RESUMO
In the rat, some aromatic solvents cause a high level of ototoxicity that is characterized by damage to outer hair cells in the cochlea, which results in irreversible hearing loss. However, there is a vast difference in their potency. Among the three isomers of xylene, only para-xylene has been shown to be ototoxic in the rat. Moreover, all the species do not show the same susceptibility to ototoxic solvents, the rat being the most susceptible and the guinea pig seeming resistant to this ototoxic effect. The objective of the study was to determine whether toxicokinetic factors could explain the differences in ototoxicity observed among the three isomers of xylene in the rat and the species-dependent ototoxicity in the rat and the guinea pig. Blood and brain concentrations of each isomer were monitored in Sprague-Dawley rats treated orally by gastric intubation with a single dose or a 10 day-repeated treatment of 8.47 mmol/kg (an ototoxic dosage for para-xylene) of each isomer. Moreover, histology of the cochlea was carried out and the toxicokinetics of meta-xylene was monitored in rats treated with a single dose or a 10 day-repeated treatment of 16.94 mmol/kg meta-xylene, a non-ototoxic isomer. Similarly, histology of the cochlea was carried out and the toxicokinetics of para-xylene was followed in guinea pigs treated by gavage with a single dose or a 10 day-repeated treatment of 8.47 mmol/kg para-xylene. Finally, the blood and brain concentrations of para-xylene were measured in both the rats and the guinea pigs after a 4-h exposure to 1800 ppm of para-xylene. Among the three isomers studied, para-xylene yielded the highest blood and brain concentrations in the acutely and repeatedly exposed rats. When given a high dosage of meta-xylene (16.94 mmol/kg), the rats showed blood and brain concentrations of meta-xylene in the same order as those obtained with 8.47 mmol/kg para-xylene, but no outer hair cell loss was observed. No outer hair cell loss was observed in the guinea pigs treated with para-xylene. Whatever the exposure pattern, the blood and brain concentrations of para-xylene in the rats were 3.1-9.5 times higher than those measured in the guinea pigs. These results indicate that toxicokinetic factors cannot explain the differences in ototoxicity observed with the three isomers in the rat. However, they suggest that the differences in susceptibility to para-xylene observed between the rats and the guinea pigs might be due to toxicokinetic factors.
Assuntos
Cóclea/efeitos dos fármacos , Solventes/farmacocinética , Xilenos/farmacocinética , Animais , Cóclea/metabolismo , Cóclea/patologia , Relação Dose-Resposta a Droga , Células Ciliadas Auditivas Internas/efeitos dos fármacos , Células Ciliadas Auditivas Internas/metabolismo , Células Ciliadas Auditivas Internas/patologia , Células Ciliadas Auditivas Externas/efeitos dos fármacos , Células Ciliadas Auditivas Externas/metabolismo , Células Ciliadas Auditivas Externas/patologia , Exposição por Inalação , Isomerismo , Masculino , Ratos , Ratos Sprague-Dawley , Solventes/química , Solventes/toxicidade , Relação Estrutura-Atividade , Xilenos/química , Xilenos/toxicidadeRESUMO
At present, there is controversy over the neurotoxic potential of styrene. Several epidemiological and clinical studies have shown that styrene exposure causes alterations of central nervous system functions in humans. Neurotransmitters have been implicated in the pathogenesis of styrene neurotoxicity in rodents. Several studies carried out on postmortem brain tissue suggest that styrene may alter dopaminergic neurotransmission in rabbit or rat brain. Moreover, in vitro studies suggest that both styrene and styrene oxide inhibit the uptake of dopamine (DA) in purified synaptic vesicles prepared from rat brain striata. To date, biochemical studies on animals have explored global tissue levels of neurotransmitters with sub-acute exposures to styrene. However, extracellular levels of neurotransmitters are more closely related to behaviour than are global tissue levels. The present study determined changes in the extracellular concentrations of DA, serotonin (5-HT) and their acid metabolites, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA), in striatal dialysates from freely moving adult male rats after exposure to 750 and 1,000 ppm styrene, 6 h per day, 5 days per week for 4 weeks. We also determined the concentrations of DA, 5-HT and their acid metabolites in striatum, nucleus accumbens and prefrontal cortex obtained postmortem from similarly exposed rats. Exposure to 1,000 ppm of styrene caused a significant decrease in extracellular acid metabolite concentrations. Tissue levels of acid metabolites were also decreased to a lesser extent. The effects were observed 72 h after discontinuing exposure but had vanished 17 days later. There was no change in DA or 5-HT concentrations either in the dialysates or tissues. Exposure to 750 ppm styrene caused no changes in the concentrations of DA, 5-HT and their acid metabolites either in the dialysates or tissues. The possibility that the effect of styrene is mediated by monoamine oxidase (MAO) inhibition is discussed.
