Bioavailability of arsenic in soil impacted by smelter activities following oral administration in rabbits.

This study determined the extent of arsenic (As) absorption from soil from Anaconda, Montana. Prepubescent male and female SPF New Zealand White rabbits (5/sex/group) were given a single oral (capsule) administration of soil (3900 ppm As) at three different dose levels (0.2, 0.5, and 1.0 g of soil/kg, corresponding to 0.78, 1.95, and 3.9 mg As/kg, respectively). Standard groups included untreated controls, an intravenous sodium arsenate group (1.95 mg As/kg), and a gavage sodium arsenate group (1.95 mg As/kg). Urine, cage rinse, and feces were collected at 24-hr intervals for 5 days and were analyzed for total As concentration. Clinical signs, body weights, and food consumption for treated animals were similar to controls. Maximum As concentrations were obtained over the initial 24-hr collection interval. A dose-dependent delay in urinary As excretion, the major elimination pathway, was observed in the oral soil group compared to that in the gavage group. For the animals in the soil groups, approximately 80% of the administered As dose was eliminated in the feces compared to approximately 10 and 50% for the intravenous and oral gavage groups, respectively. The relative oral bioavailabilities (+/- SD) of As in the gavage and test soil groups based on comparison with excreta data from the intravenous group were approximately 50 +/- 5.7 and 24 +/- 3.2%, respectively (after normalization of intravenous group's As recovery data to 100%). These results indicated that As in the soil was probably in a less soluble and therefore a less absorbable form than sodium arsenate.

Relative bioavailability of lead from mining waste soil in rats.

The purposes of this study were to determine the extent of absorption of lead (Pb) in mining waste soil from Butte, Montana, and to investigate the effect of mining waste soil dose (g soil/day) on tissue lead concentrations. Young, 7- to 8-week-old male and female Sprague-Dawley rats (5/sex/group) were given mining waste soil that contained 810 or 3908 ppm lead mixed in a purified diet (AIN-76) at four different dose levels (0.2, 0.5, 2, and 5% dietary soil) for 30 consecutive days. Standard groups included untreated controls and dosed feed soluble lead acetate groups (1, 10, 25, 100, and 250 micrograms Pb/g feed). The test soil dose levels bracketed a pica child's soil exposure level and the lead acetate concentrations bracketed the test soil dose levels of lead. Liver, blood, and femur were analyzed for total lead concentration using graphite furnace atomic absorption spectroscopy. Clinical signs, body weight, food consumption, and liver weights for test soil and standard groups were similar to control. Tissue lead concentrations from test soil animals were significantly lower than the tissue concentrations for the lead acetate group. Relative percentage bioavailability values, based on lead acetate as the standard, were independent of the two different test soils, dose levels, and sex and were only slightly dependent on the tissue (blood > bone, liver). Mean relative percentage bioavailability values of lead in the Butte mining waste soil were 20% based on the blood data, 9% based on the bone data, and 8% based on the liver data. The results of this study will provide the information needed to determine the significance of lead exposure from Butte soils in assessing human health risks as part of the Superfund Remedial Investigation/Feasibility Study process.

13-week inhalation toxicity study of dimethylformamide (DMF) in cynomolgus monkeys.

This study was conducted to assess the subchronic inhalation toxicity of dimethylformamide (DMF) in the cynomolgus monkey. Particular attention was paid to the liver since DMF has been shown to produce liver damage in rodents, dogs, and humans. Groups of three cynomolgus monkeys/sex/group received whole-body exposures for 6 hr/day, 5 days/week for 13 weeks to 0, 30, 100, or 500 ppm DMF. Evaluations for toxicity included body and organ weights, clinical observations, hematology, serum chemistry, urinalysis, and gross and microscopic examinations. Clinical laboratory evaluations were conducted twice prior to the start of the study at exposure weeks 2, 4, 8, and 12 and at necropsy. Semen, collected from male monkeys three times prior to the start of the study and weekly during the course of the study, was analyzed for sample volume, sperm count, motility, and morphology. In addition, daily vaginal swabs were obtained from all females prior to exposure to determine mean menses cycle length. Although there was a slight trend toward increased cycle length, this trend could not be definitely attributed to compound exposure. Based on extensive monitoring of the monkeys' clinical condition, semen quantity and quality, and clinical and pathological evaluations, no exposure-related adverse health effects were detected following exposure to concentrations of DMF ranging from 30 to 500 ppm for 13 weeks.

