Search

Perfluoro-n-butyl iodide (PFBI) is a promising alternative to chlorofluorocarbon solvents used in aircraft ground maintenance operations and other military and commercial operations, because it cleans well, has zero ozone depletion potential, and has extremely low global warming properties. Toxicity tests were performed with PFBI to determine and evaluate its health hazard. Using standard testing guidelines (e.g., Organization for Economic Cooperation and Development [OECD]), tests included acute (4-h) and 4-week (6 h/day, 5 days/week) inhalation (nose-only) toxicity studies in rats, acute (10-min) inhalation cardiac sensitization study in dogs, in vitro chromosomal aberrations experiments in human lymphocytes, and in vitro mutagenic experiments in Salmonella typhimurium and Escherichia coli. There were no mortalities in rats (n = 10) exposed for 4 h to 10,000 ppm PFBI, but all rats (n = 10) died within 2 h when exposed to 20,000 ppm PFBI. The 4-h LC50 (95% confidence limits) was 14,000 ppm (13,000 ppm to 16,000 ppm). Signs (nasal discharge and labored breathing) observed in the rats exposed to 10,000 ppm returned to normal within 48 h. PFBI has the potential to cause cardiac sensitization in epinephrine-challenged dogs at 6200 ppm. A concentration of 3900 ppm was a no-observed-adverse-effect level (NOAEL) in the cardiac sensitization study. In the 4-week inhalation study (5 rats/sex/group), respiratory mucosal hypertrophy/hyperplasia was observed in rats of the 10,000-ppm group. A NOAEL of 1000 ppm was selected for the 4-week study on the basis that the mild increase in T4 observed at 1000 ppm was considered adaptive, not adverse, because of the absence of frank effects in the thyroid. In the in vitro studies, PFBI showed no evidence of either mutagenic or clastogenic activity. The toxicity profile of PFBI was compared to trifluoroiodomethane. In conclusion, the results of these studies indicate a low order of general toxicity and an absence of genotoxicity following PFBI exposure.

The purpose of this study was to evaluate the potential neurodevelopmental toxicity of perchlorate exposure during gestation and the first 10 days of lactation. Mated Sprague-Dawley rats (25/exposure group) were given continual access to 0, 0.1, 1.0, 3.0, or 10.0 mg/kg-day ammonium perchlorate (AP) in drinking water, starting gestation day 0 (mating) through lactation day 10 (DL 10). One pup/sex/litter/exposure group was assigned to (1) juvenile brain weights, morphometry, and neuropathology; (2) passive avoidance and watermaze testing; (3) motor activity and auditory startle habituation; and (4) adult regional brain weights, morphometry, and neuropathology. AP had no effect on body weights, feed consumption, clinical observations, or sexual maturation of pups at exposures as high as 10.0 mg/kg-day. There were no behavioral effects in the offspring exposed as high as 10.0 mg/kg-day as evaluated by passive avoidance, swimming watermaze, motor activity, and auditory startle. Increases in hypertrophy and hyperplasia of the thyroid follicular epithelium and a decrease in the thyroid follicle size were observed in culled male pups in the 10.0 mg/kg-day group on DL 5. The exposure level for effects on triiodothyroxine (T3), thyroxine (T4), and thyroid-stimulating hormone (TSH) levels for pups were 0.1, 1.0, and 3.0 mg/kg-day, respectively. There was an apparent increase in the thickness of the corpus callosum of the 10 mg/kg-day group pups on DL 12. The no-observed-adverse-effect level (NOAEL) for maternal toxicity was greater than 10.0 mg/kg-day. Based on the thyroid morphometric and histopathologic findings, the NOAEL for pup toxicity was 0.1 mg/kg-day.

Twenty-four adults (24 to 53 years old) with Attention-Deficit/Hyperactivity Disorder (ADHD), Combined Type, were studied in a double-blind, placebo-controlled, crossover study of Pycnogenol and methylphenidate. Pycnogenol is an antioxidant derived from the bark of the French maritime pine tree. Methylphenidate is a standard pharmaceutical intervention for ADHD. Anecdotal reports suggest that Pycnogenol improves concentration in adults with ADHD without adverse side effects. Participants received Pycnogenol, methylphenidate, and placebo, each for three weeks, in a randomized and counterbalanced order. Although ADHD symptoms improved during treatment, neither methylphenidate nor Pycnogenol outperformed the placebo control, as measured by self-report rating scales, rating scales completed by the individual's significant other, and a computerized continuous performance test. The conservative dosage levels and relatively brief length of treatment may have contributed to the absence of significant differences among treatment conditions. Implications for future research are noted.

