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Research is described that constitutes an extension of an earlier paper (J. Environ. Monit., 2001, 3, 177–184), in which concentrations were measured in 263 human placentas of 11 essential elements (P, Ca, Mg, Cu, S, Na, Fe, Zn, K, Se, Mn) and 5 toxic elements (Ba, Sr, Pb, Ni, Cd). The additional data considered derive from earlier visits to 4 of the original 6 communities and 3 others, all but one of which are located in northern Norway and neighbouring areas of Russia. This more than doubled the number of placental samples available (263 to 571). Unfortunately, the personal, life-style and morphometric information obtained for the first study group was not available for the additional mothers. Country differences were evident for all elements except Ba, Fe and Zn; Cd, Cu, Mn, Na, Se, Ni, Pb, Sr and S were higher and K, P, Ca and Mg were lower in Russia (p < 0.03). Not unexpectedly, the highest median lead concentration was observed for the largest city in the western arctic region of Russia, namely Murmansk. Similarly, the higher median nickel level observed for Russia reflects the established observation that urinary nickel concentrations are higher in the Russian than in the Norwegian communities. Even though sampling was performed at different times of the year and before and after a 3-year interval in four centres, inter-collection differences were of relatively small magnitude and appear not to be linked to seasonal or temporal changes. Principal component analysis (PCA) confirmed the prominence of Factor 1, which grouped those metals that are known to form insoluble phosphate complexes and whose concentrations showed a dependence on gestational age and maternal smoking in the earlier study. It is concluded that PCA is a powerful statistical tool for exploring and identifying fundamental pathways and processes involved in governing the inorganic elemental composition of placental tissue. It also has the potential of identifying study limitations and quality assurance shortfalls. Further our findings show promise that placental concentrations of toxic elements may serve as an index of exposure and of nutritional intake for selected essential micro-elements.

Abstract: Background: The feasibility study described herein was prompted by a report in 1992 of possible reproductive and developmental health concerns among female workers in a Russian nickel refinery. Objective: The primary goal was to ascertain whether medical, statistical, and occupational data bases could be accessed for information about the pregnancy histories, occupational histories, and life-style factors of the women affected. Methods: The project was facilitated by construction of a registry of all births in three towns with a nickel refinery and verification of its contents against patients' records obtained from hospital delivery and gynecology departments and community polyclinics. Municipal Registration Board, Regional Health Statistics Board, and nickel company records were also reviewed. Results: Reproductive/developmental outcome information and workplace histories were acceptable. Sample-size calculations indicated that a cohort or cross-sectional study would be amenable and suitable for the detection of an excess risk for spontaneous abortion with adequate statistical significance and power. Such investigations would need to be supplemented by workplace environmental/biological monitoring assessments for evaluation of exposure to occupational hazardous factors and a worker's questionnaire to obtain information about life-style factors. A case-control design is recommended for the study of congenital defects. Conclusions: A well-designed, comprehensive epidemiology study is technically feasible because of the availability of a favorable pool of study subjects, reproductive/developmental outcome data, information to control for major confounders, and suitable occupational records.

Using model systems, we have studied the properties of a number of zinc-chelating agents which are known to cause diabetes in laboratory animals. The abilities to permeate membranes and to complex zinc inside liposomes with the release of protons are suggested as chemical properties that can enhance diabetogenicity. When such complexing agents are added to lipid vesicles at pH 6 containing entrapped zinc ions, they acidify the contents of these vesicles. We have demonstrated this effect by measuring intravesicular pH both with a fluorine-containing F NMR probe as well as with the fluorescent probe, quinine. For example, using quinine, we observed that 0.1 mM 8-hydroxyquinoline reduced the intravesicular pH of sonicated phospholipid vesicles containing entrapped Zn2+ (as sulfate) from pH 6.0 to 2.8. These diabetogenic chelating agents also solubilized zinc-insulin precipitates from unbuffered suspensions at pH 6.0. The solubilization results from the acidification of these suspensions. Dithizone and 8-hydroxyquinoline at 4 mM solubilized 97 and 42%, respectively, of the suspended insulin. We suggest that if such proton release occurs within the zinc-containing insulin storage granules of pancreatic beta-cells, solubilization of insulin would be induced. Such an event would lead to osmotic stress and eventually to rupture of the granule. The effects of diethyldithiocarbamate (DDC), an agent that has been found to protect rabbits against the induction of diabetes by some other zinc-chelating agents, were also studied. DDC caused a decrease of 3.5 units in the intravesicular pH of zinc-containing vesicles by a mechanism not involving the release of protons upon chelation of zinc. We have demonstrated several properties of DDC which may contribute to its ability to protect against the induction of diabetes. These include its ability to store zinc as a hydrophobic complex in membranes, its consumption of protons upon spontaneous decomposition, and the ability of one of its decomposition products, diethylamine, to accelerate the dissipation of pH gradients across lipid bilayers. Diethylamine is particularly effective in stimulating a rapid dissipation of such pH gradients, even at micromolar concentrations. We have attempted to estimate quantitatively the extent of proton liberation by various zinc-chelating agents. This analysis demonstrated that partitioning of the ligand between organic and aqueous phases, ligand acidity, and zinc complex stability determine the extent of proton release.

