Inúmeros trabalhos avaliando as exigências de lisina podem ser encontrados na literatura, mas seus resultados são heterogêneos. Revisões sistemáticas e a meta-análise permitem integrar diferentes variáveis, gerar novos resultados e obter respostas ajustadas a uma maior diversidade experimental. Objetivou-se explorar as relações da lisina digestível com as variáveis de desempenho, estabelecer a exigência e avaliar a eficiência marginal da lisina segundo a lei de rendimentos decrescentes para suínos em crescimento e terminação. Para os estudos I e II, foram compilados 36 artigos publicados entre 2002 e 2013 avaliando 2.399 suínos pesando entre 15-120 kg. Para o estudo III, foram utilizados 26 artigos que avaliaram 1.820 suínos pesando entre 20-120 kg. No estudo I, o consumo diário de lisina apresentou correlações maiores com a ingestão de energia metabolizável e proteína bruta e com as deposições de proteína e lipídios. O consumo diário de lisina apresentou melhor ajuste nas equações de variância-covariância do que o nível percentual de lisina. No estudo II, o aumento no consumo diário de lisina melhorou o ganho de peso e a deposição de proteína na fase de 70-120 kg. Nas fases de 15-30; 30-70 e 70-120 kg os níveis de lisina digestível determinados para obter as melhores respostas de ganho corresponderam ao consumo diário de 14,8; 20,2 e 18,3 g lisina/dia. Os níveis de lisina digestível determinados para obter as melhores respostas de deposição de proteína corresponderam ao consumo diário de 16,3 e 24,1 g lisina/dia nas fases 15-30 e 30-70 kg. No estudo III, observamos que a medida que o animal se aproxima ou atinge o ponto de máximo desempenho, a eficiência de uso da lisina digestível diminui segundo a lei de rendimentos decrescentes. Dietas formuladas para atender 95% da máxima resposta de ganho de peso permitem uma melhora na eficiência marginal de uso da lisina da ordem de 2,4; 2,5 e 1,5 g de ganho de peso para cada g de lisina ingerida nas faixas de peso vivo 20-50; 50-70 e 70-120 kg. Sugerimos a inclusão de variáveis como a eficiência alimentar e o ganho de peso nas análises de determinação de exigências de lisina, também a escolha de metodologias analíticas adequadas e a inclusão da lei de rendimentos decrescentes da eficiência marginal de uso da lisina nos atuais modelos de determinação de exigência para evitar a superestimação observada nas tabelas de recomendação nutricional. / Several studies evaluating the lysine requirements are avaible in the literature, but its results are heterogeneous. Systematic reviews and meta-analysis allows integrating different variables, generating new results and producing answers adjusted to experimental diversity. This objective of this study was to explore the relationship among dietary lysine and the performance variables, establishing the requirement and assessing the marginal efficiency of dietary lysine according to the law of diminishing returns for growing-finishing pigs. For studies I and II, 36 articles published from 2002 to 2013 evaluating 2399 pigs weighing between 15-120 kg were compiled. And for the study III 26 articles evaluating 1820 pigs weighing between 20-120 kg were used. In the study I, daily intake of lysine showed higher correlations with the metabolizable energy intake and crude protein, with the protein deposition and lipid deposition. The daily intake of lysine showed better adjustment in the variance-covariance equations than the dietary level of lysine. In Study II, increasing the daily intake of lysine improved the weight gain and protein deposition in the 70-120 kg phase. In 15-30; 30-70 and 70-120 kg phase the levels digestible lysine that maximized weight gain reponse corresponded to the daily intake of 14.8; 20.2 and 18.3 g lysine/day. Lysine levels that maximized protein deposition reponse corresponded to daily intake of 16.3 and 24.1 g lysine/day in the phases 15-30 and 30-70 kg. In the study III, it was observed that, as the animal approaches or reaches the maximum performance the efficiency of lysine use decreases according to the law of diminishing returns. Diets formulated to meet 95% of the maximal weight gain response permit a marginal improvement in efficiency of use of the lysine the order of 2.4; 2.5 and 1.5 grams of weight gain for each lysine grams ingested in live weight phases 20-50; 50-70 and 70-120 kg respectively. It suggest the inclusion of variables feed efficiency and weight gain in analysis for the determination of lysine requirements, also the choice of appropriate analytical methods and the inclusion of diminishing returns law of marginal efficiency the dietary lysine in current models for the determination of requirements to avoid the overestimation observed in nutritional recommendation tables.