A retrospective review of all patients presenting to a tertiary referral center with acute nontraumatic upper limb ischemia between January 1992 and June 1997 was undertaken to examine the role of intraarterial thrombolysis in the management of such cases. Twenty-one patients were identified in the radiology and vascular surgery departments' registers. Twenty (95%) underwent angiography, demonstrating subclavian artery occlusion in four, axillary in two, brachial in 13, and one at the digital level. Intraarterial thrombolysis was attempted in 12 patients. There were three technical failures, all requiring embolectomy. Six had complete lysis and resolution of their symptoms. One patient had partial lysis but experienced no further rest pain. Thrombolysis was unsuccessful in two cases with one subsequently requiring embolectomy and the other surgical bypass. Three patients had surgical intervention as their primary procedure with two favorable outcomes and one ending in above-elbow amputation. Five patients were treated conservatively with heparin, resulting in three partial and two full recoveries. One patient experienced complete resolution of symptoms with an intravenous prostacyclin infusion. Both electrocardiograms (ECG) and echocardiograms (ECHO) were of limited diagnostic aid, and long-term warfarin anticoagulation was prescribed to all patients. There was no recurrence of upper limb ischemia at a median follow up of 18 months. Intraarterial thrombolysis is an effective first line treatment for acute nontraumatic upper limb ischemia in selected cases.

1. Male and female Fischer 344 rats were exposed to 2,4-pentanedione (2,4-PD) vapour acutely (4 h) at 1265 or 1811 ppm, or for 6 h day-1, 5 days a week for 14 weeks to 0, 101, 307 or 650 ppm. 2. Mortality occurred during or within a few hours of the acute exposures (10% at 1265 ppm; 70% at 1811 ppm). No animal had gross or microscopic brain lesions. 3. All female rats (20) and 10 of 30 male rats exposed to 650 ppm 2,4-PD vapour died by the 38th study day (29 exposures); there were no subsequent male deaths. Twenty-five of the 30 animals that died, and seven of the 15 males that survived, had light microscopical evidence of degenerative lesions, principally within the caudate/putamen nuclei, nuclei of the cerebellar medulla, and vestibular nuclei. Less frequently involved, in animals that died, were various regions of the cerebral cortex. The early histopathological lesions, seen from the 16th study day (12 exposures) to the 38th study day (28 exposures) were characterised by malacia. When present, lesions in male rats surviving the 14-weeks of 650 ppm 2, 4-PD exposure were characterised by malacia and gliosis. No peripheral nerve lesions were seen by light or transmission electron microscopy. 4. Neither mortality nor neuropathology were seen in rats subchronically exposed to 101 or 307 ppm, 2,4-PD vapour.

Groups of 10 male Hartley guinea pigs were exposed to 3.0, 2.0, 1.0, or 0.1% (v/v) 1,1-Dichloro-2,2,2-trifluoroethane (HCFC-123) or 1.0% (v/v) halothane by inhalation for 4 hr. A sixth group of 10 guinea pigs received only air. All animals were sacrificed 48 hr postexposure. Gross and histopathologic examination of the liver, heart, and kidney and routine hematology and clinical chemistry analyses [including isocitrate dehydrogenase (ICDH)] were done on all guinea pigs. Lesions related to HCFC-123 and halothane exposure were limited to the liver and included centrolobular vacuolar (fatty) change, multifocal random degeneration and necrosis, and centrolobular degeneration and necrosis. These lesions were observed in 90-100% of the exposed animals and were absent in the air-only controls. There was significant individual animal variation in susceptibility to both HCFC-123 and halothane, resulting in a spectrum of histologic lesions and clinical chemistry values within each exposure group. Alanine aminotransferase, aspartate aminotransferase, and ICDH were the most significant predictors of hepatocellular damage. Similarities in the response between halothane and HCFC-123 in this guinea pig model suggests that humans susceptible to halothane-induced hepatitis may be susceptible to HCFC-123 by a common mechanism of toxicity.

Fischer 344 rats were exposed by inhalation to 0, 1, 5 or 50 ppm dicyclopentadiene (DCPD) vapor 6 hr/day, 5 days/week for 13 weeks, followed by a 13-week recovery period. Animals were euthanized following completion of exposure at 2, 6, or 13 weeks and at postexposure weeks 4 or 13. No mortality, overt signs, body weight changes, hematologic or clinical chemistry values were related to DCPD exposure. In the high-exposure male rats, relative liver weights were significantly increased but with no accompanying histopathologic changes. Exposure to DCPD produced adverse kidney effects in male, but not female, rats as evidenced by the excretion of epithelial cells in the urine. Histologic changes were localized to the proximal tubules of the kidney and included increased accumulation of protein droplets, regenerative epithelium, and the presence of intraluminal proteinaceous material. In addition, several alterations in renal function were observed. Urinary Na+ excretion rates were decreased and urinary K+ excretion rates were increased throughout the exposure period; however, glucose was not present in the urine, and creatinine clearance was normal. The ability of the kidney to concentrate urine was also impaired. After the recovery period, many of the treatment-related kidney effects were not observed, including the presence of hyaline droplets in the proximal tubules and epithelial cells in the urine. These findings indicate an overall low degree of systemic toxicity following subchronic inhalation exposure of dicyclopentadiene at exposure levels up to 50 ppm. The only effect that was observed was a male rat-specific nephropathy that is characteristic of the hyaline droplet nephropathy produced by a diverse group of compounds.

