Transplacental transfer of cadmium and fetal effects.
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Cadmium↗
Biomedical subjects
R A Goyer
Publications and source records attributed to R A Goyer.
Environmentally related diseases of the urinary tract.
Nephrotoxicity from exposure to therapeutic agents and chemicals in the environment and workplace results in a broad spectrum of clinical renal disease that may mimic disorders from other causes. Nephrotoxic agents may, in fact, be responsible for some fraction of renal disease of undetermined etiology. Specific diagnosis and treatment by removal from exposure to the toxic agent is more likely in the early phase of the disorder. Measurement and characterization of proteinuria provides the most sensitive and reliable method of early detection. Increased urinary excretion of serum proteins with molecular weight in excess of 50,000, such as albumin and transferrin, is an early indicator of glomerular injury. Low-molecular-weight proteinuria (beta 2-microglobulin or retinol-binding protein) and enzymuria, particularly excretion of NAG, are sensitive indicators of renal tubular cell injury. Tests that reflect hypersensitivity reactions are often indicative of immunologically mediated nephrotoxicity but are not specific for the kidney. Cancers of the kidney and urinary bladder appear to be increasing and are most common among the socially active and affluent. Susceptibility of the urinary tract to toxicity and carcinogenicity reflect contact of excreted toxins with the epithelial cells of nephrons and urinary bladder.
Aminoglycosides↗
Lead toxicity: from overt to subclinical to subtle health effects.
Although the toxicity of lead was recognized centuries ago, concern was restricted to overt symptoms: colic, encephalopathy, anemia, or renal disease. Two major reasons for lack of progress in restricting toxicity were that interest was limited to occupational exposures and there was lack of awareness of specific biochemical or metabolic effects. Identification of subclinical effects has been possible the last 15 or 20 years because of the development of sensitive measures to detect cognitive and behavioral changes that are not apparent clinically and because of methods to measure the reduced activity of heme enzymes. This progress was driven by basic and clinical research that resulted in a better understanding of cellular toxicology. The new awareness prompted the lowering of acceptable occupational exposures, as measured by blood lead from 80 to 40 to 60 micrograms/dL range, and the establishment of maximum recommended exposures in children to a blood lead level of 25 micrograms/dL. Lowering the lead content in gasoline has been accomplished by a nearly 50% decrease in average blood levels of persons in the United States (NHANES II data). Current research implicates lead as a contributing etiologic factor in a number of common diseases affecting large portions of the population such as subtle cognitive and neurological deficits, hypertension, congenital malformations, immunotoxicity, and deficits in growth and development. For each of these disorders there may be multiple etiologic factors; the scientific challenge is to develop sensitive methodology to detect the specific role of lead. Other potential subtle health effects include the influence of small amounts of lead on cell proliferation and lead as a cofactor in carcinogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Transplacental transport of lead.
Neurotoxicity is the major health effect from exposure to lead for infants and young children, and there is current concern regarding possible toxic effects of lead on the child while in utero. There is no placental-fetal barrier to lead transport. Maternal and fetal blood lead levels are nearly identical, so lead passes through the placenta unencumbered. Lead has been measured in the fetal brain as early as the end of the first trimester (13 weeks). There is a similar rate of increase in brain size and lead content throughout pregnancy in the fetus of mothers in the general population, so concentration of lead probably does not differ greatly during gestation unless exposure of the mother changes. Cell-specific sensitivity to the toxic effects of lead, however, may be greater the younger the fetus. Lead toxicity to the nervous system is characterized by edema or swelling of the brain due to altered permeability of capillary endothelial cells. Experimental studies suggest that immature endothelial cells forming the capillaries of the developing brain are less resistant to the effects of lead, permitting fluid and cations including lead to reach newly formed components of the brain, particularly astrocytes and neurons. Also, the ability of astrocytes and neurons to sequester lead in the form of lead protein complexes occurs only in the later stages of fetal development, permitting lead in maturing brain cells to interact with vital subcellular organelles, particularly mitochondria, which are the major cellular energy source. Intracellular lead also affects binding sites for calcium which, in turn, may affect numerous cell functions including neurotransmitter release.
Animals↗
Non-metallothionein-bound cadmium in the pathogenesis of cadmium nephrotoxicity in the rat.
