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At least 253 records · Page 14Linked to original sources
PubMed1997

Teratogen update: toluene.

Extrapolating from animal data, at the level at which well-controlled occupational exposure to toluene vapor is encountered, in utero exposure does not pose a significant fetal risk. However, following chronic and excessive industrial accidents or intentional abuse, toluene exposure several orders of magnitude greater exists, and at these levels in utero exposures in both animals and humans have been shown to produce significant delays in fetal growth. At these greater exposure levels, both dose and gestational timing relationships can be demonstrated in animal models. Of note, in both animals and humans, postnatal persistence of growth deficiency has been observed. A pattern of teratogenicity similar to that of the fetal alcohol syndrome is prevalent in all human studies of excessive in utero exposure to toluene. In humans, the effects of in utero toluene exposure among intentional abusers is confounded by such variables as general health and exposure to other teratogens. Chronic toluene abuse produces a renal tubular acidosis with maternal hypokalemia and profoundly lowered serum pH. Further evaluation of greater numbers of infants with respect to maternal renal tubular acidosis will be needed to fully assess the contribution of chronic acidosis. The contribution of maternal acidosis to fetal teratogenicity remains speculative. Coabuse of additional agents, in particular alcohol, may increase the teratogenic risks. The overlap of features following in utero toluene abuse with those of fetal alcohol syndrome suggests a possible common pathway of craniofacial teratogenesis. Lastly, genetic variations that result in deficiency of ALDH2, an enzyme involved in toluene metabolism, may increase the risks of toluene teratogenicity in at-risk individuals at lower levels of exposure. Prospective studies of toluene-exposed pregnancies would provide more information on the fetal effects at these levels.

Abnormalities, Drug-Induced↗
PubMed1998

One-year follow-up of young children hospitalized for wheezing: the influence of early anti-inflammatory therapy and risk factors for subsequent wheezing and asthma.

We investigated the 1-year outcome of children hospitalized for wheezing, paying special attention to the effect of early anti-inflammatory therapy. In addition, we identified risk factors for recurrent wheezing and asthma. Eighty-eight children under 2 years old treated in the hospital for wheezing were followed for 1 year. Nebulized anti-inflammatory therapy was given for 16 weeks: 31 patients received budesonide, 29 patients cromolyn sodium, and 28 control patients received no therapy. The number of subsequent physician-diagnosed wheezing episodes was recorded. Four months of anti-inflammatory therapy did not significantly decrease the occurrence of asthma 1 year later; 45% of patients in the cromolyn group, 42% in the budesonide group, and 61% in the control group had asthma, defined as at least two bronchial obstruction episodes during the 1-year period after the original hospitalization for wheezing. An age over 12 months at the time of the initial bronchial obstructing episode [P=0.009, risk ratio (RR)=5.4, 95% confidence interval (CI)=1.53-19.31], failure to identify a viral cause (P=0.0003, RR=12.0, CI=3.16-45.40), history of wheezing (P=0.02, RR=14.6, CI=1.59-132.10), the presence of atopy (P=0.01, RR=5.3, CI=1.47-19.21), a family history of atopy (P=0.03, RR=3.6, CI =1.15-11.12), and serum eosinophil cationic protein (ECP) > or = 16 microg/L (P=0.005) were significant risk factors for asthma. We conclude that early anti-inflammatory therapy for 4 months does not significantly decrease the occurrence of asthma during the period of 1 year following hospitalization for the original episode of wheezing. Young children requiring hospital admission for wheezing during a respiratory tract infection are at increased risk of having subsequent asthma if they have wheezed previously, if they have atopy or a family history of atopy, if they have elevated serum ECP, if they are over 12 months of age at the original bronchial obstructive episode, and especially when viral studies are negative.

Administration, Inhalation↗
PubMed1999

Exhaled nitric oxide before and after montelukast sodium therapy in school-age children with chronic asthma: a preliminary study.

