Strain-dependent disposition of inorganic arsenic in the mouse.

Recent studies have suggested that polymorphisms in the methylation of inorganic arsenic (iAs) exist in animals and humans. Methylation of iAs is an important step in the elimination of arsenic. The objective of this study was to examine whether there are differences in iAs disposition, and hence methylation, between three strains of mice. Ninety-day-old female mice (strains: C3H/HeNCrlBR, C57BL/6NCrlBR, and B6C3F1/CrlBR) were administered [73As]arsenate or [73As]arsenite orally at dose levels of 0.5 or 5.0 mg As/kg. Another group of mice were administered [73As]arsenate (5.0 mg As/kg) intraperitoneally (i.p.). Disposition of [73As] was assessed by whole-body counting, and analysis of urine, feces and tissues for radioactivity. Urine was analyzed by chromatography for arsenic metabolites. Several strain- and dose-related effects in the disposition of [73As] were observed with both arsenicals. After oral administration, the clearance of [73As]arsenate, measured by whole-body counting, was dependent on the strain. However, because there was no strain dependence on clearance of [73As]arsenate administered i.p., the effect after oral administration may be due to a difference in absorption of arsenate between the strains. With increased oral dose of arsenate and arsenite, the clearance of [73As] was slower and there was higher tissue retention of [73As]. The percentage of metabolites excreted in urine also was affected by the administered dose. With increased dose, the percentage of arsenite and monomethylarsonic acid were significantly increased, and dimethylarsinic acid decreased. However, our results suggest there is no overall difference between these strains of mice with respect to disposition of iAs. A better understanding of the role of phenotype in the disposition and toxicity of iAs would reduce the uncertainty in arsenic risk assessment.

In vitro dermal absorption of flame retardant chemicals.

Flame retardant chemicals may be used in furniture fabric in the future to reduce the flammability of the fabric. As a part of the process to evaluate the potential for exposure to these chemicals, this study examined the in vitro dermal absorption of two flame retardant chemicals. The chemicals were [14C]decabromodiphenyl oxide (DBDPO) and [14C]tris-(1,3-dichloro-2-propyl)phosphate (TDCP). Skin from the adult hairless female mouse (SKH1) was removed and mounted in flow-through diffusion cells. The chemicals, at three dose levels (DBDPO: 6, 30 and 60 nmol; TDCP: 20, 100 and 200 pmol), were applied in a volatile vehicle (tetrahydrofuran for DBDPO; acetone for TDCP) to the skin. Fractions of receptor fluid, pumped below the skin, were collected over a 24-h period. The skin was washed with solvent (tetrahydrofuran for DBDPO; ethanol for TDCP) to remove unabsorbed chemical 24 h after application. The receptor fluid, skin wash and skin were analyzed for chemical-derived radioactivity. The skin from the high-dose group of both chemicals, and the receptor fluid from TDCP high-dose samples, were analyzed for parent compound and metabolites by HPLC. The 24-h cumulative percent of the dose of DBDPO in the receptor fluid was very low (0.07-0.34%). The applied dose of DBDPO detected in the skin ranged from 2 to 20%. The lowest dose of DBDPO had the highest percentage of the dose (20%) in the skin. The major portion of the applied dose was removed by washing the skin 24 h after application of DBDPO, and ranged from 77 to 92%. HPLC analysis of homogenate extract prepared from the high-dose of DBDPO-treated skin showed the presence of DBDPO and a minor unknown peak. TDCP was readily detected in the receptor fluid; 39-57% of the applied dose of TDCP was in the receptor fluid by 24 h. The solvent wash removed 11-25% of the dose from the skin and 28-35% remained in it. HPLC analysis of the skin homogenate extract and receptor fluid extract from the TDCP high-dose treated samples showed the presence of parent compound and a minor unknown peak. TDCP more readily penetrated hairless mouse skin and diffused into the receptor fluid than DBDPO. TDCP has a lower molecular weight and log octanol:water partition coefficient than DBDPO. The differences in the physico-chemical properties of these two chemicals most likely explains their dissimilar absorption through hairless mouse skin.

