Lead is highly toxic to human body especially to children and pediatric lead poisoning has been a public health problem not only in the developing countries, but also in the developed countries. Many studies have been conducted to investigate blood lead levels (BLL) of children of those countries. The mean BLL of Japanese children was among the lowest levels in the industrialized world in the early 1990's and also in the early 2000's according to our study. Fortunately the BLL of children and adults have been decreasing steadily in many countries during these two decades.
Recent studies have revealed that even low-level lead exposure (BLL less than 10μg/dl) might adversely affect growth and intellectual development of children, and it is considered now that there does not exist the safe level of blood lead.
Several studies have suggested that passive smoking causes increase of BLL of children, therefore, children should be protected from cigarette smoke for the purpose of avoiding the risk of lead exposure.

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Zinc is released with glutamate from neuron terminals in the hippocampus. Zinc may serve as a negative-feedback factor of presynaptic activity and negatively modulate postsynaptic calcium mobilization. On the other hand, the hippocampus is vulnerable to glutamate excitotoxicity, a final common pathway for numerous pathological processes such as Alzheimer's disease and amyotrophic lateral sclerosis, in addition to stroke/ischemia, temporal lobe epilepsy. The excitotoxicity is linked to the excessive influx of zinc and calcium. The crosstalk between zinc and calcium via calcium channels may play a role in both synaptic plasticity and excitotoxicity. This reviewer summarizes the involvement of zinc in neuronal death in the hippocampus focused on the crosstalk. The enhanced excitotoxicity in the hippocampus in zinc deficiency is also summarized.

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Aluminum is the most abundant metal in the earth's crust. However, it is not essential for life. Owing to its specific chemical properties, aluminum inhibits more than 200 biologically important functions and causes various adverse effects. It is suggested that the exposure to aluminum has a relationship with neurodegenerative diseases including dialysis encephalopathy, amyotrophic lateral sclerosis and Parkinsonism dementia in the Kii Peninsula and Guam, and Alzheimer's disease. However, these relationships still remain elusive. Furthermore, the complexity of bioavailability has difficulty in evaluation of aluminum toxicity. In this paper, we review the detailed characteristics of aluminum neurotoxicity and bioavailability based on the recent literatures, and discuss its biological fate and effects to human health. Considering its long half-life in the body, unnecessary exposure to aluminum should be avoided for human health.

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Selenium (Se) is an essential trace element and toxicant for mammals. In human, Se is supplied by various kinds of food. Selenomethionine (SeMet), the Se analog of methionine (Met), is the major chemical form in plants. SeMet could be metabolized by the same reactions as the metabolic reactions of Met: it is activated initially by adenosylation, demethylated, and finally converted to selenocysteine (SeCyH) via selenohomocysteine and selenocystathionine. SeCyH formed could be degraded further by selenocysteine β-lyase to hydrogen selenide (H₂Se) and might then be incorporated into functional selenoproteins as SeCyH residues via gene products though selenocysteinyl-tRNA. H₂Se is classified as a more toxic compound than other Se compounds, so an excess amount of it is immediately transformed to methylated Se compounds as detoxicant. 1β-Methylseleno-N-acetyl-D-galactosamine is excreted as the major form into urine at nutritional dose. Meanwhile, trimethylselenonium ion (TMSe) is known to be excreted into urine at high-toxic doses. Our recent work indicates that SeMet is enzymatically converted to methylselenol (MMSe), α-ketobutyrate, and ammonia by mouse hepatic enzyme. We termed the novel enzyme SeMet α, γ-elimination enzyme and purified it to homogeneity for the first time. The target enzyme was proved to be cystathionine γ-lyase by the MS analytical techniques, both the peptide mass fingerprinting search and peptide sequence tags search. The metabolic pathway that directly transforms SeMet to MMSe is more effective in the detoxification when SeMet is administered at toxic dose, because H₂Se produced in the metabolism from SeMet via SeCyH inhibits the methylation metabolism and enhances the toxicity. Furthermore, MMSe generated from SeMet by cystathionine γ-lyase is utilized for glutathione peroxidase biosynthesis. Cystathionine γ-lyase, which plays an important role in not only the Se detoxification but also the selenoproteins biosynthesis, is a notable enzyme in SeMet metabolism.

