RESUMEN
A review of the literature revealed no published inhalational developmental toxicity studies of arsenic performed according to modern regulatory guidelines and with exposure throughout gestation. In the present study, inorganic arsenic, as arsenic trioxide (As(+3), As2O3), was administered via whole-body inhalational exposure to groups of twenty-five Crl:CD(SD)BR female rats for six h per day every day, beginning fourteen days prior to mating and continuing throughout mating and gestation. Exposures were begun prior to mating in order to achieve a biological steady state of As(+3) in the dams prior to embryonal-fetal development. In a preliminary exposure range-finding study, half of the females that had been exposed to arsenic trioxide at 25 mg/m3 died or were euthanized in extremis. In the definitive study, target exposure levels were 0.3, 3.0, and 10.0 mg/m3. Maternal toxicity, which was determined by the occurrence of rales, a decrease in net body weight gain, and a decrease in food intake during pre-mating and gestational exposure, was observed only at the 10 mg/m3 exposure level. Intrauterine parameters (mean numbers of corpora lutea, implantation sites, resorptions and viable fetuses, and mean fetal weights) were unaffected by treatment. No treatment-related malformations or developmental variations were noted at any exposure level. The no-observed-adverse-effect level (NOAEL) for maternal toxicity was 3.0 mg/m3; the NOAEL for developmental toxicity was greater than or equal to 10 mg/m3, 760 times both the time-weighted average threshold limit value (TLV) and the permissible exposure limit (PEL) for humans. Based on the results of this study, we conclude that arsenic trioxide, when administered via whole-body inhalation to pregnant rats, is not a developmental toxicant.
Asunto(s)
Anomalías Inducidas por Medicamentos/etiología , Intoxicación por Arsénico , Arsenicales , Óxidos/toxicidad , Administración por Inhalación , Animales , Trióxido de Arsénico , Cámaras de Exposición Atmosférica , Peso Corporal/efectos de los fármacos , Huesos/anomalías , Huesos/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Exposición a Riesgos Ambientales , Femenino , Feto/anomalías , Feto/efectos de los fármacos , Masculino , Nivel sin Efectos Adversos Observados , Proyectos Piloto , Embarazo , Ratas , Ratas Sprague-Dawley , Reproducción/efectos de los fármacos , Ruidos Respiratorios/efectos de los fármacos , Medición de Riesgo , Pruebas de ToxicidadRESUMEN
Male Sprague-Dawley rats were treated with a cumulative dose of 0, 5, 15 and 50 mg methylmercury/kg body weight. The doses were adequate to provide a clinical neuromuscular dysfunction at the highest dose whereas no toxicity was observed at the lowest treatment level. Whole brain concentrations of tyrosine but not tryptophan were slightly reduced by the treatment. No effect of methylmercury was observed in the levels of norepinephrine (NE), dopamine (DA), serotonin (5-HT), dihydroxyphenylacetic acid (DOPAC), or 5-hydroxyindoleacetic acid (5-HIAA). The synthesis rate for DA, but not the other biogenic amines, was decreased at all treatment levels of methylmercury. The results suggested a sensitivity of dopaminergic pathways to methylmercury toxicity in the central nervous system and are consistent with interference with cholinergic mechanisms and neurotransmitter enzymes by methylmercury as previously reported.