Exhaled nitric oxide (ENO) is a surrogate marker of airway inflammation in asthma. In 12 children aged 6-11 years with mild to moderate persistent asthma, ENO concentrations were measured before and after 4 weeks of treatment with montelukast sodium, a leukotriene receptor antagonist, and 2 weeks after withdrawal of therapy. Baseline ENO levels (mean and 95% confidence interval) were significantly elevated in patients with asthma compared to age-matched nonasthmatic control subjects, with levels of 83 (42-123) vs. 13 (11-15) ppb (P < 0.001). After treatment with montelukast sodium, there was a significant (P < 0.01) reduction in ENO to 58 (27-89) ppb which again rose to 69 (38-99) ppb 2 weeks after treatment was withdrawn. During treatment, the fall in ENO was accompanied by nonsignificant improvements in prebronchodilator forced expiratory volume in 1 s (FEV(1)) from 81-85% predicted or reductions in use of albuterol from a mean of 2.5 to 1.6 puffs/day. Individual ENO measurements and change in ENO concentrations with treatment did not correlate with either pulmonary function changes or use of bronchodilator. These data show that ENO is elevated in children with relatively mild asthma treated with bronchodilator alone, and that treatment with montelukast sodium for 4 weeks results in a significant reduction in ENO concentrations, even in the absence of significant changes in pulmonary function. These findings suggest an anti-inflammatory role for leukotriene D(4) receptor antagonism in the treatment of children with mild to moderate asthma.

Acetates↗
PubMed1993

Plasma concentrations and hemodynamic effects of intravenous, sublingual, and aerosolized nitroglycerin in patients undergoing cardiac catheterization.

Intravenous, sublingual, or aerosolized nitroglycerin was administered to 19 patients with coronary artery disease during clinically indicated cardiac catheterization. Eight blood samples were collected over 15 min from each patient, and analyzed for content of nitroglycerin, 1,2-glycerol dinitrate, and 1,3-glycerol dinitrate. Simultaneously, heart rate (HR), systolic blood pressure (SBP), and left ventricular end-diastolic pressure (LVEDP) were recorded. Plasma concentrations of nitroglycerin were highest after intravenous injection and lowest after sublingual tablets. Metabolite concentrations were highest after intravenous injection at early time-points; at later time-points, no between-group differences could be detected. SBP was minimally affected by intravenous nitroglycerin but was significantly reduced by sublingual and aerosolized formulations. Minor fluctuations in HR were observed in association with all three formulations. LVEDP was reduced by all three formulations of nitroglycerin but most rapidly by the intravenous form. Overall, no differences were detected in hemodynamic responses caused by sublingual and aerosolized nitroglycerin. Efficacy of sublingual and aerosolized nitroglycerin in patients undergoing cardiac catheterization is equivalent.

Administration, Inhalation↗
PubMed1989

Comparison of oral and aerosol ribavirin regimens in the high risk elderly.

A comparison of different regiments of ribavirin (R), administered either orally or by aerosol, was performed in 16 elderly subjects (13 men, 3 women, mean age 63 +/- 8 years) considered to be in the "high-risk" category for complications from influenza as defined by the Centers for Disease Control. The subjects were divided into four groups. Group O-600 received 600 mg orally R every 8 hours for 48 hours followed by 200 mg every 8 hours for 72 hours for a total dose of 5.4 g (22.1 mmol). Group O-800 received 800 mg oral R every 8 hours for 24 hours followed by 400 mg every 12 hours for 96 hours for a total dose of 4.1 g (22.9 mMoles). Group A-40 received R (40 mg/ml) aerosolized through a small particle aerosol generator for 6 hours every 12 hours for 96 hours, yielding an average delivered dose of 6.2 g (25.4 mMoles) R. Group A-60 received aerosolized R (60 mg/mL) for 2 hours every 8 hours for 96 hours, yielding an average delivered dose of 4.6 g (18.8 mMoles) R. No hematologic or other laboratory abnormalities were associated with any of the regimens. Group O-800 and O-600 reached mean peak plasma R levels of 11.8 microM and 5.3 microM, respectively, after 18 hours of therapy. Subsequent administration of 20 mg R every 8 hours was sufficient to maintain a plasma R level greater than 7 microM. Among the aerosol groups, group A-40 approached steady state plasma R levels (8-10 microM) more quickly than group A-60.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMedDate not supplied

Riot control agents: pharmacology, toxicology, biochemistry and chemistry.

