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Despite a considerable amount of data, the molecular and cellular bases of the toxicity due to metal exposure remain unknown. Recent mechanistic models from radiobiology have emerged, pointing out that the radiation-induced nucleo-shuttling of the ATM protein (RIANS) initiates the recognition and the repair of DNA double-strand breaks (DSB) and the final response to genotoxic stress. In order to document the role of ATM-dependent DSB repair and signalling after metal exposure, we applied twelve different metal species representing nine elements (Al, Cu, Zn Ni, Pd, Cd, Pb, Cr, and Fe) to human skin, mammary, and brain cells. Our findings suggest that metals may directly or indirectly induce DSB at a rate that depends on the metal properties and concentration, and tissue type. At specific metal concentration ranges, the nucleo-shuttling of ATM can be delayed which impairs DSB recognition and repair and contributes to toxicity and carcinogenicity. Interestingly, as observed after low doses of ionizing radiation, some phenomena equivalent to the biological response observed at high metal concentrations may occur at lower concentrations. A general mechanistic model of the biological response to metal exposure based on the nucleo-shuttling of ATM is proposed to describe the metal-induced stress response and to define quantitative endpoints for toxicity and carcinogenicity.

The changes induced in bacterial strains under stress conditions provide an insight into metal resistance strategies. Trivalent chromium resistant bacterium were isolated and identified by 16S rRNA gene sequencing and designated as Alcaligenes faecalis VITSIM2. The growth pattern was monitored. The organism also showed resistance to copper, cadmium, and certain antibiotics. The differentially expressed proteins in SDS PAGE were identified by mass spectrometry as flagellin and 50S ribosomal L36 protein. The morphological changes were identified by scanning electron microscopy. The changes in the cell wall content were estimated by peptidoglycan analysis and transformation of phosphates was detected by 31 P NMR. Flow cytometry was employed to measure the membrane integrity, esterase activity and intracellular pH. In conclusion spectrum of proteomic, physiological, and morphological alterations was observed that aid the organism to overcome chromium stress., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Diabetes results in several metabolic changes, including alterations in the transport, distribution, excretion, and accumulation of metals. While changes have been examined in several rat models of insulin resistance and diabetes, the metal ion concentrations in the tissues of Zucker lean, Zucker obese (an insulin resistance and early stage diabetes model), and Zucker diabetic fatty (ZDF, a type 2 diabetes model) have not previously been examined in detail. The concentration of Cu, Zn, Fe, Mg, and Ca were examined in the liver, kidney, heart and spleen, and Cr concentration in the liver and kidney of these rats were examined. Zucker obese rats have a reduction in the concentration of Cu, Zn, Fe, Mg in the liver compared to ZDF and/or lean Zucker rats, presumably as a result of the increased fat content of the liver of the obese rats. ZDF rats have increased concentrations of kidney Cu compared to the lean rats, while kidney Ca concentrations are increased in the Zucker obese rats. Spleen Fe concentrations are decreased in Zucker obese rats compared to the lean rats. No effects on metal concentrations in the heart were observed between the lean, obese, and ZDF rats, and no effects on Cr concentrations were identified. Cr(III) complexes have previously been shown to have beneficial effects on the signs of insulin resistance in Zucker obese and ZDF rats. The effects of daily gavage administration of chromium picolinate ([Cr(pic)(3)]) (1 mg Cr/kg body mass), CrCl(3) (1 mg Cr/kg body mass), and Cr3 ([Cr(3)O(propionate)(6)(H(2)O)(3)](+)) (33 μg and 1 mg Cr/kg body mass) on metal concentrations in these tissues were examined. Treatment with CrCl(3) and Cr3, but not [Cr(pic)(3)], at 1 mg Cr/kg resulted in a statistically significant accumulation of Cr in the kidney of lean and obese but not ZDF rats but resulted in lowering the elevated levels of kidney Cu in ZDF rats, suggesting a beneficial effect on this symptom of type 2 diabetes.

The use of antimicrobials and toxic metals should be considered carefully in aquaculture and surrounding environments. We aimed to evaluate medically relevant bacteria in an aquaculture system and their susceptibility to antimicrobials and toxic metals. Selective cultures for enterobacteria (ENT), non-fermenting Gram-negative rods (NFR) and Gram-positive cocci (GPC) were obtained from water samples collected in two different year seasons. The isolated bacteria were biochemically identified and antimicrobial and toxic metal susceptibility patterns were determined. Overall, 407 representative strains were recovered. In general, bacteria isolated from fish ponds showed higher multiple antibiotic resistance indices when compared to those isolated from a water-fed canal. Resistance to penicillin and azithromycin was observed more frequently in the GPC group, whereas resistance to ampicillin and ampicillin/sulbactam or gentamicin was observed more frequently in the ENT and NFR groups, respectively. All the isolated bacteria were tolerant to nickel, zinc, chromium and copper at high levels (≥1,024 μg mL(-1)), whereas tolerance to cadmium and mercury varied among the isolated bacteria (2-1,024 μg mL(-1)). Multidrug-resistant bacteria were more frequent and diverse in fish ponds than in the water-fed canal. A positive correlation was observed between antimicrobial resistance and metal tolerance. The data point out the need for water treatment associated with the aquaculture system.

