Three-generation reproductive toxicity study of dietary bisphenol A in CD Sprague-Dawley rats.

Bisphenol A (BPA) was evaluated at concentrations of 0, 0.015, 0.3, 4.5, 75, 750, and 7500 ppm ( approximately 0.001, 0.02, 0.3, 5, 50, and 500 mg/kg/day of BPA) administered in the diet ad libitum to 30 CD((R)) Sprague-Dawley rats/sex/dose for 3 offspring generations, 1 litter/generation, through F3 adults. Adult systemic toxicity at 750 and 7500 ppm in all generations included: reduced body weights and body weight gains, reduced absolute and increased relative weanling and adult organ weights (liver, kidneys, adrenals, spleen, pituitary, and brain), and female slight/mild renal and hepatic pathology at 7500 ppm. Reproductive organ histopathology and function were unaffected. Ovarian weights as well as total pups and live pups/litter on postnatal day (PND) 0 were decreased at 7500 ppm, which exceeded the adult maximum tolerated dose (MTD). Mating, fertility, gestational indices; ovarian primordial follicle counts; estrous cyclicity; precoital interval; gestational length; offspring sex ratios; postnatal survival; nipple/areolae retention in preweanling males; epididymal sperm number, motility, morphology; daily sperm production (DSP), and efficiency of DSP were all unaffected. At 7500 ppm, vaginal patency (VP) and preputial separation (PPS) were delayed in F1, F2, and F3 offspring, associated with reduced body weights. Anogenital distance (AGD) on PND 0 was unaffected for F2 and F3 males and F3 females (F2 female AGD was increased at some doses, not at 7500 ppm, and was considered not biologically or toxicologically relevant). Adult systemic no observed adverse effect level (NOAEL) = 75 ppm (5 mg/kg/day); reproductive and postnatal NOAELs = 750 ppm (50 mg/kg/day). There were no treatment-related effects in the low-dose region (0.001-5 mg/kg/day) on any parameters and no evidence of nonmonotonic dose-response curves across generations for either sex. BPA should not be considered a selective reproductive toxicant, based on the results of this study.

Isolation of symlandine from the roots of common comfrey (Symphytum officinale) using countercurrent chromatography.

Three pyrrolizidine alkaloids, symlandine, symphytine, and echimidine (1-3), were isolated from the roots of Symphytum officinale using a one-step countercurrent chromatography procedure. The structures of 1-3 were confirmed by several spectroscopic techniques including 2D NMR methods. This is the first description of the separation of symlandine (1) from its stereoisomer, symphytine (2).

An investigation into the quality of life of individuals after laryngectomy.

BACKGROUND: Little longitudinal data are available on the general physical, psychological, and social problems experienced as a result of laryngectomy or on the preoperative status of patients in regard to these aspects. In particular, prospective longitudinal data gathered from the same group of subjects over time and examining a variety of such outcomes is rare. This descriptive study addresses these issues. METHODS: The study investigates the progress of a group of 34 laryngectomees from the preoperative stage up to 6 months after surgery. Medical complications, communication, swallowing, diet, physical, and psychosocial adjustment were measured using both the Short-Form Health Survey (SF-36) and original outcome tools. RESULTS: A large percentage of subjects demonstrated significant and persistent communication and swallowing problems throughout the period studied. Low preoperative and postoperative scores on the SF-36 demonstrate that this group had a poorer state of general health in many respects than those with serious medical conditions previously documented. CONCLUSIONS: The results suggest that communication and swallowing difficulties persist for many laryngectomees up to 6 months after surgery and still require further investigation. Poor preoperative and postoperative general health scores indicate that this group may require more long-term social support than is currently being offered to adjust to the laryngectomy.

