Cadmium

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CADMIUM

Cadmium appears to be the largest single contributor to autoimmune thyroid disease. It is a very powerful and toxic metal which seems to be placed at the very center of the thyroid story. I think you'll find this file very interesting.

Not only does cadmium appear to play a very pivotal role in thyroid disease, it is a very unique mineral. It is extremely toxic and has toxic biological effects at concentrations smaller than almost any commonly found mineral.

Despite this great toxicity, there is some evidence that cadmium is an essential nutrient with biological function. We will be exploring this dichotomy of cadmium.

One of the greatest effects of cadmium is that it depletes selenium in the body because selenium is essential for cadmium removal. Selenium atoms combine with cadmium atoms and are escorted out of the body via the bile system. When selenium is depleted by cadmium, there is less selenium to form the deiodinase enzymes which convert T4 to T3, resulting in low T3 and hypothyroidism. Also there is less selenium to form glutathione peroxidase, one of the body's prime antioxidants. This results in greater levels of reactive oxygen species and hydrogen peroxide, which lead to an increased production of thyroid hormone and damage to the thyroid gland.

The following study shows that cadmium and mercury toxicities (at high levels) will induce immediate hyperthyroidism.

Title: Thyrotoxicity of the chlorides of cadmium and mercury in rabbit.
Author: Ghosh N; Bhattacharya S
Address: Department of Zoology, Visva-Bharati University, Santiniketan, India.
Source: Biomed Environ Sci, 5(3):236-40 1992 Sep
Abstract: Exposure to heavy metals such as cadmium and mercury is of immediate environmental concern. The present study was aimed at establishing a direct relationship between heavy metal poisoning and thyroid dysfunction. Cadmium and mercury treatment at LD50 levels resulted in severe thyrotoxicosis in the rabbit. Within 24 h of intramuscular administration of cadmium chloride 15 mg.kg-1 body weight (bw) and mercury chloride 20 mg.kg-1 bw, thyroid peroxidase activity increased significantly over the control with a concomitant rise in the triiodothyronine (T3) titre. On the other hand, there was a remarkable fall in the thyroxine (T4) level, and the T3/T4 ratio was high as compared with the control. Evidence indicates that acute heavy metal lethality will induce immediate hyperthyroidism. It is suggested that T3-toxicosis may be produced by a preferential synthesis of T3 and/or preferential deiodination of T4 to T3. Measurement of T3 and T4 levels may thus be utilized as a reliable indicator of heavy metal lethality.

The following study examines the thyroidal functioning of inhabitants of a cadmium polluted river basin in Japan. Free T4 levels are found to be lower than normals but T3 levels are higher.

Title: [A study of thyroid hormone levels of inhabitants of the cadmium-polluted Kakehashi River basin]
Author: Nishijo M; Nakagawa H; Morikawa Y; Tabata M; Senma M; Miura K; Tsuritani I; Honda R; Kido T; Teranishi H; et al
Address: Department of Public Health, Kanazawa Medical University, Ishikawa, Japan.
Source: Nippon Eiseigaku Zasshi, 49(2):598-605 1994 Jun
Abstract: We compared thyroid hormone levels of inhabitants (19 men and 16 women) of the cadmium (Cd)-polluted Kakehashi River basin in Ishikawa Prefecture, with those of subjects (23 men and 47 women) living in a non-polluted area. In addition, we investigated the relationships between the thyroid hormone levels and indices of renal dysfunction induced by Cd exposure. The following results were obtained: 1) The free T4 level of females was significantly lower than that of controls. 2) The T3 level of inhabitants of both sexes was significantly higher than that of controls. 3) The level of free T4 among females became lower with the increases of urinary beta 2-microglobulin (beta 2-MG), urinary protein, urinary sugar, urinary amino acids and serum creatinine (Cr) levels, and with decreases of creatinine-clearance (CCr) and %TRP. 4) We could not find any relationship between the increase of T3 and the indices of renal dysfunction induced by Cd exposure in either sex.

The following study shows that cadmium decreases T3 by interfering with T4 to T3 conversion.

Environ Res 1987 Apr;42(2):400-5 s

Effect of cadmium on T4 outer ring monodeiodination by rat liver.

Yoshida K, Sugihira N, Suzuki M, Sakurada T, Saito S, Yoshinaga K, Saito H

The effect of cadmium on thyroxine (T4) outer ring monodeiodination was studied in vivo and in vitro in the rat liver. One microgram of T4 was incubated with rat liver homogenates in 50 mM Tris--HCl buffer, pH 7.4, with or without 0.5, 5, and 50 mM dithiothreitol (DTT) for 60 min in the presence of 10(-8) to 10(-3) M CdCl2, and the amount of 3,5,3'-triiodothyronine (T3) produced was determined by a specific radioimmunoassay. Subcutaneous injection of CdCl2, 1 mg/kg BW/day, 5 days a week for 10 weeks, to the rats resulted in a significant reduction in serum T3 concentration (by 37%) and hepatic T3 production from T4 (by 78 to 92%). In vitro addition of 1 microM to 1 mM CdCl2 to liver homogenates caused a concentration-dependent reduction in T3 generation. Without DTT a 50% reduction in the T4 to T3 converting activity was caused by 4 X 10(-6) M CdCl2. DTT (0.5 to 50 mM) partially restored T3 generation roughly in a concentration-dependent manner. These results indicate that cadmium has some effects on the metabolism of thyroid hormone.

The following study demonstrates the existence of a cadmium-binding protein (CdBP) in human thyroid tissue but not in dogs, pigs, and oxen. Cadmium accumulates in the thyroid, kidney, liver, and pancreas--all areas that seem to be involved in thyroid disease.

Toxicol Lett 1982 May;11(3-4):269-73

Cadmium-binding proteins in human organs.

Sato M, Takizawa Y

Cadmium-binding proteins (CdBPs) in the cytosol fractions from several organs of man orally exposed to cadmium (Cd) were examined by gel chromatography. In kidney and liver most of the cadmium (76-87%) in the cytosols was bound to metallothionein, and hepatic metallothionein contained zinc also at a similar level. The pancreas cytosol also contained a metallothionein-like CdBP, although its content was only one-tenth of the hepatic one. In the thyroid gland a prominent CdBP, eluting later than that of metallothionein, was observed; this CdBP was not detectable in normal dogs, pigs, and oxen. No CdBPs were observed in other organs including heart, muscle, genital organs, aorta, and bone. These results suggest that CdBPs participate in accumulation and distribution of cadmium in man, since organs containing CdBP such as kidney, liver, pancreas, and thyroid gland show a tendency to accumulate high levels of cadmium.

The following study indicates that cadmium may inhibit lipogenesis by binding with the thiol group (SH) of coenzyme A, thereby reducing the serum levels of free fatty acids and lipid peroxides. Keep in mind that all antithyroid drugs all have this thiol group and providing this may be their mode of action. Intriguingly, cadmium was found to have different effects in males and females in regard to the effects on fatty acids. This may be a possible mechanism to explain why females get thyroid diseases at a much higher rate than males. Also interesting is that cadmium by interfering with the action of the thiol group may be interfering with the metabolism of vitamin D and possibly the conversion of cholesterol into the steroid (sex) hormones. This may explain how cadmium increases osteoporosis, a phenomenon demonstrated by osteoporosis in older smokers, especially women.

Title: [Effect of cadmium on lipid components: relation of cadmium to thyroid hormone and growth hormone]
Author: Fujita D
Address: Department of Public Health, Hyogo College of Medicine, Nishinomiya.
Source: Nippon Eiseigaku Zasshi, 47(3):704-14 1992 Aug
Abstract: To clarify the relationship of cadmium (Cd), thyroid hormone (TH) and growth hormone (GH) to lipid components, 4-week-old SD rats were dosed orally with Cd (CdCl2) at a dose of 2.0 mg/kg body weight five times a week, orally with TH at a dose of 2.5 mg/kg body weight five times a week and subcutaneously with GH (somatotropin) at a dose of 1.0 IU/kg body weight three times a week, all for 4 weeks. As lipid components, the serum concentrations of triglycerides, free fatty acids, lipid peroxides and long-chain fatty acids were determined. We have devised a new method for determining the fatty acid composition in the femur using gas chromatography-mass spectrometry and made a simultaneous analysis of fatty acids, from myristic acid (C14:0) to cholesterol. The results of the present study led to the following conclusions. 1. Cd may inhibit lipogenesis by binding with SH of coenzyme A, thereby reducing the serum levels of free fatty acids and lipid peroxides. 2. When TH and Cd were administered in combination, the addition of Cd produced an inhibitory effect on lipid components, although TH given alone stimulated the lipid metabolism. Therefore, Cd and TH may have an interaction in lipid components. 3. When GH and Cd were administered in combination, Cd modulated the action of GH, which enhanced the effect of somatomedin on the lipid metabolism. The inhibitory effect of Cd on somatomedin activity via Zn was suggested. 4. A sex difference was found in the composition of fatty acids in blood. The males had higher proportions of palmitic acid (C16:0) and linoleic acid (C18:2), while the females had a higher proportion of arachidonic acid (C20:4). There was no sex difference in fatty acid composition in the femur. 5. It was confirmed that TH produced a peroxide of dehydrocholesterol, a precursor of vitamin D3, in the diaphysis of the femur in the increased metabolic state.

The following study indicates how cadmium enters the food chain. Cadmium waste from industrial production is disposed in the sewers and the sewage sludge is used for agricultural fertilizer. Also there is an indication that cadmium might be present in phosphate fertilizers since it is used in their manufacture. If this is true then virtually all non-organically grown foods are going to have higher than normal amounts of cadmium.

Title: Sources of cadmium in the environment.

Author: Hutton M
Source: Ecotoxicol Environ Saf, 7(1):9-24 1983 Feb
Abstract: This paper is concerned with quantifying the major sources of cadmium in the European Community and assessing the relative significance of such inputs to the environmental compartments, air, land, and water. The methodology involved identification of potential sources of cadmium, including natural processes, as well as those associated with human activities. This was followed by a review of any emission studies of these processes and subsequent estimation of an emission factor for each source. The emission factor was applied to the most recent production or consumption data for the process in question to obtain an estimate of the annual discharge. The steel industry and waste incineration, followed by volcanic action and zinc production, are estimated to account for the largest emissions of atmospheric cadmium in the region. Waste disposal results in the single largest input of cadmium to land; the quantity of cadmium associated with this source is greater than the total from the four other major sources--coal combustion, iron and steel production, phosphate fertilizer manufacture and use, and zinc production. The characterization of cadmium inputs to aquatic systems is incomplete but of the sources considered, the manufacture of cadmium-containing articles accounts for the largest discharge, followed by phosphate fertilizer manufacture and zinc production.

To me the following study is another indication that cadmium is a selenium antagonist. Since arsenic is just to the left of selenium in the Periodic Table and is known to be a selenium antagonist, it's not surprising that when arsenic and cadmium (also a selenium antagonist) are combined there is an increased combined effect of reducing selenium and glutathione.

The following study shows that while cadmium seems not to affect progesterone levels it does decrease estrogen (estradiol) levels. My suspicion is that cadmium accomplishes this by decreasing copper levels and that copper is essential for the conversion of progesterone to estrogen.

The following study indicates that cadmium causes emphysema, a disease characterized by extensive disruption of lung connective tissue, by inhibiting the production of connective tissue proteins (collagen).

Title: Cadmium inhibits proteoglycan and procollagen production by cultured human lung fibroblasts.
Author: Chambers RC; Laurent GJ; Westergren-Thorsson G
Address: Centre for Cardiopulmonary Biochemistry and Respiratory Medicine, University College Medical School, Rayne Institute, London, United Kingdom. R.Chambers@ucl.ac.uk
Source: Am J Respir Cell Mol Biol, 19(3):498-506 1998 Sep
Abstract: Chronic inhalation of cadmium at the workplace or in cigarette smoke is associated with emphysema, a disease characterized by extensive disruption of lung connective tissue. We have previously shown that cadmium, at noncytotoxic doses, inhibits fibroblast procollagen production in vitro, with maximal inhibitory effects of 69 +/- 6% (P < 0.01) at 30 µM cadmium chloride (CdCl2). In this paper we show that at similar doses, cadmium also inhibits proteoglycan synthesis, with values reduced by between 36 +/- 4% (P < 0.01) and 42 +/- 6% (P < 0.01) for proteoglycans secreted into the culture media and associated with the cell layer, respectively. The greatest inhibition was obtained for the major matrix-associated proteoglycans, versican, decorin, and the large heparan sulfate proteoglycans, with synthesis values reduced by between 60 and 70%. Biglycan and other heparan sulfate proteoglycans were also affected, with synthesis values reduced by between 25 and 45%. In contrast, total protein synthesis was unaffected. Furthermore, effects of cadmium at the protein level were mirrored by reduction in messenger RNA levels for alpha1(I) procollagen, versican, and decorin. These data support the hypothesis that cadmium may play an important role in the pathogenesis of emphysema associated with chronic inhalation of cadmium fumes by inhibiting the production of connective tissue proteins.

