use of sewage sludge and phosphate fertilizers containing high Cd levels. The mobility of Cd in soil depends on the chemical form, pH of the soil, occurrence of other elements, environmental conditions, and plant species (16). There are also differences in Cd concentrations in various parts of plants. A review of the concentration of Cd (17) in various leafy, legume and root vegetables, fruits, and various grains grown in nonpolluted soils suggests decreasing concentrations in the following order: roots, leaves, fruiting parts, seeds, and storage organs. It has been suggested (18) that leafy vegetables may be used as indicators for pollution of Cd in order to prevent increased food content of Cd. A considerable amount of inhaled Cd can be absorbed and retained by animals. The absorption of inhaled Cd is much higher (10-40%) than that from the intestine, which has been reported to be about 0.035-0.2% in the lactating cow (19) and 5% in swine (20). In animals, more than 50% of the total Cd is retained in liver and kidney. Cadmium ingested by animals through the food chain becomes increasingly concentrated in the kidney as the animal ages. Individual samples of kidney often contain more than 0.5 mg/kg of Cd (21). In a recent report in Canada, the Natural Resources Ministry of Ontario has warned the public not to eat liver and kidney from moose captured in Ontario because of abnormal concentrations of Cd. Since liver and kidney are considered delicacies and are normally consumed by hunters, these warnings are appropriate. Cadmium concentration in food varies considerably with the type of food and the area in which the food is produced. The concentrations of Cd in various foodstuffs are shown in Table 1. It has been established that, although Cd occurs in the marine environment in only trace concentrations, most marine organisms, especially mollusks and crustaceans, accumulate it rapidly in specific organs, such as liver, kidney, gills, and exoskeleton (9). Shellfish contain higher concentrations of Cd than most other food. With the exceptions of lobster, Biological Trace Element Research

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TABLE 1 Concentration of Cd in Food ~ Food Fruits Apples Plums Vegetables Cabbage Carrots Lettuce Potatoes Spinach Tomatoes

Cd 0.01 ~' 0.01 0.01 0.05 0.06 0.03 0.08 0.02 ~,

Food Meat, poultry Meat, beef (0.02) c'r Meat, pork Meat, poultry Beef kidney (0.04) "'1 Beef liver (0.15) ''t Pork kidney (0.18) ''~ Pork liver (0.14)"I Chicken liver (0.63) ~J Fish, seafood

Cereal products Corn grain Wheat grain Whole rice Whole maize Whole wheat Gram Wheat flour Dairy products, eggs Milk Eggs

0.03 0"04~' 0"08~ 0.06 ~ 0.09~ 0"07'~ 0.20 ~

(0.06) ''I (0"07)~1

0.02 ~' 0.03

Ground fish cod Salt cod Salmon Whelks Crabs (brown meat) Crabs (white meat) Mussels and oysters Miscellaneous Lobster parts Lobster tomale Freshwater fish

Cd 0.02 b 0.02 ~' 0.02 ~' 0.6if' 0.15 ~' 0.26 ~' 0.09~' 0.09~' 0.06 ~ 0.11 ~' 2.51 ~' 0.20" 1.8(t' 4.3C~' 0.20 0.56 ~' 0.23 ~' 3.4(Y' 1.83 t, 0.10

