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We herein describe the case of a 77-year-old woman, who presented clinical and histopathological evidence of giant cell arteritis (GCA) involving the temporal artery, together with a Churg-Strauss syndrome (CSS). Our patient presented positive anti-neutrophil cytoplasmic antibodies (ANCA), with cytoplasmic staining pattern (C-ANCA) that was specific against proteinase 3 (PR3), and also a perinuclear pattern (P-ANCA) with specificity against myeloperoxidase (MPO). To our knowledge, the simultaneous presence in the same patient of both types of antibodies has not been previously reported.

Background Polymyalgia rheumatica (PMR) may be associated with arteritis of the aorta and its major branches including temporal artery. The delay in the diagnosis of GCA and therefore, in its treatment can have serious consequences. Objectives The primary objective of this study is to evaluate by PET / CT scan the incidence of GCA in patients with PMR and the existence of underlying malignancies since, so far, no clear association has been established between them, which is a common clinical concern. The secondary objective is to study the joint involvement in PMR. Methods We studied prospectively all patients with clinical suspicion of PMR referred to the Rheumatology Unit, the Emergency Department and the Internal Medicine and Rheumatology day hospitals from January 2010 to November 2012. All patients who met the PMR EULAR / ACR 2012 classification criteria1 underwent medical history and physical examination, complete blood tests (including TSH, tumor markers and blood and urine cultures), and chest x-rays. We completed the diagnosis of the remaining patients after other pathologies were excluded, with a PET/CT scan. Results We studied a total of 26 patients, 15 women and 11 men, with a mean age of 75.9 years. Of these patients, 2 had aortic uptake confirming the diagnosis of GCA. Asthenia was observed in 79% of the patients with PMR and in all patients with GCA. 41% of the PMR patients and 50% of the ACG patients suffered weight loss. All patients had shoulder and/or hip pain. Peripheral arthritis was observed only in the PMR group (15.34%). As for the specific symptoms of GCA, 3 PMR patients and 1 with GCA patient had headaches. Only 1 patient with a final diagnosis of GCA referred amaurosis fugax and none had jaw claudication. We observed similar values of mean ESR (71.8 mm / hour in PMR and 62.5mm/hour in GCA) and mean CRP (55.4 mg/l in PMR and 43.9 mg / l in ACG). Rheumatoid factor and anti-CCP antibodies were negative in all cases. Regarding the results of the PET, besides the two vasculitis, we also diagnosed 1 patient with lymphoma and 1 with colon adenoma with high grade dysplasia (both later confirmed by biopsy). Girdles uptake was observed in 84.6% (n = 22)of the patients, 76.9% (n = 20) in the scapular and 61.5% (n = 16)in the pelvic girdle. There was uptake in the spinal column in 31.6% (n = 9) of the patients and 11% (n = 4) of the patients had uptake in peripheral joints. All patients diagnosed from neoplasia or vasculitis presented uptake in at list one girdle. Conclusions The PET modified the diagnosis in 4 patients (15.38%), confirming the presence of a disease significant enough to suggest the performance of this study in the diagnostic algorithm of the disease. A larger sample is needed to confirm our initial results. The PET helped diagnose joint involvement in over 80% of the cases. We observed no clinical or laboratory features that may help in the differential diagnosis of patients. References Dasgupta B, Cimmino MA, Kremers HM, et al. 2012 Provisional classification criteria for polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative. Arthritis Rheum 2012;64:943-54. Disclosure of Interest None Declared

Manganese is embryotoxic and fetotoxic in mammals. The aim of this study was to determine whether the day of exposure would modify the developmental toxicity of manganese (II). Pregnant Swiss mice were given single sc doses of 50 mg manganese chloride tetrahydrate/kg on day 9, 10, 11 or 12 of gestation. No maternal deaths, abortions or early deliveries were observed. Dams were killed on gestational day 18 and the uterine contents examined. Embryotoxicity, evidenced by significant increases in number of late resorptions and in percentage of postimplantation loss, was especially relevant in groups dosed on gestational days 9 or 10. Fetotoxicity (reduced fetal body weight and increased incidence of skeletal defects) was also especially remarkable from doses on days 9 or 10 of gestation. However, no teratogenic effects were noted in any group. Although mouse conceptus are adversely affected by sc exposure to manganese on any of the gestational days 9-12, days 9 and 10 of gestation are the most sensitive for manganese-induced embryo/fetal toxicity in mice.

