Renal Accumulation Of Cadmium Research Articles

Sexual Maturity and Life Stage Influences Toxic Metal Accumulation in Croatian Brown Bears.

The influence of reproductive and (early) life stages on toxic metal levels was investigated in the brown bear (Ursus arctos), the largest mammalian predator species in Croatia. The purpose was to examine critical clusters in a population that might be at a higher risk of adverse health effects caused by metals as environmental contaminants. Levels of cadmium, mercury and lead in muscle, liver and kidney cortex of 325 male and 139 female bears, quantified by inductively coupled plasma mass spectrometry, were analysed according to distinct bear life stages (young: cub, yearling, subadult; mature: adult). Metal levels did not differ among sexes in young animals (<4years), except for mercury in muscles (higher in females), and adult females had higher cadmium and mercury. A trend of renal cadmium accumulation with age in immature male animals disappeared once they reached maturity, whereas for females this trend has only slowly declined in mature compared to immature bears. In early life stage (<1year), bear cubs had lower cadmium, comparable mercury, and higher lead in the kidneys than the bears of the following age category (yearlings). Due to a higher proportion ofrenal lead transfer from the mother to the cub compared with cadmium, it may be that the high burden of cadmium found inkidneys of older females has lower toxicological concern for their cubs than the lead content. Sex, reproductive, and life stages of bears were confirmed as important in assessing toxic metal burden.

Dietary Deficiency of Calcium and/or Iron, an Age-Related Risk Factor for Renal Accumulation of Cadmium in Mice.

The major route of cadmium (Cd) intake by non-smokers is through food ingestion. Cd is a non-essential metal absorbed through one or more transporters of essential metal ions. Expression of these transporters is affected by nutritional status. To investigate the risk factors for Cd toxicity, the effects of deficiency of essential metals on hepatic and renal accumulation of Cd were studied in mice of different ages. Mice were administered a control diet or one of the essential metal-deficient diets, administered Cd by gavage for 6 weeks, and killed; then, Cd accumulation was evaluated. Iron deficiency (FeDF) or calcium deficiency (CaDF) resulted in remarkable increases in hepatic and renal Cd accumulation compared with control-diet mice and other essential metal-deficient mice. Cd accumulation in hepatic and renal tissue was increased significantly at all ages tested in FeDF and CaDF mice. Renal Cd concentrations were higher in 4-week-old mice than in 8- and 25-week-old mice. Increase in intestinal mRNA expression of calcium transporter (CaT)1, divalent metal ion transporter-1, and metallothionein (MT)1 was also higher in 4-week-old mice than in other mice. Renal accumulation of Cd showed strong correlation with intestinal mRNA expression of CaT1 and MT1. These data suggest that CaDF and FeDF at younger ages can be a risk factor for Cd toxicity.

Roles of ZIP8, ZIP14, and DMT1 in transport of cadmium and manganese in mouse kidney proximal tubule cells

Chronic exposure to cadmium causes preferential accumulation of cadmium in the kidney, leading to nephrotoxicity. In the process of renal cadmium accumulation, the cadmium bound to a low-molecular-weight metal-binding protein, metallothionein, has been considered to play an important role in reabsorption by epithelial cells of proximal tubules in the kidney. However, the role and mechanism of the transport of Cd(2+) ions in proximal tubule cells remain unclear. Zinc transporters such as Zrt, Irt-related protein 8 (ZIP8) and ZIP14, and divalent metal transporter 1 (DMT1) have been reported to have affinities for Cd(2+) and Mn(2+). To examine the roles of these metal transporters in the absorption of luminal Cd(2+) and Mn(2+) into proximal tubule cells, we utilized a cell culture system, in which apical and basolateral transport of metals can be separately examined. The uptake of Cd(2+) and Mn(2+) from the apical side of proximal tubule cells was inhibited by simultaneous addition of Mn(2+) and Cd(2+), respectively. The knockdown of ZIP8, ZIP14 or DMT1 by siRNA transfection significantly reduced the uptake of Cd(2+) and Mn(2+) from the apical membrane. The excretion of Cd(2+) and Mn(2+) was detected predominantly in the apical side of the proximal tubule cells. In situ hybridization of these transporters revealed that ZIP8 and ZIP14 are highly expressed in the proximal tubules of the outer stripe of the outer medulla. These results suggest that ZIP8 and ZIP14 expressed in the S3 segment of proximal tubules play significant roles in the absorption of Cd(2+) and Mn(2+) in the kidney.

