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The screening of phyto-pesticides for potential adverse effects on human healthShoko, Yeukai Phoebe January 2010 (has links)
<p>Pesticides are designed to control or eliminate pests such as insects, rodents, weeds,<br />
bacteria, and fungi. They are used at a global scale for agricultural produce. Although<br />
pesticides play a significant role in increasing food production and eliminating diseases,<br />
exposure to pesticides may be harmful to non-target organisms. As a result concern over<br />
safety and resistance to pesticides has increased and there is pressure to reduce use and<br />
search for more environmentally and toxicologically safe and efficacious pesticides. Most<br />
pesticides currently in use are synthetic / therefore an alternative to synthetic pesticides is<br />
the use of naturally occurring products/ botanicals with pesticidal properties.</p>
<p>Two plants indigenous to South African with pesticidal properties were chosen for this<br />
study. Dicerothamnus rhinocerotis (D. rhinocerotis) and Galenia africana (G. africana)<br />
have potential antifungal properties thus, may have potential use on agricultural produce<br />
as fungicides. Galenia africana and D. rhinocerotis extracts inhibit growth of B. cinerea<br />
(a fungal pathogen) at concentrations greater than 31.25 mg/ml and 125mg/ml<br />
respectively. A major consideration in approving pesticides for use is whether they pose<br />
an unreasonable risk to humans and to the environment. Toxicity studies are required to<br />
determine the safety of the plant extracts.</p>
<p>The purpose of this study was to evaluate potential toxicity of ethanol extracts of D.<br />
rhinocerotis and G. africana, which is important when designing practices to reduce or<br />
eliminate excess exposure to them. Natural plant products with pesticidal properties could<br />
provide an alternative to synthetic pesticides and may thus effectively reduce resistance<br />
levels.<br />
<br />
<br />
  / </p>
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The screening of phyto-pesticides for potential adverse effects on human healthShoko, Yeukai Phoebe January 2010 (has links)
<p>Pesticides are designed to control or eliminate pests such as insects, rodents, weeds,<br />
bacteria, and fungi. They are used at a global scale for agricultural produce. Although<br />
pesticides play a significant role in increasing food production and eliminating diseases,<br />
exposure to pesticides may be harmful to non-target organisms. As a result concern over<br />
safety and resistance to pesticides has increased and there is pressure to reduce use and<br />
search for more environmentally and toxicologically safe and efficacious pesticides. Most<br />
pesticides currently in use are synthetic / therefore an alternative to synthetic pesticides is<br />
the use of naturally occurring products/ botanicals with pesticidal properties.</p>
<p>Two plants indigenous to South African with pesticidal properties were chosen for this<br />
study. Dicerothamnus rhinocerotis (D. rhinocerotis) and Galenia africana (G. africana)<br />
have potential antifungal properties thus, may have potential use on agricultural produce<br />
as fungicides. Galenia africana and D. rhinocerotis extracts inhibit growth of B. cinerea<br />
(a fungal pathogen) at concentrations greater than 31.25 mg/ml and 125mg/ml<br />
respectively. A major consideration in approving pesticides for use is whether they pose<br />
an unreasonable risk to humans and to the environment. Toxicity studies are required to<br />
determine the safety of the plant extracts.</p>
<p>The purpose of this study was to evaluate potential toxicity of ethanol extracts of D.<br />
rhinocerotis and G. africana, which is important when designing practices to reduce or<br />
eliminate excess exposure to them. Natural plant products with pesticidal properties could<br />
provide an alternative to synthetic pesticides and may thus effectively reduce resistance<br />
levels.<br />
<br />
<br />
  / </p>
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Avaliação do potencial tóxico do extrato hidroalcoólico de Pradosia huberi Ducke sobre o sistema reprodutor masculino e órgãos vitais de ratos e sua prole / Evaluation of the toxic potential of hydroalcoholic extract of Pradosia huberi Ducke on the male reproductive system and vital organs of rats and their offspringSantos, Elane Cristina Silva dos 29 February 2012 (has links)
