Fipronil sulfone induced higher cytotoxicity than fipronil in SH-SY5Y cells: Protection by antioxidants.

Fipronil is a broad spectrum insecticide from the phenyl pyrazole family, which targets GABA receptor. Limited information is available about the metabolite fipronil sulfone cytotoxic actions. This study examined in vitro neurotoxicity of fipronil and fipronil sulfone and evaluated Trolox (vitamin E analog) (0.3, 1µM), N-acetyl-cysteine (0.5, 1mM), melatonin (0.1, 1µM) and Tempol (superoxide dismutase analog) (0.3, 0.5mM) protective role in SH-SY5Y cells. MTT and LDH assays were carried out to assess the cytotoxicity of fipronil and fipronil sulfone at 3-100µM concentrations. Fipronil sulfone was more toxic than fipronil. Tempol showed the best neuroprotectant profile against fipronil (50 and 150µM) and fipronil sulfone (3 and 10µM) reaching control levels. Fipronil (100µM) and fipronil sulfone (3µM) treatments induced a 4.7- and 5-fold increases in lipid peroxides measured as malondialdehyde (MDA) and a 2.2- and 2.0-fold increases in the levels of nitric oxide (NO). These results suggest that oxidative stress observed may be one of the major mechanisms of fipronil-induced neurotoxicity and it may be attributed in part to fipronil disposition and metabolism. Our results led us postulate that metabolite fipronil sulfone might be responsible for the fipronil-induced toxicity rather than fipronil itself.

Effects of exposure to pyrethroid cyfluthrin on serotonin and dopamine levels in brain regions of male rats.

The effects of cyfluthrin oral exposure (1, 5, 10 and 20mg/kg bw, 6 days) on brain region monoamine levels of male rats were examined. Cyfluthrin-treated rats (1, 5 and 10mg/kg bw, orally 6 days), had no visible injury, i.e., no clinical signs of dysfunction were observed. However, rats treated with cyfluthrin at the highest dose (20mg/kg bw, orally 6 days) showed skeletal muscle contraction in the hind limbs, slight movement incoordination without any signs of dyskinesia and tremor after 1-2h of treatment. These signs were reversible at 6h after dose. After last dose of cyfluthrin, dopamine (DA) and serotonin (5-HT) and its metabolites levels were determined in brain regions hypothalamus, midbrain, hippocampus, striatum and prefrontal cortex by HPLC. Cyfluthrin (1mg/kg bw, orally 6 days) did not affect the DA, 5-HT and metabolites levels in the brain regions studied. Cyfluthrin (5, 10 and 20mg/kg bw, orally 6 days) caused a statistically significant decrease in DA and its metabolites DOPAC and HVA levels and in 5-HT and its metabolite 5-HIAA levels in a brain region- and dose-related manner. Moreover, cyfluthrin (20mg/kg bw, orally 6 days) evoked a statistically significant increase in 5-HT turnover in striatum and midbrain, and in DA turnover in striatum and prefrontal cortex. These findings indicate that serotoninergic and dopaminergic neurotransmission is affected by exposure to cyfluthrin and may contribute to the overall spectrum of neurotoxicity caused by this pyrethroid.

Fipronil induces CYP isoforms in rats.

The goal of the present study was to evaluate fipronil effects on the activities of drug metabolizing enzymes in rat liver microsomes. Rats were orally treated with fipronil at doses of 1, 5, 10 and 15 mg/kg bw/day for 6 days. Determinations of cytochrome P450 (CYP) enzyme activities were carried out in hepatic microsomes isolated from treated rats. The activities of some members of CYP2E, CYP1A, CYP2A, CYP2B and CYP3A subfamilies significantly increased after fipronil treatment in a dose-dependent manner as compared to control. The major effects were observed in the O-deethylation of ethoxyresorufin and O-demethylation of methoxyresorufin (reflecting CYP1A1/2 activities), in the O-depenthylation of pentoxyresorufin and 16ß-hydroxylation of testosterone (reflecting CYP2B1/2 activities), and in the N-demethylation of erythromycin and 6ß-hydroxylation of testosterone (reflecting CYP3A1/2 activities). Immunoblot studies revealed that fipronil increased the apoprotein levels of CYP1A1. Our results suggest that fipronil is an inducer of hepatic phase I CYP enzymes, causing an increased potential to interact with a wide range of xenobiotics or endogenous chemicals that are substrates of the CYP1A, CYP2B and CYP3A subfamilies. Further investigations are required to in vivo evaluate the potential of the metabolite fipronil sulfone as an inducer of phase I CYP enzymes.

