An apparatus for studying electrical breakdown in liquid helium at 0.4 K and testing electrode materials for the neutron electric dipole moment experiment at the Spallation Neutron Source.

We have constructed an apparatus to study DC electrical breakdown in liquid helium at temperatures as low as 0.4 K and at pressures between the saturated vapor pressure and ∼600 Torr. The apparatus can house a set of electrodes that are 12 cm in diameter with a gap of 1-2 cm between them, and a potential up to ±50 kV can be applied to each electrode. Initial results demonstrated that it is possible to apply fields exceeding 100 kV/cm in a 1 cm gap between two electropolished stainless steel electrodes 12 cm in diameter for a wide range of pressures at 0.4 K. We also measured the current between two electrodes. Our initial results, I < 1 pA at 45 kV, correspond to a lower bound on the effective volume resistivity of liquid helium of ρV > 5 × 10(18) Ω cm. This lower bound is 5 times larger than the bound previously measured. We report the design, construction, and operational experience of the apparatus, as well as initial results.

Determination of the axial-vector weak coupling constant with ultracold neutrons.

A precise measurement of the neutron decay ß asymmetry A0 has been carried out using polarized ultracold neutrons from the pulsed spallation ultracold neutron source at the Los Alamos Neutron Science Center. Combining data obtained in 2008 and 2009, we report A0 = -0.119 66±0.000 89{-0.001 40}{+0.001 23}, from which we determine the ratio of the axial-vector to vector weak coupling of the nucleon g{A}/g{V}=-1.275 90{-0.004 45}{+0.004 09}.

First measurement of the neutron beta asymmetry with ultracold neutrons.

We report the first measurement of an angular correlation parameter in neutron beta decay using polarized ultracold neutrons (UCN). We utilize UCN with energies below about 200 neV, which we guide and store for approximately 30 s in a Cu decay volume. The interaction of the neutron magnetic dipole moment with a static 7 T field external to the decay volume provides a 420 neV potential energy barrier to the spin state parallel to the field, polarizing the UCN before they pass through an adiabatic fast passage spin flipper and enter a decay volume, situated within a 1 T field in a 2x2pi solenoidal spectrometer. We determine a value for the beta-asymmetry parameter A_{0}=-0.1138+/-0.0046+/-0.0021.

Instillation of bacillus Calmette-Guerin into the renal pelvis of a solitary kidney for the treatment of transitional cell carcinoma.

Intravesical bacillus Calmette-Guerin is effective in the treatment and prophylaxis of superficial urothelial cancer of the bladder. There have been few reports of its efficacy and toxicity when instilled into the upper urinary tract. We elected to use intracavitary bacillus Calmette-Guerin in a patient with recurrent high grade transitional cell carcinoma in the renal pelvis of a solitary autotransplanted kidney. The patient required hospitalization and triple-drug therapy after 5 instillations. She was free of tumor 1 year after bacillus Calmette-Guerin instillations.

A physiologically based description of the inhalation pharmacokinetics of styrene in rats and humans.

A physiologically based pharmacokinetic model which describes the behavior of inhaled styrene in rats accurately predicts the behavior of inhaled styrene in humans. The model consists of a series of mass-balance differential equations which quantify the time course of styrene concentration within four tissue groups representing (1) highly perfused organs, (2) moderately perfused tissues such as muscle, (3) slowly perfused fat tissue, and (4) organs with high capacity to metabolize styrene (principally liver). The pulmonary compartment of the model incorporates uptake of styrene controlled by ventilation and perfusion rates and the blood:air partition coefficient. The metabolizing tissue group incorporates saturable Michaelis-Menten metabolism controlled by the biochemical constants Vmax and Km. With a single set of physiological and biochemical constants, the model adequately simulates styrene concentrations in blood and fat of rats exposed to 80, 200, 600, or 1200 ppm styrene (data from previously published studies). The simulated behavior of styrene is particularly sensitive to changes in the constants describing the fat tissue group, and to the maximum metabolic rate described by Vmax. The constants used to simulate the fate of styrene in rats were scaled up to represent humans. Simulated styrene concentrations in blood and exhaled air of humans are in good agreement with previously published data. Model simulations show that styrene metabolism is saturated at inhaled concentrations above approximately 200 ppm in mice, rats, and humans. At inhaled concentrations below 200 ppm, the ratio of styrene concentration in blood to inhaled air is controlled by perfusion limited metabolism. At inhaled concentrations above 200 ppm, this ratio is controlled by the blood:air partition coefficient and is not linearly related to the ratio attained at lower (nonsaturating) exposure concentrations. These results show that physiologically based pharmacokinetic models provide a rational basis with which (1) to explain the relationship between blood concentration and air concentration of an inhaled chemical, and (2) to extrapolate this relationship from experimental animals to humans.