The therapeutic efficacy of monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS), on arsenite-induced maternal and developmental toxicity was evaluated in the pregnant mouse. Sodium arsenite (12 mg/kg) was intraperitoneally injected into Swiss mice on day 9 of gestation, whereas Mi-ADMS was given subcutaneously at 0.25, 5, 24, and 48 hr after arsenite exposure. Amelioration by Mi-ADMS of arsenite-induced maternal and embryofetal toxicity was assessed at 23.8, 47.5, and 95 mg/kg/day. Controls received 0.9% saline with or without arsenite. Cesarean sections were performed on gestation day 18. In the positive control group (treated with arsenite only), 20.8% of the pregnant animals died, whereas 37.5% of the dams were carrying completely resorbed litters. No arsenite-induced maternal lethality was seen following treatment with Mi-ADMS at 23.8, 47.5 and 95 mg/kg/day. Also, administration of the drug at these doses significantly reduced the embryolethality, as well as the incidence of some skeletal variations provoked by sodium arsenite. Although based on these findings, Mi-ADMS might be suggested as a potential antidote to prevent the arsenite-induced maternal and developmental toxicity, due to their reduced toxicity compared to Mi-ADMS, DMSA and DMPS would probably be more advisable for pregnant women exposed to arsenite.

A short-term oral toxicity study of 1,2-dimethyl-3-hydroxypyrid-4-one (L1), a promising oral chelating agent for the treatment of iron and aluminum overload, was carried out in uremic rats. L1 was administered to male uremic rats by gastric intubation at 0, 20, 40, 80 or 160 mg/kg/d for 4 w. Body weight and food and fluid intake were monitored daily. Complete hematologic examinations, serum biochemical parameter determinations and histological examinations were carried out. Although body weight gain was significantly reduced at 80 and 160 mg/kg/d, there were no effects of L1 on food and fluid consumption. There were no significant differences between controls and L1-treated groups in most of the hematological and biochemical parameters analyzed. No significant dose-dependent changes in relative organ weights were noted. The non-observed-adverse-effect level (NOAEL) for L1 in uremic rats was 40 mg/kg/d. According to the results of this study, uremia did not increase the toxic effects of L1.

Cyclohexanediaminetetraacetic acid (CDTA), an effective antagonist for the treatment of zinc, lead, and manganese poisoning was evaluated for maternal and developmental toxicity in pregnant Swiss mice. CDTA was given intraperitoneally on gestation days 6-15 at doses of 0, 270, 540, and 1080 mg/kg/day. On gestational day 18, the fetuses were examined for external, visceral, and skeletal malformations and variations. Treatment with CDTA at 1080 mg/kg/day resulted in a high level of maternal deaths, as well as less severe clinical signs (significant reduction in weight gain and food consumption). Increased resorptions, fetal deaths, and decreased number of live fetuses per litter were observed at 1080 mg/kg/day. Mean fetal body weights were also significantly decreased in this group. At 1080 mg/kg/day, CDTA caused external malformations, while the development of skeletal tissues was less affected. The no observable adverse effect level (NOAEL) for maternal and developmental toxicity of CDTA in mice was 540 mg/kg/day. Analyses of maternal and fetal tissues revealed only slight effects of CDTA on concentrations of calcium, magnesium, zinc, copper and iron. According to these results, the alterations in mineral metabolism should not be the major reason for CDTA-induced developmental toxicity.