Evidence for dose-additive effects of a type II pyrethroid mixture. In vitro assessment.

Despite the widespread use of pyrethroid insecticides that led to common exposure in the population, few studies have been conducted to quantitatively assess dose-additive effects of pyrethroids using a funcional measure involved in the common toxic mode of action. The aim of this study was to evaluate the potency and efficacy of 6 Type II pyretroids (α-cypermethrin, cyfluthrin, λ-cyhalothrin, deltamethrin, cyphenothrin and esfenvalerate) to evoke induction of both nitric oxide and lipid peroxides levels measured as malondialdehyde in three in vitro models (SH-SY5Y, HepG2 and Caco-2 human cells) as well as to test the hypothesis of dose additivity for mixtures of these same 6 pyrethroids. Concentration-responses for 6 pyrethroids were determined as well as the response to mixtures of all 6 pyrethroids. Additivity was tested assuming a dose-additive model. The human neuroblastoma SH-SY5Y cell line was the most sensitive in vitro model. The rank order of potency for cell SH-SY5Y viability MTT assay was deltamethrin>cyphenothrin>λ-cyhalothrin>cyfluthrin>esfenvalerate>α-cypermethrin. When 6 pyrethroids were present in the mixture at an equitoxic mixing ratio, the action on nitric oxide (NO) and lipid peroxides measured as malondialdehyde (MDA) production was consistent with a dose-additive model. The results of the present study are consistent with previous reports of additivity of pyrethroids in vivo e in vitro.

Differential induction of cytochrome P450 isoforms and peroxisomal proliferation by cyfluthrin in male Wistar rats.

Cyfluthrin effects on in vivo drug metabolizing enzymes were evaluated using the oxidative substrate antipyrine. Antipyrine pharmacokinetics in plasma and urinary excretion of its major metabolites with and without cyfluthrin oral treatment (20mg/kg/day for 6 days) were investigated in rats. Cyfluthrin increased the apparent intrinsic clearance and decreased the antipyrine half-life at ß phase. Cyfluthrin also increased the clearance of the antipyrine metabolites, norantipyrine, 4-hydroxyantipyrine and 3-hydroxymethylantipyrine and the formation rate constants for each of the three metabolites measured in urine. These results suggest that cyfluthrin affects hepatic cytochrome P450 (CYP) system. In order to confirm, a second experiment was carried out. We evaluated the effects of repeated exposure to cyfluthrin on hepatic and renal CYP2E, CYP1A and CYP4A subfamilies and peroxisomal proliferation in rats following oral administration (10 and 20mg/kg/day for 6 days). At the highest dose, cyfluthrin increased renal and hepatic O-deethylation of ethoxyresorufin and O-demethylation of methoxyresorufin, metabolism mediated by the CYP1A subfamily. Liver and kidney were susceptible to cyfluthrin-dependent induction of 12- and 11-hydroxylation of lauric acid, suggesting CYP4A subfamily induction. Also cyfluthrin increased the ß-oxidation of palmitoyl-coenzyme A and carnitine acetyltransferase activity, supporting cyfluthrin as a peroxisome proliferator. In conclusion, the demonstration that cyfluthrin induced hepatic CYP1A, CYP4A subfamilies and peroxisomal proliferation raises the possibility of cyfluthrin could produce changes in oxidative stress.

Effects of exposure to amitraz on noradrenaline, serotonin and dopamine levels in brain regions of 30 and 60 days old male rats.

