Bioaccessibility and excretion of arsenic in Niu Huang Jie Du Pian pills

Traditional Chinese medicines (TCMs) often contain significant levels of potentially toxic elements, including arsenic. Niu Huang Jie Du Pian pills were analyzed to determine the concentration, bioaccessibility (arsenic fraction soluble in the human gastrointestinal system) and chemical form (speciation) of arsenic. Arsenic excretion in urine (including speciation) and facial hair were studied after a one-time ingestion. The pills contained arsenic in the form of realgar, and although the total arsenic that was present in a single pill was high (28 mg), the low bioaccessibility of this form of arsenic predicted that only 4% of it was available for absorption into the bloodstream (1 mg of arsenic per pill). The species of arsenic that were solubilized were inorganic arsenate (As(V)) and arsenite (As(III)) but DMAA and MMAA were detected in urine. Two urinary arsenic excretion peaks were observed: an initial peak several (4-8) hours after ingestion corresponding to the excretion of predominantly As(III), and a larger peak at 14 h corresponding predominantly to DMAA and MMAA. No methylated As(III) species were observed. Facial hair analysis revealed that arsenic concentrations did not increase significantly as a result of the ingestion. Arsenic is incompletely soluble under human gastrointestinal conditions, and is metabolized from the inorganic to organic forms found in urine. Bioaccessible arsenic is comparable to the quantity excreted. Facial hair as a bio-indicator should be further tested.     

Dimercaptan metal-binding agents influence the biotransformation of arsenite in the rabbit

The urinary metabolites of sodium arsenite have been investigated in rabbits given sodium arsenite and water-soluble dimercaptans. Rabbits injected sc with NaAsO2 (1 mg As/kg) were given, im 1 hr later, either saline, 2,3-dimercapto-1-propanesulfonic acid (DMPS), mesodimercaptosuccinic acid (DMSA), or N-(2,3-dimercaptopropyl)phthalamidic acid (DMPA) at 0.2 mmol/kg. Arsenic metabolites in urine collected from treated rabbits were isolated by combined anion-cation-exchange chromatography. Column fractions were acid-digested and analyzed for arsenic by direct hydride-flame atomic absorption spectrophotometry. The relative amounts of inorganic arsenic, methylarsonate, and dimethylarsinate found in 0 to 24 hr urine of rabbits given only sodium arsenite agreed closely with those reported for human subjects given arsenite po. This finding suggests that the rabbit biotransforms arsenite in a manner very similar to that of man. The urinary excretion of total arsenic between 0 and 24 hr was elevated after dimercaptan administration, but urinary excretion of total arsenic between 0 and 48 hr was unaffected. This result indicates that the action of these dimercaptans occurs early after treatment. In addition, the dimercaptans influenced differently the amounts of the arsenic metabolites excreted in the urine between 0 and 24 hr. DMPS, DMSA, or DMPA increased arsenite excretion but decreased dimethylarsinate excretion. DMPS or DMPA treatment increased methylarsonate excretion but DMSA did not. Arsenate excretion increased after DMPS or DMSA treatment but was not affected by DMPA treatment. These results suggest that the dimercaptans, in addition to increasing arsenic excretion, also influence the biotransformation of arsenite to less toxic species. The different effects on the urinary excretion of arsenic metabolites suggest that these dimercaptan metal binding agents have mechanisms of action in addition to simple chelation of inorganic arsenic.     

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.     

Urinary excretion of phenobarbital and its metabolite p-hydroxyphenobarbital in convulsing and non-convulsing patients.