~ 1 mg/kg fresh weight. t'Canada NRC Report (22A). 'Ministry of Agriculture, UK, 1973 (23A). JNath et al., 1982 (21). 'KjellstrOm, 1979 (26). Data in parentheses--contaminated area. w h e l k (1.8 mg/kg), a n d crab (4.3 mg/kg), shellfish t a k e n f r o m u n p o l l u t e d w a t e r rarely c o n t a i n Cd in excess of 1 m g / k g (22). The c o n c e n t r a t i o n of Cd in m e a t is a b o u t 0.05 mg/kg. C h e e s e , butter, oil, a n d fats c o n t a i n u n i f o r m l y low c o n c e n t r a t i o n of Cd, w i t h a n a v e r a g e n o t e x c e e d i n g 0.05 m g / k g , a n d individual s a m p l e s rarely e x c e e d m o r e t h a n 0.1 mg/kg. N o r m a l a v e r a g e c o n c e n t r a t i o n s in c o w ' s milk are g e n e r ally less t h a n 0.005 a n d in eggs, 0.010 mg/kg. Eggs m a y c o n t a i n a b o u t 0.05 m g / k g w h e n the f e e d contains a b o u t 13 m g / k g (23). Recent investigations m a d e in a C d - c o n t a m i n a t e d village, S h i p h a m , in S o m e r s e t , E n g l a n d , s h o w e d soil c o n c e n t r a t i o n s of m o r e t h a n 100 m g / k g , a n d s o m e vegetable s a m p l e s c o n t a i n e d m o r e t h a n 1 m g C d / k g (24). T h e r e is s o m e q u e s t i o n c o n c e r n i n g w h e t h e r the c o n c e n t r a t i o n of Cd in f o o d s t u f f s h a s r e m a i n e d historically constant. It is g e n e r a l l y a g r e e d that t h e a m o u n t of Cd available in the e n v i r o n m e n t for plant a n d a n i m a l Biological Trace Element Research

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uptake is increasing (25). One of the few studies that considered Cd intake in historical terms indicated that levels in Swedish wheat and barley increased linearly from 1916 to 1972 (26).

DIETARY INTAKE OF Cd IN VARIOUS COUNTRIES The estimation of average daily intake of Cd through food in a population should consider both the diet composition and the concentration of Cd in foodstuffs. Different methods have been used for estimation of daily dietary Cd intake in different studies. The content of Cd in various foodstuffs can be estimated, and the total daily intake of Cd can be calculated from a survey of their intake. This type of estimation is known as the market basket method. Another method is based on the actual measurement of Cd in all the food eaten by an individual during one or more days and is known as the total diet collection method. In certain studies (27), the estimation of daily fecal excretion of Cd from individuals also has been used to calculate the daily intake of Cd. In such studies, a constant low GI absorption of 5% of total intake was assumed. It may also be possible to compare the daily intake of Cd on a population basis by measuring the liver and kidney concentrations of Cd in autopsy samples because of the long biological half-life of Cd. However, a number of other factors, such as age of the individual, type of chronic diseases, smoking, and occupational history, should be considered for the evaluation of the data. The estimation of daily intake of Cd by the market basket method may provide reliable results for individuals living in cities of developed countries because they are not dependent on locally grown crops and mostly eat commercial products. However, this method may not be appropriate for those living in a rural community and in other countries in which people depend mostly on locally grown foodstuffs. Great care must be taken when analyzing trace elements in food, not only because of their low concentrations, but also because of the variable matrix effect of the different food items. A method of sample preparation suitable for one metal may not necessarily be applicable to another. A summary of the reported values of the dietary intakes of Cd in various countries is shown in Table 2. It is difficult to compare directly these values from one country to another because of the different methods used for estimation. However, the values from most of the countries, except Japan and Canada, are generally less than the provisional tolerable daily intake (500--600 ~g Cd/wk) described by the WHO. The high concentration of Cd in the renal cortex and liver of Japanese living in nonpolluted areas (28) suggests that the high daily intake of Cd calculated for Japan may be correct. But this may not be true for Canadians because a recent report (29) shows low levels of Cd in liver and kidney cortices of Canadians with no known occupational

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Cadmium/Vletabolism and Toxicity

TABLE 2 Dietary Intakes (Mean) of Cd in Various Countries" Country Australia Australia Belgium Belgium Canada Canada Czechoslovakia Denmark France Germany Germany Germany Great Britain Great Britain Great Britain Great Britain Italy India Japan Japan Japan Japan Japan Japan Japan N e w Zealand N e w Zealand Netherlands Poland Rumania Sweden Sweden Sweden USA USA USA USA USA USA USA