Tissue factor pathway inhibitor, vascular risk factors and subclinical atherosclerosis: the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Tissue factor pathway inhibitor (TFPI) is an endothelial membrane-associated anticoagulant protein. Higher circulating levels might reflect endothelial damage. OBJECTIVE: We hypothesized an association of higher total TFPI with subclinical atherosclerosis. PATIENTS/METHODS: Total TFPI was measured in 1000 participants of the Multi-Ethnic Study of Atherosclerosis, a cohort of 6814 men and women without clinical vascular disease, aged 45-84, from four ethnic groups. Subclinical atherosclerosis measures were coronary artery calcium (CAC), carotid intima-media thickness (IMT) and ankle-brachial index (ABI). RESULTS: TFPI was higher with age, male gender, higher LDL-cholesterol, smoking and diabetes, but not ethnicity. Adjusting for risk factors, TFPI in the 4th quartile versus 1st quartile was associated with a 1.2-fold increased risk of detectable CAC (95% CI 1.0-1.4), a 2.1-fold increased risk of CAC >400 Agatston units (95% CI 1.1-4.0) and a 1.6-fold (95% CI 1.1-2.5) increased risk of internal carotid IMT above the 80th percentile, but not with external carotid IMT or low ABI. Findings were consistent across ethnic groups. CONCLUSIONS: In this diverse population, higher total TFPI was associated with prevalent CAC (limited to levels >400 units), and elevated internal carotid IMT, independent of other factors. Higher TFPI may indicate endothelial dysfunction. Further study is needed of TFPI and progression of atherosclerosis.

The perception of time in scale model environments.

It has been claimed that when subjects observe differently-scaled model environments their experience of temporal duration is compressed relative to standard clock time in the same proportion as the scale of the model being observed. A series of experiments is reported in which subjects made judgements of duration while observing model environments of different scale. In each experiment, two similar model environments of different scale were presented. Three different kinds of model were used: scale model railways, sitting-room models, and abstract nonrepresentional models. Despite considerable individual variability, significant effects were obtained. Smaller scale was, up to a point, related to a compression of subjective time relative to clock time, although the effect was nowhere near as great as that previously reported. Also, when scale was reduced beyond a certain point the effect on judgements of duration was eliminated, or even reversed. It is suggested that the effect of time compression is related to differences in the density of the information to be processed in environments of different scale, and that there may be an optimum value for information density related both to the scale and to the type of environment.

In vitro percutaneous absorption of dimethylarsinic acid in mice.

The objective of this study was to investigate the in vitro dermal absorption of [14C]dimethylarsinic acid. This organic arsenical is used as a herbicide and is a product of the mammalian metabolism of inorganic arsenic. Discs of preclipped dorsal skin were cut from adult female B6C3F1 mice and mounted in flow-through diffusion cells. HEPES-buffered Hanks balanced salt solution was used as receptor fluid. Doses of dimethylarsinic acid included 10, 100, and 500 micrograms and were applied onto the skin (0.64 cm2). Experiments (24 h) were conducted using solid compound and aqueous solution (20, 100, and 250 microliters) and soil (23 mg/cm2) as vehicles. The epidermal surface was washed at 24 h to remove compound that did not penetrate. The wash contained the greatest percentage of the dose in all experiments. Absorption of the compound into the skin and receptor fluid was observed and ranged from < 1 to 40% of the dose in experiments with the three exposure scenarios. The rank order of the various exposure conditions of dimethylarsinic acid absorption (10 micrograms) into the skin and receptor fluid was 20 microliters water > 100 microliters water > solid > 250 microliters water > soil. No dose or pH effects on absorption of dimethylarsinic acid was observed. There was also no pH effect on the partitioning of dimethylarsinic acid between 1-octanol and buffer. Short-term (1 h) exposure of dimethylarsinic acid in water followed by wash of the skin resulted in < 1% of the dose being absorbed. Thus, vehicles and duration of exposure have important roles on the in vitro dermal absorption of dimethylarsinic acid in mouse skin.