Experimental study on the toxicokinetics and gastrointestinal damage in rats poisoned with acute diquat poisoning at different exposure doses / 中华危重病急救医学

OBJECTIVE@#To observe the toxicokinetic parameters, absorption characteristics and pathomorphological damage in different parts of the gastrointestinal tract of rats poisoned with different doses of diquat (DQ).@*METHODS@#Ninety-six healthy male Wistar rats were randomly divided into a control group (six rats) and low (115.5 mg/kg), medium (231.0 mg/kg) and high (346.5 mg/kg) dose DQ poisoning groups (thirty rats in each dose group), and then the poisoning groups were randomly divided into 5 subgroups according to the time after exposure (15 minutes and 1, 3, 12, 36 hours; six rats in each subgroup). All rats in the exposure groups were given a single dose of DQ by gavage. Rats in the control group was given the same amount of saline by gavage. The general condition of the rats was recorded. Blood was collected from the inner canthus of the eye at 3 time points in each subgroup, and rats were sacrificed after the third blood collection to obtain gastrointestinal specimens. DQ concentrations in plasma and tissues were determined by ultra-high performance liquid chromatography and mass spectrometry (UPHLC-MS), and the toxic concentration-time curves were plotted to calculate the toxicokinetic parameters; the morphological structure of the intestine was observed under light microscopy, and the villi height and crypt depth were determined and the ratio (V/C) was calculated.@*RESULTS@#DQ was detected in the plasma of the rats in the low, medium and high dose groups 5 minutes after exposure. The time to maximum plasma concentration (Tmax) was (0.85±0.22), (0.75±0.25) and (0.25±0.00) hours, respectively. The trend of plasma DQ concentration over time was similar in the three dose groups, but the plasma DQ concentration increased again at 36 hours in the high dose group. In terms of DQ concentration in gastrointestinal tissues, the highest concentrations of DQ were found in the stomach and small intestine from 15 minutes to 1 hour and in the colon at 3 hours. By 36 hours after poisoning, the concentrations of DQ in all parts of the stomach and intestine in the low and medium dose groups had decreased to lower levels. Gastrointestinal tissue (except jejunum) DQ concentrations in the high dose group tended to increase from 12 hours. Higher doses of DQ were still detectable [gastric, duodenal, ileal and colonic DQ concentrations of 6 400.0 (1 232.5), 4 889.0 (6 070.5), 10 300.0 (3 565.0) and 1 835.0 (202.5) mg/kg respectively]. Light microscopic observation of morphological and histopathological changes in the intestine shows that acute damage to the stomach, duodenum and jejunum of rats was observed 15 minutes after each dose of DQ, pathological lesions were observed in the ileum and colon 1 hour after exposure, the most severe gastrointestinal injury occurred at 12 hours, significant reduction in villi height, significant increase in crypt depth and lowest V/C ratio in all segments of the small intestine, damage begins to diminish by 36-hour post-intoxication. At the same time, morphological and histopathological damage to the intestine of rats at all time points increased significantly with increasing doses of the toxin.@*CONCLUSIONS@#The absorption of DQ in the digestive tract is rapid, and all segments of the gastrointestinal tract may absorb DQ. The toxicokinetics of DQ-tainted rats at different times and doses have different characteristics. In terms of timing, gastrointestinal damage was seen at 15 minutes after DQ, and began to diminish at 36 hours. In terms of dose, Tmax was advanced with the increase of dose and the peak time was shorter. The damage to the digestive system of DQ is closely related to the dose and retention time of the poison exposure.

