Cluster of exertional rhabdomyolysis in three young women.

Three young women, aged 18-24 years, presented to general practice with signs and symptoms of exertional rhabdomyolysis in 2016. All attended the same gym and had undertaken an intensive physical workout. Presenting symptoms were severe muscle pain and swelling, significantly reduced range of motion in affected muscles and, in two cases, dark-coloured urine. One case had presented to the out-of-hours service 4 months previously with similar symptoms but rhabdomyolysis was not considered, although retrospective history taking suggests that was the likely diagnosis. All three women were admitted to hospital, treated with intravenous fluids and discharged between 1 and 6 days later. All made a full recovery with no renal sequelae. The cases were questioned about potential risk factors, and the only commonality was unaccustomed strenuous exercise.

Impact of DNA polymerase ζ mutations on genotoxic thresholds of oxidative mutagens.

In regulatory genetic toxicology, it is an axiom that there is no threshold for genotoxicity of chemicals, such that genotoxic chemicals may impose carcinogenic risk on humans even at very low doses. This paradigm is counterintuitive, however, because humans possess a number of self-defense mechanisms that may suppress the genotoxicity at these low doses and therefore manifest a practical threshold. DNA polymerase zeta (Pol ζ) is a specialized Pol that plays an important role in DNA synthesis across DNA damage, thereby modulating cell survival and genotoxicity. In this study, we compared the sensitivity of three types of human cells: D2781N, L2618M, and their wild-type (WT) cells, to the low dose effects of genotoxicity of the oxidizing agents, potassium bromate (KBrO3) and sodium dichromate (Na2Cr2O7). D2781N cells express a variant form of Pol ζ, whose activity is weaker than that of the WT enzyme. L2618M cells express another variant form of Pol ζ, whose fidelity of DNA replication is lower than that of the WT enzyme. D2781N exhibited the highest sensitivity for TK gene mutation and micronucleus (MN) formation and displayed the lowest practical threshold for MN induction by KBrO3. In contrast, L2618M exhibited the lowest practical threshold for sister-chromatid exchange (SCE) induction by both chemicals. These results suggest that Pol ζ mutations have significant impacts on practical thresholds of genotoxicity; the factors affecting the practical threshold can differ depending on the endpoint of genotoxicity. Roles of the variant forms of Pol ζ in genotoxicity by the oxidizing agents are discussed.

Prolonged exposure to particulate chromate inhibits RAD51 nuclear import mediator proteins.

Particulate hexavalent chromium (Cr(VI)) is a human lung carcinogen and a human health concern. The induction of structural chromosome instability is considered to be a driving mechanism of Cr(VI)-induced carcinogenesis. Homologous recombination repair protects against Cr(VI)-induced chromosome damage, due to its highly accurate repair of Cr(VI)-induced DNA double strand breaks. However, recent studies demonstrate Cr(VI) inhibits homologous recombination repair through the misregulation of RAD51. RAD51 is an essential protein in HR repair that facilitates the search for a homologous sequence. Recent studies show prolonged Cr(VI) exposure prevents proper RAD51 subcellular localization, causing it to accumulate in the cytoplasm. Since nuclear import of RAD51 is crucial to its function, this study investigated the effect of Cr(VI) on the RAD51 nuclear import mediators, RAD51C and BRCA2. We show acute (24h) Cr(VI) exposure induces the proper localization of RAD51C and BRCA2. In contrast, prolonged (120h) exposure increased the cytoplasmic localization of both proteins, although RAD51C localization was more severely impaired. These results correlate temporally with the previously reported Cr(VI)-induced RAD51 cytoplasmic accumulation. In addition, we found Cr(VI) does not inhibit interaction between RAD51 and its nuclear import mediators. Altogether, our results suggest prolonged Cr(VI) exposure inhibits the nuclear import of RAD51C, and to a lesser extent, BRCA2, which results in the cytoplasmic accumulation of RAD51. Cr(VI)-induced inhibition of nuclear import may play a key role in its carcinogenic mechanism since the nuclear import of many tumor suppressor proteins and DNA repair proteins is crucial to their function.