The desired effect of all riot control agents is the temporary disablement of individuals by way of intense irritation of the mucous membranes and skin. Generally, riot control agents can produce acute site-specific toxicity where sensory irritation occurs. Early riot control agents, namely, chloroacetophenone (CN) and chlorodihydrophenarsazine (DM), have been replaced with 'safer' agents such as o-chlorobenzylidene malononitrile (CS) and oleoresin of capsicum (OC). Riot control agents are safe when used as intended: however, the widespread use of riot control agents raises questions and concerns regarding their health effects and safety. A large margin exists between dosages that produce harassment and dosages likely to cause adverse health effects for modern riot control agents such as CS and dibenz[b,f]1 : 4-oxazepine (CR). Yet, despite the low toxicity of modern riot control agents, these compounds are not entirely without risk. The risk of toxicity increases with higher exposure levels and prolonged exposure durations. Ocular, pulmonary and dermal injury may occur on exposure to high levels of these substances, and exposure to riot control agents in enclosed spaces may produce significant toxic effects. Reported deaths are few involving riot control agents, and then only under conditions of prolonged exposure and high concentrations. Recently, concern has focused on the deaths resulting from law enforcement use of OC, a riot control agent generally regarded as safe because it is a natural product. As with other xenobiotics, not enough is known concerning the long-term/chronic effects of riot control agents. Clearly, there is considerable need for additional research to define and delineate the biological and toxicological actions of riot control agents and to illuminate the full health consequences of these compounds as riot control agents.

Administration, Inhalation↗
PubMed2001

Genotypic characterization of Pseudomonas aeruginosa strains recovered from patients with cystic fibrosis after initial and subsequent colonization.

Chronic infection by Pseudomonas aeruginosa (PA) in patients with cystic fibrosis (CF) is preceded by a period of colonization and acute infection. Early aggressive antibiotic treatment of initial colonisation may prevent or at least delay chronic pulmonary infection. We initiated treatment with a combination of IV beta-lactam tobramycin, followed by nebulized colistin when PA was first isolated from patients with CF. Subsequent serial PA isolates obtained from these colonized CF patients were characterized by means of molecular methods to determine whether they were genetically related to the initial strain. Initial colonization was eradicated in all 19 patients. All patients reacquired PA within 3-25 months during the 3 years of follow-up. Fourteen patients acquired a new PA strain with a distinct genotypic profile, suggesting a new source of contamination. Five patients had two PA isolates with identical genotypes, suggesting either previous undetected respiratory tract colonization or a persistent environmental source of contamination.

Administration, Inhalation↗
PubMed1994

Pulmonary mechanics in ventilated preterm infants with respiratory distress syndrome after exogenous surfactant administration: a comparison between two surfactant preparations.

