Levels of PAHs in soil and vegetation samples from Tarragona County, Spain.

The levels of 16 polycyclic aromatic hydrocarbons (PAHs) were determined in 24 soil and 12 wild chard samples collected in Tarragona County (Catalonia, Spain), an area with an important number of chemical and petrochemical industries. Samples were also collected in urban/residential zones and in presumably unpolluted sites (control samples). In soils, the sum of the 16 PAHs ranged between 1002 and 112 ng/g (dry weight) for samples collected near chemical industries and unpolluted sites, respectively. With the exception of acenaphthylene, acenaphthene, anthracene and benzo[k]fluoranthene, no significant differences in the levels of the remaining PAHs were found among the different zones of sample collection. In chard samples, the highest value (sum of 16 PAHs) was observed in the residential area, followed by the industrial and the unpolluted zones, with concentrations of 179, 58 and 28 ng/g (dry weight), respectively. In general terms, the current PAH concentrations in soil and vegetation are lower than the levels reported in a number of investigations from different regions and countries. They are also below the maximum PAH concentrations allowed by the Catalan legislation for different uses of soil.

Metal pollution of soils and vegetation in an area with petrochemical industry.

The aim of this study was to determine the concentrations of arsenic (As), cadmium (Cd), chromium (Cr), mercury (Hg), manganese (Mn), lead (Pb), and vanadium (V) in soil and chard samples collected in various industrial sites of Tarragona County (Spain), an area with an important number of petrochemical industries. Samples were also collected in urban (Tarragona downtown) and presumably unpolluted (blank samples) sites. Human health risks derived from metal inhalation and ingestion of soils were also assessed. With the exception of an increase in the levels of Cd and V, significant differences in soil samples from the industrial and the unpolluted zone were not found. In chard samples, significant differences between collection sites were only noted for V concentrations. For non-carcinogenic risks, the current levels of metals in the industrial area were lower than those considered as safe for the general population. In relation to carcinogenic risks, only As ingestion and Cr inhalation in the industrial zone might potentially cause an increase of the cases of cancer. A Kohonen self-organized map (an Artificial Neural Network) showed differences in metal concentrations according to the zone of origin of the samples. The current results suggest that although in general terms the petrochemical complex is not a relevant metal pollution source for the area, attention should be paid to As, Cr and V.

Aluminum-induced pro-oxidant effects in rats: protective role of exogenous melatonin.

In recent years, it has been suggested that oxidative stress is a feature of Alzheimer's disease in which aluminum (Al) could exacerbate oxidative events. The goal of the present study was to assess in rats the pro-oxidant effects induced by Al exposure, as well as the protective role of exogenous melatonin. Two groups of male rats were intraperitoneally injected with Al only or melatonin only, at doses of 5 and 10 mg/kg/day, respectively for 8 wk. During this period, a third group of animals received Al (5 mg/kg/day) and melatonin (10 mg/kg/day). At the end of the treatment period, rats were anesthesized and arterial blood was obtained. Thereafter, animals were killed and liver and brain (cortex, hippocampus and cerebellum) were removed. These tissues were processed to examine oxidative stress markers: glutathione transferase (GST), reduced glutathione (GSH), oxidized glutathione (GSSG), superoxide dismutase (SOD), glutathione reductase (GR), glutathione peroxidase (GPx), catalase (CAT), thiobarbituric acid reactive substances (TBARS), as well as protein content. Samples of these tissues were also used to determine Al, Fe, Mn, Cu and Zn concentrations. The results show that Al exposure promotes oxidative stress in different neural areas, including those in which Al concentrations were not significantly increased. The biochemical changes observed in neural tissues show that Al acts as pro-oxidant, while melatonin exerts an antioxidant action in Al-treated animals. The protective effects of melatonin against cellular damage caused by Al-induced oxidative stress, together with its low toxicity, make melatonin worthy of investigation as a potential supplement to be included in the treatment of neurological disorders in which the oxidative effects must be minimized.

Reproductive and developmental toxicity of natural and depleted uranium: a review.