Prolonged particulate chromate exposure does not inhibit homologous recombination repair in North Atlantic right whale (Eubalaena glacialis) lung cells.

Chromosome instability is a common feature of cancers that forms due to the misrepair of DNA double strand breaks. Homologous recombination (HR) repair is a high fidelity DNA repair pathway that utilizes a homologous DNA sequence to accurately repair such damage and protect the genome. Prolonged exposure (>72h) to the human lung carcinogen, particulate hexavalent chromium (Cr(VI)), inhibits HR repair, resulting in increased chromosome instability in human cells. Comparative studies have shown acute Cr(VI) exposure induces less chromosome damage in whale cells than human cells, suggesting investigating the effect of this carcinogen in other species may inform efforts to prevent Cr(VI)-induced chromosome instability. Thus, the goal of this study was to determine the effect of prolonged Cr(VI) exposure on HR repair and clastogenesis in North Atlantic right whale (Eubalaena glacialis) lung cells. We show particulate Cr(VI) induces HR repair activity after both acute (24h) and prolonged (120h) exposure in North Atlantic right whale cells. Although the RAD51 response was lower following prolonged Cr(VI) exposure compared to acute exposure, the response was sufficient for HR repair to occur. In accordance with active HR repair, no increase in Cr(VI)-induced clastogenesis was observed with increased exposure time. These results suggest prolonged Cr(VI) exposure affects HR repair and genomic stability differently in whale and human lung cells. Future investigation of the differences in how human and whale cells respond to chemical carcinogens may provide valuable insight into mechanisms of preventing chemical carcinogenesis.

Chronic Exposure to Particulate Chromate Induces Premature Centrosome Separation and Centriole Disengagement in Human Lung Cells.

Particulate hexavalent chromium (Cr(VI)) is a well-established human lung carcinogen. Lung tumors are characterized by structural and numerical chromosome instability. Centrosome amplification is a phenotype commonly found in solid tumors, including lung tumors, which strongly correlates with chromosome instability. Human lung cells exposed to Cr(VI) exhibit centrosome amplification but the underlying phenotypes and mechanisms remain unknown. In this study, we further characterize the phenotypes of Cr(VI)-induced centrosome abnormalities. We show that Cr(VI)-induced centrosome amplification correlates with numerical chromosome instability. We also show chronic exposure to particulate Cr(VI) induces centrosomes with supernumerary centrioles and acentriolar centrosomes in human lung cells. Moreover, chronic exposure to particulate Cr(VI) affects the timing of important centriolar events. Specifically, chronic exposure to particulate Cr(VI) causes premature centriole disengagement in S and G2 phase cells. It also induces premature centrosome separation in interphase. Altogether, our data suggest that chronic exposure to particulate Cr(VI) targets the protein linkers that hold centrioles together. These centriolar linkers are important for key events of the centrosome cycle and their premature disruption might underlie Cr(VI)-induced centrosome amplification.

Plasma exchange successfully treats central pontine myelinolysis after acute hypernatremia from intravenous sodium bicarbonate therapy.