The effects of two surfactant preparations on lung mechanics have been studied on 24 ventilated premature infants with respiratory distress syndrome (RDS): 13 were given artificial surfactant (Exosurf Neonatal, Burroughs-Wellcome) and 11 natural porcine surfactant (Curosurf, Laboratoire Serono France). Measurements of respiratory system compliance (Cdyn, Crs) and resistance (Rrs) were performed immediately before surfactant administration and repeated 6, 18, 24, 48, and 72 hours later. With Exosurf treatment, 6 hours after surfactant administration inhaled O2 concentration (FlO2) could be lowered from (0.72 +/- 0.20, to 0.62 +/- 0.33; P < 0.05), whereas Crs did not change (0.37 mL/cmH2O/kg, +/- 0.14 vs. 0.39 +/- 0.12, NS). After 24 hours and during the following days a significant increase in Crs occurred (24 hours post-Exosurf: 0.51 +/- 0.18, P < 0.05). With Curosurf treatment, the improvement in oxygenation was greater and FlO2 could be lowered much more after 6 hours (from FlO2, 0.78 +/- 0.23 to 0.34 +/- 0.11, P < 0.01). This was associated with an increase in Crs (from 0.39 +/- 0.09 to 0.59 +/- 0.17, P < 0.05). During the following days, Crs was significantly higher in the group treated with Curosurf. Resistance was not altered by the type of surfactant preparation used except after 72 hours, when Rrs increased in the group treated with Exosurf. In conclusion, Curosurf appears to be more effective than Exosurf with regard to immediate pulmonary changes in ventilator treated premature infants with RDS. A rapid increase in Crs after Curosurf treatment indicates that recruitment of new functional areas of the lung is likely to be associated with a stabilization of small airways and alveolar units.

Airway Resistance↗
PubMed1995

Assessment of the developmental toxicity of ethylene glycol applied cutaneously to CD-1 mice.

Ethylene glycol (EG; CAS No. 107-21-1) is teratogenic to mice by whole-body exposure to an aerosol at high concentrations, but results were confounded by possible exposure from ingestion after grooming and/or from percutaneous absorption. Therefore, CD-1 mice were exposed to EG on Gestational Days (GD) 6 through 15, 6 hr/day by occluded cutaneous application at 0, 12.5, 50, or 100% (undiluted) EG (0.1 ml/animal, equivalent to approximately 0, 404, 1677, or 3549 mg/kg/day [10 ml/kg, positive control gavage (PCGG)], 30 females/group. Dams were weighed and evaluated daily (including application site) for clinical signs and water consumption throughout gestation. On GD 18, maternal uterus, liver, and paired kidneys were weighed; kidneys of 0 and 100% and the PCGG were examined microscopically. Corpora lutea and implantation sites were recorded. Live fetuses were weighed, sexed, and examined for structural alterations. For cutaneously exposed dams, there was no treatment-related maternal, no differences in pre- or postimplantation loss in fetal body weights/litter, and no increased incidences of any fetal malformations. Two skeletal variations, increased at 100% may represent effects of restraint stress and/or findings due to chance. In the PCGG, 8 females (26.7%) died, water consumption was increased, fetal body weights/litter were reduced, and fetal malformations and variations were increased. PCGG kidneys exhibited tubular nephrosis and tubular cell degeneration, with no oxalate crystals, documenting renal toxicity at this oral dose in mice. Minimal-grade renal tubular lesions observed in 3 mice (of 30) at 100% EG may represent treatment-related or incidental findings. Therefore, exposure of pregnant CD-1 to 0, 12.5, 50 or 100% EG during organogenesis by occluded cutaneous application resulted in minimal or no observable maternal or developmental toxicity at 100% (approximately 3549 mg/kg/day), the NOEL.

Abnormalities, Drug-Induced↗
PubMed1996

Comparative short-term effects of methyl tertiary butyl ether and unleaded gasoline vapor in female B6C3F1 mice.

