ABRAÇA SUA HISTÓRIA MUDE SEU FUTURO Os lançamentos de produtos e apresentações de negócios raramente me impressionam porque não conseguem alcançar as mentes e tocar os corações. Há uma abundância de bons comunicadores que podem projetar um slide PowerPoint razoavelmente atraente e falar com ele com confiança. Mas líderes que podem cativar. Ler mais Especialista em mídia social Andy Hill featured 8220The Storyteller8217s Secret8221 nesta lista de 3 livros que mudam a vida. 8220I garanto que se você ler este livro você aprenderá como se comunicar mais efetivamente com suas equipes e seus clientes.8221 O ex-CEO da Apple, John Sculley, reforça o ponto de que cada grande inovação ou progresso de Moonshot começa com uma causa nobre, uma visão dos fundadores de Tornar o mundo um lugar melhor. Donald Trump não repetiu o mantra Drain the Swamp em seu discurso de vitória na manhã de quarta-feira de manhã, mas a metáfora pode ter desempenhado um pequeno papel em ajudá-lo a ganhar a eleição presidencial de 2016. Steve Young deixou uma vez 4 milhões em cheques sem salário em uma mesa de cabeceira ao lado de sua cama. No final da temporada de futebol da NFL 1989, o San Francisco 49ers venceu o Denver Broncos 55 10 no Super Bowl XXIV. Joe Montana foi nomeado MVP e jogou cinco passes de touchdown. Montanas apoio, Steve Young, jogou os últimos quatro minutos. Primeiro, as más notícias. Não há atalhos no caminho para se tornar um palestrante excepcional. Agora, a boa notícia. Qualquer um que coloca no trabalho pode melhorar radicalmente suas habilidades de comunicação. Como usar storytelling para aumentar o sucesso de suas marcas. Carmine entrevistou para o pequeno negócio popular. Ler mais Em uma época em que os robôs estão deslocando pessoas, uma habilidade humana continua sendo a habilidade de contar uma história. Ouça Carmine Gallo falar com a Bloomberg Advantage na Bloomberg Radio e Sirius. Ler mais Breakthrough Business Strategy Entrevista com Michele Price. Tópico: O que é o poder de violar as expectativas da audiência Leia mais Entrevista com a Wharton School of Business. Como storytelling pode crescer seu negócio, marca e carreira. Transcrição completa da entrevista de Carmines para a escola de Wharton. Leia mais entrevista Carmine8217s em MSNBC8217s Seu Negócio com JJ Ramberg. Tópico: Fazendo o seu negócio Pitch Irresistible Watch. Leia mais Nesta entrevista para o popular podcast GenX Amplified, Carmine explica como os Gen-Xers podem usar histórias para inspirar, motivar, educar e desencadear movimentos que mudam o mundo. Carmine Gallo sobre Por que Storytelling é o Segredo para Liderança e Sucesso Empresarial. Leia maisGet Free Weekly Updates da CT R ecord labels existem para descobrir e desenvolver artistas com o objetivo de produzir, distribuir e promover sua música. Essa função não mudou, mas as práticas da empresa têm nesta nova era de música digital, auto-publicação, gravação em casa e MySpace. O que as empresas estão fazendo para mudar com os tempos e conectar artistas com os ouvintes Há uma declaração curiosa sobre a tampa traseira do CD Sevenglory Over the Rooftops. Para baixo na cópia fina onde os direitos reservados usuais e os disclaimers legais vivem: PERMISSÃO CONCEDIDA: sinta livre queimar uma cópia das trilhas 1 e 2 para tantos amigos como você gosta. Não é o tipo de coisa que você esperaria em uma época em que a indústria de gravação teve um relacionamento querelante com os ouvintes que ignoram rigorosos avisos de direitos autorais. Apenas quando você pensou que você tinha aqueles rótulos de registro grandes, famintos de dinheiro figurado para fora, um vem longitudinalmente e convida-o a copí sua música. Tal é a 7Spin Music, uma gravadora que nasceu nos tumultuosos dias de downloads ilegais que mudaram a indústria e seu modelo de negócios para sempre. Fundada em 2004 por Peter Khosla, 7Spin é um rótulo não convencional em um cenário incomum, localizado na pequena cidade de Valparaíso, Indiana. Mas pode muito bem estar desenhando o roteiro para o futuro da indústria da música. Dizer que as gravadoras estão em um estado de fluxo é um eufemismo. A redução das vendas de CDs levou as marcas a repensar e reavaliar quase tudo o que fazem. Pareceria então uma aposta entrar nessa briga com um registro novo. Você chegou ao final deste artigo Preview Para continuar lendo, inscreva-se agora. Os assinantes têm acesso digital completo. Approaches para estabelecer limites para alergenos alimentares importantes e para o glúten em alimentos. III, IV, V. III. Doença Celíaca A. Introdução A doença celíaca (também conhecida por enteropatia celíaca e enteropatia sensível ao glúten) é uma doença inflamatória crônica caracterizada por lesão da mucosa no intestino delgado, levando a doenças gastrointestinais, malabsorção de nutrientes e uma ampla gama de manifestações clínicas (NIH, 2004). Shan, et al., 2002). Existe uma opinião consensual de que a doença celíaca é causada por uma resposta imune aberrante (linfócitos T) aos glútenos alimentares predominantemente encontrados no trigo, cevada e centeio (NIH, 2004). No entanto, há evidências de que pelo menos algumas pessoas que têm doença celíaca podem não tolerar a aveia (Lundin et al., 2003 Arentz-Hansen et al., 2004). Aqueles indivíduos que têm uma predisposição genética à doença celíaca reagem a peptídeos dentro das frações proteicas ricas em prolina e glutamina dos grãos (Dewar et al., 2004). Para os indivíduos afetados, a doença celíaca é uma condição vitalícia e, se não tratada, está associada com morbidade significativa e aumento da mortalidade (Fasano, 2003). Não há cura para a doença celíaca (NIH, 2004). A única forma conhecida de prevenir completamente as complicações clínicas e patológicas da doença celíaca é a prevenção rigorosa de concentrações potencialmente nocivas de glútenos na dieta (NIH, 2004 Fasano e Catassi, 2001). B. Mecanismo de Patogênese A doença celíaca é caracterizada por lesão da mucosa do intestino delgado e alveja especificamente as projeções tipo dedo, chamadas vilosidades, onde ocorre a absorção de nutrientes-chave (Figura III-1). Acredita-se que esta lesão seja devida a um distúrbio autoimune que envolve a modificação da apresentação antigénica do glúten no tracto intestinal de indivíduos geneticamente predispostos que expressam os haplótipos de histocompatibilidade principal HLA-DQ2 ou HLA-DQ8 (Farrell and Kelly, 2002 Fasano, 2003). Nesses indivíduos, a ligação da enzima transglutaminase de tecido (tTG) ao glúten de trigo (uma proteína rica em glutamina) potencia a captação e apresentação pelas células apresentadoras de antígeno na lâmina própria, desencadeando uma vigorosa resposta de células T (Schuppan e Hahn, 2002) , Levando à produção de anticorpos IgG e IgA dirigidos a péptidos de glúten de trigo (ie gliadinas e gluteninas) e à transglutaminase tecidual (tTG). As células T activadas são responsáveis pelos danos da mucosa observados na doença celíaca (Fasano e Catrassi, 2001). Este dano mediado pela imunidade ocorre em dois compartimentos, o epitélio ea lâmina própria (Green e Jabri, 2003). A doença intestinal precoce é caracterizada por um número aumentado de linfócitos intraepiteliais intestinais (IELs). À medida que a doença progride, um número crescente de linfócitos e células plasmáticas infiltra-se na lâmina própria. Este aumento no número de células leva ao alongamento das criptas intestinais e encurtamento das vilosidades, o que acaba por resultar em atrofia vilosa parcial ou total (James, 2005). A eliminação do glúten intestinal resulta na modificação das respostas dos linfócitos T e anticorpos e, na maioria dos casos, na recuperação completa da mucosa (Kaukinen et al., 1999, Fasano e Catassi, 2001). Figura III-1. Mecanismo da doença celíaca C. Faixa de efeitos adversos As manifestações clínicas da doença celíaca são altamente variáveis em caráter e gravidade. As razões para esta diversidade são desconhecidas, mas podem depender da idade e estado imunológico do indivíduo, da quantidade, duração ou momento da exposição ao glúten e da área específica e extensão do tracto gastrointestinal envolvido pela doença (Dewar et al. 2004). Estas manifestações clínicas podem ser divididas em manifestações gastrointestinais, ou quotclásicas, e não gastrointestinais. As manifestações gastrointestinais geralmente ocorrem em crianças de 4 a 24 meses de idade e incluem dor abdominal e cólicas, inchaço, diarréia recorrente ou crônica em associação com perda de peso, crescimento deficiente, deficiência de nutrientes e (em casos raros) uma emergência metabólica ameaçadora chamada celíaca Crise, caracterizada por hipocalemia e acidose secundária à diarréia profusa (Farrell e Kelly, 2002 Baranwal et al., 2003). As manifestações não gastrointestinais são mais insidiosas e altamente variáveis e são os sinais comuns de apresentação em crianças mais velhas e adultos. Estas manifestações são freqüentemente o resultado de malabsorção de nutrientes a longo prazo, incluindo anemia por deficiência de ferro, baixa estatura, puberdade retardada, infertilidade e osteoporose ou osteopenia (Fasano, 2003). Em crianças, a má absorção progressiva