Magnetic properties of nanoparticles as a function of their spatial distribution on liposomes and cells.

The aggregation processes of magnetic nanoparticles in biosystems are analysed by comparing the magnetic properties of three systems with different spatial distributions of the nanoparticles. The first one is iron oxide nanoparticles (NPs) of 14 nm synthesized by coprecipitation with two coatings, (3-aminopropyl)trimethoxysilane (APS) and dimercaptosuccinic acid (DMSA). The second one is liposomes with encapsulated nanoparticles, which have different configurations depending on the NP coating (NPs attached to the liposome surface or encapsulated in its aqueous volume). The last system consists of two cell lines (Pan02 and Jurkat) incubated with the NPs. Dynamic magnetic behaviour (AC) was analysed in liquid samples, maintaining their colloidal properties, while quasi-static (DC) magnetic measurements were performed on lyophilised samples. AC measurements provide a direct method for determining the effect of the environment on the magnetization relaxation of nanoparticles. Thus, the imaginary (χ'') component shifts to lower frequencies as the aggregation state increases from free nanoparticles to those attached or embedded into liposomes in cell culture media and more pronounced when internalized by the cells. DC magnetization curves show no degradation of the NPs after interaction with biosystems in the analysed timescale. However, the blocking temperature is shifted to higher temperatures for the nanoparticles in contact with the cells, regardless of the location, the incubation time, the cell line and the nanoparticle coating, supporting AC susceptibility data. These results indicate that the simple fact of being in contact with the cells makes the nanoparticles aggregate in a non-controlled way, which is not the same kind of aggregation caused by the contact with the cell medium nor inside liposomes.

Succimer chelation improves learning, attention, and arousal regulation in lead-exposed rats but produces lasting cognitive impairment in the absence of lead exposure.

BACKGROUND: There is growing pressure for clinicians to prescribe chelation therapy at only slightly elevated blood lead levels. However, very few studies have evaluated whether chelation improves cognitive outcomes in Pb-exposed children, or whether these agents have adverse effects that may affect brain development in the absence of Pb exposure. OBJECTIVES: The present study was designed to answer these questions, using a rodent model of early childhood Pb exposure and treatment with succimer, a widely used chelating agent for the treatment of Pb poisoning. RESULTS: Pb exposure produced lasting impairments in learning, attention, inhibitory control, and arousal regulation, paralleling the areas of dysfunction seen in Pb-exposed children. Succimer treatment of the Pb-exposed rats significantly improved learning, attention, and arousal regulation, although the efficacy of the treatment varied as a function of the Pb exposure level and the specific functional deficit. In contrast, succimer treatment of rats not previously exposed to Pb produced lasting and pervasive cognitive and affective dysfunction comparable in magnitude to that produced by the higher Pb exposure regimen. CONCLUSIONS: These are the first data, to our knowledge, to show that treatment with any chelating agent can alleviate cognitive deficits due to Pb exposure. These findings suggest that it may be possible to identify a succimer treatment protocol that improves cognitive outcomes in Pb-exposed children. However, they also suggest that succimer treatment should be strongly discouraged for children who do not have elevated tissue levels of Pb or other heavy metals.

Dithiol compounds at low concentrations increase arsenite toxicity.

Inorganic trivalent arsenicals are vicinal thiol-reacting agents, and dithiothreitol (DTT) is a well-known dithiol agent. Interestingly, both decreasing and increasing effects of DTT on arsenic trioxide-induced apoptosis have been reported. We now provide data to show that, at high concentrations, DTT, dimercaptosuccinic acid (DMSA), and dimercaptopropanesulfonic acid (DMPS) decreased arsenic trioxide-induced apoptosis in NB4 cells, a human promyelocytic leukemia cell line. In contrast, at low concentrations DTT, DMSA, and DMPS increased the arsenic trioxide-induced apoptosis. DTT at a high concentration (3 mM) decreased, whereas at a low concentration (0.1 mM), it increased the cell growth inhibition of arsenic trioxide, methylarsonous acid (MMA(III)), and dimethylarsinous acid (DMA(III)) in NB4 cells. DMSA and DMPS are currently used as antidotes for acute arsenic poisoning. These two dithiol compounds also show an inverse-hormetic effect on arsenic toxicity in terms of DNA damage, micronucleus induction, apoptosis, and colony formation in experiments using human epithelial cell lines derived from arsenic target tissues such as the kidney and bladder. With the oral administration of dithiols, the concentrations of these dithiol compounds in the human body are likely to be low. Therefore, the present results suggest the necessity of reevaluating the therapeutic effect of these dithiol compounds for arsenic poisoning.

