ABSTRACT
This study presents a step-wise development of a quantitative pharmaceutical risk assessment (QPhRA, hereafter) framework, including Monte Carlo uncertainty analysis for meprobamate, carbamazepine, and phenytoin during (1) accidental exposures of stream water and fish consumption and (2) direct ingestion of finished drinking water for children and adults. Average hazard quotients of these pharmaceuticals (i.e., the ratio of values of chronic daily intake to acceptable daily intake) were found to lie between 1x10(-10) and 3x10(-5) and 99 th percentile values of hazard quotients were found to be less than 1x10(-4) for both sub-populations, indicating no potential risks of adverse effects due to pharmaceuticals exposures. In addition, pharmaceutical concentrations were also observed to be lower than their respective calculated acceptable daily intake-equivalent drinking water levels, indicating no potential human health risks. To the authors' knowledge, for the first time in QPhRA studies, this study has attempted to characterize and quantify effects of factors, such as considerations for sensitive sub-populations using subpopulation-specific toxic endpoints and use of pharmaceutical concentrations in stream and finished drinking waters on risk estimates. Acceptable daily intake was observed to be the primary contributor (>93% variance contribution) in the overall uncertainties of estimates of hazard quotients, followed by fish consumptions and pharmaceutical concentrations in water. Further research efforts are required to standardize use of acceptable daily intake values to reduce large variability in estimation of hazard quotients.
Subject(s)
Carbamazepine/toxicity , Environmental Exposure , Meprobamate/toxicity , Phenytoin/toxicity , Water Pollutants, Chemical/toxicity , Adolescent , Adult , Aged , Animals , Carbamazepine/analysis , Carbamazepine/pharmacokinetics , Child , Child, Preschool , Drinking , Endpoint Determination , Environmental Exposure/adverse effects , Environmental Exposure/analysis , Environmental Exposure/statistics & numerical data , Fishes/metabolism , Food Chain , Humans , Infant , Meprobamate/analysis , Meprobamate/pharmacokinetics , Middle Aged , No-Observed-Adverse-Effect Level , Phenytoin/analysis , Phenytoin/pharmacokinetics , Risk Assessment , Seafood/analysis , Uncertainty , Water Pollutants, Chemical/analysis , Water Pollutants, Chemical/pharmacokinetics , Young AdultABSTRACT
El objetivo de este trabajo es estudiar la actividad genética como inductores de recombinación mitótica y de delecciones, de dos medicamentos: meprobamato y pirimetamina, utilizando el ascomiceto Aspergillus nidulans como organismo de ensayo. Para el primer caso se utilizó una cepa diploide heterocigótica para marcadores del color de los conidios, y en el segundo caso, la cepa llevaba una duplicación de parte del genoma en el grupo de ligamento II. Para cada medicamento se probaron varias concentraciones diferentes; 6 para el meprobamato y 4 para la pirimetamina. Los resultados obtenidos indican que el meprobamato induce delecciones a las dosis de 10mM, 5mM y 2,5mM. La pirimetamina, a su vez, presentó un efecto positivo como inductora de recombinación mitótica a la dosis de 50*g/ml. Estos resultados indican que estos medicamentos, de amplio uso en nuestro país, presentan cierto tipo de actividad genética, detectada en las condiciones experimentales usadas por nosotros en este trabajo
Subject(s)
Pyrimethamine/toxicity , Meprobamate/toxicity , Aspergillus nidulans , Recombination, Genetic , Aspergillus nidulans/genetics , Chromosome DeletionABSTRACT
