The main threats to human health from heavy metals are associated with exposure to lead, cadmium, mercury and arsenic. These metals have been extensively studied and their effects on human health regularly reviewed by international bodies such as the WHO. Heavy metals have been used by humans for thousands of years. Although several adverse health effects of heavy metals have been known for a long time, exposure to heavy metals continues, and is even increasing in some parts of the world, in particular in less developed countries, though emissions have declined in most developed countries over the last 100 years. Cadmium compounds are currently mainly used in re-chargeable nickel-cadmium batteries. Cadmium emissions have increased dramatically during the 20th century, one reason being that cadmium-containing products are rarely re-cycled, but often dumped together with household waste. Cigarette smoking is a major source of cadmium exposure. In non-smokers, food is the most important source of cadmium exposure. Recent data indicate that adverse health effects of cadmium exposure may occur at lower exposure levels than previously anticipated, primarily in the form of kidney damage but possibly also bone effects and fractures. Many individuals in Europe already exceed these exposure levels and the margin is very narrow for large groups. Therefore, measures should be taken to reduce cadmium exposure in the general population in order to minimize the risk of adverse health effects. The general population is primarily exposed to mercury via food, fish being a major source of methyl mercury exposure, and dental amalgam. The general population does not face a significant health risk from methyl mercury, although certain groups with high fish consumption may attain blood levels associated with a low risk of neurological damage to adults. Since there is a risk to the fetus in particular, pregnant women should avoid a high intake of certain fish, such as shark, swordfish and tuna; fish (such as pike, walleye and bass) taken from polluted fresh waters should especially be avoided. There has been a debate on the safety of dental amalgams and claims have been made that mercury from amalgam may cause a variety of diseases. However, there are no studies so far that have been able to show any associations between amalgam fillings and ill health. The general population is exposed to lead from air and food in roughly equal proportions. During the last century, lead emissions to ambient air have caused considerable pollution, mainly due to lead emissions from petrol. Children are particularly susceptible to lead exposure due to high gastrointestinal uptake and the permeable blood-brain barrier. Blood levels in children should be reduced below the levels so far considered acceptable, recent data indicating that there may be neurotoxic effects of lead at lower levels of exposure than previously anticipated. Although lead in petrol has dramatically decreased over the last decades, thereby reducing environmental exposure, phasing out any remaining uses of lead additives in motor fuels should be encouraged. The use of lead-based paints should be abandoned, and lead should not be used in food containers. In particular, the public should be aware of glazed food containers, which may leach lead into food. Exposure to arsenic is mainly via intake of food and drinking water, food being the most important source in most populations. Long-term exposure to arsenic in drinking-water is mainly related to increased risks of skin cancer, but also some other cancers, as well as other skin lesions such as hyperkeratosis and pigmentation changes. Occupational exposure to arsenic, primarily by inhalation, is causally associated with lung cancer. Clear exposure-response relationships and high risks have been observed.

/pdf/hazards-of-heavy-metal-contamination-ytc24a1l2a.pdf

Hazards of heavy metal contamination.

Essentiality Toxicity Carcinogenicity Lead(Pb) Exposure Toxicokinetics Toxicity Neurologic, Neurobehavioral, and Developmental Effects in Children Mechanisms of Effects on the Developing Nervous System Peripheral Neuropathy Hematologic Effects Renal Toxicity Lead and Gout Effects on Cardiovascular System Immunotoxicity Bone Effects Reproductive Effects Birth Outcomes Carcinogenicity Other Effects Dose Response Treatment Organic Lead Compounds Mercury (Hg) Exposure Disposition and Toxicokinetics Metabolic Transformation Cellular Metabolism Toxicology Biological Indicators Treatment Nickel (Ni) Exposure Toxicokinetics Essentiality Toxicity Nickel Carbonyl Poisoning Dermatitis Indicators of Nickel Toxicity

/pdf/toxic-effects-of-metals-2t2btb1i7f.pdf

Toxic effects of metals

Cardiac hypertrophy is the heart's response to a variety of extrinsic and intrinsic stimuli that impose increased biomechanical stress. While hypertrophy can eventually normalize wall tension, it is associated with an unfavorable outcome and threatens affected patients with sudden death or progression to overt heart failure. Accumulating evidence from studies in human patients and animal models suggests that in most instances hypertrophy is not a compensatory response to the change in mechanical load, but rather is a maladaptive process. Accordingly, modulation of myocardial growth without adversely affecting contractile function is increasingly recognized as a potentially auspicious approach in the prevention and treatment of heart failure. In this review, we summarize recent insights into hypertrophic signaling and consider several novel antihypertrophic strategies.