Assuntos
Poluentes Atmosféricos/toxicidade , Encéfalo/efeitos dos fármacos , Dopamina/metabolismo , Exposição por Inalação , Serotonina/metabolismo , Estireno/toxicidade , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Ácido Homovanílico/metabolismo , Ácido Hidroxi-Indolacético/metabolismo , Masculino , Microdiálise , Movimento/fisiologia , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
Male Sprague-Dawley rats were exposed to ortho-, meta- or para-xylene by inhalation (450, 900 and 1,800 p.p.m., 6 hr/day, 6 days/week for 13 weeks) and sacrificed for morphological investigations 8 weeks after the end of exposure. Brainstem auditory-evoked responses were used to determine auditory thresholds at different frequencies. Among the three isomers studied, only para-xylene produced moderate to severe ototoxicity in rats exposed at 900 and 1,800 p.p.m. Increased auditory thresholds were observed at 2, 4, 8 and 16 kHz in rats exposed to 1800 p.p.m. para-xylene. The auditory threshold shifts (35 to 38 dB) did not reverse after 8 weeks of recovery Moderate and severe losses of outer hair cells of the organ of Corti occurred in animals exposed to 900 and 1800 p.p.m. para-xylene respectively. Thus, the no observed effect level of para-xylene was 450 p.p.m. based on the loss of outer hair cells observed by light and electron microscopy.
Assuntos
Potenciais Evocados Auditivos/efeitos dos fármacos , Células Ciliadas Auditivas/efeitos dos fármacos , Xilenos/toxicidade , Administração por Inalação , Animais , Câmaras de Exposição Atmosférica , Audiometria , Isomerismo , Masculino , Microscopia Eletrônica de Varredura , Ratos , Ratos Sprague-Dawley , Xilenos/administração & dosagemRESUMO
Brainstem auditory and visual evoked-potentials were studied in male Sprague-Dawley rats during subchronic oral treatment with three unsaturated aliphatic nitriles. The rats were given, by gastric intubation, doses of 10, 20 and 40 mg x kg(-1) 3-butenenitrile (allyl cyanide) and 25, 50 and 100 mg x kg(-1) of either cis/trans-2-butenenitrile (crotononitrile) or cis-2-pentenenitrile once a day, 5 days per week for 12 weeks. Oral administration of the three unsaturated nitriles produced deafness and absence of reaction when the animals were subject to droptest. Rats in the high dosage groups exhibited a complete disappearance of the five waves of the auditory evoked-potentials. There was a decrease in the amplitudes of the 2nd component of the auditory evoked-potentials. Those changes were not reversible at the 8th week of the recovery period. A dose-dependent effect on inner and outer hair cells was observed in the organ of Corti. The basal part of the cochlea was the most affected. Though no measurements were made of systemic exposure, a tentative ranking of decreasing ototoxicity of these three unsaturated nitriles might be proposed based on the electrophysiological deficiencies and histological losses observed: 3-butenenitrile >cis-2-pentenenitrile >cis/trans-2-butenenitrile. Moreover, rats treated with those nitriles showed a corneal opacity as well as a decrease in the amplitude and lengthening of the peak latencies of the visual evoked-potentials. These latter changes were reversible by the end of the 8th week of the recovery period and appeared to be related to the opacity of the cornea.
