Yukio Yamamura

Biological monitoring of arsenic exposure of gallium arsenide- and inorganic arsenic-exposed workers by determination of inorganic arsenic and its metabolites in urine and hair

In an attempt to establish a method for biological monitoring of inorganic arsenic exposure, the chemical species of arsenic were measured in the urine and hair of gallium arsenide (GaAs) plant and copper smelter workers. Determination of urinary inorganic arsenic concentration proved sensitive enough to monitor the low-level inorganic arsenic exposure of the GaAs plant workers. The urinary inorganic arsenic concentration in the copper smelter workers was far higher than that of a control group and was associated with high urinary concentrations of the inorganic arsenic metabolites, methylarsonic acid (MAA) and dimethylarsinic acid (DMAA). The results established a method for exposure level-dependent biological monitoring of inorganic arsenic exposure. Low-level exposures could be monitored only by determining urinary inorganic arsenic concentration. High-level exposures clearly produced an increased urinary inorganic arsenic concentration, with an increased sum of urinary concentrations of inorganic arsenic and its metabolites (inorganic arsenic + MAA + DMAA). The determination of urinary arsenobetaine proved to determine specifically the seafood-derived arsenic, allowing this arsenic to be distinguished clearly from the arsenic from occupational exposure. Monitoring arsenic exposure by determining the arsenic in the hair appeared to be of value only when used for environmental monitoring of arsenic contamination rather than for biological monitoring.

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 and intraperitoneally administered gallium arsenide in the hamster.

This study deals with the metabolism of gallium arsenide (GaAs). GaAs was shown to be soluble in various media. Since this compound could dissolve in aqueous solvents, in vivo dissolution was investigated. Hamsters were used to study the dissolution and subsequent pharmacokinetics of any liberated arsenic species. The fecal and urinary excretion data following oral and intraperitoneal administration showed that GaAs, when administered orally, is mostly excreted in the feces but poorly in the urine, and that the compound, when administered intraperitoneally, is poorly excreted in both the feces and urine. Analysis of tissues for arsenic levels yielded concentrations in the ppb range, which further verified this fact. Most interesting was the fact that dimethylarsinic acid (DMAA) and methylarsonic acid (MAA) along with inorganic arsenic were found in the urine and tissues. GaAs was shown to dissolve in vivo and the released arsenic species were metabolized as other inorganic arsenics were found in the urine and tissues. GaAs was shown to dissolve in vivo and the released arsenic species were metabolized as other inorganic arsenic containing compounds. The low solubility and poor oral absorption may make this compound less toxic than other inorganic arsenic compounds.

Distribution of mercury in guinea pig offspring after in utero exposure to mercury vapor during late gestation

Organ distribution of mercury after in utero mercury vapor exposure was investigated in neonatal guinea pigs. Mother guinea pigs in late gestation were exposed to 0.2–0.3 mg/m3 mercury vapor 2 h per day until giving birth.Mercury concentrations in neonatal brain, lungs, heart, kidneys, plasma and erythrocytes were much lower than those of maternal organs and tissues. Neonatal liver, however, showed a mercury concentration twice as high as maternal liver. Mercury concentration ratios of erythrocytes to plasma in offspring were quite different from those of mothers, being 0.2–0.4 for offspring, and 1.3–3.0 for mothers.These results suggested that mercury vapor metabolism in fetuses was quite different from that in their mothers. This may be due to the different blood circulation, as mercury vapor transferred through the placental barrier would be rapidly oxidized into ionic mercury in fetal liver and accumulated in the organ.The different mercury vapor metabolism may prevent fetal brain, which is rapidly developing, and thus vulnerable, from being exposed to excessive mercury vapor.

Metabolism and excretion of orally and intraperitoneally administered methylarsonic acid in the hamster

Abstract When trimethylarsine oxide (TMAO) was administered orally to hamsters once only, 86.9±11.1% of the administered dose of the compound was exreted in the urine during the following 24 hours: TMAO proved to be an arsenic compound eliminated extremely rapidly. The unchanged form of TMAO was the one and only trimethylarsenic compound (TMA) detected in the urine: in othe words, TMAO proved neither to be demethylated nor to be converted to arsenobetaine. It was shown, on the other hand, that TMAO is partly reduced in vivo and that only trimethylarsine was detected in expired air.

Metabolism and excretion of orally ingested trimethylarsenic in man

Fishes and shellfishes are rich in trimethylarsenic (TMA). The reports of the chemical structure of TMA in organisms and the production of TMA in vivo have been on the steady increase in recent years. On the other hand, there are only a few reports of the in vivo metabolism and excretion of TMA. For purposes of unveiling the mechanisms of in vivo metabolism and excretion of TMA in man, the authors observed the chemical species and output of arsenic in the urine and the TMA levels in the blood with the passage of time following oral ingestion of TMA-rich foods once only.