Dublin weights remain more or less constant, at a relatively low level, during the period of wing moult. Possibly reduced flight-efficiency at this time requires such a strategy.

At physiologic pH values, histidine-containing nickel(II) oligopeptides reduced the flux of superoxide anion (O2) generated in the hypoxanthine/xanthine oxidase system. The postulated involvement of the Ni(III)/Ni(II) redox couple in this apparent dismutation receives indirect support from electron-spin resonance data. These complexes also catalyzed the disproportionation of hydrogen peroxide, a process which generates active intermediates capable of hydroxylating p-nitrophenol and oxidizing uric acid to allantoin. An oxene moiety, namely [Nio]2+, is postulated as the active species in these H2O2-dependent reactions. Spectral analysis showed that monovalent, divalent and trivalent ions induced cooperative conformational changes in synthetic polydeoxynucleotides. For the nickel(II) ion, resistance to DNase-I activity clearly showed that an alternating G-C sequence is required for the observed transitions. It is concluded that the ability of nickel(II) peptide complexes to participate in active oxygen biochemistry suggests a possible role for nickel as a chemical promoter of cancer, whereas the capacity of the nickel(II) ion to induce conformational changes in DNA could, in principle, affect gene expression. Of course, the validity of both hypotheses require that the observed reactions be verified as biologically significant.

To help to evaluate the role of metallothionein (MT) in peripheral-blood leucocytes, we examined MT protein and mRNA levels in these cells before and after exposure to CdCl2 in culture. Protein was assayed by 109Cd2+ binding, and RNA by dot-blot hybridization. MT was induced in both lymphocytes and adherent monocytes about 10-fold with a 12 h exposure to 10 microM-CdCl2, but absolute levels were 3-fold higher in monocytes: 57 x 10(5) (+Cd2+) versus 6 x 10(5) (-Cd2+) molecules/cell for monocytes; 18 x 10(5) (+Cd2+) versus 2 x 10(5) (-Cd2+) for lymphocytes. Polymorphonuclear cells expressed relatively little MT (0.6 x 10(5) molecules/cell), and this did not change with phorbol ester stimulation or exposure to Cd2+, arguing against a direct protective role for MT in activated neutrophils. MT mRNA levels corresponded qualitatively to expression of protein in these cells. Our data provide quantitative comparisons of leucocyte MT expression and regulation in the human population. Variation in both basal and induced MT mRNA levels reflects environmental or experimental (intra-individual) and possibly genetic (inter-individual) differences.

Efforts to relate metal-complex stability constants to some property of the metal ions involved have led to the development of a correlating numerical index Qwith the following characteristics: (i) Qis a two parameter quantity involving ionic charge and electronegativity, which may assume different values for a particular metal according to the type of ligand with which complexes are formed; (ii) linear relationships are obtained for plots of log KMLvs. Qfor various metals and more than thirty ligands. The effect of the thermodynamic and structural properties of ligands and metal complexes on the slope and intercept in this correlation is discussed. Two new indices to class b behavior are introduced, one for metal ions and one for ligands. The index Qis shown to be related to other published indices of ionic or covalent, class a or class b, behavior of metals and ligands; the alternative ways of assigning Qmay be regarded as reflecting the varying degrees of ionic or covalent character in the complexes of a given metal.

This paper discusses factors predisposing to linear free energy relationships among families of metal complexes. It is postulated that changes occurring at a reaction site in a test series of reactions and the corresponding changes in a reference series have their origins in the same independent variables. Linearity is seen to be favored when changes in the reaction site or in ligand substituents are small, and in the absence of strong interactions with the solvent. In addition to such considerations of a molecular sort, a number of relationships among the thermodynamic quantities ΔH0, ΔS0, and ΔG0which have been identified as having a significant influence on rate and equilibrium relationships in series of organic reactions are discussed in terms of their effect on metal–ligand systems.

After a review of previous semi-empirical free-energy relationships applying to the formation of metal complexes, the following equations are derived within a framework of logical assumptionsThese compare stability constants of complexes formed by a metal ion M and a ligand L with those formed by a reference metal Msand a reference ligand Lo. The derivation of these equations reveals an inherent relationship between the constants Band C, which is formulated through an "exactness" test. The application of these relationships to stoichiometric equilibrium constants is discussed.In the testing of the foregoing equations with data for various ligand families reacting with numerous metal ions, two principal modes of behavior were noted. In one, there was a mutual dependence of Bon the particular metal ions compared and of Con the particular ligands compared. In the other, all values of Band Cwere found to equal unity irrespective of metal ion or ligand compared. The cause of this distinction is not yet understood.