Assuntos
Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Potenciais Evocados Visuais/efeitos dos fármacos , Nitrilas/toxicidade , Solventes/toxicidade , Administração Oral , Animais , Relação Dose-Resposta a Droga , Masculino , Nitrilas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Solventes/administração & dosagemRESUMO
Motor and sensory conduction velocities and amplitudes of the sensory and motor action potentials of the tail nerve were studied in male Sprague-Dawley rats during subchronic oral treatment with three unsaturated aliphatic nitriles. The rats were given, by gastric intubation, doses of 10, 20 and 40 mg x kg(-1) 3-butenenitrile (allyl cyanide) and 25, 50 and 100 mg x kg(-1) of either cis/trans-2-butenenitrile (crotononitrile) or cis-2-pentenenitrile once a day, 5 days per week for 12 weeks. Moreover, 3,3'-iminodipropionitrile was administered likewise at doses of 25, 50 and 100 mg x kg(-1) as reference neurotoxicant. Oral administration of the three unsaturated nitriles produced deafness and absence of reaction when the animals were subject to droptest. Moreover, rats exhibited both time- and concentration-dependent decreases in motor and sensory conduction velocities and amplitudes of the sensory action potentials. Nerve conduction velocities were partially reversible after 8 weeks of recovery. Rats receiving 3,3'-iminodipropionitrile developed deafness, head weaving and significant irreversive deficiencies in all the electrophysiological parameters studied. Further toxicological studies with related unsaturated nitriles should be carried out to determine the potential importance of the cis/trans isomerism in the observed neurotoxicity.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Surdez/induzido quimicamente , Condução Nervosa/efeitos dos fármacos , Nitrilas/toxicidade , Nervos Periféricos/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Eletrofisiologia , Masculino , Nervos Periféricos/fisiologia , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Fatores de TempoRESUMO
Motor and sensory conduction velocities (MCV and SCV) and amplitudes of the sensory and motor action potentials (ASAP and AMAP) of the tail nerve were studied in male Sprague-Dawley rats during chronic oral treatment with five unsaturated aliphatic nitriles. Rats were given doses of 12.5, 25 and 50 mg kg(-1) of acrylonitrile, 50, 70 and 90 mg kg(-1) of methacrylonitrile, 25, 50 and 100 mg kg(-1) of trans-3-pentenenitrile and 50, 100 and 200 mg kg(-1) of either 3-methyl-2-butenenitrile or 4-pentenenitrile once a day, 5 days per week for 12 weeks. Moreover, due the the early results obtained after oral treatment, neurophysiological examinations were also carried out in rats exposed by inhalation to 25, 50 and 100 ppm of acrylonitrile for 6 h a day, 5 days per week for 24 weeks. Rats given acrylonitrile orally developed behavioural sensitization characterized by salivation, locomotor hyperactivity and moderately intense stereotypies. Moreover, rats in the high dose group developed weakness in hindlimbs associated with decreases in SCV and ASAP. Rats exposed to acrylonitrile vapours exhibited time- and concentration-dependent decreases in MCV, SCV and ASAP, which were partially reversible after 8 weeks of recovery. None of the other four nitriles caused any abnormal behaviour or any changes in the electrophysiological parameters in spite of an obvious general toxicity. Based upon these results, it can be concluded that the nervous system of the rat appears to be a target following either oral or inhalation exposures of acrylonitrile.
Assuntos
Nitrilas/toxicidade , Nervos Periféricos/efeitos dos fármacos , Acrilonitrila/administração & dosagem , Acrilonitrila/toxicidade , Administração por Inalação , Administração Oral , Animais , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Eletrofisiologia , Membro Posterior/efeitos dos fármacos , Membro Posterior/inervação , Hipercinese/induzido quimicamente , Masculino , Metacrilatos/administração & dosagem , Metacrilatos/toxicidade , Atividade Motora/efeitos dos fármacos , Nitrilas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Salivação/efeitos dos fármacos , Comportamento Estereotipado/efeitos dos fármacos , Relação Estrutura-Atividade , Cauda/efeitos dos fármacos , Cauda/inervação , Fatores de TempoRESUMO
The role of tachykinins in toluene diisocyanate (TDI)-induced non-specific bronchial hyperreactivity (NSBH) in guinea pigs was investigated, and it was determined whether or not the activity of airway neutral endopeptidase (NEP) was inhibited in conditions where a bronchial hyperreactivity to acetylcholine (ACh) was observed. Exposures to 3 ppm TDI for 1 h, or to 0.029 ppm for 8 weeks caused a significant bronchial hyperreactivity to ACh. The depletion of tachykinins by a pretreatment with capsaicin (140 mg/kg) eliminated the TDI-induced airway hyperresponsiveness in both patterns of exposure to TDI. Capsaicin treatment had no effect on the response to ACh in guinea-pigs exposed to air (controls). Bronchial NEP activity determined by histoenzymology was significantly less 4 and 24 h after the end of a 1-h exposure to 3 ppm TDI than after exposure to air. Bronchial NEP activity evaluated 24 h after the end of a 48-h exposure to 0.116 ppm TDI, or a 1-week exposure to 0.050 ppm TDI was not significantly different from those of controls exposed to air, whereas in the same conditions of exposure a NSBH is observed in guinea-pigs. These data suggest that tachykinins released from C-fibers upon acute or repeated exposures to high or low concentrations of TDI, respectively, play an essential role in the observed bronchial hyperreactivity, and that the inhibition of NEP by TDI cannot completely account for the observed airway hyperreactivity.