In Vitro and In Vivo evaluation of montmorillonite for paraquat poisoning

Abstract Evaluation of montmorillonite for paraquat by in vitro and in vivo test. In vitro test were evaluated by a batch test, taking the paraquat concentration, adsorbents, reaction environment and time as indices, the absorption rate was screened by orthogonal design. In vivo test was executed with rabbits. Group 1: 4 rabbits dosed with montmorillonite. Group 2: 8 rabbits dosed with 200 mg/kg paraquat. Group 3: 6 rabbits dosed with 200 mg/kg paraquat then gavage with montmorillonite 5 min later. Group 4: 6 rabbits dosed with 200 mg/kg paraquat then gavage with montmorillonite 30 min later. Blood paraquat concentration, serum cytokines, blood gas analysis and histopathology of lung were implemented. In vitro test found that all the four factors influence the absorption rate of paraquat (P < 0.05). In vitro test found that oral montmorillonite could change toxicokinetics parameters of paraquat (P < 0.05); decrease raised serum TGF-ß1 and HMGB1 (P < 0.05) and alleviate the histopathology damage of lung. Montmorillonite might exert its protective effects on paraquat induced damage

Intoxicaciones agudas por medicamentos consumidos con fines de abuso / Acute poisoning due to medications used for abuse purposes

Introducción: El consumo de sustancias con fines de abuso y entre ellas los medicamentos, se ha incrementado a nivel mundial. Objetivo: Caracterizar a los pacientes atendidos por intoxicaciones agudas debido a medicamentos consumidos con fines de abuso. Métodos: El universo estuvo constituido por consultas de 961 pacientes, realizadas al servicio de información toxicológica de urgencia del Centro Nacional de Toxicología, durante el período 2010 al 2014. Fueron todas las intoxicaciones agudas por consumo de sustancias con fines de abuso. La serie incluyó 578 pacientes con intoxicaciones agudas con fines de abuso, donde el agente causal fueron los medicamentos. Se recopilaron los datos sociales y biológicos, formas de consumo, grupos farmacológicos, manifestaciones clínicas, aspectos de la toxicocinética y la toxicodinamia. Resultados: Los consumidores de medicamentos con fines de abuso, representaron el 60,14 por ciento de las consultas por consumo de sustancias con fines de abuso. El grupo etario de hasta 20 años fue el de mayor consumo (360 consultas; 62,28 por ciento) y el sexo masculino el más frecuente (447 pacientes; 77,3 por ciento). La combinación de medicamentos más alcohol fue la forma de consumo más empleada (292 consultas; 50,5 por ciento). La carbamazepina fue el medicamento más consumido (305 consultas; 52,7 por ciento). Conclusiones: Predominó la intoxicación aguda en el grupo etario de 10-20 años y del sexo masculino. La ingestión de medicamentos más alcohol, fue la forma de consumo más empleada. El grupo farmacológico más utilizado con fines no médicos, fue el de los anticonvulsivantes (carbamazepina), seguido de las benzodiacepinas y los opiáceos. Las manifestaciones clínicas que predominaron fueron del sistema neurológico, seguido del cardiovascular y el digestivo(AU)

ABSTRACT Introduction: The consumption of substances for the purpose of abuse, including drugs, has increased worldwide. Objective: To characterize patients treated for acute intoxications due to drugs consumed for abuse purposes. Methods: The universe was constituted by consultations of 961 patients, made to the emergency toxicology information service of the National Center of Toxicology, during the period from 2010 to 2014. They were all acute intoxications due to the consumption of substances for the purpose of abuse. The series included 578 patients with acute intoxications for abuse, where the causative agent was medication. We collected social and biological data, forms of consumption, pharmacological groups, clinical manifestations, aspects of toxicokinetics and toxicodynamics. Results: Consumers of medications for the purpose of abuse accounted for 60.14 percent of consultations for the consumption of substances for the purpose of abuse. The age group of up to 20 years consumed the most (360 consultations, 62.28 percent) and the most frequent was the male sex (447 patients, 77.3 percent). The combination of drugs plus alcohol was the most used form of consumption (292 consultations, 50.5 percent). Carbamazepine was the most commonly used medication (305 consultations, 52.7 percent). Conclusions: Acute intoxication predominated in the age group of 10-20 years and of the male sex. The ingestion of drugs plus alcohol was the most used form of consumption. The most used pharmacological group for non-medical purposes was the anticonvulsant group (carbamazepine), followed by benzodiazepines and opiates. The clinical manifestations that predominated were of the neurological system, followed by cardiovascular and digestive(AU)

