Swertiamarin attenuates paraquat-induced pulmonary epithelial-like cell apoptosis via NOX4-mediated regulation of redox and mitochondrial function

Abstract The aim of the present study was to investigate the effect of swertiamarin (STM) in attenuating paraquat (PQ)-induced human lung alveolar epithelial-like cell (A549) apoptosis and the underlying mechanisms. A549 cells were pretreated with different concentrations of STM for 2 hr and then cultured with or without PQ (700 µM) for 24 hr. Cell survival was determined using the CCK8 assay. Morphological changes, MDA content, inflammatory factors, fibrogenesis parameters, apoptosis rates, redox status and mitochondrial membrane potential (MMP) were evaluated. The expression of several genes involved in the modulation of redox status was measured by Western blotting. Cell viability and MMP were decreased, but the apoptosis rate and DCFH oxidation were elevated by PQ exposure. STM pretreatment notably increased cell viability and MMP and reduced the apoptosis rate and DCFH oxidation. Furthermore, TLR4- NOX4 signaling was significantly inhibited by STM. The downregulation of NOX4 by siRNA exerted the same protective effects as STM. This study provides the first evidence that STM attenuates PQ-induced pulmonary epithelial-like cell apoptosis via NOX4-mediated regulation of redox and mitochondrial function

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

Miocarditis aguda por Paraquat. Presentación de un caso y revisión de la literatura / Acute paraquat myocarditis. Case report and literature review

Resumen Paciente masculino de 41 años vecino de Jicaral de Puntarenas. Sin antecedentes personales patológicos de importancia quien es referido al Servicio de Emergencias del Hospital Víctor Manuel Sanabria Martínez por consumo de aproximadamente 20 mililitros de Paraquat el día anterior con propósitos autolíticos. El paciente es ingresado en el Servicio de Medicina Interna y al momento de la valoración presenta únicamente lesiones ulceradas a nivel de la lengua. Durante su internamiento presenta deterioro en la función renal y alteraciones electrolíticas y al décimo día presenta cuadro de dolor torácico tipo opresivo acompañado de datos de insuficiencia cardiaca aguda. Los biomarcadores de laboratorio presentan incremento de la Troponina I y del Péptico Natriurético Cerebral. La radiografía de tórax mostró una cardiomegalia grado II con signos de falla cardiaca. Se le realiza un ecocardiograma que documentó trastornos en la contractilidad de manera difusa con deterioro en la función ventricular y dilatación de las cámaras cardiacas. Se le realiza una arteriografía coronaria que documenta arterias coronarias epicárdicas sin lesiones significativas. Se confirma el diagnóstico de miocarditis aguda por Paraquat y se da tratamiento para la insuficiencia cardiaca presentando una evolución satisfactoria y recuperación de la función cardiaca evidenciada por ecocardiograma control a los 9 meses posterior a el episodio inicial.

Summary Acute paraquat myocarditis. Case report and literature review A 41-year-old male patient from Jicaral of Puntarenas. Without significant pathological personals backgroun of importance who is referred to the Emergency Service of the Victor Manuel Sanabria Martínez Hospital for consumption of approximately 20 milliliters of Paraquat the previous day for autolytic purposes. The patient is admitted to the Internal Medicine Service and at the time of the evaluation presents only ulcerated lesions at the level of the tongue. During hospitalization, there is deterioration in renal function and electrolyte disturbances and on the tenth day, he presents a episode of oppressive chest pain accompanied by data on acute heart failure. Laboratory biomarkers show an increase in Troponin I and Brain Natriuretic Peptic. Chest radiography showed grade II cardiomegaly with signs of heart failure. An echocardiogram was performed which documented diffuse contractility disorders with deterioration in ventricular function and dilation of the cardiac chambers. A coronary arteriography is performed that documents epicardial coronary arteries without significant injuries. The diagnosis of acute Paraquat myocarditis is confirmed and treatment for heart failure is presented, the patient presenting a satisfactory evolution and recovery of heart function evidenced by a control echocardiogram at 9 months after the initial episode.

Chronic pesticide mixture exposure including paraquat and respiratory outcomes among Colombian farmers.

