Arsenic metabolites in urine and feces of hamsters pretreated with PCB

High pressure liquid chromatography and graphite tube atomizing atomic absorption spectrometry were used to quantify monomethyl arsonic acid (MMA), dimethyl arsinic acid (DMA), and inorganic arsenic (IA: arsenite plus arsenate) in the urine and feces of male and female hamsters pretreated with a single ip injection of PCB (100 mg/kg) and 4 days later given a single po dose of arsenite (10 mg As/kg). Approximately 17 to 23% and 35 to 63% of the arsenic given was eliminated in the urine and feces, respectively, during the 5 days after the administration of arsenic. Both DMA and MMA were found in the urine but only MMA was detected in the feces, as methylated metabolite. Fecal excretion of arsenic was significantly larger in female than in males. PCB influenced the metabolism of arsenic by significantly increasing the proportion of DMA excreted into the urine of female hamsters during the 5 days after the arsenic administration, but did not alter the total amount of arsenic metabolites in any group of male or female hamsters. PCB did not affect the cumulative amounts of fecal arsenic in any group, although the excretion in the PCB-treated group of females reached the maximum level 1 day earlier than in the controls. These results suggest that the metabolism of arsenic may be regulated by certain sex-relating factors which are influenced by PCB.     

URINARY EXCRETION OF ARSENIC METABOLITES AFTER LONG-TERM ORAL ADMINISTRATION OF VARIOUS ARSENIC COMPOUNDS TO RATS

The metabolism of arsenic compounds in rats was studied by comparing urinary metabolites of arsenic compounds administered for 1 wk or 7 mo. Male F344/DuCrj rats were given 100 mg As/L as monomethylarsonic acid (MMA), dimethylarsinic acid (DMA), trimethylarsine oxide (TMAO), or arsenobetaine (AsBe), or 10 mg As/L as arsenite \[As(III)] via drinking water for 7 mo. Urine was collected by forced urination after 1 wk or 7 mo. Arsenic metabolites in urine were analyzed by ion chromatography with inductively coupled plasma mass spectrometry. In the case of As(III) ingestion, a small portion of all arsenic excreted in urine (about 6% ) was excreted in inorganic form, while most arsenic was excreted as methylated arsenic metabolites. Following MMA treatments for 1 wk or 7 mo, the predominant products excreted were unchanged MMA and DMA accompanied by small amounts of TMAO and tetramethylarsonium (TeMA). In the case of DMA treatment the urinary compounds found were mainly the parent DMA and TMAO with minute amounts of TeMA. TMAO was methylated to TeMA to a slight extent after 1 wk and 7 mo of administration, although most TMAO was excreted in the form of unchanged TMAO. AsBe was predominantly eliminated in urine without any transformation. Two unidentified metabolites were detected in urine after 7 mo of arsenic species exposure; the amounts of these metabolites increased in the order DMA > MMA > TMAO with only small quantities of these detected in the As(III)-treated group. These results suggest that these unidentified metabolites are formed during a demethylation process, and not during methylation. Our findings indicate that long-term exposure to As(III), MMA, or DMA decreases the proportion of TMAO elimination in urine and increases that of DMA, M-1, and M-2, and that further methylation to TMAO to TeMA does occur to a slight extent following long-term exposure to arsenical compounds in rats.     

Metabolism of subcutaneous administered indium arsenide in the hamster.

Indium arsenide (InAs) is partially dissociated in vivo to form inorganic arsenic and indium and excreted into the urine and feces. InAs dissolves slowly over time with deposits at the site of injection. Results of this study demonstrated that the principal metabolite of arsenic in the urine of hamsters was dimethylated arsenic (DMA). Inorganic arsenic and DMA accumulated in the fur, but the concentrations of indium were very low in this matrix. Urine and feces were the principal routes of elimination from the body. Analysis of tissues for arsenic demonstrated as concentrations in the parts per billion range. Results of these studies indicate that InAs is dissociated in vivo with release of both the indium and arsenic moieties to target tissues.     