Asunto(s)
Aminas Biogénicas/biosíntesis , Encéfalo/metabolismo , Compuestos de Metilmercurio/farmacología , Animales , Encéfalo/efectos de los fármacos , Dopamina/biosíntesis , Masculino , Norepinefrina/biosíntesis , Ratas , Ratas Endogámicas , Serotonina/biosíntesisRESUMEN
A critical analysis of the literature base regarding the reproductive and developmental toxicity of arsenic compounds, with emphasis on inorganic arsenicals, was conducted. The analysis was stimulated by the great number of papers that have purported to have shown an association between exposure of pregnant laboratory animals to arsenic compounds and the occurrence of offspring with cranial neural tube defects, particularly exencephaly. For the most part, the literature reports of arsenic developmental toxicity in experimental animals are inadequate for human risk assessment purposes. Despite the shortcomings of the experimental database, several conclusions are readily apparent when the animal studies are viewed collectively. First, cranial neural tube defects are induced in rodents only when arsenic exposure has occurred early in gestation (on Days 7 [hamster, mouse], 8 [mouse], or 9 [rat]). Second, arsenic exposures that cause cranial neural tube defects are single doses that are so high as to be lethal (or nearly so) to the pregnant animal. Third, the effective routes of exposure are by injection directly into the venous system or the peritoneal cavity; even massive oral exposures do not cause increases in the incidence of total gross malformations. Fourth, repetition of similar study designs employing exaggerated parenteral doses is the source of the large number of papers reporting neural tube defects associated with prenatal arsenic exposure. Fifth, in five repeated dose studies carried out following EPA Guidelines for assessing developmental toxicity, arsenic was not teratogenic in rats (AsIII, 101 micromol/kg/d, oral gavage; 101 micromol/m3, inhalation), mice (AsV, 338 micromol/kg/d, oral gavage; est. 402 micromol/kg/d, diet), or rabbits (AsV, 21 micromol/kg/d, oral gavage). Data regarding arsenic exposure and adverse outcomes of pregnancy in humans are limited to several ecologic epidemiology studies of drinking water, airborne dusts, and smelter environs. These studies failed to (1) obtain accurate measurements of maternal exposure during the critical period of organogenesis and (2) control for recognized confounders. The lone study that examined maternal arsenic exposure during pregnancy and the presence of neural tube defects in progeny failed to confirm a relationship between the two. It is concluded that under environmentally relevant exposure scenarios (e.g., 100 ppm in soil), inorganic arsenic is unlikely to pose a risk to pregnant women and their offspring.
Asunto(s)
Anomalías Inducidas por Medicamentos , Arsénico/toxicidad , Feto/efectos de los fármacos , Reproducción/efectos de los fármacos , Animales , Arsénico/farmacocinética , Femenino , Humanos , Ratones , Defectos del Tubo Neural/inducido químicamente , Técnicas de Cultivo de Órganos , Embarazo , Conejos , Ratas , Contaminantes Químicos del Agua/toxicidadRESUMEN
To evaluate potential effects of exposure to inorganic arsenic throughout major organogenesis, CD-1 mice and New Zealand White rabbits were gavaged with arsenic acid dosages of 0, 7.5, 24, or 48 mg/kg/d on gestation days (GD) 6 through 15 (mice) or 0, 0.19, 0.75, or 3.0 mg/kg/d on GD 6 through 18 (rabbits) and examined at sacrifice (GD 18, mice; GD 29, rabbits) for evidence of toxicity. Two high-dose mice died, and survivors at the high and intermediate doses had decreased weight gains. High-dose-group fetal weights were decreased; no significant decreases in fetal weight or increases in prenatal mortality were seen at other dosages. Similar incidences of malformations occurred in all groups of mice, including controls. At the high dose in rabbits, seven does died or became moribund, and prenatal mortality was increased; surviving does had signs of toxicity, including decreased body weight. Does given lower doses appeared unaffected. Fetal weights were unaffected by treatment, and there were no effects at other doses. These data revealed an absence of dose-related effects in both species at arsenic exposures that were not maternally toxic. In mice, 7.5 mg/kg/d was the maternal No-Observed-Adverse-Effect-Level (NOAEL); the developmental toxicity NOAEL, while less well defined, was judged to be 7.5 mg/kg/d. In rabbits, 0.75 mg/kg/d was the NOAEL for both maternal and developmental toxicity.