Monoisoamyl dimercaptosuccinic acid induced changes in pregnant female rats during late gestation and lactation.

Monoisoamyl dimercaptosuccinic acid (MiADMSA), a vicinal thiol chelating agent and an analogue of a conventional metal chelating agent, meso-2,3-dimercaptosuccinic acid (DMSA) has recently been gaining recognition to be more effective chelating agent than DMSA in mobilizing lead, mercury and arsenic. However, very little information is available on the toxicological properties of this chelator. In the present study, MiADMSA was administered to pregnant female rats from day 14 of gestation to day 21 of lactation at different doses through oral (p.o.) and intraperitoneal (i.p.) routes to examine the toxicity in the pups and dams. Results suggested that MiADMSA had no effect on period of gestation, litter-size, sex ratio, and viability and lactation. No skeletal defects were observed following the administration of the chelator. However, MiADMSA administration produced few signs of oxidative stress in dams particularly at the higher doses (100 and 200mg/kg) as evident from increased thiobarbituric acid reactive substances (TBARS) in RBCs and decrease in the delta-aminolevulinic acid dehydratase (ALAD) activity. Administration of MiADMSA also caused some alterations in the essential metal concentration in the soft tissues especially tissue copper loss in lactating mothers and pups, which would be of some concern. Apart from copper, changes were also observed in the tissue zinc concentrations in mothers and pups following MiADMSA administration. The study thus suggests that the chelator is relatively safe during late gestation and it does not cause any major alteration in the mothers and the developing pups. However, detailed studies with MiADMSA, post-toxic metal exposure in pregnant animals may provide useful information.

BAL modulates glutamate transport in synaptosomes and synaptic vesicles from rat brain.

The therapeutic use of BAL (2,3-dimercaptopropanol) as treatment for poisoning has been halted by data suggesting serious neurotoxicity. This article is a report on the effects of BAL and other dithiols, DMSA (meso-2,3-dimercaptosuccinic acid) and DMPS (2,3-dimercaptopropane-1-sulfonic acid), on [3H]glutamate release and uptake by rat brain synaptosomes and [3H]glutamate uptake by synaptic vesicles. BAL (100 microM) inhibited glutamate uptake (30%) and stimulated its basal release (30%) in synaptosomes, without affecting K+-stimulated release. BAL also inhibited glutamate uptake by synaptic vesicles (up to 60%). DMPS and DMSA (100 microM) had no significant effects on these parameters. The data reported here provide some evidence of glutamate involvement in BAL-induced neurotoxicity by demonstrating direct effects of BAL on glutamatergic system modulation.

Mobilization of lead in mice by administration of monoalkyl esters of meso-2,3-dimercaptosuccinic acid.

The following six monoalkyl esters of meso-2,3-dimercaptosuccinic acid (DMSA) were synthesized and evaluated for relative activities in mobilizing lead from kidneys and brains of lead-bearing mice: n-propyl (Mn-PDMS), i-propyl (Mi-PDMS), n-butyl (Mn-BDMS), i-butyl (Mi-BDMS), n-amyl (Mn-ADMS) and i-amyl meso-2,3-dimercaptosuccinate (Mi-ADMS). DMSA was used as a positive control. When each was administered intraperitoneally (i.p.) as a single dose of 2.0 mmol/kg, DMSA lowered the kidney lead concentration 52%, while the monoesters effected reductions of 54-75%. Mn-ADMS was toxic at this dose. DMSA lowered the brain lead level 20% when given as a single dose, while the monoesters conferred reductions of 64-87%. When given as 5 daily i.p. injections at 0.5 mmol/kg, DMSA reduced the kidney lead concentration 45%, while the monoesters caused reductions of 56-73%. DMSA lowered the brain lead concentration 35% on the 5-day treatment regimen, while the monoesters evoked reductions of 59-75%. Mi-ADMS was equally effective when given orally or i.p. The i.p. LD50 value of this analog in mice is 3.0 mmol/kg, a value which lies between the reported LD50 doses of DMSA (16.0 mmol/kg) and dimercaprol (1.1 mmol/kg). It is suggested that the ability of these monoesters to cross cell membranes may account for their superiority to DMSA in mobilizing brain lead in this animal model.

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.