The effects of amitraz oral exposure (20, 50 and 80mg/kg bw, 5 days) on brain region monoamine levels of male rats at 30 and 60 days of age were examined. The amitraz-treated rats at the oral doses of 20 and 50mg/kg bw had no visible injury, i.e., any clinical signs of dysfunction observed in any of the animals. However, rats treated with amitraz at the highest dose (80mg/kg bw, 5 days) showed a slight motor incoordination after 1-2h of treatment. These signs were reversible approximately at 6h after dose. After the last dose of amitraz, NE, DA and 5-HT and its metabolites levels were determined in the brain regions hypothalamus, midbrain, prefrontal cortex, striatum and hippocampus by HPLC. Amitraz caused changes in the NE, DA and 5-HT and their metabolite levels in a brain regional-, dose- and age-related manner. In the brain regions studied, amitraz induced a statistically significant increase in 5-HT, NE and DA content with age interaction, but the NE increases in prefrontal cortex and hippocampus was without age interaction. Moreover, in the brain regions studied, amitraz induced a statistically significant decrease in the metabolite 5-HIAA, MHPG, DOPAC and HVA levels displaying an age interaction, excepting the 5-HIAA decrease in midbrain and the DOPAC decrease in hypothalamus and striatum which were without age interaction. Furthermore, amitraz evoked a statistically significant decrease in 5-HT, NE and DA turnover in the brain regions studied. The present findings indicate that amitraz significantly altered CNS monoaminergic neurotransmitters in a brain regional-, dose- and age-related manner.

Effects of prenatal and postnatal exposure to amitraz on norepinephrine, serotonin and dopamine levels in brain regions of male and female rats.

The effects of maternal exposure to amitraz on brain region monoamine levels of male and female offspring rats at 60 days of age were observed. Maternal and offspring body weight, physical and general activity development were unaffected by the exposure of dams to amitraz (20mg/kgbw, orally on days 6-21 of pregnancy and 1-10 of lactation). Male and female offspring were sacrificed at 60 days of age and possible alterations in the content and metabolism of NE, DA and 5-HT were determined in brain regions by HPLC. The results showed that all these neurotransmitter systems were altered in a brain regional-related manner. In male and female offspring, amitraz induced a significant decrease in the prefrontal cortex 5-HT and its metabolite 5-HIAA and DA and its metabolites DOPAC and HVA levels with interaction of sex. Nevertheless, we verified that striatum DA and 5-HT and corresponding metabolite contents decreased in male and female offspring without statistical distinction of sex. In contrast, amitraz did not modify 5-HT content, but caused an increase in 5-HIAA content in the medulla oblongata and hippocampus in male and female offspring. Alterations in the hippocampus DA, DOPAC and HVA levels after amitraz exposure were also observed displaying a sex interaction. NE levels also showed a decrease after amitraz treatment in the prefrontal cortex and striatum without statistical sex interaction, but MHPG levels decreased in both regions with a sex interaction. Amitraz evoked increases in 5-HT turnover in the prefrontal cortex as well as in DA turnover in the striatum and hippocampus but decreases in NE turnover in the hypothalamus, prefrontal cortex and striatum. The present findings indicated that maternal exposure to amitraz altered noradrenergic, serotonergic and dopaminergic neurochemistry in their offspring in the prefrontal cortex, striatum and hippocampus, and those variations could be related to several alterations in the functions in which these brain regions are involved.

Development and validation of a liquid chromatography-fluorescence-mass spectrometry method to measure glyphosate and aminomethylphosphonic acid in rat plasma.

A simple and fast method has been developed and validated to measure glyphosate (GLYP) and aminomethylphosphonic acid (AMPA) in rat plasma based on reversed-phase high performance liquid chromatography (RP-HPLC) coupled to fluorescence (FLD) and electrospray ionization mass spectrometry (ESI-MS) detection. After protein precipitation with acetonitrile, GLYP and AMPA were derivatized with 9-fluorenylmethylchloroformate (FMOC-Cl) and then separated on a C(12) column (250mm×4.60mm i.d.) using a gradient of an ammonium formate (20mM, pH 8.5) and acetonitrile mobile phase. Selected ion monitoring (SIM) mode of the MS was used to obtain maximum sensitivity when quantifying GLYP and AMPA. The validation shows the method to be consistent and reliable, with an intra- and inter-day precision for GLYP and AMPA>9% for both detectors. For both compounds the accuracy ranged from 2.1% to 7.8% for the intra-day readings, and from 4.1% to 8.6% for the inter-day values. The efficacy of GLYP extraction ranged from 87% to 93% and it was between 76% and 88% for AMPA. Moreover, the limits of quantification (LOQ) for GLYP and AMPA were 5 and 10ng/mL, respectively with FLD, and 0.4 and 2ng/mL with ESI-MS. The method was successfully applied to simultaneously measure both compounds in rat plasma samples several days after oral administration of glyphosate.