Male rats were injected SC with 0.6 mg Cd/kg/day for 5 days per week for 2, 4, 6, and 8 weeks. Liver and kidney were examined morphologically and analyzed for metallothionein, cadmium, zinc, and copper. Morphologic changes were found in kidney but not in liver. The earliest ultrastructural change consisted of myelin figures in vacuoles in cytoplasm of proximal tubular lining cells reflecting degeneration of membranes. This change occurred after 4 weeks with 801 +/- 25 nmol/g (89.9 micrograms/g) total kidney cadmium or 390 nmol/g (43.7 micrograms/g) of cadmium not bound to metallothionein. Similar changes were observed after 6 weeks but after 8 weeks pathological changes consisted of focal cellular necrosis and interstitial fibrosis. Other ultrastructural changes included altered mitochondria and increased numbers of microbodies. Renal cadmium after 8 weeks exposure was 1827 +/- 48 nmol/g (215.3 +/- 5.8 micrograms/g) or 628 nmol/g (70.2 micrograms/g) of cadmium not bound to metallothionein. Total cadmium was higher in liver than in kidney but partitioning between bound and nonbound cadmium differed in the two organs. The fraction not bound to metallothionein increased with time of exposure in both liver and kidney. However, total cadmium in the liver did not exceed potentially available binding sites of metallothionein, whereas total cadmium did exceed potentially available binding sites of metallothionein in the kidney where pathologic changes occurred. The results indicated that degeneration of cellular membranes is an early cellular effect of cadmium exposure followed later by toxicity to organelles, cellular necrosis, and interstitial fibrosis. Cadmium-induced cellular toxicity is more directly related to the fraction of cadmium in the kidney that is not bound to metallothionein than is total cadmium per se.
Animals↗
Mechanisms of lead and cadmium nephrotoxicity.
Exposure to lead results in accumulation in proximal renal tubular lining cells in the form of morphologically discernible inclusion bodies which are lead-protein complexes. Acute nephrotoxicity consists of proximal tubular dysfunction and can be reversed by treatment with chelating agents. Chronic lead nephrotoxicity consists of interstitial fibrosis and progressive nephron loss, azotaemia and renal failure. Potential complications of lead nephropathy include gout and hypertension. Cadmium accumulates in renal tubular lining cells bound to metallothionein, a small protein containing 30% cystine. Metallothionein protects against nephrotoxicity by binding cadmium in a nontoxic form. Renal tubular dysfunction and chronic interstitial fibrosis occur when cadmium levels in the renal cortex exceed the critical concentration of about 200 micrograms/g. Recommendations are made for specific research needs.
Acute Kidney Injury↗
Effect of different levels and periods of lead exposure on tissue levels and excretion of lead, zinc, and calcium in the rat.
Influence of lead on tissue content and urinary excretion of lead, zinc, and calcium in rats was studied following various exposure periods. Weanling male rats were fed a trace mineral-sufficient diet with either 0, 200, 500, or 1000 ppm lead (as acetate) in drinking water for 4, 8, or 12 weeks. Blood lead ranged from 40 to over 100 micrograms/dl; kidney lead was highest at 4 weeks. Urinary lead excretion was highest at 4 weeks and declined with longer exposure. Urinary zinc excretion correlated positively with lead excretion at the lower excretion rates but plateaued at higher lead excretion rates. After 12 weeks exposure at each lead dose employed, decrease zinc concentration was observed in testes, bone, and brain. Plasma, erythrocyte, and kidney zinc were not affected, while pancreas and liver zinc were slightly elevated. Urine calcium was increased significantly only in rats exposed to 1000 ppm, possibly reflecting renal cell damage as determined by elevated renal calcium levels. These results indicate that lead dose is more important than exposure period for determining kidney lead levels, while urinary lead excretion rate is both dose and time dependent. Blood lead clearance values are relatively independent of dose and fall as exposure continues. Essential trace metal balance for zinc, especially, and to a lesser extent for calcium, is affected by the dose and length of chronic lead exposure.
Animals↗
Partitioning of renal zinc between metallothionein and ethylenediaminetetraacetic acid (EDTA) after treatment of rats with Ca(Na)2EDTA.