Nos últimos anos, em áreas de produção de culturas transgênicas resistentes ao glyphosate, falhas no controle do capim-pé-de-galinha (Eleusine indica) são cada vez mais frequentes, estando provavelmente relacionadas ao uso indiscriminado do glyphosate e ao consequente aumento da pressão de seleção de biótipos de plantas daninhas resistentes a esse herbicida. Este trabalho teve como objetivo comparar a suscetibilidade de quatro populações de capim-pé-de-galinha ao herbicida glyphosate em diferentes estádios de desenvolvimento, bem como estudar a eficácia de herbicidas alternativos ao glyphosate no controle de plantas desta espécie na pré e pós-emergência das mesmas. Também foi objetivo deste trabalho estudar aspectos da biologia, tais como: crescimento, número de sementes produzidas por uma planta e influência da escarificação mecânica sobre a germinação do capim-pé-de- galinha. Foi verificado que existem diferenças na suscetibilidade das populações ao glyphosate, no qual a população denominada EIR2 proveniente de Primavera do Leste - MT foi a que necessitou de maiores doses para ser controlada, sendo caracterizada como um caso de resistência de nível baixo, pois a dose máxima de bula recomendada para a espécie é capaz de controlar todas as populações do estudo. Os herbicidas mais indicados para o controle de capim-pé-de-galinha na pré-emergência foram o flumioxazin, sulfentrazone, clomazone e trifluralina, apresentando maiores níveis de controle e efeito residual mais prolongado. O controle do capim-pé-de-galinha na pós-emergência inicial (2 a 3 perfilhos) e no estádio intermediário (6 a 8 perfilhos) foi eficiente com todos os herbicidas testados. No estádio mais avançado (10 a 12 perfilhos) o herbicida sethoxydim não controlou nenhuma das populações, não sendo indicado para plantas com mais de 6 perfilhos. Foram identificadas diferenças significativas entre o controle das populações com os inibidores da ACCase, sendo necessários outros estudos para confirmação da resistência a esses herbicidas. O capim-pé-de-galinha apresentou de maneira geral elevado acúmulo de matéria seca total, sendo considerado altamente competitivo. Foram encontradas diferenças entre o crescimento das populações, não havendo relação com a suscetibilidade diferencial ao glyphosate existente entre as mesmas. O perfilhamento iniciou-se aos 28 dias após a emergência (DAE), com um pico de crescimento dos 42 aos 63 DAE quando as plantas atingiram o ápice do acúmulo foliar e matéria seca, entrando posteriormente na senescência. O florescimento iniciou-se entre 42 e 49 DAE e perdurou até os 63 DAE. Uma planta da espécie Eleusine indica produziu em média 45000 sementes e não foram encontradas diferenças significativas na produção de sementes entre as populações. A escarificação mecânica das sementes acelerou o processo de germinação e aumentou a germinação final das populações de capim-pé-de-galinha. O mecanismo que confere a dormência física das sementes de capim-pé-de-galinha está relacionado com a impermeabilidade do tegumento. / Lately, in the areas of production of transgenic crops resistant to glyphosate failures in control of goosegrass has been reported frequently, probably by an intense using of glyphosate and consequent increasing in selection pressure of weeds resistant to glyphosate. For this reason this work was carried out in order to compare the susceptibility of four goosegrass populations to glyphosate in different stages of development, as well as studying the effectiveness of alternative herbicides to glyphosate in the control of such species in pre and post-emergence. It was also a goal of this work study biological aspects, such as growth, weed number produced by a plant and influence of mechanical scarification on the germination of the goosegrass. It was found that there are differences in the susceptibility of populations to glyphosate, in which EIR2 population from Primavera do Leste - MT was the one that required higher doses to be controlled, being characterized as a case of low-level resistance because of the maximum recommended dose is able to control all the populations studied. Herbicides the most suitable to control pre-emergence were flumioxazin, sulfentrazone, clomazone and trifluralin, with high levels of control were used a longer residual effect. The control of goosegrass in the early post-emergence (2-3 tillers) and the intermediate stage (6-8 tillers) was efficient with all the tested herbicides. In the most advanced stage (10 to 12 tillers) the herbicide sethoxydim did not control any of populations, was not were used suitable for plants with more than 6 tillers. Remarkable differences were identified between the control of populations with ACCase inhibitors. Other studies are necessary to confirm the resistance to these herbicides. The goosegrass showed high accumulation of total dry matter, being considered highly competitive. Some differences were found among the growth of the populations, with no relation to the differential susceptibility to glyphosate existing between them. The tillering began at 28 days after emergence (DAE), with a growth between of 42 to 63 DAE when the plants reached the apex of the leaf and dry matter accumulation, later entering senescence. The flowering started between 42 and 49 DAE and lasted until 63 DAE. A plant of Eleusine indica produced on average 45 000 seeds and there were no important differences between seed production among populations. Mechanical scarification of seeds accelerated the germination and increased the final germination populations of goosegrass. The mechanism that confers the physical dormancy of goosegrass seeds is related to the impermeability of the integument.