Acute and repeated dose (4 weeks) oral toxicity studies of two antihypertensive peptides, RYLGY and AYFYPEL, that correspond to fragments (90-94) and (143-149) from alpha(s1)-casein.

The Lowpept is a powdered casein hydrolysate containing the antihypertensive peptides RYLGY and AYFYPEL, two sequences that correspond to alpha(s1)-casein f (90-94) (RYLGY) and alpha(s1)-casein f (143-149) (AYFYPEL). To support the safety, Lowpept has been examined in an acute and in a 4-week repeated dose oral toxicity studies in rats. Powdered casein hydrolysate administered in a single oral gavage dose of 2000 mg/kg resulted in no adverse events or mortality. Also, casein hydrolysate administered as a daily dose of 1000 mg/kg for 4 weeks by gavage resulted in no adverse events or mortality. No evidence or treatment-related toxicity was detected during both studies. Data analysis of body weight gain, food consumption, clinical observations, blood biochemical, haematology, organ weight ratios and histopathological findings did not show significant differences between control and treated groups. It is concluded that the casein hydrolysate containing the peptides RYLGY and AYFYPEL orally administered to rats was safe and that not treatment-related toxicity was detected even at the highest doses investigated in both acute (2000 mg/kg of body weight) and repeated dose (4 weeks) oral (1000 mg/kg of body weight) toxicity studies.

Toxicokinetics of glyphosate and its metabolite aminomethyl phosphonic acid in rats.

The toxicokinetics of glyphosate after single 100 mgkg(-1) intravenous (i.v.) and 400 mgkg(-1) oral doses were studied in rats. Serial blood samples were obtained after i.v. and oral administration. Plasma concentrations of glyphosate and its metabolite amiomethyl phosphonic acid (AMPA) were determined by HPLC method. After i.v. and oral administration, plasma concentration-time curves were best described by a two-compartment open model. For glyphosate, the elimination half-lives (T(1/2beta)) from plasma were 9.99 h after i.v. and 14.38 h after oral administration. The total plasma clearance was not influenced by dose concentration or route and reached a value of 0.995 l h(-1)kg(-1). After i.v. administration, the apparent volume of distribution in the second compartment (V(2)) and volume of distribution at steady state (V(ss)) were 2.39 and 2.99 l kg(-1), respectively, suggesting a considerable diffusion of the herbicide into tissues. After oral administration, glyphosate was partially and slowly absorbed with a T(max) of 5.16 h. The oral bioavailability of glyphosate was found to be 23.21%. Glyphosate was converted to AMPA. The metabolite AMPA represented 6.49% of the parent drug plasma concentrations. The maximum plasma concentrations of glyphosate and AMPA were 4.62 and 0.416 microg ml(-1), respectively. The maximum plasma concentration of AMPA was achieved at 2.42 h. For AMPA, the elimination half-life (T(1/2beta)) was 15.08 h after oral administration of glyphosate parent compound.

Use and abuse of pyrethrins and synthetic pyrethroids in veterinary medicine.

Pyrethrin and pyrethroid insecticides are widely used in veterinary medicine for agricultural and domestic purposes. Although pyrethrins and pyrethroids are generally regarded as safe to animals, there have been reports of systemic poisoning in veterinary species. This review summarises the use of pyrethrins and pyrethroids in companion and food producing animals, including their mechanism of action and toxicity. The toxicokinetics of pyrethrins and pyrethroids are described, including absorption, distribution, metabolism (including interactions with other compounds affecting drug metabolising enzymes) and excretion, leading to the application of toxicokinetic/toxicodynamic concepts. Specific cases of pyrethroid poisoning in laboratory animals (including age-related toxicity), fish, companion and large animals are considered, including the high incidence of feline pyrethroids toxicosis following the extra-label use of topical formulations.

Oral bioavailability, tissue distribution and depletion of flumequine in the food producing animal, chicken for fattening.