The following study indicates that copper protects cells from cadmium toxicity.

Title: Protective effect of copper against cadmium cytotoxicity on cultured vascular endothelial cells.
Author: Kaji T; Fujiwara Y; Koyanagi E; Yamamoto C; Mishima A; Sakamoto M; Kozuka H
Address: Department of Environmental Science, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan.
Source: Toxicol Lett, 63(1):13-20 1992 Oct
Abstract: We investigated the effect of copper on cadmium-induced cytotoxicity on vascular endothelial cells from bovine aorta in a culture system. Cytotoxicity was evaluated by the [3H]adenine release assay and the histological observation. After a 24-h incubation, cadmium exhibited a significant cytotoxicity on confluent cultures of endothelial cells in a dose-dependent manner, while copper only slightly did after a 24-h incubation. It was found that copper (5 microM) significantly decreased cadmium (1 and 2 microM) cytotoxicity; histologically, formation of de-endothelialized areas in the cell layer caused by cadmium was reduced by copper. The accumulation of cadmium in the cell layer was significantly decreased by copper; however, that of copper was unaffected by cadmium. It was therefore suggested that copper significantly protects cadmium-induced cytotoxicity on cultured endothelial cells primarily through decreasing the cellular cadmium accumulation.

The following study is significant because it shows that alcohol increases cadmium uptake into the body and have a combined stronger effect in decreasing copper and zinc levels. This demonstrates the danger of combined smoking and drinking in damaging the thyroid.

Title

Effect of ethanol on cadmium uptake and metabolism of zinc and copper in rats exposed to cadmium.
Author: Sharma G; Sandhir R; Nath R; Gill K
Address: Department of Biochemistry, Postgraduate Institute, Medical Education and Research, Chandigarh, India.
Source: J Nutr, 121(1):87-91 1991 Jan
Abstract: Effects of chronic administration of cadmium and ethanol, alone as well as in combination, on the uptake of cadmium and its interaction with other essential trace elements in various tissues of adult rats were investigated. Cadmium given in combination with ethanol led to a pronounced increase in cadmium absorption and accumulation in all the tissues studied relative to both non-exposed controls and rats treated with cadmium alone. Both cadmium and ethanol exhibited specific effects on copper and zinc levels of the tissues. These effects often were significantly altered when the animals were co-exposed to cadmium and ethanol. The results suggested that although both cadmium and ethanol individually pose a hazard to essential trace metal homeostasis of various organs, co-exposure can pose a major threat since animals exposed to ethanol absorb much more cadmium than their unexposed counterparts.

The following study suggests that the mechanism by which cadmium antagonizes zinc may be from its ability to substitute for zinc in the zinc finger DNA binding domain and this may be the way cadmium causes toxicity and cancer.

Title: Effect of replacement of "zinc finger zinc" on estrogen receptor DNA interactions.
Author: Predki PF; Sarkar B
Address: Department of Biochemistry Research, Hospital for Sick Children, Toronto, Ontario, Canada.
Source: J Biol Chem, 267(9):5842-6 1992 Mar 25
Abstract: Exposure of bovine estrogen receptor to the metal chelators EDTA and 1,10-phenanthroline results in a loss of nonspecific DNA binding, presumably because of the removal of "zinc finger zinc." Nonspecific DNA binding, as measured by a DNA-cellulose binding assay, can be restored by dialysis of the aporeceptor against buffer containing zinc, cadmium, and cobalt but not with buffer containing copper or nickel. More detailed studies were carried out using a bacterially expressed polypeptide encompassing the DNA binding domain of the human estrogen receptor. Apopolypeptide fails to bind DNA specifically, as measured by mobility shift assay using a consensus estrogen response element hexamer containing oligonucleotide, but DNA binding was restored by dialysis of the apopolypeptide against buffer containing zinc, cadmium, and cobalt but not with buffer containing copper or nickel. Dissociation constants of zinc- and cadmium-reconstituted polypeptide for the estrogen response element hexamer (66 and 48 nM, respectively) are virtually indistinguishable from native polypeptide (Kd = 48 nM) whereas cobalt-reconstituted polypeptide has a lower affinity (Kd = 720 nM). However, native, zinc-, cadmium-, and cobalt-reconstituted polypeptides gave identical results in a methylation interference assay. Competition experiments with zinc and copper or nickel suggest that copper and nickel are able to bind to zinc finger residues but do so nonproductively. The relative affinities copper greater than cadmium greater than zinc greater than cobalt greater than nickel for the polypeptide were determined by a zinc blot competition assay. The ability of cadmium and cobalt to substitute for zinc in the zinc fingers demonstrates a structural "flexibility in the DNA binding domain as each of these metals has slightly different ionic radii. On the other hand, subtle differences in DNA binding affinity and/or specificity could exist, which may not be detectable here. Also, the ability of metals to substitute for zinc in the DNA binding domain suggests that metal substitution in these zinc fingers in vivo may be of relevance to the toxicity and/or carcinogenicity of some of these metals.

The following study shows that cadmium damages the cells of the thyroid, reduces thyroglobulin producing cells, and decreases both T4 and T3.

The following study shows that cadmium decreases T3, probably by inhibiting hepatic 5'-monodeiodinase (5'D-I) activity, which is a selenium dependent function. Cadmium is a known selenium antagonist while vitamin E facilitates selenium metabolism. Vitamin E was shown to protect against cadmium toxicity and maintain 5'D-I activity and T3 levels. While the experimenters concluded that "the metal-induced inhibition in hepatic 5'D-I activity is mediated through LPO (lipid peroxidation)" my conclusion is that the cadmium inhibited 5'D-I activity by decreasing selenium. While vitamin E does decrease lipid peroxidation, it does this by facilitating selenium metabolism and selenium is the key metal in glutathione peroxidase which is a potent inhibitor of lipid peroxidation.

The following study shows that vitamin C (ascorbic acid, AA) can prevent the decrease in 5'D-I activity caused by cadmium and thereby maintain T3 levels, but it can't restore T4 levels.


The following study, while it has no abstract, indicates that testosterone reduces the cadmium induced inhibition of thyroid function. Other studies indicate that testosterone facilitates cadmium excretion from the body. This is another indication that there are sex differences in cadmium induced inhibition of thyroid function.


The significance of the following study is that in addition to showing that cadmium decreases both T4 and T3, cadmium prevents TSH from rising to correct the low T4 and T3 problem. This means that in our era when doctors test only TSH to determine thyroidal function, many people have undetected low thyroid function. This is a very important finding since we see so many people with problems of low energy and weight gain, but their doctors are telling them their thyroid function is normal. This one study demonstrates the extreme importance of testing T4 and T3 and not just TSH.

The following study might indicate that thyroid hormones are essential to repair the damage caused by cadmium. This mechanism might explain why ophthalmopathy increases in RAI treated humans.

Title: Cadmium-induced acute lung injury: compromised repair response following thyroidectomy.
Author: Palmer KC; Mari F; Malian MS
Source: Environ Res, 41(2):568-84 1986 Dec
Abstract: The role of thyroid hormone in the pulmonary repair process following cadmium chloride-induced acute injury, was assessed in the present study. Thyroidectomized (Thyx), male Sprague-Dawley rats were exposed by inhalation to cadmium chloride aerosol (CdCl2, 10 mg/m3). Rats were sacrificed 1 hr after [3H]thymidine (3H-T) injection at intervals up to 10 days after exposure. Thyroidectomy, followed by CdCl2, produced earlier and more severe acute injury in the form of alveolar hemorrhage edema and hyaline membrane formation, than CdCl2 alone. However, Type 2 cell hyperplasia was markedly reduced in this group of rats compared with CdCl2 controls. Uptake of 3H-T by Thyx-CdCl2 lung tissue was only 40% of that measured in CdCl2 controls. Autoradiographic studies indicated that Type 2 cell labeling was less than 66% of controls up to 3 days after exposure. Cells obtained by lung lavage of Thyx-CdCl2 rats were reduced in number up to 60% with respect to controls, during the first week after exposure. Additionally, the activities of lung antioxidant enzymes (glucose-6-phosphate dehydrogenase, superoxide dismutase, and glutathione peroxidase were significantly inhibited (45-55%) throughout the experiment in Thyx-CdCl2 animals compared with normal rats. In summary, thyroidectomy impairs the repair response in CdCl2 lung damage by enhancing Type 2 cell damage, reducing Type 2 cell proliferation, altering alveolar macrophage populations, and depressing antioxidant defense systems.

The following study demonstrates the presence of cadmium-binding proteins (CdBPs) present in humans in the kidney, liver, pancreas, and thyroid gland, offering evidence that could be interpreted that cadmium is an essential nutrient since the body has specific proteins to transport it.

Title

Cadmium-binding proteins in human organs.
Author: Sato M; Takizawa Y
Source: Toxicol Lett, 11(3-4):269-73 1982 May
Abstract: Cadmium-binding proteins (CdBPs) in the cytosol fractions from several organs of man orally exposed to cadmium (Cd) were examined by gel chromatography. In kidney and liver most of the cadmium (76-87%) in the cytosols was bound to metallothionein, and hepatic metallothionein contained zinc also at a similar level. The pancreas cytosol also contained a metallothionein-like CdBP, although its content was only one-tenth of the hepatic one. In the thyroid gland a prominent CdBP, eluting later than that of metallothionein, was observed; this CdBP was not detectable in normal dogs, pigs, and oxen. No CdBPs were observed in other organs including heart, muscle, genital organs, aorta, and bone. These results suggest that CdBPs participate in accumulation and distribution of cadmium in man, since organs containing CdBP such as kidney, liver, pancreas, and thyroid gland show a tendency to accumulate high levels of cadmium.


The following study shows that testosterone pretreatment protects certain species, but not all species, from cadmium toxicity. The method of protection is hypothesized to be increased production of metallothionein, a protein that transports metals including cadmium and zinc.

Title

Testosterone pretreatment mitigates cadmium toxicity in male C57 mice but not in C3H mice.
Author: Shimada H; Bare RM; Hochadel JF; Waalkes MP
Address: Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick Cancer Research and Development Center, MD 21702-1201, USA.
Source: Toxicology, 116(1-3):183-91 1997 Jan 15
Abstract: Previous work has indicated that testosterone pretreatment protects against cadmium-induced toxicity in male rats while other data indicate that pretreatment of mice with testosterone offers no such protection against cadmium. Since cadmium toxicity may vary widely with species and strain, we examined the effect of testosterone pretreatment on cadmium toxicity in two strains of mice, one that is sensitive (C3H) and one that is resistant (C57) to cadmium toxicity. A single sc injection of 20 micromol CdCl2/kg to C3H mice or 45 micromol CdCl2/kg to C57 mice proved very toxic, causing 50%, and 44% mortalities, respectively. However, when C57 mice were pretreated with testosterone (5 mg/kg, s.c., at - 48, - 24, and 0 h) prior to cadmium (45 micromol/kg), complete resistance to cadmium-induced lethality developed. Testosterone had no effect on cadmium-induced lethality in C3H mice. Testosterone prevented extensive hepatocellular damage caused by cadmium in C57 mice and also significantly reduced cadmium-induced elevations in serum lactate dehydrogenase (LDH) activity and blood urea nitrogen (BUN), which are indicators of hepatic and renal function, respectively. The toxicokinetics of cadmium were apparently not affected by testosterone pretreatment, as the distribution of cadmium to liver in either strain was unchanged by the steroid. Cadmium-induced metallothionein (MT) levels in liver and kidney of C57 mice were increased in testosterone-pretreated mice given the higher doses of metal but no such enhancement of MT synthesis occurred in C3H mice. This increase in MT may provide some level of protection against cadmium toxicity in the C57 mice. These results indicate that testosterone pretreatment prevents toxicity of cadmium in male C57 mice, possibly through enhancement of MT synthesis, but has no effect in male C3H mice.

Testosterone protects the body from cadmium toxicity. This study shows that cadmium in turn decreases testosterone. Since cadmium is a zinc antagonist and zinc is essential for the formation of testosterone, cadmium may decrease testosterone production by zinc reduction.

This effect suggests interesting hypotheses about why people smoke. Perhaps people smoke to reduce testosterone and become more relaxed, since testosterone is a known activity stimulant. Women might reduce their testosterone by smoking and "feel more feminine". Just speculation, of course.

Unfortunately, taking up smoking has serious long-term health consequences such as increased testicular cancer in men and increased thyroid disease in women.