Stable, membrane-permeating nitroxide radicals have been reported to possess antioxidant activity in various experimental systems while, in parallel, they have been considered to be evidently harmful oxidants. The aim of this study was to evaluate the role of the piperidine nitroxide 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol) in the modulation of cyto- and genotoxicity in human lymphocytes in vitro by cadmium and chromium, which depend, at least in part, on formation of reactive oxygen species. The cytokinesis-block micronucleus (CBMN) assay to measure micronucleus (MN) formation, the nuclear division index (NDI) and the percentage of apoptotic and necrotic cells were assessed after exposure human lymphocytes to Cd(II), Cr(III) and Cr(VI) or co-incubation with these metals and Tempol. We found a significant ability of 5-50 microM Tempol to diminish toxic effects of the agents tested. In every system studied, Tempol decreased the micronucleus frequency and the percentage of apoptotic and necrotic cells, while it increased the nuclear division index (p<0.05). We observed adverse effects when 0.1-1 mM Tempol alone was used: inhibition of cell growth, induction of apoptotic and necrotic cell death and chromosomal damage (p<0.05). Collectively, we demonstrated that Tempol can be considered as a potent anti-apoptotic and antigenotoxic agent, but also as a cytotoxic and clastogenic chemical, depending on the concentration applied.

Effects of fifteen particulate objects, fourteen metals and one non-metal on cell viability of osteoblast-like cells were studied in vitro, to determine whether an adverse effect on cells could be induced by the particulate form or soluble ions. The Al, Ti, Zr, Nb, Ta, Cr, Mo, and Fe particulates depressed cell viability at higher particulate concentrations, but their extracts yielded no effect on cells except for Mo. On the other hand, little difference in cell viability between particulates and extracts was observed for Cu, Si, V, W, and Co. However, Mn and Ni yielded more adverse effects on cells in the case of the particulates than the extracts. These findings suggested that the effects of particulates on cells depended upon the direct effects of contact between particulates and cells, the indirect effects of dissolved ions and the kinds of particulate elements.

Background: Manufactures of orthopaedic fracture implants have turned to titanium in a pure form and an alloy during the past ten to fifteen years. Although primarily because of the biomechanical properties of this metal, concern for allergy to nickel and chromium ions in stainless steel was a factor in these decisions., Objectives: To document the incidence of baseline sensitivity to metal ions and the incidence of conversion to sensitivity to one of three ions in stainless steel in a population of trauma patients at a Level I trauma center., Design: Prospective, consecutive patient series., Setting: Level I trauma center., Patients: Patients eighteen years of age and older with no history of metallic implants were recruited for this study between October 1995 and July 1997. Four hundred ninety-three patients had a Finn chamber device with chromium, nickel, and cobalt ions, which were read using a photographic scale on day three. Two hundred forty-two of these patients had placement of a second patch, at a mean interval of 187 days (range 45 to 589 days)., Intervention: Internal fixation of fracture or osteotomy with metal implant. MAIN OUTCOME MANAGEMENT: Cutaneous reactivity to metal ions., Results: Prevalence of sensitivity to chromium was 0.2 percent, to nickel 1.3 percent, and to cobalt 1.8 percent. Rates for conversion from a negative to positive status were 2.7 percent for chromium, 3.8 percent for nickel, and 3.8 percent for cobalt. Rates for desensitization (i.e., converting from a positive to negative status) were 2.1 percent for nickel and 3.8 percent for cobalt., Conclusion: The prevalence of sensitivity to nickel, cobalt, and chromium is apparently low. Similarly, internal fixation devices composed of stainless steel appear to result in an equal incidence of conversion to metal ionic sensitivity and desensitization to metal ions. It is conceivable that cutaneous sensitivity is not representative of deep immune response.

Most cellular functions evaluated for biocompatibility are high-energy processes such as proliferation and therefore are not usually affected before a decrease in energy production is observed. Several studies have shown that metabolic functions are altered at much lower concentrations than several normally used biocompatibility tests such as viability. Therefore, the purpose of this study was to provide an in-depth evaluation of metallic ion effects on mitochondria function and thereby biocompatibility. These studies evaluated the mitochondrial function of human gingival fibroblasts exposed to the salt solutions of ions released from nickel-based dental alloys, particularly beryllium (Be(2+)), chromium (Cr(6+) and Cr(3+)), nickel (Ni(2+)), and molybdenum (Mo(6+)). Mitochondrial function was examined by NADH:CoQ reductase activity, succinate dehydrogenase activity, and oxygen consumption., (Copyright 2000 John Wiley & Sons, Inc.)