Chickens were used to investigate kinetic properties including metabolism of flumequine after single IV and oral dose, and to study tissue depletion of flumequine after multiple oral doses. Plasma and tissue (muscle, kidney, liver and skin plus fat) concentrations of flumequine and its metabolite 7-hydroxyflumequine were determined using a HPLC method. After IV and oral administration (single-dose of 12 mg flumequine/kg bw), plasma concentration-time curves were best described by a two-compartment open model. Elimination half-life and mean residence time of flumequine in plasma were 6.91 and 5.90 h, respectively, after IV administration and 10.32 and 8.95 h after oral administration. Maximum plasma concentration was 3.62 microg/ml and interval from oral administration until maximum concentration was 1.43 h. Oral bioavailability was found to be 57%. Flumequine was converted to 7-hydroxyflumequine. After oral administration (24 mg/kg bw every 24 h for 5 days), renal and hepatic concentrations of flumequine (18-25 microg/kg) persisted for 4 days; however, at that time, flumequine residues were not detected in skin plus fat and muscle tissues. Flumequine administered at a dosage of 24 mg/kg bw every 24h for 5 days, with a withdrawal time of 2d ays, resulted in flumequine concentrations in target tissues that were less than the European Union maximal residue limits.

Toxicokinetics of lambda-cyhalothrin in rats.

The toxicokinetics of lambda-cyhalothrin after single 20 mg kg(-1) oral and 3 mg kg(-1) intravenous doses were studied in rats. Serial blood samples were obtained after oral and intravenous administration. Liver, brain, spinal cord, sciatic nerve, vas deferens, anococcygeus and myenteric plexus tissue samples were also collected. Plasma, liver, hypothalamus, cerebellum, medulla oblongata, frontal cortex, striatum, hippocampus, midbrain, spinal cord, vas deferens, anococcygeus, myenteric plexus and sciatic nerve concentrations of lambda-cyhalothrin were determined by HPLC. The plasma and tissue concentration-time data for lambda-cyhalothrin were found to fit a two-compartment open model. For lambda-cyhalothrin, the elimination half-life (T1/2beta) and the mean residence time from plasma were 7.55 and 8.55 h after i.v. and 10.27 and 14.43 h after oral administration. The total plasma clearance was not influenced by dose concentration or route and reached a value of 0.060l h(-1)kg(-1). After i.v. administration, the apparent volume of distribution and at steady state were 0.68 and 0.53l kg(-1), suggesting a diffusion of the pyrethroid into tissue. After oral administration, lambda-cyhalothrin was extensively but slowly absorbed (Tmax, 2.69 h). The oral bioavailability was found to be 67.37%. Significant differences in the kinetic parameters between nervous tissues and plasma was observed. The maximum concentrations in hypothalamus (Cmax, 24.12 microg g(-1)) and myenteric plexus (Cmax, 25.12 microg g(-1)) were about 1.5 times higher than in plasma (Cmax, 15.65 microg ml(-1)) and 1.3 times higher than in liver (Cmax, 18.42 microg ml(-1)). Nervous tissue accumulation of lambda-cyhalothrin was also reflected by the area under the concentration curve ratios of tissue/plasma (liver). The T1/2beta for lambda-cyhalothrin was significantly greater for the nerve tissues, including neuromuscular fibres, (range 12-26 and 15-34 h, after i.v. and oral doses) than for plasma (7.55 and 10.27 h, respectively).

Clasificación toxicológica, envasado y etiquetado de productos químicos / Toxicological classification, packaging and labelling of chemical products

Las Organizaciones Internacionales han desarrollado a lo largo de los años normas legales, reglamentarias y administrativas relativas al uso de sustancias peligrosas que permiten la transmisión de la información de prevención y control, mediante etiquetas o fichas de datos de seguridad, a los usuarios de dichos productos químicos. A este respecto, la Unión Europea ha introducido legislación específica diseñada para proteger la salud humana y el medio ambiente. Una correcta clasificación, envasado y etiquetado de los productos químicos es fundamental para identificar los peligros derivados de sus usos. La etiqueta es, a menudo, la única información de los peligros de la que disponen tanto los usuarios como los trabajadores. En materia de sustancias y preparados peligrosos existe legislación europea desde 1967, fecha en que se reconoció que las disposiciones nacionales sobre clasificación, envasado y etiquetado de productos químicos (fundamentalmente productos industriales peligrosos) debían de armonizarse en el seno de la Unión Europea para la prevención y control de los riesgos derivados, y para eliminar las barreras comerciales que podían suponer las disposiciones nacionales en los Estados miembros. El objetivo de este trabajo es presentar una revisión de toda la legislación en la Unión Europea sobre clasificación, envasado y etiquetado de productos químicos y los principios de su evaluación del riesgo