An investigation into the quality of life of individuals after laryngectomy

BACKGROUND: Little longitudinal data are available on the general physical, psychological, and social problems experienced as a result of laryngectomy or on the preoperative status of patients in regard to these aspects. In particular, prospective longitudinal data gathered from the same group of subjects over time and examining a variety of such outcomes is rare. This descriptive study addresses these issues. METHODS: The study investigates the progress of a group of 34 laryngectomees from the preoperative stage up to 6 months after surgery. Medical complications, communication, swallowing, diet, physical, and psychosocial adjustment were measured using both the Short-Form Health Survey (SF-36) and original outcome tools. RESULTS: A large percentage of subjects demonstrated significant and persistent communication and swallowing problems throughout the period studied. Low preoperative and postoperative scores on the SF-36 demonstrate that this group had a poorer state of general health in many respects than those with serious medical conditions previously documented. CONCLUSIONS: The results suggest that communication and swallowing difficulties persist for many laryngectomees up to 6 months after surgery and still require further investigation. Poor preoperative and postoperative general health scores indicate that this group may require more long-term social support than is currently being offered to adjust to the laryngectomy. Copyright 2000 John Wiley & Sons, Inc. Head Neck 23: 16-24, 2001.

Two-generation reproduction study with para-tert-octylphenol in rats.

Octylphenol (OP) is a commercial intermediate used primarily for the production of octylphenol polyethoxylate surfactants. To determine potential reproductive toxicity of OP, a two-generation reproduction study was conducted according to U.S. EPA OPPTS Guideline 870.3800 (draft 1996). Additional measurements were made on retained F2 offspring. OP was administered ad libitum to five groups of rats (30/sex) at dietary concentrations of 0, 0.2, 20, 200, or 2000 ppm. The 0.2 ppm concentration was included to evaluate potential low dose effects. Effects were observed only at 2000 ppm, including decreased body weights in adults and during the latter portion of lactation in offspring and minor body weight-related delays in acquisition of vaginal opening and preputial separation. No effects on reproductive parameters, testes, prostate, or ovary weights or morphology, on sperm counts, motility, morphology, production, or on estrous cyclicity were observed. No estrogen-like effects were evident. The NOAELs for systemic and postnatal toxicity were 200 ppm and at or above 2000 ppm for reproductive toxicity. This study supports the increasing evidence that screening assays for estrogenic activity or studies with limited numbers of animals and/or unrealistic dose regimens are inappropriate for use in the assessment of human health and environmental risk. It does not support previous preliminary data on low dose effects of OP.

Pancreaticobiliary carcinoma associated with a large choledochal cyst: role of MRI and MR cholangiopancreatography in diagnosis and preoperative assessment.

The role of magnetic resonance (MR) imaging and MR cholangiopancreatography is demonstrated in a case of pancreaticobiliary carcinoma associated with a large choledochal cyst. The size of the cyst presented considerable difficulty in evaluation with both endoscopic retrograde cholangiopancreatography and computed tomography.

Two-generation reproductive toxicity study of dietary tributyl phosphate in CD rats.

Tributyl phosphate (TBP) was tested for reproductive toxicity in rats. Thirty weanlings/sex (F0) were exposed to TBP in the diet ad libitum at 0, 200, 700, or 3000 ppm for 10 weeks and then randomly mated within groups for 3 weeks with continued exposure. F0 parents and 10 F1 weanlings/sex/dose were necropsied, and adult reproductive organs, urinary bladders (both sexes), kidneys (males), and livers (females) were evaluated histologically. Thirty F1 weanlings/sex/dose continued exposure for 11 weeks and were bred as described above. F1 parents and F2 weanlings, 10/sex/dose, were then necropsied as described above. Adult toxicity was observed in both sexes and generations at 700 and 3000 ppm; observations included reduced body weights, weight gain and feed consumption, urinary bladder epithelial hyperplasia (both sexes), renal pelvis epithelial hyperplasia only at 3000 ppm (male kidneys), and centrilobular hypertrophy (female livers). At 200 ppm, transient reductions in body weight were observed in F0 and F1 females, with urinary bladder epithelial hyperplasia in F0 males and females and in F1 males. There was no evidence of reproductive toxicity, of reproductive organ pathology, or of effects on gestation or lactation at any dose tested. Postnatal toxicity was evidenced by consistent reductions in F1 and F2 pup body weights at 3000 ppm and by occasional weight reductions in F2 litters at 700 ppm, and was associated with maternal toxicity observed at these doses and times. Under the conditions of this study, a NOAEL was not determined for adult toxicity; the NOAEL for reproductive toxicity was at least 3000 ppm and the NOAEL for postnatal toxicity was approximately 200 ppm.

