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PubMed1990

Guidelines for the definition of environmental action alert thresholds for polychlorodibenzodioxins and polychlorodibenzofurans.

In July 1986, a 314-ha area surrounding the municipal solid waste incinerator of San Donnino (Florence, Italy) was subjected to hygienic and sanitary measures as polychlorodibenzodioxins (PCDDs) and polychlorodibenzofurans (PCDFs) had been detected in soil at levels higher than the "reference technical limits" adopted by the National Toxicology Commission in 1985. In this report the case of San Donnino is the starting point used to define "maximum tolerable environmental limits" for complex mixtures of PCDDs and PCDFs. Limits are expressed in "2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity equivalence" units according to a relative toxicity ranking where the toxic potency of the aforementioned chemical is considered the highest and set equal to unit. Man's exposure to PCDDs and PCDFs is estimated on the basis of experimental findings and with reference to such limits.

Administration, Inhalation↗
PubMed1989

Influence of 2,3-dimercaptopropane-1-sulfonate and dimercaptosuccinic acid on the mobilization of mercury from tissues of rats pretreated with mercuric chloride, phenylmercury acetate or mercury vapors.

The efficiency of the sodium salt of 2,3-dimercaptopropanesulfonic acid (DMPS) and meso-dimercaptosuccinic acid (DMSA) to mobilize mercury from tissues has been assessed in rats pretreated with different doses of HgCl2, phenylmercury acetate or exposed to different concentrations of mercury vapors. These pretreatments increase the mercury concentration in the kidney and to a lower extent in the liver. Only exposure to metallic mercury vapor leads to mercury accumulation in the brain. Both chelators mobilize mercury stored in the kidney and the amount of metal excreted in urine following a single administration of DMSA is a good indicator of the renal burden of mercury. The rate of removal is greater after DMPS administration than after DMSA but repeated administration of either agents eventually leads to the same total amount of mercury mobilized from the kidney. The loss of mercury from the liver can be slightly accelerated by repeated administration of the chelators. However, the chelators are inefficient in removing mercury from the brain.

Administration, Inhalation↗
PubMed1995

Toxicology of chemical mixtures: challenges for today and the future.

A major challenge for the toxicologist involved in safety evaluation of chemical mixtures is to test the hypothesis that as a rule exposure to mixtures of chemicals at (low) non-toxic doses of the individual chemicals is of no health concern. A series of repeated dose studies in rats with defined mixtures of chemicals with the same or different target organs revealed that exposure to a combination of chemicals compared with exposure to the individual compounds did not constitute an evidently increased hazard, provided each chemical was administered at a level similar to, or slightly lower than, its own 'No-Observed-Adverse-Effect-Level'. The results of subacute oral toxicity studies in rats with defined mixtures of nephrotoxicants with similar mode of action underlined the applicability of the additivity assumption for a mixture of chemicals with simple similar action. Safety evaluation of complex chemical mixtures is a challenge that can be tackled as follows: first, identify the (e.g. ten) most risky chemicals in the mixture, and, second, assess the hazard and the potential health risk of the mixture of the most risky chemicals, using procedures developed for defined mixtures. To identify interactions between individual compounds, a most promising testing strategy appeared to be a statistical approach using a fractional two-level factorial design. A challenge for today and the future is to gradually substitute mixture-oriented (real life-oriented) standard setting for (unrealistic) single chemical-oriented standard setting.

Administration, Inhalation↗
PubMed1994

Vaccination of maternally immune pigs with a live Aujeszky's disease vaccine by coarse spray and other routes.

33 ten weeks old passively immune weaners were inoculated with live, attenuated Aujeszky's disease (AD) vaccine, according to four different vaccination protocols: (groups A/A2) 3 x coarse spray vaccination at 10, 11 and 13 weeks of age, (groups B/B2) 1 x coarse spray at 10 weeks of age followed by 1 x intramuscularly at 13 weeks, (C) 1 x intranasal instillation at 10 weeks of age, and (groups D/D2) 2 x intramuscularly at 10 and 13 weeks of age. A further 10 weaners were included as unvaccinated controls (E/E2). Spray vaccination was technically simple to perform but on average, 20% of subjects were reluctant to expose themselves to the spray. Clinical reactions were absent apart from mild fever in one pig from group B. Weight gains between 10 and 17 weeks of age were slightly lower in group A and group B weaners, compared to control unvaccinated pigs and pigs vaccinated by other routes. Virus neutralising (VN) antibody response was extremely uneven between individuals in groups A and B. Group D pigs vaccinated 2 x intramuscularly showed a 3 week lag in developing high levels of antibody but the intramuscular route, as well vaccination by intransal instillation, proved to be the most dependable technique for inducing uniformly high levels of VN antibody. Challenge with virulent ADV at 17 weeks of age resulted in death from Aujeszky's disease of all five control pigs. One pig in group A which had no VN antibody, also died. All other pigs were protected against death.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1993

Variability of physiologically based pharmacokinetic (PBPK) model parameters and their effects on PBPK model predictions in a risk assessment for perchloroethylene (PCE).