El objetivo de este trabajo es estudiar la actividad genética como inductores de recombinación mitótica y de delecciones, de dos medicamentos: meprobamato y pirimetamina, utilizando el ascomiceto Aspergillus nidulans como organismo de ensayo. Para el primer caso se utilizó una cepa diploide heterocigótica para marcadores del color de los conidios, y en el segundo caso, la cepa llevaba una duplicación de parte del genoma en el grupo de ligamento II. Para cada medicamento se probaron varias concentraciones diferentes; 6 para el meprobamato y 4 para la pirimetamina. Los resultados obtenidos indican que el meprobamato induce delecciones a las dosis de 10mM, 5mM y 2,5mM. La pirimetamina, a su vez, presentó un efecto positivo como inductora de recombinación mitótica a la dosis de 50*g/ml. Estos resultados indican que estos medicamentos, de amplio uso en nuestro país, presentan cierto tipo de actividad genética, detectada en las condiciones experimentales usadas por nosotros en este trabajo
Subject(s)
Aspergillus nidulans/drug effects , Aspergillus nidulans/genetics , Chromosome Deletion/drug effects , Meprobamate/toxicity , Pyrimethamine/toxicity , Recombination, Genetic/drug effectsABSTRACT
Tests set up on mice and rats brought evidence that spironolactone, progesterone, testosterone-propionate, methylandostendiol, desoxycorticosterone-acetate, methyltosterone, diethylstilbestrol, preparation PCN, megesterol-acetate and mestranol disply a catatoxic action, whose degree depends upon the method of evaluation and the animal species. A pattern for selection of catatoxic agents is proposed and some aspects of their mode of action are discussed.
Subject(s)
Steroids/pharmacology , Animals , Drug Interactions , Female , Liver/drug effects , Meprobamate/toxicity , Mice , Mice, Inbred Strains , Organ Size/drug effects , Rats , Sleep/drug effects , Species Specificity , Time FactorsSubject(s)
Tranquilizing Agents/therapeutic use , Adult , Ambulatory Care , Depression/drug therapy , Drug Combinations , Drug Evaluation , Ethanol/analysis , Ethanol/therapeutic use , Ethanol/toxicity , Female , Humans , Male , Meprobamate/therapeutic use , Meprobamate/toxicity , Methaqualone/therapeutic use , Methaqualone/toxicity , Middle Aged , Neurotic Disorders/drug therapy , Tranquilizing Agents/toxicitySubject(s)
Thiamine Deficiency/physiopathology , Analgesia , Animals , Appetite/drug effects , Body Weight/drug effects , Brain/metabolism , Chlordiazepoxide/pharmacology , Chlordiazepoxide/toxicity , Dextroamphetamine/pharmacology , Dextroamphetamine/toxicity , Lethal Dose 50 , Liver/metabolism , Male , Meprobamate/pharmacology , Meprobamate/toxicity , Mice , Mice, Inbred Strains , Morphine/pharmacology , Morphine/toxicity , Pentobarbital/toxicity , Phenobarbital/toxicity , Thiamine/metabolism , Time FactorsSubject(s)
Carbamates/toxicity , Mandelic Acids/toxicity , Meprobamate/toxicity , Parasympatholytics/toxicity , Phenobarbital/toxicity , Pyrrolidines/toxicity , Quaternary Ammonium Compounds/toxicity , Tranquilizing Agents/toxicity , Animals , Ataxia/chemically induced , Body Weight/drug effects , Catechols , Dogs , Feeding Behavior/drug effects , Female , Glycopyrrolate/toxicity , Hypothermia/chemically induced , Lethal Dose 50 , Male , Motor Activity/drug effects , Organ Size , Oxazoles/toxicity , Phenothiazines/toxicity , Piperazines/toxicity , Pupil/drug effects , Rats , Xerostomia/chemically inducedABSTRACT
The authors carried out long-term clinical and E.E.G. studies on 100 cases of acute drug poisoning. They made the following conclusions: - in unexplained coma, the E.E.G. can indicate toxic aetiology and may sometimes even suggest which drug is responsible, especially for certain chemical groups (barbiturates, phenothiasines, benzodiazepines); - the E.E.G. picture contributes a valuable indication of the depth of coma; the way in which it evolves affects the prognosis; - the effectiveness of therapy may be judged by monitoring cerebral electrical activity.