Hepatic and renal cadmium accumulation is associated with mass-specific daily metabolic rate in the bank vole ( Clethrionomys glareolus)

Previous study has shown that photoperiod and age affect tissue accumulation of cadmium (Cd) in a small rodent, the bank vole. Since the body mass is also influenced by these factors, the present study was designed to determine whether mass-specific daily metabolic rate might be responsible for differential accumulation of Cd in the liver and kidneys of the short- and long-photoperiod bank voles as well as of the young and old animals. One- and five-month old male bank voles were held under short (8 h light / 16 h dark) or long (16 h light / 8 h dark) photoperiods and exposed to dietary Cd (100 μg/g) for 6 weeks. The bank voles raised under the short photoperiod and those injected subcutaneously with melatonin (7 μmol/kg/day) under the long photoperiod showed significantly higher concentrations of Cd in the liver (43–60%) and kidneys (40–47%) than the age-matched long-photoperiod animals. The old bank voles accumulated significantly less Cd in both organs than the young animals. These differences in Cd accumulation appeared not to be associated with the relative Cd intake. However, the hepatic and renal Cd levels followed a pattern similar to that of the mass-specific daily metabolic rate (or energy expenditure) and energy assimilation efficiency. These data indicate that mass-specific daily metabolic rate and energy assimilation efficiency (an indicative of digestive and absorptive processes) may be responsible for differential tissue Cd accumulation in the bank vole.

Cadmium levels in the lung, liver, kidney cortex, and urine samples from Australians without occupational exposure to metals.

The authors undertook this study to assess levels of cadmium exposure in the general population. Samples of lung, liver, and kidney were obtained from 61 cadavers (43 males, 18 females; 2-89 yr of age, mean age = 38.5 yr) who died from accidental causes and who were subject to postmortem examinations at the John Tonge Centre for Forensic Sciences, Queensland Health Scientific Services, Brisbane, Australia, in 1997 and 1998. Samples of bladder urine were also obtained from 22 cadavers. Tissue and urine samples were analyzed for cadmium, zinc, and copper with inductively coupled plasm (ICP) mass spectrometry. The overall mean values for cadmium in the lung, liver, and kidney cortex samples were 0.13, 0.95, and 15.45 microg/gm wet tissue weight. The average renal cadmium level in subjects with high lung-cadmium levels (n = 13) was 6 microg/gm wet tissue weight higher than that of similarly aged subjects who had medium lung-cadmium levels (n = 30). In females, the average level of cadmium in the liver was 74% greater than in males, and the average liver cadmium in females with high lung-cadmium levels was 100% higher than in males in the same age range who had the same high lung-cadmium levels. Renal cadmium accumulation tended to be greater in females than in males who were in the same age range and who had similar lung-cadmium levels, a result that suggested that there was a higher absorption rate of cadmium in females. The mean value for a urinary cadmium excretion of 2.30 microg/gm creatinine was found in a subset of samples that had a mean age of 39 yr and a renal cortex cadmium concentration of 18.6 microg/gm wet tissue weight. Urinary cadmium excretion rates were correlated more strongly with lung and kidney cadmium content than with age or liver cadmium levels. The results suggest that urinary cadmium excretion may be increased in smokers and could provide some estimate of body cadmium burdens in future Australian epidemiological studies.

Evidence for Basolateral Uptake of Cadmium in the Kidneys of Rats

In three separate sets of studies, the effects of ureteral ligation and coadministration of cadmium with cysteine or glutathione (GSH) (in either a 4:1 or 2:1 ratio of thiol to cadmium) on the renal disposition of cadmium were assessed in rats 1 h after the administration of cadmium. In all experiments, co-administration of cadmium with either cysteine or GSH caused the renal accumulation of cadmium to increase significantly (by approximately 60–70%) 1 h after injection. Moreover, in all experiments in which both ureters had been ligated in a rat prior to the administration of cadmium, the net total renal accumulation of cadmium was only about 20% less than that in control animals that had not undergone bilateral ureteral ligation when cadmium was administered as cadmium chloride. Furthermore, in animals in which only one ureter had been ligated, the net accumulation of cadmium in the kidney whose ureter had been ligated was between 25 and 30% less than that in the contralateral kidney. Coadministration of cadmium with cysteine or GSH also caused the net accumulation of cadmium to be increased in rats whose ureter(s) had been ligated. Overall, the present findings indicate that there is a significant basolateral component in the acute, in vivo, renal tubular uptake of cadmium. Moreover, the findings indicate that the basolateral uptake of cadmium is enhanced when cadmium is coadministered with cysteine or GSH.