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Previous issue date: 2012-02-29 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Since ancient times plants are used for medicinal purposes to treat, cure and prevention diseases. Pradosia huberi Ducke (Sapotaceae) is a medicinal plant commonly used by Amazonian communities for their antiulcerogenic and gastroprotective activities. Considering the popular use of this species, the presence of bioactive compounds with potential toxic effects on the male reproductive system, and the lack of scientific studies on the reproductive toxicity, this work aimed to investigate the toxic effects of P. huberi on fertility, offspring and vital, reproductive organs of rats. Wistar rats were divided into control and treated groups (n = 15). The control and treated groups received distilled water and hydroalcoholic extract of the stem bark of P. Huberi (PH-EHA), respectively, at doses of 1.22, 6.1 and 30.5 mg/kg body weight, orally and once daily, for 63 days, a period that correspond to the complete spermatogenic cycle of this species and the period of epididymal transit. The animals were killed on day 64. To investigate the toxic potential of PH-EHA on the reproductive system of rats the following parameters were evaluated: occurrence of clinical signs of general toxicity, daily consumption of water and food, biochemical and hematological tests, body weight, weight of vital organs, the reproductive organs and the accessory sex glands, sperm production, sexual behavior, genotoxicity and general development, and behavior of the offspring. The oral exposure to PH-EHA at doses of 1.22 and 6.1 mg/kg did not alter the body weight of rats, though the dose of 30.5 mg/kg caused a reduction in body weight of animals from the 35th day of treatment. This finding was corroborated by the decrease in food intake by these animals. The weight of kidneys, liver, lung, brain and pituitary, the testis, epididymis, seminal vesicles and prostate of the treated animals did not significantly change in relation to the weights of the control group. The administration of the extract did not cause significant changes in the hematologic and biochemical profile of rats. The production of gametes and their morphology did not differ between control and treated groups. Treatment with PH-EHA did not affect male sexual behavior, but caused an increase of 14.3% and 10.8% in the pre-implantation loss index, a reduction of 14.3% and 10.8% in implantation index, and a reduction of 5.6% and 8.2% in the post-implantation loss index of female rats mated with rats treated with 6.1 mg/kg and 30.5 mg/kg of PH-EHA, respectively. Morphological abnormalities were observed in stillborn offspring from dams mated with rats exposed to 30 mg/kg of PH-EHA. The general development, Reflexology and behavioral of the offspring were not affected by treatment. The results indicate a possible toxic action of EHA-PH in Wistar rats, with evidence of mutagenic and adverse effect on fetal development, as evidenced in the experimental model studied. / Desde a antiguidade as plantas são utilizadas com fins medicinais para o tratamento, cura e prevenção de doenças. Pradosia huberi Ducke (Sapotaceae) é uma planta medicinal comumente usada pelas comunidades amazônicas por suas atividades gastroprotetora e antiulcerogênica. Considerando-se o uso popular dessa espécie e a presença de compostos bioativos com potencial tóxico sobre o sistema reprodutor masculino, além da inexistência de estudos científicos de toxicidade reprodutiva dessa espécie, esse trabalho teve como propósito investigar os efeitos tóxicos de P. huberi sobre a fertilidade, órgãos vitais e prole de ratos. Ratos Wistar foram divididos em grupos controle e tratados (n = 15). Os animais dos grupos controle e tratados receberam, respectivamente, água destilada e o extrato hidroalcoólico das cascas do caule de P. huberi (EHA-PH) nas doses de 1,22, 6,1 e 30,5 mg/kg de peso corporal, por via oral, uma vez ao dia, por 63 dias, período que compreende o ciclo espermatogênico completo dessa espécie mais o período de trânsito epididimário, e foram eutanasiados no 64º dia. Para a investigação do potencial tóxico do EHA-PH sobre o sistema reprodutor de ratos, os seguintes parâmetros foram avaliados: ocorrência de sinais clínicos gerais de toxicidade, consumo diário de água e ração, análises bioquímicas e hematológicas, peso corporal, de órgãos vitais, do sistema reprodutor e das glândulas sexuais acessórias, produção de espermatozoides, comportamento sexual, genotoxicidade e desenvolvimento geral, reflexológico e comportamental da prole. A exposição oral ao EHA-PH nas doses de 1,22 e 6,1 mg/kg não alterou o peso corporal de ratos, entretanto a administração da dose de 30,5 mg/kg causou redução do peso corporal dos animais a partir do 35º dia de tratamento. Esse achado foi corroborado pela diminuição na ingestão de ração por esses animais. O peso de rins, fígado, pulmão, cérebro, hipófise, testículo, epidídimo, vesícula seminal e próstáta dos animais tratados não se alteraram em relação aos pesos dos animais