Cytokines produced by leukocytes in the periprosthetic membranes surrounding joint replacements have been implicated as causal agents in osteolysis and prosthetic loosening. In this study, we used an in vitro leukocyte culture system to monitor the response of leukocytes to various metal ions and their possible roles in the mechanism of aseptic loosening. Human peripheral leukocytes were isolated and incubated with various concentrations of Co2+, Cr3+, and Ti3+ ions. Leukocyte cell counts and the levels of the tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), interleukin-6 (IL-6) and prostaglandin E2 (PGE2) released into the media were analyzed at 1 h, 3 h, and 1, 3, and 7 day intervals. The results showed that adding different metal ions into leukocyte cultures did not affect the cell counts. Exposure of leukocytes to Co2+ ion increased the release of TNF-alpha, IL-6, and PGE2. Exposure of leukocytes to Cr3+ ion did not increase the release of TNF-alpha but increased the secretion of IL-6 and PGE2. In contrast, exposure of the leukocytes to Ti3+ ions was associated with a decrease in the release of TNF-alpha and PGE2 and a minimal change in IL-6 noted after 7 days' culture. The present study elucidated the possible mechanisms involved in periprosthetic osteolysis and the inflammatory response of human leukocytes to metal ions. We found that cobalt ion is the most potent stimulant for cytokines and prostaglandin secretion by leukocytes. This elucidation, in combination with other efforts to reduce the generation of wear debris and metal ions, may improve the longevity of orthopedic implants.

We have previously shown that in vitro exposure to metallic compounds enhances expression of interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha in human bronchial epithelial cells. To characterize signaling pathways involved in metal-induced expression of inflammatory mediators and to identify metals that activate them, we studied the effects of As, Cr, Cu, Fe, Ni, V, and Zn on the mitogen-activated protein kinases (MAPK) extracellular receptor kinase (ERK), c-Jun NH2-terminal kinase (JNK), and P38 in BEAS cells. Noncytotoxic concentrations of As, V, and Zn induced a rapid phosphorylation of MAPK in BEAS cells. Activity assays confirmed marked activation of ERK, JNK, and P38 in BEAS cells exposed to As, V, and Zn. Cr and Cu exposure resulted in a relatively small activation of MAPK, whereas Fe and Ni did not activate MAPK under these conditions. Similarly, the transcription factors c-Jun and ATF-2, substrates of JNK and P38, respectively, were markedly phosphorylated in BEAS cells treated with As, Cr, Cu, V, and Zn. The same acute exposure to As, V, or Zn that activated MAPK was sufficient to induce a subsequent increase in IL-8 protein expression in BEAS cells. These data suggest that MAPK may mediate metal-induced expression of inflammatory proteins in human bronchial epithelial cells.

Heavy metal intoxication leads to a number of reabsorptive and secretory defects in renal transport systems. We have studied the effects of several heavy metals on the expression of the renal Na-Si cotransporter NaSi-1. NaSi-1 cRNA was injected into Xenopus oocytes, and Na-Si cotransport activity was measured in the presence of mercury, lead, cadmium, or chromium. Mercury strongly inhibited NaSi-1 transport irreversibly by reducing both maximal velocity (Vmax) and Michaelis constant (Km) for inorganic sulfate (Si). Lead inhibited NaSi-1 transport reversibly by decreasing Vmax but not Km for Si. Cadmium showed weak reversible inhibition of NaSi-1 transport by decreasing only NaSi-1 Vmax. Chromium strongly inhibited NaSi-1 cotransport reversibly by reducing Km for Si by sevenfold, most probably by binding to the Si site, due to the strong structural similarity between the CrO4(2-) and SO4(2-) substrates. In conclusion, this study presents an initial report demonstrating heavy metals inhibit renal brush border Na-Si cotransport via the NaSi-1 protein through various mechanisms and that this blockade may be responsible for sulfaturia following heavy metal intoxication.