de nutrientes pode levar a atrasos de crescimento, desenvolvimento ou neurológicos (Catassi e Fasano, 2004). Manifestações extra-intestinais como dermatite herpetiforme, hepatite, neuropatia periférica, ataxia e epilepsia também foram associadas à doença celíaca (Fasano e Catassi, 2001). Indivíduos com doença celíaca não tratada também estão em risco aumentado de condições médicas potencialmente graves, tais como outras doenças auto-imunes (por exemplo, diabetes mellitus tipo I) e cancros intestinais associados com elevada mortalidade (Farrell et al., 2003 Catassi et al. , 2002). Por exemplo, indivíduos com doença celíaca têm um risco 80 vezes maior de desenvolver adenocarcinoma do intestino delgado, um risco maior que duas vezes maior para linfomas intestinais ou extraintestinais (Green e Jabri, 2003) e um risco 20 vezes maior de Desenvolver linfoma de células T associado a enteropatia (EATL) (Catassi et al., 2005a). São neoplasias intestinais raras com alta taxa de mortalidade. Além disso, o risco relativo de desenvolver linfomas não-Hodgkin, intestinal ou extra-intestinal, é três vezes maior do que na população geral (Catassi et al., 2002). Esses cânceres contribuem para quase dois terços das mortes por doença celíaca e são uma das principais razões para o aumento de quase duas vezes na mortalidade geral de pacientes adultos com doença celíaca em comparação com a população em geral (Corrao et al., 2001). Atualmente, acredita-se que indivíduos com manifestações clínicas ou doença celíaca quotsintomática, representam uma pequena porção da população total afetada (Maumlki e Collin, 1997). Acredita-se que um maior número de indivíduos tenha doença celíaca quotsilentquot, caracterizada por sorologia positiva e anormalidades da mucosa intestinal na ausência de sintomas ou deficiências nutricionais. Maumlki e Collin (1997) também sugeriram que há uma população ainda maior com doença celíaca quotlatentquot, indivíduos que são positivos para marcadores sorológicos ou susceptibilidade genética à doença e são totalmente assintomáticos. É geralmente aceito que indivíduos com doença silenciosa ou latente, embora assintomáticos, têm a capacidade de manifestar respostas imunes aberrantes após a exposição a glútenos dietéticos e estão, portanto, em risco aumentado de complicações agudas e de longo prazo da doença celíaca (Fasano, 2003 Schuppan, 2000). No entanto, o benefício a longo prazo da estrita evitação do glúten para esses indivíduos não está provado (Green e Jabri, 2003). D. Prevalência Até recentemente, a doença celíaca era considerada uma doença rara nos EUA com uma taxa de prevalência estimada de 1: 5.000 (Talley, 1994). No entanto, um grande estudo epidemiológico avaliou mais de 13.000 pessoas em 23 estados e estimou uma taxa de prevalência de 1: 133 dentro da população geral dos EUA (Fasano et al., 2003). Os Institutos Nacionais de Saúde Consenso Declaração da Conferência de Desenvolvimento sobre a doença celíaca atualmente estima que 3 milhões de americanos, um pouco menos de 1 por cento da população, pode ter doença celíaca (NIH, 2004). A doença celíaca ocorre amplamente entre as populações norte-americanas e européias, onde o trigo é um alimento básico, mas é infreqüente entre os descendentes nativos da China e do Japão e aqueles com um fundo afro-caribenho, onde o trigo não é tão consumido (Farrell e Kelly, 2002 ). Dados de prevalência precisos para a doença celíaca não estão disponíveis. Esta doença é muitas vezes diagnosticada como outra desordem gastrointestinal malabsorptive (por exemplo, síndrome do intestino irritável) devido a semelhanças em seus sintomas (Sanders et al., 2001). Devido à existência de casos silenciosos ou latentes, presume-se que a incidência de doença celíaca é subnotificada (Maumlki e Collin, 1997). Estas formas de doença celíaca podem passar despercebidas em indivíduos durante anos antes de desenvolverem sintomas que os levem a procurar atendimento médico (Green e Jabri, 2003). Maumlki e Collin (1997) postularam que há muitos mais indivíduos saudáveis que estão geneticamente predispostos a desenvolver doença celíaca nos próximos anos do que indivíduos que agora são afetados pela doença celíaca. Só recentemente a comunidade médica tornou-se mais consciente da necessidade de se pesquisar a doença celíaca quando os pacientes experimentam problemas de saúde que podem estar associados com a doença ou quando os pacientes têm familiares, especialmente os familiares de primeiro e segundo graus, que têm doença celíaca ( NIH, 2004). E. Alimentos celíacos de interesse A doença celíaca é causada por uma resposta imune em indivíduos geneticamente predispostos a proteínas de armazenamento específicas, comumente referidas como quotlútens, que ocorrem naturalmente em grãos de cereais (Shan et al., 2002). Tecnicamente, quotgluten é um termo aplicado especificamente à combinação das proteínas prolaminas chamadas quotgliadinas e as proteínas glutelin chamadas quotgluteninas encontradas no trigo (Brown, 2004). No entanto, o termo quotgluteno tem sido utilizado genericamente para se referir a prolamina e misturas de proteínas de glutelina encontradas em outros grãos de cereais (Kasarda, 2005, comunicação pessoal). Embora todos os grãos de cereais contenham proteínas prolamina e glutelina, essas proteínas não são idênticas em grãos diferentes. Essas proteínas diferem em suas seqüências de aminoácidos em diferentes grãos, e nem todos têm demonstrado que evocam uma resposta imune anormal que afeta o revestimento intestinal de pessoas geneticamente suscetíveis à doença celíaca (Kasarda, 2003). O termo quotgluten� ser� utilizado neste relat�io no sentido mais geral da combina�o de prote�as prolamina e glutelina encontradas em gr�s de cereais. Os grãos considerados susceptíveis de produzir efeitos adversos em indivíduos com doença celíaca incluem as diferentes espécies de trigo (por exemplo, trigo duro, espelta, kamut), cevada, centeio e seus híbridos cruzados (por exemplo, triticale, que é um cruzamento genético entre Trigo e centeio) (Kasarda, 1994 Kasarda, 2004). Há também evidências de que alguns indivíduos com doença celíaca podem reagir adversamente à aveia (Lundin et al., 2003 Arentz-Hansen, 2004). Estes grãos são todos membros da família de grama (Gramineae, também conhecida como Poaceae) e estão intimamente relacionados taxonomicamente. Os grãos de cereais que se supõe serem seguros para pessoas com doença celíaca incluem amaranto, trigo mourisco, milho, arroz indiano, lágrimas de Jobs, milho, quinoa, ragi, arroz, sorgo, teff e arroz selvagem (Kasarda, 2001 Johnson et al. 2002 Kasarda, 2004b Kupper, 2004). As prolaminas de grãos de interesse incluem gliadina em trigo, secalina em centeio, hordeína em cevada (Thompson, 2001 Green e Jabri, 2003 Kagnoff, 2005) e possivelmente avenina em aveia (Arentz-Hansen et al., 2004 Lundin et al. 2003). Existem evidências substanciais de que tanto as proteínas de prolamina (isto é, as gliadinas) como as proteínas de glutelina (ou seja, as gluteninas) no trigo afectam indivíduos com doença celíaca (Shan et al., 2002 Vacher et al., 2002 van de Wal et al. Molberg et al., 2003). Os subtipos de gliadina do trigo, alfa, beta, gama e ômega, têm demonstrado afetar indivíduos com doença celíaca (Ciclitira et al., 1984, EFSA, 2004). O centeio, a cevada e o triticale estão taxonomicamente relacionados com o trigo, expressam peptídeos estruturalmente semelhantes aos encontrados no trigo e têm sido relatados como afetando indivíduos com doença celíaca (Vader et al., 2002 Kasarda, 2001 Kasarda, 2004b). Em contraste, as prolaminas de outros grãos de cereais (por exemplo, zeína no milho e orzenina no arroz) mostraram não afectar indivíduos com doença celíaca (EFSA, 2004 Kasarda, 2004b). No entanto, muito ainda é desconhecido sobre quais proteínas nos diferentes grãos podem afetar indivíduos com doença celíaca (Kasarda, 2001). A informação analítica não está disponível sobre a quantidade real de proteínas de glúten em diferentes ingredientes alimentares derivados de cereais ou alimentos acabados. Para alimentos de ingrediente único feitos de trigo, centeio, cevada, triticale e aveia, a simples presença de quotprotein naquele alimento pode ser usada como um indicador de que as proteínas de glúten estão presentes. O USDA National Nutrient Database para Referência Padrão, Versão 17 (USDA, 2004), a principal fonte de dados de composição para alimentos nos EUA inclui centenas de itens alimentares que contêm trigo, centeio, cevada, triticale ou aveia como ingrediente. O trigo, em particular, é utilizado para fabricar uma vasta gama de ingredientes alimentares e alimentos acabados. Rye, cevada, triticale e aveia são usados para fazer substancialmente menos produtos alimentares. Koehler e FDA (2005) estimaram a quantidade média de grãos totais e tipos individuais de grãos disponíveis para consumo por pessoa nos Estados Unidos ea exposição total a proteínas formadoras de glúten que resultariam desse consumo de grãos. A média estimada de consumo diário foi de aproximadamente 250 gramas de grãos per capita. O trigo forneceu 180 dos 187 gramas por pessoa e por dia