Asunto(s)
Arseniatos/toxicidad , Peso Corporal/efectos de los fármacos , Desarrollo Embrionario y Fetal/efectos de los fármacos , Intercambio Materno-Fetal/efectos de los fármacos , Teratógenos/toxicidad , Animales , Relación Dosis-Respuesta a Droga , Femenino , Ratones , Nivel sin Efectos Adversos Observados , Embarazo , Conejos , Tasa de SupervivenciaRESUMEN
Sprague-Dawley derived rats were gavaged with daily doses of 2,5-hexanedione, a neurotoxic metabolite of both methyl n-butyl ketone and n-hexane. Seven daily doses of 0, 30, 100 or 300 mg 2,5-hexanedione/kg caused neuromuscular incoordination at the highest dose level while no effect was seen at the lowest level. Intravenous injections of either tritiated tyrosine or tryptophan, followed by exact time-interval sacrifices, facilitated the determination of synthesis rates and metabolism of various brain amines. At a cumulative dose of 210 mg 2,5-hexanedione/kg, the dopamine turnover rate was significantly increased, while precursor and metabolite levels were unchanged. Levels of serotonin as well as the serotonin synthesis rate remained unchanged, but levels of 5-hydroxyindoleacetic acid increased significantly in a dose dependent manner. The rise in 5-hydroxyindoleacetic acid levels inconjunction with no effects on other indoleamione parameters in 2,5-hexanedione-fed animals, suggests a possible inhibition of the energy-dependent 5-hydroxyindoleacetic acid efflux system in the brain.
Asunto(s)
Aminas Biogénicas/metabolismo , Encéfalo/efectos de los fármacos , Animales , Encéfalo/metabolismo , Dopamina/metabolismo , Relación Dosis-Respuesta a Droga , Hexanonas , Masculino , Norepinefrina/metabolismo , Ratas , Ratas Endogámicas , Serotonina/metabolismoRESUMEN
A thorough review of the literature revealed no published repeated-dose oral developmental toxicity studies of inorganic arsenic in rats. In the present study, which was conducted according to modern regulatory guidelines, arsenic trioxide was administered orally beginning 14 days prior to mating and continuing through mating and gestation until gestational day 19. Exposures began prior to mating in an attempt to achieve a steady state of arsenic in the bloodstream of dams prior to embryo-foetal development. Groups of 25 Crl:CD(SD)BR female rats received doses of 0, 1, 2.5, 5 or 10mg/kg/day by gavage. The selection of these dose levels was based on a preliminary range-finding study, in which excessive post-implantation loss and markedly decreased foetal weight occurred at doses of 15 mg/kg/day and maternal deaths occurred at higher doses. Maternal toxicity in the 10mg/kg/day group was evidenced by decreased food consumption and decreased net body weight gain during gestation, increased liver and kidney weights, and stomach abnormalities (adhesions and eroded areas). Transient decreases in food consumption in the 5mg/kg/day group caused the maternal no-observed-adverse-effect level (NOAEL) to be determined as 2. 5mg/kg/day. Intrauterine parameters were unaffected by arsenic trioxide. No treatment-related foetal malformations were noted in any dose group. Increased skeletal variations at 10mg/kg/day were attributed to reduced foetal weight at that dose level. The developmental NOAEL was thus 5mg/kg/day. Based on this study, orally administered arsenic trioxide cannot be considered to be a selective developmental toxicant (i.e. it is not more toxic to the conceptus than to the maternal organism), nor does it exhibit any propensity to cause neural tube defects, even at maternally toxic dose levels.
Asunto(s)
Intoxicación por Arsénico/patología , Arsenicales/farmacología , Desarrollo Embrionario y Fetal/efectos de los fármacos , Óxidos/farmacología , Anomalías Inducidas por Medicamentos/patología , Administración Oral , Animales , Trióxido de Arsénico , Peso Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Femenino , Feto/patología , Nivel sin Efectos Adversos Observados , Tamaño de los Órganos/efectos de los fármacos , Embarazo , Ratas , Reproducción/efectos de los fármacos , Medición de RiesgoRESUMEN
A battery of in vitro and in vivo tests were conducted on HCFC-141b as a vapour. Bacterial gene mutation assays with Escherichia coli and Salmonella typhimurium were negative in all tester strains. In vitro chromosomal aberration assays were positive on CHO cells but negative on human lymphocytes. Moreover, HCFC-141b was negative in vivo in a mouse micronucleus inhalation assay. On the basis of these data and previously reported genotoxicity testing, HCFC-141b is considered non-genotoxic. Groups of 80 male and 80 female Sprague-Dawley rats were exposed, by inhalation (6 hr/day, 5 days/wk) to vapours of HCFC-141b for 104 wk at target concentrations of 0 (control), 1500, 5000 and 20,000 ppm (increased from 15,000 ppm after 17 wk of exposure). No exposure-related effects of toxicological significance were noted with respect to survival, clinical signs, ophthalmoscopy, haematology, clinical chemistry, urinalysis or organ weight analysis. Reduced food intake and body weight gain were noted in both sexes of the 15,000 ppm group during the first 16 wk; thereafter, body weight gains in all groups were similar although the intergroup differences in body weight remained evident. Reduced food intake persisted in both sexes through wk 52 and in females during the second year of exposure. Treatment-related effects on macroscopic pathology were confined to increased incidences of testicular masses and altered appearance. Microscopic pathology examinations confirmed the testes as the target organ with findings of increased incidences of benign interstitial cell tumours and hyperplasia at 5000 and 20,000 ppm. The no-observable-adverse-effect level (NOAEL) was 1500 ppm. The testicular changes at high exposure levels were considered to be due to a change of the senile hormonal imbalance in geriatric rats and of little significance for the assessment of human health effects.