do grupo controle. A administração do extrato não causou mudanças significativas no perfil bioquímico e hematológico dos ratos. A produção de gametas e a sua morfologia não diferiram entre os grupos controle e tratados. O tratamento com o EHA-PH também não alterou o comportamento sexual masculino, porém provocou um aumento de 14,3 % e 10,8% nos índices de perdas pré-implantação e uma redução de 14,3 % e 10,8% nos índices de implantação, além de uma redução de 5,6% e 8,2% nos índices de perdas pós-implantação das ratas acasaladas com ratos que receberam 6,1 mg/kg e 30,5 mg/kg do EHA-PH, respectivamente. Anormalidades morfológicas foram observadas em natimortos descendentes de progenitoras acasaladas com ratos expostos à dose de 30 mg/kg do EHA-PH. O desenvolvimento geral, reflexológico e comportamental da prole não foram alterados pelo tratamento. Os resultados indicam uma possível ação tóxica do EHA-PH em ratos Wistar, com indícios de efeito mutagênico e adverso no desenvolvimento fetal, evidenciado no modelo experimental estudado.
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The screening of phyto-pesticides for potential adverse effects on human healthShoko, Yeukai Phoebe January 2010 (has links)
Philosophiae Doctor - PhD / Pesticides are designed to control or eliminate pests such as insects, rodents, weeds, bacteria, and fungi. They are used at a global scale for agricultural produce. Although pesticides play a significant role in increasing food production and eliminating diseases, exposure to pesticides may be harmful to non-target organisms. As a result concern over safety and esistance to pesticides has increased and there is pressure to reduce use and search for more environmentally and toxicologically safe and efficacious pesticides. Most pesticides currently in use are synthetic; therefore an alternative to synthetic pesticides is the use of naturally occurring products/ botanicals with pesticidal properties. Two plants indigenous to South African with pesticidal properties were chosen for this study. Dicerothamnus rhinocerotis (D. rhinocerotis) and Galenia africana (G. africana) have potential antifungal properties thus, may have potential use on agricultural produce as fungicides. Galenia africana and D. rhinocerotis extracts inhibit growth of B. cinerea (a fungal pathogen) at concentrations greater than 31.25 mg/ml and 125mg/ml respectively. A major consideration in approving pesticides for use is whether they pose
an unreasonable risk to humans and to the environment. Toxicity studies are required to determine the safety of the plant extracts.
The purpose of this study was to evaluate potential toxicity of ethanol extracts of D. rhinocerotis and G. africana, which is important when designing practices to reduce or eliminate excess exposure to them. Natural plant products with pesticidal properties could provide an alternative to synthetic pesticides and may thus effectively reduce resistance levels. This first objective of this study was to assess the cytotoxicity of D. rhinocerotis and G. africana on human cell cultures. Human whole blood and the human breast adenocarcinoma cell line (MCF-7) were treated with varying concentrations of the plant extracts and cytotoxicity determined. Cytotoxicity was measured using several biomarkers. Inhibiotory concentration for a 50% effect (IC50) and no observable effect
level (NOEL) values were obtained for D. rhinocerotis and G. africana. The results showed that extracts of D. rhinocerotis and G. africana had cytotoxic effects on the cell cultures. The second objective of this study was to determine the ecotoxicity of D. rhinocerotis and G. africana. A series of acute toxicity tests, with effective concentration for a 50% effect (EC50) and lethal concentration for a 50% effect (LC50) as biomarkers, were
conducted to estimate the potential environmental effect of the two plants. The tests were carried out using Vibrio fischeri, Selenastrum capricornutum, Daphnia pulex, and Poecilia reticulata as bioindicators. Results obtained showed that G. africana had higher toxicity units than D. rhinocerotis, thus showing that G. africana is more toxic to the aquatic species used as compared to D. rhinocerotis. The third objective of this study was to investigate the immunomodulatory effects of the two plant extracts. This was achieved by using mouse spleen cell cultures. Exposure of pesticides to the immune system may result in alteration of the normal immune functions. The cytokines IFN-γ and IL-4 were used as biomarkers to determine the T-cell activity of the immune system when exposed to the two botanical products. The results obtained showed that both D. rhinocerotis and G. africana decrease of the cytokines interferongamma
(IFN-γ) and interleukin-4 (IL-4), thus may have immunotoxic effects.