Tissue dosimetry, metabolism and excretion of pentavalent and trivalent dimethylated arsenic in mice after oral administration

Dimethylarsinic acid (DMA(V)) is a rat bladder carcinogen and the major urinary metabolite of administered inorganic arsenic in most mammals. This study examined the disposition of pentavalent and trivalent dimethylated arsenic in mice after acute oral administration. Adult female mice were administered [(14)C]-DMA(V) (0.6 or 60 mg As/kg) and sacrificed serially over 24 h. Tissues and excreta were collected for analysis of radioactivity. Other mice were administered unlabeled DMA(V) (0.6 or 60 mg As/kg) or dimethylarsinous acid (DMA(III)) (0.6 mg As/kg) and sacrificed at 2 or 24 h. Tissues (2 h) and urine (24 h) were collected and analyzed for arsenicals. Absorption, distribution and excretion of [(14)C]-DMA(V) were rapid, as radioactivity was detected in tissues and urine at 0.25 h. For low dose DMA(V) mice, there was a greater fractional absorption of DMA(V) and significantly greater tissue concentrations of radioactivity at several time points. Radioactivity distributed greatest to the liver (1-2% of dose) and declined to less than 0.05% in all tissues examined at 24 h. Urinary excretion of radioactivity was significantly greater in the 0.6 mg As/kg DMA(V) group. Conversely, fecal excretion of radioactivity was significantly greater in the high dose group. Urinary metabolites of DMA(V) included DMA(III), trimethylarsine oxide (TMAO), dimethylthioarsinic acid and trimethylarsine sulfide. Urinary metabolites of DMA(III) included TMAO, dimethylthioarsinic acid and trimethylarsine sulfide. DMA(V) was also excreted by DMA(III)-treated mice, showing its sensitivity to oxidation. TMAO was detected in tissues of the high dose DMA(V) group. The low acute toxicity of DMA(V) in the mouse appears to be due in part to its minimal retention and rapid elimination.     

Metabolism and excretion of orally administrated arsenic trioxide in the hamster

It was shown that a single dose of arsenic trioxide administered to hamsters was chiefly methylated in vivo into methylarsonic acid (MAA) and dimethylarsinic acid (DMAA), and that inorganic arsenic accounted for the major portion of total arsenic that deposited in organs and tissues, followed by MAA and DMAA in decreasing sequence of significance. The single oral dose of arsenic trioxide was followed by a very small amount of trimethylarsenic compounds (TMA) occurring only in the liver but not in any other organs, tissues, blood or feces. The distribution pattern of arsenic in the blood following the single oral dose of arsenic trioxide was such that inorganic arsenic and MAA occurred chiefly in the blood cells; DMAA, chiefly in the plasma; and the arsenic compounds disappeared rapidly from blood. The single oral dose of arsenic trioxide was further followed by excretion of an amount of arsenic equivalent to about 60% of the administered dose: 49% in the urine and 11% in the feces. In other words, more arsenic tended to be excreted in the urine. DMAA accounted for the major portion of arsenic excreted in the urine and feces, and this finding re-confirmed that DMAA is the major metabolite of arsenic trioxide. Although it is believed that arsenic trioxide is not converted into TMA, the results of the present study suggest that a very small amount of arsenic trioxide is converted into TMA in the liver.     

Metabolism and excretion of orally administered dimethylarsinic acid in the hamster

We administered a single po dose of dimethylarsinic acid ( DMAA ) to hamsters by stomach tube and determined the in vivo accumulation of the arsenic and its excretion in the urine and feces. It was shown that a part of the DMAA was further methylated to a trimethylarsenic compound (TMA). During the 24 hr following the administration of DMAA , a total of 80% was excreted in the urine and feces: 45% in the urine (made up of 67.9% DMAA and 32.0% TMA), and 34.7% in the feces (almost completely made up of DMAA but no TMA). The findings show that DMAA and the TMA are rapidly excreted and do not accumulate in the body.     