Asunto(s)
Clorofluorocarburos/toxicidad , Mutágenos/toxicidad , Administración por Inhalación , Animales , Peso Corporal , Células CHO , Carcinógenos/toxicidad , Clorofluorocarburos de Etano , Aberraciones Cromosómicas , Cricetinae , Femenino , Humanos , Masculino , Pruebas de Micronúcleos , Pruebas de Mutagenicidad , Ratas , Ratas Sprague-Dawley , Medición de Riesgo , Salmonella typhimurium , Factores de TiempoRESUMEN
Acrylic acid, methyl acrylate, ethyl acrylate, and butyl acrylate are commercially important and widely used materials. This paper reports the results of a series of fate and aquatic toxicity studies. The mobility in soil of acrylic acid and its esters ranged from 'medium' to 'very high'. Calculated bioconcentration factors ranged from 1 to 37, suggesting a low bioconcentration potential. Acrylic acid and methyl acrylate showed limited biodegradability in the five day biochemical oxygen demand (BOD5) test, while ethyl acrylate and butyl acrylate were degraded easily (77% and 56%, respectively). Using the OECD method 301D 28-d closed bottle test, degradability for acrylic acid was 81% at 28 days, while the acrylic esters ranged from 57% to 60%. Acrylic acid degraded rapidly to carbon dioxide in soil (t1/2 < 1 day). Toxicity tests were conducted using freshwater and marine fish, invertebrates, and algae. Acrylic acid effect concentrations for fish and invertebrates ranged from 27 to 236 mg/l. Effect concentrations (LC50 or EC50) for fish and invertebrates using methyl acrylate, ethyl acrylate, and butyl acrylate ranged from 1.1 to 8.2 mg/l. The chronic MATC for acrylic acid with Daphnia magna was 27 mg/l based on length and young produced per adult reproduction day and for ethyl acrylate was 0.29 mg/l based on both the reproductive and growth endpoints. Overall these studies show that acrylic acid and the acrylic esters studied can rapidly biodegrade, have a low potential for persistence or bioaccumulation in the environment, and have low to moderate toxicity.
Asunto(s)
Acrilatos/toxicidad , Mutágenos/toxicidad , Contaminantes Químicos del Agua/toxicidad , Acrilatos/análisis , Animales , Biodegradación Ambiental , Cyprinidae , Daphnia , Decápodos , Mutágenos/análisis , Oncorhynchus mykiss , Contaminantes Químicos del Agua/análisisRESUMEN
Human occupational exposure to sufficiently high levels of arsenic in air has been associated with lung cancer, but generally not other types of cancer. Thus, a better understanding of the relationship between airborne arsenic exposures and systemic uptake is essential. In this study, rabbits were exposed to one of four levels of arsenic trioxide in air for 8 h/day, 7 days/week, for 8 weeks (0.05, 0.1, 0.22, or 1.1 mg/m3). Plasma levels of inorganic arsenic, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) were measured following the last exposure. Although there was a dose-related increase in plasma levels of methylated arsenic metabolites, statistically significant increases in mean inorganic arsenic levels in plasma were observed only in male rabbits exposed to 0.22 mg/m3, and in both males and females exposed to 1.1 mg/m3. Mean inorganic arsenic levels in plasma in males and females exposed to 0.05 and 0.1 mg/m3, and females exposed to 0.22 mg/m3, were not significantly elevated compared to controls. These results suggest that arsenic inhalation has a negligible impact on body burden of inorganic arsenic until air levels are significantly elevated. Based on plasma measurements of inorganic arsenic, the two lowest exposure levels in this study (0.05 and 0.1 mg/m3) are indistinguishable from background.