Meso-2,3-dimercaptosuccinic acid induces calcium transients in cultured rhesus monkey kidney cells.

The maintenance of intracellular Ca2+ homeostasis is critical to many cellular functions that rely on the calcium ion as a messenger. While attempting to characterize the effects of lead on intracellular calcium levels ([Ca2+]i) in LLC-MK2 Rhesus Monkey kidney cells, we observed that treatment with the metal chelating drug, meso-2,3-dimer-captosuccinic acid (DMSA) evoked transient increases in [Ca2+]i. Changes in [Ca2+]i were monitored using the Ca2+ indicator dye Fura-2 and a dual wavelength fluorescence imaging system. In the presence of 2 mM extracellular Ca2+, DMSA treatment caused a concentration-dependent (15-500 microM) transient increase in [Ca2+]i returning to baseline levels within 30-60 s. Pharmacologic concentrations of DMSA (30 microM) stimulated a three-fold increase in [Ca2+]i, which was spatiotemporally comparable to Ca2+ transients induced by other calcium agonists. Depletion of inositol trisphosphate (IP3)-sensitive [Ca2+]i stores with the smooth endoplasmic reticulum calcium-ATPase (SERCA) inhibitor thapsigargin did not prevent DMSA-elicited increases in [Ca2+]i, suggesting that Ca2+ mobilized by DMSA was either extracellular or from an non-IP3 releasable Ca2+ pool. Treatment with glutathione, cysteine, or 2-mercaptoethanol caused similar but not identical calcium transients. Adenosine-5'-trisphosphate (ATP) also elicited transient increases in [Ca2+]i similar to those of DMSA. No transient increases in [Ca2+]i were elicited by DMSA or ATP in the absence of extracellular calcium. These data indicate that DMSA and other sulfhydryl compounds trigger an influx of extracellular calcium, suggesting a previously unobserved and unanticipated interaction between DMSA and the Ca2+ messenger system.

Effects of oral meso-2,3-dimercaptosuccinic acid (DMSA) administration on late gestation and postnatal development in the mouse.

The present study was conducted to evaluate the effects of meso-2,3-dimercaptosuccinic acid (DMSA) on late gestation and postnatal viability and growth in the mouse. DMSA was given po to four groups of pregnant Swiss mice at 0, 200, 400, and 800 mg/kg/day from day 14 of pregnancy until postnatal day 21. At birth, the following data were recorded: length of gestation, number of live, dead, and abnormal pups, sex, and individual pup weights. Each pup was weighed again on day 4, 14, and 21 of lactation. Pinna detachment, incisor eruption and eye opening were also monitored. No treatment-related signs of toxicity were noted in any of the dams during the study. No adverse effects on offspring survival or development were evident in the 200 or 400 mg DMSA/kg/day groups. However, on days 14 and 21 of lactation a significant decrease in pup body weight was observed in the 800 mg/kg/day group. Also, a significant increase in the relative weight of the brain was seen in this group. The "no observable effect level" (NOEL) for health hazards to the developing pup was greater than 400 mg/kg/day. This dose is higher than the amounts of DMSA usually given in the treatment of human heavy metal intoxications.

Are we ready to replace dimercaprol (BAL) as an arsenic antidote?

1 Dimercaprol (BAL), 2,3-dimercaptopropanesulphonate sodium (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA) are effective arsenic antidotes, but the question which one is preferable for optimal therapy of arsenic poisoning is still open to discussion. Major drawbacks of BAL include (a) its low therapeutic index, (b) its tendency to redistribute arsenic to brain and testes, for example, (c) the need for (painful) intramuscular injection and (d) its unpleasant odour. 2 The newer antidotes DMPS and DMSA feature low toxicity and high therapeutic index. They can be given orally or intravenously due to their high water solubility. While these advantages make it likely that DMPS and DMSA will replace BAL for the treatment of chronic arsenic poisoning, acute intoxication-especially with lipophilic organoarsenicals-may pose a problem for the hydrophilic antidotes, because their ionic nature can adversely affect intracellular availability. 3 This article focuses on aspects dealing with the power of BAL, DMPS, and DMSA to mobilize tissue-bound arsenic in various experimental models, such as monolayers of MDCK (= Madin-Darby canine kidney) cells from dog kidney, isolated perfused liver from guinea-pigs, and perfused jejunal segments from rat small intestine. 4 The results show that hydrophilic DMPS and DMSA may fail to rapidly and completely remove arsenic that has escaped from the extracellular space across tight epithelial barriers. However, owing to their low toxicity, which allows larger doses to be applied, and the potential modification of their pharmacokinetics by means of inert oral anion-exchange resins, DMPS and DMSA may advantageously replace BAL whenever intervention time is not critical. With severe intoxication by organic arsenicals, when the point-of-no-return is a limiting factor, BAL may still have a place as an arsenic antidote.