As part of an investigation of phenobarbital (PB) pharmacokinetics in patients with status epilepticus (SE), urinary excretion of PB and its main metabolite, hydroxyphenobarbital (HPB), was studied in patients who had an episode of SE, as well as in non-convulsing ones. Eleven in-patients were studied:(group 1) five patients (4 M + 1 F; 48 +/- 28 years old; 64 +/- 6 kg body weight; mean +/- SD) with convulsive status epilepticus, and (group 2) six patients (5 M + 1 F; 37 +/- 13 years old; 71 +/- 15 kg body weight) with epilepsy, seizure-free at the moment of PB administration and without established anti-epileptic therapy. All subjects received a single intravenous dose of PB (15 mg/kg) at a rate of 100 mg/min. PB and HPB concentrations were measured by high performance liquid chromatography with UV detection at 220 nm in urine samples collected throughout 24 h. The comparison of pharmacokinetic parameters of urinary excretion of PB and HPB showed a statistically significant difference in the values of recovery of HPB and total barbiturate (higher values in the patients with SE) in 24 h urine. Differences in the excretion of PB between the two groups of patients--higher values in the patients who had had an episode of SE, and in urine flow--slightly elevated volumes in the same group, failed to reach statistical significance, probably due to the small number of participants in the study.     

Urinary 8-hydroxydeoxyguanosine and urothelial carcinoma risk in low arsenic exposure area

Arsenic is a well-documented human carcinogen and is known to cause oxidative stress in cultured cells and animals. A hospital-based case-control study was conducted to evaluate the relationship among the levels of urinary 8-hydroxydeoxyguanosine (8-OHdG), the arsenic profile, and urothelial carcinoma (UC). Urinary 8-OHdG was measured by using high-sensitivity enzyme-linked immunosorbent assay (ELISA) kits. The urinary species of inorganic arsenic and their metabolites were analyzed by high-performance liquid chromatography (HPLC) and hydride generator-atomic absorption spectrometry (HG-AAS). This study showed that the mean urinary concentration of total arsenics was significantly higher, at 37.67+/-2.98 microg/g creatinine, for UC patients than for healthy controls of 21.10+/-0.79 microg/g creatinine (p<0.01). Urinary 8-OHdG levels correlated with urinary total arsenic concentrations (r=0.19, p<0.01). There were significantly higher 8-OHdG levels, of 7.48+/-0.97 ng/mg creatinine in UC patients, compared to healthy controls of 5.95+/-0.21 ng/mg creatinine. Furthermore, female UC patients had higher 8-OHdG levels of 9.22+/-0.75 than those of males at 5.76+/-0.25 ng/mg creatinine (p<0.01). Multiple linear regression analyses revealed that high urinary 8-OHdG levels were associated with increased total arsenic concentrations, inorganic arsenite, monomethylarsonic acid (MMA), and dimethylarsenate (DMA) as well as the primary methylation index (PMI) even after adjusting for age, gender, and UC status. The results suggest that oxidative DNA damage was associated with arsenic exposure, even at low urinary level of arsenic.     

Genetic polymorphisms in AS3MT and arsenic metabolism in residents of the Red River Delta, Vietnam

To elucidate the role of genetic factors in arsenic (As) metabolism, we studied associations of single nucleotide polymorphisms (SNPs) in As (+ 3 oxidation state) methyltransferase (AS3MT) with the As concentrations in hair and urine, and urinary As profile in residents in the Red River Delta, Vietnam. Concentrations of total As in groundwater were 0.7-502 μg/l. Total As levels in groundwater drastically decreased by using sand filter, indicating that the filter could be effective to remove As from raw groundwater. Concentrations of inorganic As (IAs) in urine and total As in hair of males were higher than those of females. A significant positive correlation between monomethylarsonic acid (MMA)/IAs and age in females indicates that older females have higher methylation capacity from IAs to MMA. Body mass index negatively correlated with urinary As concentrations in males. Homozygote for SNPs 4602AA, 35991GG, and 37853GG, which showed strong linkage disequilibrium (LD), had higher percentage (%) of dimethylarsinic acid (DMA) in urine. SNPs 4740 and 12590 had strong LD and associated with urinary %DMA. Although SNPs 6144, 12390, 14215, and 35587 comprised LD cluster, homozygotes in SNPs 12390GG and 35587CC had lower DMA/MMA in urine, suggesting low methylation capacity from MMA to DMA in homo types for these SNPs. SNPs 5913 and 8973 correlated with %MMA and %DMA, respectively. Heterozygote for SNP 14458TC had higher MMA/IAs in urine than TT homozygote, indicating that the heterozygote may have stronger methylation ability of IAs. To our knowledge, this is the first study on the association of genetic factors with As metabolism in Vietnamese.     