Asunto(s)
Contaminantes Atmosféricos/farmacocinética , Arsénico/farmacocinética , Administración por Inhalación , Contaminantes Atmosféricos/sangre , Animales , Arsénico/administración & dosificación , Arsénico/sangre , Arsenicales/análisis , Ácido Cacodílico/análisis , Masculino , Conejos , Factores de TiempoRESUMEN
The effects of prostaglandin (PG) F-2 alpha and E-2, cyclic GMP, testosterone and 2,4'-dibromoacetophenone (DBA) on rat seminiferous tubules in vitro were ascertained by measuring contractile frequency, size of contractions and tone (tubular diameter). PGF-2 alpha (10(-9)--10(-5) M) increased frequency and tone but not magnitude of contraction. Contraction frequency and tone were decreased by PGE-2 (10(-9)--10(-5) M) but the size of contractions was again unaffected. Cyclic GMP (10(-10)--10(-6) M) increased the frequency of contractions and tone and decreased size of contractions. Testosterone decreased the frequency and size of contractions and increased tone at concentrations of 10(-9) to 10(-7) but higher concentrations (10(-6) M) reversed these changes. DBA (10(-7)--10(-3) M) greatly decreased the frequency and size of contractions and tone and spontaneous contractions were abolished at 10(-3) M. Our data strongly suggest that PGs, cyclic nucleotides and testosterone are all important in vivo in modulating contractility of seminiferous tubules and as such would participate in sperm transport from the testes.
Asunto(s)
Acetofenonas/farmacología , GMP Cíclico/farmacología , Contracción Muscular/efectos de los fármacos , Prostaglandinas/farmacología , Túbulos Seminíferos/fisiología , Testículo/fisiología , Testosterona/farmacología , Animales , Técnicas In Vitro , Masculino , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Ratas , Túbulos Seminíferos/efectos de los fármacosRESUMEN
Leptophos is a potent acetylcholinesterase inhibitor which causes delayed central-peripheral neuropathy. Rats were administered multiple doses of leptophos until motor deficits were observed in rotorod performance in the highest dosage group. Doses lower than the median effective dose were then administered to other rats and alterations of brain catecholamine and serotonin levels and turnover rates were determined. Turnover rates of brain norepinephrine and dopamine were elevated in rats administered cumulative doses of 75 mg/kg leptophos over a 15-day period. Levels of the major dopamine metabolite, 3,4-dihydroxyphenylacetic acid, appeared to be slightly elevated at this dose level and levels of dopamine were also higher than controls. These observations suggest that leptophos increases brain adrenergic activity. Rats administered the same dose levels had significantly reduced serotonin turnover rates. This observation was possibly artifactual, because rats administered a cumulative dose of 225 mg/kg leptophos showed no difference from controls.
Asunto(s)
Aminas Biogénicas/metabolismo , Química Encefálica/efectos de los fármacos , Encéfalo/metabolismo , Insecticidas/toxicidad , Leptofos/toxicidad , Animales , Dopamina/análisis , Masculino , Ratas , Ratas Endogámicas , Serotonina/metabolismoRESUMEN
Acrylamide, a widely used and chemically active substance, has caused delayed distal neuropathy in man and in experimental animals. Male rats administered 50 mg/kg/day acrylamide for 5 days demonstrated ataxia in preliminary rotorod experiments. Additional groups of rats were dosed with 5, 15 or 50 mg/kg/day acrylamide for 5 days, then sacrificed on day 6 at various time intervals after iv injections of tritiated tyrosine (Tyr) or tryptophan (Trp). Brain levels of Tyr, Trp, norepinephrine (NE), dopamine (DA), serotonin (5-HT), and respective metabolites, 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MOPEG-sulfate), 3,4-dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindoleacetic acid (5-HIAA) were assayed fluorometrically. Turnover rates of NE, DA and 5-HT were estimated by evaluating the rates of specific activity changes in neurotransmitters and precursor amino acids over time. A slight reduction of whole brain NE content was observed in rats administered 50 mg/kg/day acrylamide. Other neurotransmitter levels were not affected by acrylamide levels administered, nor were turnover rates affected. Levels of MOPEG-sulfate and DOPAC were unchanged at any dose tested. Increased levels of 5-HIAA were observed in rats receiving 15 and 50 mg/kg/day acrylamide. Results suggest that acrylamide neurotoxicity does not entail widespread damage to the neurons associated with these biogenic amines; however, the acid metabolite efflux from brain was significantly inhibited.