Assuntos
Hiper-Reatividade Brônquica/induzido quimicamente , Hiper-Reatividade Brônquica/fisiopatologia , Neprilisina/metabolismo , Taquicininas/fisiologia , Tolueno 2,4-Di-Isocianato/toxicidade , Animais , Hiper-Reatividade Brônquica/enzimologia , Capsaicina/farmacologia , Relação Dose-Resposta a Droga , Feminino , Cobaias , Neprilisina/antagonistas & inibidores , Taquicininas/metabolismoRESUMO
The question of whether or not toluene diisocyanate (TDI)-induced airway hyperresponsiveness in the guinea-pig is accompanied by neutrophil influx into bronchoalveolar lavage fluid (BALF) was addressed. Two modes of exposure were studied; (1) acute exposures where animals were exposed to 3 ppm TDI for 1 h and experiments were carried out 30 min, 4 h, 24 h, 48 h and 1 week after the TDI exposures; (2) subacute exposures where animals were exposed to 0.080 and 0.046 ppm TDI for 48 h 1 week, respectively, and experiments were carried out 24 h after the TDI exposures. The changes in airway responsiveness to increasing doses of intravenous acetylcholine (ACh) in anaesthetized and tracheotomized spontaneously breathing guinea-pigs were examined. In order to elucidate the possible relationships of airway responsiveness to cellular infiltration, bronchoalveolar lavage was performed in additional group of guinea-pigs exposed to the same conditions. After acute exposure to 3 ppm TDI, increased bronchial responsiveness was evident within 30 min, lasted 48 h, but had vanished 1 week after the exposure. An influx of neutrophils occurred into the BALF within 1 h after exposure. The influx of neutrophil into BALF lasted 48 h and vanished 1 week after the end of exposure. After 48 h of exposure to TDI at 0.080 ppm, or 0.046 ppm for 1 week, increased bronchial responsiveness was evident 24 h after the end of the both modes of exposure, but no influx of neutrophils was observed into the BALF. It was concluded that even though the neutrophil influx and hyperresponsiveness evolve in the same way after acute exposure to a high concentration of TDI (3 ppm), this is not the case after subchronic exposure to low concentrations of TDI, where a bronchial hyperresponsiveness is observed without detectable neutrophil influx.
Assuntos
Brônquios/efeitos dos fármacos , Hiper-Reatividade Brônquica/induzido quimicamente , Inflamação/induzido quimicamente , Neutrófilos/efeitos dos fármacos , Tolueno 2,4-Di-Isocianato/toxicidade , Acetilcolina/administração & dosagem , Administração por Inalação , Animais , Líquido da Lavagem Broncoalveolar/citologia , Feminino , Cobaias , Neutrófilos/fisiologia , Fatores de Tempo , Tolueno 2,4-Di-Isocianato/administração & dosagemRESUMO
The expiratory bradypnoea indicative of upper airway irritation in mice was evaluated during a 60-min oronasal exposure to increasing concentrations of chlorine and nitrogen trichloride. The airborne concentration resulting in a 50% decrease in the respiratory rate of mice (RD50) was calculated for each chemical. Chlorine and nitrogen trichloride showed dissimilar concentration-response curves. While the maximal response of nitrogen trichloride was reached in 10 min, the maximal response of chlorine was reached between 45 and 60 min of exposure. The results showed both chemicals to have an irritant potency of the same order of magnitude. The RD50 values of chlorine and nitrogen trichloride were 3.5 and 2.5 ppm, respectively. On the basis of a TLV-STEL (threshold limit value for short-term exposure limit) equal to 0.1 RD50 and a TLV-TWA (time-weighted average) equal to 0.03 RD50, the current TLVs for chlorine seem too high (1 and 0.5 ppm, respectively) and should be reduced to 0.5 and 0.1 ppm, respectively. For nitrogen trichloride, 0.3 ppm and 0.1 ppm are proposed as TLV-STEL and TLV-TWA, respectively.