Determination of the Content of 4-FMA in Rat Plasma Samples by HPLC-MS/MS Method / 法医学杂志

Objective To develop a high performance liquid chromatography-tandem mass spectrometry （HPLC-MS/MS） method for the determination of the content of 4-fluoromethamphetamine （4-FMA） in rat plasma, and to provide a methodological basis for the study of the toxicokinetics of 4-FMA in rats. Methods Rat plasma samples were added into internal standard methamphetamine （MA）. Its proteins were precipitated with methanol and then separated with Poroshell 120 EC-C18 chromatographic column. A 0.1% formic acid aqueous solution and a 0.1% formic acid acetonitrile solution were used as the mobile phase at the flow rate of 0.4 mL/min. Electrospray ionization source was used for detection in the multiple reaction monitoring （MRM） mode. Results The linear relationship was good when the mass concentration of 4-FMA in plasma samples was in the range of 5-1 000 ng/mL （r>0.999）. The limit of detection （LOD） was 3 ng/mL and the limit of quantification （LOQ） was 5 ng/mL. The accuracy was expressed as relative error （RE）, and in the range of ±5%, the intra-day precision and inter-day precision （relative standard deviation, RSD） less than 9%, and the extraction recovery rate was more than 90%. The analysis and detection of plasma samples were completed within 2.5 min. Conclusion This study developed a HPLC-MS/MS method for the determination of 4-FMA in rat plasma samples. This method is accurate, rapid, simple and sensitive and can be applied to the study of toxicokinetics of 4-FMA.

Long-circulating and target-specific distributions of cyanine 5.5-labeled hyaluronic acid nanoparticles in mouse organs during 28 days after a single administration / 대한수의학회지

Although hyaluronic acid (HA) has been developed as a nanoparticle (NP; 320–400 nm) for a drug delivery system, the tissue targeting efficacy and the pharmacokinetics of HA-NPs are not yet fully understood. After a dose of 5 mg/kg of cyanine 5.5-labeled HA-NPs or HA-polymers was intravenously administrated into mice, the fluorescence was measured from 0.5 h to 28 days. The HA-NPs fluorescence was generally stronger than that of HA-polymers, which was maintained at a high level over 7 days in vivo, after which it gradually decreased. Upon ex vivo imaging, liver, spleen, kidney, lung, testis and sublingual gland fluorescences were much higher than that of other organs. The fluorescence of HA-NPs in the liver, spleen and kidney was highest at 30 min, where it was generally maintained until 4 h, while it drastically decreased at 1 day. However, the fluorescence in the liver and spleen increased sharply at 7 days relative to 3 days, then decreased drastically at 14 days. Conversely, the fluorescence of HA-polymers in the lymph node was higher than that of HA-NPs. The results presented herein may have important clinical implications regarding the safety of as self-assembled HA-NPs, which can be widely used in biomedical applications.

Relação entre concentração sanguínea de cocaí­na e cocaetileno com a gravidade das manifestações clí­nicas apresentadas por pacientes com diagnóstico de intoxicação por cocaína / Relationship between blood concentration of cocaine and cocaethylene with the severity of clinical manifestations presented by patients diagnosed with cocaine intoxication