The International Agencies have developed the approximation of laws, regulations and administrative provisions relating to the use of dangerous substances which make possible to transfer information for protecting the public and control these products with requirements concerning labelling and safety data sheets. The European Union has introduced specific legislation designed to protect human health and the environment. A good classification, packaging and labelling of chemical products is basic to identify the hazards of the uses. The labelling is the first and often the only information on the hazards of a chemical that reaches the user, which could be a consumer or a worker. There are european legislation about dangerous susbstances and preparations since 1967, which it was recognized that the national dispositions about classification, packaging and labelling of chemicals should be harmonised in the European Union to prevent and control the risks from chemicals and eliminate barriers. The aim of this paper is to review the current legislation in the European Union on classification, packaging and labelling of chemicals and the principles of their risk assessment

Regulation of genetically modified organisms (GMOs) in the European Union: principles of risk assessment.

The establishment of regulations for genetically modified organisms and the application of environmental risk assessment principles within the European Union are documented.

Pharmacokinetics of amoxycillin and the rate of depletion of its residues in pigs.

Six pigs were used in a two-period crossover study to investigate the pharmacokinetics of amoxycillin after single intravenous and oral doses of 20 mg/kg bodyweight. Twelve pigs were used to study the residues of the drug in muscle, kidney, liver and fat after they had received daily oral doses of 20 mg/kg amoxycillin for five days. The mean (sd) elimination half life (t1/2beta) and mean residence time of amoxycillin in plasma were 3.38 (0.30) and 3.54 (0.43) hours, respectively, after intravenous administration and 4.13 (0.50) and 4.47 (0.30) hours, respectively, after oral administration. After oral administration, the maximum plasma concentration (Cmax) was 7.37 (0.42) microg/ml and it was reached after 0.97 (0.29) hours. Six days after the last oral dose, the mean concentration of amoxycillin in the pigs' kidneys was 21.38 ng/g and in the liver it was 12.32 ng/g, but no amoxycillin could be detected in fat or muscle; the concentrations of amoxycillin in edible tissues were less than the European Union maximal residue limit of 50 microg/kg.

Ricina: una fitotoxina de uso potencial como arma / Ricin: a phytotoxin with potential use as a weapon

La ricina es una fitotoxina con actividad citotóxica que está presente en las semillas de ricino ( Ricinus communis L.). Su estructura consta de dos cadenas polipeptídicas: una con propiedades de lectina, que le permite fijarse a glicolípidos y glicoproteínas presentes en la superficie de la membrana celular, y otra capaz de inhibir la síntesis de proteínas a nivel de los ribosomas. El acceso desde la superficie de la célula hasta los ribosomas supone un complejo proceso que incluye un transporte retrógrado desde el aparato de Golgi hasta el retículo endoplasmático, donde se produce la translocación al citosol. Hoy se sabe que algunas publicaciones paramilitares y manuales relacionados con la red terrorista Al Qaeda explican procedimientos para la extracción de ricina a partir de las semillas de ricino. Esto ha llevado a la actual preocupación por que la ricina pueda ser empleada con fines terroristas. La ricina fue incluida en los programas de armamento químico y biológico de distintos países, en los que se comprobó la dificultad que presenta para ser diseminada de forma eficaz con el fin de causar un elevado número de afectados. Las ventajas que presentaría la intoxicación por ricina, utilizada como arma, incluyen: un período de latencia de varias horas; la poca especificidad de los síntomas y signos por cualquier vía de exposición; y la inexistencia de un tratamiento antidótico (AU)

Ricin is a phytotoxin with cytotoxic activity present in castor plant ( Ricinus communis L.) seeds. Its structure consists of two polypeptide chains: one with lectin properties that allows it to bind to glycoproteins and glycolipids on the cell surface and the other one which inhibits protein synthesis at the ribosomes level. Access of the toxin from the cell surface to the ribosomes is a complex process with retrograde transport from the Golgi complex to the endoplasmic reticulum, followed by translocation to the cytosol. It is now known that some paramilitary publications and manuals related to the Al Qaeda terrorist network detail procedures regarding the method for extracting ricin from the castor plant seeds. This has increased the fear that ricin may be used for terrorist purposes. Ricin has been part of the chemical and biological weapons programs in different countries and it was found that this toxin is not easy to disseminate for the purpose of causing a large number of casualties. Advantages of ricin intoxication, if used as a weapon, include a latency period of several hours; nonspecific symptoms and signs regardless of the exposure route; and the lack of an antidotal treatment (AU)

