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Weanling male rats were fed a purified iron-adequate, a purified iron-deficient or a commercial diet for 12 weeks. At that time the rats were sacrificed, their hearts and livers were excised, and blood samples were taken. Heart and liver weights were recorded; organ tissue and serum samples were analyzed for Zn, Cu and Fe. Hemoglobin and hematocrit values were also obtained. The iron-deficient rats grew much more slowly than controls on the iron-adequate or commercial diets. The iron-deficient rats were severely anemic and had enlarged hearts (cardiomegaly). A histopathologic examination of the hearts of all animals showed that each heart of the iron-deficient rats had lesions characteristic of cardiomyopathy by dilatation, whereas none of the hearts of the iron-adequate group or the chow controls showed any lesions at all. The iron-deficient animals had only about 25% of the hepatic iron found in the iron-adequate animals but about 5 times the hepatic copper of the latter group or the chow controls. Heart iron of the iron-deficient group was 27% of the concentration found in hearts of the iron-adequate rats; heart copper was similar in all groups. Animals on the commercial stock diet accumulated significantly more iron in their hearts than did those on the purified iron-adequate diet but not in the livers. There was also a direct correlation of heart iron or heart zinc with log concentrations of dietary iron and consequently a direct correlation between heart iron and zinc concentrations.

Manganese, copper, iron, zinc, and specific organ weights (relative to body weight) of the heart, liver, and kidney were compared between a 65% diet-restricted group and an ad lib-fed control group of young male Sprague-Dawley rats. Elevated concentrations of Cu (12%) in the liver, and of Mn (12-26%) and Fe (17-69%) in all three organs, occurred in the diet-restricted group. Specific heart weight was unchanged despite the 40% difference in group body weights. Specific liver weight decreased 13% and specific kidney weight increased 13%.

A brief review of the literature indicates that nutritional deficiencies have been shown to increase the absorption and toxicity of orally ingested lead and cadmium. Results from recent studies indicates that low level oral ingestion of cadmium and lead perturbs the metabolism of zinc, copper, and iron and that these changes may be the earliest manifestation of the toxicity of lead and cadmium. The significance of these findings reveals itself in two ways: namely, that toxicologic investigations of lead and cadmium, whether experimental or clinical, must be based on a definitive consideration of the nutritional status of animals or people, and, secondly, that the preventive role of nutrition, especially that of trace metal intakes, must be taken seriously when establishing measures for reducing, eliminating, or combatting the toxic effects of widespread exposure to lead and cadmium in humans.

A patient who had hereditary tyrosinemia was observed during two illnesses to have characteristics of acute intermittent porphyria with associated hypertension. Metabolic studies revealed elevated levels of urinary aminolevulinic acid but normal levels of porphyrin metabolites associated with, and possibly explained by, decreased red blood cell activity of the zinc-dependent enzyme, aminolevulinic acid dehydratase. Zinc deficiency could not be directly associated with the diminished enzyme activity. The patient's hypertension appeared to be related to increased urinary excretion of catecholamines and to elevated renin activity in peripheral venous blood.

A lead-intoxicated patient with extremely high blood lead levels and unexpectedly mild symptoms was studied prior to and following treatment with calcium disodium edetate (ethylenediaminetetraacetic acid) and then prior to and following oral administration of zinc sulfate. During chelation therapy, erythrocyte (delta)-aminolevulinic acid dehydratase (ALAD) activity decreased as blood lead levels fell. Urinary excretion of zinc increased and was more than 3.5 times greater than that of lead. The ratio of blood lead to serum zinc was greatest (1.47) when ALAD activity was lowest. Oral administration of zinc sulfate following chelation therapy resulted in a significant increase in mean ALAD activity. In vitro additions of zinc chloride to the patient's erythrocytes resulted in reactivation of ALAD activity. These studies suggest that zinc is an important element in the ALAD system in man. Zinc may play a protective role in lead toxicity, and zinc supplementation may be a useful adjunct to chelation therapy for lead toxicity.

Lead-induced anemia in rats, which is of a microcytic, hypochromic type, has been shown to be a result of an interference with the metabolism of copper and iron. In this complex interaction, copper may be the target upon which ingested lead has its antagonistic effect on hematopoiesis. The depressions in hematocrit and hemoglobin levels resulting from exposure to lead may occur secondarily to the effects of a lead-induced copper deficiency on iron mobilization and utilization. The metabolic fault induced by lead is seen in a reduction of serum iron, elevation of serum iron binding capacity, and increase in liver iron, all manifestations of systemic effects related to an interference with copper metabolism. These results relate many of the characteristics of the lead-induced anemia to those found in the copper-deficiency anemia.