Intake, p,g/daiIy

References

20 30-50 45 15 60-80 52 60 39 20-30 48 55 30 15-35 18 20 8.6 55 96 68~4 59-113 31 40 59 35 40 2.5-27 15 32 20 48 10-20 12 17 26-51 26-61 39 17 33 13-16 23-30

115 116 117 30 118 119 120 121 79 122 123 124 125 126 127 128 129 130 131 132 133 134 120 26 135 136 137 138 120 138 139 140 26 120 141 142 26 143 144 25

'q'he World Health Organization (WHO) has recommended a provisional tolerable intake level of 500 I~g Cd/wk in food (WHO Technical Report Series No. 505, Geneva, 1972).


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exposure to Cd. The report from the Canadian study shows a low daily intake of Cd in Canadians similar to those reported from the USA and European countries. One-hundred-and-twenty-four daily meals collected in three areas of Belgium were analyzed for their content of several metals (30). About 1-20% of the daily meals sampled had Cd contents that exceeded the tolerable level proposed by the WHO.

ADDmONAL SOURCES OF Cd INTAKE Although food is the major environmental source of Cd in the general public, there are other factors that can contribute to the daily intake of Cd. It is kn ow n that tobacco samples analyzed from different countries contain high concentrations of Cd (31). One cigaret contains about 0.5--1.5 ~g Cd and cigaret smoking can result in a significant increase of the total daily intake of Cd. It should also be pointed out that the absorption rate of inhaled Cd is much higher (40-60%) than that of the GI tract (2-5%). Cadmium levels in maternal blood, cord blood, and placental tissue of pregnant women who smoked were all higher than the levels of Cd in the same tissue and blood of pregnant women who did not smoke. The Cd levels in the maternal blood of smokers were significantly higher than levels of Cd in the cord blood of their infants (32,33). Some recent reports (34) confirmed the high body burden of Cd in smokers. From the kidney and liver values of Cd content, the body burden of Cd was calculated in a population from a southern Bavarian area with no known occupational exposure to Cd. The calculated body burden of Cd in nonsmokers and moderate and heavy smokers was 13.5, 22.5, and 33.2 mg, respectively, from 263 autopsy cases studied. Lauwerys et al. (35) have reported that a group of elderly women who had spent most of their lives in a town with a high level of Cd pollution (Liege, Belgium) had a higher Cd exposure level than did w o men of the same age who had lived in another industrial area with much less Cd pollution. H u m a n exposure to Cd can also occur from contamination of food supplies. There are isolated reports (22,36) on exposure to Cd through contaminated soft drinks. The disposal of Cd-Ni batteries can also increase the environmental exposure to Cd.

INTERACTIONS BETWEEN Cd AND OTHER ELEMENTS IN THE GI TRACT The finding that certain substances in the diet and nutritional status of the people can affect the adverse health effects of Cd suggests that interactions may play a major role on the absorption and retention of Cd and its compounds. The factors that control the absorption of toxic metBiological Trace Element Research

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als from the GI tract are not well-defined. It is known that there are specific homeostatic mechanisms that control the absorption of essential metals, such as iron (Fe), Zn, and copper (Cu), in humans. However, there is no evidence for such a control mechanism in the absorption of nonessential metals, such as Cd, and this may occur by a passivediffusion process.