When used in the risk assessment process, the output from physiologically based pharmacokinetic (PBPK) models has usually been considered as an exact estimate of dose, ignoring uncertainties in the parameter values used in the model and their impact on model predictions. We have collected experimental data on the variability of key parameters in a PBPK model for tetrachloroethylene (PCE) and have used Monte Carlo analysis to estimate the resulting variability in the model predictions. Blood/air and tissue/blood partition coefficients and the interanimal variability of these data were determined for tetrachloroethylene (PCE). The mean values and variability for these and other published model parameters were incorporated into a PBPK model for PCE and a Monte Carlo analysis (n = 600) was performed to determine the effect on model predicted dose surrogates for a PCE risk assessment. For a typical dose surrogate, area under the blood time curve for metabolite in the liver (AUCLM), the coefficient of variation was 25% and the mean value for AUCLM was within a factor of two of the maximum and minimum values generated in the 600 simulations. These calculations demonstrate that parameter uncertainty is not a significant potential source of variability in the use of PBPK models in risk assessment. However, we did not in this study consider uncertainties as to metabolic pathways, mechanism of carcinogenicity, or appropriateness of dose surrogates.

Administration, Inhalation↗
PubMed1996

Transport of reactive metabolites of procarcinogens between different liver cell types, as demonstrated by the single cell microgel electrophoresis assay.

Procarcinogens have to be activated by specific cytochromes before showing adverse effects. Freshly isolated hepatocytes (parenchymal liver cells, PC) are characterized by a high content of such xenobiotic enzymes and are widely used to investigate chemically induced DNA damage. But in many cases liver tumors caused by indirect acting carcinogens can also originate from non-parenchymal liver cells (NPC). We used freshly isolated rat PC and NPC to demonstrate that only PC have activation capacity when treated in vitro with different genotoxic procarcinogens (N-nitrosodimethylamine, NDMA; vinyl chloride, VC). The alkaline single cell microgel electrophoresis assay was applied to measure the genotoxic activity of the activated compounds. In order to test the hypothesis that reactive metabolites can be transported from PC to NPC, we performed additional in vivo studies as well as studies in which PC were incubated together with NPC, only separated by a dialysis tube (in vitro coincubation). The results indicate that reactive metabolites of both NDMA and VC are stable enough to be transported intercellularly from PC to NPC.

Administration, Inhalation↗
PubMed1994

Salvia divinorum and salvinorin A: new pharmacologic findings.

The diterpene salvinorin A from Salvia divinorum (Epling and Jativa-M), in doses of 200-500 micrograms produces effects which are subjectively identical to those experienced when the whole herb is ingested. Salvinorin A is effectively deactivated by the gastrointestinal system, so alternative routes of absorption must be used to maintain its activity. Traditionally the herb is consumed either by chewing the fresh leaves or by drinking the juices of freshly crushed leaves. The effects of the herb when consumed this way depend on absorption of salvinorin A through the oral mucosa before the herb is swallowed.

Abietanes↗
PubMed1996

Postmortem diffusion of ingested and aspirated paint thinner.

Post mortem diffusion of paint thinner (toluene/ethyl acetate/isobutanol 8:1:1 v/v) from gastric residue (25 ml or 100 ml) and airways contamination (25 ml) was assessed in a human cadaver model, with sampling after 24 h at room temperature. Four torso blood samples showed less toluene diffusion after gastric instillation (0.5-3.8 micrograms/ml) than after tracheal instillation (10.5-421 micrograms/ml). Isobutanol diffused more readily than toluene with four torso blood samples 1.8-256 micrograms/ml after gastric instillation and 26-576 micrograms/ml after tracheal instillation. Following 25 ml gastric instillation, toluene concentrations (microgram/ml or microgram/mg) were: pericardial fluid 0.7-4.0; bile 0.5-0.6; urine 0-0.6; brainstem 1.1; lung 0.4-4.4; liver 0-162; spleen 0.6-0.7; kidneys 0.4-0.6; peri-renal fat 0.3-30.3; psoas muscle 0.3-0.8; concentrations of toluene and isobutanol were markedly higher in the left lobe of the liver than the right. Ethyl acetate was mostly undetectable in tissue samples but variably present in five blood samples: 0-21.2 micrograms/ml following 25 ml or 100 ml gastric instillation and 0-198 micrograms/ml following 25 ml tracheal instillation. Ethyl acetate was always detectable in pericardial fluid but not always detectable in gastric contents. We conclude that post mortem diffusion of toluene from gastric residue or airways contamination is unlikely to compromise the analytical validity of femoral venous blood samples, brain, or liver from deep within the right lobe. Analysis of pericardial fluid and gastric contents allows identification of ethyl acetate and isobutanol thus implicating thinner solution.