Rats were fed a purified egg white-based diet containing 5 ppm Cu and 2, 14, or 57 ppm Zn. Zinc and copper balances were determined for eight consecutive weekly trial periods. The zinc-deficient group almost ceased to gain weight and was in slightly negative zinc balance. Groups of rats fed 14 and 57 ppm Zn gained weight at equal rates. These groups were in strongly positive zinc balance for four weeks; thereafter, they fed 57 ppm Zn retained about two times as much zinc as did the group fed the diet containing 14 ppm Zn. All groups were in null or slightly negative copper balance throughout the trial. These results suggest that zinc accumulation may be homeostatically controlled to a level in excess of that needed for maximum growth.

Both dietary iron and copper were inversely related to lead absorption as indicated by erythrocyte and kidney lead levels, dietary iron having the greatest effect. Kidney copper values were depressed when dietary iron was low, a condition which was worsened by lead. Lead tended to lower heart cytochrome c oxidase especially when dietary copper was low, but also when dietary copper and zinc were high. Lead interfered with hematopoiesis when dietary copper and/or iron were low, the effect being expecially severe when both essential nutrients were low. These results show the importance of copper and iron nutriture and metabolism as factors which reduce lead toxicity, and emphasize the necessity of considering nutritional status in evaluating lead toxicity.

Seven para-substituted [phenylglyoxal bis(4-methyl-3-thiosemicarbazone)]copper (II) chelates (12-18) have been designed, synthesized, and tested for their ability to inhibit the respiration of rat liver slices as a normal cell model and Ehrlich ascites cells as a tumor cell model. Relationships between chemical structure and respiratory inhibition are described on a quantitative basis using substituent contants (pi, Es, and sigmap) by computerized multiparameter regression analyses. The correlations indicate that changes in Es have the largest effect on liver slice toxicity of chelates while pi and sigmap account for most of the variation in toxicity to ascites cells. A comparative analysis strongly suggests that electron-donating substituents with greater water solubility should increase cytotoxicity to ascites cells at the expense of cytotoxicity to the rat liver cells. The predictions of the equations were checked by synthesizing and testing an additional derivative. The results strengthen the initial predictions.

Data are presented to show that ingestion of cadmium chloride by rats at low levels leads to alteration of zinc metabolism in the liver, even though the formation of metallothionein is not evident. A dose-response relationship between amount of cadmium ingested and degree of perturbation of zinc metabolism in liver was found. Oral cadmium was shown to cause emphysema and reduce pulmonary function in male rats; the effect was less severe or delayed in onset if dietary zinc concentration was high. Interference with copper and iron metabolism was shown to occur in rats given low levels of cadmium orally. Depression of copper and iron metabolism of the rat fetus was found to occur when dams received very low doses of cadmium during gestation, even though very little cadmium passed the placental barrier.

Weanling rats were fed a copper-deficient purified diet. The effects of varying the type of protein and supplements of copper and zinc on cardiovascular pathology and some biochemical parameters were investigated. It was found that cardiomyopathy developed in the copper-deficient groups. Milk powder caused significant exacerbation of this development relative to dietary casein or egg white. Angiopathy developed only when dietary zinc was 20 ppm. Dietary copper did not change this situation. Serum cholesterol was elevated when copper was low and casein or milk powder were the protein source. The data point to an interaction between type of protein and dietary copper or zinc in the pathogenesis of cardiovascular lesions.

Kidney copper increased 12- to 18-fold above the normal level in rats administered alpha-mercapto-beta-(2-furyl)acrylic acid (MFA). Kidney zinc increased twofold; plasma zinc increased more than 10-fold and liver zinc increased 30-50%. No other changes in copper, iron, and zinc concentrations were found in these tissues or in bone, brain, heart, lung, skeletal muscle, spleen, or testis. Related compounds produced similar effects, although MFA and its disulfide were the most potent of the compounds tested. These increases in tissue copper and zinc were largely complete after 2-5 d of daily administration of compound. Increased plasma zinc returned toward normal with a half-life of 1.0 d for the process, after dosing was ended; albumin was identified as the species binding the excess zinc in plasma. Kidney copper and zinc, which had increased in the ratio of 3 Cu/Zn, returned to normal levels after dosing was stopped with half-lives of 2.1-2.5 d. Consistent with the observations of highly tissuespecific effects of MFA, copper and zinc balances over 8 weeks of trials were found to be not greatly affected by administration of the compound. Thus, it was not established whether excess metal in affected organs derived from enhanced retention of dietary metal or redistribution from other tissues. Kidney copper and zinc and serum zinc increased even in zinc-deficient rats administered MFA.

The chemical constituents of coal have not been fully characterized in relation to the incidence of coal workers' pneumoconiosis (CWP). In this study two soft coals obtained from mines in which workers had high and low incidences of CWP were leached with aqueous base and acid to remove their acidic and basic components. The results suggest that humic substances similar to those found in soil are present in the coal samples. Further, differences in the quantity of material removed ant its metal-binding and enzyme inhibitory activity are related to disease incidence.