As intoxicações decorrentes do uso de drogas de abuso representam atualmente um grave problema para a saúde pública. Dentre os principais agentes envolvidos, destaca-se a cocaína. Ela se tornou uma das drogas mais consumidas ao redor do mundo, sendo um dos principais motivos de atendimentos em pronto-socorro (PS) devido ao uso de substâncias ilícitas. Seu uso ocorre principalmente em associação com bebida alcóolica. Existem poucos estudos realizados que relacionem a concentração sanguínea de cocaína e a gravidade das manifestações clínicas em populações que a utilizam como droga de abuso, e que envolvam pacientes atendidos em PS. O objetivo do presente estudo foi verificar a possível relação entre concentração sanguínea de cocaína e cocaetileno (produto da interação de cocaína com etanol) com a gravidade das manifestações clínicas apresentadas por pacientes com hipótese diagnóstica de intoxicação por cocaína. As concentrações sanguíneas foram determinadas por cromatografia líquida de alta eficiência (HPLC) e a gravidade das manifestações clínicas foi avaliada através do Stimulant Intoxication Score (SIS). Dos 81 pacientes incluídos no estudo 77,8% são homens com idade média de 32,5 anos ± 8,5 e SIS médio de 3,4 ± 2,5. Do total de pacientes incluídos no estudo 20 (24,7%) tiveram resultados positivos em sangue para os analitos de interesse, sendo a concentração sanguínea média de cocaína igual a 0,34 µg/mL ± 0,45 e de cocaetileno igual a 0,38 µg/mL ± 0,34. A concentração sanguínea de cocaína e cocaetileno não se mostrou informação útil para tratamento e prognóstico dos pacientes, porém a detecção no sangue destas substâncias no momento do atendimento, independentemente de sua concentração, pode ser um indicador de gravidade, mostrando que quaisquer concentrações destas substâncias devem ser consideradas potencialmente tóxicas. A aplicação do score SIS revelou-se como importante alternativa capaz de predizer a gravidade dos pacientes atendidos devido a intoxicação por cocaína de maneira rápida e simplificada

Currently, poisoning resulting from the abuse of drug represents a serious problem for public health. Among the main agents involved, cocaine stands out. It became one of the most abused drugs around the world, being one of the main reasons for visits to the emergency room due to the use of illicit substances. The use of cocaine is primarily in combination with alcoholic beverages. There are few studies that relate cocaine blood concentration and the severity of its clinical manifestations in patients attended in the Emergency Room. The aim of the present study was to verify the possible relationship between the blood concentration of cocaine and cocaethylene (product of the interaction of cocaine with ethanol) with the severity of the clinical manifestations presented by patients with cocaine intoxication. Blood levels were measured by high-performance liquid chromatography (HPLC) and the severity of clinical manifestations was assessed using the Stimulant Intoxication Score (SIS). Of the 81 patients included in the study, 77.8% were men with a mean age of 32.5 years ± 8.5 and mean of SIS 3.4 ± 2.5. From the total of patients included in the study 20 (24.7%) had positive blood results for the analytes of interest, being the mean blood concentration of cocaine equal to 0,34 µg/mL ± 0,45 and of cocaethylene equal to 0,38 µg/mL ± 0,34. The blood concentration of cocaine and cocaethylene has not been shown to be useful information for the treatment and prognosis of patients, but blood levels of these substances at the time of treatment, regardless of their concentration, may be an indicator of severity, showing that any concentrations of these substances should be considered as potentially toxic. The application of the SIS score proved to be an important alternative capable of predicting the severity of the patients attended due to cocaine intoxication in a fast and simplified way

Toxicant-nutrient interaction as a veritable host resistance against chemical toxicity in the rapidly industrializing developing nations