Arsenic speciation in urine from acute promyelocytic leukemia patients undergoing arsenic trioxide treatment

Arsenic has been used successfully in clinical trials for treating acute promyelocytic leukemia (APL). Although sublethal doses of inorganic arsenic are used, little is known about the pharmacokinetics and metabolism of the high levels of arsenic in APL patients. To fill this important gap, this study describes the speciation of arsenic in urine from four APL patients treated with arsenic. Each patient was injected daily with an arsenite (As(III)) solution that contained 10 mg of As(2)O(3) precursor. Speciation analysis of the patient urine samples collected consecutively for 48 h, encompassing two intravenous injections of arsenic, revealed the presence of monomethylarsonous acid (MMA(III)), dimethylarsinous acid (DMA(III)), monomethylarsonic acid (MMA(V)), and dimethylarsinic acid (DMA(V)). The intermediate methyl arsenic metabolites, MMA(III) and DMA(III), were detected in most urine samples from all of the patients when a preservative, diethyldithiocarbomate, was added to the urine samples to stabilize these trivalent arsenic species. The major arsenic species detected in the urine samples from the patients were As(III), MMA(V), and DMA(V), accounting for >95% of the total arsenic excreted. The relative proportions of As(III), As(V), MMA(V), and DMA(V) in urine samples collected 24 h after the injections of As(III) were 27.6 +/- 6.1, 2.8 +/- 2.0, 22.8 +/- 8.1, and 43.7 +/- 13.3%, respectively. The relatively lower fraction of the methylated arsenic species in these APL patients under arsenic treatment as compared with that from the general population exposed to much lower levels of arsenic suggests that the high levels of As(III) inhibit the methylation of arsenic (inhibits the formation of methyl arsenic metabolites). The arsenic species excreted into the urine accounted for 32-65% of the total arsenic injected. These results suggest that other pathways of excretion, such as through the bile, may play an important role in eliminating (removing) arsenic from the human body when challenged by high levels of As(III).     

Arsenic excretion after treatment of arsenic poisoning with DMSA or DMPS in mice

The effects of 2,3-dimercaptosuccinic acid (DMSA) and 2,3-dimercaptopropane-1-sulfonic acid, Na salt (DMPS) on arsenic excretion in arsenic poisoning were studied using ICR mice. One group of mice was given arsenic trioxide (5 mg As/kg, s.c.) and another two groups were given DMSA or DMPS (100 mg/kg, i.p.) immediately after administration of the arsenic (5 mg/kg, s.c.). Arsenic excretion in urine and feces was determined by atomic absorption spectrophotometry. Results obtained showed a marked arsenic excretion in the urine collected at the first 12 hr in the group treated with DMSA. Further remarkable arsenic excretion in the feces was seen in the group treated with DMPS, suggesting that arsenic might have been excreted in the bile.     