Cardiac Hypertrophy: The Good, the Bad, and the Ugly

This report provides a review of the cadmium exposure situation in Sweden and updates the information on health risk assessment according to recent studies on the health effects of cadmium. The report focuses on the health effects of low cadmium doses and the identification of high-risk groups. The diet is the main source of cadmium exposure in the Swedish nonsmoking general population. The average daily dietary intake is about 15 micrograms/day, but there are great individual variations due to differences in energy intake and dietary habits. It has been shown that a high fiber diet and a diet rich in shellfish increase the dietary cadmium intake substantially. Cadmium concentrations in agricultural soil and wheat have increased continuously during the last century. At present, soil cadmium concentrations increase by about 0.2% per year. Cadmium accumulates in the kidneys. Human kidney concentrations of cadmium have increased several fold during the last century. Cadmium in pig kidney has been shown to have increased by about 2% per year from 1984-1992. There is no tendency towards decreasing cadmium exposure among the general nonsmoking population. The absorption of cadmium in the lungs is 10-50%, while the absorption in the gastrointestinal tract is only a few percent. Smokers have about 4-5 times higher blood cadmium concentrations (about 1.5 micrograms/l), and twice as high kidney cortex cadmium concentrations (about 20-30 micrograms/g wet weight) as nonsmokers. Similarly, the blood cadmium concentrations are substantially elevated in persons with low body iron stores, indicating increased gastrointestinal absorption. About 10-40% of Swedish women of child-bearing age are reported to have empty iron stores (S-ferritin < 12 micrograms/l). In general, women have higher concentrations of cadmium in blood, urine, and kidney than men. The population groups at highest risk are probably smokers, women with low body iron stores, and people habitually eating a diet rich in cadmium. According to current knowledge, renal tubular damage is probably the critical health effect of cadmium exposure, both in the general population and in occupationally exposed workers. Tubular damage may develop at much lower levels than previously estimated, as shown in this report. Data from several recent reports from different countries indicate that an average urinary cadmium excretion of 2.5 micrograms/g creatinine is related to an excess prevalence of renal tubular damage of 4%. An average urinary excretion of 2.5 micrograms/g creatinine corresponds to an average concentration of cadmium in renal cortex of 50 micrograms/g, which would be the result of long-term (decades) intake of 50 micrograms per day. When the critical concentrations for adverse effects due to cadmium accumulation are being evaluated, it is crucial to consider both the individual variation in kidney cadmium concentrations and the variations in sensitivity within the general population. Even if the population average kidney concentration is relatively low for the general population, a certain proportion will have values exceeding the concentration where renal tubular damage can occur. It can be estimated that, at the present average daily intake of cadmium in Sweden, about 1% of women with low body iron stores and smokers may experience adverse renal effects related to cadmium. If the average daily intake of cadmium would increase to 30 micrograms/day, about 1% of the entire population would have cadmium-induced tubular damage. In risk groups, for example, women with low iron stores, the percentage would be higher, up to 5%. Both human and animal studies indicate that skeletal damage (osteoporosis) may be a critical effect of cadmium exposure. We conclude, however, that the present evidence is not sufficient to permit such a conclusion for humans. We would like to stress, however, that osteoporosis is a very important public health problem worldwide, but especially in the Scandinav

Health effects of cadmium exposure - a review of the literature and a risk estimate

Metallothioneins (MTs) are intracellular, low molecular, low molecular weight, cysteine-rich proteins. Ubiquitous in eukaryotes, MTs have unique structural characteristics to give potent metal-binding and redox capabilities. A primary role has not been identified, and remains elusive, as further functions continue to be discovered. The most widely expressed isoforms in mammals, MT-1 and MT-2, are rapidly induced in the liver by a wide range of metals, drugs and inflammatory mediators. In teh gut and pancreas, MT responds mainly to Zn status. A brain isoform, MT-3, has a specific neuronal growth inhibitory activity, while MT-1 and MT-2 have more diverse functions related to their thiolate cluster structure. These include involvement in Zn homeostasis, protection against heavy metal (especially Cd) and oxidant damage, and metabolic regulation via Zn donation, sequestration and/or redox control. Use of mice with altered gene expression has enhance our understanding of the multifaceted role of MT, emphasised in this review.

Metallothionein: the multipurpose protein

The serum ferritin concentration was measured in 1417 Indians and 310 Inuit aged 1 to 89 years. The subjects were initially selected to produce a representative sample of the entire native population, but the rate of nonresponse was high, and the results reported in this paper are representative only of the people studied.

In males the median serum ferritin values increased during early life and tended to plateau after the age of 30 years. In females the median values rose during childhood, tended to plateau during adolescence, increased slightly during the reproductive period, then gradually rose thereafter. Ranges of values were wide in all age groups, reflecting the variations in body iron stores. When compared with the Inuit, the Indians had a significantly higher prevalence of abnormal serum ferritin values.