Acetates↗
PubMed1992

Anti-infectious effect of C granulosum-derived P40 immunomodulator given by aerosolization and intranasal instillation.

It is known that C granulosum-derived P40 immunomodulator displays strong anti-microbial effects in mice by the intravenous route. Since microbial contamination of humans occurs in many instances via the airways, the effect of P40 on infections was investigated when it was given intranasally or by aerosolization. In order to augment its bioavailability, P40 was derivatized by coupling with polylysine chains (P40-PL). The results showed that P40-PL exercised a significant protective effect, both by the intranasal route and by aerosolization on both influenza and K pneumoniae infections produced by aerosolization or intranasal instillation. Stimulation of the phagocytic capacity of alveolar macrophages by these types of treatment is likely to account for the increased resistance of mice toward microbial infections.

Adjuvants, Immunologic↗
PubMed1993

Cystic fibrosis: antibiotic prescribing practices in the United Kingdom and Eire.

The antimicrobial prescribing practices of 26 physicians from the U.K. and Eire who care for patients with cystic fibrosis (CF) were assessed by postal questionnaire. Our main aim was to delineate divergent practices which may reveal a need for controlled prospective studies. For first-line intravenous (i.v.) therapy of acute exacerbations associated with Pseudomonas aeruginosa, 20 physicians (76.9%) combine a penicillin derivative with an aminoglycoside, in contrast to five (19.2%) who regularly use i.v. monotherapy with ceftazidime and one who combines i.v. ceftazidime with an aminoglycoside. When i.v. therapy is considered inappropriate, oral ciprofloxacin is sometimes used by all clinicians and oral broad spectrum agents are used in addition by 13, chloramphenicol being prescribed most often. Excluding allergy, the most important factor influencing choice of agents by 19 (73.1%) physicians is the most recent sputum susceptibility results. For maintenance therapy, 21 prescribe oral anti-staphylococcal agents if Staphylococcus aureus is isolated; of these, eight do so only if lung function deteriorates, nine after repeated isolation and four after first isolation of S. aureus. The remaining five physicians give anti-staphylococcal drugs to all patients once the diagnosis of CF is made. For maintenance of lung function in patients with persistent P. aeruginosa, all physicians used nebulized antibiotics, the indications for which vary between units. There was general concordance in the therapy of exacerbations associated with P. aeruginosa, whereas the use of agents to maintain lung function is more varied. We suggest that prospective studies address practices which vary greatly, such as the route, the duration and the timing of initiating antibiotic therapy given to maintain lung function.

Administration, Inhalation↗
PubMed1994

Evaluation of 153Sm-diethylenetriaminepentaacetic acid for radiolabelling of pharmaceutical dosage forms by neutron activation.

153Sm-DTPA provides a suitable alternative to 99mTc-DTPA and 111In-DTPA as a water soluble tracer for the evaluation of pharmaceutical preparations. The chelate was handled biologically in a similar way to 99mTc-DTPA and 111In-DTPA. The chelate can be incorporated into the formulation as a non-radioactive excipient and the intact dosage form can then be neutron activated to produce 153Sm.

Administration, Inhalation↗
PubMed2003

The bioavailability of intranasal and smoked methamphetamine.