It has been shown that improvement of glucose homeostasis by oral vanadate or vanadyl treatment in streptozotocin-induced diabetic rats is accompanied by severe negative side effects (some deaths, decreased weight gain, alteration in renal function as well as tissue vanadium accumulation) which argue against the use of vanadium compounds in diabetes treatment. The present study was undertaken to assess the effectiveness in alleviating some signs of diabetes in streptozotocin-treated rats with oral therapy with sodium metavanadate (NaVO3) and sodium 4,5 dihydroxybenzene-1,3-disulfonate (Tiron), a chelating agent effective in mobilizing vanadium. In a preliminary experiment, diabetic rats were given aqueous solutions of 0.20 mg NaVO3/ml for 4 days. Vanadium-treated rats which showed blood glucose levels significantly lower (p0.001) than vanadate-untreated diabetic rats were selected for subsequent experiments. These animals were given 0.20 mg NaVO3/ml in drinking water and 0, 125.6, 314 or 628 mg Tiron/kg/d by gavage for 2 w. Although most of the animals did not become normoglycemic, several characteristic signs of diabetes (hyperglycemia, hyperphagia and polydipsia) were alleviated by the NaVO3 treatment. The administration of 314 mg Tiron/kg/d (approximately 1 NaVO3: 5 Tiron, mole ratio) did not diminish the ameliorative effects of NaVO3 with respect to diabetes, but significantly decreased the level of vanadium accumulation in target organs. These results show that some of the beneficial effects of NaVO3 are maintained in diabetic animals given Tiron, while the administration of the chelator results in a significant decrease in tissue vanadium accumulation. Accordingly, this would diminish the possibility of toxic side effects derived from prolonged oral vanadium administration.

The influence of some frequent dietary constituents on gastrointestinal absorption of aluminum from drinking water and diet was investigated in mice. Eight groups of male mice received lactic (57.6 mg/kg/day), tartaric (96 mg/kg/day), gluconic (125.4 mg/kg/day), malic (85.8 mg/kg/day), succinic (75.6 mg/kg/day), ascorbic (112.6 mg/kg/day), citric (124 mg/kg/day), and oxalic (80.6 mg/kg/day) acids in the drinking water for one month. At the end of this period, animals were killed and aluminum concentrations in liver, spleen, kidney, brain, and bone were determined. All the dietary constituents significantly increased the aluminum levels in bone, whereas brain aluminum concentrations were also raised by the intake of lactic, gluconic, malic, citric, and oxalic acids. The levels of aluminum found in spleen were significantly increased by gluconic and ascorbic acids, whereas gluconic and oxalic acids also raised the concentrations of aluminum found in kidneys. Because of the wide presence and consumption of the above dietary constituents, in order to prevent aluminum accumulation and toxicity we suggest a drastic limitation of human exposure to aluminum.

The aim of this study was to assess the variability in the developmental toxicity of vanadate with the day of administration during gestation. Single ip injections of 25 mg sodium metavanadata/kg were given to albino Swiss mice on one of the days 9-12 of gestation. Dams were killed on day 18 of pregnancy, and fetuses were examined for external, internal and skeletal malformations and variations. The number of dead or resorbed fetuses/litter, as well as the percentage of postimplantation loss, were significantly increased with injections on days 9-12 of gestation. However, the most sensitive time for the induction of metavanadate embryotoxicity was gestational day 12. Metavanadate treatment on day 12, but not days 9-11, resulted in a significant decrease in the fetal body weight/litter. There were no external, internal or skeletal malformations, whereas the most common skeletal variations were a reduced ossification in the parietal bone, metatarsals and metacarpals, bipartite sternebrae and fused ribs. The highest percentage of total skeletal defects was found on day 12 (82.3%). Gestational day 12 is the most sensitive time for metavanadate-induced developmental toxicity in mice.