From an analysis of the serum ferritin values in Indians it is probable that iron stores were reduced in approximately 30% of children, 40% of adolescents, 34% of nonpregnant women of reproductive age, 11% of older women and 5% of adult males. The corresponding figures for the Inuit were 15%, 23%, 22%, 6% and 1%. In contrast, iron deficiency anemia was found in only 3% to 4% of native peoples. If “normality” requires more than small amounts of iron stores to meet physiologic needs, the results suggest a high probability of iron deficiency in 20% to 40% of native children, adolescents and nonpregnant women of reproductive age, and in 0% to 10% of other subjects; but if “normality” is defined as adequate iron stores for erythropoiesis the prevalence of iron deficiency was approximately 1% to 2% in children and adolescents, 3% to 5% in women and less than 1% in adult males.

Evaluation of the body iron status of native Canadians

Aims Cardiac glycosides induce cardiomyocyte hypertrophy via yet to be defined mechanisms. These hypertrophic effects are likely related to changes in intracellular signalling secondary to Na+-K+ ATPase (NKA) inhibition which would produce elevations in intracellular sodium concentrations. Sodium–hydrogen exchanger isoform 1 (NHE-1) also contributes to intracellular sodium regulation. Accordingly, we determined the contribution of NHE-1 to cardiac glycoside-induced hypertrophy.

Methods and results The majority of the experiments were performed on cultured neonatal rat ventricular myocytes exposed to either ouabain (100 µM) or digoxin (40 µM) for 24 h, although additional experiments were also done using adult left ventricular myocytes with 30 µM of either glycoside. Both glycosides increased cell surface area by 30% and atrial natriuretic peptide gene expression by two- to three-fold ( P < 0.05 for both). These effects were associated with a significant reduction in the expression of two NKA isoforms, α2 and α3, whereas the α1 isoform was unaffected. Conversely, both glycosides increased NHE-1 expression in cardiomyocytes by approximately two-fold and significantly increased intracellular sodium concentrations by more than 60% ( P < 0.05). Both ouabain and digoxin were also found to significantly increase phosphorylation of mitogen-activated protein kinases. All these effect were prevented when identical experiments were carried out in the presence of the NHE-1 inhibitors EMD 87580 or AVE 4890. Identical results were obtained using adult myocytes, although this was associated with downregulation of all three NKA isoforms. Glycoside-induced increase in cell shortening or intracellular Ca2+ transients was not significantly affected by NHE-1 inhibition.

Conclusion When taken together, these studies show that NHE-1 inhibition attenuates the hypertrophic effect of cardiac glycosides without affecting inotropic parameters and suggest a possible approach to limiting glycoside-induced hypertrophic responses while preserving therapeutic, i.e. inotropic, actions.

Sodium-hydrogen exchange inhibition attenuates glycoside-induced hypertrophy in rat ventricular myocytes

https://www.gastrojournal.org/article/0016-5085(91)90204-X/pdf

Mucosal iron in the control of iron absorption in a rat intestinal transplant model.

Objective: The aim was to examine the cardiac effects of phorbol esters over a wide concentration range and to determine if the effects are related to Ca2+ availability. Methods: Studies were carried out using isolated rat hearts exposed for 60 min either to phorbol 12-myristate 13-acetate (PMA, 10−11 to 10−6 M) or phorbol 12,13-dibutyrate (PDBu, 10−12 to 10−7 M) in the presence of either 1.25 or 2.50 mM CaCl2. Experiments were also done to assess the effect of BAY K8644, a Ca2+ agonist, on phorbol ester effects. After treatment, hearts were freeze clamped for later analysis of energy products. Results: At the lowest concentrations studied, both PMA and PDBu produced positive inotropic effects, whereas higher concentrations resulted in a loss of contractile force in hearts perfused with 1.25 mM CaCl2. Doubling the CaCl2 concentration or the presence of BAY K8644 had little effect on the negative inotropic influence of either phorbol ester but reversed the positive inotropic effect to a negative inotropic one. Neither treatment had any effect on the coronary constricting effects of phorbol esters. Increases in resting tension and reductions in high energy phosphate content were evident only with the highest phorbol ester concentrations and were unaffected either by changes in CaCl2 concentrations or the presence of BAY K8644. Conclusions: At picomolar and nanomolar concentrations phorbol esters produce positive inotropic actions which are probably mediated by enhanced Ca2+ influx. Although higher concentrations produce negative inotropic effects, these are not influenced by [Ca2+]o nor are they related to disturbances in energy metabolism except at the highest concentrations. We conclude that phorbol esters produce complex concentration dependent cardiac effects which are not mediated by a single mechanism of action.

Cardiovascular Research 1993; 27 :390-395

James V. Haist

Papers

Evaluation of the body iron status of native Canadians

Sodium-hydrogen exchange inhibition attenuates glycoside-induced hypertrophy in rat ventricular myocytes

Mucosal iron in the control of iron absorption in a rat intestinal transplant model.

Calcium dependent positive inotropic effects of low phorbol ester concentrations in isolated rat hearts

The intestinal adaptive response to iron deficiency increases dietary cadmium absorption in mice and human subjects