Acute immunotoxicity of p-chloronitrobenzene in mice : II. Effect of p-chloronitrobenzene on the immunophenotype of murine splenocytes determined by flow cytometry

To evaluate the immunotoxicity of p-chloronitrobenzene (p-CNB), we investigated its effect on the immunophenotype of murine splenocytes. BDF1 male mice were randomly divided into exposed and control groups: the exposed group received p-CNB at 300 mg/kg dissolved in olive oil, while the control group received only olive oil, by a single intraperitoneal (i.p.) or subcutaneous (s.c.) injection. On days 3, 5, 7, and 10 after the injection, splenocytes were harvested from both groups, and the following cell phenotypes were quantified by flow cytometry: (1) B cells (CD45R/B220); (2) T cells (CD3e); (3) T-cell subsets (CD4 and CD8a); (4) natural killer (NK) cells (NK-1.1); (5) macrophages (CD11b; Mac-1); (6) nucleated erythrocytes (Ter-119); and (7) dead cells with propidium iodide (PI). The percentages and numbers of B, T, subsets of T (CD4 and CD8), and NK cells in the exposed mice significantly decreased as compared with the respective control. On the other hand, macrophages (Mac-1+ cells), nucleated erythrocytes (Ter-119+ cells), and dead cells in the exposed mice markedly increased as compared with the respective control after i.p. injection of p-CNB. The above findings indicate that p-CNB has an immunotoxic effect on mice.

Milk transfer and tissue uptake of mercury in suckling offspring after exposure of lactating maternal guinea pigs to inorganic or methylmercury

Maternal guinea pigs were injected with mercuric chloride (HgCl2; 1 mg Hg/kg body weight) or methylmercury (MeHg; 1 mg Hg/kg) 12 h after parturition, and exposure of the offspring to mercury (Hg) via breast milk were studied on days 3, 5 and 10 postpartum. Milk Hg concentrations were lower than maternal plasma Hg concentrations regardless of the form of Hg given to the dams. Milk Hg was higher in HgCl2-treated dams than in MeHg-treated dams. In MeHg-treated dams, MeHg was separately determined. While the ratio of MeHg to T-Hg decreased in the dams’ plasma, it did not in the milk. There was a strong correlation between milk and plasma T-Hg concentrations in HgCl2 treated dams. In the milk of MeHg-treated dams, the plasma MeHg concentrations correlated better than did the plasma T-Hg concentrations. In the offspring, regardless of the chemical forms of Hg given to the dams, the highest Hg concentrations were found in the kidney, followed by the liver and the brain. Brain Hg concentrations were, however, significantly higher in the offspring of MeHg-treated dams than in those of HgCl2-treated dams. In addition, Hg levels in the major organs of the offspring of HgCl2-treated dams peaked on day 5 postpartum, while those of MeHg-treated dams did not show a significant decrease up to day 10 postpartum. These facts indicate that the two chemical forms of Hg were transferred to the offspring via the breast milk and were distributed differently, depending on the chemical form, to the offspring’s tissues.

Induction of lipid peroxidation in tissues of thallous malonate-treated hamster

Thallous malonate was administered orally to hamsters in a single dose of 10 mg Tl/kg or 50 mg Tl/kg body weight. After 1 day and 3 days the levels of lipid peroxidation and non-protein sulfhydryls (NPSH) and glutathione peroxidase (GSH-Px) activity in tissues were measured. At a thallium dose of 10 mg/kg, increases in lipid peroxidation were already apparent in the kidney after 1 day. On the other hand, a marked increase in lipid peroxidation with decrease in NPSH content and GSH-Px activity in the kidney and liver were found 3 days after administration of the 50 mg Tl/kg dose, and renal and liver damage also developed. These results suggested that thallous malonate-induced tissue damage may be associated with the development of peroxidative processes caused by depression of GSH and inhibition of the GSH-Px activity-linked defensive system.

Toxicity and metabolism of trimethylarsine in mice and hamsters

Trimethylarsine (TM-As) proved to be an arsenic compound of low toxicity, with a po LD50 of 7870 mg/kg in mice. A single po dose of 10 mg/kg of TM-As caused no hemolysis, but a single po dose of 750 mg/kg induced mild, transient hemolysis in hamsters. TM-As was very rapidly eliminated into the urine, with a biological half-life of 3.7 hr. TM-As was oxidized in vivo to form trimethylarsine oxide (TMAO) and excreted as such into the urine. TM-As was never demethylated in vivo. A mechanism was demonstrated by which a part of TM-As was eliminated directly into the expired air. We drew a conclusion that TM-As is far less an toxic than arsine, most probably due to its in vivo conversion to TMAO.