Human Data The early studies on health surveys of Cd-polluted areas in Japan

(37,38) revealed that multiple nutritional factors, such as deficiency of vitamin D, low intake of calcium (Ca), and generalized malnutrition problems, might have contributed to the effects of high intake of Cd in rice and the cause of Itai-Itai disease and osteomalacia in these areas. In some of these cases, the daily intake of Cd from rice was as high as 177-211 ~g (39). The high intake of Cd in various parts of Japan has been substantiated by high Cd levels of about 20 ~g/g in liver and 100 ~,g/g or more in kidney by recent reports from Japan (28). However, there are no new reports of Itai-Itai disease in Japan from people consuming high amounts of Cd. Decalcification of bone was a prominent feature of Itai-Itai disease in the Jintzu River Basin in Japan, and this was first diagnosed as a vitaminD-resistant osteomalacia (2, 40, 41). Even though excessive Cd intake in food was a major factor in the development of this disease, other factors, such as deficiencies of Ca and vitamin D, might have significantly contributed to extensive osteoporosis. Cases of osteomalacia were not detected in Cd-polluted areas other than the Jintzu River Basin, despite a high prevalence of renal tubular dysfunction in all these areas. It would appear, therefore, that when osteomalacia is observed in Cd poisoning, it is likely that nutritional deficiencies have also been present. In countries in which a malnourished population is a significant part of the total population, the increase in exposure to Cd may result in a greater susceptibility and an early onset of renal damage. Itai-Itai disease in Japan was reported almost exclusively in postmenopausal women over the age of 50, who lived predominantly on a rice diet containing a high Cd level. In addition, there were multiple dietary deficiencies (Ca, protein, and vitamins C and D). The population living on subsistence diets or diets deficient in Ca, Fe, and/or Zn may be at increased risk from Cd exposure. The GI absorption of Cd from its salts is estimated to be about 6% of the ingested dose in humans (2). A similar absorption has been reported for Cd from rice grown in certain polluted areas in Japan (42). A number of studies in both human and experimental animals suggest that the absorption of Cd from the GI tract may be significantly influenced by Fe status (43-45), Ca intake (46), age (47), and other nutritional factors. A study on human volunteers (45) showed that the GI absorption of Cd salts was directly related to serum ferritin levels--i.e., the Fe store in the body. The absorption of Cd increased markedly in persons with low Biological Trace Element Research

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serum ferritin levels, and it can be as high as 22% of the administered dose. Therefore, it was suggested that Cd may directly compete with Fe at the binding sites of the Fe-transfer system in the human GI tract. The high GI absorption of Cd in humans with low Fe stores was later confirmed by others (48). Metabolic-balance studies for Cd in healthy elderly people also suggested a direct interaction between Fe and Cd. Bunker et al. (47) demonstrated a significant inverse correlation between Cd absorption and body Fe stores, measured by serum Fe, ferritin, and percentage of Fe saturation. The effect of Zn status on GI absorption of Cd in humans is less understood than that of Fe. However, early studies by Schroeder et al. (49) suggested that the renal Cd to Zn ratio may be a determining factor in the Cd-induced human hypertensive cardiovascular disease and renal toxicity of Cd. A direct role of Cd in human hypertension is controversial and lacks supporting epidemiological data (50). The increased accumulation of both Zn and Cd in kidney cortex with age and a ratio of Cd/Zn in renal cortex of 0.5-0.6 for the age group of 35-55 yr are reported in the Swedish population by Piscator and Lind (51). The ratio of Cd/Zn in renal cortex of 0.45--0.57 and also 0.75 are reported, respectively, from India and Japan (52,53). A significant positive correlation was found between metallothionein and Cd or Zn in renal cortex in Canadians without any occupational exposure (29). The other factors that may influence human GI absorption of Cd may be its chemical form in the food. Most of the Cd in beef liver and kidney and also in some shellfish is present in the form of metallothionein-like proteins. Reports (54) suggest that the form of Cd in plants and vegetables may also be similar to metallothionein. Although there are no human studies on absorption and organ distribution of Cd from metallothionein, animal experiments show an increased renal deposition of Cd from Cd-metallothionein than from Cd salts (55). A detailed study (6) in New Zealand oyster fishermen who consume high-Cdcontent oysters during a certain fishing season showed only a small increase in blood Cd levels compared to a control group. However, at the end of the season, in spite of a very high intake of Cd-containing oysters, the concentration of Cd in whole blood and urine was not elevated in proportion to the intake in this group, although there was an increased Cd blood level in a control group of cigaret smokers. Thus, this study suggests that cigarette smoking had a more pronounced and significant effect on whole blood Cd levels than the dietary intake of Cd-containing oysters. Further long-term followup studies on these fishermen and the intestinal absorption of Cd from oyster meal may be useful for a better understanding of long-term effects of high dietary Cd intake in this population.

