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.

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.

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.

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.

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.

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.

Haematological, hepatic and renal alterations after repeated oral and intraperitoneal administration of monoisoamyl DMSA. II. Changes in female rats.

We recently reported the effects of repeated administration of the monoisoamyl ester of dimercaptosuccinic acid (MiADMSA) on a few selected biochemical variables indicative of haematopoietic, liver, kidney and brain toxicity, oxidative stress and essential metal status in male rats. The present investigation studies similar changes in female rats to fi nd out if the changes are independent of gender. The results suggest significant and pronounced toxic effects of MiADMSA on haem biosynthesis, liver and kidneys in female rats exposed to higher doses of orally (p.o.) or intraperitoneally (i.p.) administered MiADMSA, compared with the effects in male rats. No effects on brain tissues were seen. A pronounced depletion of copper was noted in the blood and liver of MiADMSA administered rats, irrespective of route of exposure. It can be concluded that the administration of MiADMSA in female rats is confounded with side-effects and may require caution during its use and further exploration.

Haematological, hepatic and renal alterations after repeated oral or intraperitoneal administration of monoisoamyl DMSA. I. Changes in male rats.

Monoisoamyl 2,3-dimercaptosuccinic acid (MiADMSA), a vicinal thiol chelator, is gaining recognition recently as a better chelator than meso 2,3-dimercaptosuccinic acid (DMSA) in decreasing heavy metal burden in tissues because of its lipophilic character. There is, however, little information available on the toxicological properties of this chelator after repeated administration in animals. In the present study, we investigated the dose-dependent effect of MiADMSA on various biochemical parameters suggestive of alterations in haem biosynthesis and hepatic, renal and brain oxidative stress after 21 days of repeated intraperitoneal (i.p.) or oral (p.o.) administration to rats. The concentration of essential metals in blood and soft tissues was determined along with histopathological observations of hepatic and renal tissues. The results suggest that MiADMSA administration had no effect on blood delta-aminolevulinic acid dehydratase activity. However, an increase in zinc protoporphyrin and a decrease in haemoglobin levels were noted in animals given MiADMSA i.p. A moderate increase in serum alkaline phosphatase suggested mild hepatotoxicity at the highest dose (100 mg kg(-1), i.p.). This was confirmed by histopathological examinations, which identified basophilic stippling, granulation of the cytoplasm, haemorrhage and congestion. At the highest dose, levels of hepatic thiobarbituric acid reactive substance and oxidized glutathione were increased above those of control values. Levels of hepatic reduced glutathione were decreased. Taken together, these observations point to oxidative stress. In animals administered MiADMSA i.p. there was an increase in the brain malondialdehyde levels at the two higher doses (50 and 100 mg kg(-1)). Essential metal status revealed a significant effect of MiADMSA (p.o.) in increasing blood zinc while significantly decreasing the kidney zinc level. The most significant adverse effect of MiADMSA was on copper concentration, which showed significant depletion from almost all major organs. Magnesium levels in blood decreased but increased in liver of MiADMSA-administered rats. Histopathological observations of liver and kidneys suggest few moderate lesions. It can be concluded that repeated administration of MiADMSA is compromised with some mild toxic effect, particularly the loss of copper. The effects during oral administration are comparatively less pronounced than by the i.p. route.

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.

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.

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.

Meso-2,3-dimercaptosuccinic acid mono-N-alkylamides: syntheses and biological activity as novel in vivo cadmium mobilizing agents.

Three meso-2,3-dimercaptosuccinic acid mono-N-alkylamides (meso-RNHCOCH(SH)CH(SH)-COOH, where R = CHMe2, Mi-PDMA; CH2CHMe2, Mi-BDMA; and CH2CH2CHMe2, Mi-ADMA), were prepared via a synthetic route using the sulfhydryl-protected anhydride. 2,2-Dimethyl-1,3-dithiolane-4,5-cis-dicarboxylic acid anhydride was opened up with 1 mol of corresponding amine to give the SH-protected monoamide. Subsequent deblocking of the vicinal dithiol functionality was accomplished by conversion of the dithiolane into the mercury complex followed by reaction with H2S to give the target molecule. The potential utility of these compounds in chronic cadmium intoxication was examined by evaluation of their cadmium mobilizing efficacy in vivo in cadmium-loaded female albino rats using sodium N-benzyl-D-glucamine-N-carbodithioate (BGDTC) as the standard drug. Compared to BGDTC, the new compounds were, except at the highest dosage studied, equally or more effective in decreasing retention of hepatic cadmium, while mostly less effective in decreasing renal cadmium. The greatest reductions were obtained with Mi-BDMS at 4 x 1.5 mmol/kg, where liver and kidney cadmium levels were reduced to 12% and 59% of control levels, while at the same dosage BGDTC induced a reduction to 50% and 13% of control levels. The order of the efficacy of the monoamides as hepatic cadmium mobilizing agents was found to be Mi-PDMA > Mi-BDMA > Mi-ADMA. However, the isopropyl analog, though very effective at reducing hepatic cadmium at a low dosage, was found to be more toxic than the isobutyl and isoamyl monoamides. While the new compounds were shown to be effective cadmium mobilizing agents, the specific compounds examined did not possess optimized structures in terms of the balance between effectiveness and toxicity.

Effects of monoisoamyl meso-2,3-dimercaptosuccinate on arsenite-induced maternal and developmental toxicity in mice.

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

Antidotal efficacy of newly synthesized dimercaptosuccinic acid (DMSA) monoesters in experimental arsenic poisoning in mice.

The efficacy of four newly synthesized monoesters of meso-2,3-dimercaptosuccinic acid (DMSA), mono-i-amyl- (Mi-ADMS), mono-n-amyl- (Mn-ADMS), mono-i-butyl- (Mi-BDMS), and mono-n-butyl-meso-2,3-dimercaptosuccinate (Mn-BDMS) in increasing survival and arsenic elimination in experimental arsenic poisoning was investigated. Male mice (strain NMRI) received arsenite sc (survival study: 130 mumol/kg, 7 mice/group; elimination study: 85 mumol/kg (LD5) together with a tracer dose of 73As(III), 6 mice/group). After 30 min mice were treated with 0.7 mmol/kg of DMSA or a monoester ip or via gastric tube (ig). Control animals received saline ip. In the survival study mice were observed for 30 days. In the elimination study, the 73-arsenic content of several organs (blood, liver, heart, lung, kidneys, spleen, testes, brain, small intestine, large intestine, muscle, and skin) was measured 0.5, 2, 4, 6, and 8 hr after the arsenic injection using a gamma counter. Survival increased correspondingly well with the increase of arsenic elimination. DMSA, Mi-ADMS, Mn-ADMS, Mi-BDMS, and Mn-BDMS markedly decreased arsenic content in most organs as soon as 1.5 hr after treatment. Only in small and large intestine were higher arsenic amounts found, indicating a shift in arsenic elimination from the renal to the fecal route, and thereby suggesting a protective effect for the kidneys. Given ip, the monoesters turned out to be similarly as effective as the parent drug DMSA. Following ig treatment, the DMSA monoesters Mi-ADMS and Mn-ADMS seemed to be superior to DMSA with regard to survival.(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.

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.