Effects of DMSA-coated Fe3O4 nanoparticles on the transcription of genes related to iron and osmosis homeostasis.

In this article, we checked the effect of 2,3-dimercaptosuccinic acid-coated Fe(3)O(4) nanoparticles on gene expression of mouse macrophage RAW264.7 cells and found that the transcription of several important genes related to intracellular iron homeostasis were significantly changed. We thus speculated that the cellular iron homeostasis might be disturbed by this nanoparticle through releasing iron ion in cells. To verify this speculation, we first confirmed the transcriptional changes of several key iron homeostasis- related genes, such as Tfrc, Trf, and Lcn2, using quantitative PCR, and found that an iron ion chelator, desferrioxamine, could alleviate the transcriptional alterations of two typical genes, Tfrc and Lcn2. Then, we designed and validated a method based on centrifugation for assaying intracellular irons in ion and nanoparticle state. After extensive measures of intracellular iron in two forms and total iron, we found that the intracellular iron ion significantly increased with intracellular total iron and nanoparticle iron, demonstrating degradation of this nanoparticle into iron ion in cells. We next mimicked the intralysosomal environment in vitro and verified that the internalized iron nanoparticle could release iron ion in lysosome. We found that as another important compensatory response to intracellular overload of iron ion, cells significantly downregulated the expressions of genes belonging to solute carrier family which are responsible for transferring many organic solutes into cells, such as Slc5a3 and Slc44a1, in order to prevent more organic solutes into cells and thus lower the intracellular osmosis. Based on these findings, we profiled a map of gene effects after cells were treated with this iron nanoparticle and concluded that the iron nanoparticles might be more detrimental to cell than iron ion due to its intracellular internalization fashion, nonspecific endocytosis.

Long term biotransformation and toxicity of dimercaptosuccinic acid-coated magnetic nanoparticles support their use in biomedical applications.

Although iron oxide magnetic nanoparticles (MNP) have been proposed for numerous biomedical applications, little is known about their biotransformation and long-term toxicity in the body. Dimercaptosuccinic acid (DMSA)-coated magnetic nanoparticles have been proven efficient for in vivo drug delivery, but these results must nonetheless be sustained by comprehensive studies of long-term distribution, degradation and toxicity. We studied DMSA-coated magnetic nanoparticle effects in vitro on NCTC 1469 non-parenchymal hepatocytes, and analyzed their biodistribution and biotransformation in vivo in C57BL/6 mice. Our results indicate that DMSA-coated magnetic nanoparticles have little effect on cell viability, oxidative stress, cell cycle or apoptosis on NCTC 1469 cells in vitro. In vivo distribution and transformation were studied by alternating current magnetic susceptibility measurements, a technique that permits distinction of MNP from other iron species. Our results show that DMSA-coated MNP accumulate in spleen, liver and lung tissues for extended periods of time, in which nanoparticles undergo a process of conversion from superparamagnetic iron oxide nanoparticles to other non-superparamagnetic iron forms, with no significant signs of toxicity. This work provides the first evidence of DMSA-coated magnetite nanoparticle biotransformation in vivo.

In vitro interactions between DMSA-coated maghemite nanoparticles and human fibroblasts: A physicochemical and cyto-genotoxical study.

Although the current production of oxide nanoparticles may be modest, the wide range of proposed applications and forecasted growth in production has raised questions about the potential impact of these nanoparticles on the environment and human health. Iron oxide nanoparticles have been proposed for an increasing number of biomedical applications although in vitro toxicity depending on the particles coating has been evidenced. The aim of this study was to examine the potential in vitro cyto- and genotoxicity on human dermal fibroblasts of DMSA-coated maghemite nanoparticles (NmDMSA) as a function of well-defined physicochemical states. Well-stabilized NmDMSA produced weak cytotoxic and no genotoxic effects. This is attributed in part to the DMSA coating, which serves as a barrier for a direct contact between nano-oxide and fibroblasts, inhibiting a potential toxic effect.

Antidotal effects of dimercaptosuccinic acid.