BACKGROUND: Patients in harm-reduction treatment programs are switching from intravenous to other routes of methamphetamine (INN, metamfetamine) administration to avoid risks associated with needle use. Relatively little has been reported about the bioavailability of methamphetamine when smoked or used intranasally. METHODS: Eight experienced methamphetamine users were administered smoked or intranasal methamphetamine concurrently with an intravenous dose of deuterium-labeled methamphetamine. Plasma and urine concentrations were measured for calculation of bioavailability and other pharmacokinetic parameters by noncompartmental methods. RESULTS: Methamphetamine was well absorbed after smoking or intranasal administration, with bioavailabilities of 79% after intranasal administration and 67% of the estimated delivered dose or 37.4% of the absolute (pipe) dose after smoking. Maximum methamphetamine concentrations occurred at 2.7 and 2.5 hours after intranasal and smoked doses. The elimination half-life was similar for intravenous (11.4 hours), intranasal (10.7 hours), and smoked (10.7 hours) methamphetamine. Clearance (272 mL x h(-1) x kg(-1)), steady-state volume of distribution (4.2 L/kg), and mean residence time (16 hours) of the intravenous dose were similar to previously reported values. Dextroamphetamine (INN, dexamfetamine) half-life (all routes) was 16.2 hours. Methamphetamine and dextroamphetamine renal clearances (all routes) were about 100 and 1100 mL x h(-1) x kg(-1), respectively. CONCLUSIONS: Intranasal and smoked methamphetamine are well absorbed. Although intranasal or smoked routes may decrease the risk of transmission of blood-borne diseases, exposure to methamphetamine and the possibility of drug-related complications remain substantial.

Administration, Inhalation↗
PubMed2005

Paediatric eosinophilic oesophagitis: towards early diagnosis and best treatment.

UNLABELLED: Eosinophilic oesophagitis is an emerging disease, well known also in paediatric age, probably caused by both IgE and non-IgE mediated food allergies, diagnosed by upper endoscopy with biopsy. The most severe complication is oesophageal stenosis. The identification of the offending allergens is often difficult; therapy is focused to eliminate the supposed antigenic stimulus, to control the acute symptoms and to induce long-term remission. AIM: We report the clinical outcome and the typical endoscopic findings of children and adolescents affected by eosinophilic oesophagitis, referring a proposal of diagnostic and treatment protocol. PATIENTS AND METHODS: Twelve patients, affected by eosinophilic oesophagitis with a histological diagnosis, underwent radiographic upper gastro-intestinal series, 24 h pH-probe and standardised allergic testing; they were treated with steroids (oral prednisone and swallowed aerosolised fluticasone) and elimination diet. Dilations were performed when eosinophilic oesophagitis was not yet diagnosed, or in patients resistant to conventional treatment. RESULTS: Two patients were lost to follow up (mean follow up: 1 year 11 months); seven patients have no symptoms and normal histology, five of them on restricted diet (without cow's milk protein) and two patients on elemental diet (amino acid formula). In two patients (no allergens identified), mild dysphagia and eosinophilic infiltration persist; one patients underwent Nissen fundoplication for Barrett's oesophagus: he has no symptoms and normal oesophagus, on restricted diet (without cow's milk/eggs protein and wheat). CONCLUSION: The recognition of typical endoscopic picture with careful biopsies extended to the whole oesophagus, even in emergency, could more quickly lead to the correct diagnosis and avoid severe complications of eosinophilic oesophagitis in children, as stricture and failure to growth. Elimination diet is the key of resolution when the allergens are identified. A great challenge remains the relation between gastro-oesophageal reflux disease and eosinophilic oesophagitis, which should however be explained.

Administration, Inhalation↗
PubMed2006

The total antioxidant status in the brain after ethanol or 4-methylpyrazole administration to rats intoxicated with methanol.

In the study, the potential interaction of methanol/ethanol and methanol/4-methylpyrazole within the scope of the total antioxidant status (TAS) in rat brain was investigated. The experiment was carried out on rats exposed to N2O/O2 mixture (1:1 v/v) which enable to obtain similar response of rat organism to methanol poisoning as that observed in humans. The rats were exposed to N2O/O2 mixture 4h before the administration of methanol or saline. The exposure to N2O/O2 was continued throughout the experiment. Methanol was administered orally at a dose of 3.0 g/kg, then, after next 4 h ethanol (0.5 or 1g/kg) or 4-methylpyrazole (4-MP) (15.0 or 50.0 mg/kg.) was administered by i.p. injection. TAS in rat brain homogenates was assayed spectrophotometrically at lambda=600. The mean concentration of TAS in rats exposed to N2O/O2 mixture did not differ from that determined for control rats. A slight decrease in TAS concentration was found in all groups of rats intoxicated with methanol and ethanol or 4-MP and methanol alone. There was no interaction between methanol and 4-MP. However, a significant decrease in TAS concentration was observed in rats following the ingestion of methanol and than after the administration of 1.0 g/kg of ethanol in comparison to rats receiving methanol alone (p<0.05). This phenomenon suggests an adverse interaction of methanol/ethanol within scope of the brain antioxidant status equilibrium.

Administration, Inhalation↗