A olanzapina é um fármaco antipsicótico atípico utilizado no tratamento da esquizofrenia. Como efeitos adversos relacionados ao seu uso, encontram-se obesidade, hiperlipidemia, Diabetes Mellitus tipo II, entre outros. O presente trabalho avaliou os efeitos adversos passíveis de desenvolvimento em pacientes esquizofrênicos que fazem uso deste medicamento, avaliando o indivíduo antes de começar o tratamento, 30 e 60 dias após o início (T0, T1 e T2) através de dosagens antropométricas (peso, IMC, circunferência abdominal e porcentagens de tecido adiposo no organismo), hemodinâmicas (pressão arterial, frequência cardíaca), perfil lipídico (colesterol total, LDL-col, HDL-col e triglicérides), glicêmico (resistência à insulina HOMA-R, QUICKI e razão G/I; glicemia de jejum) e bioquímico (avaliação da função renal, hepática e dosagem de homocisteína, um marcador de risco cardiovascular). A olanzapina plasmática foi dosada nos mesmos tempos com intenção de se buscar uma correlação de dose-resposta (efeito adverso). A análise estatística foi realizada com auxílio dos \"softwares\" Graphpad Instat e Statgraphics, para o estudo e análise das médias (ANOVA), e análise de comparação múltipla entre os grupos (Tukey-Kramer). O nível de significância foi fixado em p<0,05. Para os grupos sem diferença estatística relevante, foram utilizadas técnicas de estatística descritiva para se observar diferenças mais sutis ou com relevância clínica. As altas concentrações plasmáticas encontradas não foram concordantes com os estudos prévios de outros autores, já que não foram mais propensos a desenvolver ganho de peso. Este efeito adverso foi encontrado no nosso grupo, porém sem apresentar uma correlação direta com a concentração plasmática. / The olanzapine is an atypical antipsychotic drug used to treat schizophrenia. The adverse effects related to its use are obesity, hyperlipidemia, diabetes mellitus type II and others. This study evaluated the adverse effects likely to develop in schizophrenia patients who use this drug, assessing the individual before starting treatment, 30 and 60 days after the start (T0, T1 and T2) by anthropometric measurements (weight, BMI , waist circumference and percentage of fat in the body), hemodynamic (blood pressure, heart rate), lipid profile (total cholesterol, LDL-col, col-HDL and triglycerides), glucose (insulin resistance - HOMA-R, QUICKI, G/I ratio and fasting plasma glucose) and biochemical (measurement of renal function, liver and determination of homocysteine, a marker of cardiovascular risk). The olanzapine plasma was measured at the same time looking for a dose-response (effect) correlation. Statistical analysis was performed using the \"software\" Statgraphics and GraphPad Instat for the study and analysis of means (ANOVA) and analysis of variance between groups (Tukey-Kramer). The significance level was set at p <0.05. For groups without statistical significant difference were used descriptive statistical techniques to observe more subtle differences or clinical relevance. The high plasma concentrations found were not consistent with previous studies of other authors, since there were more likely to develop weight gain. This adverse effect was found in our group, but without a direct correlation with plasma concentration.

