RESUMEN
Solvent abuse during pregnancy may cause "fetal solvent syndrome", which is characterized by mild brain atrophy and associated with behavioral, cognitive, and emotional abnormalities. The present study investigated whether solvent inhalation during the preweaning period (P2-P21) alters the morphological maturation of frontal, parietal, and occipital cortical neurons. Twelve hours after delivery (postnatal day 0, P0), litters were cross-fostered, culled to 8 pups/dam and housed together with a dam in standard laboratory cages. Litters were randomly assigned to the "air-only" group (n=64, 8 litters) and to the "solvent-sniffer" group (n=72, 9 litters). During P2-P21, each animal was exposed daily to either organic solvent vapors (75% toluene and 18% n-hexane, a solvent mixture commonly found in glues and adhesives) or clean air. To determine the impact of early solvent inhalation on cortical neuronal differentiation, brains were stained using the Golgi-Cox-Sholl procedure to quantitatively assess neocortical pyramidal cell dendrogenesis. Preweaning, solvent-exposed animals displayed dramatic impairments in dendritic growth as well as significant reductions in brain weight and size.
Asunto(s)
Envejecimiento/patología , Envejecimiento/fisiología , Corteza Cerebral/crecimiento & desarrollo , Corteza Cerebral/patología , Hexanos/toxicidad , Neuronas/patología , Neuronas/fisiología , Tolueno/toxicidad , Administración por Inhalación , Envejecimiento/efectos de los fármacos , Animales , Corteza Cerebral/efectos de los fármacos , Combinación de Medicamentos , Femenino , Hexanos/administración & dosificación , Masculino , Ratas , Tolueno/administración & dosificaciónRESUMEN
Verapamil (VER) is commercialized as a racemic mixture of the (+)-(R)-VER and (-)-(S)-VER enantiomers. VER is biotransformed into norverapamil (NOR) and other metabolites through CYP-dependent pathways. N-hexane is a solvent that can alter the metabolism of CYP-dependent drugs. The present study investigated the influence of n-hexane (nose-only inhalation exposure chamber at concentrations of 88, 176, and 352 mg/m3) on the kinetic disposition of the (+)-(R)-VER, (-)-(S)-VER, (R)-NOR and (S)-NOR in rats treated with a single dose of racemic VER (10 mg/kg). VER and NOR enantiomers in rat plasma was analyzed by LC-MS/MS (m/z = 441.3 > 165.5 for the NOR and m/z 455.3 > 165.5 for the VER enantiomers) using a Chiralpak AD column. Pharmacokinetic analysis was performed using a monocompartmental model. The pharmacokinetics of VER was enantioselective in control rats, with higher plasma proportions of the (-)-(S)-VER eutomer (AUC(0-infinity) = 250.8 vs. 120.4 ng/ml/h; P < or = 0.05, Wilcoxon test). The (S)-NOR metabolite was also found to accumulate in plasma of control animals, with an S/R AUC(0-infinity) ratio of 1.5. The pharmacokinetic parameters AUC(0-infinity), Cl/F, Vd/F, and t(1/2) obtained for VER and NOR enantiomers were not altered by nose-only exposure to n-hexane at concentrations of 88, 176, or 352 mg/m3 (P > 0.05, Kruskal-Wallis test). However, the verapamil kinetic disposition was not enantioselective for the animals exposed to n-hexane at concentrations equal to or higher than the TLV-TWA. This finding is relevant considering that the (-)-(S)-VER eutomer is 10-20 times more potent than R-(+)-VER in terms of its chronotropic effect on atrioventricular conduction in rats and humans.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacocinética , Hexanos/administración & dosificación , Verapamilo/farmacocinética , Administración por Inhalación , Animales , Área Bajo la Curva , Interacciones Farmacológicas , Ratas , EstereoisomerismoRESUMEN
Urinary 2,5-hexanedione (2,5-HD) is used as a biomarker for biological monitoring of workers exposed to n-hexane. The purpose of this study was to compare two types of treatment of urine samples during clean-up (with and without acidic hydrolysis) and to study the exposure situation of workers exposed to n-hexane during shoe manufacturing. There, various glues containing n-hexane are used. Quantification of 2,5-HD was carried out by gas chromatography and flame ionization detection (GC-FID). Fifty-two urine samples taken from workers of seven shoe factories were analyzed. Thirty-four persons from the administrative staff of the same factories served as controls. They were not known to be exposed to n-hexane. The samples treated with acidic hydrolysis showed levels (average 0.94 mg/l) approximately 10 times higher than samples without acidic hydrolysis (0.09 mg/l). The difference is predominantly caused by the conversion of other metabolites of n-hexane (e.g. 4,5-dihydroxy-2-hexanone) to 2,5-HD in the presence of acids. Our results also show, that exposure to n-hexane is different between various industries. Levels of 2,5-HD in urine are predominantly dependent on the type of operation (how the glue is applied on the leather during shoe manufacturing). Simple measures, e.g. using a glue handgun instead of a paintbrush significantly decreased exposure to n-hexane.