Animal Studies In addition to limited data on the interaction of other metals with the GI absorption and retention of Cd in humans, there are a number of Biological Trace Element Research

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studies in experimental animals. However, these results may have only limited applications because of the differences in species and multiple interactions. Most of these studies have little relevance to environmental exposure to Cd because the mode of administration of Cd and other elements are by injection. As in humans, the interaction between Fe and Cd has been reported in animals (56). The effect of essential minerals on Cd toxicity is reviewed by Fox (43). In situ intestinal perfusion experiments showed a greater absorption of Cd in Fe-deficient mice (57). Both Fe and Cd may use the same transfer system in the mucosal epithelium of the intestine, consisting of transferrin and ferritin. Feeding of Cd can cause microcytic anemia associated with increased levels of plasma transferrin and decreased Fe stores in Japanese quail (58). Since Cd can bind with transferrin (59), the intestinal absorption of both Cd and Fe are increased in Fe deficiency. Decreased Fe retention, with acute and subchronic ingestions of Cd (60) has also been reported. The Cd-induced anemia in growing rats can be prevented by oral administration of Fe (61). Other nutrients, such as protein (62), Zn (63-65), Cu (66, 67), Ca (68, 69), manganese (67), and ascorbic acid (70), are also shown to have a significant role in Cd absorption and retention. The effects of Zn on Cd toxicity may vary between species and will depend to some extent on whether Zn interacts directly with Cd, in which it may have a protective role, or whether it is acting as an antagonist of Cu, in which case it will exacerbate the effect of Cd. Some of the toxic effects of Cd and the protective effects of essential elements might be attributed to competition for binding sites on ligands that have important roles in homeostasis. Possibly, the binding of Cu, Cd, and Zn to metallothionein is an example of such competition for intracellular bioligands. Both Cd and Zn are known to accumulate in edible tissues of animals and result in increased dietary intake of metals (71). However, simultaneous feeding of higher levels of dietary Zn was shown to reduce Cd accumulation in calves in a dose-dependent manner (72) and was probably a result of a direct effect on absorption. Long-term dietary administration of Cd can result in a dosedependent accumulation of Cd in liver and kidney (73-75). In addition to Cd accumulation, increased deposition of Zn in the liver and Cu in the kidney are also reported in experimental animals after continuous feeding of Cd salts. There is considerable experimental evidence in animals on the biological interaction between Cd and selenium (Se). Although Se itself is toxic, equimolar doses of Se and Cd can interact with each other and reduce their toxicity. Selenium can also alter the binding of Cd to plasma proteins and thus affect its bioavailability (76). Inorganic salts of Se are rapidly reduced in tissues of animals to selenotrisulfides, hydrogen selenides, methyl selenides, and other low-molecular-weight metabolites and protein derivatives. These complexes can cause decreased elimination of Cd and other metals and also decrease their toxicity. Biological Trace Element Research