Nonclinical, adolescent children of alcoholics (COAs) and their peers from nonalcoholic homes (CONAs) responded to questionnaires of environmental variables, depression, and anxiety. Multivariate (discriminant) analyses revealed several meaningful differences between the two groups. Although the two groups differed on the measures of anxiety and depression, environmental stressors contributed most to the discriminant function that differentiated between the two groups. Also, gender differences were discovered, suggesting that males and females perceive problem drinking differently and that home environments may be different for the two genders. Implications for research and intervention are discussed.

The acute handling hazards of tris(dimethylamino)silane [TDMAS] were investigated. The acute male rat peroral LD50 (with 95% confidence limits) was 0.71 (0.51-0.97) ml/kg, and the acute male rabbit percutaneous LD50 was 0.57 (0.35-0.92) ml/kg. The liquid was severely irritating to the rabbit eye and skin, and the vapor severely irritating to the rat eye. The dynamically generated saturated vapor Lt50 in female rats was 12 (9.7-15) min. The effect of varying the atmospheric concentration of vapor from TDMAS on acute inhalation toxicity was investigated by passing ordinary moist air countercurrent to liquid TDMAS metered into a slightly heated glass tube. Based on nominal concentrations, the 4 hr-LC50 for vapor from TDMAS was 734 (603-893) ppm in female rats by this procedure. Stoichiometrically, this accords with toxicity due to liberation of dimethylamine (DMA) from TDMAS. In a subsequent study designed to assess the influence of relative humidity on vapor toxicity, nitrogen was passed over heated liquid TDMAS and the resultant atmosphere was introduced into the air intake duct of the inhalation exposure chamber. Gas chromatographically measured TDMAS concentrations (+/- SD) were 395 +/- 111, 127 +/- 25, 62 +/- 8 and 23 +/- 21 ppm; the corresponding DMA vapor concentrations were 112 +/- 171, 31 +/- 43, 10 +/- 6 and 26 +/- 44 ppm. The 4-hr LC50 (males and females) was 38 (34-43) ppm TDMAS vapor. Thus, TDMAS is of moderate acute peroral and percutaneous toxicity, a severe primary skin and eye irritant, an aspiration hazard, and of high intrinsic acute inhalation toxicity, but in moist air conditions lethal toxicity may be reduced and in such circumstances DMA may be a significant factor in toxicity.

Misoprostol, a synthetic prostaglandin E1 methyl ester analogue with anti-ulcer potential, was evaluated for its carcinogenic potential in CD-1 strain mice. The compound was given daily by gavage at 160, 1,600, and 16,000 micrograms/kg for 21 months. Necropsies were done on all animals and the incidences of non-neoplastic and neoplastic changes analyzed for significance by life table methods. The only statistically significant non-neoplastic compound-related findings were epithelial hyperplasia and hyperkeratosis of the gastric mucosa and hyperostosis of bone in the marrow cavity of sternebrae and femurs. The changes in the gastric epithelium are characteristic of some prostaglandins and were expected. The bone hyperostosis was associated with misoprostol in high dosages, and was considered unique to the mouse. Other non-neoplastic findings were typical of known spontaneous conditions in mice. The most frequent neoplasm was the hepatocellular adenoma followed by lymphosarcoma, lung alveolar carcinoma, and Harderian gland adenoma. Several proliferative lesions of the duodenum were considered to be spontaneous. These were focal avillous hyperplasia, focal atypical hyperplasia, and junctional polyp. There was no evidence that misoprostol is carcinogenic for CD-1 mice.

Disseminated panarteritis was found in 16 (9 males and 7 females) of 49 laboratory beagle dogs (25 males and 24 females) from one breeding kennel. The dogs had been used in a 6-month oral toxicity study. Panarteritis was not associated with clinical or gross abnormalities. The incidence was similar in the control and test article-treated groups. Mainly medium-sized arteries throughout the body, particularly intercostal arteries (at their aortic origin), and coronary, epididymal and thymic vessels were affected. Chronic mononuclear-cell periarteritis was the predominant feature. Mixed cellular inflammation of the wall, proliferation or degeneration of muscle cells, focal "fibrinoid" material in the tunica media, fragmented internal elastic lamina and intimal thickening associated with myointimal cellular proliferation also occurred. These histologic changes are compatible with those of immune arteritis. Round worm intestinal infestation and granulomas of visceral larva migrans were common in several organs. Statistical analyses suggested that the pedigree of dogs is related to panarteritis, but the presence or absence of parasitization alone is not. The possible roles of genetic predilection and/or parasites in the pathogenesis are discussed. This panarteritis is spontaneous and may complicate the interpretation of lesions in toxicity studies.

