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We investigated the relationship between the pharmacokinetics and pharmacodynamics of cyclosporine in 15 stable renal transplant patients in order to define an effective and safe therapeutic range. The area under the curve of the first 4 h (AUC(0-4)), trough (C(0)) and 2 h (C(2)) levels showed median values of 1655 ng x h/ml, 114 ng/ml and 384 ng/ml, respectively. C(2) showed a strong correlation with AUC(0-4) (r=0.942, p=0.0005). C(0) correlated poorly with C(2) and AUC(0-4) (r=0.596, p=0.019 and r=0.538, p=0.031, respectively). Calcineurine activity (CNa) was 6.74% at 0 h and 3.90% at 2 h, representing significant reductions (82% and 89.6%, respectively; p0.0005) compared with normal healthy controls (median basal value 37.4%). IL-2 production was 349 pg/ml at 0 h and 276.35 pg/ml at 2 h; both results were significantly lower (reductions of 44.5% and 56.1%, respectively; p=0.04 and 0.005) than the controls of 629.1 pg/ml. IFN-gamma at 2 h post-dose (8.16 UI/ml) was significantly lower (72.1% reduction, p=0.005) than in controls (29.2 UI/ml). There was a good correlation between CNa and IFN-gamma production, particularly at 2 h post-dose (r=0.537, p=0.007), and a fair correlation between CNa and IL-2 concentration (p=0.030, r=0.426). C(2) showed an inverse significant correlation with CNa (Spearman's p=0.000, r=-0.753), IL-2 (p=0.000, r=-0.725) and IFN-gamma (p=0.000, r=-0.701) production. In treated patients, the Emax inhibitory sigmoidal model showed that a C(2) of 279 ng/ml was needed to achieve a 50% inhibition (EC50) of IL-2 and INF-gamma production. The results demonstrated a significant inhibition of calcineurin activity and IL-2 and IFN-gamma production in patients receiving cyclosporine monotherapy compared to healthy controls. A median C(2) value of 384 ng/ml was associated with a good degree of inhibition of CNa and IL-2 and IFN-gamma synthesis, and the lack of rejection episodes and relevant toxicity.

The aim of the Multicentric Liver Transplant Spanish Study was to evaluate tacrolimus therapy at the reduced, initial oral dose of 0.1 mg/kg per day to maintain the immunosuppressive potency of the drug and to avoid toxicity. The dosage of tacrolimus (D), the trough blood concentrations (C), and the evolution of the ratio (D/C) were followed up for 2 years after transplantation in 50 adult patients (38 men, 12 women) undergoing liver allograft transplantation. A total of 1732 samples were analyzed using the IMx tacrolimus method. The overall mean+/-SD concentrations were 10.84 ng/ml+/-5.32 ng/ml. During the first month, the median of the tacrolimus levels was 8.40 ng/ml, and 73.1% of the analyzed samples were within the established therapeutic range. The median oral tacrolimus dose was progressively reduced from 0.12 mg/kg per day during the first month to 0.058 mg/kg per day at the end of study period. A significant negative association was observed between the ratio of D/C and the post-transplantation period (r=-0.3624; p < 0.001). The median D/C ratio ranged from 0.0144 at the end of the first month to 0.0053 at 1 year. Significant declines in D/C were observed after the first and the third months after transplantation. The decrease in corticosteroid doses and the increase in serum albumin may explain the reduction in clearance with time.

Allele and genotype frequencies for the 3'-ApoB locus were determined in a population sample from Catalonia (northeast Spain) using PCR amplification and nonradioactive detection. In a total of 308 unrelated individuals, 16 alleles and 50 genotypes were observed. The 3'-ApoB locus demonstrated a heterozygosity of 80%. The distribution of genotypes is in agreement with expected values according to the Hardy-Weinberg equilibrium.

A vegetable foreign body located inside the testicular parenchyma is presented. It's about an unexpected pathological finding in an orchidectomy sample, performed on account of testicular atrophy secondary to very advanced funicular twist. The finding of a vegetal material inside the testis is outstanding. In our knowledge we don't know about another similar case. Pathologic aspects, including granulomatous reaction, regarding arguments of testicular atrophy and the foreign body eruption mechanism are discussed. The handling of the scrotum by paramedical people could justify his presence.