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Chemical forms of Cd in the diet may also influence its uptake and fate in experimental animals. Feeding of Cd in the form of Cd salts or Cd-metallothionein to mice resulted in similar absorption, but different tissue distribution (55,77,78). Kidney was the primary site of Cd deposition from Cd-metallothionein, whereas liver was the major deposition site from Cd salts. TOXIC E F F E C T S O F Cd In earlier reports (2), GI effects were common findings in acute poisoning resulting from the ingestion of food contaminated with Cd. The contamination is usually caused by storage of food in Cd-plated containers, cans, and the like. A poisoning incident among Swedish school children was caused by fruit juice contaminated in vending machines that had a Cd-plated reservoir (36). Cadmium is a powerful emetic. The highest no-effect level of Cd administered as a single oral dose to man is estimated at 3 mg, and the lethal dose range is about 350 mg (79). Symptoms are severe nausea, vomiting, salivation, abdominal cramps, and diarrhea. Catarrhal and ulcerative gastroenteritis, congestion, pulmonary infarcts, and subdural hemorrhages may be found at necropsy (2). Following long-term exposure, Cd may exert various toxic effects, such as renal disturbances, osteomalacia, anemia, and anosmia. The signs of renal damage, such as proteinuria, enzymuria, glucosuria, and increased excretion of Ca and phosphates, were reported in Itai--Itai patients. The disturbances in Ca and phosphorus metabolism may also lead to the formation of kidney stones and/or demineralization of bones. Bone lesions are usually a late manifestation of a severe, chronic Cd poisoning. They are characterized by osteomalacia, osteoporosis, and spontaneous fractures (39). A number of epidemiological studies have been undertaken to determine if Cd is linked to human hypertension and cardiovascular disease (80,81). There is as yet no firm evidence that Cd, either in acutely toxic amounts or with chronic low-level exposure, plays a role in human hypertension. There are a number of reports on the effects of Cd ingestion in mice (82), rats (83), rabbits (84), Japanese quail (85), cats (86), dogs (87), goats (88), and cattle (89). These studies show various toxic effects, such as anemia (90,91), ulceration and enteropathy (85), and damage to liver and kidney (74,91-94), after long-term feeding of Cd salts. The toxicity of oral administration of Cd depends both on the dose and time of feeding. Reports (74,91) show that feeding of 25 ppm Cd, as CdCI2, for 24 wk did not show any toxicity. A comparative study on oral and inhalative Cd uptake in rats (91) showed that Cd accumulated mainly in liver and kidney, with an increased deposition of Cd in liver after oral administration. High blood Cd levels and proteinuria were observed mainly after oral administration. Biological Trace Element Research

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The most striking morphological effect of long-term Cd ingestion in rabbits was interlobular hepatic and interstitial renal fibrosis (93). The renal dysfunction following Cd treatment is mainly a tubular type of damage resulting in low-molecular-weight proteinuria. The reported changes in alkaline phosphatase and other related enzymes (39) themselves may result in Ca metabolism and changes in bone mineralization. However, most of the changes in the skeleton are observed in nutritional deficiency together with Cd exposure. Feeding studies in monkeys (39) showed that long-term feeding of Cd salts can result in aminoaciduria followed by other renal dysfunctions. The tubular damage can progress to glomerular dysfunction on continuous Cd exposures. Although animal studies have suggested a critical concentration of 200 ~g Cd/g for renal function, this value is controversial and may depend on various factors and the species. Other experimental studies also suggest that high doses of Cd can result in reproductive toxicity associated with alterations in uteroplacental blood flow (95), placental accumulation of Cd (96), and intrauterine growth retardation (97). Although a number of toxic effects of Cd have been reported in experimental animals following oral administration of Cd salts, they may vary depending on the species and experimental conditions. The major chronic toxic effects are observed in the kidney; this may result from mobilization of Cd from the liver. Recent studies (98) on injection of Cd salts suggested definite changes in metabolism of essential elements, such as Zn and Cu, in the kidney when the renal Cd concentration reaches as little as 10 ~g/g. The significance of these results and whether such changes can occur after environmental exposure to Cd are unclear.

BIOLOGICAL INDICATORS FOR DIETARY Cd EXPOSURE Extensive epidemiological studies have been carried out in Cdexposed areas in Japan (99-101), Belgium (102), and Shipham, England (103-105) in order to determine not only the mechanism of environmental Cd toxicity, but to identify biological indicators for detection of excessive Cd exposure and estimation of body burden of Cd. In occupational Cd exposures, blood Cd levels and increased urinary Cd excretion have been used as indicators of acute and chronic Cd exposures, respectively (102). Since renal dysfunction and tubular proteinuria are common in Cdexposed workers, various markers for renal damage are widely used as biological indicators for Cd exposure (106). The situation is different for environmental exposure to Cd in the general population, who are continuously exposed to moderate levels of widely dispersed Cd. The relationship between indicators of early effects of excessive Cd exposure and long-term low-level exposure to Cd is less clear. However, renal damage has been reported widely in people living in Cd-polluted areas in various parts of the world. A higher incidence of Biological Trace Element Research