INFLUENCE OF DIFFERENT DEGREES OF REDUCED RENAL MASS ON THE RENAL AND HEPATIC DISPOSITION OF ADMINISTERED CADMIUM

Abstract The present study was designed to evaluate, in rats, the effect of varying degrees of reduced renal mass on the disposition of administered cadmium. As part of this evalua tion, the intrarenal, hepatic, and hematological disposition of cadmium and the urinary and fecal excretion of cadmium were studied and characterized in control, uninephrec-tomized (NPX), and 75% nephrectomized (75% NPX) rats 1 d, 2 d, and 7 d after the intravenous injection of a nonnephrotoxic 8.9 μmol/kg dose of cadmium chloride. Renal accumulation of cadmium, especially in the cortex and outer stripe of the outer medulla, was reduced significantly in the 75% NPX rats, but not in the NPX rats, between d 2 and 7 after the injection of cadmium. The diminution in the renal accumulation of cadmium in the 75% NPX rats was most likely due to diminished glomerular filtration rate and renal clearance of cadmium induced by 75% nephrectomy. Despite reduced glomerular filtra tion rate, the cumulative urinary excretion of cadmium in the 75% NPX rats was signifi cantly greater than that in either the NPX rats or the control rats. It should be mentioned, however, that very little of the administered dose of cadmium was excreted in the urine by any of the three groups of rats. Interestingly, the content of cadmium in the liver was significantly greater in 75% NPX rats than in NPX or control rats between d 1 and 7 after the injection of cadmium. Moreover, the 75% NPX rats excreted significantly less cadmium in the feces over the 7 d of study than did the other 2 groups of rats, indicating that 75% nephrectomy causes a significant alteration in one or more of the mechanisms involved in the fecal excretion of cadmium. In summary, the findings from the present study indicate that the renal and hepatic handling of administered cadmium in rats changes significantly when renal mass is reduced by 75%. Further studies are needed to better characterize the effects of reductions of renal mass, which impair renal function significantly, on both the disposition and toxicity of cadmium in renal and hepatic tissues.

INFLUENCE OF DIFFERENT DEGREES OF REDUCED RENAL MASS ON THE RENAL AND HEPATIC DISPOSITION OF ADMINISTERED CADMIUM

The present study was designed to evaluate, in rats, the effect of varying degrees of reduced renal mass on the disposition of administered cadmium. As part of this evalua tion, the intrarenal, hepatic, and hematological disposition of cadmium and the urinary and fecal excretion of cadmium were studied and characterized in control, uninephrec-tomized (NPX), and 75% nephrectomized (75% NPX) rats 1 d, 2 d, and 7 d after the intravenous injection of a nonnephrotoxic 8.9 μmol/kg dose of cadmium chloride. Renal accumulation of cadmium, especially in the cortex and outer stripe of the outer medulla, was reduced significantly in the 75% NPX rats, but not in the NPX rats, between d 2 and 7 after the injection of cadmium. The diminution in the renal accumulation of cadmium in the 75% NPX rats was most likely due to diminished glomerular filtration rate and renal clearance of cadmium induced by 75% nephrectomy. Despite reduced glomerular filtra tion rate, the cumulative urinary excretion of cadmium in the 75% NPX rats was signifi cantly greater than that in either the NPX rats or the control rats. It should be mentioned, however, that very little of the administered dose of cadmium was excreted in the urine by any of the three groups of rats. Interestingly, the content of cadmium in the liver was significantly greater in 75% NPX rats than in NPX or control rats between d 1 and 7 after the injection of cadmium. Moreover, the 75% NPX rats excreted significantly less cadmium in the feces over the 7 d of study than did the other 2 groups of rats, indicating that 75% nephrectomy causes a significant alteration in one or more of the mechanisms involved in the fecal excretion of cadmium. In summary, the findings from the present study indicate that the renal and hepatic handling of administered cadmium in rats changes significantly when renal mass is reduced by 75%. Further studies are needed to better characterize the effects of reductions of renal mass, which impair renal function significantly, on both the disposition and toxicity of cadmium in renal and hepatic tissues.