de grãos que são motivo de preocupação para indivíduos com doença celíaca. Não há consenso sobre se a aveia apresenta um perigo para todos os indivíduos com doença celíaca. Vários estudos, incluindo um que durou 5 anos, relataram que a maioria dos participantes do estudo celíacos tolerou quantidades moderadas (por exemplo, 50-70 gramas por dia) de aveia (Janatuinen et al., 1995, Janatuinen et al., 2002, Lundin et al. 2003 Arentz-Hansen et al., 2004). A aveia utilizada por Lundin et al. (2003) e Arentz-Hansen et ai. (2004) foram testados para garantir que eles não contêm proteínas glúten de trigo, centeio ou cevada. F. Contaminação de Grãos com Glúten Nos EUA, acredita-se que os produtos de aveia mais comercialmente disponíveis contenham algumas proteínas de glúten de trigo, centeio ou cevada devido ao contato cruzado com esses grãos durante o crescimento, colheita, transporte, armazenamento ou processamento (Kasarda, 1999 Kasarda, 2001 AGA, 2001 Thompson, 2003). Em um estudo recente, Thompson (2004) analisou quatro lotes de três marcas de aveia laminada ou cortada em aço comercialmente disponíveis nos EUA para prolaminas de trigo, cevada ou centeio. Para uma marca, todas as amostras continham 338 a 1807 ppm de glúten (expressas como a média de determinações em duplicado). Para cada uma das outras duas marcas, o nível de glúten detectado em todos os lotes excepto um variou de 12-725 ppm numa marca e 120-131 ppm na outra marca (expressa como a média de determinações em duplicado). Assim, apenas um lote destas duas marcas foi negativo para o glúten. Thompson (2004) concluiu que nenhuma dessas três marcas poderia ser considerada uma fonte confiável de aveia livre de proteínas glúten potencialmente nocivas. Os grãos que não contêm glúten podem ficar contaminados com grãos que contêm glúten em qualquer etapa do continuum farm-to-table, particularmente se o equipamento compartilhado não for completamente limpo entre os usos. É difícil, se não impossível, evitar todas as situações de contato cruzado, considerando as toneladas de grãos manuseadas diariamente pelo equipamento agrícola, armazenamento a granel e recipientes de transporte. De fato, os Padrões Oficiais dos Estados Unidos para os Grãos (USDA, 1999) pressupõem que a maioria dos grãos que possuem uma norma americana estabelecida conterá uma pequena porcentagem de outros grãos. G. Estudos de Desafio de Glúten Há pouca informação na literatura sobre a doença mínima - induzindo doses de glúten para indivíduos sensíveis. Os desafios de glúten têm sido geralmente realizados em indivíduos onde o diagnóstico é incerto (por exemplo, lactentes, Laurin et al., 2002) ou em indivíduos com resultados de patologia intestinal pouco claros (Wahab et al., 2001). Desafios também foram realizados para determinar o tempo de recidiva da doença após um período prolongado de evitação do glúten (Mayer et al., 1989). Na maioria dos casos, os desafios de glúten têm sido realizados para induzir ou confirmar a doença em vez de medir o nível de sensibilidade (Farrell e Kelly, 2002). Não há um protocolo padrão para os desafios de glúten, e os estudos de desafio têm variado muito na quantidade e duração da exposição ao glúten. Embora alguns estudos tenham sido concebidos para determinar os efeitos agudos (ou seja, após 4 horas) de exposição ao glúten (Sturgess et al., 1994, Ciclitira et al., 1984), a maioria dos desafios consiste em um desafio aberto a uma dose fixa ou incremental de glúten diário Durante um período mínimo de 4 semanas. Muitos estudos de desafio usam uma alta exposição ao glúten (ge 10 g / dia), porque acredita-se que isso diminua o tempo até a confirmação da doença ou recaída e, portanto, para minimizar o desconforto para os indivíduos (Rolles e McNeish, 1976). No entanto, alguns estudos mostraram que as baixas exposições diárias ao glúten também podem provocar uma resposta da doença (Catassi et al., 1993, Laurin et al., 2002, Hamilton e McNeill, 1972). Catassi et ai. (1993) relataram que as crianças, cuja doença celíaca haviam sido previamente controladas em dieta isenta de glúten, tinham evidência de alterações intestinais da mucosa ou imunológicas (alterações na contagem de linfócitos intraepiteliais e a relação altura vilosa / profundidade da cripta) após 100 mg ou 500 mg de Gliadina diária durante 4 semanas isto corresponde a 200 mg e 1000 mg de glúten diário, respectivamente (Collin et al., 2004). O grau de inflamação foi dependente da dose. No entanto, este estudo teve várias limitações importantes, que incluem o seguimento a curto prazo (4 semanas), o teste em crianças pequenas, o pequeno número de indivíduos (n20) ea falta de grupos de controle. Além disso, apesar de se acreditar que a gliadina é a maior porção imunogénica do glúten, as células T do intestino delgado de doentes com doença celíaca demonstraram ser sensíveis a péptidos da porção de glutenina também (Van de Wal et al., 1999). Assim, o estudo de Castissi et al. (1993) estudo também foi limitado pelo uso de gliadina em vez de glúten. A estimativa de danos potenciais por extrapolação a partir dos níveis de gliadina pode não ser representativa do dano resultante da exposição total ao glúten. Um estudo em curso O italiano Microchallenge Estudo alargou o âmbito destes resultados anteriores, avaliando os efeitos da exposição a 10 ou 50 mg de glúten purificado por dia durante 3 meses com uma população de 36 indivíduos com doença celíaca em um duplo-cego , Estudo controlado por placebo (Catassi et al., 2005b). Os resultados preliminares não publicados sugerem que ocorrem anormalidades mínimas na mucosa com uma dieta sem glúten rigorosa, que tanto o glúten diário de 10 mg como o de 50 mg são bem tolerados, mas que existe uma tendência de ocorrência de alterações mucosas na dose de 50 mg. Estes resultados podem ser comparados com as exposições estimadas de glúten a partir de dietas isentas de glúten contendo vários níveis de contaminação por glúten (Tabela III-1, de Collin et al., 2004, reproduzida a seguir). Fasano (2005 comunicação pessoal) usou estes valores para sugerir que um limiar conservador para a exposição de glúten para indivíduos sensíveis ficaria entre 20 e 100 ppm. Tabela III-1. Consumo diário estimado de glúten a partir de combinações de diferentes quantidades de alimentos que contêm diferentes níveis de teor de glúten em alimentos (ppm a) Quantidade diária de alimentos sem glúten consumidos (g) Fonte: Collin et al. 2004. Nota: O conteúdo de glúten em alimentos multiplicado por alimentos consumidos é igual ao consumo de glúten. Seis fatias de pão equivalem a aproximadamente 100 g de mistura para assar. Numa abordagem alternativa, Collin et al. (2004) analisaram os níveis de glúten em um número de diferentes tipos de farinha de trigo (n24) e naturalmente sem glúten (n59) consumidas por 76 indivíduos com doença celíaca que tinham sido sem glúten dietas de 1 a 10 anos. Estes indivíduos não apresentaram evidência de deterioração da mucosa ou provocação significativa de sinais ou sintomas durante esta dieta. A gama de glúten encontrada nestes produtos foi de 0 a 200 ppm. Collin et ai. (2004) estimaram então que o consumo diário total de farinha para estes indivíduos era de 10-300 gm (mediana 80 gm). Com base nessa estimativa e no teor de glúten da farinha, foi desenvolvido um gráfico representando as exposições diárias estimadas de glúten (Collin et al., 2004). Collin et ai. (2004) usaram este gráfico e dados de estudos de baixa dose de desafio com glúten para sugerir o uso de um limiar de 100 ppm de glúten. As principais limitações deste estudo incluem a ausência de um desenho prospectivo do estudo (para a informação dose-resposta real) e a falta de informação detalhando a avaliação diagnóstica (isto é, envolvimento mínimo da mucosa) para caracterizar a recaída mucosa nestes indivíduos. H. Medição de Glúten em Alimentos Atualmente, os kits de teste ELISA de imunologia comercial para a detecção de glúten em alimentos são fabricados pela Immunotech (República Checa), Ingenasa (Espanha), Morinaga (Japão), Diffchamb (Suécia), Neogen Corporation ), R-Biopharm (Alemanha) e Tepnel BioSystems (UK). Todos estes detectam prolaminas, as proteínas encontradas em extratos de álcoois aquosos solúveis de cereais. Nenhum é projetado para detectar todas as proteínas associadas à doença celíaca. Cinco dos ensaios foram submetidos separadamente a estudos de validação multi-laboratoriais (Skerritt e Hill, 1991, Akiyama et al., 2004, Gabrovskacute et al., 2004, Immer et al., 2003). Cada um destes estudos empregou diferentes níveis de alvo e matrizes. O kit Tepnel foi validado por AOAC a gt160 ppm de glúten (Skerritt e Hill, 1991). Todos os kits ELISA dependem da preparação de extractos de álcool aquoso como amostras analíticas e quatro dos fabricantes incluem a utilização de condições de redução-desnaturação para a análise de produtos cozidos. Durante a 25ª sessão do Comité do Codex sobre Nutrição e Alimentos para Regimes Especiais em 2003, o método R5-Mendez ELISA, que implica a utilização de condições de redução / desnaturação, foi encaminhado ao Comité do Codex sobre Métodos de Análise e