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Imposex, the superimposition of male type genital organs (penis and vas deferens) on female gastropod molluscs, is cause-specific and induced by low concentrations of certain organotins such as tributyltin (TBT) and triphenyltin (TPT) from antifouling paints. Reproductive failure may be observed at severely affected stages, resulting in declining the populations. Fundamental knowledge of the endocrinology of gastropods is briefly described. Although some papers have suggested that steroids also function as sex hormones in gastropods, similarly to vertebrates, it is still unclear. Meanwhile, neuropeptides have been reported to control the reproduction in gastropods. Four hypotheses, such as aromatase-inhibition, regarding the induction mechanism of imposex induced by organotins in gastropods are reviewed. Finally, a new hypothesis that states that RXR plays an important role in inducing the development of imposex, the differentiation and growth of male type genitalia in female gastropods, is reviewed and discussed toward the elucidation of the entire mode of action of TBT or TPT in the development of imposex in gastropods.

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An overview is presented of vanadium-based insulinomimetic and anti-diabetic complexes aiming at the development of clinically useful anti-diabetic medicines as replacements of daily insulin injections for type 1 diabetes and synthetic antidiabetic drugs. After described on the advantage for the use of vanadyl ion (oxovanadium(IV), +4 oxidation state of vanadium, VO²⁺) in terms of toxicity in animals and bio-state of the metal ion, recent progress on the development of antidiabetic vanadyl complexes proposed in our research group is reviewed with emphasis of the importance of the study on structure-activity relationship for vanadyl-picolinate complexes to find more active complexes than the leading compound and of the development of new drug delivery system either the enteric-coated capsule containing simple vanadyl sulfate or the use of a biopolymer, poly(γ-glutamic) acid, bound with vanadyl sulfate. The challenges for future research are also described.

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Genetic disorders of copper metabolism are reviewed, particularly in Menkes disease and Wilson's disease. The responsible genes for Menkes disease and Wilson's disease are ATP7A and ATP7B, respectively, with the both proteins responsible for transporting copper from the cytosol to the Golgi apparatus in cells. However, the pathology of Menkes disease is completely different from that of Wilson's disease, with Menkes disease characterized by a copper deficiency and Wilson's disease by a toxic excess of copper. The reason for this difference is related to the particular cell types in which the ATP7A and ATP7B proteins are expressed. ATP7A is expressed in almost all cells, except hepatocytes, where ATP7B is expressed in hepatocytes.
Menkes disease is an X-linked recessive disorder characterized by copper deficiency. The typical features, such as neurological disturbances, connective tissue disorders and hair abnormalities, can be explained by the abnormally low activity of copper-dependent enzymes. The treatment is so far parenteral administrations of copper-histidine. When the treatment is started in patients more than 2 months of age, however, the neurological disturbances cannot be improved. Moreover, the treatment does not improve the connective tissue disorders. Thus an alternative treatment needs to be found.
Wilson's disease is an autosomal recessive disorder characterized by the toxic effects of copper. The clinical symptoms mainly appear as diseases of the liver and nervous system. However, various other symptoms can also be observed and can sometimes make an early diagnosis difficult. All the patients should be treated with chelating agents or zinc. However, the treatments are ineffective in patients with fulminant hepatic failure. Liver transplantation is accepted for these patients. In these cases also, the disturbances are prevented by early treatments. Thus, early diagnosis is important. Screening in early infants should be established for early diagnosis of this disease.

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The development of metallic compounds for the diagnosis and therapy of diseases has been expected to open a new field of medicinal science. These compounds are required to exhibit biological activity and a specific localization to the target tissue. These demands constitute a great challenge on the rational design of metallic compounds and we have proposed two approaches, a pendant approach and an integrated approach in order to achieve this purpose. The pendant approach involves designing a biologically active compound by the attachment of a chelating group for binding the metal ion to a mother compound without the effect on the inherent biospecificity of the mother compound. A typical example of the pendant approach is bifunctional radiopharmaceuticals used for nuclear medical diagnosis and internal radiotherapy. The integrated approach involves designing a metallic compound with a biologically activity and physicochemical properties suitable for target-specific delivery by coordination to a mother compound with metal ion.
This review will describe our recent progress in research on a bifunctional radiopharamceutical labeled with metallic radionuclides, Rhenium-186 for therapy of painful bone metastases as an example of the pendant approach and a lipophilic zinc complex with protective effect against ischemic neuronal injury as an example of the integrated approach.