2,4-Pentanedione (2,4-PD: CAS No. 123-54-6) is a volatile industrial chemical of moderate acute toxicity, centrally neurotoxic by repeated exposure to high vapor concentrations, fetotoxic, and clastogenic. Its wide use and known toxicology indicated the conduct of a dominant lethal assay. Male Fischer 344 rats, 20 per group, were exposed to 2,4-PD vapor concentrations (mean +/- SD) of 0, 99.1 +/- 2.2, 412 +/- 12.6 and 694 +/- 9.1 ppm, for 6 hr/day for 5 consecutive days. The day following the final exposure they were bred to unexposed female Fischer 344 rats, 2 per week for 8 consecutive weeks. Weight loss occurred with males during 2,4-PD exposure for the 412 and 694 ppm groups, with compensatory increased weight at 694 ppm, for the first two weeks postexposure. No histopathological change was seen in brain, testes or thymus from high concentration males sacrificed after eight weeks of mating. Minor transient reproductive and gestational effects were present at 412 and 694 ppm. At week 2 there was a reduction, not statistically significant, in the number of corpora lutea and total and viable implants per dam at 694 ppm, and a slight increase in preimplantation loss. At week 3 the number of pregnant females was slightly reduced at 412 and 694 ppm, causing a lowered female fertility index. At week 4 there was a slight reduction in the number of total and viable implants per litter and a significant preimplantation loss at 694 ppm. The dominant lethal factor (FL%) was increased slightly at 694 ppm for weeks 2 and 4. Thus, the "no observable effect" level for dominant lethal effects was 99 ppm. The results, although not statistically significant, are dose-related and compatible with a transient slight dominant lethal effect at the spermatid stage of spermatogenesis.

The carcinogenic potential of misoprostol, a synthetic prostaglandin E1 analogue with anti-ulcer potential, was evaluated in CD Sprague-Dawley rats. The compound was given daily by gavage at 24, 240, and 2,400 micrograms/kg, up to 150 times the daily human dose for 2 years. Necropsies were done on all animals and the incidences of non-neoplastic and neoplastic changes analyzed for significance by life table methods. The only statistically significant non-neoplastic finding was epithelial hyperplasia and hyperkeratosis of the gastric mucosa. These changes, which are characteristic of some prostaglandins, were expected. Other non-neoplastic findings were typical of known spontaneous conditions in this strain of rats. The most frequent neoplasm was the pituitary adenoma, followed by the mammary fibroadenoma, mammary adenoma, mammary adenocarcinoma, and thyroid C-cell adenoma. A rare neoplasm, squamous cell carcinoma of the ovary was found in two rats. There was no evidence that misoprostol is carcinogenic for CD Sprague-Dawley rats.

Four groups, each consisting of 10 male and 10 female Fischer-344 rats, were exposed 6 h/day, 5 days/week, for 9 days to diisobutyl ketone (DIBK) vapor at concentrations of 905, 300, 98, or 0 (control) ppm. An additional 10 rats/sex were assigned to the 905 and 0 ppm groups and allowed two weeks recovery prior to sacrifice. Rats exposed to 905 ppm had mild ocular irritation (lacrimation) and evidence of kidney toxicity, manifested as: 1) an increase in absolute and relative (as a percentage of body weight) kidney weights, 2) an increase in urine volume (and water intake) with a concomitant decrease in urine osmolality (males only), and 3) an increase in severity of hyalin droplet nephrosis in the proximal tubules (males only). Absolute and relative liver weights were also increased in both male and female rats of the 905 and 300 ppm groups. These effects either disappeared or lessened in severity following the 2-week recovery period. Male rats exposed to 300 ppm had similar renal alterations to the males of the 905 ppm group, although the alterations were fewer in number and smaller in magnitude. Kidney weights and renal histology of the males of the 98 ppm group were similar to the control male rats, although an increase in urine volume with a decrease in urine osmolality was observed. The kidney findings in this study were not surprising because of the chemical relationship of DIBK with other aliphatic ketones (e.g., methyl isobutyl ketone, methyl isoamyl ketone) which, after repeated inhalation exposure, cause hyalin droplet nephropathy in male rats. The significance of this male rat nephrosis with regard to human exposure is unknown.