Amostragem para (Comissão do Codex Alimentarius, 2003). Estes kits de teste de ELISA reagem em diferentes graus, com prolaminas derivadas de trigo, centeio e cevada. Nenhum dos kits de teste reage de forma cruzada com extractos proteicos de aveia (Gabrovskacute et al., 2004 Nonaka, 2004 Abouzied, 2004 Brewer et al., 2004). Como tal, os kits de teste ELISA não fornecem proteção a indivíduos com doença celíaca que são sensíveis à aveia (Peraaho et al., 2004). Os estudos de ensaios de proficiência conduzidos pelo FAPASreg (Food Analysis Performance Assessment Scheme) demonstraram variabilidade entre os kits de ensaios ELISA de prolamina (Laboratório Central de Ciências, FAPAS Series 27 Round 05, Relatório No. 2705, 2003), indicando que mais estudos de validação destes kits Devem ser realizadas em condições comparáveis. Além dos kits de teste ELISA, dois dos fabricantes, Tepnel BioSystems e R-Biopharm, comercializam dispositivos de fluxo lateral para a detecção de glúten. Até à data, nenhum destes foi validado. Neste momento, não há informação correlativa sobre a eficácia do uso destes testes para prever ou ajudar a prevenir efeitos adversos em indivíduos com doença celíaca. I. Rotulagem sem glúten Embora dietas sem glúten são consideradas o único tratamento eficaz para indivíduos com doença celíaca, tem sido reconhecido que é difícil, senão impossível, manter uma dieta que é completamente desprovida de glúten (Collin et al 2004). Portanto, várias tentativas foram feitas para definir sem glúten em contextos regulatórios. Os esforços desenvolvidos pelo Codex Alimentarius para definir uma norma internacional para a rotulagem de frutose sem gluten datam de 1981. Nessa altura, devido à falta de métodos analíticos específicos e sensíveis, foi fixado um valor limiar de 0,05 g de azoto por 100 g de matéria seca Amido de trigo, partindo do pressuposto de que a proteína de trigo seria a única fonte de nitrogênio no amido (Norma Codex 118-1981). O Comité do Codex sobre Nutrição e Alimentos para Regimes Especiais está a desenvolver uma norma revista. O presente projecto de proposta definirá três categorias de alimentos isentos de glúten: alimentos processados que são naturalmente isentos de glúten (20 ppm de glúten), produtos que foram tornados sem glúten por transformação (le 200 ppm) e qualquer mistura de Os dois (le 200 ppm). A Agência Alimentar da Austrália Nova Zelândia (ANZFA) define glúten para significar a proteína principal em trigo, centeio, aveia, cevada, triticale e soletrado relevantes para as condições médicas, doença celíaca e dermatite hepetiformis. ANZFA reconhece duas classes de alimentos, (Sem glúten detectável) e alimentos com baixo teor de glúten (não mais do que 20 mg de glúten por 100 g de alimento) (Norma Alimentar ANZFA 1.2.8). O padrão canadense para o quotgluten-freequot é mais geral, indicando simplesmente que nenhuma pessoa rotulará, empacotará, venderá ou anunciará um alimento em uma maneira provável criar uma impressão que é um alimento quotgluten-freequot a menos que o alimento não contiver o trigo, Incluindo a espelta e o kamut, ou aveia, cevada, centeio, triticale ou qualquer parte do mesmo (Regulamentação B.24.018 da Lei de Alimentos e Medicamentos do Canadá). IV. Discussão e Recomendações A. Abordagens Gerais Foram identificadas quatro abordagens gerais que poderiam ser utilizadas para estabelecer limiares para alérgenos e glútenos: métodos baseados em métodos analíticos, baseados na avaliação de segurança, baseados na avaliação de riscos e estatutariamente derivados. Com qualquer uma dessas abordagens, a reavaliação iterativa planejada de valores limiares deve ser realizada à medida que novos conhecimentos se tornam disponíveis. Estas abordagens estão resumidas na Tabela IV-1 e descritas em detalhe abaixo. Tabela IV-1. Abordagens para Estabelecer Limiares Tipo de Abordagem 1. Abordagem Baseada em Métodos Analíticos. Numa abordagem baseada em métodos analíticos, os limiares são determinados pela sensibilidade do (s) método (s) analítico (s) que podem ser utilizados para verificar a conformidade. Isto estabelece efectivamente um limiar quotregulatório, embora este limiar não esteja necessariamente correlacionado com efeitos biológicos. Esta abordagem tem sido utilizada na rotulagem dos alimentos. Por exemplo, a exigência de declarar sulfitizantes nos rótulos dos produtos quando os alimentos contêm 10 ppm ou mais é baseada no limite de sensibilidade do método analítico utilizado para medir estes agentes. As questões que devem ser consideradas quando se utiliza uma abordagem baseada em métodos analíticos para estabelecer um limiar incluem: Quais são a sensibilidade e especificidade do método? O método foi adequadamente validado? Como o método será usado? Como o limite será modificado quando melhorado Métodos são desenvolvidos A força desta abordagem é que é relativamente simples, simples e fácil de implementar. However, it is appropriate to use an analytical methods-based approach to establish thresholds for allergens or gluten only if analytical techniques are available for the food allergen and celiac-associated glutens. 2. Safety Assessment-Based Approach . Safety assessments are routinely applied to public health issues related to substances in foods, such as chemical contaminants or food additives, particularly when a biological threshold can be justified scientifically. The definition of quotsafequot varies according to the applicable legal provision. For example, for contaminants, the statutory definitions of safety are proscribed in section 402(a)(1). Food is considered adulterated if an added contaminant is in the food in a quantityquot. which may render it the food injurious to healthquot, or, if the substance is an inherent natural constituent of the food (i. e. quotnot an added substancequot) and is in the food in a quantity that would quotordinarily render it the food injurious to healthquot. As another example, the phrase quotreasonable certainty that no harm will resultquot is used in section 408 (a)(4) regarding the safety of tolerances for a pesticide chemical residue in or on a food. For a safety assessment, the term quotsafetyquot has connotations involving both the degree of certainty and an assumption of quotnegligible risk. quot The prototype chemical safety assessment is the Acceptable Daily Intake (ADI) method which was first articulated by Fitzhugh and Lehman (1954) for use in considering the significance of available animal data. This approach or variations of it are used throughout the world (WHO, 1987). The ADI for a chemical is calculated from the No Observed Adverse Effect Level (NOAEL) and Uncertainty Factor (UF) using the following equation: The same basic methodology can be used to derive other regulatory standards such as Tolerable Daily Intake (TDI), Reference Dose (RfD), and Minimal Risk Level (MRL). These values are derived from controlled animal studies, human clinical studies, or epidemiological studies that provide the exposure level for which there is no apparent adverse effect or which identify the lowest observable adverse effect level (i. e. NOAEL, LOAEL). These adverse effect levels are also considered in conjunction with one or more uncertainty factor(s). Uncertainty factors are applied to account for inter-species and inter-individual differences and other uncertainties in the data (WHO, 2004). There have been consistent efforts to improve this process to make better use of scientific knowledge. These efforts have focused on both replacing the NOAEL approach and refining the development of uncertainty factors. One example is the development of the benchmark dose (BMD) concept (Crump, 1984 Kimmel and Gaylor, 1988). The BMD concept involves fitting a dose-response model to all the available data and to determine the statistical lower bound of the BMD (i. e. the BMDL). The major advantage of the approach is that the BMDLis not constrained to one of the experimental doses from a controlled study, as is the case with the NOAEL (Crump, 1994). The U. S. Environmental Protection Agency (EPA) uses the BMD method in health risk assessments (Filipsson et al . 2003). 3. Risk Assessment-Based Approach . A risk assessment is a systematic, scientific examination of known or potential adverse heath effects resulting from human exposure to a hazard. The generally accepted paradigm separates risk assessment into four components: hazard identification, exposure assessment, hazard characterization (dose-response), and risk characterization. This framework allows for organization of information, definition of uncertainties, and identification of data gaps. Risk assessments can describe the likelihood of adverse health effects either quantitatively or qualitatively depending on the extent of the knowledge available, the complexity of the problem, and the time available to conduct the assessment. In quantitative risk assessments, risk is expressed as a numerical estimate of the chance of illness or death after exposure to a specific hazard. This estimate represents the cumulative probabilities of certain events happening and the uncertainty associated with those events. A qualitative risk assessment, on the other hand, uses verbal descriptors of the risk and uncertainties, and often involves the aggregation of expert opinions. Of the four approaches, the quantitative risk assessment-based approach is the most scientifically rigorous and provides insight into the level of risk associated with specific exposures and the degree of uncertainty inherent in the risk estimate. An example of the use of a risk estimate and associated uncertainty is the current standard for hypoallergenic infant formulas, where there is 95 certainty that 90 of the sensitive population will not react (American Academy of Pediatrics, 2000). The risk assessment-based approach is preferred when a biological threshold cannot be justified scientifically. Several recent papers have discussed the application of the risk assessment-based approach to food allergens (Bindslev-Jensen et al . 