Growing evidence indicates that chemical utilization including toxic waste in the developing countries is on the increase. These nations have limited facilities for sound chemical management involving production, use and disposal of chemicals with minimal adverse effects on human and environmental health. Though concerns are important to all nations, they appear particularly salient to the industrializing countries under pressures to achieve development and eradicate poverty yet with limited capacity for sound chemical management. This increases the risk of chemical toxicity, with consequences such as genotoxicity, cancer and teratogenicity. The growing chemical burden implies the need for an efficient and effective means of xenobiotic metabolism and host resistance. Relevant literature on nutrients and toxicants interaction in various search engines were reviewed. The possible role of host resistance, essentially involving nutritional modulation has been ignored. Nutrient-toxicant response pathways could be affordable strategies against excessive chemical exposure. Zinc, a prime micronutrient is an antioxidant [Cu-Zn superoxide dismutase (SOD)], component of p53, guardian of the genome; active in the repair of DNA damage and apoptosis; protective against carcinogenesis. Zinc also plays an important role in vitamin A metabolism, in turn important in differentiation and central to retinoids involved in gene expression. Zinc is important in all the stages of the cell cycle, derangement of which may be a pathway to carcinogenesis. Use of this and other protective nutrients including folate and selenium, among others, appears a veritable approach to improving host resistance against chemical toxicity and should be considered promising in developing nations

Preclinical development of a humanized neutralizing antibody targeting HGF

Hepatocyte growth factor (HGF) and its receptor, cMET, play critical roles in cell proliferation, angiogenesis and invasion in a wide variety of cancers. We therefore examined the anti-tumor activity of the humanized monoclonal anti-HGF antibody, YYB-101, in nude mice bearing human glioblastoma xenografts as a single agent or in combination with temozolomide. HGF neutralization, The extracellular signal-related kinases 1 and 2 (ERK1/2) phosphorylation, and HGF-induced scattering were assessed in HGF-expressing cell lines treated with YYB-101. To support clinical development, we also evaluated the preclinical pharmacokinetics and toxicokinetics in cynomolgus monkeys, and human and cynomolgus monkey tissue was stained with YYB-101 to test tissue cross-reactivity. We found that YYB-101 inhibited cMET activation in vitro and suppressed tumor growth in the orthotopic mouse model of human glioblastoma. Combination treatment with YYB-101 and temozolomide decreased tumor growth and increased overall survival compared with the effects of either agent alone. Five cancer-related genes (TMEM119, FST, RSPO3, ROS1 and NBL1) were overexpressed in YYB-101-treated mice that showed tumor regrowth. In the tissue cross-reactivity assay, critical cross-reactivity was not observed. The terminal elimination half-life was 21.7 days. Taken together, the in vitro and in vivo data demonstrated the anti-tumor efficacy of YYB-101, which appeared to be mediated by blocking the HGF/cMET interaction. The preclinical pharmacokinetics, toxicokinetics and tissue cross-reactivity data support the clinical development of YYB-101 for advanced cancer.

Low-Dose Bisphenol A Increases Bile Duct Proliferation in Juvenile Rats: A Possible Evidence for Risk of Liver Cancer in the Exposed Population?

Increasing concern is being given to the association between risk of cancer and exposure to low-dose bisphenol A (BPA), especially in young-aged population. In this study, we investigated the effects of repeated oral treatment of low to high dose BPA in juvenile Sprague-Dawley rats. Exposing juvenile rats to BPA (0, 0.5, 5, 50, and 250 mg/kg oral gavage) from post-natal day 9 for 90 days resulted in higher food intakes and increased body weights in biphasic dose-effect relationship. Male mammary glands were atrophied at high dose, which coincided with sexual pre-maturation of females. Notably, proliferative changes with altered cell foci and focal inflammation were observed around bile ducts in the liver of all BPA-dosed groups in males, which achieved statistical significance from 0.5 mg/kg (ANOVA, Dunnett’s test, p<0.05). Toxicokinetic analysis revealed that systemic exposure to BPA was greater at early age (e.g., 210-fold in C(max), and 26-fold in AUC at 50 mg/kg in male on day 1 over day 90) and in females (e.g., 4-fold in C(max) and 1.6-fold in AUC at 50 mg/kg vs. male on day 1), which might have stemmed from either age- or gender-dependent differences in metabolic capacity. These results may serve as evidence for the association between risk of cancer and exposure to low-dose BPA, especially in young children, as well as for varying toxicity of xenobiotics in different age and gender groups.