The fourth objective was to investigate the hepatotoxicity of the two plant extracts. Injury to the liver was investigated using a range of clinical biochemical tests that monitor liver enzyme activity and metabolic activity. Primary liver cell cultures were exposed to the plant products in question, after which the biochemical tests were carried out. The enzymes that were monitored were alanine aminotrasferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH). The results obtained showed that both of D. rhinocerotis and G. africana may have effects on the liver, as shown by the increased levels of enzymes released from cells upon exposure to plant extracts. The final objective of this study was to investigate the effect of the two plants on the male reproductive system. Injury to the male reproductive system was investigated using testicular cell cultures. Primary cell cultures were stimulated with luteinizing-hormone (LH) and exposed to the plant extracts. LH results in the production of testosterone, thus
testosterone was used as a biomarker for assessing reproductive toxicity. The results obtained showed that both of D. rhinocerotis and G. africana have effects on the male reproductive system, as shown by the decreased testosterone secretion. Botanicals provide a simple, inexpensive and environmentally friendly (non-pollution and lesser toxicological concerns) alternative for pest control. However, motivation for the commercial use of botanicals as pesticides requires validating the efficacy of the plant as a pesticide, and also assessing its effects on human health and the environment. An important component of this evaluation involves toxicity studies, which enables cautions of dangerous practices and toxic effects of the plants to be issued. / South Africa
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The screening of phyto-pesticides for potential adverse effects on human healthShoko, Yeukai Phoebe January 2010 (has links)
Philosophiae Doctor - PhD / Pesticides are designed to control or eliminate pests such as insects, rodents, weeds, bacteria, and fungi. They are used at a global scale for agricultural produce. Although pesticides playa significant role in increasing food production and eliminating diseases, exposure to pesticides may be harmful to non-target organisms. As a result concern over safety and resistance to pesticides has increased and there is pressure to reduce use and search for more environmentally and toxicologically safe and efficacious pesticides. Most pesticides currently in use are synthetic; therefore an alternative to synthetic pesticides is the use of naturally occurring products! botanicals with pesticidal properties.
Two plants indigenous to South African with pesticidal properties were chosen for this study. Dicerothamnus rhinocerotis (D. rhinocerotis) and Galenia africana (G. africana) have potential antifungal properties thus, may have potential use on agricultural produce as fungicides. Galenia africana and D. rhinocerotis extracts inhibit growth of B. cinerea (a fungal pathogen) at concentrations greater than 31.25 mg/ml and 125mg/ml respectively. A major consideration in approving pesticides for use is whether they pose an unreasonable risk to humans and to the environment. Toxicity studies are required to determine the safety of the plant extracts. The purpose of this study was to evaluate potential toxicity of ethanol extracts of D. rhinocerotis and G. africana, which is important when designing practices to reduce or eliminate excess exposure to them. Natural plant products with pesticidal properties could provide an alternative to synthetic pesticides and may thus effectively reduce resistance levels. This first objective of this study was to assess the cytotoxicity of D. rhinocerotis and G. africana on human cell cultures. Human whole blood and the human breast adenocarcinoma cell line (MCF-7) were treated with varying concentrations of the plant extracts and cytotoxicity determined. Cytotoxicity was measured using several biomarkers. Inhibiotory concentration for a 50% effect (ICso) and no observable effect level (NOEL) values were obtained for D. rhinocerotis and G. africana. The results showed that extracts of D. rhinocerotis and G. africana had cytotoxic effects on the cell cultures. The second objective of this study was to determine the ecotoxicity of D. rhinocerotis and G. africana. A series of acute toxicity tests, with effective concentration for a 50% effect (ECso) and lethal concentration for a 50% effect (LCso) as biomarkers, were conducted to estimate the potential environmental effect of the two plants. The tests were
carried out using Vibrio fischeri, Selenastrum capricornutum, Daphnia pulex, and Poecilia reticulata as bioindicators. Results obtained showed that G. africana had higher toxicity units than D. rhinocerotis, thus showing that G. africana is more toxic to the aquatic species used as compared to D. rhinocerotis. The third objective of this study was to investigate the immunomodulatory effects of the two plant extracts. This was achieved by using mouse spleen cell cultures. Exposure of pesticides to the immune system may result in alteration of the normal immune functions. The cytokines IFN-y and IL-4 were used as biomarkers to determine the T-cell activity of the immune system when exposed to the two botanical products. The results obtained showed that both D. rhinocerotis and G. africana decrease of the cytokines interferon gamma (IFN-y) and interleukin-4 (IL-4), thus may have immunotoxic effects. The fourth objective was to investigate the hepatotoxicity of the two plant extracts. Injury to the liver was investigated using a range of clinical biochemical tests that monitor liver enzyme activity and metabolic activity. Primary liver cell cultures were exposed to the plant products in question, after which the biochemical tests were carried