Biological monitoring of cadmium exposure and renal effects in a population group residing in a polluted area in China

In an area of China, not previously studied in detail concerning cadmium pollution and possible adverse effects on the kidney of exposed populations, concentrations of cadmium in urine as an indicator of renal accumulation of cadmium was studied and related to indicators of renal dysfunction in order to examine if a relationship could be documented. Cadmium concentrations in urine were analysed by graphite furnace atomic absorption spectrometry and urinary beta-2 microglobulin (UBM) and albumin (UALB) were measured as indicators of renal dysfunction. Rice samples and urine samples were obtained from three areas in Zhejiang province, China, representing a highly exposed area, a medium exposed area and a control area, respectively. Cadmium concentrations in rice were 3.70, 0.51 and 0.072 mg/kg for the heavily, medium polluted areas and the control area, respectively. Cadmium concentrations in urine (geometric means) were 10.7, 1.62 and 0.40 μg/l in the high, medium and control areas respectively. There was a clear increase in UBM and UALB in the heavily exposed group in comparison to the control group and a slight increase in the medium exposed group. There was a statistically significant dose-response relationship between cadmium in urine and β 2-microglobulin excretion in urine, which is similar to what has previously been reported in other countries. The findings constitute the first report concerning a dose-response relationship in this population group in Zhejiang province in China.

Changes of Renal Cadmium Accumulation Levels and Urinary Cadmium Excretion Levels Induced by Long-term Cadmium Exposure in Rats

Changes of Renal Cadmium Accumulation Levels and Urinary Cadmium Excretion Levels Induced by Long-term Cadmium Exposure in Rats

Renal accumulation of cadmium and nephropathy following long-termadministration of cadmium-metallothionein

Cadmium-metallothionein (Cd-MT) is selectively distributed to the kidney, producing nephropathy similar to that seen following chronic exposure to Cd. The critical concentration of Cd after an injection of Cd-MT (about 10 μg/g) is much lower than that following chronic Cd exposure (130–200 μg/g). To investigate whether administration of Cd-MT at nonacute toxic dosages can induce chronic nephrotoxicity similar to inorganic Cd, i.e., renal accumulation of Cd and nephropathy, repeated injections of 109Cd-MT at two doses, 25 or 80 μg/kg/day, were given to rats. The concentration of 109Cd in kidney was 7–10 times higher than that in liver at each treatment level. Concentrations of 109Cd were highest in the kidney and reached a plateau following repeated injections of 109Cd-MT at both doses. The renal 109Cd levels found here (200 and 140 μg/g) were in the same range as the concentrations found at a plateau following repeated CdCl2 injection. Indications of nephrotoxicity following repeated injections of 109Cd-MT did not occur until renal Cd leveled off. The majority of intracellular Cd is sequestered by endogenous MT in the kidney. After renal Cd leveled off, the hepatic concentration of 109Cd did not markedly increase, but urinary excretion of 109Cd increased significantly. In addition both urinary protein and glucose also increased significantly, indicating that the appearance of nephrotoxicity is dependent on renal Cd saturation following long-term administration of Cd-MT. This is similar to what is seen following chronic inorganic cadmium exposure. These results support the suggestion that Cd-MT plays a major role in the initiation and development of Cd-induced renal damage.

Lung deposition, lung clearance and renal accumulation of inhaled cadmium chloride and cadmium sulphide in rats

Rats were exposed 6 h/day over 10 days to 0.3 mg/m 3 of water soluble cadmium chloride and 0.2, 1.0 and 8.0 mg/m 3 of insoluble cadmium sulphide, then killed at intervals over a 3-month period for serial measurements of lung, renal and faecal cadmium. CdCl 2 and high-dose CdS animals showed a transient increase in lung weight. Clearance of both compounds was biphasic. Approximately 40% of deposited material was cleared during the 10-day exposure period. For CdCl 2, only 9% of the lung burden was cleared rapidly after the last exposure (half-life 1.0 days) and 47% slowly (half-life 87 days), leaving a residual lung burden of 44%. For CdS, 41% of the lung burden was cleared rapidly (half-life 1.4 days) and 40% slowly (half-life 42 days), leaving a final residue 19%. In the CdS high-dose group, the retention of CdS in the lung was greater than that in the CdS low-dose groups, indicating that clearance mechanisms may possibly have been impaired in the high-dose group by too great a lung burden. For both compounds, faecal cadmium was initially high. Renal accumulation of cadmium was substantial for CdCl 2 during the exposure period and continued over the following months until it represented approximately 35% of the total cadmium cleared from the lung. For CdS, renal accumulation was only 1% of the amount cleared from the lung. The bioavailability of Cd from CdS is thus poor, the majority being cleared from the lungs and excreted in the faeces. However, the bioavailability of inhaled CdS measured as cadmium in the kidney is greater than the bioavailability of orally ingested CdS.