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Wilson's disease (WD) is an autosomal recessive disorder of copper transport characterized by the accumulation of intracellular copper in the liver and extrahepatic tissues. The WD gene (ATP7B) encodes a copper transporting P-type ATPase with 50-70% similarity to the Menkes disease (MNK) protein, and is primarily expressed in the liver, while the MNK gene (ATP7A) is almost ubiquitously expressed in a variety of tissues, but not in the liver. The ATP7B gene, but not ATP7A, contains several metal response elements (MRE) and MRE-like sequences (MLS) in the promotor region that seem to play important roles during the ATP7B gene expression. We previously reported that in 40 WD patients mutations were found in 83.8% (67/80) of alleles on direct sequencing of polymerase chain reaction products of all exons of the ATP7B gene. It is possible that disease-caused mutations may exist in the promotor, 5' untranslated region, or introns. So far, only two mutations have been reported in the promotor region of the ATP7B gene. In the present study we identified one mutation and seven polymorphisms in the promotor region of the ATP7B gene in Chinese population. The mutation -215 A to C, occurred close to MREd, between MREd and the E-box. The results of the present study suggest that mutations in the regulatory elements of ATP7B that result in WD are rare in Chinese patients with WD. These results will be very useful in facilitating the molecular diagnosis and counseling of WD patients in the Chinese population.

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Osteoporosis is a major public health problem in Japan. Although bone mineral density is often used as an indicator to evaluate bone fragility, it isn't always reflected in bone strength. We have maintained spontaneously obese rats with abnormal lipid metabolism selected among Wistar rat (Minko rat). In this study, we reported the difference of bone strength and bone mineral concentrations between male and female Minko rats. The bone strength was tested by the three-point bending method. Mineral (Mg, Ca, P, Na, S, K, Zn, Sr, Fe) concentrations were measured by ICP-AES. Mechanical study indicated that the bone strength of male rats was significantly high compared to that of female rats. On the other hand, Ca, P, Mg, Na, Zn, Fe and Sr concentrations in bone of male rats were significantly low compared to that of female rats, and S and K concentrations in male rats were high compared to that of female rats. There was significantly positive correlation between mineral concentrations in bone of female rats as follows; Ca and P, Ca and Mg, Ca and Na, P and Mg, P and Na, Mg and Na, S and K. There was significantly positive correlation between mineral concentrations in bone of male rats as follows; Ca and P, Ca and Mg, Ca and Na, P and Mg, P and S, P and Sr, Mg and Na. A significant positive correlation between stiffness and Zn concentration in bone of female rats was found. In male and female rats, there was no correlation between bone strength and Ca or P. These results suggest that bone strength is not always related to the concentrations of Ca or P, principal minerals in bone.

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Obesity has become prevalent as a result of changes in our eating habit. We examined the effect of 20% restricted diet (80% diet) on lipid metabolism and mineral status of spontaneously obese rats (Minko rats) with abnormal lipid metabolism segregated from Wistar rats. Female Minko rats (27 weeks old) were separated each into two groups. Normal diet group (control) was fed normal diet freely and other group (80% diet) was fed 80% diet (20% restricted diet) for the diet fed control group rats. These dietary regimens were performed for 14 weeks. The concentrations of Ca, P, Mg, Na, K, S, Fe, Zn and Sr in bone, blood and liver, and biochemical plasma test of the rats were determined. Triglyceride and non esterified fatty acid concentrations were significantly low, and HDL-cholesterol concentrations were significantly high in plasma of rats fed 80% diet (20% restricted diet) compared to that of normal group rats. These results suggest that lipid metabolic status were improved. We previously reported that 50% dietary restriction induced hypoproteinemia and mineral imbalance in liver. Although the composition of diet was same, lipid metabolism and mineral concentrations were affected by restricted diet

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Recently eating habits are characterized by over intake of energy and insufficiency of vitamins and minerals. To examine mineral nutritional status of adult men, 20 healthy volunteer men (average age: 42) were selected and their blood samples were collected. Hematological parameters in blood and biochemical parameters in plasma were monitored. Concentrations of calcium(Ca), phosphorus(P), potassium(K), sodium(Na), magnesium(Mg), sulfur(S), iron(Fe), copper(Cu) and strontium(Sr) in blood after wet digestion by nitric acid were measured by inductively coupled plasma-atomic emission spectrometry (ICP-AES: Perkin Elmer Co. Ltd). Blood mineral levels were as follows (average); Ca: 56.9μg/ml, P: 404.2μg/ml, K: 1.74 mg/ml, Na: 1.88 mg/ml, Mg: 37.1μg/ml, S: 1.52 mg/ml, Zn: 7.75μg/ml, Fe: 530.0μg/ml, Cu: 0.75μg/ml, Sr: 24.0 ng/ml. Mineral intake were as follows (average; mg/day); Na: 4967, K: 2944, Ca: 480, Mg: 342, P: 1275, Fe: 9.3, Zn: 10.4, Cu: 1.3, Mn: 3.9. Mineral sufficiency rates to the Recommend Dietary Allowance (RDA) for Japanese men were as follows (average: %/RDA); K: 147, Ca: 80, Mg: 108, P: 182, Fe: 93, Zn: 88, Cu: 73. There were suggested that sufficiency rates on Ca, Fe, Zn and Cu were low and P was high. These results were consistent with the National Nutrition Survey 2002 in Japan. P concentration in plasma was correlated with T-Cho and TG. Cu concentration in plasma was correlated TP and negatively correlated A/G.