The cytocompatibility of stainless steel 316L (SS 316L) corrosion products was investigated with particular focus on the dose- and time-effect of electrochemically dissolved SS and the corresponding separate metal ions on osteogenic bone marrow derived cells. Type AISI 316L stainless steel (Fe 63.9%, Cr 18.0%, Ni 12.5%, Mo 2.8%, Si 1.2%, Mn 1.6% and C 0.025%, weight for weight) was anodically dissolved in Hank's Balanced Salt Solution (HBSS) and diluted to the following concentrations: 500 microg ml(-1) of Fe, 122 microg ml(-1) of Cr and 101 microg ml(-1) of Ni, as estimated by atomic absorption spectrometry. Similarly, salt solutions containing 50 microg ml(-1) of Fe (FeCl3 x 6H2O), 122 microg ml(-1) of Cr (CrCl3 x 6H2O) or 101 microg ml(-1) of Ni (NiNO3) were prepared. All solutions were diluted 1:10(3), 1:10(4) and 1:10(5) and their effects on cell proliferation and function of rabbit bone marrow cells were studied up to 28 days of culture. Bone marrow cells (second subculture) were cultured in alpha-Minimal Essential Medium (alpha-MEM) supplemented with 10% fetal bovine serum 10(-8) mol l(-1) dexamethasone, 2.52 x 10(-4) mol l(-1) ascorbic acid and 10(-2) mol l(-1) beta-glycerophosphate. The osteoblast response to the presence of metal ions was evaluated by biochemical assays (enzymatic reduction of MTT for evaluation of cell viability/proliferation, and estimation of alkaline phosphatase (ALP) activity) and histochemical assays (identification of ALP positive cells and calcium and phosphates deposits). Results suggest a decrease in the expression of the osteoblast phenotype in the presence of ion and alloy solutions. Stainless steel corrosion products elicited slight effects but the corresponding metal ions produced pronounced effects on the osteoblast phenotype, namely an alteration in the levels and temporal expression of ALP and lower and retarded tissue mineralization ability.

The responses of human peripheral blood monocytes of 10 normal volunteers and 14 patients with total hip replacements to particles of commercially pure titanium and chromium orthophosphate (a corrosion product from cobalt-chromium alloy implants) were studied. In addition, these phagocytosable particles were added to cultured mononuclear cells isolated from the interfacial membrane of 14 patients with failed implants. Peripheral blood monocytes from patients who had had a total hip replacement produced significantly higher levels of interleukin-1 (both interleukin-1 alpha and interleukin-1 beta) and prostaglandin E2 following particulate stimulation than those from normal volunteers. Supernatants from both titanium and chromium orthophosphate-stimulated peripheral blood monocytes from the volunteers and patients with total hip replacement induced bone resorption (assayed in organ cultures of newborn mouse calvariae) and the proliferation of human fibroblasts. The levels of bone resorption were significantly higher (p < 0.05) in patients with implants than in normal volunteers. There were no significant differences in the responses of cells between patients with focal osteolysis and those without osteolysis. Interfacial membrane mononuclear cells also produced high levels of interleukin-1 alpha, interleukin-1 beta, and prostaglandin E2 and expressed bone resorptive activities following stimulation with either titanium or chromium orthophosphate. More importantly, interfacial membrane mononuclear cells "spontaneously" produced high levels of prostaglandin E2 that were comparable with the response of peripheral blood monocytes stimulated with particulate wear debris. The clinical relevance of this study is 2-fold. First, mononuclear cells from patients with total hip replacement were some-how "sensitized" to metal particles in comparison with mononuclear cells from individuals without an implant. Second, the chromium orthophosphate corrosion product was a potent macrophage/monocyte activator and may contribute to macrophage-mediated osteolysis and aseptic loosening.

Several chromosome- and plasmid-encoded metal resistance genetic systems have been studied in Pseudomonas and related bacteria. Some systems are known with molecular detail whereas others are still poorly understood. The former include resistance genes for cations derived from mercury, cadmium and copper and anions from arsenic and chromium. Except for mercury, where a redox transformation occurs, extrusion of the toxic ions from the bacterial cytoplasm appears to be the most common mechanism of resistance.

Recent data suggest that under certain conditions, various metal cations are released from dental alloys. These ions may produce adverse effects in various cell types in vivo. In this study, the cytopathogenic effects of 13 metal cations on murine L-929 fibroblasts, human gingival fibroblasts, and human tissue mast cells were analyzed in vitro. Several metal cations (dose range, from 0.0033 to 1.0 mmol/L) were found to induce dose-dependent inhibition of 3H-thymidine incorporation into cultured fibroblasts. The rank order of potency (lowest observed effect level, LOEL) for L-929 fibroblasts was: Ag+ > Pt4+ > Co2+ > In3+ > Ga3+ > Au3+ > Cu2+ > Ni2+ > Zn2+ > Pd2+ > Mo5+ > Sn2+ > Cr2+. A similar rank order of potency was obtained for primary human gingival fibroblasts: Pt4+ > Ag+ > Au3+ > In3+ > Ga3+ > Ni2+ > Co2+ > Zn2+ > Cu2+ > Cr2+ > Pd2+ > Mo5+ > Sn2+. In primary human mast cells, Ag+ and Au3+ caused dose-dependent toxic histamine release, whereas the other metal cations were ineffective over the dose range tested. To investigate the mechanism of metal cation-induced effects, we performed DNA as well as electron microscopic analyses on cultured fibroblasts. Both the DNA pattern and the ultrastructure of L-929 cells and gingival fibroblasts after exposure to cytopathogenic metal cations revealed signs of necrosis but no signs of apoptosis. Together, our data provide evidence that various metal cations produce dose-dependent cytopathogenic effects in distinct cell types, including human gingival fibroblasts and human tissue mast cells.(ABSTRACT TRUNCATED AT 250 WORDS)