Orientador: Antonio Celso Pezzato / Banca: Dirlei Antonio Berto / Banca: Manoel Garcia Neto / Resumo: O presente estudo objetivou avaliar os efeitos da suplementação de diferentes níveis de metionina digestível nas dietas de frangos de corte de 1 a 21 dias de idade, sobre o desempenho animal e o rendimento de carcaça, pelo do método tradicional de dose-resposta, e utilizar a técnica de isótopos estáveis através do turnover tecidual para certificar este procedimento de exigência nutricional. Foram realizados dois ensaios em delineamento inteiramente casualizado, com sete tratamentos que consistiram de níveis de metionina digestível para as fases pré-inicial e inicial, respectivamente: 70% (0,320 e 0,307), 80% (0,360 e 0,331), 90% (0,410 e 0,380), 100% (0,450 e 0,417), 110% (0,500 e 0,460), 120% (0,540 e 0,510) e 130% (0,591 e 0,540) de metionina digestível correspondentes às exigências preconizadas por Rostagno et al. (2011). No ensaio I foram utilizados 875 pintos de corte de um dia de idade alojados em 35 unidades experimentais e avaliou-se o desempenho e o rendimento de carcaça. No ensaio II foram alojados 567 pintos de corte de um dia de idade e avaliou-se o turnover do 13C no músculo peitoral e fígado. Todos os animais foram submetidos à dieta a base de arroz e farelo de soja do primeiro aos 21 dias de idade. No ensaio I foi verificado melhora no desempenho de 1 a 7 dias de idade nos tratamentos 100% e 120% para peso corporal e ganho de peso e de 1 a 21 dias de idade nos tratamentos 100%, 110%, 120% para ganho de peso e peso corporal. Observou-se melhora na conversão alimentar com os tratamentos 100%, 110%, 120% e 130%. Os tratamentos 100% e 120% apresentaram melhora no rendimento de peito, o 110% para gordura abdominal e o 120% para o peso do fígado aos 21 dias de idade. No ensaio II foi verificado diminuição da meia-vida e aumento da taxa metabólica para o músculo peitoral no tratamento 130% e para o fígado no tratamento 80%. Pode-se observar que os tratamentos 100%, 11 ... / Abstract: The present study aimed to evaluate the effects of different levels of digestible methionine in broiler diets on performance, carcass yield through the traditional method of dose-response, and use the stable isotopic of tissue turnover to certificate this procedure of nutritional requirement. Two trials were conducted in a completely randomized design with seven treatments that consisted in levels of digestible methionine to pre-starter and initial phase, respectively: 70% (0,320 e 0,307), 80% (0,360 e 0,331), 90% (0,410 e 0,380), 100% (0,450 e 0,417), 110% (0,500 e 0,460), 120% (0,540 e 0,510) e 130% (0,591 e 0,540) of digestible methionine corresponding to the requirements recommended by Rostagno et al. (2011). In the first trial, 875 one day old chicks were housed in 35 pens to evaluate the performance and carcass yield. In the second trial, 567 one day old chicks were housed to determinate the turnover of carbon-13 in the pectoral muscle and liver. All birds were fed a diet based on rice and soybean meal (predominantly C3) for the first 21 days of life. In the first trial was verified improved performance at 7 days old on treatments 100% and 120% for body weight and weight gain and at 21 days old on treatments 100%, 110% and 120% for body weight and weight gain. It was noted improving on feed conversion with treatments 100%, 110%, 120% and 130%. The treatments 100% and 120% showed improvement on breast yield, the 110% to fat abdominal and the 120% for liver weight at 21 days old. In the second trial was verified reduction of half-life and increase of metabolic rate to the breast muscle on treatment 130% and for liver on treatment 80%. It could be noted that treatments 100%, 110% and 120% improvement the animal performance / Mestre

O interesse em efeitos sinérgicos ou antagônicos através de experiências com associações cresceu imensamente nas últimas décadas. Com o objetivo de estudar a associação de dois herbicidas inibidores da ALS (sulfometuron-methyl e chlorimuron-ethyl) em Digitaria insularis, empregou-se dos métodos estatísticos fornecidos por meio das curvas dose-resposta e isobologramas. O conceito de curvas dose-resposta tem sido amplamente utilizado para avaliar os resultados das experiências com herbicidas. No entanto, a abordagem estatística em torno das curvas deve ser cuidadosa; cosiderar as curvas dose-resposta semelhantes quando elas não são pode influenciar muito na comparação entre as moléculas e afetar o cálculo da potência relativa. A