Asunto(s)
Acrilamidas/farmacología , Aminas Biogénicas/metabolismo , Química Encefálica/efectos de los fármacos , Acrilamida , Animales , Catecolaminas/metabolismo , Dopamina/biosíntesis , Cinética , Masculino , Norepinefrina/biosíntesis , Equilibrio Postural/efectos de los fármacos , Ratas , Ratas Endogámicas , Serotonina/metabolismoRESUMEN
The developmental toxicity of di-n-butyltin dichloride (DBT-dC) was evaluated in Wistar rats following oral administration. No maternal toxicity, embryotoxicity, or malformations were observed at 1, 2.5, or 5 mg DBT-dC/kg body weight. Signs of maternal toxicity, including decreased food consumption, body weight gain, and thymus weight, were observed at 10 mg/kg body weight DBT-dC. At this dose, no evidence of embryotoxicity, including such measures as total resorptions, viable fetuses, or fetal weights, was noted in any litter data. There was a slightly increased frequency of total malformations at the 10 mg/kg dose level of 4/262 treated vs. 1/269 control fetuses. All defects occurred singly with no clustering nor organ system pattern of occurrence, which would be indicative of a teratogenic effect. The no-observed-adverse-effect-level (NOAEL) for prenatal as well as maternal toxicity was considered to be 5 mg DBT-dC/kg body weight. The interpretation and utility of previously published studies on the developmental toxicity of dibutyltin compounds are confounded by dose regimen and data reporting deficiencies. These studies suggest that, after oral administration during days 6-17 of pregnancy, the NOAEL for malformations in rats of different strains ranges from 1.7 to 5 mg/kg body weight. In these studies, the maternal LD50 was reported to be about 8 mg/kg body weight in one study but at greater than 15 mg/kg in others. Thus, the NOAEL for teratogenicity may be roughly estimated to be from one-tenth to one-third of the maternal LD50. When evaluated, thymus involution, a typical but reversible effect of di- and tri-butyltin compounds, was also observed at 5-10 mg/kg body weight. The most susceptible time for inducing teratogenic effects is reported to be days 7-9 of pregnancy, but malformations have also been found with dosing over longer duration at lower doses. It is doubtful that the findings of malformations at highly toxic doses in animals has any health hazard significance, especially when human exposure to dibutyltins typically occurs at several orders of magnitude lower than the doses used in these studies. Further comparative pharmacokinetic studies would be necessary in order to refine the hazard characterization.
Asunto(s)
Anomalías Inducidas por Medicamentos , Compuestos Orgánicos de Estaño/toxicidad , Animales , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Dosificación Letal Mediana , Nivel sin Efectos Adversos Observados , Embarazo , Ratas , Ratas WistarRESUMEN
BACKGROUND: Assessing risks to human development from chemical exposure typically requires integrating findings from laboratory animal and human studies. METHODS: Using a case study approach, we present a program designed to assess the risk of the occurrence of malformations from inorganic arsenic exposure. We discuss how epidemiological data should be evaluated for quality and criteria for determining whether an association is causal. In this case study, adequate epidemiological data were not available for evaluating the potential effect of arsenic on development. Consequently, results from appropriately designed, conducted, and interpreted developmental toxicity studies, which have been shown to be predictive of human risk under numerous scenarios, were used. In our case study, the existing animal data were not designed appropriately to assess risk from environmental exposures, although such studies may be useful for hazard identification. Because the human and animal databases were deficient, a research program comprising modern guideline toxicological studies was designed and conducted. RESULTS: The results of those studies in rats, mice, and rabbits indicate that oral and inhalational exposures to inorganic arsenic do not cause structural malformations, and inhalational exposures produced no developmental effects at all. The new study results are discussed in conjunction with considerations of metabolism, toxicokinetics, and maternal toxicity. CONCLUSIONS: Based on the available experimental data, and absent contrary findings from adequately conducted epidemiological studies, we conclude that exposure to inorganic arsenic by environmentally relevant routes poses no risk of the occurrence of malformations and little risk of other prenatal developmental toxicity in developing humans without concomitant and near-lethal toxicological effects in mothers.