Assuntos
Cloretos/toxicidade , Cloro/toxicidade , Irritantes/toxicidade , Compostos de Nitrogênio/toxicidade , Respiração/efeitos dos fármacos , Administração por Inalação , Animais , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos EndogâmicosRESUMO
A concentration-dependent expiratory bradypnea, indicative of sensory irritation, occurred during a 15-min oronasal exposure of mice to glutaraldehyde in the concentration range of 0.7-4.5 ppm. The level of exposure which led to a 50% decrease in the respiratory rate (RD50) was found to be 2.6 ppm. For assessment of nasal toxicity, mice were exposed to glutaraldehyde vapours with concentrations of 2.6, 1.0, 0.3 ppm for periods of 6 h/day over the course of 4, 9 and 14 days and were immediately killed. Recovery was studied with another group of mice exposed to 1.0 ppm for 14 days and sacrificed after 1, 2 and 4 weeks rest time. Control groups were concurrently exposed to clean filtered air. The earliest lesions were observed in the respiratory epithelium of the septum, the naso- and maxilloturbinates, after 4 days of exposure to 0.3 ppm. Severe histopathological changes were still observed 2 weeks after the end of the exposure to 1.0 ppm. No exposure-related histological abnormalities were detected in the trachea and lungs. In conclusion, this experiment demonstrates that repeated exposure to 1/10 RD50 is associated with upper respiratory tract damage in mice, and this value does not seem to be an acceptable concentration limit for occupational exposure.
Assuntos
Glutaral/toxicidade , Pulmão/efeitos dos fármacos , Cavidade Nasal/efeitos dos fármacos , Administração por Inalação , Animais , Relação Dose-Resposta a Droga , Glutaral/administração & dosagem , Pulmão/patologia , Masculino , Camundongos , Cavidade Nasal/patologia , Necrose , Respiração/efeitos dos fármacos , Conchas Nasais/efeitos dos fármacos , Conchas Nasais/patologiaRESUMO
1,2,4-Triethylbenzene (1,2,4-TEB) and 1,3,5-triethylbenzene (1,3,5-TEB) were administered orally to male Sprague-Dawley rats. Experimental and appropriate control rats were examined electrophysiologically for motor and sensory conduction velocities (MCV and SCV), and the amplitudes of the sensory (ASAP) and muscular action potentials (AMAP), at bi-weekly intervals. Oral administration of 1,2,4-TEB (200 or 400 mg kg-1, once daily, 4 days per week for 8 weeks) produced a time- and dose-dependent decrease in MCV, SCV, AMAP and ASAP. Rats treated with 1,2,4-TEB exhibited a bluish discoloration of the skin and the urine was greyish-greenish. No changes in MCV, SCV, AMAP and ASAP developed in rats given 1,3,5-TEB orally (200 or 400 mg kg-1, daily, 4 days per week for 8 weeks). The results indicate that 1,2,4-TEB is a neurotoxic isomer of TEB and that the presence of two ethyl radicals in the ortho-position on an aromatic ring could be a critical molecular arrangement resulting in chromogenic and neurotoxic properties.
Assuntos
Derivados de Benzeno/toxicidade , Doença dos Neurônios Motores/induzido quimicamente , Doenças do Sistema Nervoso/induzido quimicamente , Neurônios Aferentes/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Estimulação Elétrica , Eletrofisiologia , Isomerismo , Masculino , Doença dos Neurônios Motores/fisiopatologia , Doenças do Sistema Nervoso/fisiopatologia , Condução Nervosa/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Cauda/fisiologiaRESUMO
The expiratory bradypnea indicative of upper airway irritation in mice was evaluated during a 15-min oronasal exposure to increasing concentrations of sixteen aliphatic amines. The airborne concentration resulting in a 50% decrease in the respiratory rate of mice (RD50) was calculated for each test compound. Moreover, the sixteen amines were tested for pulmonary irritation by measuring the decrease in respiratory rate of (non-anaesthetized) tracheally cannulated mice (RD50 TC). The RD50 and RD50 TC values and their ratios were related to n-octanol/water partition coefficients (log P). The RD50 values associated with exposure to saturated amines ranged from 17 to 300 ppm. The RD50TC values for these saturated amines ranged from 35 to 489 ppm. The RD50 and RD50TC values of saturated amines were closely related to the n-octanol/water partition coefficient, indicating that the more lipophilic amines are more irritant for the upper and lower respiratory tracts. The RD50TC/RD50 values were much less closely related to the n-octanol/water partition coefficient. Based on the results, tentative standards are suggested for the studied amines.