A chromogenic strain of Streptomyces galbus 5ME-13 producing an antifungal antibiotic was used to study the effects of some heavy metals on growth, melanoid pigment and antibiotic production in culture. Mercury and nickel were highly toxic followed by cadmium while cobalt and chromium appeared to be less toxic. All the metals inhibited growth, pigment and antibiotic production with widely variable IC50 values. Cadmium and chromium at lower concentrations unusually stimulated growth and enhanced pigment production in the strain.

Many metal materials are used in clinical medicine and the number used is increasing. However, there are a few papers concerning the biological effects, especially effects of clinically used metals on cellular immunity. In this paper, silver (Ag), nickel (Ni), cobalt (Co), and chromium (Cr), clinically commonly used metals, the effects of which on neutrophilic activity have already reported using the luminol-dependent chemiluminescence (LDCL) method, were examined to determine their influence on the reactive oxygen species (ROS) generating capacity of human neutrophils and on a serum opsonic activity. Silver suppressed the ROS generating capacity of neutrophils in a dose-dependent manner but did not affect the serum opsonic activity. Nickel also suppressed the ROS generating capacity of neutrophils but, at some concentrations, caused the serum opsonic activity to increase. In contrast, Cobalt increased both the ROS generating capacity of neutrophils and the serum opsonic activity. Like silver, chromium did not affect the serum opsonic activity and suppressed the ROS generating capacity of neutrophils. However, the suppression of ROS generating by chromium occurred differently from that of silver. In the cases of nickel and cobalt, effects of these metals on hemolyzing activity of serum complements (CH-50) were measured and consumption of complements was observed at the same metal concentration at which serum opsonic activity was elevated. In this paper, we report that some metals influence not only the ROS generating capacity of neutrophils but also the serum opsonic activity, results thought to be important for more details studies of the effects of metals on cellular immunity.

Bovine synovial fibroblasts in primary monolayer culture were exposed to particulate metallic debris. The effects of the metallic particles on the synthesis and secretion of proteolytic enzymes and on cell proliferation and viability were examined. Uniform suspensions of titanium, titanium-aluminum, cobalt, and chromium particles, ranging in size from approximately 0.1 to ten micrometers (average, one to three micrometers), were prepared; the particle concentrations (the volume of particles divided by the total volume of the suspension) ranged from 0.0005 to 5 per cent. Aliquots of the particle suspensions were added to the synovial fibroblast cultures. The final particle concentrations in the media ranged from 0.0000083 to 0.83 per cent. After seventy-two hours of exposure, each medium was harvested and was assayed for proteolytic and collagenolytic activity and for hexosaminidase levels. Neutral metalloproteases, quantified by collagenolytic and caseinolytic (proteolytic) activity, represent enzymes, secreted by cells, that are capable of degrading extracellular matrix. Hexosaminidase is a marker for lysosomal enzyme activity that can include more than thirty enzymes, such as proteases, lipases, nucleases, and phosphatases. Cell proliferation was quantified by uptake of 3H-thymidine. Cell morphology was examined by scanning electron microscopy. Titanium, titanium-aluminum, and chromium significantly stimulated 3H-thymidine uptake at low particle concentrations (p < 0.01, p < 0.002, and p < 0.002, respectively). Exposure to cobalt, even at the lowest particle concentration, resulted in a significant decrease in thymidine uptake (p = 0.027). At the highest particle concentrations, all particles were toxic, as evidenced by the absence of thymidine uptake. At high particle concentrations, all of the metals caused a decrease in caseinolytic (proteolytic) and collagenolytic activity in the culture media. Titanium elevated the lysosomal enzyme marker, hexosaminidase, except at high concentrations. Chromium and titanium-aluminum had no significant effect on hexosaminidase at any particle concentration, while cobalt decreased all enzyme markers at mid-particle to high-particle concentrations. Scanning electron microscopy demonstrated that the morphological response of fibroblasts to titanium included membrane-ruffling and extension of filopodia, typical of active fibroblasts. In contrast, exposure to cobalt at the same concentration resulted in cell crenation, indicative of cell death.