2002 Moneret-Vautrin and Kanny, 2004 Cordle, 2004 Wensing et al . 2002a). The issues that need to be considered when using a risk assessment-based approach include: What is the biological endpoint or biomarker of concern Is the response measurable What is the population (or sub-population) of interest What are the exposure levels What data and assumptions are needed for the assessment, and how do gaps in the existing data affect the level of uncertainty Other issues that should be considered in regard to understanding the relationship between the exposure level and nature of the response include: How sensitive and accurate are the available analytical methods How do changes in individual sensitivities over time and within populations contribute to the overall uncertainty What are the limitations of the clinical studies (e. g. small number of volunteers, not testing the most sensitive subpopulation) that are used to determine the dose-response relationship and how do these limitations contribute to the overall uncertainty Which dose-response models (e. g. threshold, non-threshold) are appropriate It is not clear whether the data and modeling techniques available at the present time are sufficient to allow use of the risk assessment-based approach to establish thresholds for food allergens and for gluten. As an example of the complexity of this approach, the following describes the process of developing a dose-response model that can be used in a quantitative risk assessment: Steps in Developing a Dose-Response Model Determine the population of concern (e. g. infants, children, pregnant women). Determine the endpoint or biomarker of concern (e. g. death, severe illness requiring hospitalization, subjective reactions such as tingling of lip). Identify available relevant data including animal studies, human clinical studies, and epidemiological data that relate dose to frequency or severity of response. Select the appropriate dose-response model(s) that characterize the shape of the dose-response curve. Fit the selected model(s) to the data. Characterize the uncertainty (i. e. curve weighting and/or use of alternative plausible models). 4. Statutorily-Derived Approach . The statutorily-derived approach establishes a threshold by extrapolating from an exemption established by Congress for another purpose. For example, the FALCPA defines quotmajor food allergen quot to include a food ingredient quotthat contains protein derived quot from one of eight foods or food groups, quotexcept. any highly refined oil quot derived from one of those foods. If consumption of highly refined oils is not associated with allergic reactions, and if there is nothing unique about the proteins in highly refined oils, then consumption of another food containing levels of protein that result in an exposure that is equal to or less than the level in a typical serving of highly refined oils should not be associated with allergic reactions. Thus, a threshold could be established for all food allergen proteins based on the level of protein in highly refined oils. There is no comparable statutory standard for gluten. B. General Criteria for Evaluating and Selecting Approaches to Establish Thresholds The general criteria used to evaluate the four approaches to establish thresholds for allergens and gluten are shown in Table IV-2. Specific criteria related to food allergens are given in Section IV-C and gluten in section IV-D. The specific criteria should be weighted appropriately when implementing a particular approach. The general criteria focus on data availability and data quality. The Threshold Working Group recognizes that scientific knowledge is the product of a process which is inherently imperfect and often incomplete. As such, the degree of uncertainty in the data is a key consideration. It is expected that any decisions on approaches for establishing thresholds for food allergens or for gluten would require consideration of additional factors not covered in the current report. For example, ease of compliance and enforcement, stakeholder concerns (i. e. industry, consumers, and other interested parties), economics (e. g. cost/benefit analysis), trade issues, and legal authorities are all significant factors that are likely to influence the practicality of implementing any approach. One option that is implicit in the following discussion of potential approaches is a decision not to establish thresholds at this time, at least for food allergens. Table IV-2. General Criteria for Evaluating and Selecting Recommended Approaches to Establish Thresholds 6. Is the method practical The method should use common laboratory equipment and supplies. The response of sensitive consumers to exposure to an allergen is dependent on the levels of the allergen in the food and the amount of food consumed, two factors for which there is both variability and uncertainty. The levels of allergen in foods may not be known for a number of reasons, particularly when the presence of the allergen is the result of cross-contact. Even in highly controlled clinical studies, questions regarding the level of allergen arise due to differences in the methods used to process and prepare the test material, incomplete characterization of this material, variability in allergen levels among different sources of the food, lack of standardized reference materials, and differences in the analytical methods used to quantify the levels of the allergen. The methods used to quantify and express the doses received during clinical studies and adverse event investigations are not consistent, and this increases the uncertainty associated with the available data. The amount of an allergen consumed has been described in terms of total weight of a food consumed, total protein from an allergenic ingredient, or amount of specific allergenic proteins. Although the last description is scientifically the most accurate, it is also the most difficult to use because not all individuals are allergic to the same proteins in a food allergen and all the allergenic proteins may not have been identified for a particular food. Measurements based on the whole foods are simple, but increase the level of uncertainty because the composition of the food may vary. For example, changes in water content of a food would change the relative amount of allergenic protein present in serving sizes of a specified mass. Further, the amount of protein present as a percent of the total weight of the food may vary due to maturation, environmental factors, seasonal factors, production variability, or between different cultivars or strains. The Threshold Working Group recognized that the scientifically most accurate means of assessing exposure would be to quantify individual allergenic proteins, but concluded that the most practical approach for evaluating the currently available data is to measure exposure in terms of the total protein from a food allergen. This is also consistent with current technology for detecting food allergens. It should also be noted that, while clinical exposures are expressed in terms of doses (i. e. g, mg, or mug), allergen levels in foods are actually measured as concentrations (i. e. ppm, percent, or mg/kg). These values can be related by defining a standard serving size, usually 100 g. However, it is well documented that the actual serving eaten by consumers should be treated as a variable and a source of uncertainty when assessing exposures. D. Challenge Studies. Clinical food challenge studies are recognized to be the most accurate way to diagnose allergies and to measure sensitivity to an allergen (Sampson, 2005). Unfortunately, the design of these food challenge studies varies widely. The lack of standardized protocols, variations in the dosing regimes (including number of doses, the interval between doses, and the relative size of the doses), and differences in the food sources (including differences in preparation and presentation) result in uncertainties when comparing the results of different studies. Double-blind placebo-controlled food challenges (DBPCFC) are considered the most robust clinical studies and data from these studies should be given preference whenever they are available. Food challenge studies are generally not designed to determine a lack of reaction (i. e. NOAEL). Instead, the doses that produce positive allergic reactions are generally reported, providing an estimate of the LOAEL for the population being studied. Despite the uncertainties associated with food challenge data from the literature, LOAELs from human clinical trials currently provide the best data for estimating population-based reactions to food allergens. In a safety assessment-based approach, the use of LOAELs instead of NOAELs would introduce additional uncertainty. A standard DBPCFC protocol has been proposed to identify NOAELs for various food allergens, but few publicly available, peer-reviewed data of this nature are available at this time. The specific criteria used to evaluate food challenge studies are shown in Table IV-4, and applied in Appendix 2. Table IV-4. Specific Criteria for Evaluating Allergen Oral Challenge Studies 1. Has the study been published in a peer-reviewed journal Published, peer-reviewed studies are preferred although unpublished studies may be considered. 