Title

The effects of continuous testosterone exposure on spontaneous and cadmium-induced tumors in the male Fischer (F344/NCr) rat: loss of testicular response.
Author: Waalkes MP; Rehm S; Devor DE
Address: Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, Division of Basic Sciences, National Cancer Institute, Frederick Cancer Research and Development Center, Maryland 21702-1201, USA.
Source: Toxicol Appl Pharmacol, 142(1):40-6 1997 Jan
Abstract: In the rodent testes, cadmium induces severe necrosis followed by chronic degeneration. Cadmium is also an effective testicular tumorigen, and a single dose produces a high incidence of Leydig cell tumors. The mechanism of tumor formation is unknown, but pituitary feedback, i.e., increased luteinizing hormone (LH) production due to low circulating androgen, has been implicated in causation of proliferative lesions within degenerate, hypofunctioning testes. Thus, the effects of androgen replacement on the testicular toxicity of cadmium in Fischer (F344/NCr) rats was studied. Groups (n = 50) of 10-week-old rats either received testosterone implants that approximate normal circulating levels in castrated rats or were left untreated. After 2 weeks of stabilization, rats were given either 20 micromol CdCl2/kg, s.c., weekly for the next 5 weeks (total dose 100 micromol/kg) or saline for a total of four treatment groups (control, testosterone alone, testosterone + cadmium, or cadmium alone). Portions of each group were killed either 10 weeks after initiation of cadmium exposure (n = 10), for assessment of endocrine function, or over the next 2 years (n = 40), for assessment of testicular neoplastic lesions. At 10 weeks, cadmium reduced circulating testosterone in nonimplanted rats by nearly 80% and induced a marked weight loss of the testes (>70%) and sex accessory glands (reflected in a 50% reduction in prostate mass). Testosterone implantation restored circulating testosterone levels in cadmium-treated rats and prevented Cd-induced weight loss of the sex accessory glands but not of the testes. Over 2 years, cadmium alone induced a >84% incidence of Leydig cell neoplasia and a >97% incidence of chronic degeneration, both significant increases over control rates (60 and 0%, respectively). Testosterone implantation abolished both cadmium-induced and spontaneously occurring Leydig cell tumors but had no effect on cadmium-induced chronic testicular degeneration. Thus cadmium-induced hypofunction of the testes, and subsequent loss of circulating testosterone, appears to be a critical aspect in cadmium induction of tumors in the rat testes.

The following study demonstrates that estradiol (estrogen) causes a more rapid uptake of cadmium by the liver and also an enhanced induction of metallothionein (MT) in both the liver and kidney. This is very good evidence that women are going to have greater cadmium accumulation and this may be the mechanism by which women have a greater incidence of thyroid disease than men. The question remaining is why does estradiol increase cadmium accumulation? Is it just a by-product of metallothionein production? Increased metallothionein production would be beneficial for females because it increases the storage of trace elements such as zinc which are needed for pregnancy. Perhaps the problem is that our industrialized society has significantly increased concentrations of cadmium. Then estradiol causes the inadvertent accumulation of cadmium into female bodies because of this increased concentration in our environment.

In contrast to the prior study, these researchers conclude that estradiol increases the accumulation of cadmium without inducing the synthesis of metallothionein. However, they agree that estradiol does increase the accumulation of cadmium.

Title: Stimulation of cadmium uptake by estradiol in the kidney of male rats treated with cadmium.
Author: Nishiyama S; Onosaka S; Taguchi T; Konishi Y; Tanaka K; Kinebuchi H
Address: Department of Environmental and Occupational Health, Kochi Medical School, Japan.
Source: Biochem Pharmacol, 37(16):3091-6 1988 Aug 15
Abstract: The present study was carried out to analyze the sex differences in the retention of Cd in rats treated with a small amount of Cd, and its mechanisms. Cd and Zn concentrations in the kidney and liver of female rats treated with 28 nmol Cd or 1 nmole Zn were significantly higher than those in male rats. Pretreatment with estradiol (1.8 mumol/kg of b.w., twice a day, 6 consecutive days) increased the Cd and Zn concentrations in the kidney of male rats treated with Cd or Zn. Incubation of MDCK cells with 10(-5) M estradiol, 10(-5) M stilboestrol and 10(-5) M progesterone caused a significant increase in Cd uptake. These results suggest that endogenous female sex hormones may play a role in a higher concentration of Cd and Zn in the kidney of female rats than that in male rats. The basal level of metallothionein (MT) in the liver and kidney of control female rats was within the same range as that in the control male rats. Cd and Zn accumulations caused by pretreatment with estradiol in the kidney of male rats treated with Cd or Zn were so low (Cd: 38 ppb, Zn: 1.0 ppb) as to be probably unable to induce the synthesis of MT. An increase in the concentration of Cd in the cultured renal cells occurred 1 hr after treatment with estradiol and Cd. Pretreatment with estradiol alone also resulted in a modification of the concentration of Na and K, which cannot be bound to MT. Together, all of the above findings suggest that estradiol directly increases the accumulation of Cd into the renal cells without inducing the synthesis of MT.

The following study shows that in a population of women, cadmium concentrations increase with age and the cadmium/zinc ratio increases with age indicating that zinc does not increase in proportion to cadmium. This declining zinc/cadmium ratio could be an explanation for increased incidence of hypothyroidism with age.

Title: Cadmium and zinc concentrations in human placentas.
Author: Fiala J; Hrub´a D; R´ezl P
Address: Institute of Preventive Medicine, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
Source: Cent Eur J Public Health, 6(3):241-8 1998 Aug
Abstract: Cadmium and zinc levels in placentae of 688 women who delivered their children in two university hospitals in Brno and in the regional hospital in Znojmo during January-June 1992 were determined using AAS analytical method. Average value of zinc (54.6 micrograms/g) and cadmium (18.02 ng/g) concentrations found out in our file are in accord with those ones reported in literature. Individual differences in zinc contained in placentae occur uniformly. Very low concentrations prevail for cadmium; values exceeding 100 ng/g of dry basis are sporadic only. Zinc vs. cadmium concentrations values in placenta are mutually positively correlated [correlation coefficient (factor) r = +0.13, p < 0.001]. Cadmium content in placenta depends on mothers' age and it is significantly higher in older women. No changes in zinc contained in the placental tissue depending on mothers' age were found out. The mutual ratio of zinc vs. cadmium content in a placental tissue is significantly decreased in older mother (23.8 in older women, 41.2 in younger women, p < 0.01).

The following study clearly indicates that cadmium is associated with and probably causes bone demineralization, decreased bone density in women, and decreased height in men. People living downwind of zinc smelters face increased dangers because cadmium and zinc are found in the same ore. Since all industrialized areas have increased amounts of air-, water-, and food-borne cadmium, everyone is at risk for cadmium toxicity and resultant osteoporosis.

Title

Environmental exposure to cadmium, forearm bone density, and risk of fractures: prospective population study. Public Health and Environmental Exposure to Cadmium (PheeCad) Study Group.
Author: Staessen JA; Roels HA; Emelianov D; Kuznetsova T; Thijs L; Vangronsveld J; Fagard R
Address: The Hypertensie en Cardiovasculaire Revalidatie Eenheid, Departement Moleculair en Cardiovasculair Onderzoek, Katholieke Universiteit Leuven, Belgium. jan.staessen@med.kuleuven.ac.be
Source: Lancet, 353(9159):1140-4 1999 Apr 3
Abstract: BACKGROUND: Chronic low-level exposure to cadmium may promote calcium loss via urinary excretion. We undertook a prospective population study to investigate whether environmental exposure to cadmium lowers bone density and increases risk of fractures. METHODS: We measured urinary cadmium excretion, a biomarker of lifetime exposure, in people from ten districts of Belgium, of which six districts bordered on three zinc smelters. We also measured cadmium in soil and in vegetables from the districts, and collected data on incidence of fractures and height loss. Bone density was measured at the forearm just above the wrist by single photon absorptiometry, and calculated as the mean of six proximal and four distal scans. FINDINGS: Mean cadmium excretion at baseline was 8.7 nmol daily. Across the ten districts, mean cadmium concentration in soil ranged from 0.8 to 14.7 mg/kg, and from 0.1 to 4.0 mg/kg dry weight in vegetables. Median follow-up was 6.6 years. Mean forearm bone density in proximal and distal scans was 0.54 g/cm2 and 0.43 g/cm2 in men, and 0.44 g/cm2 and 0.34 g/cm2 in women. In postmenopausal women, a twofold increase in urinary cadmium correlated with 0.01 g/cm2 decrease in bone density (p<0.02). The relative risks associated with doubled urinary cadmium were 1.73 (95% CI 1.16-2.57; p=0.007) for fractures in women and 1.60 (0.94-2.72, p=0.08) for height loss in men. Cadmium excretion in districts near smelters was 22.8% higher (p=0.001) than in other districts, with fracture rates of 16.0 and 10.3 cases per 1000 person-years, respectively, and a population-attributable risk of 35.0%. INTERPRETATION: Even at a low degree of environmental exposure, cadmium may promote skeletal demineralisation, which may lead to increased bone fragility and raised risk of fractures.

The following study supports the hypothesis that cadmium toxicity effects are mediated by decreases in selenium and glutathione peroxidase (a selenium-based antioxidant). Also noted, and this may be very important, is that cadmium causes copper, zinc, and manganese to transfer out of the mitochondria of cells. Other evidence suggests that a copper deficiency in the mitochondria is a factor in the genesis of hyperthyroidism.

Title [Changes in trace elements contents of renal cells in cadmium poisoning]

Author: Long M; Zhao J; Wang S
Address: Department of Preventive Medicine, Guiyang Medical College, Guizhou.
Source: Chung Hua Yu Fang I Hsueh Tsa Chih, 32(2):73-5 1998 Mar
Abstract: OBJECTIVE: To understand the possible role of trace elements in renal damage caused by cadmium poisoning and its mechanism. METHODS: An experimental animal model with renal damage caused by cadmium poisoning was prepared, and trace elements contents in subcellular components in renal cells, lipid peroxidation reaction, renal function and its ultrastructural changes were determined. RESULTS: Uptake of cadmium could cause transfer of copper, zinc and manganese mainly distributed in the mitochondrion to cell nuclei and cytoplasm, and content of selenium and activity of glutathione-peroxidase (GSH-px) in cytosol declined and content of propandiolal increased. CONCLUSION: It suggests that changes in trace elements contents, especially in selenium content, during renal damage caused by cadmium poisoning, could correlate with the increase of lipid peroxidation, and abnormal subcellular distribution of trace elements was one of the important roles in renal damage caused by cadmium poisoning.

The following study demonstrates that fasting or interrupting the nutrient supply decreases the body's resistance to cadmium toxicity.

Title: Effects of fasting on cadmium toxicity, glutathione metabolism, and metallothionein synthesis in rats.
Author: Shimizu M; Morita S
Address: Department of Environmental Health, Osaka City Institute of Public Health and Environmental Sciences, Japan.
Source: Toxicol Appl Pharmacol, 103(1):28-39 1990 Mar 15
Abstract: Acute oral toxicity of Cd (as cadmium chloride) was enhanced in rats fasted 24 hr, as shown by a markedly decreased LD50. To examine the relationship among Cd toxicity, hepatic glutathione (GSH), and metallothionein (MT) during fasting, rats were administered 75 mg Cd/kg orally 24 hr after fasting and euthanized after a further 4 or 24 hr for various assays. Serum glutamic-pyruvic transaminase activity 24 hr after Cd treatment was higher in fasted rats than in fed rats. Both total GSH and nonprotein sulfhydryl (NPSH) concentrations in liver decreased to 50% of control levels after 28 hr of fasting and returned to 75% of control values by 48 hr. Total hepatic GSH concentration in fed rats decreased 4 and 24 hr after Cd treatment, whereas that in fasted rats remained unchanged at 4 hr and decreased significantly at 24 hr. Cd uptake by the liver (both concentration and content) 24 hr after Cd treatment was higher in fasted rats than in fed rats. Hepatic MT concentration was markedly increased by Cd treatment and higher in fasted rats than in fed rats. There was no relationship between Cd toxicity and hepatic thiobarbituric acid (TBA) value, an indicator of lipid peroxidation. Fasting had no effect on hepatic GSH peroxidase and GSH reductase activities. These enzymes probably are not involved in Cd toxicity. On histological examination, focal degenerative and necrotic changes were observed from the midlobular to the pericentral region in the livers of fed rats 24 hr after Cd treatment. These changes were enhanced by fasting, diffusing from the pericentral to the periportal region. Histochemical examination revealed a heterogeneous distribution of GSH in the livers of fed rats, with strong staining of GSH in the periportal region. This heterogeneous distribution of GSH in liver was not observed in fed rats 4 hr after Cd treatment or in fasted rats at 24 hr. The present results suggest that hepatic GSH plays an important role in protection against Cd toxicity before the onset of MT synthesis. Animals in bad condition, such as that resulting from interruption of nutrient supply, cannot be protected against Cd toxicity even if the hepatic MT level is high.

The following study indicates that vitamin C (ascorbic acid) protects against cadmium toxicity without inducing metallothionein production.