Arsenic metabolism and thioarsenicals in hamsters and rats

The tissue distribution and chemical forms of arsenic were compared in two animal species with different metabolic capacity and toxicity to arsenic. Hamsters and rats were given a single oral dose of arsenite (iAsIII) at 5.0 mg As/kg body weight, and then the concentrations of arsenic were determined; more than 75% of the dose accumulated in rat red blood cells (RBCs) in the form of dimethylarsinous acid (DMAIII), whereas less than 0.8% of the dose accumulated in hamster RBCs, mostly in the form of monomethylarsonous acid (MMAIII). Reflecting the low accumulation in RBCs, more than 63% of the dose was recovered in hamster urine within one week (7.8-fold higher than that in rat urine). The quantity of arsenic distributed in the liver and kidneys was significantly higher in hamsters than in rats, and arsenic in livers stayed much longer in hamsters than in rats. Arsenic accumulated more and was retained longer in the kidneys than in the livers in both animals, and in hamster kidneys, it accumulated at levels higher than those in rat kidneys in the form of MMAIII bound to proteins. In the first 24 h urine, dimethylmonothioarsinic (DMMTAV) and dimethyldithioarsinic (DMDTAV) acids were detected in hamsters, but only DMMTAV was found in rats, together with an unknown arsenic metabolite in both animals. The unknown urinary arsenic metabolite was identified as monomethylmonothioarsonic acid (MMMTAV; CH3As(=S)(OH)2). The present results indicate that in hamsters, arsenic does not accumulate in RBCs, and therefore, hamsters exhibit a more uniform tissue distribution and faster urinary excretion of arsenic than rats. In addition, arsenic was thiolated more in hamsters than in rats excreting mono and dimethylated thioarsenicals in urine.     

Clinical pharmacokinetic study of arsenic trioxide in an acute promyelocytic leukemia (APL) patient: speciation of arsenic metabolites in serum and urine

The pharmacokinetics of arsenic species in a Japanese patient with relapsed acute promyelocytic leukemia (APL) treated with arsenic trioxide at a daily dose of 0.08 mg/kg was investigated. After achieving complete remission on Day 35 during the induction therapy of arsenic trioxide, we collected the serum and urine samples on Days 4 and 5 during the consolidation therapy of arsenic trioxide. The concentrations of inorganic arsenic and the methylated metabolites in serum and urine were measured by HPLC/ICP-MS. The patient restricted taking the seafood for 3 d before the start of administration and during the sampling period in order to avoid the influence of arsenic derived from seafood. Arsenite (As(III)), methylarsonic acid (MMAs(V)), and dimethylarsinic acid (DMAs(V)) were detected in serum and urine. The total concentration of As(III), MMAs(V) and DMAs(V) in serum ranged from 18 to 41 microg/l (240-547 nM) during 24 h on Day 4. The amount of total arsenic (As(III)+MMAs(V)+DMAs(V)) in urine was 4464 microg/d on Day 4. These results suggest that not the micro-molar but the nano-molar order of arsenic in serum is sufficient to produce the therapeutic effect on APL cells.     

Understanding arsenic metabolism through a comparative study of arsenic levels in the urine, hair and fingernails of healthy volunteers from three unexposed ethnic groups in the United Kingdom

Very little is known about arsenic (As) metabolism in healthy populations that are not exposed to high concentrations of As in their food or water. Here we present a study with healthy volunteers from three different ethnic groups, residing in Leicester, UK, which reveals statistically significant differences in the levels of total As in urine and fingernail samples. Urine (n = 63), hair (n = 36) and fingernail (n = 36) samples from Asians, Somali Black-Africans and Whites were analysed using inductively coupled plasma mass spectrometry (ICP-MS) and graphite furnace atomic absorption spectroscopy (GF-AAS). The results clearly show that the total concentrations of As in urine and fingernail samples of a Somali Black-African population (urine 7.2 microg/g creatinine; fingernails 723.1 microg/kg) are significantly (P < 0.05) different from the Asian (urine 24.5 microg/g creatinine; fingernails 153.9 microg/kg) and White groups (urine 20.9 microg/g creatinine; fingernails 177.0 microg/kg). The chemical speciation of As in the urine of the three groups was also measured using high performance liquid chromatography coupled to ICP-MS. This showed that the proportion of the total urinary As present as dimethylarsenate (DMA) was higher for the Somali Black-African group (50%) compared to the Asians (16%) and Whites (22%). However, there was no significant difference (P > 0.05) in the level of As in the hair samples from these three groups; Somali Black-Africans (116.0 microg/kg), Asians (117.4 microg/kg) and Whites (141.2 microg/kg). Significantly different levels of total As in fingernail and urine and a higher percentage of urinary DMA in the Somali Black-Africans are suggestive of a different pattern of As metabolism in this ethnic group.     