This study was conducted to investigate the specific in vitro antibacterial effect of seven dental implant metals on oral bacteria which have often been identified in failing implants. The metals chosen for evaluation were titanium, chromium, cobalt, aluminum, iron, gold, and vanadium. These metals were selected because they are contained in many commonly used dental implants. The bacteria selected for this study included isolates of Porphyromonas endodontalis, Porphyromonas gingivalis, Prevotella intermedia, Prevotella melaniogenica, Actinobacillus actinomycetemcomitans, Actinomyces naeslundii, and Actinomyces viscosus. Sets of tubes containing either supplemented trypticase soy broth, brain-heart infusion-yeast extract, or brain-heart infusion-yeast extract with 5 percent defibrinated rabbit blood were aseptically prepared with doubling dilutions of the seven metals starting at an initial concentration of 500 micrograms/ml and terminating at 0 microgram/ml. Cultures of each organism were inoculated into each set of broth tubes containing all concentrations of metals. Tubes were incubated either anaerobically or in an atmosphere of 5 percent carbon dioxide for 48 hours at 35 degrees C and then assayed for ATP content which was proportional to the viable cellular biomass. The results showed that, although being bacteria and concentration dependent, all seven metals suppressed the growth of each organism. The rank order of antibacterial activity expressed by dental implant metals was gold > titanium > cobalt > vanadium > aluminum > chromium > iron.

Several heavy metal salts [NiSO4, Cd(CH3COO)2, Pb(CH3COO)2, K2CrO4, CrCl3] were examined for their effects on intercellular communication in primary Syrian hamster embryo (SHE) cells and in the 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-sensitive SHE cell line BPNi. Two exposure regimes were used: the standard regime where the exposure occurred after the cells had grown to confluence; and a non-standard regime where a high number of cells were seeded in a medium containing the metal salts. None of the chemicals were potent inhibitors of communication, i.e. effects were only found at concentrations that were non-compatible with long-term survival of the cells. NiSO4 inhibited communication in both regimes and in both cell types, but the effect was more pronounced for BPNi cells in the non-standard regime. K2CrO4 inhibited communication in the non-standard regime in both cell types, but significantly increased communication in the standard regime in BPNi cells. Similar effects were not found with CrCl3 or KCl. Thus, they were due to the properties of the CrO4(2-) ion. K2CrO4 upregulated communication in TPA-exposed BPNi cells. A high concentration of SO4(2-) did not influence the K2CrO4 inhibition in the non-standard regime, but it significantly inhibited the K2CrO4-induced increase in communication in the standard regime in BPNi cells. This suggests that K2CrO4 acts through two different mechanisms in the two exposure regimes. The CrO4(2-)-sensitive site that causes enhancement of communication in the standard regime is probably intracellular, while the site causing CrO4(2-) inhibition in the formation of gap junctional communication in the non-standard regime is most likely to be extracellular.

Certain metals added as salts to a defined basal culture medium influenced the level of aflatoxin production by Aspergillus parasiticus in the low micrograms-per-milliliter range of the added metal. In many cases no change or a relatively small change in mat weight and final pH of the medium accompanied this effect. With zinc at added levels of 0 to 10 mug/ml in the medium, aflatoxin increased 30-to 1,000-fold with increasing of zinc, whereas mat weight increased less than threefold. At 25 mug of added zinc per ml, aflatoxin decreased, but mat weight did not. At an added level of 25 mug or less of the metal per ml, salts of iron, manganese, cooper, cadmium, trivalent chromium, silver, and mercury partly or completelyinhibited aflatoxin production, without influencing mat weight.

Groups of rabbits were exposed by inhalation to chlorides of cobalt, nickel, and manganese as well as to tri- and hexavalent chromium at metal concentrations ranging from 0.4 to 3.9 mg/m3 for 1-4 months (5 days/week, 6 hr/day). Fibronectin content and lysozyme (muramidase) activity in lavage fluid were measured after all treatments and in alveolar macrophages after treatment with nickel chloride. In the lavage fluid no marked changes were seen in fibronectin content and lysozyme activity after exposure to tri- or hexavalent chromium or manganese. Nickel exposure significantly decreased the lysozyme activity in the lavage fluid and in the macrophages whereas the fibronectin content was unchanged in the lavage fluid and significantly increased in the macrophages. Both fibronectin content and lysozyme activity were increased markedly in the lavage fluid after cobalt exposure.

The inhibitory effect of several first transition metal ions on growth and pigment formation on three strains of Serratia marcescens was studied by the method of minimal inhibitory concentration. From this study it can be concluded that several of the first transition metal ions, namely Cr (II), Mn (II), Fe (II), Co (II) and Cu (II), with the inclusion of Zn (II), have a definite inhibitory effect on both growth (strains 08, WF, 933) and pigment formation (strain 08) of Serratia marcescens. Based on their electron configuration and their effectiveness, these first transition metal ions can be divided into two groups: Cr (II), Mn (II), Fe (II) and Co (II), Ni (II), Cu (II) and Zn (II). Several suggestions were made to explain their inhibitory actions.