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proteinuria, glucosuria, and B2 microglobulinuria, which are common indicators of renal damage, has been observed in the Jintzu River Basin In Toyama prefecture, where Itai-Itai disease was first detected, and in other areas in Japan where high concentrations of Cd were found in rice. It has been suggested from observed results that people who consume rice containing 0.6 ppm Cd or more may develop renal damage in their fifties (101). Studies in Belgium on environmental Cd exposure in an industrially polluted area also suggest age-related renal dysfunction in elderly residents (107). Similarly, a mortality study (105) carried out in a Cdpolluted town, Shipham, England, also suggests slight increases in the standardized mortality ratios from nephrosis and nephritis in inhabitants of this area. Therefore, indicators of renal dysfunction may be useful indicators for excessive environmental Cd exposures. Long-term moderate exposure to Cd may induce increased urinary excretion of proteins by two different mechanisms: decreased tubular reabsorption and increased glomerular permeability (108). The relative importance of both mechanisms may depend on the rate of Cd absorption, age of the exposed person, and, possibly, immunological responses. Increased urinary excretion of low- and high-molecular-weight proteins can occur independently. The value of 200 p~g/gcreatinine for urinary B2 microglobulinemia as an indicator of Cd-induced renal dysfunction has been criticized (39) because it is highly correlated with age in both high- and low-Cd-exposure population groups (109). The elevated urinary B2 microglobulin analysis has been used widely to screen the Cd health effects of inhabitants in Cd-polluted areas in Japan. Increased excretion of B2 microglobulin in Cd-exposed people in Japan was strongly related to residence time in the exposed area as well as to the use of contaminated river water in the household. There was also a correlation between Cd levels in the blood and B2 microglobulin excretion in this population (101). However, age factor and the other diseases causing renal dysfunction also should be considered in the evaluation of health effects of Cd, using B2 microglobulinuria as an indicator. Urinary excretion of B2 microglobulin was more closely related to urine Cu than to urine Cd in certain reports (39,110). Metallothionein concentrations in the urine of environmentally Cd-exposed people in Japan, including Itai-Itai and suspected patients, were also closely related to urinary levels of Cd, Cu, and other indicators of renal damage (111). Other low-molecular-weight proteins, such as retinol-binding proteins, also were detected in urine after Cd exposure. Studies from Japan (100,112) showed a significant increase in retinol-binding protein in urine along with other low-molecular-weight proteins in people living in Cdpolluted areas. Increased excretion of urinary lysozyme also has been reported in chronic Cd exposure (112). A number of other indicators of renal damage has been used for detection of Cd exposure in Cd-polluted areas. However, none of them, other than estimation of Cd itself, can be Biological Trace Element Research

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considered specific indicators of excessive Cd exposures. The various biological indicators for Cd exposure and toxicity were critically reviewed recently (113). When the exposure to Cd is moderate and the body burden has not yet reached the critical level to cause renal dysfunction, the Cd levels in urine are believed to represent the body burden of Cd rather than recent exposure. Under these conditions, urinary Cd levels rarely exceed 10 ~g/g creatinine (108). Therefore, the estimation of urinary Cd may not be a sensitive indicator for environmental exposure to Cd, and other parameters should also be studied. A study carried out to assess the human exposure to Cd (11) in different areas of the world showed that geometric means for blood Cd ranged from 0.5 ~g/L in Stockholm and Jerusalem to about 1.2 ~g/L in Tokyo and Brussels. In some population groups, the mean concentration of Cd in the kidney cortex at the age of 50 was only 2-5 times lower than the critical level for renal damage. The relationships between Cd exposure and indicators of kidney function were reviewed in a technical report by Hutton. It is concluded by statistical analysis that a weekly intake of less than 500-600 ~g Cd in the diet, a provisional tolerable intake value previously proposed by WHO (114), will not result in any adverse health effects from Cd in a large majority of the population. The renal dysfunction has been considered in the evaluation of health effects of Cd in this report.