Estado actual del pretratamiento de las intoxicaciones por agentes neurotóxicos de guerra con piridostigmina y otras alternativas farmacológicas / Current status of nerve agent intoxication pretreatment with pyridostigmine and other pharmacological alternatives

El bromuro de piridostigmina (bromuro de 3-dimetilaminocarboniloxi-N-metilpiridinio) se utiliza como pretratamiento en escenarios en los que existe riesgo de utilización de agentes neurotóxicos de guerra. De hecho, este pretratamiento fue utilizado por las tropas Aliadas durante la Guerra del Golfo Pérsico. Desde su vuelta a casa muchos veteranos de esta guerra se han quejado de padecer síntomas debidos a lesiones que afectan al sistema nervioso. Las causas de estos síntomas son aún desconocidas, pero el pretratamiento con piridostigmina se está estudiando como posible factor causal. Aunque a la dosis empleada en el pretratamiento los efectos secundarios son mínimos y no se han observado efectos a largo plazo, se ha planteado la posibilidad de que en situaciones de estrés los efectos de la piridostigmina a nivel del sistema nervioso central se vean incrementados, si bien los distintos estudios in vivo arrojan resultados contradictorios. Otros estudios in vivo, sin embargo, sí han observado un incremento de la actividad central de la piridostigmina al coadministrarse con DEET (N,N-dietil-m-toluamida), utilizado como repelente de insectos por algunas tropas durante la Guerra del Golfo Pérsico. Este hecho recomendaría la necesidad de controlar la utilización de repelentes de insectos en caso de que sea necesario llevar a cabo un pretratamiento con piridostigmina. Recientemente se han empezado a estudiar nuevas alternativas en el pretratamiento de las intoxicaciones por agentes neurotóxicos de guerra de las cuales destaca la huperzina A (9-amino-13-etilidén-11-metil-4-azatriciclo[7.3.1.0(3,8)]trideca-3(8),6,11-trien-5-ona) por sus propiedades farmacocinéticas y mayor eficacia. (AU)

Scientific basis and regulatory aspects for the toxicology of plant protection products in the European Union.

Authorization of plant protection products/agrochemicals/pesticides in the European Union is done on the basis of their toxicological properties. This paper reviews the current legislation for placing an agrochemical on the market (ie a new substance or a existing active substance), and the toxicology studies needed for inclusion of a substance in any of the annexes of the Council Directive of the European Economic Community 91/414/ EEC. Risk analysis and its steps is discussed. The "threshold toxicity" employed to allow risk characterisation of plant protection products is described, such as acceptable daily intake, acceptable operator exposure level, acute reference dose, and maximum admissible concentration in water.

Pharmacokinetics and residues of ciprofloxacin and its metabolites in broiler chickens.

The pharmacokinetic properties of ciprofloxacin and its metabolites were determined in healthy chickens after single i.v. and oral dosage of 8 mg ciprofloxacin kg(-1) bodyweight. After i.v. and oral administration, the plasma concentration-time graph was characteristic of a two-compartment open model. Mean (SD) elimination half-life and mean residence time of ciprofloxacin in plasma were 8.84 (2.13) and 8.54 (1.64) hours, respectively, after i.v. administration and 11.89 (1.95) and 13.32 (2.65) hours, respectively, after oral administration. Mean maximal plasma concentration of ciprofloxacin was 2.63 (0.20) microg ml(-1), and the interval from oral administration until maximum concentration was 0.36 (0.07) hours. The mean oral bioavailability of ciprofloxacin was found to be 69.12 (6.95) per cent. Ciprofloxacin was mainly converted to oxociprofloxacin and desethyleneciprofloxacin. Considerable kidney, liver, muscle and skin + fat tissue concentrations of ciprofloxacin and its metabolites oxociprofloxacin and desethyleneciprofloxacin were found when ciprofloxacin was administered orally (8 mg kg(-1) on 3 successive days). It was estimated that mean tissue concentrations of ciprofloxacin and its metabolites ranging between 0.011 to 0.75 microg g(-1) persisted for 5 days.