Cocaína / Cocaine

La cocaína es la droga ilícita que provoca mayor demanda por urgencias en centros asistenciales de Argentina, luego del alcohol y los medicamentos. Pertenece al grupo de drogas simpaticomiméticas y estimulantes del Sistema Nervioso Central. Es el principal alcaloide de un arbusto perteneciente a la especie Erythroxylon, originario de los Andes. Existen varias formas de producir cocaína para sus diferentes formas de consumo. Los cultivadores pueden comercializar la hoja de coca o procesarla hasta pasta de coca o base de cocaína y en laboratorios clandestinos transformarse en clorhidrato de cocaína. En la búsqueda de euforia y agitación entre otros efectos, el consumo agudo puede producir daño en casi todos los órganos como consecuencia del vasoespasmo, hemorragias vasculares y alteraciones en la coagulación. La ingesta crónica puede producir agitación psicomotriz, anorexia, pérdida de peso, miocardiopatías, insuficiencia renal, deterioro mental y alucinaciones. La suspensión abrupta puede desencadenar un síndrome de abstinencia psicológica y física...

The rabbit experimental study for toxicokinetics of chlorpyrifos impacted by hemoperfusion / 中华劳动卫生职业病杂志

<p><b>OBJECTIVE</b>To investigate toxicokinetic parameters impacted by hemoperfusion after oral chlorpyrifos exposure, to investigate the adsorption effect of hemoperhusion for chlorpyrifos poisoning.</p><p><b>METHODS</b>12 rabbits were divided into two groups after oral exposure with chlorpyrifos 300 mg/kg body weight. Control group: without hemoperfusion; hemoperfusion group: hemoperfusion starts 0.5 h after chlorpyrifos exposure and lasts for 2h. Blood samples were collected at different times, concentrations of chlorpyrifos were tested by GC, then, toxicokinetic parameterswere calculated and analysis by DAS3.0.</p><p><b>RESULTS</b>In hemoperfusion group, peak time was (7.19±3.74) h, peak concentrations was (1.37±0.56) mg/L, clearance rate was (13.93±10.27) L/h/kg, apparent volume of distribution was (418.18±147.15) L/kg The difference of these parameter were statistically significant compared with control group (P<0.05).</p><p><b>CONCLUSION</b>Hmoperfusion will decrease the inner exposure and load dose of rabbits with chlorpyrifos poisoning.</p>

Toxicokinetics of bakuchiol, hepatic and renal toxicity in rats after single oral administration of Psoraleae Fructus and combination with Glycyrrhizae Radix et Rhizoma / 中国中药杂志

To study the toxicokinetics of bakuchiol, hepatic and renal toxicity in rats after single oral administration of Psoraleae Fructus and combined with Glycyrrhizae Radix et Rhizoma, in order to provide scientific evidences for clinical safe medication use. A total of 35 SD rats were randomly divided into seven groups: vehicle (distilled water) control group, Glycyrrhizae Radix et Rhizoma group, positive control (aristolochic acid A) group, Psoraleae Fructus (40 g x kg(-1)) group( both male and female rats), Psoraleae Fructus and Glycyrrhizae Radix et Rhizoma (40 +20) g x kg(-1) group (both male and female rats). HPLC-UV method was used to determine the concentration of bakuchiol in rat plasma at different time points after single oral administration. Plasma alanine transaminase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), plasma creatinine (Cr), N-acetyl-β-D-glucosaminidase (NAG) and kidney injury molecule 1 (Kim-1) were measured after administration for 24 h. The main toxicokinetics parameters of bakuchiol in rats exert significantly gender difference. When Psoraleae Fructus combination with Glycyrrhizae Radix et Rhizoma, the total area under the plasma concentration-time curve( AUC), C(max), and plasma clearance (CL) of bakuchiol were increased, respectively; CL, half-life (t½) were decreased, and T(max) were prolonged. The biochemical indicators (including ALT, AST, BUN, Cr and KIM-1 level) in different dose of Psoraleae Fructus groups, were found no statistically significant difference when compared with vehicle control group. The level of NAG in both Psoraleae Fructus and compatibility with Glycyrrhizae Radix et Rhizoma groups were significant increased (P < 0.05). There are obvious effects on toxicokinetics of bakuchiol in rats when Psoraleae Fructus combined with Glycyrrhizae Radix et Rhizoma. Renal toxicity induced by Psoraleae Fructus at high dose was observed after single oral administration and no liver damage in rats was found.