Asunto(s)
Hexanos/administración & dosificación , Hexanonas/orina , Exposición Profesional , Brasil , Calibración , Cromatografía de Gases/métodos , Femenino , Humanos , Masculino , Control de Calidad , Sensibilidad y EspecificidadRESUMEN
Industrial organic solvents present in glue are among the common used psychotropic drugs in Brazil and perhaps worldwide; but few data are available concerning the toxic effects of glue sniffing, with almost no information about immunotoxicity. This seems interesting because several drugs and environmental chemicals are recognized as potential immunotoxicants. The present study investigated the effects of forced inhalation of a toluene/n-hexane 1:1 mixture on hamster resistance to Mycobacterium bovis. Adult hamsters were divided at random into 3 equal groups. Animals of Groups E and E inhaled the mixture of toluene/n-hexane twice daily for 37 d. Group C was placed for the same period of time in identical chambers free of solvents. Two days after the beginning of the experiment, Groups E and C were injected ip with 0.5 ml of an activated suspension of M. bovis; Group E received the same volume of a control solution. Hamsters inhaling the toluene/n-hexane mixture (E) exhibited increased weight loss, increased scores of M. bovis colony forming units isolated from liver, lung and spleen, increased granulomatous areas in the liver, lung and spleen. Inhalation of the toluene/n-hexane mixture for 37 d also increased serum cortisol compared to control hamsters. Tuberculosis is an infection with an intracellular bacterium in which sensitivity is determined mainly by host response. The present data demonstrated impaired defense against M. bovis in hamsters inhaling a toluene/n-hexane mixture for 37 d. Since macrophages are the architectural and functional units of the granulomas in tuberculosis, and no data were found about glue solvent effects on cellular immunity, the present data suggest an indirect effect of glue solvents on macrophage/lymphocyte activity via stress induction and central nervous system stimulation of hormonal (ACTH/cortisol) secretion and/or autonomic nervous system activity.
Asunto(s)
Hexanos/toxicidad , Sistema Inmunológico/efectos de los fármacos , Infecciones por Mycobacterium/inmunología , Mycobacterium bovis/efectos de los fármacos , Solventes/toxicidad , Tolueno/toxicidad , Animales , Cámaras de Exposición Atmosférica , Peso Corporal/efectos de los fármacos , Cricetinae , Hexanos/administración & dosificación , Hígado/efectos de los fármacos , Pulmón/efectos de los fármacos , Masculino , Mesocricetus , Infecciones por Mycobacterium/patología , Mycobacterium bovis/inmunología , Solventes/administración & dosificación , Bazo/efectos de los fármacos , Trastornos Relacionados con Sustancias , Tolueno/administración & dosificaciónRESUMEN
La inhalación de solventes orgánicos volátiles (en especial el contenido en pegamentos) es una práctica frecuentemente observada en niños pertenecientes a estratos socioeconómicos y culturales deprivados. Evidencias clínicas hans demostrado que los adictos a estas sustancias psicotrópicas, sufren marcados trastornos conductuales, potenciados por grados variables de alcoholismo, desnutrición, etc. Tales influencias adversas, resultan difíciles de aislar clínicamente. El objetivo del presente estudio fue evaluar experimentalmente los probables efectos negatios que produce la inhalación crónica de solventes volátiles, realizada durante el período crítico del desarrollo, sobre la oncogenia cerebral y conductual. 64 ratas albinas de la cepa Sprague-Dawley fueron expuestas a inhalación de tolueno y hexano (contenidos en pegamentos) entre los días postnatales 2 y 21. La dosis fue determinada (previa estandarización realizada en estudio piloto) por el tiempo de inhalación, el tamaño de la superficie de emanación y frecuencia de exposiciones diarias. Se estudió la oncogenia de conductas neuromotoras básicas conjuntamente con mediciones encefálicas macroscópicas (peso cerebral y cerebeloso, diámetros cerebrales). Los resultados obtenidos indican que los sujetos expuestos al solvente presentan grados variables de retraso, tanto a nivel conductual (natación, geotaxia negativa, trepa en cuerda, reacción de apoyo, coordinación-equilibrio, evitación de precipicio y exploratividad en campo abierto) como cerebral (peso y diámetros cerebrales)