Dimercaptosuccinic acid (DMS), HOOC-CH(SH)-CH(SH)-COOH, was first developed in China as an effective antidote for poisoning from many heavy metals, such as Pb, Hg, As, Cd, Sb, Tl, Au, Zn, Ni, Pt, Ag, Co and Sn. DMS increases the excretion of Ce, Pm, Sr and Po from the body. Hundreds of patients suffering from hepatolenticular degeneration (Wilson's disease) have been treated successfully with DMS. Recently, DMS was found to be effective also in treating certain non-metallic intoxications, like some of the new non-phosphate pesticides and mushroom poisonings.

meso-2,3-Dimercaptosuccinic acid: chemical, pharmacological and toxicological properties of an orally effective metal chelating agent.

The primary purpose of this article is to summarize the recent investigations dealing with the pharmacology and toxicology of meso-2,3-dimercaptosuccinic acid, an orally effective chelating agent. The need for a better chelating agent for treating young children and pregnant women with lead intoxication has been apparent for some time. Preclinical and clinical evidence now indicate that meso-2,3-dimercaptosuccinic acid, an Orphan Drug, shows the most promise for being effective in this regard. It has an extracellular distribution that may be responsible for its low toxicity compared to other dithiols. No attempt has been made to compare it in a rigorous and thorough manner with other chelating agents. That has not been the purpose of this review. The advantages of meso-DMSA, however, compared to CaNa2EDTA for the treatment of lead intoxication, have been outlined. Significant advances have been made recently in elucidating the structures of the metal chelates of DMSA. There is a striking difference between the structures of the lead chelate of meso-DMSA and those of racemic-DMSA. The former chelates by coordination of one sulfur and one oxygen atom with Pb. The latter can form chelates via the two sulfur atoms or via one oxygen and one sulfur atom. Solubility of the lead chelates depends on the ionization of the noncoordinated thiol and carboxylic acid groups. Bimane derivatization, HPLC, and fluorescence, as well as gas chromatography can be used for analysis of DMSA in biological fluids. The acid dissociation constants for meso- and racemic-DMSA have been summarized from the literature as have the formation constants of some of the DMSA chelates. DMSA is biotransformed to a mixed disulfide in humans. By 14 hr after DMSA administration (10 mg/kg), only 2.5% of the administered DMSA is excreted in the urine as unaltered DMSA and 18.1% of the dose is found in the urine as altered forms of DMSA. Most altered DMSA in the urine is in the form of a mixed disulfide. It consists of DMSA in disulfide linkages with two molecules of L-cysteine. One molecule of cysteine is attached to each of the sulfur atoms of DMSA. The remaining 10% of the altered DMSA was in the form of cyclic disulfides of DMSA. So far, the mixed disulfide has been found in human but not in rabbit, mouse, or rat urine. Apparently there are species differences in how organisms metabolize meso-DMSA.(ABSTRACT TRUNCATED AT 400 WORDS)

The pharmacology of 2,3-dimercaptosuccinic acid and its potential use in arsenic poisoning.

Arsenic (As2O3)-poisoned rats were treated with either 2,3-dimercaptosuccinic acid (DMS) or dimercaptopropanol (BAL) at doses of 30 mg/kg/day. A control group received no treatment. The total quantity of arsenic excreted was not significantly different in response to 4 days of treatment with either DMS or BAL. In addition, there was no difference between the two drug treatment groups in the residual arsenic content of brain, liver, kidney and spleen after treatment. Both drugs reduced the arsenic content of each tissue to approximately 40% of that of untreated controls. Previous studies have shown that DMS is orally effective for the treatment of lead poisoning. The LD50 of DMS was determined to be in excess of 3 g/kg in rats and mice, approximately 30 times the LD50 of BAL. No gross, histopathological or biochemical evidence of toxicity was observed in mice, rats or dogs which received DMS 5 days per week for 6 months. DMS did not affect the excretion of zinc, iron, calcium or magnesium. Urinary copper excretion was significantly elevated in response to 30 mg/kg of DMS, suggesting that the drug might also be useful for the treatment of Wilson's disease.

Efficacy of various dithiol compounds in acute As2O3 poisoning in mice.