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Co-occurrence of iron and zinc deficiencies is suspected to be prevalent in human populations, because dietary sources such as red meat and major absorption inhibitors such as calcium and phytate are common for iron and zinc. The experiment described here was designed to determine the effect of dietary iron and zinc deficiencies and their interactions on plasma mineral concentrations in rats. Forty 4-week-old male Sprague-Dawley rats were assigned into 4 dietary treatment groups of 10 each for the 4-week study: iron-deficient group (FD), zinc-deficient group (ZD), iron/zinc-deficient group (FZD), and control group (Cont). Mineral concentrations (Mg, Ca, Mn, Ni, Cu, Zn, As, Se and Mo) were measured by ICP-MS. Fe concentration was measured by the colorimetric kit. Differences between groups were tested by Tukey's multiple comparison test and two-way ANOVA. P value less than 0.05 was considered significant. Plasma Fe concentration was decreased by iron deficiency. Plasma Zn concentration was decreased by iron and/or zinc deficiency. Plasma Mg concentration was increased by iron deficiency. Plasma Mo and Mn concentrations were decreased by iron deficiency. Plasma Se concentration was decreased by single iron deficiency and was however unchanged by combined deficiency of iron and zinc. There were no significant effects of dietary iron and zinc and their interaction on plasma Cu, Ni and As concentrations. These results suggest that sufficient cautions are required for evaluation of Mg, Mn, Se and Mo status by plasma analyses in patients with iron deficiency anemia.

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Determination of mineral requirements is crucial in developing dietary guidelines. The established methods for estimating mineral requirements are balance method, factorial method and saturation method. As an alternative, a mathematical approach for estimating mineral requirements from the population data of mineral status (distribution of dietary intake and the prevalence of inadequate status) has been proposed. The prevalence (D) of inadequate nutritional status is the proportion of individuals with inadequate nutritional status: D=(Sum of individuals whose dietary intake < requirement)/(total number of individuals). Assuming that requirements and dietary intakes follow a certain distribution function, an estimated mean requirement is obtained as a solution of the integral equation describing the above relationship. The appropriate distribution function for iron requirement and iron intake was elaborated for the specific age-sex group. The population data of iron status obtained from the National Health and Nutrition Survey in Japan, 2003 were analyzed, assuming a coefficient of variation of 10% for iron requirements. The estimated median iron requirement was 3.7, 4.1, 5.4 and 6.0 mg/d for Japanese males aged 18-29, 30-49, 50-69, and ≥ 70 years old, respectively; and was 8.4, 9.3, 6.3 and 6.0 mg/d for Japanese females aged 18-29, 30-49, 50-69, and ≥ 70 years old, respectively. The estimated mean iron requirements were same as the corresponding medians except for females aged 18-29 and 30-49 years old. The estimated mean iron requirement was 9.2 and 10.1 mg/d for females aged 18-29 and 30-49 years old, respectively. In the framework of Dietary Reference Intakes both in Japan and the US, the estimated average requirement (EAR) is defined as the median of the estimated requirement. We propose that the mathematical approach using populational nutriture data can be useful to estimate mineral requirements and to make up dietary guidelines for minerals.

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The acute toxicity of hydrofluoric acid (HFA) was investigated in a 24-hour lethal dose study of intravenous injection in rats. The LD₅₀ and LD₉₀ were 17.4 and 23.0 mg/kg, respectively. Harmful systemic effects were also studied 1 hour after acute sublethal exposure to HFA. Rats were injected with HFA (1.6, 3.2, 6.4, or 9.6(LD₅) mg/kg) or saline. Blood samples were obtained from the carotid artery. BUN and Cr were significantly increased in response to HFA concentrations greater than 3.2 mg/kg. Acute glomerular dysfunction also occurred at HFA concentrations greater than 3.2 mg/kg. PCO₂, HCO₃^- and base excess were significantly decreased in the 6.4 and 9.6 mg/kg groups. Total and ionized calcium was significantly decreased, and potassium was increased in the 9.6 mg/kg group. Ionized fluoride exposure directly affected serum electrolytes. Mortality was thought to be due to cardiac arrhythmia resulting from hypocalcemia and hyperkalemia. Metabolic acidosis and renal failure were severe in response to HFA exposure. Even low exposure to HFA can cause acute renal dysfunction, electrolyte abnormalities and metabolic acidosis. These complications result in a poor prognosis.

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