Assuntos
Aminas/toxicidade , Irritantes/toxicidade , Pneumopatias/induzido quimicamente , Neurônios Aferentes/efeitos dos fármacos , Administração por Inalação , Ar/análise , Animais , Fenômenos Químicos , Físico-Química , Lipídeos/química , Pneumopatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos , Mucosa Nasal/efeitos dos fármacos , Análise de Regressão , Relação Estrutura-Atividade , Fatores de TempoRESUMO
Male Sprague-Dawley rats were treated either with 1,2-diethylbenzene (1,2-DEB) or its putative active metabolite, 1,2-diacetylbenzene (1,2-DAB). Experimental rats and appropriate controls were examined electrophysiologically for brainstem auditory evoked potentials (BAEP). Oral administration of 1,2-DEB (75 or 100 mg kg-1 once a day, 4 days a week, for 8 weeks) and intraperitoneal injection of 1,2-DAB (10 or 15 mg kg-1 once a day, 4 days a week, for 8 weeks) produced time- and dose-dependent increases in the peak latencies of all BAEP components as well as in interpeak (I-V) differences, and a decrease in the amplitudes of all the components. The absolute and interpeak latencies recovered partially during an 8-week (1,2-DEB) or a 10-week (1,2-DAB) recovery period, whereas there were long-lasting decreases in peak amplitudes.
Assuntos
Acetofenonas/toxicidade , Derivados de Benzeno/toxicidade , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Administração Oral , Animais , Doenças do Sistema Nervoso Central/induzido quimicamente , Doenças do Sistema Nervoso Central/fisiopatologia , Relação Dose-Resposta a Droga , Injeções Intraperitoneais , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
Motor and sensory conduction velocities (MCV and SCV), amplitude of the sensory action potential (ASAP) of the tail nerve and parameters of brainstem auditory evoked potentials (BAEP) were studied in male Sprague-Dawley rats after prolonged inhalation exposure to a commercial isomer mixture of diethylbenzene (DEB mixture) containing 6% 1,2-DEB. The MCV, SCV and ASAP were studied in one control group (10 rats) and three groups of 12 rats exposed to 500, 700 or 900 ppm DEB mixture for 6 h daily, 5 days per week, for 18 weeks. Rats used for recording BAEP (one control group and two other groups of 15 rats) were exposed to 600 and 800 ppm DEB mixture. The exposure time was the same. Rats exposed to DEB mixture exhibited a time- and concentration-dependent decrease in MCV, SCV and ASAP and a time- and concentration-dependent increase of both the peak latencies of all BAEP components and the interpeak (I-V) differences.
Assuntos
Derivados de Benzeno/toxicidade , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Administração por Inalação , Animais , Doenças do Sistema Nervoso Central/induzido quimicamente , Doenças do Sistema Nervoso Central/fisiopatologia , Relação Dose-Resposta a Droga , Eletrofisiologia , Masculino , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/fisiologia , Neurônios Aferentes/efeitos dos fármacos , Neurônios Aferentes/fisiologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Desempenho Psicomotor/efeitos dos fármacos , Desempenho Psicomotor/fisiologia , Ratos , Ratos Sprague-Dawley , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologiaRESUMO
The role of 1,2-diacetylbenzene (1,2-DAB) in the peripheral nerve toxicity of 1,2-diethylbenzene (1,2-DEB) was investigated in rats. Gas chromatography-mass spectrometry identified 1,2-DAB in the urine samples of rats given 165 mg kg-1 1,2-DEB orally on four consecutive days. 1,2-DAB shared not only the ability of 1,2-DEB to cause bluish discoloration of skin, internal organs and urine, but unlike 1,2-DEB it turned hair blue at the site of intraperitoneal injection. Intraperitoneal administration of 10 mg kg-1 and 20 mg kg-1 1,2-DAB to groups of 12 rats, 4 days a week for 11 and 6 weeks, caused a dose- and time-dependent decrease in mean sensory and motor conduction velocities. Recovery in a 5-week post-exposure period was gradual but consistent. The effect of 1,2-DAB on the amplitude of the sensory action potential was ambiguous. The findings support the hypothesis that the formation of 1,2-diacetylbenzene derivatives contributes to the neurotoxicity of 1,2-DEB.