Although the biokinetics, metabolism, and chemical toxicity of uranium are well known, until recently little attention was paid to the potential toxic effects of uranium on reproduction and development in mammals. In recent years, it has been shown that uranium is a developmental toxicant when given orally or subcutaneously (SC) to mice. Decreased fertility, embryo/fetal toxicity including teratogenicity, and reduced growth of the offspring have been observed following uranium exposure at different gestation periods. The reproductive toxicity, maternal toxicity, embryo/fetal toxicity, and postnatal effects of uranium, as well as the prevention by chelating agents of uranium-induced maternal and developmental toxicity are reviewed here. Data on the toxic effects of depleted uranium on reproduction and development are also reviewed.

Nephrotoxicity of simultaneous exposure to mercury and uranium in comparison to individual effects of these metals in rats.

Both inorganic mercury and uranium are known nephrotoxicants in mammals. In this study, the renal toxicity of a concurrent exposure to inorganic mercury and uranium was compared with the nephrotoxic effects of the individual metals in a rat model. Eight groups of rats, 10 animals per group, were subcutaneously given a single administration of mercuric chloride (HgCl2, 0.34 mg/kg and 0.68 mg/kg), uranyl acetate dihydrate (UAD, 2.5 mg/kg and 5 mg/kg), or combinations of both compounds at the same doses. A ninth group of rats received sc injections of 0.9% saline and was designated as the control group. Necrosis of proximal tubules, which was observed in all experimental groups, was the most relevant morphologic abnormality. Marked changes, which were remarkably greater than those induced by the individual elements, were noted in some urinary parameters in the groups concurrently exposed to HgCl2 and UAD. It could be an indicator of a synergistic interaction between mercury and uranium. In contrast, compared with the urinary levels found after individual administration of the highest doses of mercury and uranium, significant reductions in the urinary concentrations of these elements were noted following simultaneous exposure to both metals. At these doses, the reduction in the urinary metal excretion was also accompanied by significant decreases in the renal content of mercury and uranium. Whereas the results of some parameters pointed out a possible synergistic interaction between mercury and uranium, other measures hinted that an antagonistic interaction between these elements is also present.

Chelation therapy in aluminum-loaded rats: influence of age.

The influence of age at which aluminum (Al) exposure was initiated on the efficacy of chelation therapy in mobilizing Al was investigated in two groups of male rats exposed to this element at two different stages of the life cycle. Young (21 days old) and old (18 months) rats were exposed to 0 and 50 mg Al/kg/day administered as Al nitrate in drinking water for a preliminary period of 14 days followed by a period of 100 days, in which Al-exposed animals received 100 mg Al/kg/day. At the end of the period of exposure, Al-loaded rats in each age group were given one of the following treatments: s.c. deferoxamine (DFO), oral 1,2-dimethyl-3-hydroxypyrid-4-one (L1) and 1-(p-methylbenzyl)-2-ethyl-3-hydroxypyrid-4-one (MeBzEM) at doses of 0.89 mmol/kg/day for 5 consecutive days. Another group of Al-exposed rats received a concurrent administration of s.c. DFO and oral L1 both at 0.45 mmol/kg/day. During chelation therapy urines were collected daily. Control groups included rats exposed and unexposed to Al. Oral administration of L1 was the most effective treatment in enhancing urinary Al excretion in both age groups of Al-loaded rats. This beneficial effect was similar for old and young animals. Concurrent administration of DFO and L1 had no advantages over the use of either single agent, while MeBzEM was not effective in mobilizing Al from Al-exposed rats.

Developmental toxicity of metal chelating agents.

Chelation therapy is the basis for the treatment of metal poisoning. A number of chelating agents have been widely used since the 1950s. Since these agents can be potentially given to a metal-intoxicated pregnant woman, their intrinsic developmental toxicities are a matter of concern. While the embryo/fetal toxic effects of some chelators have been reported to occur at doses higher than those currently given in the medical treatment of metal poisoning, according to experimental data the potential use of other metal antidotes is controversial. In those cases, the benefits and risks of usage should be carefully weighed. The developmental toxicity of known chelators of clinical interest is presented here. Chelating agents were divided according to the following structurally related categories: polyaminocarboxylic acids, chelators with vicinal -SH groups, beta-mercapto-alpha-aminoacids, hydroxamic acids, ortho-hydroxycarboxylic acids, and miscellaneous agents. Since it has been demonstrated that the teratogenic potential of most chelators is, at least in part, due to induced trace element deficiencies, the advisability of mineral supplements during chelation treatment is also discussed.