The influence of lactate on the potential developmental toxicity of high doses of aluminum (57.5 mg/kg/day) was evaluated. Three groups of pregnant Swiss mice were given by gavage daily doses of Al(OH)3 (166 mg/kg), aluminum lactate (627 mg/kg), or Al(OH)3 (166 mg/kg) concurrent with lactic acid (570 mg/kg) on gestational days 6-15. An additional group of pregnant mice received lactic acid (570 mg/kg) during the same period. Cesarean sections were performed on gestation day 18, and live fetuses were sexed, weighed and examined for morphological defects. Maternal toxicity was observed in the groups treated with aluminum lactate, and Al(OH)3 concurrent with lactic acid. The reproductive data did not show embryotoxic effects in any group, whereas fetal body weight was significantly reduced in the aluminum lactate group. In this group, morphological changes included cleft palate and an increased incidence of parietals with delayed ossification. Although not statistically significant, the incidence of skeletal variations was also increased in the group given Al(OH)3 concurrent with lactic acid. Taken together the present data, as well as the results of previous studies strongly suggest that the consumption of high doses of aluminum-containing compounds should be avoided during pregnancy.

Vanadyl sulfate trihydrate was given by gavage to streptozotocin-induced diabetic rats for 21 days at doses of 0, 25, 50, or 75 mg/kg/day. In marked contrast to the reduction in plasma glucose observed in diabetic animals given vanadyl sulfate via drinking water, diabetic rats given vanadyl by gavage were not characterized by normoglycemia. Similarly, in contrast to the normalizing effect of vanadyl in drinking water, vanadyl by gavage had only a minimal influence on diabetes associated hyperphagia and polydipsia. Despite the lack of marked effect of vanadyl by gavage on the above parameters, tissue vanadium accumulation in the gavaged rats was similar to that reported for rats given vanadium by drinking water. The present results (taken together with previous data) show that the administration of vanadium by gavage is not a viable alternative to the use of insulin in diabetes treatment.

Diethylenetriaminepentaacetic acid (DTPA), ethylenglycolbis-(beta-amino-ethylether)-N,N-tetraacetic acid (EGTA), tartaric acid, KRYPTOFIX 222, and KRYPTOFIX 5 were evaluated for their efficacy in mobilization of strontium from the body of mice which had received 20 sc injections of strontium nitrate (95 mg/kg/injection) for 4 w. Twenty-four hours after the last strontium injection, ip administration of 1 of the various chelators or 0.9% saline was initiated and continued daily for 5 d. Mice were housed in metabolic cages, and urine and feces were collected daily for 5 d. After this period, the animals were killed and tissues removed. Tartaric acid, KRYPTOFIX 222, and KRYPTOFIX 5 had no effect on urinary or fecal strontium elimination, whereas DTPA and EGTA significantly decreased the fecal strontium excretion. The concentration of strontium in bone was only lowered in tartaric-treated mice. This study indicates the use of the above chelators is not an effective treatment to enhance the removal of strontium following repeated parenteral strontium administration.

Tiron (sodium 4,5-dihydroxybenzene-1,3-disulfonate), a chelating agent used in the treatment of experimental metal poisoning, was evaluated for developmental toxicity in pregnant Swiss mice. Tiron was administered intraperitoneally on gestational days 6 through 15 at doses of 0, 750, 1500, or 3000 mg/kg/day. Cesarean sections were performed on gestation day 18. All fetuses were examined for external, visceral, and skeletal malformations and variations. Treatment with Tiron resulted in maternal toxicity at 3000 mg/kg/day as evidenced by a high number of deaths, reduced body weight during gestation and increased relative liver and kidney weights. There were no significant differences between treated and control animals on the number of total implants, dead fetuses, or sex ratio. However, embryo fetotoxicity was evidenced at 3000 mg/kg/day by a significant increase in the number of resorptions per litter, and a significant decrease in the average fetal body weight. There were no significant changes in the incidence of abnormalities (expressed as total, individual, external, visceral, or skeletal). The no observable adverse effect level (NOAEL) for maternal and developmental toxicity was 1500 mg Tiron/kg/day.