Urinary acetylated metabolites and N-acetyltransferase-2 genotype in human subjects treated with a para-phenylenediamine-containing oxidative hair dye.

In the organism of mammals, important detoxification pathways of arylamines are catalysed by N-acetyltransferase 2 (NAT2). A recent case-control epidemiology study suggested that human NAT2 slow acetylators exposed to oxidative hair dyes may be at greater risk to develop bladder cancer. We therefore profiled urinary [(14)C]-metabolites and NAT2 genotype in eight human subjects following treatment with a dark-shade oxidative hair dye containing [(14)C]-para-phenylenediamine (PPD). Genotyping identified three subjects as slow, and five subjects as intermediate NAT2 acetylators. Within 24 h after treatment, the study subjects excreted a mean total of 0.43+/-0.24% of the applied [(14)C] in the urine, where five different metabolites were found. The major urinary metabolites were concluded to be N-mono-acetylated and N,N'-diacetylated PPD. They were present in all urine samples and amounted to 80-95% of the total urinary [(14)C]. Another metabolite, possibly a glucuronic acid conjugate, was found in 6/8 urine samples at 5-13% of the total urinary [(14)C]. All metabolites appeared to be related to PPD, no evidence of the presence of high-molecular weight dye-intermediates or corresponding metabolites was found. The metabolite profile in the study subjects showed no significant differences between the NAT2 intermediate and NAT2 slow acetylator subgroups. Urine of NAT2 slow acetylators contained N-mono-acetylated-PPD at 42.2+/-10.2% and N,N'-di-acetylated-PPD at 54.1+/-7.6% of total urinary radioactivity, while the corresponding values of intermediate acetylators were 46.0+/-8.9% and 45.7+/-9.9%, respectively. Overall, our results suggest that the human acetylation rate of PPD after topical application is independent of the NAT2 genotype status, most likely due to metabolism by epidermal NAT1 prior to systemic absorption.     

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 &gt; MMA &gt; 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.     

Occurrence of monomethylarsonous acid in urine of humans exposed to inorganic arsenic

Monomethylarsonous acid (MMA(III)) has been detected for the first time in the urine of some humans exposed to inorganic arsenic in their drinking water. Our experiments have dealt with subjects in Romania who have been exposed to 2.8, 29, 84, or 161 microg of As/L in their drinking water. In the latter two groups, MMA(III) was 11 and 7% of the urinary arsenic while the monomethylarsonic acid (MMA(V)) was 14 and 13%, respectively. Of our 58 subjects, 17% had MMA(III) in their urine. MMA(III) was not found in urine of any members of the group with the lowest level of As exposure. If the lowest-level As exposure group is excluded, 23% of our subjects had MMA(III) in their urine. Our results indicate that (a) future studies concerning urinary arsenic profiles of arsenic-exposed humans must determine MMA(III) concentrations, (b) previous studies of urinary profiles dealing with humans exposed to arsenic need to be re-examined and re-evaluated, and (c) since MMA(III) is more toxic than inorganic arsenite, a re-examination is needed of the two hypotheses which hold that methylation is a detoxication process for inorganic arsenite and that inorganic arsenite is the major cause of the toxicity and carcinogenicity of inorganic arsenic.     