Pregnancy-associated changes in plasma metallothionein concentration and renal cadmium accumulation in rats.

Pregnancy-associated changes in metallothionein (MT) concentrations in blood plasma were examined using a competitive enzyme-linked immunosorbent assay with a rabbit polyclonal antibody to rat liver MT. Plasma MT of pregnant rats significantly increased after 8 days of gestation and remained high during pregnancy and for 7 days after delivery. Gel filtration showed that both Cu and Zn were associated with the plasma MT of pregnant rats. These results suggest that plasma MT may play a role in the transport of essential metals such as Cu and Zn to fetus during pregnancy, but the source of plasma MT is unknown. Injections of cadmium chloride and cadmium-metallothionein to pregnant rats further increased the plasma MT concentrations. After injection of CdCl2, both MT and Cd concentrations in the liver of the pregnant rats were significantly lower than those of the nonpregnant rats, whereas renal Cd and MT levels were higher in pregnant rats. This increased accumulation of Cd in the kidney of pregnant rats may be related to the increase of plasma MT during pregnancy. About 5% of 6 pg of in vitro added Cd (20 pg/ml) was bound to the MT in the plasma. Therefore, Cd may be transported by the circulating MT to the kidney, leading to an increase in renal accumulation of Cd in pregnant rats.

Sex differences in hepatic and renal cadmium accumulation and metallothionein induction: Role of estradiol

The role of estradiol in sex differences in hepatic and renal cadmium accumulation and metallothionein (MT) induction was investigated. Male and female rats and castrated males pretreated with estradiol were injected either i.v. or s.c. with 10 μmol CdCl 2/kg. Sex differences in cadmium accumulation and MT induction were apparent after s.c. but not i.v. administration. The female rats accumulated a significantly greater concentration of cadmium in their liver than did the males, as early as 1 hr after the s.c. injection. The elevated levels of cadmium in the females were maintained for at least 10 days. Pretreatment of castrated males with estradiol caused a similarly greater accumulation of cadmium in the liver. Hepatic MT levels peaked in the females at 24 hr and in males 48–72 hr after the cadmium injection and then declined to lower levels. This superinduction of MT occurred only after the s.c. administration of cadmium. MT levels in both sexes plateaued 5 days after the s.c. injection to the levels that were similar to those seen in male and female rats 24 hr after an i.v. injection. In animals injected s.c. with cadmium the renal cadmium levels continued to rise for 5–10 days; however, in animals injected i.v. the levels stabilized within 2hr. The renal MT levels in the females were significantly higher than in the males. Estradiol pretreatment induced renal MT but did not affect renal cadmium accumulation. Thus, the sex differences in hepatic cadmium accumulation and MT induction are affected by the route and time after the administration of cadmium. Furthermore, estradiol causes a more rapid uptake of cadmium by the liver and also an enhanced induction of MT in both the liver and kidney.

Cadmium accumulation and toxicity in the kidney of the bay scallop Argopecten irradians

Specimes of bay scallops, Argopecten irradians, collected from shallow-water eel-grass beds near Beaufort, North Carolina (USA) in September 1979, were exposed to 0.7 ppm cadmium in flowing seawater for 5 d. This exposure resulted in a massive extrusion of the calcified concretions of most of the kidney epithelial cells, although marked morphological damage consisting of cytoplasmc degeneration was apparent in only a few focal areas of the kidney. In addition, unique cytoplasmic membrane-bound bodies were observed in epithelial cells of cadmium-treated but not control scallop kidneys. In some cells, these bodies appeared to fuse with the main concretion vacuole. Kidneys of cadmium-treated scallops accumulated cadmium to 200 ppm on a wet wt basis; of this 60% was associated with concretions (2 000 ppm dry wt) and 38% with the membranous pellet obtained after ultracentrifugation at 105 000 g for 1 h. Approximately 2% of total kidney cadmium was associated with the cytosolic fractions but, unlike zinc or manganese, which were bound to either high or low molecular weight species, a large component of the cadmium in this fraction was bound to a protein peak of approximately 21 000 daltons. Results of this study indicate that kidney concretions of A. irradians play a major role in the control of renal cadmium accumulation and excretion and hence the toxicity of cadmium to this organism.