Silicon reduces aluminum accumulation in rats: relevance to the aluminum hypothesis of Alzheimer disease.

In recent years, a possible relation between the aluminum and silicon levels in drinking water and the risk of Alzheimer disease (AD) has been established. It has been suggested that silicon may have a protective effect in limiting oral aluminum absorption. The present study was undertaken to examine the influence of supplementing silicon in the diet to prevent tissue aluminum retention in rats exposed to oral aluminum. Three groups of adult male rats were given by gavage 450 mg/kg/day of aluminum nitrate nonahydrate 5 days a week for 5 weeks. Concurrently, animals received silicon in the drinking water at 0 (positive control), 59, and 118 mg Si/L. A fourth group (-Al, - Si) was designated as a negative control group. At the end of the period of aluminum and silicon administration, urines were collected for 4 consecutive days, and the urinary aluminum levels were determined. The aluminum concentrations in the brain (various regions), liver, bone, spleen, and kidney were also measured. For all tissues, aluminum levels were significantly lower in the groups exposed to 59 and 118 mg Si/L than in the positive control group; significant reductions in the urinary aluminum levels of the same groups were also found. The current results corroborate that silicon effectively prevents gastrointestinal aluminum absorption, which may be of concern in protecting against the neurotoxic effects of aluminum.

Comparative effects of the chelators sodium 4,5-dihydroxybenzene-1,3-disulfonate (Tiron) and diethylenetriaminepentaacetic acid (DTPA) on acute uranium nephrotoxicity in rats.

Sodium 4,5-dihydroxybenzene-1,3-disulfonate (Tiron) and diethylenetriaminepentaacetic acid (DTPA) are two chelating agents that have been demonstrated to be effective in the treatment of experimental poisoning by a number of heavy metals. In this study, the effects of Tiron and DTPA on uranium-induced nephrotoxicity were evaluated in a rat model. A series of four Tiron or DTPA injections was administered intraperitoneally to adult male Sprague-Dawley rats immediately after a single subcutaneous injection of uranyl acetate dihydrate (5 mg/kg) and at 24, 48 and 72 h thereafter. Positive and negative control groups received 0.9% saline with or without uranyl acetate, respectively. Tiron effectiveness was assessed at 400, 800 and 1600 mg/kg, whereas DTPA was administered at 250, 500 and 1000 mg/kg. Although the urinary excretion of uranium was significantly enhanced by Tiron administration, significant amounts of uranium still remained in the kidney at the end of the treatment. However, the partial reduction of the renal uranium concentrations was in accordance with the amelioration noted in some urinary and serum indicators of uranium nephrotoxicity. Moreover, Tiron administration also reduced the severity of the uranium-induced histological alterations in the kidney. According to these results, Tiron offers only a modest encouragement with regard to its possible therapeutic potential to treat acute uranium-induced nephrotoxic effects. In turn, DTPA was less effective than Tiron in protecting against the nephrotoxicity of uranium in rats.

Prevention and treatment of aluminum toxicity including chelation therapy: status and research needs.

The prevention and treatment of aluminum (Al) accumulation and toxicity are reviewed. Recommendations to further our understanding of desferrioxamine (deferoxamine, DFO) treatment and to develop more effective chelation approaches are provided. Reduction of Al accumulation and toxicity may benefit end-stage renal disease (ESRD) patients and perhaps those suffering from specific neurodegenerative disorders as well as workers with Al-induced neurocognitive disorders. The clearance of Al may be increased by extracorporeal chelation, renal transplantation, perhaps complexation with simple ligands such as silicon (Si), and systemic chelation therapy. The abilities of extracorporeal chelation and Si to reduce Al accumulation require further evaluation. Although it may not be possible to design Al-specific chelators, chelators with greater Al selectivity are desired. Aluminum-selective chelation might be achieved by targeted chelator distribution or by the use of adjuvants with the chelator. The ability of carboxylic acids to facilitate Al elimination, under specific conditions, warrants further study. Desferrioxamine does not produce significant biliary Al excretion. A chelator with this property may be useful in ESRD patients. The necessity for an Al chelator to distribute extravascularly to be effective is unknown and should be determined to guide the selection of alternatives to DFO. The lack of oral efficacy and occasional side effects of DFO encourage identification of orally effective, safer Al chelators. The bidentate 3-hydroxypyridin-4-ones are currently the most encouraging alternatives to DFO. They have been shown to increase urinary Al excretion in rats and rabbits, but to have toxicity comparable to, or greater than, DFO. Their toxicity may relate to incomplete metal complexation. The ability of orally effective chelators to increase absorption of chelated metal from the gastrointestinal (Gl) tract needs to be evaluated. Orally effective, safe Al chelators would be of benefit to peritoneal dialysis patients and those with neurodegenerative disorders, if Al chelation therapy is indicated. The reduction of Alzheimer's disease (AD) progression and the reversal of Al-induced behavioral deficits and neurofibrillary tangles by DFO encourage further study of Al chelation therapy for selected neurodegenerative disorders.