out. The enzymes that were monitored were alanine aminotrasferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH). The results obtained showed that both of D. rhinocerotis and G. africana may have effects on the liver, as shown by the increased levels of enzymes released from cells upon exposure to plant extracts. The final objective of this study was to investigate the effect of the two plants on the male reproductive system. Injury to the male reproductive system was investigated using
testicular cell cultures. Primary cell cultures were stimulated with luteinizing-hormone (LH) and exposed to the plant extracts. LH results in the production of testosterone, thus testosterone was used as a biomarker for assessing reproductive toxicity. The results obtained showed that both of D. rhinocerotis and G. africana have effects on the male reproductive system, as shown by the decreased testosterone secretion. Botanicals provide a simple, inexpensive and environmentally friendly (non-pollution and lesser toxicological concerns) alternative for pest control. However, motivation for the commercial use of botanicals as pesticides requires validating the efficacy of the plant as a pesticide, and also assessing its effects on human health and the environment. An important component of this evaluation involves toxicity studies, which enables cautions of dangerous practices and toxic effects of the plants to be issued.
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THE MOUSE MAMMARY GLAND: A TOOL TO EVALUATE THE ENVIRONMENTAL CHEMICAL BUTYL BENZYL PHTHALATE, AND APPROACHES TO IMPROVE REGULATORY TESTINGDaum, Jessica 28 October 2022 (has links)
In the first part of this thesis, we utilize the mouse model to evaluate the environmental chemical Butyl Benzyl Phthalate. Due to lack of research on female exposure to BBP, this thesis focuses on quantifying the effects of gestational exposure on the female mammary gland Here male and female parental mice were exposed before mating and through pregnancy and lactation to one of three doses of BBP or the control via oral ingestion. After weaning, offspring were sacrificed at puberty or early adulthood and evaluated for altered mammary gland morphology or hormonal receptor expression. Results indicate a persistent statistically significant increase in weight among the highest BBP dose group. Additionally, the high-dose adult treatment group demonstrated a statistically significant decrease in terminal ends. Finally, the mid-dose adult group demonstrated significantly higher expression of the progesterone receptor compared to the low and high-dose BBP groups. There were no significant findings in pubertal female outcomes.
In the second part of this thesis, we evaluate the existing OECD Extended One-Generation Reproductive Toxicity Guidelines (TG 443). First by summarizing the endpoints and outcomes evaluated in studies that implement these guidelines, and additionally discussing the current OECD recommendations for mammary gland evaluation. We conclude with outlining the remaining questions to be evaluated and further research necessary to establish that the mammary gland should be added to TG 443.
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Development of an in vitro test system for assessment of male, reproductive toxicity.Habas, Khaled S.A., Anderson, Diana, Brinkworth, Martin H. 2013 October 1928 (has links)
Yes / There is a need for improved reproductive toxicology assays that do not require large numbers of animals but are sensitive and informative. Therefore, Staput velocity-sedimentation separation followed by culture of specific mouse testicular cells was used as such a system. The specificity of separation was assessed using immunocytochemistry to identify spermatids, spermatocytes and spermatogonia. The efficacy of the system to detect toxicity was then evaluated by analysing the effects of hydrogen peroxide (H2O2) by the terminal uridine-deoxynucleotide end-labelling (TUNEL) assay to show the rate of apoptosis induced among the different types of germ cells. We found that 2 h of treatment at both 1 and 10 μM induced increases of over ∼10-fold in the percentage of apoptotic cells (p ≤ 0.001), confirming that testicular germ cells are prone to apoptosis at very low concentrations of H2O2. It was also demonstrated for the first time for this compound that spermatogonia are significantly more susceptible than spermatocytes, which are more affected than spermatids. This reflects the proportion of actively dividing cells in these cell types, suggesting a mechanism for the differential sensitivity. The approach should thus form the basis of a useful test system for reproductive and genetic toxicology in the future.