The effects of repeated ip administration of diethylenetriaminepentaacetic acid (DTPA), Kryptofix 222, 1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6), ethylenglycol-bis-(beta-amino-ethylether)-N,N'-tetraacetic acid (EGTA), and Kryptofix 5 on the distribution and excretion of sc-injected strontium were investigated in male Swiss mice. Groups of 20 animals received 95 mg strontium nitrate/kg, and 10 min later ip treatment with one of the chelators or 0.9% saline was initiated and continued for 10 d. The animals were housed in plastic metabolism cages, and urine and feces were collected daily during the period of treatment. At the end of this period, the animals were killed and the concentration of strontium determined in their tissues. Only Kryptofix 5 and EGTA significantly increased the amount of strontium excreted into feces, whereas none of the chelators significantly enhanced the urinary elimination of strontium. Treatment with Kryptofix 5 significantly decreased the concentration of strontium in all tissues analyzed. Kryptofix 5 was the most effective agent of those tested in the removal of strontium after a single dose of strontium nitrate.

The effects of repeated ip administration of diethylenetriamine-pentaacetic acid (DTPA), ethylenglycol-bis-(-amino-ethlylether)-N,N'-tetraacetic acid (EGTA), Kryptofix 222, tartaric acid, and Kryptofix 5 on strontium (Sr) excretion and Sr levels in selected mouse tissues were investigated following semichronic strontium nitrate ingestion (284 mg/kg/day) for four weeks. Chelating agents were injected daily for five days at 1/4 of their respective LD50 in two equally divided doses. Only Kryptofix 5 significantly increased the amount of Sr excreted into urine, whereas none of the chelators enhanced the fecal Sr elimination. A significant decrease in the concentration of Sr in bone, the primary tissue of Sr deposition, was observed after treatment with EGTA. Under these experimental conditions, none of the chelators tested was able to remove significant amounts of Sr following Sr ingestion for four weeks.

The potential of aluminum hydroxide [Al (OH)3] to induce developmental toxicity in rats was evaluated in the present study. Al (OH)3 was given by gavage at dose levels of 192, 384, and 768 mg/kg/day to groups of pregnant rats from day 6 through day 15 of gestation. Control animals received distilled water. Pregnant rats were evaluated for body weight, weight gain, food consumption, appearance, behavior and reproduction data. Cesarean sections were performed on gestation day 20, and the fetuses were removed for teratological evaluation. No significant maternal or developmental toxicity was observed at any Al (OH)3 dose level. Consequently, the no-observed-effect level (NOEL) for Al(OH)3 maternal or developmental toxicity would be greater than or equal to 768 mg/kg/day, which was the highest dose tested. This dose would be equivalent to a 60 kg person ingesting 16 g Al/day.

Effects of ip treatment with diethylenetriaminepentaacetic acid (DTPA), and cyclohexanediaminetetraacetic acid (CDTA) on the zinc (Zn) excretion and Zn levels in selected mouse organs and tissues were assessed after mice were offered deionized water containing zinc acetate dihydrate (108 mg/kg/day) as the sole drinking fluid for 4 weeks. Following this period, the Zn-containing water was replaced by tap water and therapy with DTPA or CDTA was initiated. The animals received 6 injections of chelators or 0.9% saline (control group) on alternate days for 2 weeks of treatment. The dose of chelating agents was approximately equal to 1/4 of their respective ip LD50 values. Mice were housed in metabolic cages, and urine and feces were collected 24 hr after the first, fourth and sixth administration of the chelators. Six animals in each group were sacrificed at the same days. Although feces was the predominant route of elimination for Zn, only DTPA significantly increased the fecal excretion of Zn after the first administration of chelator. Treatment with DTPA or CDTA resulted in a significant decrease in the concentration of Zn in brain, spleen, and heart after the first injection. DTPA was consistently the most effective in increasing the urinary and fecal excretion of Zn and reducing the concentration of the metal found in various tissues. CDTA would be considered as a possible alternative.