Arsenic species excretion after dimercaptopropanesulfonic acid (DMPS) treatment of an acute arsenic trioxide poisoning

We studied the urinary excretion of the different arsenic species in urine samples from a young man who tried to commit suicide by ingesting about 0.6 g arsenic trioxide. He received immediate therapy with dimercaptopropanesulfonic acid (DMPS) after his delivery into the hospital. We assessed urinary arsenite (inorganic trivalent arsenic), arsenate (inorganic pentavalent arsenic), pentavalent dimethylarsinic acid (DMA) and pentavalent monomethylarsonic acid (MMA) in urine with ion-exchange chromatography and on-line hydride-technique atomic absorption spectrometry. The predominant amount of the excreted arsenic was unchanged trivalent inorganic arsenic (37.4%), followed by pentavalent inorganic arsenic (2.6%), MMA (2.1%), DMA (0.2%) and one unidentified arsenic species (0.7%, if calculated as DMA). In the first urine voiding in the clinic, the total arsenic concentration was 215 mg/l, which fell 1000-fold after 8 days of DMPS therapy. A most striking finding was the almost complete inhibition of the second methylation step in arsenic metabolism. As mechanisms for the reduced methylation efficiency, the saturation of the enzymatic process of arsenic methylation, the high dosage of antidote DMPS, which might inhibit the activity of the methyl transferases, and analytical reasons are discussed. The high dosage of DMPS is the most likely explanation. The patient left the hospital after a 12-day treatment with antidote.     

Study of factors influencing the in vivo methylation of inorganic arsenic in rats

Previous studies have shown that several factors may influence the methylation of inorganic arsenic by rat liver in vitro (Buchet and Lauwerys, 1985). The present study attempts to assess the relevance of these observations in vivo. Like man, rat inactivates inorganic arsenic by methylation to monomethylarsonic (MMA) and dimethylarsinic (DMA) acids which are excreted in urine along with unchanged inorganic arsenic (Asi). The administration of S-adenosylmethionine alone or in association with reduced (GSH) or oxidized glutathione or acetylcysteine and the increase of hepatic GSH level by butylated hydroxytoluene pretreatment do not stimulate the urinary excretion of the methylated arsenic metabolites following a challenge dose of inorganic arsenic. Conversely a reduction of the hepatic GSH level by phorone pretreatment greatly modifies the metabolism of inorganic arsenic in vivo. A reduction exceeding 90% of the control value leads to a decreased urinary excretion of MMA and DMA and an increased urinary excretion of inorganic arsenic. This is also associated with an increased accumulation of inorganic arsenic in the liver. This suggests that a drastic reduction of GSH level in liver not only impairs the methylation of inorganic arsenic but also impairs its biliary excretion. When GSH depletion is less severe, the total amount of arsenic excreted in urine after a challenge dose of NaAsO2 is not significantly different from that found in unpretreated animals but the proportion of the three metabolic forms is different: MMA is reduced whereas Asi and DMA tend to increase. These changes resemble those found in patients with liver insufficiency (J.P. Buchet, A. Geubel, S. Pauwels, P. Mahieu, and R. Lauwerys (1984). The influence of liver disease on the methylation of arsenite in humans. Arch. Toxicol. 55, 151-154). Long-term pretreatment of rats with CCl4 slightly reduces the amount of MMA and DMA excreted in urine following a challenge dose of inorganic arsenic. This effect may result from a reduction of GSH transferase activity by CCl4. This study demonstrates the important role of liver GSH in the metabolism of inorganic arsenic in vivo.     

Dose-Dependent Disposition of Sodium Arsenate in Mice Following Acute Oral Exposure