CALCINEURIN INHIBITORS (CNIs) have been the mainstays of immunosuppression after renal transplantation, but the nephrotoxicity associated with these agents may lead to graft dysfunction. In renal transplant recipients, sirolimus (SRL), a non-nephrotoxic agent, has been studied extensively in combination with cyclosporine (CsA), but relatively few studies have assessed the combination of sirolimus and tacrolimus (TRL). Recent reports from clinical trials have shown that combinations of SRL and TRL, at subclinical concentrations, display potent inhibitions of lymphocyte proliferation and IL-2 expression, and claim excellent results with this therapy in kidney and liver transplantation. We describe a pilot study to evaluate the appropriate initial doses of SRL and TRL in adult renal transplant patients to obtain therapeutic levels of both immunosuppressants and to prevent acute rejection in the early posttransplant period.

The human GSTTP1 gene is polymorphic with an A--G transition in exon 5 causing a replacement 105 Ile--Val in the GSTP1 protein. The two isoforms, encoded by the alleles GSTP1*A and GSTP1*B, respectively, show different catalytic efficiencies towards some carcinogenic epoxides. In this study we have addressed the possible role of the Ile105Val GSTP1 polymorphism in lung cancer susceptibility.The polymorphic site was genotyped by RFLP in a group of lung cancer patients (n = 164) and in two control groups (healthy smokers, n = 132; general population, n = 200). All patients and controls were Northwestern Mediterranean Caucasians of the same ethnic origin.The cancer patients showed frequencies of GSTP1*A/A; GSTP1*A/B and GSTP1*B/B (50%, 38%, 11%, respectively) very similar to those of both control groups (healthy smokers: 48%, 41%, 11%). After adjusting for age, sex and smoking status, no association was found between the GSTP1*B allele and lung cancer risk (OR: 1.18; 95% CI: 0.67-2.07). The Ile105val GSTP1 polymorphism was also analysed in combination with the GSTM1 and GSTT1 genes. The results showed that allelism at GSTP1 did not increase the risk associated with the GSTM1 or GSTT1 deletions.

Allele and genotype frequencies of DNA polymorphisms were determined in a population sample of Quechua (n = 113) using the polymerase chain reaction (PCR). We report data on the frequencies of HLA-DQ alpha, YNZ22, 3'ApoB, HUMTH01 and HUMVWA31A alleles and the distribution of the different genotypes. No significant deviations between observed and expected numbers were found, thus assuming the Hardy-Weinberg equilibrium.

Several polymorphic genes have been reported to be possibly involved in modifying lung cancer risk in smokers. The gene GSTM1 is frequently deleted in human populations, and the null genotype has been reported to be a risk factor for developing lung carcinoma. A germline polymorphism of p53 with a single-base change at codon 72 that causes an amino acid replacement of arginine (Arg; CGC) by proline (PRO; CCC) has also been reported to be associated with cancer susceptibility in a Japanese population. Both polymorphisms were genotyped by PCR in a northwestern Mediterranean healthy population (n = 147) and in a group of lung cancer patients (n = 139). The results showed that the frequency of the GSTM1 null genotype was higher in the lung cancer patients compared to the controls [odds ratio (OR), 1.57; 95% confidence interval (CI), 0.99-2.51]. The histological subtypes most clearly modified were small cell carcinoma (OR, 1.89; CI, 0.97-3.65) and adenocarcinoma (OR, 1.93; CI, 0.90-4.14). The null GSTM1 genotype was more frequent among those cancer patients who were medium/ light smokers (or = 50 pack-years) and in those who showed an onset of the disease at a more advanced age. The study of the p53 polymorphism in the healthy population showed allele frequencies of 0.79 (Arg) and 0.21 (Pro). The frequencies found in the lung cancer patients were statistically similar. Both polymorphisms were studied together, and the relative risk of the combination null GSTM1 and Pro/Pro or Arg/Pro genotypes was calculated taking the combination of GTSM1 + together with Arq/Arg as a baseline. The OR found (1.97; CI, 1.03-3.73) suggests that the Pro allele of the p53 germline polymorphism may slightly increase the risk fo the GSTM1 null genotype among smokers.

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.

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.

Between 1986 and 1989, 3226 violent deaths were recorded in Barcelona, 489 of which were due to poisoning. The yearly distribution of these 489 deaths was: 1986, 74; 1987, 98; 1988, 134; and 1989, 183. Of all poisoning deaths, 316 were due to narcotic opiates use, 54 to the inhalation of toxic gases, 49 to the use of psychoactive agents, 37 to caustic products and the others 33 cases to various toxic agents (insecticides, methanol, solvents, mushrooms, etc.). Opioid use is currently the leading cause of death by poisoning in Barcelona, and affects a young population with a mean age between 25 and 27 years. In the groups corresponding to toxic gases and psychoactive drugs, the mean ages are 48 and 45.7 years, respectively. The oldest population was found in the group where death was caused by caustic agents, where the mean age is 56.5 years. The male sex was predominant in all groups except that of caustic agents, where 56.8% of the victims were women. This study confirms the notable increase in opiate- related deaths in the city of Barcelona (up from 27 cases in 1987 to 158 in 1989) and shows stability in the numbers for the other groups. Among the different hypotheses concerning of this remarkable increase in deaths related to opiate use, the aging of consumers and changes in the purity or composition of the product seem to be the most probable.