This study explored the potential association between chronic exposure to pesticide mixtures including paraquat and respiratory outcomes among Colombian farmers. Sociodemographic and occupational data, respiratory symptoms and spirometric data were collected. Paraquat in spot urine samples were quantified with solid-phase extraction high-performance liquid chromatography. Multiple Poisson regressions with robust variance were used to determine factors associated with respiratory outcomes. Profiles of pesticide mixtures used were identified among 217 farmworkers, but profenofos and methamidophos-based mixtures were more frequent. Chronic paraquat exposure was slightly associated with self-reported asthma (PR: 1.06; 95% CI 1.00 to 1.13). Different pesticide mixtures were associated with flu, thoracic pain, allergic rhinitis, and obstructive pattern in spirometry. Although acute exposure to paraquat is low among Colombian farmers participating in the study, associations between respiratory outcomes and chronic pesticide mixtures exposure including profenofos, methamidophos or glyphosate require further specific studies.

Efeito protetor da melatonina sobre intoxicações por herbicidas / Protective effect of melatonin on poisoning by herbicides

O uso inadequado de herbicidas pode resultar em intoxicações agudas e, às vezes, crônicas por exposição em longo prazo a baixos níveis desses agentes tóxicos, podendo o herbicida atuar também como agentes teratogênicos, mutagênicos, cancerígenos e desreguladores endócrinos, com o aparecimento de doenças neurodegenerativas e distúrbios reprodutivos. Estudos têm revelado que a melatonina tem propriedades antioxidantes, anti-inflamatórias e imunomoduladoras e atua na reprodução. Essa indolamina está entre os agentes que têm se mostrado benéfico em intoxicações por herbicidas, porém não há relatos do uso de melatonina contra intoxicações por Glifosato-Roundup®, muito menos em associação com o Paraquat. Dessa forma, o maior interesse no tratamento das intoxicações por herbicidas, tem-se concentrado em medidas que impeçam ou minimizem as lesões celulares provocadas nos diversos sistemas biológicos. Assim, a melatonina, como antioxidante conhecido, pode ser mais uma alternativa contra as intoxicações por herbicidas associados e/ou individuais.

The inadequate use of herbicides may cause serious and sometimes chronic poisoning due to long exposure to low levels of toxic agents. Herbicides may also be teratogenic, mutagenic, cancerigenous agents and endocrine disruptors, with the occurrence of neurodegenerative diseases and reproduction disorders. Several studies have shown that melatonin has antioxidant, anti-inflammatory and immune-modulating qualities, besides affecting the reproduction system. It is among the agents which are beneficent in poisoning by herbicides even though no reports are extant on the use of melatonin against poisoning by Glyphosate-Roundup® alone or associated with Paraquat. Solutions that prevent or minimize cell lesions caused by several biological systems have been focused upon in the treatment for poisoning with herbicides. Thus, melatonin, a known antioxidant, may be an alternative against the poisoning by single or associated herbicides.

Efeito protetor da melatonina sobre intoxicações por herbicidas / Protective effect of melatonin on poisoning by herbicides

O uso inadequado de herbicidas pode resultar em intoxicações agudas e, às vezes, crônicas por exposição em longo prazo a baixos níveis desses agentes tóxicos, podendo o herbicida atuar também como agentes teratogênicos, mutagênicos, cancerígenos e desreguladores endócrinos, com o aparecimento de doenças neurodegenerativas e distúrbios reprodutivos. Estudos têm revelado que a melatonina tem propriedades antioxidantes, anti-inflamatórias e imunomoduladoras e atua na reprodução. Essa indolamina está entre os agentes que têm se mostrado benéfico em intoxicações por herbicidas, porém não há relatos do uso de melatonina contra intoxicações por Glifosato-Roundup®, muito menos em associação com o Paraquat. Dessa forma, o maior interesse no tratamento das intoxicações por herbicidas, tem-se concentrado em medidas que impeçam ou minimizem as lesões celulares provocadas nos diversos sistemas biológicos. Assim, a melatonina, como antioxidante conhecido, pode ser mais uma alternativa contra as intoxicações por herbicidas associados e/ou individuais.(AU)