The efficacy of DL-dimercaptopropanol (British Anti-Lewisite, BAL), DL-dimercaptopropanesulfonate (DMPS), and meso-dimercaptosuccinic acid (DMSA) was compared in reducing the acute As2O3 toxicity in mice. Mice were treated with a single equimolar dose of a dithiol compound (0.7 mmol/kg i.p.) 0.5 or 30 min after the s.c. injection of various doses of As2O3. Both DMPS and DMSA were significantly (p less than or equal to 0.05) more effective in mice treated 0.5 min after the poisoning if compared to BAL on an equimolar level. The highest potency ratio (PR) (LD50 with treatment/LD50 without treatment) was found in animals injected with DMSA (PR = 8.6). The corresponding value for DMPS was 4.2, and for BAL 2.1, respectively. In animals treated 30 min after poisoning the efficacy of DMPS (PR = 2.6) was similar to the efficacy of DMSA 2.4, both being only slightly superior to BAL 2.0. DMPS and DMSA were found to be much less toxic than BAL. The LD50 of arsenic was 0.057 mmol/kg. The efficacy of BAL, DMPS, and DMSA in reducing the tissue content of arsenic following acute As2O3 poisoning was investigated in mice (n = 6/group) and guinea pigs (n = 3-4/group). The animals were injected s.c. with 0.043 mmol/kg As2O3 (containing a tracer dose of 74As(III)). Thirty minutes later the antidotes were administered i.p. (0.7 mmol/kg). From 2 to 4 h after As2O3 poisoning bile was collected from guinea pigs. Four h after As2O3 injection the content of 74As in blood, liver, kidneys, spleen, heart, lungs, brain, testes, skeletal muscle, and skin in mice and guinea pigs was measured.(ABSTRACT TRUNCATED AT 250 WORDS)

A methylmercury toxicity model to test for possible adverse effects resulting from chelating agent therapy.

A daily dosing model for methylmercury (MM) intoxication was developed for the purpose of testing for possible adverse effects resulting from the administration of complexing agents used in the treatment of MM poisoning. The dithiol complexing agents 2,3-dimercaptopropanol (BAL) and meso-2,3-dimercaptosuccinic acid (DMSA) were chosen to test the discriminative ability of this model, since the former is contraindicated for MM poisoning and causes an increase in target organ MM burden, while the latter compound is known to be efficacious in reducing both toxicity and brain MM content. The basic design of the model called for daily observation of treated animals with identification of the following signs of MM intoxication: loss of body weight, onset of signs of toxicity, and mortality. The degree of toxicity was evaluated, and a toxicity score (0-5) was provided for each animal. A dose-dependent decrease in body weight was found in MM-treated mice. The latent period for development of signs of intoxication varied inversely with the dose rate. The rate of progression of severity of signs of intoxication was also dependent upon the dose. A dose rate of 14 mg Hg per kg per day was utilized to test the effects of BAL and DMSA on the onset and progression of signs of MM intoxication. Onset and progression of signs of methylmercury intoxication were similar for animals receiving methylmercury either alone or with administration of BAL at 2 mg per kg per day. Animals which received BAL at a dose rate of 20 mg per kg per day developed signs of intoxication significantly earlier.(ABSTRACT TRUNCATED AT 250 WORDS)

Developmental toxicity evaluation of monoisoamyl meso-2,3-dimercaptosuccinate in mice.

Monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS), a new dimercaptosuccinic acid (DMSA) analog with enhanced lipophilic properties, was evaluated for potential developmental toxicity. Intraperitoneal injections of Mi-ADMS were given to female Swiss mice (0, 47.5, 95, and 190 mg/kg) on gestational d 6-15. The maternal clinical status was monitored daily during treatment. At termination (gestational d 18), dams were evaluated for clinical status and gestational outcome. Each live fetus was weighed and examined for external, visceral, and skeletal abnormalities. Although no maternal mortality was observed, treatment with 95 and 190 mg/kg resulted in maternal toxicity, manifested as reduced body weight gain during treatment and increased relative liver weight. Embryo/fetal toxicity, consisting of a significant increase in the number of late resorptions as well as in the percentage of postimplantation loss, reduced (nonsignificant) fetal body weight, and an increase in the incidence of skeletal defects, was also observed at 190 mg/kg/d. However, no treatment-related external or soft-tissue malformations or developmental variations were found in any group. The no-observed-adverse-effect level (NOAEL) for maternal toxicity was 47.5 mg/kg/d, whereas the NOAEL for developmental toxicity was 95 mg/kg/d. These results indicate that Mi-ADMS did not produce developmental toxicity in mice in the absence of maternal toxicity.