PS-6 unleaded gasoline (UG) and methyl tert-butyl ether (MTBE), an UG additive, with long-term exposure at high concentrations increased liver tumors selectively in female mice. PS-6 UG is a liver tumor promoter in N-nitrosodiethylamine-initiated female mice and produces short-term effects potentially relevant to its tumor promoting ability. The new formulation of UG (91-01) and MTBE were evaluated for similar short-term effects in mouse liver. Mice were exposed to 7814 ppm MTBE, 2014 ppm 91-01 UG, or 2028 ppm PS-6 UG vapor for 3 or 21 days, 6 hr/day, 5 day/week. Relative liver weights increased and uterine weights decreased in MTBE-, 91-01 UG-, and PS-6 UG-exposed mice. Because the decrease in relative uterine weight is suggestive of hormonal modulation, we evaluated the effects of MTBE, 91-01 UG, and PS-6 UG in vivo on hepatic 17-beta estradiol metabolism in vitro. Gavage treatment with either blend of UG and with MTBE increased estrogen metabolism in isolated mouse hepatocytes. Hepatic microsomal P450 activity was assessed by 7-pentoxyresorufin-O-dealkylase (PROD) and 7-ethoxyresorufin-O-deethylase (EROD) activities. Similar increases in P450 content and PROD and EROD activities were observed in all exposed mice as compared to controls. No hepatoxicity was observed in any treatment group. The hepatic labeling index, as measured by the incorporation of 5-bromo-2'-deoxyuridine, was increased in all exposed mice at 3 days but not 21 days, indicating that MTBE and 91-01 UG are also hepatic mitogens. These data demonstrate that a newer blend of UG and the UG additive MTBE elicit short-term effects similar to those of PS-6 UG. Given that these effects are potentially related to tumor promotion and the general lack of genotoxic activity, MTBE and 91-01 UG may exhibit tumor promoting activity similar to that seen with PS-6 UG. Since the liver is under multihormonal control, the increase in hepatic estrogen metabolism and uterine effects supports a potential role for endocrine modulations in both MTBE-and UG-induced hepatocarcinogenesis.

Administration, Inhalation↗
PubMed1997

Chloroform mode of action: implications for cancer risk assessment.

Risk assessment methodology, particularly pertaining to potential human carcinogenic risks from exposures to environmental chemicals, is undergoing intense scrutiny from scientists, regulators, and legislators. The current practice of estimating human cancer risk is based almost exclusively on extrapolating the results of chronic, high-dose studies in rodents to estimate potential risk in humans. However, many scientists are questioning whether the logic used in this current risk assessment methodology is the best way to safeguard public health. A major tool of human cancer risk assessment is the linearized multistage (LMS) model. The LMS model has been identified as an aspect of risk assessment that could be improved. One way to facilitate this improvement is by developing a way to incorporate a carefully derived, more biologically relevant mechanism of action data on carcinogenesis. Recent data on chloroform indicate that the dose-response relationship for chloroform-induced tumors in rats and mice is nonlinear, based upon events secondary to cell necrosis and subsequent regeneration as the likely mode of action for the carcinogenic effects of chloroform. In light of these data, there is a sound scientific basis for removing some of the uncertainty that accompanies current cancer risk assessments of chloroform. The following points summarize the critical data: (1) a substantial body of data demonstrates a lack of direct in vivo or in vitro genotoxicity of chloroform; (2) chloroform induces liver and kidney tumors in long-term rodent cancer bioassays only at doses that induce frank toxicity at these target sites; (3) the chloroform doses required to produce tumors in susceptible species exceed the MTD, often by a considerable margin; (4) cytotoxicity and compensatory cell proliferation are associated with the chloroform doses required to induce liver or kidney tumors in susceptible rodent species; (5) there are no instances of chloroform-induced tumors that are not preceded by this pattern of dose-dependent toxic responses; (6) it is biologically plausible that cytolethality leads to chronically stimulated cell proliferation and related events such as inflammation and growth stimulation which act to initiate and promote the carcinogenic process; and (7) the consistently linked cellular events of cytolethality and subsequent cell proliferation, for which doses of no adverse effect have been clearly shown to exist, are one of the biological prerequisites for chloroform-induced tumors in animals. Based on these data, it is inappropriate to extrapolate cancer risk from high doses that produce necrosis and regenerative cell proliferation to low doses that do not with a model that presumes genotoxicity and a linear dose-response relationship. The weight of the scientific evidence concerning chloroform-induced tumors in rodents is consistent with and supports a cancer risk assessment methodology based on mode of action as the basis for establishing regulatory standards for this compound.

Administration, Inhalation↗