The inadequate use of herbicides may cause serious and sometimes chronic poisoning due to long exposure to low levels of toxic agents. Herbicides may also be teratogenic, mutagenic, cancerigenous agents and endocrine disruptors, with the occurrence of neurodegenerative diseases and reproduction disorders. Several studies have shown that melatonin has antioxidant, anti-inflammatory and immune-modulating qualities, besides affecting the reproduction system. It is among the agents which are beneficent in poisoning by herbicides even though no reports are extant on the use of melatonin against poisoning by Glyphosate-Roundup® alone or associated with Paraquat. Solutions that prevent or minimize cell lesions caused by several biological systems have been focused upon in the treatment for poisoning with herbicides. Thus, melatonin, a known antioxidant, may be an alternative against the poisoning by single or associated herbicides.(AU)

Intoxicaciones por paraquat reportadas en el Centro Toxicológico de la Región Centro Occidental "Antonio M. Pineda de Venezuela: período 1997-2000 / Paraquat intoxications reported in the Toxicological Center Antonio M. Pineda: from Venezuela 1997-2000

En Venezuela, es frecuente la utilización de plaguicidas como el paraguat en la actividad agrícola, por ello las intoxicaciones y fallecimientos que se producen anualmente por su mal uso, y manejo es importante. Se analizaron retrospectivamente los casos de intoxicaciones por paraquat registrados en el Centro Toxicológico de la Región Centro Occidental de Venezuela, durante los años 1997-2000, para evaluar frecuencia, causas, vías de ingreso y evaluación de los pacientes intoxicados. La investigación fue descriptiva, de registros médicos. Se registraron 79 pacientes; 44 pacientes del género masculino y 29 del género femenino y 6 no identificados en los registros. El promedio de edad fue de 24,22 ± 12,47 años. La principal vía de ingreso del tóxico fue oral 83.5%, y las causas de intoxicación identificadas fueron: 75,9% ocupacional y 22,8% accidental. El 49,3% de los pacientes fue dado de alta., mientras que el 8,8% falleció

In Venezuela, it is frequent the use of pesticides such as paraquat in agriculture, so poisonings and deaths that occur annually for their improper use and handling its important. We retrospectively analyzed the cases of paraquat poisoning recorded in the Poison Center of the Midwestern Region of Venezuela during the years 1997-2000, to assess prevalence, causes, access routes and evolution of poisoned patients. The research was descriptive, of medical records. There were 79 patienrs, 44 males and 29 females and 6 are not identified in the records. The average age was 24.22 ± 12.47 years. The main route of the toxic was oral 83.5%, and the causes of poisoning identified were: occupational 75.9% and accidental 22.8%. The 49.3% of patients were discharged, while 8.8% died

[Parkinson's disease due to laboral exposition to paraquat]. / Enfermedad de Parkinson por exposición ocupacional a paraquat.

Parkinson's disease is considered a neurodegenerative disorder, which involves environmental factors in the etiology of the disease. Such as chemical agents with neuromolecular effect among which is the MPTP (1-methyl-4-phenyl-1, 2, 3, 6 tetra-hydropyridine), MPP (1-methyl-4-phenyl hypyridinium), paraquat, the latter used as a herbicide in the agricultural fields of our country. It has been documented in epidemiological and experimental studies the association of occupational exposure to paraquat and Parkinson's disease. The aim of this paper is to describe a clinical case of occupational medicine in Parkinson's disease in occupationally exposed workers to paraquat, elevating the importance of medical history work, which was the key to the clinical case study.

Paraquat induces behavioral changes and cortical and striatal mitochondrial dysfunction.