Title: Effect of L-ascorbic acid pretreatment on cadmium toxicity in the male Fischer (F344/NCr) rat.
Author: Shiraishi N; Uno H; Waalkes MP
Address: Inorganic Carcinogenesis Section, National Cancer Institute, Frederick Cancer Research and Development Center, MD 21702-1201.
Source: Toxicology, 85(2-3):85-100 1993 Dec 31
Abstract: Some studies have indicated that cadmium-induced lethality and selective injurious effects to specific tissues, such as testes or liver, can be prevented by pretreatment with the antioxidant L-ascorbic acid (ascorbic acid). However, the basis of this tolerance is unclear. We examined the effects of ascorbic acid pretreatment on cadmium toxicity in male Fischer (F344/NCr) rats. Cadmium treatment alone (25 mumol CdCl2/kg, s.c.) proved lethal, causing a 93% mortality within 72 h, but in rats pretreated with ascorbic acid (2 g/kg, s.c. 24, 12 and 1 h) cadmium-induced lethality was nearly prevented. Hepatic lesions, including hepatocellular necrosis, induced by cadmium were at least partially ameliorated by ascorbic acid pretreatment. Ascorbic acid pretreatment had no effect on cadmium-induced testicular lesions nor on cadmium content in testes, liver, kidney and urine. Ascorbic acid alone modestly increased hepatic metallothionein (MT), but not renal MT and had no effect on induction of hepatic or renal MT by cadmium. In contrast to liver and kidney, testicular cadmium-binding protein (TCBP) in rats exposed to cadmium alone decreased markedly. Moreover, the level of TCBP decreased unexpectedly in ascorbic acid pretreated rats as compared with control. These results indicate that ascorbic acid pretreatment decreases the toxicity of cadmium in the rat without markedly modifying its toxicokinetics or markedly stimulating MT synthesis.

The following two studies demonstrate the protective effect of selenium against cadmium toxicity.

Title: [The protective effect of simultaneous selenium administration on acute cadmium toxicity and metallothionein]
Author: Ohta H; Imamiya S; Yoshikawa H
Address: Department of Health Administration, School of Hygenic Sciences, Kitasato University.
Source: Sangyo Igaku, 30(6):451-8 1988 Nov
Abstract: The present study was conducted to elucidate the protective action of simultaneous selenium administration against acute cadmium toxicity. The remarkable testicular damages caused by cadmium, that is, hemorrhagic inflammation, atrophy and necrosis, were lessened by simultaneous selenium administration. Cadmium concentration in blood, especially in plasma, increased significantly during the early period after cadmium administration with selenium. Cadmium and selenium in plasma were found in the same fractions of high molecular weight reported by previous workers as the high molecular weight complex containing cadmium and selenium. Cadmium in testis was also noted in the high molecular weight fraction during the early period. However, cadmium in the high molecular weight fraction of plasma and testis were unstable and decreased rapidly by lapse in time. Cadmium concentration in liver was lower than that in the group administered cadmium alone during the increasing phase of plasma cadmium. However, in contrast with the decreased cadmium level in plasma, cadmium in liver and testis increased gradually. Cadmium increased in liver and testis were also found in the metallothionein fraction. In the testis protected from acute cadmium toxicity, the inhibitory effect of glutathione S-transferase activity by cadmium was not detectable and the activity was maintained at the level of the control (saline administered group). Moreover, the increased cadmium in the metallothionein fraction was related to the decrease of cadmium in the high molecular weight fraction of the testis homogenate. In addition, a positive correlation was observed between metallothionein concentration and glutathione S-transferase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Biometals 1999 Dec;12(4):353-9

The following study demonstrates the protective effect of zinc against the toxicity of cadmium in preembryos.

Title: Zinc amelioration of cadmium toxicity on preimplantation mouse zygotes in vitro.
Author: Yu HS; Chan ST
Address: Department of Zoology, University of Hong Kong.
Source: Teratology, 37(1):13-9 1988 Jan
Abstract: Zinc, at a concentration of 5 or 10 micrograms/ml medium, has been shown to protect mouse preembryos in vitro from the toxicity of cadmium at a concentration of 5 micrograms/ml medium after a simultaneous treatment of the ions from four-cell to morula or from morula to blastocyst for 24 hours. Such an amelioration indicates that cadmium toxicity is a result of the unique property of the cadmium ion and is not due to an alteration in the culture medium after the addition of an extra metallic ion. Zinc probably ameliorates cadmium-treated mouse preembryo by competing with cadmium for uptake or some other metabolic processes. In view of the well-documented competition between cadmium and zinc ions for binding sites in many other cell types, some macromolecules to which similar divalent metallic ions bind competitively may also exist in the mouse preembryo. This suggests that a protective mechanism dependent on the metal-metal interactions begins to operate in the mouse preembryo at a very early stage of differentiation before implantation.

Following is a summary the health problems caused by cadmium and techniques for the removal of cadmium from the body. Particularly important is the statement that cadmium has a half-life of over 10 years in the body.

Title

Cadmium therapeutic agents.
Author: Kelley C
Address: Department of Chemistry, Northern Arizona University, Flagstaff, AZ 86011-5698, USA.Colleen.Kelley@nau.edu
Source: Curr Pharm Des, 5(4):229-40 1999 Apr
Abstract: Pollution of the environment with toxic metals has increased dramatically since the beginning of the industrial revolution. Cadmium is of particular concern because it accumulates in the human body with a half-life exceeding 10 years and has been linked with a number of health problems including renal tubular dysfunction, pulmonary emphysema, significant kidney damage, and possibly osteoporosis. Moreover, in 1993 the International Agency for Research on Cancer (IARC) classified cadmium and compounds containing cadmium as human carcinogens. The field of cadmium intoxication therapy has seen increases in interest due to its poignant toxicity in both humans and animals. Preliminary attempts to combat acute cadmium poisoning included the use of the chelating agents ethylenediaminetetraacetic acid (EDTA) and British anti-Lewisite (BAL). This review will focus on the chemistry, biology, and effectiveness of cadmium intoxication therapy to date. The toxicokinetics of cadmium mammals will be discussed briefly to understand the extent and severity of overexposure. An overview of cadmium chelation therapy will be given with an emphasis on the measurable effectiveness of each and significant structure activity relationships. Cadmium intoxication therapy will be reviewed by their indicated routes of action: direct (chelation and antagonism), indirect (induction), and symptom alleviation. The methods by which cadmium therapeutics are evaluated (in vivo, in vitro) are to be discussed. An evaluation of the clinical potential for promising therapeutics will be given.

Here is a great study which shows that cadmium toxicity decreases blood levels of magnesium. We see that in Graves' disease there is evidence of cadmium toxicity and magnesium deficiency, manifested by increased heart rate, heart arrhythmias, and tremors. The connection fits with our observations.

Title: Contribution to interaction between magnesium and toxic metals: the effect of prolonged cadmium intoxication on magnesium metabolism in rabbits.
Author: Soldatovi´c D; Matovi´c V; Vujanovi´c D; Stojanovi´c Z
Address: Department of Toxicological Chemistry, Faculty of Pharmacy, University of Belgrade, Yugoslavia.
Source: Magnes Res, 11(4):283-8 1998 Dec
Abstract: The results obtained up to now indicate that increased intake of some heavy metals causes disorder of bioelements metabolism leading to their blood and organs decrease and higher elimination via the urine. As to lead and magnesium, our investigations indicated that the reaction is reversible and that increased intake of Mg eliminates Pb via urine. Some other findings suggest similar relations between Mg and certain heavy metals, thus pointing to significant role of Mg in toxicology of heavy metals and announcing a new chapter in the toxicology of metals entitled 'Mg in professional and ecotoxicology'. In this report we present the results of our investigations on the effect of Cd on Mg metabolism. The experiment was performed on rabbits given orally, every day, for 4 weeks 10 mg Cd/kg b.w. as aqueous solution of CdCl2. Magnesium content was determined in blood, urine, soft tissues and bones by the AAS method. Under the experimental conditions, Cd lead to statistically significant decrease of blood Mg (p < 0.001 after day 16) which was associated with increased Mg elimination via urine (p < 0.01). Statistically significant changes were not detected in the tissues, except in the liver where we found enhanced Mg content (p < 0.05), while its level in the muscles decreased (p < 0.01).

As the following study indicates, cadmium has been implicated in the formation of cataracts in chronic smokers. This study shows that in addition to cadmium there is an accumulation of iron in the lens. Vitamin E is shown to protect the lens by blocking iron accumulation rather than blocking cadmium accumulation.

Title: Cadmium and iron accumulation in rat lens after cigarette smoke exposure and the effect of vitamin E (alpha-tocopherol) treatment.
Author: Avunduk AM; Yardimci S; Avunduk MC; Kurnaz L
Address: Karadeniz Technical University, School of Medicine, Department of Ophthalmology, Trabzon, Turkey. avunduk@meds.ktu.edu.tr
Source: Curr Eye Res, 18(6):403-7 1999 Jun
Abstract: PURPOSE: Cadmium accumulation in the lens has been implicated in cataractogenesis of chronic smokers. This study was planned to evaluate whether or not in vivo cigarette smoke exposure causes cadmium accumulation in rat lens, and possible protective effect and mechanism of alpha-tocopherol (vitamin E) treatment on cataractogenesis. METHODS: 28 male Wistar rats were randomly divided into four equal groups. Group 3 and 4 rats were exposed to cigarette smoke over ninety consecutive days, and Group 1 and 2 rats were treated in a similar fashion but exposed only to room air. Additionally, vitamin E was given to Group 2 and 4 rats. RESULTS: Significantly higher iron levels were observed in the lenses of Group 3 rats compared to other groups. With respect to cadmium, Group 3 and 4 rats had significantly higher levels compared to Group 1 and 2 rats. Although vitamin E treatment prevented iron accumulation in Group 4 rats, it had no effect on cadmium concentrations. Distinct histopathological changes observed in Group 3 rats were not present in Group 4 rats. CONCLUSION: Our study demonstrates that in vivo cigarette smoke exposure causes accumulation of cadmium in rat lens and IM vitamin E treatment does not affect this accumulation. The protective effect of vitamin E treatment on smoke exposed rat lens seems to be mediated by blockage of iron accumulation in the lens.

The following study shows that cadmium causes decreases of selenium and calcium in the eye and increases of iron and copper in the eye when selenium levels are low. Copper accumulation in the eye is characteristic of certain copper accumulation diseases like Wilson's disease and schizophrenia. Perhaps the copper accumulates there because of low selenium and selenium supplementation might help those individuals' ability to metabolize copper properly.

Title

Cadmium-induced alterations in ocular trace elements. Influence of dietary selenium and copper.
Author: Jamall IS; Roque H
Address: Department of Health Services, Toxic Substances Control Division, Technical Services, Sacramento, CA 94234-7320.
Source: Biol Trace Elem Res, 23():55-63 1989-90 Winter
Abstract: The present report demonstrates, for the first time, that feeding rats 50 ppm cadmium for just 7 wk results in detectable levels of cadmium in the eye of rats. Furthermore, these ocular cadmium concentrations affect significant alterations in the levels of the essential trace elements selenium, calcium, iron, and copper in the eye. Rats were fed a low-selenium (less than 0.02 ppm selenium), high-copper basal diet (50 ppm copper) supplemented with 0, 0.1, and 0.5 ppm selenium. The animals were either untreated or treated with 50 ppm cadmium admixed with their feed. Cadmium treatment resulted in significant reductions (up to 50%) in ocular selenium. Furthermore, rats fed the basal diet and given 100 ppm cadmium via their feed for 6 wk exhibited a 69% reduction in the activity of the selenoenzyme, glutathione peroxidase, in the eye. Cadmium treatment also resulted in reductions of up to 50% in ocular calcium, irrespective of dietary selenium supplementation. Iron levels were increased by 30% in rats fed the low-selenium diet and decreased by as much as 40% in rats fed the selenium-supplemented diets, compared to animals fed identical levels of selenium without cadmium. Ocular copper levels were significantly increased only in rats fed the low-selenium diet and treated with cadmium. Ocular zinc levels were not significantly affected by dietary cadmium or selenium.

In the following two studies, a connection is shown between cadmium toxicity and anosmia (loss of smell.) Brain accumulation of injected cadmium was determined by using radioactive cadmium. Cadmium was found to accumulate in the choroid plexus, pineal gland, area postrema, trigeminal ganglia, and olfactory bulb. In the eye, cadmium accumulates in the iris, ciliary body, and choroid. It is speculated that cadmium accumulation in the olfactory bulb is related to the loss of ability to smell (anosmia) seen in workers exposed to cadmium.

Interestingly, I have a friend who developed anosmia after a fasting and cleansing diet high in green juices. He lives far from pollution in the mountains and has never smoked tobacco. This may well be good evidence that cadmium toxicity can result from excessive intake of green leafy vegetables as well as from inhaling the smoke of another green leafy vegetable, tobacco. As a possible testament to the long half-life of cadmium, his anosmia lasted for two years.