2. Were the criteria for selecting the test population clearly and completely described, and are they appropriate This information is needed to evaluate how the study results apply to at-risk populations (i. e. was the tested population allergic to the tested food). 3. Was the test material clearly and completely described This information is needed to determine the amount of allergenic protein in the test material. 4. Was the lowest tested dose of allergen described, or can it be calculated This information is needed to determine a NOAEL or LOAEL. 5. Were the total number and progression of dose levels described, or can they be calculated (i. e. can the entire dose series be explicitly determined) This information is not needed for a safety assessment, but is needed for a risk assessment. 6. Did some of the test population respond to the lowest dose NOAELs and LOAELs cannot be determined in studies in which reactions occurred at the lowest dose tested. 7. Were the allergic reactions observed clearly described Objective reactions are preferred for both safety and risk assessments. 8. Were the data sufficient to describe the dose-response pattern for the population tested (e. g. for determining a cumulative dose-response curve) This information is needed for a risk assessment. E. Differences Among Food Allergens. Allergens differ widely both in their potential to elicit allergic reactions and in the severity of these reactions. The simplest approach to dealing with these differences would be to establish a single threshold based on sensitivities to the most potent allergens. This threshold is likely to be unduly restrictive for many allergic consumers. Alternatively, separate thresholds could be established for each food allergen. However, the data needed for the separate threshold approach are not available for many allergens. The Threshold Working Group concluded that, to the extent possible, each food allergen should be treated independently but that a single threshold should be established if independent treatment is not possible. If a single threshold is established, it could be based on the allergenic food that elicits an allergenic reaction at the lowest total protein level. Some of the major allergens identified in the FALCPA consist of multiple species (i. e. tree nuts, fish, crustacean shellfish). Because consumers who are sensitive to one species in a group are also likely to be sensitive to other members of the group, the Threshold Working Group concluded that any thresholds established for these allergens should be based on the combined amount of protein from these species present. F. Processing and Matrix Effects. Most of the food allergens identified in the FALCPA are eaten in a processed form. The existing data show that processing can increase, decrease, modify, or have no affect on allergenicity depending on the allergen, the process, and the matrix involved. A process that modifies the structure of an allergenic protein could reduce allergenicity for one population of susceptible individuals while simultaneously increasing allergenicity for a separate susceptible population. Most clinical studies are conducted using test materials that have been processed, such as peanut butter prepared from roasted peanuts. Therefore, these studies are likely to mimic actual consumer exposure to the allergen. However, some uncertainty remains because consumers are exposed to food allergens processed in many different ways and in many matrices. It would not be practical to conduct the large number of clinical studies that would be necessary to reduce this uncertainty. Fish appears to be an important exception because raw fish is often used as a test material. Most people eat cooked fish and this should be taken into account when evaluating the results of these studies. 2. Options and Findings There are four general approaches that could be used to establish thresholds for food allergens - analytical methods-based, safety assessment-based, risk assessment-based, and statutorily-derived. Each approach has strengths and weaknesses, and the application of each is limited by the availability of appropriate data. It is likely that there will be significant scientific advances in the near future that will address a number of the limitations identified in this report. The Threshold Working Group was aware of several potentially important studies that are currently in progress, but was unable to fully consider them because the data or analyses were incomplete. Finding 1 . The initial approach selected to establish thresholds for major food allergens, the threshold values, and any uncertainty factors used in establishing the threshold values should be reviewed and reconsidered periodically in light of new scientific knowledge and clinical findings. uma. Analytical Methods-Based Approach. The analytical methods-based approach could be used to establish thresholds if the available data are insufficient to establish thresholds using one of the other approaches. This approach requires that analytical methods be available to detect each major food allergen. Thresholds would be defined by the limits of detection of the available analytical methods, but there would be no relationship between these thresholds and the biological response thresholds. Currently, the lower detection limits for commercially available allergen ELISA or immunoassay test kits are in the range of 0.1 to 1.0 microg protein/g of food, but such kits are not available for all food allergens. Establishing thresholds at levels higher than the lower detection limits of the analytical methods would require the use of assumptions about the biological response thresholds. In that case, the thresholds are actually based on using another approach and should not be considered an analytical methods-based threshold. Advantages. When accurate, validated methods are available to measure food allergens, determining a threshold based on these methods can be a straightforward way to establish that products are in compliance with this defined level. Limitations. There are several disadvantages to using this approach in determining thresholds for food allergens: The approach is not risk-based and it is likely that the appropriateness of any thresholds established using this approach will be questioned as existing methods are improved or new methods are developed. Further, in the absence of information on biological response thresholds, it is difficult to assess how well thresholds established using this approach protect public health. Validated analytical methods are currently not available for all of the major food allergens. However, this is likely to change rapidly if there is a need for such analytical capability. There is uncertainty as to the performance of the available analytical methods in the wide variety of food matrices that are likely to be encountered. Theoretically, the test methods should be validated for all foods and food matrices, but this is not practical. Current methods, which are based on a foods total protein content, will not be sufficient in the future if techniques and technologies for reducing the levels of specific allergenic proteins are developed. Presumably, the analytical methods used to establish thresholds in this approach could also be used to evaluate compliance with any applicable legal requirements. However, the ability to use these methods to help prevent the introduction of unlawful product into the market place would require that the methods be applied in a scientifically supportable manner. This would require the establishment of a statistically supportable sampling plan. The cost of the sampling to a degree sufficient to provide reasonable statistical confidence is potentially an issue. Finding 2. The analytical methods-based approach could be used to establish thresholds for those food allergens for which validated analytical methods are available. However, if this approach is used, the thresholds