Paraquat is a highly toxic quaternary nitrogen herbicide capable of increasing superoxide anion production. The aim of this research was to evaluate various behavioral changes and study cortical, hippocampal, and striatal mitochondrial function in an experimental model of paraquat toxicity in rats. Paraquat (10mg/kg ip) was administered weekly for a month. Anxiety-like behavior was evidenced in the paraquat-treated group as shown by a diminished time spent in, and fewer entries into, the open arms of an elevated-plus maze. Also, paraquat treatment induced a deficit in the sense of smell. In biochemical assays, NADH-cytochrome c reductase activity was significantly inhibited by 25 and 34% in cortical and striatal submitochondrial membranes, respectively. Striatal cytochrome oxidase activity was decreased by 24% after paraquat treatment. Also, cortical and striatal mitochondria showed 55 and 74% increased State 4 respiratory rates, respectively. Paraquat treatment decreased striatal State 3 oxygen consumption by 33%. Respiratory controls were markedly decreased in cortical and striatal mitochondria, indicating mitochondrial dysfunction after paraquat treatment, together with mitochondrial depolarization and increased hydrogen peroxide production rates. We demonstrate that paraquat induced alterations in nonmotor symptoms and cortical and striatal mitochondrial dysfunction.

Efectos de la exposición prenatal a paraquat sobre el desarrollo de la transmisión sináptica aminoacídica en la corteza cerebral parietal del ratón / Effects of prenatal expossure to paraquat on the development of amino acid synaptic transmission in mouse cerebral parietal cortex

Se estudiaron los efectos de la exposición prenatal al paraquat (PQ), sobre el desarrollo postnatal de la transmisión sináptica aminoacídica de la corteza cerebral parietal del ratón. Las ratonas NMRI preñadas del grupo experimental recibieron 5 dosis de 10mg/kg de peso corporal de PQ, entre el día de gestación (G)12 y G20, y el grupo control recibió solución salina. Mediante HPLC, se determinaron los niveles de aspartato, glutamato, glicina, GABA y taurina de las crías, entre la edad postnatal (P)1 y P30. Entre P3 y P15, se observó un incremento significativo de los neurotransmisores excitatorios, aspartato y glutamato, en los ratones expuestos a PQ. Con respecto a la neurotransmisión inhibidora, los cambios más importantes se observaron en glicina: sus niveles se mantuvieron significativamente por debajo del grupo control entre P1 y P7, y significativamente por encima en P11 y P15. Para taurina, entre P1 y P7 sus niveles se mantuvieron significativamente altos con respecto al grupo control. En P30, los niveles de todos los neurotransmisores se encontraron significativamente por debajo del grupo control. En conclusión, podríamos decir que la exposición prenatal a PQ tuvo efectos tóxicos que se reflejaron en una alteración de los niveles basales de los neurotransmisores aminoacídicos durante el desarrollo postnatal de la corteza parietal del ratón, predominando la excitación sobre la inhibición durante todo el período estudiado. Estas alteraciones podrían indicar la ocurrencia de importantes daños corticales, tales como la disminución de algunas poblaciones neuronales, la inadecuada formación de los circuitos corticales y alteraciones en el proceso de sinaptogénesis.

The effects of prenatal expossure to paraquat (PQ) were studied on postnatal development of mouse parietal cerebral cortex, in particular, the ontogenesis of amino acid synaptic transmission. Pregnant NMRI mice were separated into two groups: the experimental group received 5 doses of 10mg PQ/kg body weight, between days of gestation (G)12 and G20, whereas the control group received physiological saline solution. Levels of neurotransmitter amino acids: Asp, Glu, Gly, GABA and Tau were determined by HPLC between postnatal (P) days P1 and P30. Between P3 and P15, a significant increment in the levels of excitatory amino acids, Asp and Glu, were observed in mice exposed to PQ, as compared with the control group. With respect to the inhibitory neurotransmitter levels, in the group exposed to PQ, the more important changes were observed in Gly between P1 and P15. In relation to taurine, its levels remained significantly higher between P1 and P7 with respect to the control group. It is important to emphasize that at P30, the levels of all neurotransmitters in the experimental group were significantly lower than those of control. In conclusion, prenatal exposure to PQ caused neurotoxicity in the developing mouse parietal cortex, as shown by the alterations in the basal levels of amino acid neurotransmitters, with the excitatory predominating over inhibitory neurotransmission, throughout the studied developmental period. These alterations could indicate the occurrence of important cortical injuries, such as decrement in some neuronal populations, inadequate formation of intrinsic cortical circuits and alterations in synaptogenic processes.