BACKGROUND: Osmotic demyelination syndrome (ODS) primarily occurs after rapid correction of severe hyponatremia. There are no proven effective therapies for ODS, but we describe the first case showing the successful treatment of central pontine myelinolysis (CPM) by plasma exchange, which occurred after rapid development of hypernatremia from intravenous sodium bicarbonate therapy. CASE PRESENTATION: A 40-year-old woman presented with general weakness, hypokalemia, and metabolic acidosis. The patient was treated with oral and intravenous potassium chloride, along with intravenous sodium bicarbonate. Although her bicarbonate deficit was 365 mEq, we treated her with an overdose of intravenous sodium bicarbonate, 480 mEq for 24 hours, due to the severity of her acidemia and her altered mental status. The next day, she developed hypernatremia with serum sodium levels rising from 142.8 mEq/L to 172.8 mEq/L. Six days after developing hypernatremia, she exhibited tetraparesis, drooling, difficulty swallowing, and dysarthria, and a brain MRI revealed high signal intensity in the central pons with sparing of the peripheral portion, suggesting CPM. We diagnosed her with CPM associated with the rapid development of hypernatremia after intravenous sodium bicarbonate therapy and treated her with plasma exchange. After two consecutive plasma exchange sessions, her neurologic symptoms were markedly improved except for mild diplopia. After the plasma exchange sessions, we examined the patient to determine the reason for her symptoms upon presentation to the hospital. She had normal anion gap metabolic acidosis, low blood bicarbonate levels, a urine pH of 6.5, and a calyceal stone in her left kidney. We performed a sodium bicarbonate loading test and diagnosed distal renal tubular acidosis (RTA). We also found that she had Sjögren's syndrome after a positive screen for anti-Lo, anti-Ra, and after the results of Schirmer's test and a lower lip biopsy. She was discharged and treated as an outpatient with oral sodium bicarbonate and potassium chloride. CONCLUSION: This case indicates that serum sodium concentrations should be carefully monitored in patients with distal RTA receiving intravenous sodium bicarbonate therapy. We should keep in mind that acute hypernatremia and CPM can be associated with intravenous sodium bicarbonate therapy, and that CPM due to acute hypernatremia may be effectively treated with plasma exchange.

Multi-element distribution profile in Sprague-Dawley rats: effects of intratracheal instillation of Cr(VI) and Zn intervention.

Our previous epidemiological study revealed that co-exposure of [Cr(VI)] with small amount of heavy metals could induce peripheral blood element imbalance, but little was known about the contribution of Cr(VI) itself and the multi-element distribution profile in other target tissues. We explored element homeostasis in the blood, RBC, serum and lung after Cr(VI) exposure and Zn intervention. 60 Sprague-Dawley male rats received intratracheal instillation of Cr(VI) (0, 0.063, 0.630mgCr/kg) weekly and/or intragastric administration of zinc sulfate (0, 10mgZn/kg) daily for one month. Element contents and urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) concentrations were determined. Dose-response relationship was observed among rats exposed to Cr(VI). Ca, Mg, Mn in the blood, Fe, Mg, Se in the serum, and Mg and Zn in lung tissue decreased significantly, while Ca, Co, Cr, Mg, Mn, Se in RBC, and Ca, Co, Mo in the lung increased after Cr(VI) exposure. The alteration trends manifested differently, with RBC the most sensitive. Cr induced increase of urinary 8-OHdG, which decreased after Zn intervention. Zn intervention could help to restore element homeostasis after Cr(VI) exposure, especially for Ca, Fe, Mg and Se.

Hexavalent chromium inhibited the expression of RKIP of heart in vivo and in vitro.

BACKGROUND: Chromium (Cr) is considered to be a risk factor to the cardiovascular effects of fine particulate matter components to PM2.5 from traffic in highway patrol officers. RKIP (raf kinase inhibitor protein) is a physiological inhibitor of GRK-2 (G-protein-coupled receptor kinase 2) and affects ß-adrenergic signaling and contractile activity in cardiomyocytes. OBJECTIVES: In this study, we explored the change of RKIP in heart of chromium (VI)-exposed rats and cultured myocardial cells with chromium (VI) treatment. METHOD: Wistar rats were divided into six groups which were chronically fed with 250, 500, 750, 1000, and 1250 ppm Na(2)Cr(2)O(7) and water for 60 days, respectively. Na(2)Cr(2)O(7) dose of 0.25, 0.5, 1.5, 3, 4.5, and 0 ppm (control group) was applied in cultured myocardial cells. The level of heart Cr (VI) was determined by electrothermal atomic absorption spectrometry. The expression of RKIP was measured by Western blot method. The MTT assay was used to measure the toxicity of myocardial cells with Cr (VI) treatment. The apoptosis test of myocardial cells was determined by caspase-3 colorimetric assay kit. RESULT: The result showed that the expression of RKIP in heart (in vivo) and myocardial cells (in vitro) was decreased following Cr (VI) dose-dependent treatment. CONCLUSION: We suggested that the decrement of RKIP of heart and myocardial cells with Cr (VI) treatment resulted in the function of cardiovascular system decreased.