Inhalation pharmacokinetics: evaluating systemic extraction, total in vivo metabolism, and the time course of enzyme induction for inhaled styrene in rats based on arterial blood:inhaled air concentration ratios.

A method is described for evaluating systemic extraction of soluble vapors during inhalation exposures. The physiological basis of the method is the inability to achieve complete equilibrium of vapor between arterial blood and inhaled air whenever there is substantial extraction of the soluble vapor during a single pass through the systemic circulation. The technique was applied to estimate styrene extraction ratios at the end of 6-hr exposures in male rats exposed to various concentrations of inhaled styrene. From extraction ratios and several physiological constants, metabolic constants were evaluated for styrene metabolism in vivo. In naive rats, the maximum velocity of metabolism was 10.0 mg/kg/hr, and Km was of the order of 0.2 mg/liter. Pretreatment with pyrazole (320 mg/kg, 1/2 hr before exposure) essentially abolished in vivo styrene metabolism, while pretreatment with phenobarbital (80 mg/kg/day for the 4 days before styrene exposure) increased Vmax about sixfold. Prior exposure to styrene (1000 ppm for 6 hr/day on each of 4 days before experimentation) increased Vmax by a factor of 2. Significant induction of styrene metabolism in vivo was observed in 24-hr continuous exposure to 400, 600, or 1200 ppm. A curve fitting routine was employed with a physiological model of styrene inhalation kinetics to estimate the dynamics of the induction process in the 24-hr exposures. At 400 ppm, induction began after a lag of 15.5 hr, had a half-life of 3.5 hr, and reached 2.7 times the Vmax in naive rats. At 600 ppm, it began after 10.6 hr, proceeded with a half-life of 2.2 hr, and increased Vmax by 3.4 times. At 1200 ppm, induction began earlier, 4.6 hr, and reached a greater value, 4.4 times Vmax, but had a half-life similar to that at 600 ppm. No induction occurred in 48-hr exposure to 200 ppm. Induction complicates kinetic modeling of continuous inhalation with soluble, well-metabolized vapors because it is time and concentration dependent. These methods should prove useful for studying the in vivo metabolism of other soluble, well-metabolized vapors and for examining the time course of induction of the metabolizing enzymes for these chemicals.

Blood-flow distribution in the mouse.

Blood-flow distribution was determined in pentobarbital-anesthetized male B6C3F1 mice, using intracardially administered 141Ce-radiolabelled microspheres (10 micro Ci). The proportion of cardiac output and blood flow per g tissue was determined in 18 organs and tissues, including the nasal cavity, lobes of the liver, individual kidneys and sections of the intestinal tract. To provide comparative data, blood-flow distribution was also determined in pentobarbital-anaesthetized male Fischer 344 rats. In general, there was close agreement between the distribution of blood flow between these two rodent species. The bladder and large intestine of mice appear to receive more, while the testes receive less, of the cardiac output than in rats. Rat liver and kidney, however, appear to receive approximately twice the amount of blood on a weight basis as in the mouse.

Pulmonary physiology and inhalation dosimetry in rats: development of a method and two examples.