Assessment of the protective activity of monisoamyl meso-2,3-dimercaptosuccinate against methylmercury-induced maternal and embryo/fetal toxicity in mice.

The protective activity of monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS), a new monoester of 2,3-dimercaptosuccinic acid (DMSA), on methylmercury-induced maternal and developmental toxicity was assessed in mice. A series of four Mi-ADMS injections was given s.c. at 0.25, 6, 24, and 48 h after oral administration of 25 mg/kg of methylmercury chloride (MMC) given on day 10 of gestation. Mi-ADMS effectiveness was tested at 0, 23.8, 47.6 and 95 mg/kg. Cesarean sections were performed on gestation day 18. All live fetuses were examined for external, internal, and skeletal abnormalities. Oral MMC administration resulted in an increase in the number of resorptions, and a decrease in fetal body weight, whereas the incidence of cleft palate, micrognathia, and skeletal variations was also increased in the fetuses of the MMC-treated groups. Although significant amelioration of MMC-induced embryolethality by Mi-ADMS was not noted at any dose, MMC-induced fetotoxicity was reduced by administration of this agent at 23.8, 47.6, and 95 mg/kg. However, the intrinsic toxicity of Mi-ADMS would be a restrictive factor for the possible therapeutic use of this chelator in pregnant women exposed to organic mercury.

Effects of some chelating agents on urinary copper excretion by the rat.

In order to estimate the potential advantages of new chelating agents which can enhance copper excretion in the chronic copper intoxication arising in Wilson's disease, the relative ability of none chelating agents to induce the urinary excretion of copper was compared with that of D-penicillamine (DPA) and triethylenetetramine.2HCl (TRIEN), all given ip at 1 mmol/kg to male Sprague-Dawley rats. The compounds examined were as follows: tris(2-aminoethyl)-amine.3HCl (TREN), tetraethylenepentamine.5HCl (TETREN), pentaethylenehexamine.6HCl (PENTEN), 1,4,7,11-tetraazaundecane.4HCl (TAUD), 1,5,8,12-tetraazadodecane.4HCl (TADD), 1-N-benzyltriethylenetetramine.4HCl (BzTT), 4,7,10,13-tetraazatridecanoic acid.2H2SO4 (TTPA), 1,10-bis(2-pyridylmethyl)-1,4,7,10-tetraazadecane.4HCl (BPTETA), and N,N-bis(2-pyridylmethyl)-4-(aminomethyl)benzoic acid (4ABA). Of these, BzTT, TTPA, and 4ABA are new chelating agents not previously reported. The factors by which these chelating agents enhanced copper excretion over control (untreated) levels were as follows: DPA, 7.2; TREN, 1.6; TRIEN, 4.0; TETREN, 10.1; PENTEN, 7.8; TAUD, 7.8; TADD, 2.6; TTPA, 5.6; BzTT, 1.8; and 4ABA, 5.5. The results indicate that it may well be possible to develop additional chelating agents which are equal or superior to those now used in the treatment of Wilson's disease, as well as structural types whose immunological properties may be significantly different from DPA or TRIEN, the compounds currently used in the clinic for this disorder.

Prevention by chelating agents of metal-induced developmental toxicity.