Reproductive toxicity evaluation of methylethyl ketoxime by gavage in CD rats.

Methylethyl ketoxime (CAS No. 96-29-7; MEKO; 2-butanone oxime), an antioxidant agent used in paints, resins, and adhesives, was tested for reproductive toxicity in a two-generation study with CD (Sprague-Dawley) rats. Thirty-eight-week-old rats/sex/group (F0) were administered MEKO in water, by gavage, at 0, 10, 100, or 200 mg/kg/day (at a dosing volume of 2 ml/kg), 5 days/week for 10 weeks with vaginal cytology evaluation (VCE) of F0 females during the last 3 weeks of the prebreed period. Animals were mated within groups for 3 weeks with dosing during mating, gestation, and lactation for 7 days/week. F0 parents and F1 weanlings, 10/sex/dose, were necropsied (after a 2-week postwean VCE in F0 females) with hematologic evaluation (including methemoglobin) and histology of adult livers, spleens, and reproductive organs. F1 weanlings, 30/sex/dose, were dosed for 11 weeks and mated as described above. Because of poor reproductive performance, not treatment related, F1 animals with no F2a litters were rebred to produce F2b litters. F1 parents and F2a weanlings, 10/sex/dose, were necropsied and evaluated as described above. Inguinal mammary glands were examined histologically from all nonselected F1 and F2 (a and b) female weanlings. Adult toxicity was observed in both generations and both sexes at all doses. Treatment-related parental deaths occurred at 200 mg/kg/day. At 100 and 200 mg/kg/day, parents exhibited dose-related reduced body weights and weight gains, reduced feed consumption, clinical signs of toxicity, and anemia with concomitant extramedullary hematopoiesis and hemosiderosis in livers and spleens (and increased spleen weights). At 10 mg/kg/day, only adult liver and spleen histologic effects were present. There was no evidence of reproductive organ or mammary glad pathology or of reproductive or postnatal toxicity at any dose tested. There was no adult "no observable adverse effect level" (NOAEL) established; the NOAEL for reproductive and postnatal toxicity was at least 200 mg/kg/day for rats in this study.

Pyrolysis products of heroin.

Heating of heroin hydrochloride or of heroin at 250 degrees C led to extensive degradation. Major components of the pyrolysate were identified as heroin, 6-acetylmorphine, N,6-diacetylnormorphine, and N-acetylnorheroin by comparison of mass spectra and 13C- and 1H-nuclear magnetic resonance (NMR) spectra with those of authentic compounds. There was evidence for degradation of the piperidino moiety and the structure 3,4-diacetoxyphenanthrene was proposed for a minor product.

Naltrexone disposition in man after subcutaneous administration.

The metabolism, excretion, and pharmacokinetics of [15,16-3H2]naltrexone were studied in six human males after sc administration of the hydrochloride salt. Biological fluids were analyzed by a combination of high performance liquid chromatography with liquid scintillation measurement of radioactivity. After administration, naltrexone was rapidly absorbed into the systemic circulation. The mean absorption rate constant was 0.091 +/- 0.008 min-1 (half-life of 7.6 min). In general the metabolic, excretory, and pharmacokinetic patterns for naltrexone were similar to those observed after iv administration of naltrexone to man. The terminal phase plasma rate constant was 0.413 +/- 0.035 hr-1 (half-life of 1.68 hr) for parent drug and 0.0786 +/- 0.0090 hr-1 (half-life of 8.8 hr) for the major metabolite, 6 beta-naltrexone. An average of 76 +/- 6% (+/- SD) of the total radioactivity was recovered in the urine within 72 hr after administration. Naltrexone was found in the urine in both the free (3.4 +/- 0.8% of dose) and conjugated (6.8 +/- 2.1% of dose) form. 6 beta-Naltrexol was present in urine largely in the unconjugated form (28 +/- 7% of dose) but the conjugated form was also found (12 +/- 3% of dose).