potência relativa ajuda a entender qual é a relação de potência entre as moléculas, esse conhecimento é fundamental para os estudos com os herbicidas em associação. Sabendo-se disso foram conduzidos experimentos do tipo dose-resposta em dois tipos de substratos utilizando Digitaria insularis como planta daninha indicadora. Os experimentos foram conduzidos em casa de vegetação do Centro de Pesquisa e Desenvolvimento da DuPont em Paulínia (SP). Para cada molécula foram aplicadas, em pré-emergência, oito doses com quatro repetições cada e quatro plantas testemunha nos diferentes substratos. O substrato A é somente substrato comercial (marca Tropstrato HT&reg;) puro; E o substrato B é uma mistura de solo arenoso, peneirado e livre de contaminação mais substrato comercial na proporção 3:1 v/v. Neste caso ficou evidente a maior capacidade do sulfometuronmethyl em reduzir a biomassa da espécie, as curvas dose-resposta foram descritas pelo modelo log-logístico com os valores de ED50 e as declividades de cada curva variando livremente, pois as hipóteses testadas nos diferentes substratos de curvas paralelas foram rejeitadas. O valor calculado da potência relativa para o nível de resposta de 50% entre os herbicidas CLASSIC&reg; (chlorimuron-ethyl) e CURAVIAL&reg; (sulfometuron-methyl) nas condições desse estudo foi de 8,596 e 44,047 nos Substrato A e B respectivamente. A partir dessa informação foram utilizadas as mesmas condições do experimento anterior para o experimento com as isoboles dos herbicidas em associação, cinco curvas dose-resposta, foram propostas, duas curvas para os produtos isolados e três curvas para as associações em diferentes proporções [(25% : 75%); (50% : 50%); (75% : 25%)] chlorimuron-ethyl / sulfometuron-methyl, totalizando 144 parcelas. Vários modelos isoboles foram testados, o modelo de Concentração Aditiva foi significativamente descartado, mas foi levado em consideração para testar teoricamente o grau de sinergia ou antagonismo que modelos mais complexos podiam fornecer. O modelo de isobole proposto por Hewlett e Plackett (1959) teve ajuste significativo e parâmetro de interação menor que um (&lambda;=0,33). O modelo que mais se ajustou aos dados foi o proposto por Vølund e os resultados também mostraram que nessas condições a associação de sulfometuron-methyl com chlorimuron-ethyl foi antagônica; as isoboles são potentes ferramentas para capturar e descrever associações de herbicidas. Entretanto a literatura mostra que associar duas moléculas e testar em um sistema biológico complexo sofrendo variações das diferentes condições ambientais possíveis pode gerar respostas variáveis, portanto esses resultados devem ser repetidos em outras condições para validar as conclusões ou então serem executados em condições controladas de laboratório e usar organismos vivos de menor complexidade como bioindicador. / The interest in synergistic or antagonistic effects through experiences with associations has immensely grown in recent decades. In order to study the association of two ALS inhibitor herbicides (sulfometuron-methyl and chlorimuronethyl) in Digitaria insularis, the statistical methods provided by the dose-response curves and isobolograms were used. The concept of dose-response curves has been widely used to evaluate the results of herbicide experiments. However, the statistical approach around curves must be careful; considering the dose-response curves when they are not can greatly influence the comparison between molecules and affect the calculation of relative potency. Relative potency helps to understand what the power ratio is between molecules, this knowledge is fundamental for studies with herbicides in association. Knowing this, dose-response experiments were conducted on two types of substrates using Digitaria insularis as an indicator weed. The experiments were conducted in a greenhouse of the DuPont Research and Development Center in Paulínia (SP). For each molecule were applied, in pre-emergence, eight doses with four replicates each and four control plants on different substrates. Substrate A is pure commercial substrate (brand Tropstrato HT&reg;); and substrate B is a mixture of sandy soil, sifted and contamination-free plus commercial substrate in the ratio 3:1 v/v. In this case it was evident the greater capacity of the sulfometuron-methyl to reduce the biomass of the species, the dose-response curves were described by the log-logistic model with the values of ED50 and the slopes of each curve varying