Calcium disodium edtate (EDTA) is a widely used chelator in the treatment of lead poisoning, although it also mobilizes other trace metals such as zinc. We have found that daily injection of 400 mg EDTA/kg body wt ip to rats results in an increase in the concentration of zinc (Zn) in the kidney when measured by atomic absorption spectroscopy. This increase is not associated with an induction of metallothionein (MT), a protein normally involved in the homeostasis of zinc. In fact, separation of kidney homogenate on a column of Sephadex G-75 demonstrates that virtually no Zn-MT remains in the kidney 24 hr after an EDTA injection, although after 3 days, Zn-MT levels appear to return to normal. Instead, increased renal Zn is found associated with residual EDTA. False high measurements of MT can be obtained from the Cd-saturation/hemoglobin assay due to the presence of residual EDTA in the kidney. Although nearly all of an injected dose of radiolabeled EDTA is rapidly excreted, 0.2 to 0.1% is retained in the kidney 1 day later; this is sufficient to account for the additional Zn. We propose that the small proportion of EDTA incorporated by pinocytosis into lysosomes in the renal cortical cells binds with all free Zn and subsequently depletes the MT concentration. Although the concentration of Zn measured in the kidney is elevated, there is actually less available for Zn-dependent activity.
Animals↗
Essential trace metal excretion from rats with lead exposure and during chelation therapy.
Urinary excretion of lead, zinc, calcium, magnesium, iron, copper, sodium, and potassium was measured in rats daily for 1 week after a 6-week exposure to 10,000 micrograms/ml lead in drinking water. Beginning on the third day, half of the lead-exposed and control rats were injected intraperitoneally with calcium disodium ethylenediaminetetraacetate (EDTA) daily for 3 days. Whole blood, plasma, and kidney metal concentrations were determined from samples obtained at the end of the experiment. Exposure to lead increased urinary excretion, not only of lead, but also of calcium, magnesium, zinc, copper, and iron. Excretion of sodium and potassium was not altered. Chelation therapy further increased excretion of lead, zinc, copper, and iron, but not magnesium. The increase in calcium excretion during chelation treatment (beyond that resulting from lead exposure per se) was accounted for by the Ca content of CaNa2-EDTA. EDTA treatment increased renal concentration of zinc but lowered renal concentration of lead, copper, and iron. These multimetal alterations may have implications for essential metal supplementation, particularly zinc, in persons being given chelation agents for excess lead exposure and in infants and children with low-level lead exposure not necessarily requiring chelation therapy.
Animals↗
Potential human health effects of acid rain: report of a workshop.
This report summarizes the potential impact of the acid precipitation phenomenon on human health. There are two major components to this phenomenon: the predepositional phase, during which there is direct human exposure to acidic substances from ambient air, and the post-depositional phase, in which the deposition of acid materials on water and soil results in the mobilization, transport, and even chemical transformation of toxic metals. Acidification increases bioconversion of mercury to methylmercury, which accumulates in fish, increasing the risk to toxicity in people who eat fish. Increase in water and soil content of lead and cadmium increases human exposure to these metals which become additive to other sources presently under regulatory control. The potential adverse health effects of increased human exposure to aluminum is not known at the present time.
Acids↗
Impact of effects of acid precipitation on toxicity of metals.
Acid precipitation may increase human exposure to several potentially toxic metals by increasing metal concentrations in major pathways to man, particularly food and water, and in some instances by enhancing the conversion of metal species to more toxic forms. Human exposures to methylmercury are almost entirely by way of consumption of fish and seafood. In some countries, intakes by this route may approach the levels that can give rise to adverse health effects for population groups with a high consumption of these food items. A possible increase in methylmercury concentrations in fish from lakes affected by acid precipitation may thus be of concern to selected population groups. Human exposures to lead reach levels that are near those associated with adverse health effects in certain sensitive segments of the general population in several countries. The possibility exists that increased exposures to lead may be caused by acid precipitation through a mobilization of lead from soils into crops. A route of exposure to lead that may possibly be influenced by acid precipitation is an increased deterioration of surface materials containing lead and a subsequent ingestion by small children. A similar situation with regard to uptake from food exists for cadmium (at least in some countries). Human metal exposures via drinking water may be increased by acid precipitation. Decreasing pH increases corrosiveness of water enhancing the mobilization of metal salts from soil; metallic compounds may be mobilized from minerals, which may eventually reach drinking water. Also, the dissolution of metals (Pb, Cd, Cu) from piping systems for drinking water by soft acidic waters of high corrosivity may increase metal concentrations in drinking water. Exposures have occasionally reached concentrations which are in the range where adverse health effects may be expected in otherwise healthy persons. Dissolution from piping systems can be prevented by neutralizing the water before distribution. Increased aluminum concentrations in water is a result mainly of the occurrence of Al in acidified natural waters and the use of Al chemicals in drinking water purification. If such water is used for dialysis in patients with chronic renal failure, it may give rise to cases of dialysis dementia and other disorders. A possible influence on health of persons with normal renal function (e.g., causing Alzheimer's disease) is uncertain and requires further investigation.(ABSTRACT TRUNCATED AT 400 WORDS)
Acids↗
Correlation of parameters of cadmium exposure with onset of cadmium-induced nephropathy in rats.