The effect of dose on arsenate disposition was studied in adultfemale B6C3FI mice, dosed po with 0.5 to 5000 µ/kg [⁷³As]-arsenatein water. Urine was collected at 1, 2, 4, 8, 12, 24, and 48hr and feces at 24 and 48 hr postexposure. The mice were euthanizedat 48 hr and tissues were removed. Recovery of ar senate-derivedradioactivity ranged from 83 to 89%; 66–79% of the dosewas excreted in urine, 10–18% in feces, and <1% remainedin the tissues. Although dose had no effect on the 48-hr excretionof radioactivity, the level of radioactivity in several tissuesincreased significantly with dose. The urine was analyzed forarsenic metabolites by using ion chromatography to analyze forarsenate, methylarsonic acid (MMA), and dimethylarsinic acid(DMA); ion-pairing high-performance liquid chromatogra phy wasused for arsenite analysis. Arsenate elimination ranged from3 to 15%. DMA was the predominant metabolite excreted (51-64%of dose), but no effect of dose on its elimination was detected.As the dose of arsenate increased, the amount of MMA excreted(0.1-1.0% of dose) significantly increased. At 5000 µg/kgarsenate, a significant increase in arsenite excretion was observed.At doses of arsenate <500 µg/kg, peak elimina tionof DMA occurred within 4 hr postexposure. At the 5000 µg/kgdose, DMA peak elimination shifted to 8 hr and a lower amountwas excreted. In addition, at the 5000 sg/kg dose, there wasan increase of arsenate and arsenite in the 1- and 2-hr urines.These results suggest that an acute dose of arsenate can affectthe metabolism of arsenicals. High doses lead to the accumulationof intermediates that are more reactive than DMA, and this responsemay lead to increased toxicity.     

Species differences in the metabolism of a tricyclic psychotropic agent,SQ 11,290-C

The metabolism of SQ 11,290-¹⁴C (4-[3-(7-chloro-5,11-dihydrodibenz[b,e]-[1,4]-oxazepin-5-yl)propyl]-α,β-¹⁴C₂-1-piperazineethanol, dihydrochloride) was studied in mice, rats, guinea pigs, hamsters, New Zealand White or Dutch rabbits, monkeys and man after po administration. The excretion of SQ 11,290-¹⁴C, its metabolites, or both, was chiefly in the feces (with the exception of hamsters and man). Rats and rabbits of either strain excreted 2–5% of the dose—mice and hamsters excreted 20–42%—as ¹⁴CO₂. Hamsters appeared to excrete radioactivity in a quantitative manner most similar to that observed in man, but the metabolites found in the urine and feces of these 2 species were not similar. The disposition of SQ 11,290-¹⁴C in albino and pigmented rabbits cannot be distinguished on the basis of the excretion of radioactivity, but different metabolites appear to be excreted in the urine. No unchanged SQ 11,290-¹⁴C was detected in the excreta of humans. One percent of the dose or less was present as unchanged SQ 11,290-¹⁴C in the urine of any animal species. In the feces, an average of 2–6% of the dose was excreted by animal species as unchanged SQ 11,290-¹⁴C. Whereas albino rabbits excreted in the feces only 3.6% of the dose as unchanged drug, Dutch rabbits excreted about 16.7% of the dose as unchanged drug. In those human subjects excreting large amounts of radioactivity as ¹⁴CO₂, cleavage or degradation of the side chain, or both, rather than hydroxylation of the ring system as had been found previously in dogs, appeared to be a major metabolic pathway.     

Whole body retention and excretion of [74As] arsenic acid in the adult beagle dog

To assess the whole body retention and excretion of inorganic arsenic, 4 male and 4 female dogs were given either a single oral or i.V. dose of ⁷⁴As ($\text{\$}\text{?}$0.17 mCi/dog; 0.3 μg arsenic/dog) as arsenic acid. ⁷⁴As in the whole body of the dogs and in the urine and feces was measured for up to 98 days. The half-period of elimination for the first component (85% of the dose) was 5.9 h; the second component (14% of the dose) had a half-period of 2.4 days. Essentially all of the arsenic was excreted in the urine, while less than 5% was recovered in the feces.     

Effects of glutathione depletion on the acute nephrotoxic potential of arsenite and on arsenic metabolism in hamsters