Identification of in vitro rat metabolites of 1-phenylcyclohexene.

In vitro metabolites of 1-phenylcyclohexene produced by the 10,000g supernatant fraction from rat liver homogenates were identified by a combination of spectrometric, chromatographic, and synthetic techniques. Initial oxidation occurred in the 3-position of 1-phenylcyclohexene to yield 1-phenyl-1-cyclohexen-3-one and 1-phenyl-1-cyclohexen-3-ol. Further allylic oxidation at the 6-position occurred to form 1-phenyl-6-hydroxy-1-cyclohexen-3-one and 1-phenyl-1-cyclohexene-3,6-diol. Trans-1-phenyl-1-cyclohexene-3,4-diol was also found and may have resulted from hydroxylation of 1-phenyl-1-cyclohexen-3-one alpha to the carbonyl to yield 4-hydroxy-1-phenyl-1-cyclohexen-3-one (not isolated) followed by carbonyl reduction. Oxidation of the double bond also occurred to give the cis and trans isomers of 1-phenylcyclohexane-1,2-diol as well as a compound postulated to be 1-phenylcyclohexane-1,2,3-triol.

Metabolism, disposition, and kinetics of delta-9-tetrahydrocannabinol in men and women.

A comparative study was done in women and men of the effects of delta 9-tetrahydrocannabinol (delta 9-THC), intravenously or orally, on dynamic activity, metabolism, excretion, and kinetics. In general no differences between the two sexes were observed. delta 9-THC is converted by microsomal hydroxylation to 11-hydroxy-delta 9-THC (11-OH-delta 9-THC), which is both a key intermediate for further metabolism to 11-nor-delta 9-THC-9-carboxylic acid (11-nor-acid) by liver alcohol-dehydrogenase enzymes and a potent psychoactive metabolite. Major differences in the ratio of the concentration of 11-OH-delta 9-THC to that of delta 9-THC in plasma were found after intravenous dosing (ratio 1:10 to 20) compared with oral administration (ratio 0.5 to 1:1). The final metabolic products are the 11-nor-acids and the related, more polar acids. Urinary excretion of delta 9-THC is restricted to acidic nonconjugated and conjugated metabolites. After 72 hr mean cumulative urinary excretion, noted for both routes and for both sexes, ranged from 13% to 17% of the total dose. After 72 hr the cumulative fecal excretion for both sexes after intravenous administration ranged from 25% to 30%; after oral administration the range was 48% to 53%. Metabolites were found in the feces in large concentration in the nonconjugated form; concentrations of 11-OH-delta 9-THC were particularly noteworthy. Kinetics of delta 9-THC and metabolites were much the same for female and male subjects. For delta 9-THC, terminal-phase t1/2s for both sexes, irrespective of the route, ranged from 25 to 36 hr. A comparison of the results for AUC/dose (delta 9-THC) after oral dosing with comparable data from intravenous administration indicated bioavailability of the order of 10% to 20% for both sexes. After intravenous delta 9-THC, large apparent volumes of distribution were noted (about 10 l/kg for both sexes).

Phencyclidine disposition in humans after small doses of radiolabeled drug.

Administration of small doses of radiolabeled phencyclidine hydrochloride (PCP X HCl) to normal volunteers has resulted in basic information on the disposition of PCP in humans. The drug and its metabolites were excreted mainly in the urine whether it was given orally or i.v. (73 +/- 4% of dose was recovered in urine after i.v. administration of 1 mg), with very little fecal excretion (3-5%) and some excretion in sweat. Oral bioavailability was 72 +/- 8%. Major metabolic pathways found involved hydroxylation of the cyclohexane and piperidine rings followed by conjugation. Oxidation to an aminopentanoic acid also occurred. PCP and phenylcyclohexene were inhaled when PCP was smoked. For PCP the weighted mean apparent terminal rate constant (beta) was 0.0395 +/- 0.0008 h-1 for 16 subjects, equivalent to a half-life of 17.6 h, but 2 subjects had half-lives of over 2 days. The volume of distribution (Vd, beta) was 6.2 +/- 0.3 liters/kg. At usual urinary pH, PCP excretion represented less than 10% of total clearance, but marked lowering of urinary pH can significantly increase the contribution of renal clearance to overall clearance.