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A step forward in using QSARs for regulatory hazard and exposure assessment of chemicals / Ett steg framåt i användandet av QSARs för regulatorisk riskbedömning och bedömning av exponeringen till kemikalierRybacka, Aleksandra January 2016 (has links)
According to the REACH regulation chemicals produced or imported to the European Union need to be assessed to manage the risk of potential hazard to human health and the environment. An increasing number of chemicals in commerce prompts the need for utilizing faster and cheaper alternative methods for this assessment, such as quantitative structure-activity or property relationships (QSARs or QSPRs). QSARs and QSPRs are models that seek correlation between data on chemicals molecular structure and a specific activity or property, such as environmental fate characteristics and (eco)toxicological effects. The aim of this thesis was to evaluate and develop models for the hazard assessment of industrial chemicals and the exposure assessment of pharmaceuticals. In focus were the identification of chemicals potentially demonstrating carcinogenic (C), mutagenic (M), or reprotoxic (R) effects, and endocrine disruption, the importance of metabolism in hazard identification, and the understanding of adsorption of ionisable chemicals to sludge with implications to the fate of pharmaceuticals in waste water treatment plants (WWTPs). Also, issues related to QSARs including consensus modelling, applicability domain, and ionisation of input structures were addressed. The main findings presented herein are as follows: QSARs were successful in identifying almost all carcinogens and most mutagens but worse in predicting chemicals toxic to reproduction. Metabolic activation is a key event in the identification of potentially hazardous chemicals, particularly for chemicals demonstrating estrogen (E) and transthyretin (T) related alterations of the endocrine system, but also for mutagens. The accuracy of currently available metabolism simulators is rather low for industrial chemicals. However, when combined with QSARs, the tool was found useful in identifying chemicals that demonstrated E- and T- related effects in vivo. We recommend using a consensus approach in final judgement about a compound’s toxicity that is to combine QSAR derived data to reach a consensus prediction. That is particularly useful for models based on data of slightly different molecular events or species. QSAR models need to have well-defined applicability domains (AD) to ensure their reliability, which can be reached by e.g. the conformal prediction (CP) method. By providing confidence metrics CP allows a better control over predictive boundaries of QSAR models than other distance-based AD methods. Pharmaceuticals can interact with sewage sludge by different intermolecular forces for which also the ionisation state has an impact. Developed models showed that sorption of neutral and positively-charged pharmaceuticals was mainly hydrophobicity-driven but also impacted by Pi-Pi and dipole-dipole forces. In contrast, negatively-charged molecules predominantly interacted via covalent bonding and ion-ion, ion-dipole, and dipole-dipole forces. Using ionised structures in multivariate modelling of sorption to sludge did not improve the model performance for positively- and negatively charged species but we noted an improvement for neutral chemicals that may be due to a more correct description of zwitterions. Overall, the results provided insights on the current weaknesses and strengths of QSAR approaches in hazard and exposure assessment of chemicals. QSARs have a great potential to serve as commonly used tools in hazard identification to predict various responses demanded in chemical safety assessment. In combination with other tools they can provide fundaments for integrated testing strategies that gather and generate information about compound’s toxicity and