Chelating agents such as calcium disodium ethylenediaminetetraacetate (EDTA), 2,3-dimercaptopropanol (BAL), or D-penicillamine (D-PA) have been widely used for the past 4 decades as antidotes for the treatment of acute and chronic metal poisoning. In recent years, meso-2,3-dimercaptosuccinic acid (DMSA), sodium 2,3-dimercapto-1-propanesulfonate (DMPS) and sodium 4,5-dihydroxybenzene-1,3-disulfonate (Tiron) have also shown to be effective to prevent against toxicity induced by a number of heavy metals. The purpose of the present article was to review the protective activity of various chelating agents against the embryotoxic and teratogenic effects of well-known developmental toxicants (arsenic, cadmium, lead, mercury, uranium, and vanadium). DMSA and DMPS were found to be effective in alleviating arsenate- and arsenite-induced teratogenesis, whereas BAL afforded only some protection against arsenic-induced embryo/fetal toxicity. Also, DMSA, DMPS, and Tiopronin were effective in ameliorating methyl mercury-induced developmental toxicity. Although the embryotoxic and teratogenic effects of vanadate were significantly reduced by Tiron, no significant amelioration of uranium-induced embryotoxicity was observed after treatment with this chelator.

Evaluation of potential strontium chelators in an octanol-water system.

90Sr has a physical half-life of sufficient duration to make it a potentially dangerous contaminant from nuclear accidents and radioactive wastes. In the present study, the efficacy of 16 compounds as potential chelators of strontium was tested in vitro. Strontium solubilization from strontium carbonate and its distribution in an octanol-water system (Do/w) was determined in the absence and presence of alpha-ketoglutaric acid, Kryptofix 222, ethylenglycol-bis-(beta-amino-ethylether)-N,N-tetraacetic acid, diethylentriamine pentaacetic acid, Kryptofix 5, disodium chlodronate, disodium ethidronate, oxaloacetic acid, fumaric acid, D-gluconic acid, succinic acid, citric acid, D,L-2,3-diaminopropionic acid, 1,1-cyclohexanediacetic acid, tartaric acid, and trans-1,2-cy-clohexanediol. Kryptofix 222 and Kryptofix 5 significantly increased solubilized strontium, suggesting strontium chelation potential. Since in previous in vivo studies both compounds were also effective in the removal of strontium following internal contamination, it is concluded that the octanol-water system may be useful screening compounds with strontium chelation potential.

Effects of meso-2,3-dimercaptosuccinic acid (DMSA) on methyl mercury-induced teratogenesis in mice.

Methyl mercury has been reported to be embryotoxic and teratogenic in numerous systems such as fish, birds, and mammals. meso-2,3-Dimercaptosuccinic acid (DMSA) has been useful for prevention and treatment of mercury poisoning. In this study, the protective activity of DMSA on methyl mercury-induced embryo/fetotoxicity was evaluated in mice. A series of four DMSA injections was administered subcutaneously to pregnant Swiss mice immediately after oral administration of 25 mg/kg methyl mercury chloride (MMC) given on Day 10 of gestation, and at 24, 48, and 72 hr thereafter. DMSA effectiveness was tested at 0, 80, 160, and 320 mg/kg/day. Oral administration of MMC resulted in a high rate of resorptions and dead fetuses as well as a reduced fetal body weight. Moreover, cleft palate (46.9%) and various developmental variations were found in the positive control group. Treatment with DMSA at 160 and 320 mg/kg/day significantly decreased the embryolethality of MMC, whereas at 320 mg DMSA/kg/day the incidence of skeletal anomalies and cleft palate (2.8%) was also significantly reduced. According to these results, DMSA offers encouragement with regard to its therapeutic potential for pregnant women exposed to methyl mercury.

Maternal and developmental toxicity of manganese in the mouse.

Manganese (II) chloride tetrahydrate was investigated in Swiss mice for maternal and developmental toxicity after subcutaneous (s.c.) exposure to doses of 0, 2, 4, 8 and 16 mg/kg per day from gestation day 6 through 15. Females were sacrificed on gestation day 18, and fetuses were examined for external, visceral, and skeletal abnormalities. Maternal toxicity included significant reductions in weight gain and food consumption at 8 and 16 mg/kg/day, as well as several treatment-related deaths in the high dose-group. There were no treatment-related effects on the number of total implants, early resorptions, dead fetuses or sex ratio, whereas a significant increase in the number of late resorptions was found in the 4, 8, and 16 mg/kg/day groups. Fetotoxicity, consisting primarily of reduced fetal body weight and an increased incidence of morphological defects was also observed at 8 and 16 mg/kg/day. There were no differences between control and manganese-treated groups in the incidence of individual or total malformations. The no observable adverse effect level (NOAEL) for maternal toxicity of MnCl2 x 4H(2)0 in mice was 4 mg/kg/day, while the NOAEL for embryo/fetal toxicity was 2 mg/kg/day.