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.

A case of fatal poisoning due to ingestion of the plant Rumex crispus (curled dock) is described. The patient, a 53-year-old male, presented with gastrointestinal symptoms, severe hypocalcemia, metabolic acidosis and acute hepatic insufficiency. Despite therapeutic measures, the patient died 72 h after ingestion of the plant material. Noteworthy among the pathological findings were centrolobular hepatic necrosis and birefringent crystals in the liver and kidneys that were identified by histochemical techniques and scanning electron microscopy. These observations are compared with other reports in the medical literature, with an emphasis on the risk involved in the use of these plants for culinary or medicinal purposes.

Hemodialysis, forced potassium diuresis, chelating agents per os, and Dithiocarb given intravenously during short periods of time were used for the treatment of acute thallium poisoning (ingestion of 750 mg of thallium sulfate), and the effectiveness of these different therapeutic procedures was analyzed. Chelating agents per os (Prussian blue, Dithiocarb, and Dithiozone) were ineffective in our patient, since fecal excretion of thallium was very low and unmodified by them. Forced potassium diuresis and hemodialysis were very useful therapeutic measures, especially in the first 12 days following ingestion. Dithiocarb perfusion seems to be the most effective method for enhancing urinary thallium excretion. This method might be most useful in the treatment of thallium poisoning if its deleterious effects could be eliminated.

1 A case of fatal Amanita phalloides poisoning in a 14-year-old boy is described. 2 The patient presented severe acute liver dysfunction, disseminated intravascular coagulation and refractory hypoxaemia, and died on the 9th day after mushroom ingestion. 3 Post-mortem examination revealed mesenteric venous thrombosis, massive liver necrosis and haemorrhagic pulmonary alveolitis.

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.

3 cases of suicide due to ingestion of 150, 200 and 4 gr. of paraquat, respectively, are presented. Two of them were brothers and agricultural industrialists, the other one was a farmer. The first two cases died 16 and 10 hours after intake. The farmer died 21 days after ingestion. All of them had progressive hypoxemia and renal failure the two brothers had heart conduction system glycemia (23 mg/dl) a few hours after ingestion. The postmortem study showed edema, hemorrhage and congestion of the lungs, alveolitis, fibrosis and lobar atelectasia; renal tubular necrosis adrenal necrosis; colestasia; hepatic steatosis focal miocarditis. The clinical evolution, particularly short in the first two patients, is commented on, as well as the post-mortem findings, comparing them with those described in the literature. Finally, due to the high toxicity of this herbicide, we insist in prompt transport to herbicide, we insist in prompt transport to the hospital in order to apply early treatment.

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.

Three cases of occupational poisoning by trichloroethylene, one of them fatal, are presented. The etiologic, clinical and diagnostic aspects of each case are discussed, along with a broad literature review, emphasizing preventive measures and the substitution of this chloric solvent by other, less toxic solvents, as recommended by the U.S. Food and Drug Administration.

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.

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.

Lung function and radiographic study was realized on 184 workers in a chromate producing industry (113 chronically exposed, 41 intermittently exposed and 30 unexposed). Prevalences were 22 (11.9%) cases of obstructive ventilatory pattern, 22 (11.9%) restrictive and 18 (9.7%) mixed. In the different ventilatory disfunction patterns, multivariant analysis in the three exposure groups, controlled by the tobacco variable, was statistically significant between exposure and restrictive ventilatory pattern (p = 0.0065). None of the workers presented radiologic alterations according to the ILO, 1980.

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.

Two cases of fatal hydrogen sulfide poisoning are described which occurred during cleaning of a tank that had transported polysulfides. The most characteristic findings of the autopsy were: a blackish-green pigmentation at macroscopic examination; pulmonary edema, steatosis, intrahepatic cholestasis and renal tubular necrosis at microscopic examination. The blood concentration of sulfide ions exceeded 3.5 mg/l. These cases are compared to others described in the literature. The preventive measures that should be adopted to avoid this type of poisoning are stressed.

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.