Asunto(s)
Anomalías Inducidas por Medicamentos/etiología , Arsénico/toxicidad , Anomalías Inducidas por Medicamentos/epidemiología , Animales , Arsénico/administración & dosificación , Arsénico/farmacocinética , Interpretación Estadística de Datos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Desarrollo Embrionario y Fetal/efectos de los fármacos , Exposición a Riesgos Ambientales , Métodos Epidemiológicos , Femenino , Humanos , Ratones , Embarazo , Conejos , Ratas , Medición de RiesgoRESUMEN
The mammalian testes have several mechanisms to propel the nonmotile spermatozoa in the seminiferous tubules through the rete testis into the epididymis. These include (a) contractions of the testicular capsule and the seminiferous tubules and (b) fluid flow through the excurrent ducts resulting from active transport of fluids and electrolyte into the seminiferous tubules from the extracellular space. The efflux of fluids and sperm from the testis appears to closely parallel spermiation. An increased output of fluid may result from prostaglandins (PGF2 alpha) and possibly oxytocin (not all species respond to oxytocin) as a result of capsular contractions compressing and expelling the fluid from the tubules. Seminiferous tubular contractions do not result from nervous stimulation but are linked to PGs and cyclic nucleotide generation. They are regulated to some extent by androgens and the lesser response of the tubules to 5 alpha-dihydrotestosterone compared to testosterone can be explained by their interaction with androgen binding protein and their action on phospholipase A2 activity for PG synthesis.
Asunto(s)
Túbulos Seminíferos/fisiología , Transporte Espermático , Testículo/fisiología , Proteína de Unión a Andrógenos/metabolismo , Animales , Calcio/metabolismo , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Inhibidores de la Ciclooxigenasa , Dihidrotestosterona/metabolismo , Humanos , Hidroxiprostaglandina Deshidrogenasas/metabolismo , Hormona Inhibidora de la Liberación de MSH/farmacología , Masculino , Contracción Muscular , Fosfolipasas A/metabolismo , Fosfolipasas A2 , Progesterona/farmacología , Prostaglandinas , Especificidad de la Especie , Testosterona , Vasotocina/farmacologíaRESUMEN
The subchronic toxicity of a commercial blend of partially hydrogenated terphenyl was evaluated in rats by inhalation and oral routes of exposure. Animals were exposed to target concentrations of 0, 10, 100, or 500 mg/m3 for 6 hr/day, 5 days/week or were offered diets daily with concentrations of 0, 50, 200, or 2000 ppm. Each study lasted approximately 14 weeks. The study designs included observations for clinical signs, body weights, ophthalmic exams, hematology and clinical chemistry, major organ weights, and gross and histopathology. No treatment-related effects were noted in the ophthalmic exams. Body weights were slightly depressed in high-dose males from the inhalation study and high-dose females in the dietary study. Liver and liver/body weights were increased in high-dose animals of both sexes and high- and mid-dose males in the dietary and inhalation studies, respectively. In the high-dose females of the dietary study, kidney and kidney/body weights were increased with increased adrenal and adrenal/body weights were also observed. No compound-related gross lesions nor pathological correlates to the organ weight changes were observed in either study. The no-adverse effect levels were considered to be 100 mg/m3 and 200 ppm (15.9 mg/kg) for the inhalation and dietary studies, respectively. These data indicate that a wide margin of safety exists for hydrogenated terphenyl workplace exposure.