Rats were injected daily, five days/week, with 0.6 mg Cd/kg as CdCl2 for eight weeks. Groups of rats were sacrificed weekly. Urine, plasma and tissue cadmium levels, and morphology of renal cortex were studied. No abnormal effects were found until the fifth or sixth week when cadmium in kidney reached about 100 micrograms/g tissue. At this time, renal tubular lining cells showed an increase in lysosomes, microbodies and smooth endoplasmic reticulum and a low molecular weight cadmium-binding species was detectable in plasma. These changes were followed by the onset of glycosuria and proteinuria, accompanied by abnormal mitochondrial morphology. This progressed to cellular swelling and finally necrosis at the seventh and eighth weeks when cadmium concentration of the kidney reached about 200 micrograms/g of tissue. It is concluded that there are two phases in the development of cadmium induced nephropathy. Phase I is an adaptive phase characterized by some increase in smooth endoplasmic reticulum, microbodies and secondary lysosomes and the presence of metallothionein intracellularly in liver and kidney, but no detectable metallothionein in plasma and no increase in urinary cadmium. Phase II is a toxic phase characterized by detectable low molecular weight cadmium-binding species in plasma and evidence of renal tubular dysfunction followed by lethal injury to renal tubular lining cells.
Animals↗
Introduction and overview.
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Body Burden↗
Intracellular sites of toxic metals.
In summary, this brief overview of the cellular localization of toxic metals in renal tubular cells demonstrates a spectrum of mechanisms for the sequestration of the metals. Common features are affinity for a metal-binding protein, such as insoluble acidic nuclear proteins or the soluble, low-molecular weight metallothionein. Accumulation in lysosomes follows assimilation of metal containing protein by lysosomes or autophagocytosis of degenerating metal containing mitochondria. Currently available methods have not demonstrated the presence of metals in immune complex deposits in glomerular basement membrane and epithelial cells. The principal methods employed for the localization of metals within cells have been X-ray microanalysis of thin preparation of tissue, or direct analysis of subcellular fractions by atomic absorption spectroscopy or detection of radioactive metal.
Cadmium↗
Renal tumors in rats given trisodium nitrilotriacetic acid in drinking water for 2 years.
One hundred and ninety-six albino male rats [Crl/COBS CD (SD) BR] were given 1,000 ppm trisodium nitrilotriacetic acid (NTA) in drinking water for 2 years. One hundred and ninety-two control rats were given water without NTA. Animals that had a palpable mass or that appeared clinically ill were killed. All survivors were killed at 704 days. A significantly (P less than 0.05) higher proportion of the NTA-treated rats vs. 11.2% of the controls). The largest difference between the NTA-treated rats and the controls in tumor incidence was associated with renal adenoma. The NTA-treated group contained 25 rats with renal adenomas and 4 with renal adenocarcinomas. Only 5 control rats had renal adenomas; none had renal adenocarcinomas. No statistically significant differences were observed for any of the other tumor types among the NTA-treated rats and the controls. The overall incidence of renal tubular cell hyperplasia and nephritis was similar in the treated and control groups. However, a significantly greater number of NTA-treated rats had more severe grades of hyperplasia. Thus NTA when administered continuously in drinking water at a concentration of 1,000 ppm is tumorigenic to the rat kidney.
Acetates↗
Occupational lead exposure, nephropathy, and renal cancer.
A 48-year-old lead worker was found to have a cystic renal carcinoma during an evaluation of his occupational lead poisoning. Clinical studies showed elevated blood lead levels, impaired urinary concentrating ability, and reduced creatinine clearance. Histologic and electron microscopic studies showed this cystic tumor to be similar to renal carcinomas observed in animals with prolonged lead exposure. Lead content of the tumor was elevated (2.49 micrograms/gm) in comparison with adjacent renal tissue and with normal adult levels. In light of previous animal studies, this case adds increased evidence to the concern over the carcinogenic potential of prolonged lead exposure.
Adenocarcinoma↗
Formation of lead-induced inclusion bodies in primary rat kidney epithelial cell cultures: effect of actinomycin D and cycloheximide.
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Animals↗
Ascorbic acid and EDTA treatment of lead toxicity in rats.
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Aminolevulinic Acid↗