Avaliação de aberrações cromossômicas em trabalhadores de postos de gasolina da Zona Oeste do Rio de Janeiro / Avaliação de aberrações cromossômicas em trabalhadores de postos de gasolina da Zona Oeste do Rio de Janeiro

No âmbito da saúde ocupacional, as exposições a agentes químicos recebem cada vez mais atenção. Pela análise de bioindicadores, se faz possível identificar e quantificar substâncias nocivas à saúde e seus efeitos. Trabalhadores de postos de revenda de combustíveis veiculares (PRCV) estão expostos a uma mistura de hidrocarbonetos policíclicos aromáticos (HPAs) proveniente da gasolina, e nesta mistura encontra-se o benzeno, composto hematotóxico e carcinogênico, sem níveis seguros no ambiente, fato que corrobora para a importância de ações em vigilância ocupacional nesta área. O presente estudo avaliou os efeitos genotóxicos, através do teste de Aberrações cromossômicas (ACs), de uma exposição ocupacional aos vapores de gasolina em frentistas da Zona Oeste do Rio de Janeiro. O projeto central foi aprovado pelo Comitê de Ética em Pesquisa da Ensp/Fiocruz (CAAE17438013.5.0000.5240, parecer 434.418). 39 trabalhadores de seis PRCV da área programática 5.3 (bairros de Santa Cruz, Paciência e Sepetiba) responderam a dois questionários sobre fatores socioeconômicos, processo de trabalho e histórico de saúde; amostras de sangue e urina foram coletadas para determinação de hemograma, análises bioquímicas, ACs e ácido trans, trans-mucônico urinário (ATTM). Os voluntários não apresentaram histórico de doenças de possível associação com a exposição, assim os resultados de hemograma e bioquímica, em valores médios, ficaram dentro das faixas de normalidade. Os processos de trabalho e hábitos dos trabalhadores foram avaliados e não apresentaram relação com as ACs. (...) Os resultados sugerem que o teste de ACs não deve ser utilizado de forma isolada para avaliar exposições a baixas doses de benzeno por sua inespecificidade, mas ainda representa uma ferramenta útil na avaliação de dano precoce à saúde humana...

On the Occupational Health field, exposure to chemical agents is getting more attention, since technologies’ advances allow identification of health early effects caused by such exposures. By the use of bioindicator’s analysis, it is possible to identify and quantify harmful substances and their effects. Gas station workers are exposed to a hidrocarbon’s mixture from gasoline, in which can be found benzene, carcinogenic and hematotoxic substance, with no safe levels on environment, reinforcing the need of occupational vigilance actions. This study evaluated the genotoxic effecs, using the chromosomal aberration’s test (CAs), of an occupational exposure to gasoline fumes in gas station workers from Rio de Janeiro’s West Side. The main project was approved by Ensp/Fiocruz Research’s Ethics Committee (CAAE 17438013.5.0000.5240, case 434.418). Thirty-nine workers from six gas stations from the districts of Santa Cruz, Paciência and Sepetiba answered questionnaires concerning socio-demographic, work and health questions; blood and urine samples were taken to assess CBC, biochemical factors, trans, trans-muconic acid (TTMA) and chromosomal aberrations. The subjects did not report history of diseases that could be related to the exposure, so the results of CBC and biochemical factors were at normality ranges. Work processes and the subjects’habits were assessed and were not associated to CAs. TTMA measurement and statistical evaluation through ANOVA showed a correlation between this metabolite and smoking habit (...), and the high concentration gets along with literature. (...) The results suggest chromosomal aberrations test shall not be used as the only mechanism to evaluate benzene exposure at lower doses for its inespecificity, but the test is, for it self, a useful feature for early human health damage evaluation...