NTP toxicity studies of sodium dichromate dihydrate (CAS No. 7789-12-0) administered in drinking water to male and female F344/N rats and B6C3F1 mice and male BALB/c and am3-C57BL/6 mice.

Sodium dichromate dihydrate is one of a number of inorganic compounds containing hexavalent chromium (CR VI) found in drinking water supplies as a contaminant resulting from various industrial processes including electroplating operations, leather tanning, and textile manufacturing. Because of the lack of adequate experimental data on the toxicity and carcinogenicity of hexavalent chromium ingested orally, and because hexavalent chromium has been found in human drinking water supplies, the California Congressional delegation and the California Environmental Protection Agency nominated hexavalent chromium to the NTP for study. In study 1, male and female F344/N rats and B6C3F1 mice were exposed to sodium dichromate dihydrate (greater than 99% pure) in drinking water for 3 months. In study 2, sodium dichromate dihydrate was administered in drinking water to male B6C3F1, BALB/c, and am3-C57BL/6 mice for 3 months. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. In study 1, groups of 10 male and 10 female F344/N rats and B6C3F1 mice were given drinking water containing 0, 62.5, 125, 250, 500, or 1,000 mg sodium dichromate dihydrate/L for 3 months (equivalent to average daily doses of approximately 5, 10, 17, 32, or 60 mg sodium dichromate dihydrate/kg body weight to rats and 9, 15, 26, 45, or 80 mg/kg to mice). On a molecular weight basis, these doses are equivalent to approximately 1.7, 3.5, 5.9, 11.2, and 20.9 mg hexavalent chromium/kg body weight per day to rats and 3.1, 5.2, 9.1, 15.7, and 27.9 mg/kg per day to mice. Additional groups of 10 rats per sex were exposed to the same concentrations of sodium dichromate dihydrate for 4 weeks. All rats and mice survived to the end of the study. Reduced body weights occurred in 500 and 1,000 mg/L male rats, 1,000 mg/L female rats, and in male and female mice exposed to 125 mg/L or greater. Water consumption by male and female rats exposed to 250 mg/L or greater and male and female mice exposed to 125 mg/L or greater was generally less than that by the control groups, and decreases in urine volume and increases in urine specific gravity in rats were related to reduced water consumption. Exposure to sodium dichromate dihydrate caused a microcytic hypochromic anemia in rats and mice, but the severity was less in mice. Serum cholesterol and triglyceride concentrations were decreased in rats. Increased bile acid concentrations in exposed groups of rats may have been due to altered hepatic function. The incidences of histiocytic cellular infiltration were generally significantly increased in the duodenum of rats and mice, the liver of female rats, and the mesenteric lymph node of mice exposed to 125 mg/L or greater. Significantly increased nonneoplastic lesions (focal ulceration, regenerative epithelial hyperplasia, and squamous epithelial metaplasia) occurred in the glandular stomach of male and female rats exposed to 1,000 mg/L. Incidences of epithelial hyperplasia of the duodenum were significantly increased in all exposed groups of mice. In study 2, sodium dichromate dihydrate was administered in drinking water to groups of 10 male B6C3F1, 10 male BALB/c, and five male am3-C57BL/6 mice for 3 months at exposure concentrations of 0, 62.5, 125, or 250 mg/L (equivalent to average daily doses of approximately 8, 15, or 25 mg/kg sodium dichromate dihydrate or 2.8, 5.2, or 8.7 mg/kg chromium to B6C3F1, BALB/c, and am3-C57BL/6 mice). All mice in study 2 survived until study termination. Mean body weights of 125 and 250 mg/L B6C3F1 and BALB/c mice and all exposed groups of am3-C57BL/6 mice were less than those of the control groups. Mice exposed