Title: Autoradiographic localization of cadmium in the rat brain.
Author: Arvidson B
Source: Neurotoxicology, 7(3):89-96 1986 Fall
Abstract: Adult rats were injected intravenously with 109CdCl2 and the distribution of the isotope within the brain and neighboring nervous structures was subsequently studied by autoradiography. Cadmium accumulated in regions outside the blood-brain barrier such as the choroid plexus, pineal gland and area postrema, but did not appear in the brain parenchyma. Uptake of cadmium was observed in the trigeminal ganglia close to the nerve cells and in the olfactory bulbs. In addition, cadmium accumulated in the iris, ciliary body and choroid of the eye, but not in the optic nerves. The deposition of cadmium in the olfactory bulbs may be related to the anosmia reported in workers exposed to this metal. The possible harmful effects of accumulation of cadmium in restricted regions of the brain and adjacent nervous structures are discussed.

Int J Occup Med Environ Health 1998;11(3):235-45

Olfactory disorders induced by cadmium exposure: a clinical study.
Rydzewski B, Sulkowski W, Miarzynska M
ENT Department, F. Raszeja Municipal Hospital, Poznan, Poland.

Cadmium, as a highly toxic metal, found widely in industry and in the environment, is frequently included in the list of chemicals known to cause olfactory impairment. The purpose of this study was to evaluate olfaction in workers occupationally exposed to cadmium. The correlation between olfaction and concentrations of cadmium in urine, blood and in the workplace air as well as employment duration was examined in workers of the "CENTRA" S.A., an electrochemical plant in Poznan. In this plant cadmium-nickel batteries are produced, and there is chronic occupational exposure to cadmium in quantities exceeding maximum allowable concentration (MAC). Of the 73 workers who completed the evaluation, 53 people (72.7%) were smokers (10-40 cigarettes per day). The examinations revealed numerous cases of hyposmia (26.0%) and parosmia (17.8%) and one case of anosmia (1.4%). In the majority of people with olfactory disorders, hypertrophic changes in the nasal mucosa, dependent on the duration of employment, were identified. Statistically significant relationship between olfactory impairment and cadmium concentration in blood, urine and the workplace air was observed.

In the following study it is stated that, "Chronic inhalation of cadmium at the workplace or in cigarette smoke is associated with emphysema, a disease characterized by extensive disruption of lung connective tissue." The study shows that cadmium disrupts the production of collagen in the lungs by inhibiting fibroblast procollagen and proteoglycan production. Since collagen production is dependent upon copper and cadmium appears to be a direct antagonist of copper, copper depletion may be one of the mechanisms by which cadmium disrupts collagen production.

Am J Respir Cell Mol Biol 1998 Sep;19(3):498-506

Title: Cadmium inhibits proteoglycan and procollagen production by cultured human lung fibroblasts.

Chambers RC, Laurent GJ, Westergren-Thorsson G

Centre for Cardiopulmonary Biochemistry and Respiratory Medicine, University College Medical School, Rayne Institute, London, United Kingdom. R.Chambers@ucl.ac.uk

Chronic inhalation of cadmium at the workplace or in cigarette smoke is associated with emphysema, a disease characterized by extensive disruption of lung connective tissue. We have previously shown that cadmium, at noncytotoxic doses, inhibits fibroblast procollagen production in vitro, with maximal inhibitory effects of 69 +/- 6% (P < 0.01) at 30 &microM cadmium chloride (CdCl2). In this paper we show that at similar doses, cadmium also inhibits proteoglycan synthesis, with values reduced by between 36 +/- 4% (P < 0.01) and 42 +/- 6% (P < 0.01) for proteoglycans secreted into the culture media and associated with the cell layer, respectively. The greatest inhibition was obtained for the major matrix-associated proteoglycans, versican, decorin, and the large heparan sulfate proteoglycans, with synthesis values reduced by between 60 and 70%. Biglycan and other heparan sulfate proteoglycans were also affected, with synthesis values reduced by between 25 and 45%. In contrast, total protein synthesis was unaffected. Furthermore, effects of cadmium at the protein level were mirrored by reduction in messenger RNA levels for alpha1(I) procollagen, versican, and decorin. These data support the hypothesis that cadmium may play an important role in the pathogenesis of emphysema associated with chronic inhalation of cadmium fumes by inhibiting the production of connective tissue proteins.

PMID: 9730878, UI: 98400991

The following study is very significant because it explores the mechanisms of cadmium damage to lung cells and this may give us clues about how cadmium damages the thyroid. It is shown that the cadmium induced cell injury and lipid peroxidation are inhibited by catalase and superoxide dismutase (copper, zinc based), two antioxidant enzymes.

Furthermore it was determined that hydrogen peroxide is the main reactive oxygen species (ROS) involved. Hydrogen peroxide is the ROS which stimulates thyroid hormone production in the thyroid, so this gives us a direct connection from cadmium toxicity to increased thyroid hormone production as we see in Graves' Disease.

Also it is shown that cadmium causes mitochondrial damage by "significant dose-dependent changes of mitochondrial membrane potential." This is very significant because we have been looking for a mechanism by which the mitochondrial membrane's lithium-sodium counter transport system is disrupted. This is the mechanism which appears to transport copper into the mitochondria and may be the breakdown point where mitochondrial copper deficiency is created, thereby inducing diseases such as hyperthyroidism and manic depression. Remember that these are some long hypothetical leaps, but this could provide a testable theory of the core mechanisms involved in both hyperthyroidism and hypothyroidism. Cadmium may be the most significant toxic substance in the etiology of thyroid disease.

Cadmium-induced oxidative cellular damage in human fetal lung fibroblasts (MRC-5 cells).

Yang CF, Shen HM, Shen Y, Zhuang ZX, Ong CN

School of Public Health, Tongji Medical University, Wuhan, Peoples Republic of China.

Epidemiological evidence suggests that cadmium (Cd) exposure causes pulmonary damage such as emphysema and lung cancer. However, relatively little is known about the mechanisms involved in Cd pulmonary toxicity. In the present study, the effects of Cd exposure on human fetal lung fibroblasts (MRC-5 cells) were evaluated by determination of lipid peroxidation, intra-cellular production of reactive oxygen species (ROS), and changes of mitochondrial membrane potential. A time- and dose-dependent increase of both lactate dehydrogenase leakage and malondialdehyde formation was observed in Cd-treated cells. A close correlation between these two events suggests that lipid peroxidation may be one of the main pathways causing its cytotoxicity. It was also noted that Cd-induced cell injury and lipid peroxidation were inhibited by catalase and superoxide dismutase, two antioxidant enzymes. By using the fluorescent probe 2',7'-dichlorofluorescin diacetate, a significant increase of ROS production in Cd-treated MRC-5 cells was detected. The inhibition of dichlorofluorescein fluorescence by catalase, not superoxide dismutase, suggests that hydrogen peroxide is the main ROS involved. Moreover, the significant dose-dependent changes of mitochondrial membrane potential in Cd-treated MRC-5 cells, demonstrated by increased fluorescence of rhodamine 123 examined using a laser-scanning confocal microscope, also indicate the involvement of mitochondrial damage in Cd cytotoxicity. These findings provide in vitro evidence that Cd causes oxidative cellular damage in human fetal lung fibroblasts, which may be closely associated with the pulmonary toxicity of Cd.

PMID: 9294717, UI: 97440499

The following review states that

J Environ Pathol Toxicol Oncol 2001;20(2):77-88: Oxidative mechanisms in the toxicity of chromium and cadmium ions.

Stohs SJ, Bagchi D, Hassoun E, Bagchi M.

Department of Pharmaceutical and Administrative Sciences, Creighton University School of Pharmacy and Allied Health Professions, Omaha, NE 68178, USA.

Chromium and cadmium are widely used industrial chemicals. The toxicities associated with both metal ions are well known. However, less information is available concerning the mechanisms of toxicity. The results of in vitro and in vivo studies demonstrate that both cations induce an oxidative stress that results in oxidative deterioration of biological macromolecules. However, different mechanisms are involved in the production of oxidative stress by chromium and cadmium. Chromium undergoes redox cycling, while cadmium depletes glutathione and protein-bound sulfhydryl groups, resulting in enhanced production of reactive oxygen species such as superoxide ion, hydroxyl radicals, and hydrogen peroxide. These reactive oxygen species result in increased lipid peroxidation, enhanced excretion of urinary lipid metabolites, modulation of intracellular oxidized states, DNA damage, membrane damage, altered gene expression, and apoptosis. Enhanced production of nuclear factor-kappaB and activation of protein kinase C occur. Furthermore, the p53 tumor suppressor gene is involved in the cascade of events associated with the toxicities of these cations. In summary, the results clearly indicate that although different mechanisms lead to the production of reactive oxygen species by chromium and cadmium, similar subsequent mechanisms and types of oxidative tissue damage are involved in the overall toxicities.

The following study shows that cells protect themselves from cadmium toxicity by production metallothionein (MT), which is a thiol-rich protein (contains sulfur). We have seen that cadmium induces production of hydrogen peroxide and this chemical releases free radicals which increase thyroid hormone production. Now here is evidence that sulfur groups called thiols bind with cadmium to protect cells from cadmium induced damage. Antithyroid drugs such as Tapazole and PTU contain these thiols also.

Toxicology 1995 Apr 12;98(1-3):1-13

Title: Oxidant resistance of cadmium-adapted human lung fibroblasts.

Hart BA, Prabhu RM, Eneman JD, Durieux-Lu CC, Janssen AM, Borm PJ

University of Vermont College of Medicine, Department of Biochemistry, Burlington 05405, USA.

Metallothionein (MT) is a metal and thiol-rich protein readily induced by cadmium (Cd) exposure. In vitro experiments have demonstrated that MT is able to serve as a scavenger of hydroxyl radicals as well as superoxide anions, albeit to a lesser extent. The role of MT as a mediator in Cd induced oxidant resistance was investigated in a nontransformed human lung fibroblast cell line (IMR-90). Cells were passaged three times either in a Cd-containing medium (8.9 microM CdCl2) or in a medium which lacked Cd. Cellular MT content, as quantitated by a modification of the heme/109Cd binding assay, increased significantly with each passage in Cd. Immunocytochemistry studies revealed that all Cd-pretreated cells contained MT and that MT was localized in both cytoplasmic and nuclear compartments. Immunolabeling was more intense in some cells compared to others. Very slight immunolabeling was observed in physiological control cells, grown in the absence of Cd, and virtually no staining was observed in Cd-adapted or non-adapted cells when primary antibody was omitted. Using the xanthine/xanthine oxidase system as a generating system for active oxygen species, we found that the magnitude of cell injury for Cd-adapted and non-adapted fibroblasts was dependent upon oxidant concentration and duration of oxidant exposure. Cd-adapted fibroblasts, which were characterized by over-expression of MT, were significantly more resistant to injury by active oxygen species and also exhibited a greater ability to scavenge extracellular hydrogen peroxide compared to cells with no previous history of Cd exposure. Experiments with aminotriazole demonstrated that catalase was not a major contributor to the additional hydrogen peroxide scavenging capacity of Cd-adapted cells. The data presented in this report are consistent with involvement of MT in protecting critical cellular targets from reactive oxygen species.

PMID: 7740538, UI: 95259056

The following study shows that both zinc and selenium are key mineral antagonists to cadmium and protect cells from cadmium-induced toxicity. There is also a list of chemicals which protect cells from cadmium toxicity which includes dimethyl sulfoxide (DMSO). Ethanol was shown to not protect cells from cadmium toxicity and other studies have shown that ethanol increases cadmium accumulation into the body.

Cell Biol Toxicol 1994 Jun;10(3):191-205

Title: Antagonism of cadmium cytotoxicity by differentiation inducers.

Shopsis C

Department of Chemistry, Adelphi University, Garden City, New York 11530.

Studies on the antagonism of toxicity can provide information about toxic mechanisms and suggest chemotherapeutic strategies. A rapid cell growth assay that measures the effects of test agents on the accumulation of cell protein (Shopsis and Eng, Toxicol. Lett. 1985;26:1) has been applied to studies of the antagonism of the cytotoxicity of cadmium. Exposure of Balb/c mouse 3T3 cells to 15 mumol/L Cd2+ for 24 h or 7 mumol/L Cd2+ for 48 h caused a 50% decrease in total cell protein. Zn2+ and selenite ion, antagonists of Cd toxicity in vivo, antagonized Cd2+ cytotoxicity when added in micromolar concentrations at the initiation of exposure to Cd2+. A diverse group of chemicals that can induce differentiation in vitro in cultured erythroleukemia and other cells were also found to antagonize the cytotoxic effects of Cd2+ to 3T3 cells. Dimethyl sulfoxide (DMSO), hexamethylene bisacetamide, N,N-dimethyl formamide, N-methyl formamide, dimethyl acetamide, hypoxanthine, hemin, ouabain, and sodium butyrate, when added to cultures simultaneously with Cd2+, each antagonized Cd2+ toxicity. These agents were used at concentrations equal to or lower than the concentrations at which they induce cellular differentiation. Other cytotoxicity assays and morphological studies confirmed these observations. DMSO added as much as 6 h after the initiation of a 24-h exposure to Cd2+ still protected cells; conversely, pretreatment of cultures with butyrate or DMSO for 24 h followed by their removal did not confer protection against subsequent Cd2+ challenge. Ethanol and methanol (noninducers of differentiation) did not antagonize Cd2+ cytotoxicity, and differentiation-inducing agents did not protect the cells from Zn(2+)- or Hg(2+)-induced cytotoxicity. DMSO treatment does not induce an increase in the concentrations of metallothionein or glutathione in these cells.