CONCLUSIONS Because of the increased use of sewage sludge and phosphate fertilizers containing high levels of Cd in developing countries, the environmental exposure of Cd is increasing in these countries. The widely prevalent nutritional deficiencies may also enhance the toxicity of Cd in this population. International epidemiological studies are needed to evaluate the health effects of Cd in various populations with different nutritional status and different dietary habits. The primary environmental human health concern of Cd is thus related to long-term low-level exposures. Since a long biological half-life has been suggested for Cd in the kidney, the rate of deposition of Cd in the kidney from different forms of dietary Cd should be considered in any expression of the potential adverse health effects of dietary Cd. The bioavailability of Cd from food is also difficult to determine because of the various forms of Cd and its potential interactions with other nutrients. The complexity of the nutrient interrelationships and their effects on Cd toxicity require further investigations to define mechanisms. Little information is available on the potential risk of oral Cd exposure at various age groups. Biological Trace Element Research

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A l t h o u g h a n u m b e r of indicators of renal d y s f u n c t i o n are u s e d for the evaluation of Cd toxicity, n o n e of these can be c o n s i d e r e d a specific indicator of e n v i r o n m e n t a l (via food a n d smoking) Cd exposure. The disturbances in the m e t a b o l i s m of the essential metals (Cu, Zn, Fe) in h u m a n s a n d the increase of urine levels of these metals m i g h t be a sensitive indicator for excessive Cd exposure in the general p o p u l a t i o n , a l t h o u g h it m a y n o t be a specific effect of Cd exposure.

ACKNOWLEDGMENT The authors wish to t h a n k Miss Judy Balint for her diligent t y p i n g of this m a n u s c r i p t .

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Vol. 10, 1986

Factors influencing cadmium accumulation and its toxicity to marine organisms.

Studies on the toxicity and metabolism of cadmium-thionein.

Left Ventricular Structure and Function in Relation to Environmental Exposure to Lead and Cadmium.

Effect of chronic exposure to cadmium on hepatic drug metabolism.

Cadmium accumulation and toxicity in the unicellular alga Pseudokirchneriella subcapitata: Influence of metal-binding exudates and exposure time.

Impact of environmental cadmium pollution on cadmium exposure and body burden.

Abiotic factors affecting the toxicity of lead to fungi.

Environmental Exposure to Cadmium: Health Risk Assessment and its Associations with Hypertension and Impaired Kidney Function.

Influence of some factors on cadmium pharmacokinetics and toxicity.

Exposure factors of cadmium for residents in an abandoned metal mine area in Korea.

Factors affecting squeaking in metal on metal hip resurfacings.

Environmental bromine in freshwater and freshwater organisms: factors affecting bioaccumulation.

Environmental factors affecting pregnancy: endocrine disrupters, nutrients and metabolic pathways.

Nutritional and environmental factors affecting gestation length in rhesus monkeys.

Intestinal microbial ecology and environmental factors affecting necrotizing enterocolitis.

Exposure-affecting factors of dairy farmers' exposure to inhalable dust and endotoxin.

Association of total cancer and lung cancer with environmental exposure to cadmium: the meta-analytical evidence.

Environmental Exposure to Arsenic, Lead, and Cadmium in People Living near Janghang Copper Smelter in Korea.

Cadmium toxicity to freshwater algae.

Genetic and environmental factors affecting host response to drugs and other chemical compounds in our environment.

Impairment of vitamin D metabolism due to environmental cadmium exposure, and possible relevance to sex-related differences in vulnerability to the bone damage.

Thirdhand cigarette smoke: factors affecting exposure and remediation.

Application of metallomic and metabolomic approaches in exposure experiments on laboratory mice for environmental metal toxicity assessment.

Environmental arsenic, cadmium and lead dust emissions from metal mine operations: Implications for environmental management, monitoring and human health.