Comparative sensitivity of bovine and rodent acetylcholinesterase to in vitro inhibition by organophosphate insecticides.

Biochemical studies were conducted to compare the in vitro sensitivities of bovine and rodent brain and erythrocyte cholinesterases to inhibition by Dyfonate-oxon, paraoxon, and malaoxon. This comparison was done to determine if the reported greater sensitivity of cattle to Dyfonate might be explained by a greater sensitivity of the target enzyme, acetylcholinesterase, in cattle to inhibition by Dyfonate's toxic metabolite, Dyfonate-oxon. Studies were conducted with brain homogenates and lysed erythrocytes obtained from cows and from male and female rats. Additional studies were conducted with a commercially available sample of purified bovine erythrocyte acetylcholinesterase (ACHE). In all cases, the concentrations of organophosphates required to produce 50% inhibition (IC50) of enzyme activity were determined. Cow brain ACHE was 1.7 to 3.8 times more resistant to inhibition by Dyfonate-oxon, paraoxon, and malaoxon than was brain ACHE from male or female rats. For both species, paraoxon was 1.2 to 1.6 times more potent than Dyfonate-oxon and 3.8 to 6.9 times more potent than malaoxon. The bimolecular reaction rate constants (ki) were also determined for inhibition of brain ACHE of cows and male rats by the three organophosphates. In general, the ki data were in agreement with the IC50 data indicating that cow brain ACHE was less sensitive than rat brain ACHE to inhibition. Additional IC50 studies were conducted with lysed erythrocytes from cows and from male and female rats. Both quantitative and qualitative differences between species and among the organophosphates were in excellent agreement with the results of the brain ACHE studies. Also, in related studies with purified bovine erythrocyte ACHE, there was excellent agreement with the results of tests involving ACHE inhibition in erythrocyte lysates. This study demonstrated that, as an inhibitor of ACHE in vitro, Dyfonate-oxon was equal to or slightly lower in potency than paraoxon and more potent than malaoxon. In addition, the study demonstrated that, in general, ACHE from brain or erythrocytes of cows was less sensitive to in vitro inhibition by organophosphates than was that from male or female rats. Thus, the apparent greater susceptibility of cows to Dyfonate, in vivo, cannot be explained on the basis of an unusual target enzyme (ACHE) sensitivity to inhibition by Dyfonate-oxon.

The affinity of norgestimate for uterine progestogen receptors and its direct action on the uterus.

Norgestimate is a new orally active progestational agent. Studies were conducted to demonstrate that norgestimate is active pharmacologically without requiring biotransformation to an active metabolite. In in vitro studies, norgestimate exhibited a relatively high affinity for the rabbit uterine progestogen receptor. To demonstrate that norgestimate was not being degraded to a biologically active entity, which was binding to receptor sites in the cytosol preparation, the stability of 14C-norgestimate in the preparation was determined. Following the incubation of 14C-norgestimate with the cytosol fraction used in the receptor assay, the labeled material was extracted and analyzed by reverse phase high performance liquid chromatography. 14C-Norgestimate was recovered from these incubation mixtures, confirming that norgestimate was available to bind to the progestogen receptor. In in vivo studies, norgestimate stimulated the endometrium in immature rabbits when applied directly to the uterus, again suggesting that bio-transformation to an active metabolite is not required for expression of norgestimate's pharmacological activity. These in vitro and in vivo studies, when considered with previously reported studies, show that norgestimate is a unique progestogen.