In the following study the authors speculate that cadmium toxicity is the result of cadmium's affinity for sulfhydryls and the cell protects itself from cadmium toxicity by increasing production of metallothionein, glutathione peroxidase (selenium compound), and sulfhydryls.

Toxicol Appl Pharmacol 1994 May;126(1):114-23

Title: Alterations in cytoskeletal organization and homeostasis of cellular thiols in cadmium-resistant cells.

Li W, Kagan HM, Chou IN

Department of Biochemistry, Boston University School of Medicine, Massachusetts 02118.

To understand further the mechanisms of cadmium toxicity, cytoskeletal organization and homeostasis of cellular thiols were examined in cadmium-resistant cells isolated from Swiss mouse 3T3 cells by incubation in graded concentrations of CdCl2 (Cd2+) in the culture medium. Cd(2+)-resistant cells displayed profound alterations in their cytoskeletal organization characterized by the appearance of many elongated, tadpole-shaped cells with a high density of microtubules (MT) and microfilaments (MF), with the former being mainly distributed along the long axis of the cell. Exposure of Cd(2+)-resistant cells to 50 microM Cd2+ for 16 hr did not cause apparent cytoskeletal perturbations, whereas treatment of parental cells with 5 microM Cd2+ for the same duration produced a severe loss of MT and smeared patches of MF. Thus, the cytoskeleton of Cd(2+)-resistant cells is markedly more preserved and protected against Cd2+ damage than that of their parental counterparts. Cd(2+)-resistant cells contained a higher basal level of protein sulfhydryls (PSH) in both the cytoskeletal and cytosolic fractions than the parental cells. Exposure to 50 microM Cd2+ further increased cellular PSH contents, reaching 192 and 215% of the basal levels for the cytoskeletal and cytosolic fractions, respectively. Although 5 microM Cd2+ exposure also elevated the amounts of PSH in parental cells, the "absolute" values were still below the corresponding basal levels in Cd(2+)-resistant cells. Furthermore, Cd(2+)-resistant cells also exhibited enhanced basal levels of metallothionein and cellular glutathione (GSH), amounting to 19- and 2.1-fold of the parental basal levels, respectively. Thus, the Cd(2+)-resistant cells produced larger quantities of both protein and nonprotein thiol-containing elements than the parental cells. Interestingly, exposure of Cd(2+)-resistant cells to 50 microM Cd2+ also further increased metallothionein and cellular GSH to 178 and 138% of the basal levels, respectively. Based on the affinity of Cd2+ for sulfhydryls as a mechanism of Cd2+ toxicity, we propose that the coordinately increased levels of metallothionein, GSH, and PSH in Cd(2+)-resistant cells would provide a mechanistic basis for the homeostasis of cellular thiols which may collectively contribute to the cytoskeletal preservation by protecting the cytoskeleton from Cd2+ insult.

The following study shows that transforming growth factor beta (TGF beta 1) induces a tolerance to cadmium in cultured endothelial cells.

Toxicology 1994 Mar 11;88(1-3):69-79

Transforming growth factor beta-induced tolerance to cadmium cytotoxicity in cultured vascular endothelial cells.

Kaji T, Ohkawara S, Yamamoto C, Sakamoto M, Kozuka H

Department of Environmental Science, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan.

We investigated whether or not transforming growth factor beta (TGF beta 1) affects the sensitivity to cadmium of bovine aortic endothelial cell in a culture system. Cadmium cytotoxicity was evaluated by [3H]adenine release assay. It was found that pretreatment with recombinant human TGF beta 1 (rhTGF beta 1) of the confluent cultures resulted in a reduction of cadmium cytotoxicity, suggesting that the cytokine induced a tolerance to cadmium in the cells. Such a tolerance was induced slightly by either recombinant human tumor necrosis factor alpha or recombinant human basic fibroblast growth factor but not by recombinant human interleukin-1 beta and -6; rhTGF beta 1 was the most potent inducer. rhTGF beta 1 failed to induce the tolerance in the presence of anti-rhTGF beta 1 antibody. Pretreatment with the antibody alone caused a significantly sensitive response to cadmium, suggesting that endogenous TGF beta 1 can physiologically contribute to protection against cadmium cytotoxicity in endothelial cells. The accumulation of cadmium was increased in the extracellular fraction but significantly decreased in the intracellular fraction of the cells by pretreatment with rhTGF beta 1. The cadmium content was significantly decreased in the particulate fraction but not in the cytosol fraction. Gel filtration chromatography of the cytosol fraction revealed that cadmium was bound to high-molecular-weight protein and metallothionein; both peaks were slightly increased by pretreatment with rhTGF beta 1. It was concluded that rhTGF beta 1 induces a tolerance to cadmium in cultured endothelial cells, caused by a decrease in the cadmium accumulation in the particulate fraction of the cells. TGF beta 1 may serve as a protective factor against cadmium cytotoxicity in vascular endothelial cells.

The following study shows that older cells are more sensitive to the toxic effects of cadmium because of reduced ability to produce metallothionein.

Exp Gerontol 1993 Jan-Feb;28(1):17-38

Metallothionein expression and stress responses in aging human diploid fibroblasts.

Luce MC, Schyberg JP, Bunn CL

Department of Biology, University of South Carolina, Columbia 29208.

Metallothioneins (MTs) are low molecular weight proteins with a high cysteine content that are inducible by heavy metals and by other conditions of environmental stress. This laboratory was investigated in human diploid fibroblasts the induction of MTs by cadmium and by dexamethasone, and the induction of heat shock proteins, as models for age-related changes in gene expression that reflect the ability of old cells to respond to environmental stress. Old cells were more sensitive to the toxic effects of CdCl2 in the concentration range 100-175 microM. Analysis of 35S-cysteine-labelled cell extracts by polyacrylamide gel electrophoresis and fluorography showed that in the absence of any inducer, old cells have a 3.7-fold increase over young cells in the basal level of MT. The rate and extent of induction of MT by CdCl2 was reduced in old cells: Exposure of old cells to 100 microM CdCl2 for 18 h resulted in MT levels about 33% of the amount in young cells. Northern blot analysis showed that the changes in MT protein levels occurred in parallel with changes in mRNA levels, which implicates transcriptional control as the origin of these aging changes. These young/old differences in MT synthesis were maintained in density-arrested cultures, indicating that the aging changes were not due to differences in the cell cycle status of these cell populations. The rate and extent of induction of a 68-kDa heat shock protein were also reduced in old cells, which showed an increase in basal, uninduced level of this protein similar to MT. In contrast, old cells retained the ability to synthesize MTs in response to dexamethasone at a rate similar to that in young cells.

The following study elaborates how cells develop cadmium resistance.

Life Sci 1999;65(14):PL177-82

Reduced uptake and enhanced release of cadmium in cadmium-resistant metallothionein null fibroblasts.

Yanagiya T, Imura N, Kondo Y, Himeno S

Department of Public Health and Molecular Toxicology, School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.

Metallothionein (MT) is known to play a predominant role in the protection of cells from cadmium (Cd) toxicity. To investigate other factors involved in Cd resistance, we established Cd-resistant cell lines from simian virus 40-transformed MT null fibroblasts. Cd-resistant MT null cells, Cd-rA7 and Cd-rB5, developed approximately 10-fold resistance to Cd compared to parental cells, but showed no cross-resistance to Zn, Cu, Hg, Ni, As, cisplatin or H2O2. Accumulation of Cd in the resistant cells was 13-18% of that of parental cells after treatment with Cd for 24 h. A short-term experiment revealed that the rate of Cd incorporation into the Cd-resistant cells was suppressed, and the rate of Cd release was enhanced in the resistant cells compared with that of parental cells. These results indicate that the altered transport of Cd, slow uptake and rapid release, may confer resistance to Cd on the Cd-resistant cells established from MT null fibroblasts.

PMID: 10530804, UI: 99458387

The following study should be a concern to anyone reading this on a computer. Three novel compounds which are used in the manufacture of computers were tested for toxicity. These compounds may be inhaled by workers in the semiconductor industry or users of computers. While I believe that users of computers would have very little exposure, it would be good to find out how much.

The most toxic of the three tested was found to be cadmium telluride and presumably the toxicity is due to the cadmium. I consider it another example of how cadmium from industrial uses can get into our bodies and probably cause thyroid disruption.

Comparative pulmonary absorption, distribution, and toxicity of copper gallium diselenide, copper indium diselenide, and cadmium telluride in Sprague-Dawley rats.

Morgan DL, Shines CJ, Jeter SP, Blazka ME, Elwell MR, Wilson RE, Ward SM, Price HC, Moskowitz PD

National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.

Copper gallium diselenide (CGS), copper indium diselenide (CIS), and cadmium telluride (CdTe) are novel compounds used in the photovoltaic and semiconductor industries. This study was conducted to characterize the relative toxicities of these compounds and to evaluate the pulmonary absorption and distribution after intratracheal instillation. Female Sprague-Dawley rats were administered a single equimolar dose (70 mM) of CGS (21 mg/kg), CIS (24 mg/kg), CdTe (17 mg/kg), or saline by intratracheal instillation. Bronchoalveolar lavage fluid (BALF) protein, fibronectin, inflammatory cells, lung hydroxyproline, and tissue distribution were measured 1, 3, 7, 14, and 28 days after instillation. Relative lung weights were significantly increased in CIS- and CdTe-treated rats at most time points. Inflammatory lesions in the lungs consisting of an influx of macrophages, lymphocytes, and PMNs were most severe in CdTe-treated rats, intermediate in CIS-treated rats, and minimal in rats receiving CGS. Hyperplasia of alveolar type 2 cells was present in CIS- and CdTe-treated rats and was greatest in CdTe-treated rats. Pulmonary interstitial fibrosis was observed in CdTe-treated rats at all time points. All three compounds caused marked increases in total BALF cell numbers, with the greatest increase observed in CIS-treated rats. BALF protein, fibronectin, and lung hydroxyproline were significantly increased in all treated animals and were highest in CdTe-treated animals. There was no apparent pulmonary absorption or tissue distribution of CGS. Indium levels increased in extrapulmonary tissues of CIS-treated rats, although Cu and Se levels remained unchanged. CdTe was absorbed from the lung to a greater extent than CGS and CIS. Cd and Te levels decreased in the lung and increased in extrapulmonary tissues. Of these compounds CdTe presents the greatest potential health risk because it causes severe pulmonary inflammation and fibrosis and because it is readily absorbed from the lung may potentially cause extrapulmonary toxicity.

The following study helps give us an idea about how toxic cadmium is in relation to other metals with known or presumed biological function. Cadmium is three times more toxic than arsenic. However, if it could be shown that cadmium is an essential nutrient, as I suspect all of the other metals mentioned are, then it also can give us an idea about how much we might need of it in relation to the other minerals.

J Toxicol Environ Health 1990 May;30(1):23-31

Teratogenicity of metals to chick embryos.

Gilani SH, Alibhai Y

Department of Anatomy, New Jersey Medical School, Newark 07103.

The present study examines the effects of heavy metals on chick embryogenesis. The metals included were cadmium, arsenic, cobalt, copper, indium, iron, manganese, and molybdenum. Salts of each of the metals were dissolved in saline and injected into the air sacs on d 2 of incubation. Dose levels varied with the metal to be tested. Control eggs were injected with an equivalent volume of saline (0.1 ml/egg). On d 14, the live embryos were removed from the eggs and examined for gross malformations. From the LD50 values, the toxicity relationship between the metals is cadmium greater than arsenic greater than cobalt greater than copper greater than indium greater than molybdenum greater than manganese greater than iron. The LD50 values were 3, 9, 38, 58, 121, 333, 765, and 1185 micrograms/egg, respectively. The gross malformations observed were reduced body size, micromelia, twisted neck, hemorrhage, everted viscera, and microphthalmia. Arsenic and cobalt were observed to be more teratogenic than other metals. This study showed that the metals tested were both toxic and teratogenic to varying degrees in chick embryogenesis.

The following study shows that as cadmium blood levels increase, TSH increases and FT4 decreases. Another study with implications that cadmium causes thyroid disease.

Environ Health Perspect 1999 Oct;107(10):843-9

Exposure to polychlorinated biphenyls and levels of thyroid hormones in children.