[Effects of prenatal exposure to paraquat on the development of amino acid synaptic transmission in mouse cerebral parietal cortex]. / Efectos de la exposición prenatal a paraquat sobre el desarrollo de la transmisión sináptica aminoacídica en la corteza cerebral parietal del ratón.

The effects of prenatal expossure to paraquat (PQ) were studied on postnatal development of mouse parietal cerebral cortex, in particular, the ontogenesis of amino acid synaptic transmission. Pregnant NMRI mice were separated into two groups: the experimental group received 5 doses of 10 mg PQ/kg body weight, between days of gestation (G)12 and G20, whereas the control group received physiological saline solution. Levels of neurotransmitter amino acids: Asp, Glu, Gly, GABA and Tau were determined by HPLC between postnatal (P) days P1 and P30. Between P3 and P15, a significant increment in the levels of excitatory amino acids, Asp and Glu, were observed in mice exposed to PQ, as compared with the control group. With respect to the inhibitory neurotransmitter levels, in the group exposed to PQ, the more important changes were observed in Gly between P1 and P15. In relation to taurine, its levels remained significantly higher between P1 and P7 with respect to the control group. It is important to emphasize that at P30, the levels of all neurotransmitters in the experimental group were significantly lower than those of control. In conclusion, prenatal exposure to PQ caused neurotoxicity in the developing mouse parietal cortex, as shown by the alterations in the basal levels of amino acid neurotransmitters, with the excitatory predominating over inhibitory neurotransmission, throughout the studied developmental period. These alterations could indicate the occurrence of important cortical injuries, such as decrement in some neuronal populations, inadequate formation of intrinsic cortical circuits and alterations in synaptogenic processes.

Efeito tóxico dos praguicidas maneb e paraquat sobre a atividade da enzima antioxidante catalase em ratos / Toxic effect of pesticides maneb and paraquat on catalase antioxidant enzyme activity in rats

Os radicais livres estão envolvidos em um grande número de enfermidades do ser humano.O cérebro tem níveis baixos de enzimas antioxidantes e um conteúdo lípidico elevado, tornando-se muito susceptível ao ataque de espécies reativas de oxigênio.Neste trabalho avaliou-se a lipoperoxidação em hipocampo e a atividade da enzima catalase em estriado e hipocampo de ratos tratados com o fungicida maneb (30 mg/kg) e o herbicida paraquat (10 mg/kg).Não houve alteração na lipoperoxidação nem na atividade enzimática no hipocampo dos animais tratados com ambos os praguicidas, porém foi observada uma inibição da catalase no estriado dos ratos tratados com maneb e com paraquat.Com estes resultados pode-se sugerir, de forma preliminar, uma ação tóxica maior sobre centros dopaminérgicos.Estudos sobre a toxicidade destes compostos são essenciais na compreensão do papel destes praguicidas e dos radicais livres na etiologia das doenças

Effects of prenatal paraquat and mancozeb exposure on amino acid synaptic transmission in developing mouse cerebellar cortex.

The goal of this study was to analyze the effects of prenatal exposure to the pesticides paraquat (PQ) and mancozeb (MZ) on the development of synaptic transmission in mouse cerebellar cortex. Pregnant NMRI mice were treated with either saline, 10 mg/kg PQ, 30 mg/kg MZ or the combination of PQ + MZ, between gestational days 12 (E12) and E20. Variation in the levels of amino acid neurotransmitters was determined by HPLC, between postnatal day 1 (P1) and P30. Motor coordination was assessed by locomotor activity evaluation of control and experimental pups at P14, P21 and P30. Significant reductions in the levels of excitatory neurotransmitters, aspartate and glutamate, were observed in PQ-, MZ- or combined PQ + MZ-exposed pups, with respect to control, during peak periods of excitatory innervation of Purkinje cells: between P2-P5 and P11-P15. However, at P30, lower aspartate contents, in contrast with increased glutamate levels, were detected in all experimental groups. During the first two postnatal weeks, delays in GABA and glycine ontogenesis were observed in PQ- and PQ + MZ-exposed pups, whereas notable decrements in GABA and glycine levels were seen in PQ + MZ-exposed animals. Decreased taurine contents were detected at P3 and P11 in PQ- and PQ + MZ-exposed mice. Pups in different experimental groups all showed hyperactivity at P14 and then exhibited reduced locomotor activity at P30. Taken together, our results indicate that prenatal exposure to either PQ or MZ or the combination of both could alter the chronology and magnitude of synaptic transmission in developing mouse cerebellar cortex.