freely, since the hypotheses tested in the different substrates of parallel curves were rejected. The calculated value of relative potency for the 50% response level between CLASSIC&reg; (chlorimuron-ethyl) and CURAVIAL&reg; (sulfometuron-methyl) herbicides under the conditions of this study was 8.596 and 44.047 on Substrate A and B respectively. From this information the same conditions of the previous experiment for the isoboles of the herbicides in association were used, five doseresponse curves were proposed, two curves for the isolated products and three curves for the associations in different ratios [25% : 75%); (50% : 50%); (75% : 25%)] chlorimuron-ethyl / sulfometuron-methyl, totaling 144 plots. Isoboles models were tested, the Concentration Additive model was significantly discarded, but was taken into account to theoretically test the degree of synergy or antagonism that more complex models could provide. The isobole model proposed by Hewlett and Plackett (1959) had a significant adjustment and interaction parameter smaller than 1 (&lambda; = 0.33). The model that best fit the data was the one proposed by Vølund and the results also showed that under these conditions the association of sulfometuronmethyl with chlorimuron-ethyl was antagonistic; isoboles are potent tools for capturing and describing herbicide associations. So these results must be repeated in other conditions to validate the conclusions or to be executed in controlled laboratory conditions and to use living organisms of lesser complexity as a bioindicator.

This thesis examines the overarching theme of inhaled corticosteroid (ICS) dose response effects on a variety of asthma outcome measures; with further importance placed on the application of these findings to personalising ICS dosing for the individual asthmatic. The introduction provides a detailed summary of the current recommendations for the treatment of adult asthma, with particular reference to the mechanism of action and clinical utility of ICS for the treatment of asthma. Current methods of assessing ICS dose response are presented, as well as the common influences that affect these responses. Novel therapeutic theories and the identification of specific asthmatic phenotypes are also introduced, in order to demonstrate the shift towards personalising treatment for asthma. The first two studies examine the dose response of ICS on two specific factors that influence asthma. The third study presents an examination of pharmacological manipulation of the ICS dose response using an additional agent. The following two studies address: how asthma outcomes relate to each other in patients receiving ICS; in addition to an overall assessment of the ICS dose response across a broad range of both ICS moieties and outcome measures. The final study examines for any detrimental effect of an ICS dose ramp on bone metabolism, an important potential long-term adverse effect of higher ICS dosing. The discussion draws together all the results obtained in relation to ICS dose response in asthma, and how these apply to current clinical practice for the individual patient. Furthermore, hypotheses are generated for areas of future study based on the findings from this work.

Contamination of methylmercury (MeHg) in aquatic products has been a wide spread health concern. The objective of this study is to determine total mercury (THg) and MeHg concentrations in different species of aquatic products from major offshore farms in China, and to assess health impacts from consumption. Results showed that the concentrations of THg and MeHg ranged 5.6–328.4 ng/g (wet weight) and 4.3–303.6 ng/g (wet weight) in aquatic products, respectively, and were very variable among species and origin sources. Target hazard quotient (THQ) suggested that MeHg exposure via consumption posed high health risks to children aged 2–7 and higher income families. Residents above the age of 13 and with low income have relatively lower health risk of MeHg exposure. Health impacts on heart attacks and newborns’ IQ from MeHg exposure were evaluated using dose-response relationships. Results showed that mother’s consumption of aquatic products (at 6 ounce per day) may cause a loss of 0.38 IQ points for newborns. For non-pregnant, consumption of aquatic products may cause an increase rate of mortality and morbidity of heart attacks at 10.59 and 78.45 per 100,000 persons, respectively. The negative health impact of consuming seawater fish was higher than freshwater fish.