Osius N, Karmaus W, Kruse H, Witten J

NORDIG Institute for Health Research and Prevention, Hamburg, Germany. NOsius@t-online.de

As part of an epidemiologic study on exposure to a toxic waste incineration plant we investigated whether blood concentrations of polychlorinated biphenyls (PCBs), lead, and cadmium, as well as concentration of mercury in 24-hr urine samples were associated with thyroid hormone status. As an indication of status, we determined levels of thyroid-stimulating hormone (TSH), free thyroxine (FT(4)), and free triiodothyronine (FT(3)) in children living in households where [less than/equal to] 10 cigarettes were smoked per day. Eight PCB congeners (PCBs 101, 118, 138, 153, 170, 180, 183, and 187) were measured in whole blood samples. Of these, seven congeners (PCB 101 was not detected in any sample) and the sum of all PCB congeners were analyzed as predictors for thyroid hormone status in separate linear regression models adjusted for potential confounders. In addition, the possible effects of cadmium, lead, and mercury on levels of thyroid hormones were examined. Blood concentrations and information on questionnaire data were available for 320 children 7-10 years of age. We found a statistically significant positive association between the mono-ortho congener PCB 118 and TSH as well as statistically significant negative relationships of PCBs 138, 153, 180, 183, and 187 to FT(3). There was no association for the PCB congeners and FT(4). Blood cadmium concentration was associated with increasing TSH and diminishing FT(4). Blood lead and urine concentration of mercury were of no importance to thyroid hormone levels. The results stress the need for future studies on the possible influences of PCB and cadmium exposure on thyroid hormones, particularly in children. These studies should also take neurologic development into account.

CADMIUM CHELATORS

The following study indicates that DMPA, but not DMSA or DMPS, may be an effective chelator for cadmium removal from the body.

Fundam Appl Toxicol 1990 Apr;14(3):598-607

Determination and metabolism of dithiol chelating agents. VII. Biliary excretion of dithiols and their interactions with cadmium and metallothionein.

Zheng W, Maiorino RM, Brendel K, Aposhian HV

Department of Pharmacology and Toxicology, University of Arizona, Tucson 85721.

N-(2,3-Dimercaptopropyl) phthalamidic acid (DMPA), meso-dimercaptosuccinic acid (DMSA), and 2,3-dimercapto-1-propanesulfonic acid (DMPS) are dithiol chelating agents with antidotal activity for lead, mercury, arsenic, and other heavy metals. The biliary excretion of these compounds was studied in male Sprague-Dawley rats. After iv administration of DMPA, 72% of the injected dose was recovered in the bile. Half of the recovered DMPA was in the unaltered form (parent compound) and the other half was in the altered form (parent compound recovered after chemical reduction by DTT). An altered, presumably disulfide, form of DMPS was found in the bile. Neither unaltered nor altered DMSA was detected in the bile. DMPA (0.10 mmol/kg), given to rats 3 days after exposure to Cd, elicited within 30 min a 20-fold increase in biliary Cd excretion. The increase of biliary Cd by DMPA was dose-related and not due to an increase of bile flow rate. DMSA and DMPS did not significantly affect the biliary excretion of Cd. Incubation of DMPA or DMSA with Cd-saturated metallothionein (MT) resulted in the removal of Cd from MT. DMPA was more active than DMSA in this respect. The evidence strongly supports the mechanism that the increase of biliary cadmium following DMPA administration is the result of DMPA entering cells and mobilizing and removing the cadmium from MT. The removal of cadmium from metallothionein by dithiol chelating agents provides another dimension to their mechanisms of action and may provide an important new tool for the study of cadmium as well as metallothionein.

The following study indicates that BAL is an effective chelator of cadmium.

J Toxicol Environ Health 1980 Mar;6(2):393-401

Biliary excretion of cadmium in rat. VI. Mobilization of cadmium from metallothionein by 2,3-dimercaptopropanol.

Cherian MG

Cadmium was preferentially bound to metallothionein in tissues 24 h after CdCl2 injection. Of a number of chelating agents examined, only 2,3-dimercapto-1-propanol (BAL) was effective in mobilizing Cd from metallothionein into bile. Structurally similar dithiols such as 1,3-dimercaptopropanol and 2,3-dimercapto-1-propanesulfonic acid were not effective. Diethylenetriamine pentaacetic acid increased only the urinary excretion of Cd. Biliary excretion of Cd increased with increasing dose of BAL, and there was a concurrent decrease in hepatic Cd levels without any increase in renal concentration. BAL was effective even 14 d after Cd injection. The form of Cd excreted in the bile after BAL injection in chronic exposure has not yet been characterized. Initial studies suggested that it was not metallothionein but was a low-molecular-weight Cd complex, probably with BAL.

The following study demonstrates the effectiveness of using alpha lipoic acid (a supplement available in a health food store and which I have used) in protecting the liver from cadmium toxicity.

Jpn J Med Sci Biol 1996 Apr;49(2):39-48

Relationship between glutathione and DL alpha-lipoic acid against cadmium-induced hepatotoxicity.

Sumathi R, Baskaran G, Varalakshmi P

Department of Medical Biochemistry, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, India.

Cadmium, a divalent metal toxicant, preferentially localizes in hepatocytes and causes liver injury. DL alpha-lipoic acid is a dithiol which is effective in rendering protection against cadmium-associated liver damage, by virtue of its two sulfhydryl moieties. Lipoate was administered to cadmium-exposed rats which were either prior administered with buthionine sulfoximine to deplete liver glutathione or not. During lipoate treatment, significant protection was rendered against cadmium toxicity even under glutathione-depleted experimental condition. This highlights the antioxidant property of lipoic acid and its efficacy in mitigating cadmium-associated liver assault even in the absence of glutathione synthesis.

FOOD SOURCES OF CADMIUM

The following study is important because it states that cadmium absorption is increased by co-administration of milk and in conjunction with iron deficiency. The author also states that mercury accumulation is increased by a factor of ten in suckling pigs and that milk increases the bioavailability of mercury. If the absorption of cadmium and mercury are increased significantly by milk, this is interesting because of the fact that the factor in milk that might cause this is estrogen.

We have seen that females accumulate cadmium and mercury at a much higher rate than males and it seems that estrogen is an accelerator of heavy metal (and maybe all metal) accumulation. Milk may also increase heavy metal accumulation by providing additional estrogen. It could be other factors in milk, but this hypothesis needs to be investigated.

The author states that cadmium toxicity can cause microcytic hypochromic anemia, a type of anemia where the red blood cells are both smaller and have less hemoglobin. We have seen that anemia is highly associated with thyroid disease.

Z Ernahrungswiss 1990 Mar;29(1):54-73

Title: The toxicological estimation of the heavy metal content (Cd, Hg, Pb) in food for infants and small children

[Article in German]

Schumann K

Walther-Straub-Institut fur Pharmakologie und Toxikologie der Ludwig-Maximilians-Universitat, Munchen, FRG.

There are differences between young and adult organisms regarding toxokinetic aspects and clinical manifestations of heavy metal intoxications. Chronically, toxic Cd intake causes a microcytotic hypochromic anemia in young rats at lower exposure levels and after shorter exposure periods than in adult animals. Cd absorption is increased by co-administration of milk and in conjunction with iron deficiency. After long exposure periods toxic Cd concentrations accumulate in the kidney cortex; this process starts very early in life. In 3-year-old children Cd concentrations in the kidney can reach up to one-third of those found in adults. Hg++ and methyl-Hg can cause Hg encephalopathia, and frequently cause mental retardation in adults. Correspondingly, Hg++ accumulation in the brains of suckling rats is approx. 10 times higher than in grown animals. Milk increases the bioavailability of Hg++. In suckling rats Hg is bound to a greater extent to ligands in the erythrocytes. Methyl-Hg concentrations in breast milk reach 5% of those in maternal plasma and that is a severe hazard for breastfed children of exposed mothers. Toxic Pb concentrations can lead to Pb encephalopathia. A high percentage of surviving children have seizures and show signs of mental retardation. Anemia and reduced intelligence scores were recently observed in children after exposure to very low levels of Pb. Pb absorption is increased in children and after co-administration of milk. There are no definite proofs for carcinogenesis or mutagenesis after oral exposure to Cd, Hg, and Pb in man. Heavy metal concentrations were found in the same order of magnitude in commercial infant formulas and in breast milk. When infant formulas are reconstituted with contaminated tap water, however, Pb and Cd concentrations can be much higher. The average heavy metal uptake from such diets exceeds the provisional tolerable weekly intake levels set by the WHO for adults, calculated on the basis of an average food intake and a downscaled body weight. These considerations do not even provide for differences in absorption and distribution or for the increased sensitivity of children to heavy metal exposure. However, dilution effects for essential heavy metals were observed in fast-growing young children; this effect might be extrapolated to toxic metals. These theoretical considerations are compared with epidemiological evidence. A health statistic from Baltimore shows a decline of Pb intoxications in infants. This observation correlates with a simultaneous decline in exposure to Pb which was due, for example, to decreased use of lead dyes in house paints and the abolition of tin cans for infant food.

Toxicol Appl Pharmacol 2000 May 1;164(3):264-72: Uncoupling between bone formation and resorption in ovariectomized rats with chronic cadmium exposure.

Uriu K, Morimoto I, Kai K, Okazaki Y, Okada Y, Qie YL, Okimoto N, Kaizu K, Nakamura T, Eto S

Kidney Center, First Department of Internal Medicine, Department of Orthopedic Surgery, University of Occupational and Environmental Health School of Medicine, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807, Japan.

[Medline record in process]

Osteoporosis, osteomalacia, and pathological fractures are characteristic features of Itai-Itai disease. The mechanisms of bone damage caused by cadmium (Cd) exposure have not been fully clarified. We investigated skeletal changes in ovariectomized rats with chronic Cd exposure, using bone histomorphometry and mechanical tests. Female Sprague-Dawley rats at the age of 8 weeks were ovariectomized. Eight weeks after ovariectomy, the rats were divided into two groups: Cd-OVX group (n = 15), ovariectomized rats given cadmium chloride (CdCl(2), 0.18 mg/rat) ip three times a week for 28 weeks; Cont-OVX group (n = 10), ovariectomized rats given distilled water alone for 28 weeks. Cd-OVX rats had a significant increase in serum concentration of intact osteocalcine and showed numerical but not significant increase in urinary excretion of deoxypyridinoline despite a significant decrease in glomerular filtration rate to 40% of the value in Cont-OVX rats. Bone mineral content (BMC) and density were significantly decreased in both the lumbar vertebral body and femur of Cd-OVX rats. Ultimate compressive load in the lumbar body and bending load in the midfemur were significantly lower in Cd-OVX rats than in Cont-OVX rats but the differences were not demonstrated when the values were corrected for BMC. Structural moduli in the lumbar vertebral body and the midfemur were not different between the two groups. Cd-OVX rats showed significant decreases in the trabecular bone volume and trabecular number with increased values in the indices of bone formation and resorption in the lumbar vertebral body cancellous bone in comparison with Cont-OVX rats. In the midfemur, Cd-OVX rats had significantly smaller cortical bone area than Cont-OVX rats but the moment of inertia was identical between the two groups. The indices of bone formation and resorption at endocortical surface of the midfemur were significantly increased in Cd-OVX rats over those in Cont-OVX rats, whereas the indices of bone formation at the periosteal surface were not different between the two groups. These data suggested that chronic Cd exposure exacerbated the uncoupling between bone formation and resorption in ovariectomized rats, which resulted in the osteopenia, structural changes of the bone, and decreased mechanical strength in ovariectomized rats with chronic Cd exposure. Copyright 2000 Academic Press.

The following study makes me wonder if the ear ringing experienced in thyroid disease is related to cadmium toxicity.

Hear Res 1999 Mar;129(1-2):61-70: The effect of combined administration of cadmium and furosemide on auditory function in the rat.

Whitworth CA, Hudson TE, Rybak LP

Southern Illinois University School of Medicine, Department of Surgery, Springfield 62794-1221, USA.

A number of heavy metals have been associated with toxic effects to the peripheral or central auditory system. These include lead, arsenic, mercury, platinum and organic tin compounds. In addition, the ototoxic effects of some metals may be potentiated by other factors. However, the auditory effects of cadmium have not previously been reported. The purpose of the present study was to investigate the potential ototoxic effects of cadmium from an acute dosage, and its potentiation by furosemide. Auditory brainstem response (ABR) thresholds were measured in adult Sprague-Dawley rats. Rats received either cadmium chloride (5 mg/kg, i.p.) followed by saline (4 ml/kg, i.p.). cadmium chloride followed by furosemide (200 mg/kg, i.p.), or furosemide alone. Follow-up ABRs were carried out 7 days post-treatment and threshold changes were compared between each treatment group. No significant threshold change was seen for the cadmium chloride plus saline treated or the furosemide treated animals. However, significant threshold elevations were observed in animals receiving cadmium chloride plus furosemide. In addition, scanning electron microscopy revealed extensive hair cell loss in animals treated with cadmium chloride and furosemide. Although functional auditory changes were not seen after the administration of cadmium alone, the potentiation of threshold changes by furosemide suggests that cadmium may be ototoxic under certain conditions.