should be replaced by thresholds established using another approach as quickly as possible. B. Safety Assessment-Based Approach. The safety assessment-based approach could be used to establish thresholds based on NOAELs or LOAELs reported in the literature in combination with appropriate uncertainty factors. Because very few publications report NOAELs or present results in a form that allows NOAELs to be calculated, this type of analysis would, for most food allergens, be based on LOAELs. NOAELs should be used when they are available or can be calculated (see Appendix 2). As discussed previously, there are substantial differences in the relative potency of different food allergens (e. g. peanut vs. soy). As noted in Appendix 2 and summarized in Table IV-5, the reported LOAELs for peanuts are considerably lower (maximum of 10 mg protein) compared to soy (maximum 522 mg protein). A single threshold for food allergens, based on the most potent food allergens, could be employed if, as a matter of risk management policy, a single threshold is considered desirable. However, this could be considered overly protective, particularly in the case of soy. Table IV-5. Summary of Published LOAELs for Food Allergens Range of LOAEL (mg protein) Advantages. Calculation of threshold levels based on NOAELs or LOAELs and the application of appropriate uncertainty factors to estimate exposure is relatively straightforward. When there are limited data in the literature, the application of appropriate uncertainty factors provides confidence that the majority of the sensitive populations will be protected. For a number of the major food allergens, there is reasonably good agreement among the reported LOAEL values. Establishing thresholds using the safety assessment-based approach and currently available clinical data has the advantage of being directly linked to biological effects. Limitations. There are limited clinical trial data for most allergens and most available clinical food challenge studies have not been designed to identify a NOAEL. Furthermore, an inherent, but unexamined, assumption in all clinical studies is that the reactions seen in a clinical setting are representative of the reactions to food allergen exposure that occur in the real world. Most available clinical data are primarily limited to identifying LOAELs, and there is no way to know whether doses below the observed LOAEL would still elicit a reaction. Thus, the selection of appropriate factors to account for uncertainty and inherent variability is critical in using the safety assessment-based approach. Until there is a consensus as to whether subjective symptoms are acceptable biomarkers or which objective signs are considered harmful, it appears prudent to consider as adverse any objective reaction observed in a clinical trial. We have identified several data gaps for allergens that add to the uncertainty associated with setting thresholds. Critical areas of uncertainty and variability include: Intraspecies differences. Safety assessments typically apply a 10-fold uncertainty factor to account for the variability both between individuals and variability in responses for a particular individual. Sensitive population of interest. The existence and size of highly sensitive subpopulations of allergenic individuals and their lack of participation in reported clinical trials is a potential data gap and should be included in the uncertainty factors. It is unclear whether the standard 10-fold uncertainty factor for variability within a species is sufficient to account for potential highly sensitive subpopulations. Because of the potential severity of reaction for this subpopulation it seems prudent to include an additional margin of safety (e. g. a 10-fold uncertainty factor) for this uncertainty. It is not unusual for safety assessments to provide additional protection for susceptible populations. For example, EPA uses an additional safety factor in reevaluating pesticides as per the Food Quality Protection Act (FQPA, 1996) to account for the greater susceptibility of children to certain pesticides. Adequacy of clinical trial data. Most of the available data from clinical trials report LOAELs. There is uncertainty associated with using LOAELs rather than NOAELs to establish a threshold. For peanuts, one of the few food allergens for which NOAEL values are available, the LOAELs for objective signs are approximately 2 to 3 fold greater than the NOAELs. De outros. Additional data gaps have been identified by the Threshold Working Group however, concluded that uncertainties associated with these factors were not sufficient to warrant additional uncertainty factors. These data gaps include the following: (1) the use of total protein from a food as a surrogate for measuring the level of specific allergenic proteins in clinical trials (2) variability in serving sizes and related exposure factors and (3) the incompletely defined effects of food processing on the levels and reactivity of allergenic proteins. The Threshold Working Group acknowledges that it is difficult to estimate uncertainty factors that apply in all situations for all allergen threshold determinations when using a safety assessment-based approach. We can, however, assume that a standard uncertainty factor of 10-fold should be applied for intraspecies differences in humans. Additional uncertainty factors could be added if justified from data gaps. In Table IV-6, we use peanuts, widely considered to be among the most potent food allergens, to illustrate how specific uncertainty factors may be developed for use in a safety assessment-based approach to set a threshold if that approach is adopted. Table IV-6. Example of Uncertainty Factors for the Safety Assessment-Based Approach Using Peanuts. Intraspecies difference 1 Standard factor for intraspecies variability Estimation of NOAEL 2 Two studies were identified that report NOAELs Sensitive population 3 Used to account for additional margin of protection for more susceptible populations not included in clinical trials Overall Uncertainty Factor for Peanuts 100 1 This includes both between - and within-individual variability. 2 This includes both a factor for converting the LOAEL to a NOAEL and an additional factor for the uncertainty associated with that conversion. In this example for peanuts, there are data on both subjective and objective NOAELs and LOAELs. If the NOAEL values are used, the uncertainty factor is 1-fold (i. e. not applicable). If the LOAELs had been used, this value would have been higher. If subjective symptoms observed at lower levels are used, a different uncertainty factor may be considered. 3 This includes uncertainty associated with an additional margin of protection to account for the potential severity of reaction (e. g. lethality) for the highly sensitive subpopulation. Finding 3. The safety assessment-based approach, based on currently available clinical data, is a viable way to establish thresholds for food allergens. If this approach is employed, the LOAEL or NOAEL determinations used should be based on evidence of the quotinitial objective sign. quot Individual thresholds should be established for each of the major food allergens. If it is not feasible to establish individual thresholds, a single threshold based on the most potent food allergens should be established. In those instances where a LOAEL is used rather than a NOAEL to establish a threshold, an appropriate uncertainty factor should be used. Thresholds established using this approach should be reevaluated periodically as new data and tools become available. C. Risk Assessment-Based Approach. The use of the risk assessment-based approach requires analysis of the population distributions of allergic sensitivities for each of the major food allergens. These distributions would then be used in conjunction with data on exposures to assess the probability of an adverse effect. These distributions could also be used to evaluate the likely efficacy of different risk reduction strategies. Advantages. The quantitative risk assessment-based approach is the most scientifically rigorous approach and provides the most insight into both the level of protection and the degree of uncertainty associated with an exposure level. Several recent publications that present preliminary quantitative risk assessments based on data from clinical trials suggest that this approach shows promise (Bindslev-Jensen et al . 