This is part of a larger study designed to investigate the action of particulate metals of orthopaedic interest on tissues. Damaging effects were determined by cytological examination and the assay of two enzymes. Lactic dehydrogenase (LDH) if released into the supernatant indicates a damaged cell membrane; decreased intracellular levels of glucose-6-phosphate dehydrogenase (G6PD) indicates a lowered phagocytic capacity of the cells. Soluble and wear products around implanted prostheses could facilitate late infections by impairing local reactions to bacteria. Particulate cobalt, nickel and cobalt-chromium alloy were found to damage the cells and to cause LDH release. G6PD was found to have a lower activity in the cells exposed to these materials. In contrast, titanium, chromium and molybdenum were well tolerated by macrophages and had no effect on the distribution and activity of either enzyme. The solubility of these metals in the culture medium was also measured.

Exposure levels of the principal carcinogenic and potential carcinogenic metal and mettalloid pollutants in the environment (e.g., arsenic, beryllium, chromium, nickel, cadmium, and lead) are primarily reviewed with emphasis on their environmental sources both natural and manmade. There is a general paucity of definitive information concerning aspects of material balance and chemical transformations of these elements in various chemical forms in the environment, primarily the atmosphere. Estimates of both exposure levels and risk to populations other than industrial workers of the above metals have been in most instances quite difficult to obtain and generally speculative. The trend for the immediate future appears to be of greater exposure to these metals not only as a result of generally increased usage patterns, but also because of prospective enhanced use of fossil fuels for space heating and electricity generation.

In order to answer the question whether certain biochemical reactions may influence the date of metal removal after osteosynthesis, plasmaprotein and immunoglobulin levels were checked.

Tracheal explants were used to evaluate the relative ciliostatic and cytotoxic potential of heavy metal salts (cadmium chloride, chromium chloride, nickel chloride, and copper sulfate). Explants from hamster, rat, and guinea pig were all sensitive to the metals, though guinea pig explants showed the greatest difference between the untreated and metal treated tissues. Dosage levels were 50, 100, and 500 microM, for 24 to 148 h. Cadmium caused the greatest degree of ciliostasis and cell necrosis. Copper was less toxic, and nickel and chromium caused marginal damage when tested at 100 microM or lower. In each instance, damage became detectable at approximately 24 to 48 h and was nearly stabilized by 72 h. A significant loss of ciliary motion was always accompanied by a decrease in metabolic activity (dehydrogenase activity and ATP content). Transmission and scanning electron microscopy revealed a severely necrotic epithelium after exposure to cadmium, with only subtle morphological alterations after exposure to other metals. With all of the treatments there was no overt structural damage to cilia and little alteration in membranes of cells remaining in the epithelium. Some coagulation or vacuolization was noted in cadmium and copper treated explants but most cellular organelles did not display obvious damage. The most significant changes in the tracheal epithelium exposed to heavy metal salts in vitro were a loss of ciliary motion and a decrease in total ATP content.

The haemolytic action of particulate cadmium, chromium, cobalt, iron, molybdenum, nickel, tantalum, titanium, zinc and cobalt-chromium alloy is described. Cobalt, nickel and cobalt-chromium alloy were found to be the most active and were also the most toxic for other cells in tissue culture. In contrast the other particulate metals produced only low levels of haemolysis and in general, were well tolerated by cells in culture. A dual effect of particulate metals is described due firstly to a direct interaction between the particle surface and cell membrane and secondly to the possible toxic effects of dissolved metal.

Collagen content in the liver of rats exposed to several environmentally significant metals viz. Hg, Cd, Pb, Mo, Cu, Cr, Mn, Co and Zn have been determined. All these elements except Co, Zn and Mn enhanced the collagen contents in the liver. Mechanisms elucidating the phenomenon of collagenosis have also been discussed.

The effect of mercury, cadmium, copper, zinc, chromium and lead on an environmental strain of Escherichia coli was studied. The tolerance growth limits, growth kinetics and viability were determined. It was found that metal-ion concentrations greater than the threshold values (0.005 microM Hg2+, 0.5 microM Cd2+, 5 microM Cu2+, 23 microM Cr3+, 30 microM Zn2+, 45 microM Pb2+) increase the lag-phases but do not modify the growth kinetics (Pb2+ is an exception). During the lag-phase a reduction in cell viability, varying from a maximum of 89% for lead, to a minimum of 13% for cadmium, was observed. The reduction of viability accounts for a cells physiological adaptation to the metals rather than selection of resistant mutants. Loss of the acquired metal resistance following exposure of the bacterial cells to the metals supported this last point.