Assuntos
Acetofenonas/toxicidade , Derivados de Benzeno/toxicidade , Doenças do Sistema Nervoso/induzido quimicamente , Acetofenonas/urina , Potenciais de Ação/efeitos dos fármacos , Animais , Derivados de Benzeno/urina , Estimulação Elétrica , Cromatografia Gasosa-Espectrometria de Massas , Injeções Intraperitoneais , Masculino , Neurônios Motores/efeitos dos fármacos , Doenças do Sistema Nervoso/fisiopatologia , Condução Nervosa/efeitos dos fármacos , Neurônios Aferentes/efeitos dos fármacos , Ratos , Ratos EndogâmicosRESUMO
The commercial isomer mixture of diethylbenzene (DEB mixture), 1,2-diethylbenzene (1,2-DEB), 1,3-diethylbenzene (1,3-DEB) and 1,4-diethylbenzene (1,4-DEB) were administered orally to male Sprague-Dawley rats. The experimental rats and the appropriate controls were examined electrophysiologically for motor and sensory conduction velocities (MCV and SCV), and for the amplitude of the sensory action potential (ASAP) of the tail nerve, at weekly or bi-weekly intervals. Oral administration of DEB mixture (750 or 500 mg kg-1, once daily, 5 days per week for 10 weeks) and 1,2-DEB (100 mg kg-1, once daily, 4 days per week for 8 weeks) produced a time-dependent decrease in MCV, SCV and ASAP. Rats treated with DEB mixture and 1,2-DEB exhibited a blue discoloration of tissues and urine. No changes in MCV, SCV and ASAP developed in rats administered orally with 1,3-DEP and 1,4-DEB (500 mg kg-1, once daily, 5 days per week for 8 weeks). The results indicate that 1,2-DEB is the isomer responsible for neurotoxicity and suggest that a metabolic pathway giving rise to coloured compounds is involved in the neurotoxicity of DEB.
Assuntos
Derivados de Benzeno/toxicidade , Doenças do Sistema Nervoso/induzido quimicamente , Animais , Masculino , Condução Nervosa/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Ratos , Ratos Endogâmicos , EstereoisomerismoRESUMO
The expiratory bradypnoea indicative of upper airway irritation in mice was evaluated during a 15-min oronasal exposure to increasing concentrations of twenty aliphatic amines. The airborne concentration resulting in a 50% decrease in the respiratory rate of mice (RD50) was calculated for each test compound. Moreover, eight out of the twenty amines were tested for pulmonary toxicity in mice and for the effects of a 120-min exposure on the respiratory rates of non-anaesthetized, tracheally cannulated mice (RD50TC). Both allylamine and diallylamine showed RD50 values of 9 ppm and 4 ppm, respectively, while the RD50 values associated with exposure to saturated amines ranged from 50 to 200 ppm. Among the eight amines tested for both upper airway irritation and pulmonary toxicity, diisopropylamine and di-n-butylamine showed a RD50TC/RD50 ratio of less than 1, indicating that the respiratory toxicity induced by these two amines would be related primarily to pulmonary effects. On the basis of prior predictions proposed for upper airway irritants, tentative standards are given for ten amines. Moreover, it is suggested that the basis of standards for industrial exposure to diisopropylamine and di-n-butylamine should be specified.