Methods were developed to measure simultaneously respiratory frequency, tidal volume, minute volume, and net uptake of an inhaled vapor in rats. During steady state, if metabolism is the only significant route of elimination, net uptake rate of the inhaled vapor is equal to its rate of metabolism. The rates of metabolism of methyl chloride in 50- and 1000-ppm-exposed rats were 0.20 and 3.3 nmol/min/g, respectively; the rates of metabolism of methylene chloride in 50- and 1500-ppm-exposed rats were 0.57 and 2.8 nmol/min/g, respectively. The uptake values obtained for both solvents were consistent with pharmacokinetic and metabolism data that were previously obtained in our laboratory. A pharmacokinetic model incorporating the metabolic rate at steady state, blood concentration versus time, and respiratory minute volume was used to describe the fate of inhaled methyl chloride in F344 rats, and to estimate the inhaled "effective" dose in 50- and 1000-ppm 6-hr-exposed rats (3.8 and 67 mg/kg, respectively). The approach used in these studies appears to be a useful method for the evaluation of metabolic rates and for inhalation dosimetry.

Relevance of experimental studies to human risk.

Confidence in the extrapolation of animal toxicity data to humans can be enhanced by the application of pharmacokinetic concepts integrated with chronic toxicity data and knowledge of a chemical's mechanism(s) of toxicity. Basic pharmacokinetic concepts (including dose-dependent or Michaelis-Menten kinetics) and their relationship to the risk estimation process are discussed using vinyl chloride and styrene as specific examples. Species differences in metabolic rates must be considered in order to arrive at realistic estimates of human risk to vinyl chloride-induced liver angiosarcomas utilizing vinyl chloride toxicity data observed in rats. Because small animal species generally metabolize chemicals more rapidly than larger species on a body surface area basis, small animals should be more sensitive to chemicals (such as vinyl chloride) that exert their toxicities via the metabolic formation of toxic products. Inhaled styrene is a chemical whose clearance from the blood at low exposure levels in both rats and humans follows first-order kinetics. However, at higher exposure levels, the pharmacokinetic fate of styrene in rats is dose-dependent, suggesting a saturation of styrene metabolism. These data indicate that any extrapolation of observable toxicity at elevated exposure levels in rats to anticipated responses at lower levels in either rats or humans may be invalid. An integration of the foregoing concepts provides a sound scientific basis for the use of experimental animal data to predict the risk to humans from chemical exposure.

Pharmacokinetics of 2,4,5-T PGBE ester applied dermally to rats.

The pharmacokinetic profile of the herbicide 2,4,5-T PGBE ester (propylene glycol butyl ether esters of 2,4,5-trichlorophenoxyacetic acid) 14C-labeled in the ring was examined in rats given a single dermal application of 5 mg/kg. The rate of absorption of the ester through the skin was lower than the rate of hydrolysis to 2,4,5-T acid and the rate of excretion of 2,4,5-T in the urine. Urinary excretion of radioactivity was apparently first order with a half-life of approximately 24 h. Clearance of radioactivity from blood plasma, liver kidneys, and the remaining carcass was also apparently first order with half-life values ranging from 25 to 37 h. Six days (144 h) after application of the dose, an average of 98.7 +/- 5.1% of the applied radioactivity was recovered in he urine, and approximately 97% of the urinary radioactivity was identified as 2,4,5-T acid. The tissue-to-plasma ratios of 14C activity in liver and kidney were similar to those observed previously in rats given a single iv dose of 5 mg/kg 2,4,5-T acid. The results of this study indicate that the pharmacokinetic model for 2,4,5-T PGBE ester in rats is similar to that for 2,4,5-T acid. This similarity suggests the chronic exposures to 2,4,5-T acid and its PGBE ester would be toxicologically comparable. The low rate of absorption of the ester through the skin suggests that removal of the ester from the skin by washing after exposure might substantially reduce the dose of 2,4,5-T received by this route. Since the urinary excretion rate of 2,4,5-T in humans is known, a similar pharmacokinetic model for humans may be developed to calculate the absorbed dose of 2,4,5-T based on urinary excretion data.