Crosslinking of proteins to DNA was studied in live intact Novikoff ascites hepatoma cells exposed in vitro to salts of chromium VI, III, and II, nickel II, cadmium II, and to CoCl2, As2O3, and AlK(SO4)2. DNA-protein complexes were separated by high-speed centrifugation of cells solubilized in buffered 4% sodium dodecyl sulfate and assayed by polyacrylamide gel electrophoresis. Hexavalent chromium compounds formed DNA-protein complexes very efficiently. The trivalent, poorly soluble, cupric chromite was nearly as efficient crosslinker as hexavalent Cr, perhaps because phagocytosis facilitated its entry into the cells. The more basic divalent form produced hardly any crosslinks. Most of the crosslinked proteins were common to all of the chromium salts employed. Nickel salts formed DNA-protein crosslinks less efficiently. Most proteins crosslinked by this metal had a high molecular weight ranging from 94,000 to 200,000. There was little qualitative difference between the crosslinked protein patterns for several various nickel (II) salts. Similar results were obtained for cells incubated with cadmium salts. Most of the proteins crosslinked by cadmium had high molecular weights and were similar to those crosslinked by nickel (II). Relatively weak, but significant, crosslinking was also observed when the Novikoff hepatoma cells were exposed to CoCl2, As2O3, or AlK(SO4)2.

Interactions between Cd and other metal ions are important from both nutritional and toxicological aspects. As Cd is toxic to isolated hepatocytes, these cells can be used to investigate the effects of other metals on Cd-induced cellular injury. Isolated hepatocytes were incubated at 37 degrees C with vehicle (saline); Cd (200 or 400 microM); or Cd plus Cr, Mn, Zn, Ni, Pb, Se, or Fe (200-1000 microM). Evidence of cellular injury was assessed by loss of intracellular K+ and aspartate aminotransferase from the hepatocytes. Effects on lipid peroxidation, as measured by concentration of the thiobarbituric acid reactants, were assessed. Uptake of 109Cd and interaction of the other metal ions with this accumulation were also quantitated. Cell injury due to Cd was consistently reduced by Cr, Mn, Zn, Pb, and Fe. Lipid peroxidation due to Cd was inhibited by Cr, Mn, and Zn. All the metals except Ni produced an increase in the amount of Cd accumulated by hepatocytes. There was no consistent relation between reduction of cellular toxicity and either inhibition of lipid peroxidation or uptake of Cd. These experiments show that (1) protective properties of some metals seen in vivo can be demonstrated at the cellular level and (2) protective effects of metals in general on Cd-induced cellular toxicity are not due to a decrease in either Cd uptake or lipid peroxidation.

Experiments were performed to measure the effect of trace metals on a vital function of the alveolar macrophage (AM), phagocytosis. Since certain trace metals were found to reduce the viability of AMs, a technique was developed to permit examination of live cells only for phagocytosis. Evidence is presented that Ni(2+) selectively altered the phagocytic activity of AMs at concentrations lower than those which caused cell death. It is further shown that a level of VO(3) (-) that caused extensive lysis and death did not reduce phagocytosis in surviving cells. The effects of Cd(2+), Cr(3+), and Mn(2+) on AMs were also examined.

This paper discusses metal exposure in the male, the nonpregnant female, and the maternal-offspring unit. In the first two situations, the primary targets are the gonads. In the mother-offspring unit, consideration must be given to effects on the fertilized ovum, the growth of the embryo, and, finally, to the fetal and perinatal stages. The central nervous system may be especially vulnerable during development. The placenta also undergoes development, and either the placenta or the fetus may be the primary target. In humans, certain metals may cause abortion or other effects on the conceptus. Effects may also be produced by metal exposure both in utero and in the suckling infant. For example, methylmercury gives rise to a range of effects on the central nervous system at doses lower than those producing damage to the mature nervous system. Effects of lead and arsenic are associated mainly with postnatal exposures during infancy and early childhood, but there is reason to believe from animal experiments that some effects may occur from prenatal exposures to certain metal compounds.

Five metallic cations (Fe(3+), Cr(3+), Ca(2+), Mg(2+), Mn(2+); concentration range, 1.85 x 10(-4) to 37 x 10(-4)m) were incorporated individually as chlorides into nutrient broth and agar media used for the recovery of phenol-treated Escherichia coli. The effects observed varied with the concentration and the ionic species. In nutrient agar, Fe(3+) and Cr(3+) were generally beneficial but were toxic at 37 x 10(-4)m. Of the divalent ions tested, Ca(2+) and Mg(2+) usually gave higher counts in nutrient broth, except at a concentration of 9.25 x 10(-4)m, whereas the effect of Mn(2+) was rather variable. Two possible explanations are suggested to explain these effects. Toxic materials may be removed from the media by the precipitates formed on the addition of Fe(3+) or Cr(3+), or, in the case of the divalent ions, the integrity of the bacterial cell membranes may be maintained.