to 250 mg/L consumed less water than the control groups. Exposure concentration-related decreases in mean red cell volumes and mean red cell hemoglobin values were observed in all three mouse strains. Erythrocyte counts were increased in exposed B6C3F1 and BALB/c mice but not in am3-C57BL/6 mice. Changes in organ weights were generally consistent with reduced body weights in exposed groups in all mouse strains. No biologically significant differences in reproductive parameters were observed in any strain. Histiocytic cellular infiltration and epithelial hyperplasia of the duodenum occurred in most mice exposed to 125 or 250 mg/L, and the incidences of these lesions were increased in the 62.5 mg/L group compared to controls. Secretory depletion was present in the pancreas of most mice exposed to 125 or 250 mg/L. The incidences of glycogen depletion of the liver were significantly increased in male B6C3F1 mice exposed to 125 or 250 mg/L and in all exposed groups of male am3-C57BL/6 mice. The incidence of histiocytic cellular infiltration in the mesenteric lymph node was significantly increased in the 250 mg/L group of male am3-C57BL/6 mice. Sodium dichromate dihydrate was mutagenic in S. typhimurium strains TA100 and TA98 and in E. coli strain WP2 uvrA pKM101 with and without induced rat liver S9 enzymes. The results of four micronucleus tests conducted in the three strains of mice from studies 1 and 2 were mixed. In study 1, no significant increases were seen in micronucleated normochromatic erythrocytes in peripheral blood samples from male or female B6C3F1 mice; there was a decrease in the percentage of polychromatic erythrocytes among total erythrocytes (an indication of bone marrow toxicity), but the changes were small and not well correlated with exposure concentrations. In study 2, a significant exposure concentration-related increase (P<0.001) in micronucleated normochromatic erythrocytes was seen in am3-C57BL/6 male mice. An equivocal increase in micronucleated erythrocytes was noted in male B6C3F1 mice, based on a small increase in micronucleated normochromatic erythrocytes that did not reach statistical significance. No increase in micronucleated normochromatic erythrocytes was observed in male BALB/c mice. No significant effect of sodium dichromate dihydrate exposure on the percentage of polychromatic erythrocytes was observed in any of the three micronucleus tests conducted in study 2. In summary, administration of sodium dichromate dihydrate in the drinking water to F344/N rats and B6C3F1 mice resulted in focal ulceration, hyperplasia, and metaplasia in the glandular stomach at the limiting ridge in rats in the 1,000 mg/L group and evidence of increased histiocytic infiltration in the liver (female), duodenum of the small intestine, and/or pancreatic lymph nodes at concentrations as low as 62.5 mg/L, the lowest concentration studied. In addition, a microcytic, hypochromic anemia occurred at all exposure concentrations and was considered evidence of a toxic response resulting from absorption of Cr VI following oral ingestion in rats. A similar, but less severe, anemia was evident in mice receiving drinking water containing sodium dichromate dihydrate; histiocytic infiltration was noted in the duodenum of all three strains studied (B6C3F1, BALB/c, and am3-C57BL/6) at all concentrations employed, in the mesenteric lymph nodes at 125 mg/L or greater in the B6C3F1 strain, and at 250 mg/L in the am3-C57BL/6 strain. There was no consistent evidence of hepatocyte injury in mice in any of the strains tested. Variations in glycogen content were considered more likely related to diminished food intake than to the toxicity of sodium dichromate dihydrate. Synonyms: Chromic acid; dichromic acid; disodium salt, dihydrate; disodium dichromate dihydrate; chromium VI.