Effectiveness of sodium 4,5-dihydroxybenzene-1,3-disulfonate (Tiron) in protecting against uranium-induced developmental toxicity in mice.

The effect of Tiron (sodium 4,5-dihydroxybenzene-1,3-disulfonate), a chelating agent used in the treatment of experimental poisoning by a number of heavy metals, on uranium-induced developmental toxicity was evaluated in Swiss mice. A series of four Tiron injections was administered intraperitoneally to pregnant mice immediately after a single subcutaneous injection of 4 mg/kg of uranyl acetate dihydrate given on day 10 of gestation and at 24, 48, and 72 h thereafter. Controls received 0.9% saline with or without uranyl acetate. Tiron effectiveness was assessed at 500, 1000 and 1500 mg/kg per day. Amelioration by Tiron of uranium-induced embryolethality was not noted at the two lower doses. The percentage of dead and resorbed fetuses in the Tiron-treated groups was not statistically different from that in the positive control group. However, treatment at 1500 mg/kg per day showed isolated protective effects against uranium fetotoxicity, such as that evidenced by the lack of differences in fetal body weight between this group and the uranium-untreated group, as well as by a decrease in the number of skeletal defects. According to these results, the ability of Tiron to protect the developing mouse fetus against uranium-induced developmental toxicity offers only modest encouragement with regard to its possible therapeutic potential for pregnant women exposed to this metal.

The action of chelating agents in experimental uranium intoxication in mice: variations with structure and time of administration.

The determination of the relative abilities of 11 chelating agents to enhance the urinary and fecal excretion of uranium when administered 10 min after uranyl acetate dihydrate (UAD) in mice showed that the most effective of these were Tiron, desferrioxamine, and 1,2-dimethyl-3-hydroxypyrid-4-one. An increase in the interval between UAD administration and that of the chelating agent drastically reduces the net mobilization of the uranium by the chelating agents examined. When given shortly after UAD, Tiron produced the greatest reduction in renal and bone levels of uranium. None of the chelating agents were able to affect the bone levels of uranium when administered 24 hr or more after the administration of the UAD.

Lack of effectiveness of several chelators in removing internally deposited strontium from mice following repeated parenteral strontium administration.

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.

Meso-2,3-dimercaptosuccinic acid (DMSA) affects maternal and fetal copper metabolism in Swiss mice.

Meso-2,3-dimercaptosuccinic acid (DMSA) is a chelating agent used to treat heavy metal intoxication. DMSA has been reported to be teratogenic in the mouse, and it has been suggested that this teratogenicity may be secondary to DMSA-induced alterations in Zn metabolism. In the present study, 0, 400 or 800 mg DMSA/kg body weight were administered on gestation days 6-15 to pregnant Swiss mice by gavage (PO) or subcutaneous injection (SC). Mice were fed a diet containing 14 micrograms Zn, 10 micrograms Cu, 120 micrograms Fe, 1175 micrograms Mg and 6.8 mg Ca/g diet. A sub-group of mice in the 800 mg DMSA/kg SC group was fed a diet containing 250 micrograms Zn/g. DMSA administration did not result in overt maternal toxicity. There was no effect of the drug on fetal or placental weight, or on crown-rump length. However, some fetuses from DMSA-treated dams were characterized by skeletal abnormalities including supernumerary ribs, unossified anterior phalanges and malformed sternebrae. Drug exposure was not associated with consistent changes in tissue Zn, Fe, Ca or Mg levels. Supplemental Zn had no marked effects on the fetus. Fetal liver Cu concentrations exhibited dose-dependent decreases with increasing DMSA dose. This finding suggests that the developmental toxicity of DMSA may be mediated through disturbed maternal/fetal copper metabolism.