Uric acid plasma level and urine pH in rats treated with ambroxol

It was a chance discovery that ambroxol parenteral administration led to urinary bladder stone formation in rats. This study was undertaken to examine the serum uric acid levels and urine pH in rats after ambroxol parenteral treatment. Ambroxol influence on the uric acid level was measured in 5 rats (Rattus sp.) treated with 60 mg/kg (dissolved in injection water, sc, daily) during 2 weeks. Ambroxol influence on urine pH was examined on 45 rats divided into 3 groups. Rats from the 1st and 2nd group received 30 and 60 mg/kg/24h ambroxol, respectively. Urine was collected once daily and measured with strip kit. All values were presented as the means with standard deviations. The Student t test was used to compare the means, p < 0.05 was considered as significant. Dynamics of pH changes was measured in 4 rats treated with 60 mg/kg/24h of ambroxol. Controls received 1 mL of injection water sc. Serum uric acid level increased up to 8.7 +/- 1.0 mg/dL vs. 5.7 +/- 1.0 mg/dL in control (p < 0.002). In the 1st and 2nd group urine pH increased up to 7.5 +/- 0.5 and 7.6 +/- 0.5 vs. 6.7 +/- 0.4 (p < 0.05). Ambroxol withdrawal resulted in sequential urine pH decrease. 11 days after interruption of ambroxol therapy pH reached the starting value. Urine pH changes and possible disturbances in uric acid metabolic pathway may influence on the stone formation in rats after ambroxol parenteral treatment. The influence of ambroxol on urinary tract GAG layer and the balance between xanthine and CaOx in the urine should be checked.     

Biotransformation of dimethylarsinic acid in mouse, hamster and man

The metabolism of dimethylarsinic acid (DMA) a common pesticide and the main metabolite of inorganic arsenic in mammals, has been studied in mice, hamsters and man. Mice and hamsters were administered a single dose of 74As-DMA (40 mg As/kg body weight) orally, while a human subject ingested DMA corresponding to 0.1 mg As/kg body weight. Ion exchange chromatography, paper electrophoresis, thin layer chromatography as well as arsine generation--gas chromatography combined with atomic absorption spectrophotometry or mass spectrometry were used to characterize the arsenic metabolites in urine and feces collected over 48 hours after treatment. In mice and hamsters 3.5% and 6.4% of the dose, respectively, were excreted in urine in the form of trimethylarsine oxide (TMAO). No TMAO was found in feces. A DMA-complex was detected in urine and feces. It amounted to about 13% of the dose in mice and 15% in hamsters. About 80-85% of the dose was eliminated in urine and feces in the form of unmetabolized DMA. No demethylation of DMA to inorganic arsenic was observed. In man, about 4% of the dose was excreted in urine as TMAO and about 80% as DMA.     

Hexachlorobenzene stimulates uroporphyria in low affinity AHR mice without increasing CYP1A2

Adult female Fisher 344 rats received drinking water containing 0, 4, 40, 100, or 200 parts per million of dimethylarsinic acid or 100 parts per million of arsenate for 14 days. Urine was collected during the last 24 h of exposure. Tissues were then taken for analysis of dimethylated and trimethylated arsenicals; urines were analyzed for these arsenicals and their thiolated derivatives. In dimethylarsinic acid-treated rats, highest concentrations of dimethylated arsenic were found in blood. In lung, liver, and kidney, concentrations of dimethylated arsenic exceeded those of trimethylated species; in urinary bladder and urine, trimethylated arsenic predominated. Dimethylthioarsinic acid and trimethylarsine sulfide were present in urine of dimethylarsinic acid-treated rats. Concentrations of dimethylated arsenicals were similar in most tissues of dimethylarsinic acid- and arsenate-treated rats, including urinary bladder which is the target for dimethylarsinic acid-induced carcinogenesis in the rat. Mean concentration of dimethylated arsenic was significantly higher (P<0.05) in urine of dimethylarsinic acid-treated rats than in arsenate-treated rats, suggesting a difference between treatment groups in the flux of dimethylated arsenic through urinary bladder. Concentrations of trimethylated arsenic concentrations were consistently higher in dimethylarsinic acid-treated rats than in arsenate-treated rats; these differences were significant (P<0.05) in liver, urinary bladder, and urine. Concentrations of dimethylthioarsinic acid and trimethylarsine sulfide were higher in urine from dimethylarsinic acid-treated rats than from arsenate-treated rats. Dimethylarsinic acid is extensively metabolized in the rat, yielding significant concentrations of trimethylated species and of thiolated derivatives. One or more of these metabolites could be the species causing alterations of cellular function that lead to tumors in the urinary bladder.     