provide insights of its potential hazard. The obtained results also show that QSARs can be utilized for pattern recognition that facilitates a better understanding of phenomena related to fate of chemicals in WWTP. / Enligt kemikalielagstiftningen REACH måste kemikalier som produceras i eller importeras till Europeiska unionen riskbedömas avseende hälso- och miljöfara. Den ökande mängden kemikalier som används i samhället kräver snabbare och billigare alternativa riskbedömningsmetoder, såsom kvantitativa struktur-aktivitets- eller egenskapssamband (QSARs eller QSPRs). QSARs och QSPRs är datamodeller där samband söks korrelationer mellan data för kemikaliers struktur-relaterade egenskaper och t.ex. kemikaliers persistens eller (eko)toxiska effekter. Målet med den här avhandlingen var att utvärdera och utveckla modeller för riskbedömning av industri kemikalier och läkemedel för att studera hur QSARs/QSPRs kan förbättra riskbedömningsprocessen. Fokus i avhandlingen var utveckling av metoder för identifiering av potentiellt cancerframkallande (C), mutagena (M), eller reproduktionstoxiska (R) kemikalier, och endokrint aktiva kemikalier, att studera betydelsen av metabolism vid riskbedömning och att öka vår förståelse för joniserbara kemikaliers adsorption till avloppsslam. Avhandlingen behandlar även konsensusmodellering, beskrivning av modellers giltighet och betydelsen av jonisering för kemiska deskriptorer. De huvudsakliga resultaten som presenteras i avhandlingen är: QSAR-modeller identifierade nästan alla cancerframkallande ämnen och de flesta mutagener men var sämre på att identifiera reproduktionstoxiska kemikalier. Metabolisk aktivering är av stor betydelse vid identifikationen av potentiellt toxiska kemikalier, speciellt för kemikalier som påvisar östrogen- (E) och sköldkörtel-relaterade (T) förändringar av det endokrina systemet men även för mutagener. Träffsäkerheten för de tillgängliga metabolismsimulatorerna är ganska låg för industriella kemikalier men i kombination med QSARs så var verktyget användbart för identifikation av kemikalier som påvisade E- och T-relaterade effekter in vivo. Vi rekommenderar att använda konsensusmodellering vid in silico baserad bedömning av kemikaliers toxicitet, d.v.s. att skapa en sammanvägd förutsägelse baserat på flera QSAR-modeller. Det är speciellt användbart för modeller som baseras på data från delvis olika mekanismer eller arter. QSAR-modeller måste ha ett väldefinierat giltighetsområde (AD) för att garantera dess pålitlighet vilket kan uppnås med t.ex. conformal prediction (CP)-metoden. CP-metoden ger en bättre kontroll över prediktiva gränser hos QSAR-modeller än andra distansbaserade AD-metoder. Läkemedel kan interagera med avloppsslam genom olika intermolekylära krafter som även påverkas av joniseringstillståndet. Modellerna visade att adsorptionen av neutrala och positivt laddade läkemedel var huvudsakligen hydrofobicitetsdrivna men också påverkade av Pi-Pi- och dipol-dipol-krafter. Negativt laddade molekyler interagerade huvudsakligen med slam via kovalent bindning och jon-jon-, jon-dipol-, och dipol-dipol-krafter. Kemiska deskriptorer baserade på joniserade molekyler förbättrade inte prestandan för adsorptionsmodeller för positiva och negativa joner men vi noterade en förbättring av modeller för neutrala substanser som kan bero på en mer korrekt beskrivning av zwitterjoner. Sammanfattningsvis visade resultaten på QSAR-modellers styrkor och svagheter för användning som verkyg vid risk- och exponeringsbedömning av kemikalier. QSARs har stor potential för bred användning vid riskidentifiering och för att förutsäga en mängd olika responser som krävs vid riskbedömning av kemikalier. I kombination med andra verktyg kan QSARs förse oss med data för användning vid integrerade bedömningar där data sammanvägs från olika metoder. De erhållna resultaten visar också att QSARs kan användas för att bedöma och ge en bättre förståelse för kemikaliers öde i vattenreningsverk.