Changes of 8-OH-dG levels in DNA and its base excision repair activity in rat lungs after inhalation exposure to hexavalent chromium.

According to the toxicological and epidemiological studies, hexavalent chromium (Cr) is associated with increase of lung cancer risk. Genotoxic effects, such as chromosomal aberrations, and cellular oxidative DNA damage by reactive oxygen species produced by hexavalent Cr exposure may play an important role in its carcinogenesis. To clarify whether reactive oxygen species are involved in its mechanism, we examined the levels of 8-hydroxydeoxyguanine (8-OH-dG) and its base excision repair activities in the lung tissues of rats that repeatedly inhaled a sodium chromate solution mist for 1, 2, and 3 weeks. The levels of 8-OH-dG increased significantly in the lung tissues of the rats exposed for 1 week at the low concentration (0.18 mg/m(3), P<0.05), as compared with the controls. However, there was no difference in the 8-OH-dG levels at the higher concentration or with more than 2 weeks of exposure. The 8-OH-dG repair activities decreased in a dose-dependent manner during 2 weeks of exposure, on the contrary they recovered at 3 weeks of repeated exposure. These results suggest that the DNA damage caused by hexavalent Cr inhalation is induced by the generation of reactive oxygen species and by inhibition of base excision repair activity during the earlier phase of exposure. However, the 8-OH-dG levels and its repair activities recovered to the level of the controls in the latter inhalation exposure period.

Chromium(VI) induced alterations in mouse spleen cells: a short-term assay.

Cr(VI), the highest oxidation state for chromium, is a carcinogenic and mutagenic agent. In vivo and in vitro Cr(VI) toxic effects are related to its intracellular fate. Once inside the cell it is reduced to stable Cr(III) by cysteine, glutathione and ascorbic acid. Additionally, as Cr(V) and/or Cr(IV) intermediates have been reported in Cr(VI) reactions with biological reductants, chromium damage is thought to originate from these chemical species. This work investigated the morphology of splenic cells after short-term exposure to Cr(VI). A dose of 30 mg of K2CrO4/kg body weight was administered to mice and the effects were studied 24 and 48 h after the injections. Histological results revealed a time-dependency effect of Cr(VI) on splenic cells. Changes included enlargement of the capsule and depletion of the red pulp cells, accompanied by an increase in macrophages, 24 h after injection. Partial restoration of red pulp was noted after 48 h.

Oxidative mechanisms in the toxicity of chromium and cadmium ions.

Chromium and cadmium are widely used industrial chemicals. The toxicities associated with both metal ions are well known. However, less information is available concerning the mechanisms of toxicity. The results of in vitro and in vivo studies demonstrate that both cations induce an oxidative stress that results in oxidative deterioration of biological macromolecules. However, different mechanisms are involved in the production of the oxidative stress by chromium and cadmium. Chromium undergoes redox cycling, while cadmium depletes glutathione and protein-bound sulfhydryl groups, resulting in enhanced production of reactive oxygen species such as superoxide ion, hydroxyl radicals, and hydrogen peroxide. These reactive oxygen species result in increased lipid peroxidation, enhanced excretion of urinary lipid metabolites, modulation of intracellular oxidized states, DNA damage, membrane damage, altered gene expression, and apoptosis. Enhanced production of nuclear factor-kappaB and activation of protein kinase C occur. Furthermore, the p53 tumor suppressor gene is involved in the cascade of events associated with the toxicities of these cations. In summary, the results clearly indicate that although different mechanisms lead to the production of reactive oxygen species by chromium and cadmium, similar subsequent mechanisms and types of oxidative tissue damage are involved in the overall toxicities.

Repeated exposures to cobalt or chromate on the hands of patients with hand eczema and contact allergy to that metal.