The following study shows that cadmium has a stronger effect in inducing selenium and vitamin E deficiencies than 11 other minerals.

Am J Vet Res 1982 May;43(5):851-7

Amounts of twelve elements required to induce selenium-vitamin E deficiency in ducklings.

Van Vleet JF

Mortality and myopathy of selenium-vitamin E (Se-E) deficiency was produced, in a concentration-dependent pattern, during a 4-week study of 750 ducklings fed a commercial duck starter mash that contained adequate amounts of Se and E, and supplemented with multiple amounts of Ag (50 to 3,000 mg/kg of feed, as acetate), Zn (3,000 to 6,000 mg/kg, as sulfate), Cd (10 to 500 mg/kg, as sulfate), Te (25-500 mg/kg, as tetrachloride), Co (100 to 1,000 mg/kg, as chloride), Cu (500 to 1,500 mg/kg, as sulfate), Hg (200 to 400 mg/kg, as chloride), and Sn (1,000 mg/kg, as chloride). Also, feeding supplements of Pb (500 mg/kg, as acetate), As (600 mg/kg, as sodium arsenilate), Fe (5,000 mg/kg, as sulfate), and S (5,000 mg/kg, as sodium sulfite) produced a low-to-medium frequency of lesions of Se-E deficiency. In ducklings with muscle lesions, the gizzard was most often affected (84.2%), followed in decreasing order by skeletal muscles (69.7%), intestine (34.9%), and heart (23.0%). The frequency of skeletal muscle lesions was high in birds fed Ag, and myocardial necrosis was frequent in ducklings fed Te and Hg. Ducklings affected with myopathy were reluctant to stand. Subcutaneous edema, with or without hemorrhages, and pale areas of myonecrosis in gizzard, skeletal muscles, intestine, and heart were seen at necropsy. Birds fed Te and Hg often had hydropericardium and hemorrhagic myocardial necrosis. Seemingly, addition of many elements to a Se-E adequate commercial diet will increase the requirement for Se-E. In our duckling model, minimal amounts shown to induce Se-E deficiency were 50 mg of Ag/kg, 3,000 mg of Zn/kg, 10 mg of Cd/kg, 25 mg of Te/kg, 1200 mg of Co/kg, 500 mg of Cu/kg, 200 mg of Hg/kg, 1,000 mg of Sn/kg, 500 mg of Pb/kg, 600 mg of As/kg, 5,000 mg of Fe/kg, and 5,000 mg of S/kg.

The following study shows that cadmium accumulates in the thyroid more than most other areas of the body. Perhaps this indicates that cadmium has a role in thyroid function.

Environ Res 2000 Nov;84(3):211-8

Mercury, selenium, and cadmium in human autopsy samples from idrija residents and mercury mine workers.

Falnoga I, Tusek-Znidaric M, Horvat M, Stegnar P

Department of Environmental Sciences, Jozef Stefan Institute, Jamova 39, Ljubljana, 1111, Slovenia.

[Medline record in process]

Total Hg and Se concentrations were determined in autopsy samples of retired Idrija mercury mine workers, Idrija residents living in a Hg-contami-nated environment, and a control group with no known Hg exposure from the environment. In selected samples we also checked the presence of MeHg. The highest Hg concentrations were found in endocrine glands and kidney cortex, regardless of the group. MeHg contributed only to a negligible degree to the total mercury concentrations in all analyzed samples. In the Hg-exposed groups the coaccumulation and retention of mercury and selenium was confirmed. Selenium coaccumulation with a Hg/Se molar ratio near 1 or higher was notable only in those tissue samples (thyroid, pituitary, kidney cortex, nucleus dentatus) where the mercury concentrations were >1 &mgr;g/g. After tissue separation of such samples the majority of these elements were found in the cell pellet. Because the general population is continuously exposed to Cd and possibly also to Pb from water, food, and/or air, in some samples the levels of these elements were also followed. In all examined control tissue samples the average values of Cd (kidney cortex, thyroid, hippocampus, cortex cerebellum, nucleus dentatus) and Pb (thyroid, hippocampus) exceeded the average values of Hg. Cd concentrations were the highest, particularly in kidney cortex and thyroids (&mgr;g/g), but no relationship between Cd and Se concentration was evident at the tissue level. Regarding the results in the control group, it is debatable which element is the more hazardous for the general population as concerns neurotoxicity. Copyright 2000 Academic Press.

J Environ Pathol Toxicol Oncol 2000;19(3):201-13: Oxidative mechanisms in the toxicity of chromium and cadmium ions.

Stohs SJ, Bagchi D, Hassoun E, Bagchi M

Department of Pharmaceutical Sciences, Creighton University School of Pharmacy and Allied Health Professions, Omaha, NE 68178, USA.

Chromium and cadmium are widely used industrial chemicals. The toxicities associated with both metal ions are well known. However, less information is available concerning the mechanisms of toxicity. The results of in vitro and in vivo studies demonstrate that both cations induce an oxidative stress that results in oxidative deterioration of biological macromolecules. However, different mechanisms are involved in the production of the oxidative stress by chromium and cadmium. Chromium undergoes redox cycling, while cadmium depletes glutathione and protein-bound sulfhydryl groups, resulting in enhanced production of reactive oxygen species such as superoxide ion, hydroxyl radicals, and hydrogen peroxide. These reactive oxygen species result in increased lipid peroxidation, enhanced excretion of urinary lipid metabolites, modulation of intracellular oxidized states, DNA damage, membrane damage, altered gene expression, and apoptosis. Enhanced production of nuclear factor-kappaB and activation of protein kinase C occur. Furthermore, the p53 tumor suppressor gene is involved in the cascade of events associated with the toxicities of these cations. In summary, the results clearly indicate that although different mechanisms lead to the production of reactive oxygen species by chromium and cadmium, similar subsequent mechanisms and types of oxidative tissue damage are involved in the overall toxicities.

The following study seems to indicate that cadmium causes iron deficiency anemia.

Jpn J Vet Res 2000 May;48(1):15-28

Experimental reproduction of itai-itai disease, a chronic cadmium poisoning of humans, in rats and monkeys.

Umemura T

Department of Veterinary Clinical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan. umemura@vetmed.hokudai.ac.jp

To establish a useful animal model of Itai-Itai disease (IID) of humans, we conducted the following experiments. Experiment 1: Toxic effects of Cd were compared between ovariectomized (OX) and non-OX rats after daily, intravenous injection of cadmium (Cd) chloride for 14 days. In this experiment, we demonstrated that OX rats were more susceptible to Cd-induced nephrotoxicity and hepatotoxicity than non-OX rats. Experiment 2: OX rats were injected with Cd at doses of 1.0 and 2.0 mg/kg, 5 days a week, for 13 weeks. The bone Cd content was gradually increased for 13 weeks in a dose-dependent manner. Calcium and phosphorus contents in the bone and serum levels of parathyroid hormone and osteocalcin were not significantly different between Cd-treated and control rats. Mild osteomalacic lesions in the cortical bones of the midshaft haversian canals as well as chronic nephropathy appeared in the rats of the 2.0 mg/kg group. Experiment 3: OX rats were treated with Cd at doses of 0.5 and 0.05 mg/kg for 70 weeks. The rats of the 0.05 mg/kg group showed slight anemia and mild degeneration of tubular epithelium after 50 weeks of treatment. In the 0.5 mg/kg group, the rats showed definite osteomalacia of bones and nephrosclerosis. The Cd concentration in the bones increased for the first 25 weeks, but was replaced gradually with iron at from 50 to 70 weeks of the administration period. Iron deficiency anemia appeared in the 0.5 mg/kg group at from 12 to 25 weeks, and changed to renal anemia after 50 weeks of administration. The anemia at 50 and 70 weeks was normocytic and normochromic, and serum erythropoietin levels were not elevated in response to the decrease of hemoglobin concentrations of red blood cells. Experiment 4: Ten, OX cynomolgus monkeys were given intravenous injections of 0, 1.0 or 2.5 mg/kg/day Cd, 2 or 3 days per week, for 13 to 15 months. Normocytic and normochromic anemia, renal lesions characterized by tubular atrophy and interstitial fibrosis (Cd nephropathy), and bone lesions characterized by an increase of osteoid and osteopenia (Cd osteopathy) were induced in the monkeys treated with Cd. These results demonstrated that chronic cadmium toxicosis similar to IID of humans was reproducible in rats and monkeys by repeated intravenous injection of Cd and that a disease entity closely resembling IID of humans could be induced in experimental animals by chronic Cd toxicosis without participation of malnutrition, vitamin D deficiency, impaired absorption at the intestinal mucosa or multiparous birth.

Med Hypotheses 1985 Jul;17(3):231-42: Zinc, cadmium, metallothionein, and progesterone: do they participate in the etiology of pregnancy induced hypertension?

Chisolm JC, Handorf CR.

Cadmium, a toxic heavy metal, has been incriminated in the etiology of essential hypertension. Zinc, an essential micronutrient necessary for growth, competes with cadmium for binding sites in biochemical processes; zinc deficiency states (i.e. pregnancy and low protein diet) might expose an individual to increased risk of cadmium toxicity. The increased sensitivity to cadmium during pregnancy could also be related to the effect of progesterone on zinc and cadmium metabolism through the actions of metallothionein (MT). MT is a low molecular weight protein believed to function in cadmium detoxification. Several studies in lab animals have documented a late gestation drop of maternal MT levels. This was thought to be due to rising progesterone levels. If there is also a late gestation drop in human maternal MT, then the propensity toward maternal cadmium toxicity would be enhanced. Therefore, we propose that when a zinc deficient woman becomes pregnant and is exposed to both the nutritional demands of the fetus and to the influence of progesterone, she will be likely to develop the manifestations of cadmium toxicity (i.e. hypertension, proteinuria, edema, etc.).

Title: Cadmium inhibits proteoglycan and procollagen production by cultured human lung fibroblasts.

Chambers RC, Laurent GJ, Westergren-Thorsson G

Cadmium-induced oxidative cellular damage in human fetal lung fibroblasts (MRC-5 cells).

Yang CF, Shen HM, Shen Y, Zhuang ZX, Ong CN

Title: Oxidant resistance of cadmium-adapted human lung fibroblasts.

Hart BA, Prabhu RM, Eneman JD, Durieux-Lu CC, Janssen AM, Borm PJ

Title: Antagonism of cadmium cytotoxicity by differentiation inducers.

Shopsis C

Title: Alterations in cytoskeletal organization and homeostasis of cellular thiols in cadmium-resistant cells.

Li W, Kagan HM, Chou IN

Transforming growth factor beta-induced tolerance to cadmium cytotoxicity in cultured vascular endothelial cells.

Kaji T, Ohkawara S, Yamamoto C, Sakamoto M, Kozuka H

Metallothionein expression and stress responses in aging human diploid fibroblasts.

Luce MC, Schyberg JP, Bunn CL

Reduced uptake and enhanced release of cadmium in cadmium-resistant metallothionein null fibroblasts.

Yanagiya T, Imura N, Kondo Y, Himeno S

Comparative pulmonary absorption, distribution, and toxicity of copper gallium diselenide, copper indium diselenide, and cadmium telluride in Sprague-Dawley rats.

Morgan DL, Shines CJ, Jeter SP, Blazka ME, Elwell MR, Wilson RE, Ward SM, Price HC, Moskowitz PD

Teratogenicity of metals to chick embryos.

Gilani SH, Alibhai Y

Exposure to polychlorinated biphenyls and levels of thyroid hormones in children.

Osius N, Karmaus W, Kruse H, Witten J

Determination and metabolism of dithiol chelating agents. VII. Biliary excretion of dithiols and their interactions with cadmium and metallothionein.

Zheng W, Maiorino RM, Brendel K, Aposhian HV

Biliary excretion of cadmium in rat. VI. Mobilization of cadmium from metallothionein by 2,3-dimercaptopropanol.

Cherian MG

Relationship between glutathione and DL alpha-lipoic acid against cadmium-induced hepatotoxicity.

Sumathi R, Baskaran G, Varalakshmi P

Accumulation of cadmium from wheat bran, sugar-beet fibre, carrots and cadmium chloride in the liver and kidneys of mice.

Lind Y, Engman J, Jorhem L, Glynn AW

Lead and cadmium contents in cereals and pulses in north-eastern China.

Zhang ZW, Watanabe T, Shimbo S, Higashikawa K, Ikeda M

Oral cadmium exposure of adults in Germany. 1: Cadmium content of foodstuffs and beverages.

Muller M, Anke M, Hartmann E, Illing-Gunther H

[The influence of culinary processing on content of lead and cadmium in carrots].

Wieczorek C, Kostrzewa M

Genetic susceptibility to age related macular degeneration.

Yates JR, Moore AT