Our previous study showed that pretreatment with buthionine sulfoximine (BSO), which inhibits glutathione synthesis, results in acute renal failure with oliguria in hamsters ingesting sodium arsenite (5 mg As/kg). For a deeper understanding of the relationship between arsenic metabolism and the subsequent development of nephrotoxicity, we studied excretion, tissue retention, biotransformation, pharmacokinetics, and histopathological events in the kidneys of hamsters both with and without BSO pretreatment. The total amount of arsenic excreted in the urine and feces within 72 hr of arsenite administration was more than fivefold lower in BSO-pretreated animals than in the controls without pretreatment (9.2 versus 53.4% of the arsenic dose). The persistence of high amounts of total arsenic was apparent in the blood, liver, and kidneys of BSO-pretreated hamsters, even though the content of inorganic arsenic steadily decreased with time. The disappearance of inorganic arsenic from the blood showed a biphasic elimination pattern characterized first by a rapid component with a half-life of 4.5 hr and second by a slower component with a half-life of 58.0 hr in the BSO-pretreated hamsters, while these half-lives were 0.6 and 11.0 hr, respectively, in the controls. BSO pretreatment not only impaired the excretion of inorganic arsenic, but also impaired its methylation. Combined BSO/arsenite treatment resulted in renal tubular necrosis which was prominent at 1 hr after arsenite administration. By 1 hr, the renal content of inorganic arsenic in the BSO-pretreated animals was 1.7 times higher than that in the controls. This study demonstrates that glutathione depletion elicits the nephrotoxic manifestations of arsenic poisoning.     

Biotransformation and intracellular binding of arsenic in tissues of rabbits after intraperitoneal administration of 74As labelled arsenite

the fate of arsenite was studied in rabbits injected i.p. with 1 μg As/kg body wt as ⁷⁴As labelled AsO₂^?. Eight tissues plus plasma and urine were analyzed for ⁷⁴As content at different times. Arsenic was rapidly metabolized and poorly retained in the tissues. The main metabolite present in urine and plasma was dimethylarsinic acid. Sixty percent of the dose was excreted via urine and 6% with feces during the first day. In plasma arsenic was present mainly in a diffusible form, showing a very poor binding afffinity to plasma proteins. Chromatographic separations and membrane ultrafiltrations showed that in liver and kidney cytosols, arsenic was significantly associated to proteins. the diffusible fraction disappeared within 48 h. The fraction of arsenic bound to proteins was suggested to be inorganic arsenic whereas the methylation process was closly related to the elimination and the detoxification of inorganic arsenic.     

Metabolic differences between two dimethylthioarsenicals in rats

Thioarsenicals are newly found arsenic metabolites in man and animals, and also in marine organisms. Dimethylmonothioarsinic acid (DMMTA(V)) and dimethyldithioarsinic acid (DMDTA(V)) are the only two thioarsenic metabolites detected in man and/or animals. However, their toxicological and biological significance is not known yet. The present study was performed to gain an insight into the significance of DMMTA(V) and DMDTA(V) in the metabolism of arsenic. The two thioarsenicals were synthesized chemically and injected intravenously into rats at the dose of 0.5 mg As/kg body weight. The distributions of arsenic in organs/tissues and body fluids were determined at 10 min and 12 h after the injection, and arsenic in liver and kidney supernatants, urine, plasma and red blood cell (RBC) lysates was subjected to speciation analysis by HPLC-ICP MS on a gel filtration GS 220 HQ column. Although both thioarsenicals are pentavalent arsenicals, they were distributed in organs/tissues and body fluids differently from the corresponding non-thiolated pentavalent arsenicals, and also from each other. Namely, DMMTA(V) was first found in organs/tissues at 10 min, and then redistributed and retained mostly in RBCs at 12 h, as in the case of trivalent dimethylarsinous acid (DMA(III)). On the other hand, although DMDTA(V) was also found in organs/tissues at 10 min, it had been efficiently excreted in urine in its intact form at 12 h. Thus, DMMTA(V) was unexpectedly distributed in and taken up by organs/tissues in a manner similar to DMA(III) rather than DMA(V), whereas DMDTA(V) was distributed similarly to DMA(V) as expected, but was much more efficiently excreted in urine.     