The present study aimed at evaluating the effects of daily repeated exposures to low cobalt or chromate concentrations on the hands of patients with hand eczema and cobalt or chromate allergy. For 2 weeks, the patients immersed a finger for 10 min daily into the appropriate metal salt solution in water. During the 1st week, this was a 10 or 50 mg/l cobalt concentration or a 10 mg/l chromate concentration, and, during the 2nd week, a 100 or 200 mg/l cobalt concentration or a 100 mg/l chromate concentration. This regimen elicited a flare of hand eczema only in the chromate-exposed chromate-sensitive patients. During the exposure period, accumulation of cobalt or chromate in the nail was demonstrated. Standardization of chemical methods of quantification of skin exposure to allergens, combined with experimental exposure studies in patients with specific contact allergy, will increase the possibility of providing evidence-based medicine in the area of allergic contact dermatitis in the future.

DNA fragmentation, DNA-protein crosslinks, postlabeled nucleotidic modifications, and 8-hydroxy-2'-deoxyguanosine in the lung but not in the liver of rats receiving intratracheal instillations of chromium(VI). Chemoprevention by oral N-acetylcysteine.

An in vivo study was carried out with the objectives of evaluating (a) the localization of DNA lesions resulting from exposure to chromium(VI) by the respiratory route, (b) the molecular nature of DNA alterations, and (c) modulation of DNA damage by a known chemopreventive agent. To this purpose, Sprague-Dawley rats received intratracheal instillations of sodium dichromate (0.25 mg/kg body weight) for three consecutive days, and the day after the last treatment lung and liver were removed for DNA purification. The results showed a selective localization of DNA lesions in the lung but not in the liver, which can be ascribed to toxicokinetics and metabolic characteristics of chromium(VI). DNA alterations included DNA-protein crosslinks, DNA fragmentation, nucleotidic modifications, and 8-hydroxy-2'-deoxyguanosine. The last two endpoints were evaluated, for the first time in chromium toxicology, by means of postlabeling procedures. This methodology was adapted to the detection of the DNA damage produced by those reactive oxygen species which result from the intracellular reduction of chromium(VI). The oral administration of the thiol N-acetylcysteine completely prevented any induction of DNA lesions in lung cells.

[The characteristics of drug distribution in the body under the influence of different types of electrical current]. / Osobennosti raspredeleniia lekarstv v organizme pod vliianiem razlichnykh vidov élektricheskogo toka.

Rabbit experiments showed that distribution of drugs in the body in intratissue electrophoresis is related to current type. The drugs reach the target organ and are deposited best under the influence of sinusoidal modulated and galvanic currents. The experiments' evidence may serve the basis for differential use of electric currents for intratissue electrophoresis.

Comparative in vitro and in vivo protein kinase C activation by selected pesticides and transition metal salts.

Various pesticides and transition metals induce oxidative deterioration of biological macromolecules. Protein kinase C (PKC) may mediate these effects. However, no information is available regarding whether these xenobiotics can modulate PKC which is a critical event signaling the increase in endothelial permeability and cell proliferation. Female Sprague-Dawley rats were treated p.o. with two 0.25 LD50 doses of selected pesticides and transition metal salts at 0 and 21 h, and killed at 24 h. PKC activities were measured in liver and brain tissues. Cultured PC-12 cells were incubated for 24 h with 50, 100 or 200 nM concentrations of these pesticides, while 0.20, 0.40 or 0.60 microM concentrations of cadmium chloride (Cd(II)) and sodium dichromate (Cr(VI)) salts were employed. PKC activations were observed in the hepatic and brain cytosol fractions by all xenobiotics. Approximately 1.4- to 2.0-fold and 1.6- to 3.5-fold increases in PKC activity in the hepatic and brain cytosol fractions were observed, respectively. In the hepatic tissues, the greatest increases in activities were observed with TCDD, chlorpyrifos, endrin and Cd(II), while chlorpyrifos and fenthion exerted the greatest increases in the brain tissues. In cultured PC-12 cells, the greatest activation of PKC was observed primarily with 100-nM concentrations of the pesticides. The maximum effects were induced by chlorpyrifos, fenthion, Cd(II) and Cr(VI) salt. The results clearly indicate that pesticides as well as Cd(II) and Cr(VI) salts can modulate a vital component of the cell signaling pathway, namely PKC activity. PKC may be a target of free radicals and oxidative stress, leading to altered cell proliferation and differentiation.