The relative efficacy of 14 chelating agents in alleviating acute cobalt (II) chloride (ip) intoxication has been determined. For a level of 0.70 mmol/kg ip of CoCl2 (slightly higher than its LD50), the ip administration of chelating agents at a 2:1 and 5:1 mole ratio resulted in a significant antidotal action for L-cysteine, N-acetyl-cysteine, L-histidine,glutathione,D,L-penicillamine, DMSA, DTPA and EDTA. For a level of 1.18 mmol/kg ip of CoCl2 (slightly higher than its LD99) only L-cysteine, N-acetylcysteine,glutathione, DMSA, DTPA and EDTA resulted in a significant enhancement of the survival rate. The therapeutic indices of these compounds were respectively: 8.3, 11.8, 10.9, 9.1, 20.5 and 26.4; with EDTA and DTPA being the most effective. However, due to their low toxicity, N-acetylcysteine and glutathione should be considered as possible alternatives.

Four groups of pregnant Wistar rats, each of which consisted of 15 animals were administered 0, 12, 14 and 48 mg/kg/day of cobalt (II) chloride from the 14th day of gestation through 21 days of lactation. The offspring were observed for mortality, body weight, body and tail length and general symptomatology after 1, 4 and 21 days of nursing. The number of litters was higher for the control group. The survival ratios were also higher for the control group. Besides, a dose-dependent delay in the growth of the living young could be observed. No significant differences in organ weights in the animals killed 21 days after birth were observed. The blood parameters analysed did not show differences between the treated and control pups. Cobalt produced toxic effects on the mothers, affecting the late gestation as well as the postnatal development of the pups.

A protein in the bone matrix that retains calcium is described. This protein seems to start the ossification process. The reaction occurs in several steps from high energy phosphorylation to the formation of aggregates and calcium phosphate.

A study in rats was made of the effects produced by L-cysteine on the acute toxicity of cobalt chloride given orally and intraperitoneally. The decrease in lethality was absolute for the different doses tested, except when the CoCl2 was given orally and L-cysteine intraperitoneally in which only 40% efficiency was obtained. No specially significant changes were observed in the blood parameters of the animals treated with the CoCl2-cysteine complex after one week. Significant differences were noted between serum parameters: glucose, triglycerides and cholesterol, measured in rats after twelve hours of receiving the CoCl2-cysteine complex, compared with the same parameters measured when the CoCl2 was given without complex.

The acute toxicities of chloride, acetate, cobalt nitrate and cobalt sulphate (II) were investigated in rats. The values obtained for the LD50 (7 days) were 133, 194, 198 and 279 mg of Co/kg respectively, when the salts were given orally. The values for intraperitoneal administration were 10.6, 8.8, 8.3 and 11.5 mg of Co/kg. The majority of deaths occurred during the first 48 hours. The physical and clinical signs appearing after the intoxication disappeared for the most part after the first 72 hours. Also, the effect produced by chloride and cobalt acetate (II) given orally and intraperitoneally, in some hematological parameters and serum parameters during the first 24 hours after intoxications, has been studied at several doses. A noteworthy increase was observed in the hemoglobin and hematocrit as well as in the plasma proteins. There was significant hyperglycemia and also significant changes in the lipid parameters such as triglycerides and cholesterol. The duration and degree of the change depended on the dose. As a general rule, no significant differences were registered between the results obtained for the two salts.