Spontaneous vesicular and prostatic gland epithelial squamous metaplasia, hyperplasia, and keratinized nodule formation in rabbits.

Histopathology of the reproductive system of 76 young adult Dutch Belted and 22 young adult or adult male New Zealand White rabbits was conducted as part of fertility studies. Thirty-five (46%) of the Dutch Belted and 11 (50%) of the New Zealand White males had multifocal vesicular gland basal epithelial cell atypia and hyperplasia without metaplasia. The affected cells were taller with pale cytoplasm and a prominent basophilic nucleus longitudinally oriented and increased in number compared to more normal adjacent epithelium. Thirty-one (41%) of the Dutch Belted and 10 (45%) of the New Zealand White males showed one or more nodules of squamous metaplasia in the alveolar epithelial lining or seen occasionally within alveolar walls of the vesicular gland. The prostate was less commonly affected and none of the early cellular atypia or later cornification changes were seen. A few cornified nodules with mitotic figures resembled "carcinoma in situ," but the morphology and available biologic data supported the judgment that the lesion was benign, metaplastic, proliferative, and clinically silent.

Interstitial cell tumors in a young adult New Zealand white rabbit.

One case of interstitial cell tumors in the testicles of a New Zealand White rabbit was reported. The rabbit was 8-10 months old and had bilateral testicular lesions. There was no enlargement of either testicle and the lesions were first seen on the cut surface. Light and electron microscopy revealed that the cellular morphology resembled the features observed for this tumor in rats, dogs, and a few other domestic animals in which reports are available.

Synthesis and estrogenic properties of 17-epi-ethynylestradiol and its ether derivatives epimestranol and epiquinestrol.

The synthesis of 17-epi-ethynylestradiol (10), the 17 beta-ethynyl-17 alpha-ol epimer of the well-known orally active estrogen, ethynylestradiol (1), was achieved by LiA1H4 reduction of epoxide 9, as well as by demethylating epimestranol (11) with CH3MgI. Compound 11 was obtained by the unusual 17 beta-ethynylation of estrone 3-methyl ether 22 under equilibrating conditions. The in vitro estrogen receptor-binding affinity and the oral estrogenicity in the rat for the 17-epi compounds 10, 11 and 20 (epiquinestrol) was evaluated. Despite moderate estrogen receptor-binding affinity, compound 10 was devoid of measurable estrogenicity at 10 mg/kg or antiestrogenicity at 3 mg/kg.

Human pharmacokinetics and comparative bioavailability of loperamide hydrochloride.

A pharmacokinetic study of the antidiarrheal agent loperamide hydrochloride (Imodium) was conducted in six male subjects. The study utilized a random crossover design and employed a 2-mg capsule and a 0.2-mg/ml syrup formulation. Each treatment consisted of a single oral dose of 8 mg loperamide HCl followed by a two-week interval before the next treatment. Serum and urine samples obtained at various times after drug administration were assayed for loperamide using a radioimmunoassay specific for the drug. The mean biologic half-life, calculated from the elimination phase of the log serum concentration-versus-time data, was 10.8 +/- 0.6 hours for the overall study, 10.2 +/- 0.6 hours for the syrup formulation, and 11.2 +/- 0.8 hours for the capsules. The loperamide from the syrup was absorbed more rapidly than from the capsule formulation, with the peak serum levels observed at a mean time of 2.4 +/- 0.7 hours for the syrup and 5.2 +/- 0.3 hours for the capsule formulation. The relative areas under the serum loperamide concentration-versus-time curves suggested that the two formulations have comparable physiologic availability. The maximum observed serum concentrations were also similar, indicating the safety of the syrup formulation. Excretion of approximately 1 per cent of the dose in the urine as unchanged loperamide after seven days was observed independent of the particular dosage form that was administered.