Intoxicación por paraquat: toxicidad sistémica después de exposición cutánea / Paraquat poisoning: systemic toxicity after dermal exposure

La ingestión del Paraquat (dicloruro de 1,1 dimetil-4,4 dipiridilio) es el caso más común de la intoxicación fatal por plaguicidas, pero no se debe descartar la posibilidad de otras vías que lleven a un daño multiorgánico, como es el caso de la absorción dérmica del Paraquat. Nosotros reportamos el caso de un agricultor quien desarrollo daño renal y hepático después de una exposición aguda de la piel escrotal con el herbicida Paraquat con recuperación eventual del paciente. Este caso demuestra que la exposición dérmica por Paraquat, especialmente del escroto, puede producir seria toxicidad sistémica; siendo el primer caso reportado en 5 años en nuestro Instituto de toxicidad sistémica por contacto cutáneo de este químico. Se debe tomar estricta precaución, incluyendo el uso de ropa protectora siempre que se va a usar este químico.

Pesticide-related symptoms among farm workers in rural Honduras.

A survey of 96 families in a rural region of Honduras, conducted in 1998, showed that 80 of these predominantly (95 or 96) farming families used pesticides in their work or at home. Paraquat was used most often, and safety measures were very rarely taken in its use. Seventy-seven families stored pesticide containers in their homes, often within the reach of children. Every worker who used paraquat had at least one symptom potentially related to its use, and the prevalences of childhood disorders in the region are abnormally high compared with national averages.

Paraquat in developing countries.

The herbicide paraquat is considered safe by industry and the bulk of regulators worldwide. However, determinants of exposure from 30 years ago persist in developing countries. Little is known about systemic absorption from occupational exposures. The relationships between exposure determinants, levels of external exposure, biomarkers of exposure, and outcomes are not clear. High rates of severe acute poisonings have been documented. In addition, topical injuries occur in as many as 50% of exposed workers. Non-worker populations are also at risk, particularly children. Long-term and delayed health effects include Parkinson's disease, lung effects, and skin cancer. Regulatory agencies have not fully recognized either the inherent toxicity of paraquat or the particular risks derived from exposures in developing countries. Independent risk assessment in the developing-country context and application of the precautionary principle are necessary to prevent adverse effects of dangerous pesticides in susceptible populations.

Paraquat: as implicações do uso inadequado de um herbicida seguro / Paraquat: the implications of improper use of a herbicide insurance

Dentre os mais importantes compostos agrotóxicos encontram-se os herbicidas por causa do seu volume de utilização. Não se pode substituí-los com métodos não químicos que são mais laborosos ou de custo mais elevado. Esta situação é uma importante razão pela qual a agricultura orgânica em larga escala foi mal projetada desde o princípio. As intoxicações por Paraquat são sempre consideradas graves e ingestões de quantidades superiores a 50ml tem prognósticos sombrios. Os acidentes com este veneno são subestimados em nosso Estado por causa da falta de uma adequada notificação e contabilização dos casos ocorridos. As tentativas de suicídio com este composto deixaram de ser raras e passam a configurar rotinas nos hospitais do interior. No Estado do Rio de Janeiro, a cidade de Nova Friburgo é a que tem notificado mais casos aos Centros de Controle de Intoxicações. As tentativas de suicídio superam o número de casos de intoxicações acidentais. Geralmente os suicidas são trabalhadores rurais com acesso ao produto. Sendo assim, a problemática da utilização do paraquat na agricultura ultrapassa a da indequada manipulação e manejo do produto nas lavouras atingindo o mérito do desvio do uso regular do herbicida, o que configura numa visão mais abrangente, um importante problema de saúde pública e por que não dizer, ocupacional.