Asunto(s)
Compuestos de Terfenilo/toxicidad , Administración por Inhalación , Administración Oral , Animales , Cámaras de Exposición Atmosférica , Recuento de Células Sanguíneas , Dieta , Ingestión de Alimentos/efectos de los fármacos , Femenino , Hígado/efectos de los fármacos , Masculino , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Endogámicas , Compuestos de Terfenilo/administración & dosificaciónRESUMEN
The toxicity potential of 1,1,1-trifluoroethane (HFC-143a), a CFC alternative, was evaluated in several acute, subchronic, and developmental toxicity studies by the inhalation route and in genotoxicity studies. HFC-143a has a very low acute inhalation toxicity potential as shown by a 4-hr LC50 of > 540,000 ppm in rats. HFC-143A has a low potential to induce cardiac sensitization in experimental screening studies in dogs; only the highest concentration tested--300,000 ppm--elicited a cardiac sensitization response. In an initial 4-week nose-only inhalation study, male and female rats were exposed 6 hr/day, 5 days/week at concentrations of 0, 2000, 10,000, or 40,000 ppm. Females showed no evidence of toxicity at any exposure level; male rats did exhibit degenerative changes only in the tests at all exposure levels. However, because of exposure system irregularities, which resulted in excessive temperature conditions and stress in the HFC-143a-exposed groups, the study was repeated in male rats exposed by whole-body inhalation. In this repeat study no toxicity was observed at < or = 40,000 ppm. Moreover, a subsequent 90-day whole-body inhalation study in rats exposed 6 hr/day, 5 days/week at 0, 2000, 10,000, or 40,000 ppm resulted in no evidence of toxicity at any exposure concentration. The results of the second 4-week and the 90-day studies using whole-body exposures indicate that the findings from the first 4-week study were related to the stress induced by excessive temperatures and nose-only restraint. Therefore, the no-observed-effect level (NOEL) for rats repeatedly exposed up to 90 days was considered to be 40,000 ppm. In developmental toxicity studies with rats and rabbits, an increase in visceral variations or skeletal malformations was observed, respectively, at HFC-143a concentrations of 2000, 10,000 or 40,000 ppm (rat) or at the low and high concentrations (rabbit). Because of the unusually low control incidence of variations (1.6% per litter in the control versus 6.8-16.8% for historical control values), the lack of a clear dose-response relationship, and the lack of other developmental effects, these findings were not considered related to HFC-143a exposure. In addition, results from genotoxicity studies (Ames, chromosomal aberration with human lymphocytes, mouse micronucleus) demonstrated that HFC-143a was not mutagenic.
Asunto(s)
Anomalías Inducidas por Medicamentos , Corazón/efectos de los fármacos , Hidrocarburos Fluorados/toxicidad , Mutágenos/toxicidad , Animales , Perros , Relación Dosis-Respuesta a Droga , Escherichia coli/efectos de los fármacos , Escherichia coli/genética , Femenino , Humanos , Linfocitos/efectos de los fármacos , Masculino , Ratones , Pruebas de Mutagenicidad , Conejos , Ratas , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/genética , Pruebas de ToxicidadRESUMEN
Numerous studies have suggested that single-day intraperitoneal (IP) injection of inorganic arsenic results in failure of neural tube closure and other malformations in rats, hamsters, and mice. Most of these studies involved treatment of limited numbers of animals with maternally toxic doses of arsenic (generally As(V)), without defining a dose-response relationship. In the present Good Laboratory Practice-compliant study, sodium arsenate (As(V)) was administered IP and arsenic trioxide (As(III)) was administered either IP or orally (by gavage) on gestational day 9 to groups of 25 mated Crl:CD(R)(SD)BR rats. Only at dose levels that caused severe maternal toxicity, including lethality, did IP injection of arsenic trioxide produce neural tube and ocular defects; oral administration of higher doses of arsenic trioxide caused some maternal deaths but no treatment-related fetal malformations. In contrast, IP injection of similar amounts of sodium arsenate (based on the molar amount of arsenic) caused mild maternal toxicity but a large increase in malformations, including neural tube, eye, and jaw defects. In summary, neural tube and craniofacial defects were observed after IP injection of both As(V) and As(III); however, no increase in malformations was seen following oral administration of As(III), even at maternally lethal doses. These results demonstrate that the frequently cited association between prenatal exposure to inorganic arsenic and malformations in laboratory animals is dependent on a route of administration that is not appropriate for human risk assessment.