Systemic absorption of delta 9-tetrahydrocannabinol after ophthalmic administration to the rabbit.

delta 9-Tetrahydrocannabinol was given by ophthalmic administration to the rabbit. Plasma concentrations were measured for two strengths of ophthalmic solution and compared with intravenous data to establish bioavailability. Absorption was variable, while maximum plasma levels were sustained for several hours.

Urine pH and phencyclidine excretion.

Subeffective doses (0.5 mg) of 3H-phencyclidine (PCP) were given intravenously to three healthy men under two regimens designed to alkalinize or acidify their urine (oral sodium bicarbonate or ammonium chloride). The concentrations of PCP and its metabolites in saliva, plasma, and urine for 7 hr after injection were determined by high-performance liquid radiochromatography. A sample of perspiration from one subject was analyzed. The effects of physical exercise on the plasma concentration and urinary excretion of PCP were also studied. Multiple linear regression analysis showed the logarithm of renal clearance the renal clearance of PCP. PCP and its metabolites are also excreted in perspiration. Our results support clinical reports of the importance of vigorous acidification of urine and diuresis in treatment of PCP intoxication.

Phencyclidine and phenylcyclohexene disposition after smoking phencyclidine.

Five men who smoked parsley cigarettes containing 100 micrograms of [3H]-phencyclidine hydrochloride (PCP.HCl) inhaled 69 +/- 5(SEM) % of the total radioactivity in the cigarette. Both PCP and its pyrolysis product, 1-phenylcyclohexene (PC), were found and measured in plasma. Calculations based on the assumption that the ratio of these two products was the same as in simulated smoking studies and based on either area under the curve or urinary excretion of PCP indicated that most of the PCP in smoke was absorbed. Mean half-life (t1/2) of PCP (24 +/- 7 hr, harmonic mean 18 hr) and ratios of metabolites in plasma and urine were close to those previously reported after intravenous and oral doses. A second peak in PCP plasma concentrations was observed, possible due to show efflux from the lungs. PC plasma concentrations (maximum 0.35 +/- 0.06 pmol/ml) were lower than those of PCP (maximum 0.62 +/- 0.09 pmol/ml) and its mean t1/2 (14 +/- 3 hr, harmonic mean 12 h) was shorter than that of PCP. Only traces of PC were found in urine. Only small amounts of metabolites from PC were found nonconjugated in plasma (to about 0.1 pmol/ml) or urine (less than 2% of radioactivity), but larger quantities were found as enzyme-hydrolyzable conjugates in urine (6% of radioactivity). Conjugates were also found in plasma (to about 0.12 pmol/ml).

Phencyclidine disposition after intravenous and oral doses.

[3H]-Phencyclidine (PCP) hydrochloride was given in intravenous (0.1 or 1 mg) or oral (1 mg) doses to male subjects. After 1 mg IV, drug and metabolites were recovered in urine (72.8 +/- 4.0% of dose), feces (4.7 +/- 0.9%), and perspiration. Fecal excretion was low (3.4 +/- 0.4%) after oral dosing and oral bioavailability was estimated at 72%. PCP comprised 16% of urinary radioactivity with 31% consisting of enzymatically hydrolyzable conjugates of hydroxylated metabolites. Both cis and trans isomers of 4-phenyl-4-(1-piperidinyl)cyclohexanol were found. Maximum average plasma PCP concentrations of 2.7 to 2.9 ng/ml were observed after oral and intravenous 1-mg doses. Blood/plasma ratios were approximately 1.0 and plasma binding was about 65%. Parent drug was found in saliva. Apparent terminal phase half-lifes averaged 21 +/- 3 hr (harmonic mean 17 hr, range 7 to 46 hr). The volume of distribution averaged 6.2 +/- 0.3 l/kg. Renal clearances were variable, but the average was 9% of the total clearance. Thus, PCP is cleared principally by metabolism.