In its latest neurotoxicity guidelines released by the US EPA Office of Prevention, Pesticides and Toxic Substances (OPPTS) in 1998, it is recommended that in a neurobehavioral testing, at a minimum, for acute studies, observations and activity testing should be made before the initiation of exposure, at the estimated TOPE (time of peak effects) within 8 hrs of dosing, and at 7 and 14 days after dosing. It is recommended that estimation of TOPE be made by dosing pairs of rats across a range of doses and making regular observations of gait and arousal. However it is well known that TOPE may vary with end points or exposure conditions. In order to derive quantitative safety measures such as the benchmark doses (BMD), dose-time-response modeling must be done first and a model-based estimate is then implied. In many cases, the overall BMD corresponds to a TOPE estimate. In such cases a substantial variation in the TOPE estimate in turn may result in substantial variation in BMD estimate. Therefore a reliable statistical estimate of TOPE is crucial to the correct determination of BMD. We therefore performed simulation studies to assess the impact of the experiment-based TOPE on the statistical estimation of the true TOPE on the basis of a fitted dose-time-response model. The simulation allows for the determination of the optimal timing range for the 2nd testing. The results indicated that given only four repeated observations, the optimal second testing time was at about midway between time zero and the true TOPE. Choosing the second testing time at the TOPE may not generate statistical estimates closer to the true TOPE.

ABSTRACT Occupational exposure to wood dust and biohazards associated with wood dust (endotoxins, (1->3)-b-D-glucans, Gram (-)ve bacteria and fungi), their correlation to respiratory function, and symptoms among woodworkers have been investigated in the present study. Wood dust, endotoxins, and allergenic fungi are the main hazards found in woodworking environments. Relatively very few studies have been done on wood dust exposure. The present study was designed to comprehensively investigate the health effects of wood dust exposure, and in particular provide new information regarding: Exposure to (1->3)-b-D-glucans in an occupational environment; Levels of exposure to wood dust and biohazards associated with wood dust in different woodworking environments; Correlations among personal exposures, especially correlations between (1->3)-b-D-glucans and fungi exposures, and endotoxins and Gram (-)ve bacteria exposures; Effects of personal exposure to biohazards on lung function; Effects of personal exposure to biohazards on work-related symptoms; and Determinants of inhalable exposures (provide which factors in the environment influence the personal inhalable exposures). Workers at four different woodworking processes; two logging sites, four sawmills, one major woodchipping operation and five joineries situated in the state of New South Wales in Australia were studied for personal exposure to inhalable dust (n=182) and respirable dust (n=81), fungi (n=120), Gram (-)ve bacteria (n=120), inhalable endotoxin (n=160), respirable endotoxin (n=79), inhalable (1->3)-b-D-glucan (n=105), and respirable (1->3)-b-D-glucan (n=62). The workers (n=168) were also tested for lung function. A questionnaire study (n=195) was carried out to determine the prevalence of work-related symptoms. The geometric mean inhalable exposure at logging sites was 0.56 mg/m3 (n=7), sawmills 1.59 mg/m3 (n=93), the woodchipping mill 1.86 mg/m3 (n=9) and joineries 3.68 mg/m3 (n=66). Overall, sixty two percent of the exposures exceeded the current standards. Among joineries, 95% of the hardwood exposures and 35% of the softwood exposures were above the relevant standards. Compared with green mills, the percentage of samples, which exceeded the hardwood standard was high for dry mills (70% in dry mills, 50% in green mills). The respirable dust exposures were high at the joineries compared with the other worksites. Exposure levels to fungi at logging sites and sawmills were in the range 103-104 cfu/m3, woodchipping 103-105 cfu/m3 and joineries 102-104 cfu/m3. The predominant fungi found at sawmills were Penicillium spp. High exposure levels of Aureobasidium pullulans were also found at two sawmills. At the woodchipping mill the predominant species were Aspergillus fumigatus, Penicillium spp., and Paecilomyces spp. The sawmills, which employed kiln drying processes, had lower exposure levels of fungi compared with the green mills. Those workplaces which had efficient dust control systems showed less exposure to fungi and bacteria. Although mean endotoxin levels were lower than the suggested threshold value of 20 ng/m3, some personal exposures at sawmills and joineries exceeded the threshold limit value. The mean inhalable (1->3)-b-D-glucan level at the woodchipping mill was 2.32 ng/m3, at sawmills 1.37 ng/m3, at logging sites 2.02 ng/m3, and at joineries 0.43 ng/m3. For the respirable size fraction, mean endotoxin