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Avaliação da administração do alcaloide boldina em ratas Wistar durante o período gestacional sobre variáveis reprodutivas e comportamentaisJardim, Lais Hartmann January 2017 (has links)
A boldina é o principal alcaloide encontrado no Peumus boldus, muito utilizado na medicina tradicional principalmente pelos seus efeitos gastrointestinais e hepáticos. Estudos indicam que apresenta diversas atividades farmacológicas como coletérica, hipnótica, citoprotetora, antitumoral, antiinflamatória, antipirética, antiplaquetária, antiplasmódica, antidiabética, antihipertensiva, inibidora da tirosinase e da acetilcolinesterase, antagonista dopaminérgico (receptores D1 e D2 like), adrenérgico (receptores α1 e α2) e serotoninérgico (receptores 5-HT3), entre outras. O chá de boldo (Peumus boldus) é muito utilizado por gestantes para aliviar os efeitos negativos da gestação como, constipação, cólicas uterinas, cefaleia e náuseas; controverso a esse uso ele também é muito utilizado como abortivo. Este estudo procurou identificar qual sua ação em ratas Wistar tratadas durante o período gestacional, GD1 ao dia anterior ao parto, nas doses de 1 mg/kg, 10 mg/kg e 100 mg/kg, uma vez ao dia, no ciclo claro, por meio gavagem. Conclui-se que o uso da boldina e do chá de P. boldus deve ser evitado durante o período gestacional pois seu uso na gestação causou alterações no desempenho reprodutiva das fêmeas, perda pré e pós implantação e mortes ao nascimento e pós-natais, além da modificação do comportamento materno (latência para lamber); foram encontradas também alterações no desenvolvimento da proles de fêmeas tratadas com boldina, em seu desempenho nos testes de reflexos (teste de endireitamento, geotaxia e agarrar), físico (abertura de olhos) e reprodutivo (abertura vaginal, descida de testículos e separação prepucial), assim como alteração no peso de órgãos de machos e fêmeas, na produção de espermatozoides e no percentual de espermatozoides com alteração (anormais). / Boldine is the main alkaloid found in Peumus boldus, widely used in traditional medicine mainly for its gastrointestinal and hepatic effects. Studies indicate that it presents several pharmacological activities as a choleretic, hypnotic, cytoprotective, anti-inflammatory, anti-plasmodic, antipyretic, antiplatelet, antidiabetic, antihypertensive, tyrosinase and acetylcholinesterase inhibitor, dopaminergic antagonist (D1 and D2 like receptors), α-adrenergic receptors antagonist (α 1 and α 2 receptors) and serotonergic receptors antagonist (5-HT 3 receptors), among others. Boldo’s tea (Peumus boldus) is widely used by pregnant women to alleviate the negative effects of pregnancy such as constipation, uterine cramps, headache and nausea; Controversely it is also widely used as an abortive substance The aim of this study was to identify the effect of boldine on Wistar rats treated during the gestational period, day 1 of gestation to the day before birth, at doses of 1mg/kg, 10mg/kg and 100mg/kg, daily, light cycle, by gavage. We concluded that the use of boldine and P. boldus tea should be avoided during the gestational period because its use in the gestacional period caused alterations in the reproductive performance of females, loss of pre and post implantation and deaths at birth and postnatal, besides modification of maternal behavior (latence to pup licking); alterations in the development of the offspring which the females were treated with boldine were observed, in their performance in the reflex tests (straightening, geotaxy and grab), physical development (eye opening) and reproductive development (vaginal opening, testicle descent and preputial separation), as well as changes in the weight of male and female organs, in the production of spermatozoa and in the percentage of abnormal spermatozoa.
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Development of an in vitro test system for assessment of male, reproductive toxicity.Habas, Khaled, Anderson, Diana, Brinkworth, Martin H. January 2014 (has links)
There is a need for improved reproductive toxicology assays that do not require large numbers of animals but are sensitive and informative. Therefore, Staput velocity-sedimentation separation followed by culture of specific mouse testicular cells was used as such a system. The specificity of separation was assessed using immunocytochemistry to identify spermatids, spermatocytes and spermatogonia. The efficacy of the system to detect toxicity was then evaluated by analysing the effects of hydrogen peroxide (H2O2) by the terminal uridine-deoxynucleotide end-labelling (TUNEL) assay to show the rate of apoptosis induced among the different types of germ cells. We found that 2 h of treatment at both 1¿M and 10¿M induced increases of over ~10-fold in the percentage of apoptotic cells (p¿0.001), confirming that testicular germ cells are prone to apoptosis at very low concentrations of H2O2. It was also demonstrated for the first time for this compound that spermatogonia are significantly more susceptible than spermatocytes, which are more affected than spermatids. This reflects the proportion of actively dividing cells in these cell types, suggesting a mechanism for the differential sensitivity. The approach should thus form the basis of a useful test system for reproductive and genetic toxicology in the future.
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