Total and inorganic arsenic concentrations in different species of economically important algae harvested from coastal zones of Chile

Chile is one of the major producers of phytocolloids extracted from seaweed. Multicellular algae are considered to be primary accumulators of arsenic. We analyzed 14 species of algae belonging to the groups Rhodophyceae (10), Phaeophyceae (3) and Chlorophyceae (1) from different coastal zones of Chile in 2003-2004. Dry ashing mineralization (for total As) and acid digestion (for inorganic As) together with quantification by flow injection hydride generation atomic absorption spectrometry (FI-HG-AAS) were employed. In general, total arsenic concentrations varied between 3.0 and 68 mg kg(-1), whereas inorganic arsenic concentrations ranged between 0.15 and 1.06 mg kg(-1). The algal species Durvillaea antarctica and Porphyra columbina, used for direct human consumption, did not have inorganic arsenic levels that represent a health risk to consumers. Among species used for phytocolloids production, such as Macrocystis piryfera, Gracilaria chilensis and Gigartina skottsbergii, observed levels of inorganic arsenic were greater than 1 mg kg(-1), the limit value established by the regulations of some countries. Among the 14 species of algae tested, inorganic arsenic levels were between 0.8% and 13% of the total arsenic concentrations; that is, arsenic present in these algae was found primarily as organic arsenic.     

Single-dose kinetics of an enteric-coated formulation of carbamazepine-10,11-epoxide, an active metabolite of carbamazepine

The kinetics of an enteric-coated formulation of carbamazepine-10,11-epoxide (CBZ-E) were studied in healthy subjects. A single oral dose of 100 mg of CBZ-E was given to eight subjects. Four of them were also given a single oral dose of 200 mg of CBZ-E. Plasma concentrations of CBZ-E and urinary excretion of the end metabolite trans-10,11-dihydroxy-10,11-dihydro-carbamazepine (trans-CBZ-diol) were determined by high performance liquid chromatography. Plasma kinetics of CBZ-E fitted an open one-compartment model with plasma elimination half-life of 7.4 +/- 1.8 h (mean +/- SD). The clearance was 105 +/- 17 ml/kg/h and the apparent volume of distribution 1.1 +/- 0.2 L/kg assuming complete bioavailability. There was no indication of dose-dependent elimination of CBZ-E. The recovery of trans-CBZ-diol in urine collected for 3 days was 67 +/- 9% of the given dose. This enteric-coated formulation may thus in the future be used for the evaluation of the clinical effects of CBZ-E in patients.     

A pilot study on the urinary excretion of porphyrins in human populations chronically exposed to arsenic in Mexico.

1 The aim of this pilot study was to investigate if the porphyrinuria produced by arsenic in rodents was present in humans chronically exposed to arsenic via drinking water. 2 The concentrations of uroporphyrin, coproporphyrin and total arsenic in urine were compared between 21 individuals exposed to arsenic in their drinking water (0.390 mg l-1) and 19 controls exposed to 0.012 mg l-1. 3 Arsenic-exposed individuals had significantly higher total arsenic concentrations in their urine than the control group. No increase in urinary porphyrin excretion was found in exposed individuals. However, an inversion of the coproporphyrin/uroporphyrin (COPRO/URO) ratio was observed in most exposed individuals. This inversion was caused both, by a decrease in coproporphyrin excretion and an increase in uroporphyrin excretion. 4 No demonstrable correlations between porphyrin excretion, the COPRO/URO ratio and total arsenic concentration in urine were found in exposed individuals.