and mean (1->3)-b-D-glucan concentrations were much lower, being similar to observed dust concentrations. Significant correlations were found between mean inhalable endotoxin and Gram (-)ve bacteria levels (p<0.0001), and mean airborne inhalable (1->3)-b-D-glucan and fungi levels (p=0.0003). The correlations between mean respirable endotoxin levels vs Gram (-)ve bacteria exposure levels (p=0.005), and respirable (1->3)-b-D-glucan exposure levels vs total fungi levels (p=0.005) were also significant. Significant correlations were found between lung function and personal exposures. Multivariate analyses showed that the effect of all the personal exposures on cross-shift decrements in lung function was more prominent among sawmill and chip mill workers compared with joinery workers. Woodworkers had markedly high prevalence of cough, phlegm, chronic bronchitis, frequent headaches, throat and eye irritations, and nasal symptoms compared with controls. Among the woodworkers, smokers had a high prevalence of chronic bronchitis (20%) compared with non-smokers (10%). Some workers also reported a variety of allergy problems due to exposure to various types of wood dust. Both joinery workers and sawmill and chip mill workers revealed significant correlations between work-related symptoms and personal exposures. Chronic bronchitis was significantly correlated with personal exposure to wood dust, endotoxin, (1->3)-b-D-glucan, fungi, and Gram (-)ve bacteria among joinery workers. Whereas among sawmill workers chronic bronchitis was significantly correlated with personal exposure to endotoxin, (1->3)-b-D-glucan, and fungi. Woodworkers showed significant positive correlations between percentage cross-shift change (decrease) in lung function and respiratory symptoms. Significant inverse correlations were also found among percentage predicted lung function and respiratory symptoms. The elevated inhalable dust exposures observed in this study can be explained by a combination of factors, including: lack of awareness of potential health effects of wood dust exposure among both management and workers, aging equipment, inadequate and ineffective dust extraction systems or usually none especially for hand held tools, poor maintenance of the ventilation system in some, non-segregation of dusty processes, dry sweeping, and the use of compressed air jets. The determinant-of-exposure analysis confirmed the field observations. The significant determinants of personal inhalable dust exposures (n=163) were found to be: local exhaust ventilation, job title, use of hand-held tools, cleaning method used, use of compressed air, and green or dry wood processed. Type of wood processed was not found to be statistically significant. A majority of workers (~90%) did not wear appropriate respirators approved for wood dust, while the workers who did wear them, used them on average less than 50% of the time. Workers should be protected by controlling dust at its source. When exposure to wood dust cannot be avoided, engineering controls should be supplemented with the use of appropriate personal protective equipment.

<p>The present thesis is focused on the development and application of dose response models for radiation therapy. Radiobiological models of tissue response to radiation are an integral part of the radiotherapeutic process and a powerful tool to optimize tumor control and minimize damage to healthy tissues for use in clinical trials. Ideally, the models could work as a historical control arm of a clinical trial eliminating the need to randomize patents to suboptimal therapies. In the thesis overview part, some of the basic properties of the dose response relation are reviewed and the most common radiobiological dose-response models are compared with regard to their ability to describe experimental dose response data for rat spinal cord using the maximum likelihood method. For vascular damage the relative seriality model was clearly superior to the other models, whereas for white matter necrosis all models were quite good except possibly the inverse tumor and critical element models. The radiation sensitivity, seriality and steepness of the dose-response relation of the spinal cord is found to vary considerably along its length. The cervical region is more radiation sensitive, more parallel, expressing much steeper dose-response relation and more volume dependent probability of inducing radiation myelitis than the thoracic part. The higher number of functional subunits (FSUs) consistent with a higher amount of white matter close to the brain may be responsible for these phenomena. With strongly heterogeneous dose delivery and due to the random location of FSUs, the effective size of the FSU and the mean dose deposited in it are of key importance and the radiation sensitivity distribution of the FSU may be an even better descriptor for the response of the organ. An individual optimization of a radiation treatment has the potential to increase the therapeutic window and improve cure for a subgroup of patients.</p>