Induction of oxidative stress by chronic administration of sodium dichromate [chromium VI] and cadmium chloride [cadmium II] to rats.

Recent studies have demonstrated that both chromium (VI) and cadmium (II) induce an oxidative stress, as determined by increased hepatic lipid peroxidation, hepatic glutathione depletion, hepatic nuclear DNA damage, and excretion of urinary lipid metabolites. However, whether chronic exposure to low levels of Cr(VI) and Cd(II) will produce an oxidative stress is not shown. The effects of oral, low (0.05 LD50) doses of sodium dichromate [Cr(VI); 2.5 mg/kg/d] and cadmium chloride [Cd(II); 4.4 mg/kg/d] in water on hepatic and brain mitochondrial and microsomal lipid peroxidation, excretion of urinary lipid metabolites including malondialdehyde, formaldehyde, acetaldehyde and acetone, and hepatic nuclear DNA-single strand breaks (SSB) were examined in female Sprague-Dawley rats over a period of 120 d. The animals were treated daily using an intragastric feeding needle. Maximum increases in hepatic and brain lipid peroxidation were observed between 60 and 75 d of treatment with both cations. Following Cr(VI) administration for 75 d, maximum increases in the urinary excretion of malondialdehyde, formaldehyde, acetaldehyde, and acetone were 2.1-, 1.8-, 2.1-, and 2.1-fold, respectively, while under the same conditions involving Cd(II) administration approximately 1.8-, 1.5-, 1.9-, and 1.5-fold increases were observed, respectively, as compared to control values. Following administration of Cr(VI) and Cd(II) for 75 d, approximately 2.4- and 3.8-fold increases in hepatic nuclear DNA-SSB were observed, respectively, while approximately 1.3- and 2.0-fold increases in brain nuclear DNA-SSB were observed, respectively. The results clearly indicate that low dose chronic administration of sodium dichromate and cadmium chloride induces an oxidative stress resulting in tissue damaging effects that may contribute to the toxicity and carcinogenicity of these two cations.

Human ingestion of chromium (VI) in drinking water: pharmacokinetics following repeated exposure.

Regulatory agencies have established safe drinking water concentrations for hexavalent chromium [Cr(VI)] based in part on the presumed capability of human gastric juices to rapidly reduce Cr(VI) to nontoxic trivalent chromium [Cr(III)] prior to systemic absorption. This study examines dose-related pharmacokinetics in humans following repeated oral exposure to Cr(VI) in drinking water. In particular, we sought to examine whether plausible drinking water exposures to Cr(VI) caused a sustained increase in red blood cell chromium levels, a specific marker for systemic uptake of Cr(VI). Adult male volunteers ingested a liter (in three volumes of 333 ml, at approximate 6-hr intervals) of deionized water containing Cr(VI) concentrations ranging from 0.1 to 10.0 mg/liter. Samples of urine, plasma, and red blood cells were collected and analyzed for chromium. A dose-related increase in urinary chromium excretion was observed in all volunteers. Red blood cell and plasma chromium concentrations became elevated in certain individuals at the highest doses. The RBC chromium profiles suggest that the ingested Cr(VI) was reduced to Cr(III) before entering the bloodstream, since the chromium concentration in the RBCs dropped rapidly postexposure. These findings suggest that the human gastrointestinal tract has the capacity to reduce ingested Cr(VI) following ingestion of up to 1 liter of water containing 10.0 mg/liter of Cr(VI), which is consistent with USEPA's position that the Cr(VI) drinking water standard of 0.10 mg Cr(VI)/liter is below the reductive capacity of the stomach.