Repeated surveillance of exposure to cadmium, manganese, and arsenic in school-age children living in rural, urban, and nonferrous smelter areas in Belgium

Once a year from 1974 to 1978, the intensity of exposure to Cd, As, Mn in groups of school-age children living around a lead smelter was assessed. By comparison, groups of children living in an urban and a rural area were also examined. The metal content of blood, urine, hand-rinsing, air, dust, and dirt collected in the school-playground was compared. The urinary excretion of cadmium in children living around the lead smelter is greater than in those living in the urban and in the rural area. In the latter there seems to exist a time-dependent trend in the renal accumulation of cadmium. This suggests that the overall pollution of the environment by cadmium in Belgium is progressively increasing. In the smelter area, both the oral and pulmonary routes play a role in the children's exposure to cadmium. Their relative contribution to the amount of cadmium absorbed appears similar. The concentration of arsenic in urine of children living around the smelter is significantly higher than that of rural children. Speciation of the chemical forms of arsenic in urine indicates that the difference is not due to different dietary habits of the children examined but to different intensity of exposure to inorganic arsenic. The amount of arsenic on the hand of children living at less than 1 km from the smelter ( X = 17.6 μg As/hand) was more than 10 times that found in children living at 2.5 km from the plant ( X = 1.5 μg As/hand) whereas that found in children living in urban and rural areas was below 0.2 μg As/hand. The arsenic concentration of dust and dirt collected in the school-playground in the different areas follows the same trend. As expected, there are strong interrelationships between the degree of hand contamination by lead, cadmium, and arsenic ( r ⩾ 0.8). No statistically significant influence of the dwelling place of the children on the manganese level in blood, urine, and hand rinsing was found. Our results demonstrate that by comparison with the rural and urban children, those living in the vicinity of a nonferrous smelter may be more exposed not only to lead, but also to cadmium and arsenic. The possible long-term effects of such exposure deserve further evaluation.

Biliary excretion of cadmium in rat. II. The role of metallothionein in the hepatobiliary transport of cadmium.

Intravenous injection of 109Cd-labeled CdCl2 (1 mg/kg) to control rats and rats that had been injected with CdCl2 (0.25 mg/kg) 24 hr earlier showed that there was a decrease in the biliary excretion of 109Cd in the latter group. The 24 hr pretreatment with CdCl2 resulted in induced synthesis of metallothionein in rat liver and kidney. The binding of cadmium to liver tissue was increased and the renal accumulation of cadmium was unaltered on cadmium pretreatment. Rat liver metallothionein was isolated from rats injected repeatedly with CdCl2. Intravenous injection of cadmium-bound metallothionein gave a different distribution of cadmium in the tissues and biological fluids as compared to injection of CdCl2. A major percentage of cadmium was deposited in the kidney with urinary excretion after injection of rat cadmium-metallothionein to control rats. The biliary excretion of cadmium after cadmium-metallothionein injection was minimal. About 90% of cadmium in the kidney cortex and urine could be recovered as cadmium-thionein in sephadex gel filtration, 3 hr after cadmium-thionein injection.

Influence of dietary cadmium on the distribution of the essential metals copper, zinc and iron in tissues of the rat

The effect of long-term dietary cadmium treatment upon the distribution of the metals copper, iron and zinc has been compared in various organs of male and female rats. The renal accumulation of cadmium was similar in both sexes without a plateau being reached. In contrast, the hepatic accumulation of cadmium was higher in the female than in the male rat and a plateau was observed after 30–35 weeks of dietary cadmium treatment. Most of the cadmium which accumulated in these organs was recovered in the metallothionein fraction and the concentration of hepatic cadmiumthionein in the female rat was correspondingly higher than in the male rat. Accumulation of cadmium was associated with an increased zinc concentration in the liver and an increased copper concentration in the kidney; these increases were correlated with increases in liver and kidney metallothioneins induced by cadmium. Uptake of cadmium into organs other than liver and kidney occurred to a small extent but was not associated with changes in the concentration of copper and zinc. Cadmium also accumulated in the intestinal mucosa where it could be recovered in a fraction corresponding to metallothionein. A loss of iron from the liver and kidney was also observed following dietary cadmium treatment and involved mainly a loss of iron from ferritin.