Dependencia de la dosis en los mecanismos de toxicidad y la evaluación de riesgo en toxicología / Dose-dependent transitions in mechanisms of toxicity and risk assessment in toxicology / Dependencia da dosagem nos mecanismos de toxicidade e avaliagáo de risco em toxicologia

En la Toxicología se presentan desafíos derivados de la complejidad creciente de los escenarios ambientales que condicionan a muchas enfermedades humanas. Cuando se analiza la curva dosis-respuesta tóxica, frecuentemente se hace evidente que pueden existir varios procesos subyacentes para la acción de cualquier xenobiótico sobre un organismo vivo. Es muy probable que los pasos críticos, limitantes en cualquier mecanismo de toxicidad, puedan verse sobrepasados con exposiciones más grandes, señalando esto la emergencia de modos nuevos de injuria tisular a dosis más altas. Por lo tanto, pueden ocurrir transiciones dependientes de la dosis en el mecanismo principal de toxicidad, que tendrían un impacto significativo en la interpretación de la colección de los datos de referencia para la evaluación del riesgo. Una explicación para las relaciones lineales dosis-respuesta en serie es la transición dosis-dependiente entre una secuencia de pasos encadenados mecanística-mente, pasos limitantes de la velocidad saturables en el proceso total, que llevan desde la exposición a la expresión de uno o más modos para la respuesta tóxica. El análisis de estos fenómenos tiene una relevancia muy grande en términos prácticos, esto es, para las consecuencias sobre la regulación del uso y exposición a sustancias peligrosas en distintos ámbitos humanos.

In Toxicology, many challenges arise from the increasing complexity of environmental scenarios conditioning human diseases. When analyzing the toxic dose response, it often becomes apparent that there may be several underlying processes for any xenobiotic action on a living organism. It is likely that the critical steps, limiting in any mechanism of toxicity, may be overwhelmed with increased exposure, indicating the emergence of new forms of tissue injury at higher doses. Therefore, transitions might occur in a dose-dependent manner in the main mechanism for toxicity, having a significant impact on the performance of the collection of baseline data for risk assessment. One explanation for the linear dose-response relationships in series is dose-dependent transition from a sequence of steps chained mechanistically, saturable rate limiting steps in the process, leading from exposition to the expression of one or more forms of toxic response. The analysis of these phenomena has a great relevance in practical terms, that is, to the effects on the regulation of the use and exposure to hazardous substances in different human situations.

Em Toxicologia apresentam-se desafios decorrentes da complexidade crescente dos cenários ambientais que condicionam muitas doengas humanas. Ao analisar a curva dosagem-resposta tóxica frequentemente se torna evidente que podem existir vários processos subjacentes para a agáo de qualquer xenobiótico num organismo vivo. É muito provável que os passos essenciais, limitantes em qualquer mecanismo de toxicidade, possam ser superados com exposigoes maiores, indicando o aparecimento de modos novos de lesáo tissular com doses mais altas. Portanto podem acontecer transigoes que dependam da dosagem no mecanismo principal de toxicidade, que teriam um impacto significativo na interpretagáo da coleta de dados de referencia para a avaliagáo do risco. Uma explicagáo para as relagoes lineares dose-resposta em série é a transigáo dose-dependente entre uma sequencia de passos encadeados mecanicamente, passos limitantes da velocidade saturáveis no processo total, que levam da exposigáo a expressáo de um ou mais modos para a resposta tóxica. A análise desses fenómenos tem grande relevancia em termos práticos, isto é, para as consequencias na regulagáo do uso e exposigáo a substancias perigosas em diferentes ámbitos humanos.