Aluminum nitrate was administered by gavage to four groups of pregnant Sprague-Dawley rats from the 14th day of gestation through 21 days of lactation at doses of 0, 180, 360 and 720 mg/kg/day. These doses did not produce overt fetotoxic effects. However, the growth of the offspring was significantly less from birth and during all the period of lactation for the higher doses of aluminum nitrate. Although very few toxic effects could be observed for the 180 mg/kg/day group (or 13 mg Al/kg/day), this quantity is similar to the amounts ingested by some people in special medical treatment (10 mg Al/kg/day). Therefore, it would seem that high amounts of aluminum should not be ingested during the periods of gestation.

Aluminum nitrate was given orally to four groups of female Sprague-Dawley rats over a period of one-hundred days at doses of 0, 360, 720 and 3600 mg/kg/day. Rats were monitored for weight gain, food intake, drinking water, hematology and plasma chemistry. The results show that the ingestion of aluminum nitrate by the rat caused a significant decrease in its growth. The nutritional parameters were always significantly lower for the treated animals. Aluminum did not accumulate dose-dependently in the organs and tissues analysed. Histopathological studies, including organ weight determinations, did not show significant changes. The possibility of oral aluminum intoxication in the human would be very low.

Four zinc compounds (acetate, nitrate, chloride and sulfate) were administered po or ip to rats and mice. The LD50 values were determined. Animals were observed for 14 days. The majority of deaths occurred during the first 48 hr. The clinical and physical signs appearing after intoxication included miosis, conjunctivitis, decreased food and water consumption and hemorrhages and hematomas in the tail. These changes decreased with time which would suggest a quick elimination of zinc. To determine the effect of 6 chelating agents on the toxicity of zinc, various doses of zinc acetate (66-330 mg/kg) were given ip to male mice followed by the injection of one of the chelators. DTPA, D-PA, CDTA and EDTA were the most effective. CDTA and DTPA were also the most effective in increasing the urinary excretion of zinc. DTPA appears to be the most effective agent of those tested in the prevention of acute zinc intoxication. However, CDTA may be considered as a possible alternative.

The effect of increasing the time interval between acute zinc exposure and chelation therapy was studied in male Swiss mice. Cyclohexanediaminetetraacetic acid (CDTA), and diethylenetriaminepentaacetic acid (DTPA) were administered ip at 0, 0.25, 0.5, 2, 12, or 24 hr after ip administration of 0.40 mmol/kg of zinc acetate dihydrate. Chelating agents were given at doses equal to 1/3 of their respective LD50 values. Effectiveness of chelation therapy was determined by measuring the ability of the chelators to increase the elimination of zinc and decrease the concentration of the metal in various tissues. Treatment with DTPA or CDTA increased significantly the urinary and fecal excretion of zinc when the chelators were administered at various times following zinc exposure. The greatest antidotal efficacy of the chelating agents was observed at 0.50 hr after zinc injection. Nevertheless, the effectiveness of DTPA and CDTA was decreasing when the chelators were administered later. DTPA was more effective than CDTA in the prevention of acute zinc intoxication. CDTA would be considered as a possible alternative.

The effect of EDTA on acute cobalt toxicity in rats was the subject of our investigation. There was complete effectiveness for two methods of treatment of the Co and EDTA, except when the CoCl2 was given orally and EDTA intraperitoneally. When the CoCl2-EDTA complex was given orally or intraperitoneally there were no deaths, not even at LD100 values of the CoCl2. No noteworthy changes were brought about in the hematological parameters and serum parameters of the animals receiving the CoCl2-EDTA complexes after a week's treatment. Significant differences appeared in the variation of some blood parameters measured 12 hours after the administration of the Co/CH3-COO)2-EDTA complex compared with the same parameters measured on giving only Co(CH3-COO)2.