Tissue dosimetry, metabolism and excretion of pentavalent and trivalent monomethylated arsenic in mice after oral administration

Exposure to monomethylarsonic acid (MMA(V)) and monomethylarsonous acid (MMA(III)) can result from their formation as metabolites of inorganic arsenic and by the use of the sodium salts of MMA(V) as herbicides. This study compared the disposition of MMA(V) and MMA(III) in adult female B6C3F1 mice. Mice were gavaged p.o. with MMA(V), either unlabeled or labeled with 14C at two dose levels (0.4 or 40 mg As/kg). Other mice were dosed p.o. with unlabeled MMA(III) at one dose level (0.4 mg As/kg). Mice were housed in metabolism cages for collection of excreta and sacrificed serially over 24 h for collection of tissues. MMA(V)-derived radioactivity was rapidly absorbed, distributed and excreted. By 8 h post-exposure, 80% of both doses of MMA(V) were eliminated in urine and feces. Absorption of MMA(V) was dose dependent; that is, there was less than a 100-fold difference between the two dose levels in the area under the curves for the concentration-time profiles of arsenic in blood and major organs. In addition, urinary excretion of MMA(V)-derived radioactivity in the low dose group was significantly greater (P < 0.05) than in the high dose group. Conversely, fecal excretion of MMA(V)-derived radioactivity was significantly greater (P < 0.05) in the high dose group than in the low dose group. Speciation of arsenic by hydride generation-atomic absorption spectrometry in urine and tissues of mice administered MMA(V) or MMA(III) found that methylation of MMA(V) was limited while the methylation of MMA(III) was extensive. Less than 10% of the dose excreted in urine of MMA(V)-treated mice was in the form of methylated products, whereas it was greater than 90% for MMA(III)-treated mice. In MMA(V)-treated mice, 25% or less of the tissue arsenic was in the form of dimethylarsenic, whereas in MMA(III)-treated mice, 75% or more of the tissue arsenic was in the form of dimethylarsenic. Based on urinary analysis, administered dose of MMA(V) did not affect the level of its metabolites excreted. In the tested range, dose affects the absorption, distribution and route of excretion of MMA(V) but not its metabolism.     

Toxicity and Metabolism of Trimethylarsine in Mice and Hamsters

Toxicity and Metabolism of Trimethylaisinc in Mice and Hamsters.YAMAUCHI, H., KAISE, T., TAKAHASHI, K., AND YAMAMURA, Y. (1990).Fundam. Appl. Toxicol. 14, 399–407. Trimethylarsine (TM-As)proved to be an arsenic compound of low toxicity, with a poLD50 of 7870 mg/kg in mice. A single po dose of 10 mg/kg ofTM-As caused no hemolysis, but a single po dose of 750 mg/kginduced mild, transient hemolysis in hamsters. TM-As was veryrapidly eliminated into the urine, with a biological half-lifeof 3.7 hr. TM-As was oxidized In vivo to form trimethylarsineoxide (TMAO) and excreted as such into the urine. TM-As wasnever demethylated In vivo. A mechanism was demonstrated bywhich a part of TM-As was eliminated directly into the expiredair. We drew a conclusion that TM-As is far less toxic thanarsine, most probably due to its In vivo conversion to TMAO.c 1990 Society of Toxicology.     

The disposition and metabolism of a hypnotic benzodiazepine, quazepam, in the hamster and mouse

The disposition of 14C-quazepam (7-chloro-(2,2,2-trifluoroethyl) [5-14C]-5-o-fluorophenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-thione), a new benzodiazepine hypnotic, was studied in hamsters and mice after iv and po dosing. In both species, quazepam was rapidly absorbed, as indicated by the plasma Cmax being reached within 1 hr of an oral dose (5 mg/kg). Also, radioactivity is essentially completely absorbed in both species, since the percentage of dose excreted in the urine was not dependent on the route of drug administration. Radioactivity was widely distributed in the tissues of both species; however, it was concentrated (relative to plasma) only in the liver and kidneys. In hamsters, 66-77% of the radioactivity was excreted within 48 hr, and 97% within 7 days of dosing (57% found in urine and 40% in feces after iv; 54% in urine and 43% in feces after po dosing). In mice, 86-88% of the radioactivity was excreted within 24 hr, and 98% within 4 days of dosing (43% in urine and 56% in feces after iv, 37% in urine and 61% in feces after po dosing). In both species, plasma levels of quazepam, measured by GLC, accounted for a very small percentage of plasma radioactivity and the elimination half-life was short (2.4 hr in hamster and 1.2 hr in mice), indicating extensive first pass metabolism for this drug. TLC analysis of plasma and urine extracts from both species showed biotransformation of quazepam involved substitution of oxygen for sulfur, followed by: (a) N-dealkylation, 3-hydroxylation, and conjugation or (b) 3-hydroxylation and conjugation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of metabolism in arsenic toxicity