Assuntos
Aminas/toxicidade , Pneumopatias/induzido quimicamente , Mucosa Nasal/efeitos dos fármacos , Animais , Irritantes/toxicidade , Masculino , Camundongos , Análise de Regressão , Doenças Respiratórias/induzido quimicamenteRESUMO
This paper deals with the conversion of the hepatotoxicity of 1,2-dichlorobenzene (DCB), the nephrotoxicity of hexachloro-1,3-butadiene (HCBD) and the respiratory effects of these two toxicants into quantal data. It aims to provide some useful information on the best strategy used for safety evaluation. A reflex bradypnea indicative of irritation of the nasal cavities of mice occurred during a 15-min oronasal exposure to each chemical. A reduction in the development of staining for liver glucose-6-phosphatase (G6-phosphatase) and an increase in the number of damaged tubules in cryostat kidney sections stained for alkaline phosphatase were the measure of toxicity in mice subjected to a whole-body 4-h exposure to DCB and HCBD vapours, respectively. The immediate irritant responses, as well as the delayed liver and kidney responses, were measured at the peak of the chemical's action. These maximum responses were then used to establish the relationships of exposure level effects and also the median active levels of exposure (MALs). The DCB and HCBD MALs responsible for a 50% decrease in the respiratory rate of mice (RD50) were 181 and 211 ppm, respectively. The MAL required for eliciting a 50% decrease in G6-phosphatase staining intensity in DCB-exposed mice was 598 ppm and that associated with 50% of damaged tubules in HCBD-exposed mice was 7.2 ppm. On the basis of these quantitative data, potency ratios indicated that irritation and kidney injury are the primary manifestations of toxicity associated with short-term exposure to DCB and HCBD, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Poluentes Atmosféricos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Irritantes/toxicidade , Nefropatias/induzido quimicamente , Fosfatase Alcalina/análise , Animais , Butadienos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Clorobenzenos/toxicidade , Glucose-6-Fosfatase/análise , Histocitoquímica , Nefropatias/enzimologia , Masculino , Camundongos , Sistema Respiratório/efeitos dos fármacosRESUMO
We examined the changes in airway responsiveness to increasing doses of intravenous acetylcholine (ACh), in groups of 10 anaesthetized and tracheotomized spontaneously breathing guinea-pigs, 20 h after inhalation exposure to toluene diisocyanate (TDI). TDI exposure consisted of a single 4-h exposure to 1.2 ppm, intermittent exposures to 1.078 and 0.126 ppm for 4 h daily for 2 consecutive days, and continuous exposures to 0.118 ppm for 48 h or to 0.045 and 0.023 ppm for 1 week. Airway resistance (Raw) of the corresponding control groups, which inhaled clean filtered air, was used as baseline, and was similar for air and TDI groups. All the patterns of exposure, except exposure to 0.126 ppm TDI for 4 h daily for 2 consecutive days, significantly reduced by 28-60% the dose of ACh calculated to cause a 200% increase in Raw (ED200). The results indicate that TDI-induced airway hyperresponsiveness to ACh in guinea-pigs can occur at a level of exposure as low as 0.023 ppm for 1 week, and is consistent with the hypothesis of a cumulative effect.
Assuntos
Acetilcolina/farmacologia , Resistência das Vias Respiratórias/efeitos dos fármacos , Cianatos/toxicidade , Tolueno 2,4-Di-Isocianato/toxicidade , Acetilcolina/administração & dosagem , Administração por Inalação , Animais , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Feminino , Cobaias , Pletismografia , Tolueno 2,4-Di-Isocianato/administração & dosagemRESUMO
A concentration-dependent expiratory bradypnea, indicative of irritation of the nasal mucosa, occurred during a 15-min oronasal exposure of mice to allyl glycidyl ether (AGE) in the concentration range of 1.9-8.6 ppm. The level of exposure responsible for a 50% decrease in the respiratory rate (RD50) was 5.7 ppm. Non-anaesthetized, tracheally cannulated mice exposed for 120 min to AGE at levels ranging from 105 to 185 ppm showed a concentration-dependent decrease in respiratory rate due to pulmonary toxicity. The level of exposure to AGE which produced a 50% decrease in the respiratory rate of tracheally cannulated mice (RD50TC) was 134 ppm. Mice were subjected to whole body exposure for 4, 9 or 14 days, 6 h/day to 7.1 or 2.5 ppm AGE. The 4-day exposure to 7.1 ppm AGE produced in the nasal cavities of mice lesions consisting of necrosis of the respiratory epithelium and complete erosion of the olfactory epithelium without pulmonary injury. Restorative responses were observed in the nasal cavities of mice exposed for 9 and 14 days to 7.1 ppm AGE. Exposure to 2.5 ppm AGE caused neither nasal nor pulmonary injury. The results indicate that AGE primarily affects the upper airways. They also make it questionable that the occupational standard of 5 ppm assures an adequate margin of protection against AGE-induced nasal effects.