The effect of the chelating agents deferoxamine mesylate (DFOA), sodium salicylate, citric acid, Na2Ca-ethylendiaminetetracetate (EDTA), nitrilotriacetic acid (NTA), L-cysteine, N-acetyl-L-cysteine (NAC) and 2, 3-dimercaptosuccinic acid (DMSA) on the lethality, elimination and tissue retention of aluminum was investigated on male Swiss mice. To determine the effect of the various chelators on the lethality of aluminium, various doses of Al (NO3)3.9H2O (3.0 - 7.5 mmol/kg) were given intraperitoneally followed immediately by the ip administration of the chelator (at dose equal to one-third of their respective LD50). Survival was recorded at the end of 14 days. Significant increases in survival were noted with citric acid and DFOA. A decrease of the aluminium concentration in various tissues, and an increase in urinary and fecal elimination of aluminium were also noted with citric acid, DFOA, and sodium salicylate. Citric acid appear to be the most effective agent of those tested in the prevention of acute aluminum intoxication.

The effects of repeated ip administration of gallic acid, 4,5-dihydroxy-1,3-benzenedisulfonic acid (Tiron), diethylenetriaminepentaacetic acid (DTPA), and 5-aminosalicylic acid (5-AS) on the distribution and excretion of uranium were assessed in male Swiss mice. Only Tiron significantly increased the amount of uranium excreted into urine and feces. A significant decrease in the concentration of uranium in liver, spleen and bone was observed after administration of Tiron, whereas injection of gallic acid or DTPA resulted in a significant decrease in the concentration of the metal in the liver. The results show that Tiron was consistently the most effective chelator of those tested in the treatment of uranium poisoning after repeated daily administration of the metal.

Pregnant Sprague-Dawley rats were given orally a daily dose of 0, 5, 10 or 20 mg NaVO3/kg from the sixth through the fourteenth day of pregnancy. Fetal examinations were performed on day 20 of gestation. Sodium metavanadate was neither embryolethal nor teratogenic in rats when administered orally at 20 mg/kg/day or lower. Nevertheless, this dose was embryotoxic.

Effects of repeated ip administration of glutathione, N-acetyl-L-cysteine (NAC), 2,3-dimercaptosuccinic acid (DMSA), ethylendiamine-tetraacetic acid (EDTA), and diethylentriamepentaacetic acid (DTPA) on the distribution and excretion of cobalt were assessed in Sprague-Dawley rats. Groups of ten animals received intraperitoneally 0.06 mmol CoCl2/kg/day, three days/week for four weeks. 24 hr after the last injection, daily chelation therapy was initiated. Rats received one of the chelators or saline for 5 days. The animals were housed in metabolic cages and urine and feces were collected daily for 5 days after which time the rats were killed and the concentration of cobalt was determined in various tissues. Glutathione, NAC and DTPA significantly increased the excretion of cobalt into urine whereas EDTA, NAC and DMSA were the most effective chelators increasing the fecal elimination of cobalt. The concentration of cobalt in the various tissues was only decreased by NAC (liver and spleen) and glutathione (spleen). The observed increase in the cobalt excretion with certain chelators would suggest that increasing the duration of chelation therapy may decrease the concentrations of cobalt in tissues and hence, reduce the toxicity of the metal.

The antidotal action of L-methionine in acute cobalt (II) chloride intoxication given orally or intraperitoneally to rats has been investigated in this paper. The doses of CoCl2 (2.73 mmole/kg oral, 0.21 mmole/kg i.p.) are always above their LD50 for both means of administration, reaching during oral administration values above its LD95 (4.20 mmole/kg). The doses of L-methionine varied from 0.63 mmole/kg (i.p.) to 8.19 mmole/kg (orally). L-methionine did not show a significant antidotal action (mortality rates) against the other sulphurous aminoacid: L-cysteine, which is considered an effective antidote. The administration of Co2+-methionine chelates prepared in vitro, showed rates of 10% mortality when given orally and 30% when given intraperitoneally, against Co2+-cysteine and co2+-N-acetylcysteine chelates with rates of 0% mortality. No significant functional changes were observed in the survivors killed seven days after administration in groups receiving L-methionine. Although L-methionine cannot be considered an effective antidote, it is likely to reduce partially the toxic effects of cobalt.