In humans, as in most mammalian species, inorganic arsenic is methylated to methylarsonic acid (MMA) and dimethylarsinic acid (DMA) by alternating reduction of pentavalent arsenic to trivalent and addition of a methyl group from S-adenosylmethionine. The methylation of inorganic arsenic may be considered a detoxification mechanism, as the end metabolites, MMA and DMA, are less reactive with tissue constituents, less toxic, and more readily excreted in the urine than is inorganic arsenic, especially the trivalent form (AsIII, arsenite). The latter is highly reactive with tissue components, due to its strong affinity for sulfhydryl groups. Thus, following exposure to AsV the first step in the biotransformation, i.e. the reduction to AsIII, may be considered a bioactivation. Also, reactive intermediate metabolites of high toxicity, mainly MMAIII, may be formed and distributed to tissues. Low levels of MMAIII and DMAIII have been detected in urine of individuals chronically exposed to inorganic arsenic via drinking water. However, the contribution of MMAIIIand DMAIII to the toxicity observed after intake of inorganic arsenic by humans remains to be elucidated. The major route of excretion of arsenic is via the kidneys. Evaluation of the methylation of arsenic is mainly based on the relative amounts of the different metabolites in urine. On average human urine contains 10-30% inorganic arsenic, 10-20% MMA and 60-80% DMA.     

Metabolism of inorganic arsenic (74As) in humans following oral ingestion

Oral doses of carrier-free ⁷⁴As (?6 μCi/man; ?0.01 μg arsenic/man) as arsenic acid were administered to six adult males. Fifty-eight percent of the ⁷⁴As dose was excreted in the urine in the first 5 days after dosing. The proportion of chemical species of arsenic in the urine was as follows: 51% dimethylarsinic acid, 21% monomethylarsenic compound, and 27% inorganic arsenic.     

DOSE-DEPENDENT EFFECTS ON THE DISPOSITION OF MONOMETHYLARSONIC ACID AND DIMETHYLARSINIC ACID IN THE MOUSE AFTER INTRAVENOUS ADMINISTRATION

The organic arsenicals monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) are the primary metabolites of inorganic arsenic, a known human carcinogen. The objective of this study was to examine if dose would affect the excretion and terminal tissue disposition of MMA and DMA in the mouse. 14C-MMA (4.84 and 484 mumol/ kg) and-DMA ( 8.04 and 804 mumol/kg) were administered to female micevia the tail vein. The mice were placed in metabolism cages for collection of urine (1, 2, 4, 8, 12, and 24 h) and feces ( 24 h) . The animals were then sacrificed at 24 h and tissues were removed and analyzed for radioactivity. The urine was also analyzed for parent compound and metabolites. Urinary excretion of MMA- and DMA-derived radioactivity predominated over fecal excretion. Dose did not affect the overall urinary excretion of both compounds. However, fecal excretion was significantly lower in the low-dose MMA-treated animals as opposed to in the high-dose group, whereas in the high-dose DMA-treated group excretion was lower than in the low-dose DMA group. The retention of radioactivity was low ( &lt;2% of dose) and the distribution pattern similar for both compounds, with carcass &gt; liver &gt;kidney &gt; lung. The concentration of radioactivity (% dose/ g tissue) was greater in kidney than in liver, lung, and blood for both compounds. The distribution and concentration of MMA-derived radioactivity was significantly greater in the liver and lung of the high-dose group. The MMA-treated animals excreted predominantly MMA in urine and lower amounts of DMA (&lt;10% of the dose). The percentage excreted as DMA was significantly higher in the low-dose MM A group. In the urine of DMA-treated anim als, an unstable metabolite and the parent compound were detected. Overall, it appears the dose of organic arsenical administered has a minimal effect on its excretion and terminal tissue disposition in the mouse. The rapid elimination and low retention of MMA and DMA explain in part their low acute toxicity.