2002 Moneret-Vautrin and Kanny, 2004 Cordle, 2004 Wensing et al., 2002a). Limitations. Quantitative risk assessments require the most data of any approach to establish thresholds for food allergens, because they are based on determining the entire dose-response curve, not simply a NOAEL or LOAEL. The data currently available in the literature for food allergens are generally not detailed enough to be useful for quantitative risk assessment. Further, the underlying mathematical procedures and assumptions have not been fully described for the models that have been published. No consensus has been reached regarding the most appropriate mathematical model to use for analyzing allergen reaction data. Finding 4. Of the four approaches described, the quantitative risk assessment-based approach provides the strongest, most transparent scientific analyses to establish thresholds for the major food allergens. However, this approach has only recently been applied to food allergens, and the currently available data are not sufficient to meet the requirements of this approach. A research program should be initiated to develop applicable risk assessment tools and to acquire and evaluate the clinical and epidemiological data needed to support the quantitative risk assessment-based approach. Thresholds established using this approach should be reevaluated periodically as new data and tools become available. D. Statutorily-Derived Approach. As discussed above, an allergen threshold could be extrapolated from a statutory exemption established by Congress for another purpose, such as the FALCPA exemption for quothighly refined oils. quot Thus, a threshold could be established for all food allergen proteins based on the level of protein in highly refined oils. There are surprisingly few data available in the published scientific literature reporting on the levels of proteins in highly refined oils. The criteria used to evaluate studies measuring protein levels in food oils are shown in Table IV-7 and applied in Appendix 3. Table IV-7. Specific Criteria for Evaluating Protein in Oil Studies Published, peer-reviewed studies are preferred although unpublished studies may be considered. 2. Were the criteria for selecting the test population clearly and completely described This information is needed to evaluate how the study results apply to the at-risk population. 3. Was the tested food material clearly and completely described It is important to know the level of gluten in the test material. 4. Was the dose regime clearly and completely described A study designed to measure chronic exposure (low doses over a long period of time) is preferable. Extrapolation of long-term effects from short-term studies increases the level of uncertainty. 5. Were the criteria for characterizing responses clearly described This information is needed to evaluate the relevance of the response measured. A definitive diagnostic assessment showing clinical signs or intestinal mucosal changes compared to controls is preferred. 6. Are response data available for each individual tested These data are needed to develop a risk assessment-based dose-response model. 2. Options and Findings The feasibility of using each of the four methods to establish a threshold for gluten was evaluated in light of the available data. As with food allergens, it is likely there will be significant scientific advances in the near future that will address a number of the limitations identified in this report. The Threshold Working Group was aware of several potentially important studies that are currently in progress, but we were unable to evaluate them because the data or analyses are incomplete. In particular, the Threshold Working Group is aware of unpublished data from an ongoing clinical trial of the subchronic effects of gluten on celiac patients. The quotItalian Microchallenge Studyquot is utilizing intestinal biopsies to relate changes in the intestinal mucosa to antibody biomarkers (Fasano, 2005 personal communication). Preliminary results indicate that daily consumption of both 10 mg and 50 mg of dietary gluten were well tolerated after three months of continuous consumption, but that minimal histological changes were seen in patients consuming 50 mg of gluten daily. Because these data have not yet been published, these results were not considered further. Finding 6 . The initial approach selected to establish a threshold for gluten, the threshold value selected, and any uncertainty factors that were used to establish the threshold should be reviewed and reconsidered periodically in light of new scientific knowledge and clinical findings. uma. Analytical Methods-Based Approach. As with food allergens, an analytical methods-based approach could be used to establish a threshold for gluten if the available clinical and epidemiological data are insufficient to use one of the other approaches. This approach requires that analytical methods be available to detect all relevant glutens. Thresholds are defined by the limits of detection of the available analytical methods, but there is no relationship between these thresholds and the biological response thresholds. At the time of this report, the lower limits of detection for the commercially available gluten test kits are in the range of 10 microg gluten/g of food, and the ability to robustly quantify samples is in the range of 20 microg gluten/g of food. Establishing thresholds at levels higher than the lower detection limits of the analytical methods requires the use of assumptions about the biological response thresholds. In that case, the thresholds are actually based on using one of the other three approaches and should not be considered an analytical methods-based threshold. Advantages. A threshold established using the analytical methods-based approach can easily be incorporated into any applicable FDA compliance programs that combine a specific standard method with a standardized sampling scheme. Limitations. Several factors limit the applicability of the analytical methods-based approach to establish a threshold for gluten. At this time, only one commercially available analytical method has been AOAC validated, and that method was validated for detection at a relatively high concentration of gluten. In addition, there are limited data on the performance of the available methods in the wide variety of food matrices that could potentially contain gluten. Therefore, further characterization of available methods would be necessary before an analytical methods-based threshold could be established. Appropriate methods would need to be developed for the detection of oat gluten. Finding 7 . The analytical methods-based approach could be used to establish a threshold for gluten. However, if this approach is used, the threshold should be replaced by a threshold established using another approach as quickly as possible. B. Safety Assessment-Based Approach. The safety assessment-based approach could be used to establish a threshold for gluten based on NOAELs or LOAELs reported in the literature in combination with appropriate uncertainty factors. Clinical data in the literature are limited, but a few studies are available that meet the Threshold Working Groups data quality criteria. The currently available clinical studies do not report NOAELs. However, studies are available that could be used to establish a LOAEL from which a threshold could be derived. Advantages. Establishing a threshold based on NOAELs or LOAELs and the application of appropriate uncertainty factors to estimated exposure levels is fairly straightforward. When there are limited data in the literature, the application of appropriate uncertainty factors can provide confidence that the majority of the sensitive populations will be protected. Establishing thresholds using the safety assessment-based approach and currently available clinical data has the advantage of being directly linked to biological effects. Limitations. The primary limitation of this approach is the dearth of available prospective clinical data and the general lack of information about the impact of chronic low-level consumption of gluten on the emergence of symptomatic disease in individuals with latent or silent celiac disease. At the current time, the size of the combined uncertainty factors needed would be substantial due to the general lack of data applying large uncertainty factors to the available data could lead to a gluten threshold that is not achievable, as a practical matter, in foods. We have identified several data gaps for gluten that contribute to current uncertainty about setting gluten thresholds. The critical areas of uncertainty and variability are: Intraspecies differences. Safety assessments typically apply a 10-fold uncertainty factor to account for the variability both between individuals and variability in responses for a particular individual. Chronic low-level exposure to gluten in quotgluten-free quot diets. Data, from either prospective studies or long-term clinical trials, are severely limited on the effect of a long-term gluten-free diet on the manifestations of celiac disease. Adequacy of clinical trial data. There is uncertainty as to whether 4-week studies, or even 4-month studies, are of sufficient duration to predict the consequences of long-term ingestion of low levels of gluten. There is additional uncertainty as to whether currently available clinical trials include the most sensitive individuals. Accordingly, there is uncertainty as to whether the standard 10-fold uncertainty factor for variability within a species is sufficient to account for potential highly sensitive individuals. Additional uncertainty arises from the fact that the published clinical trials were designed to identify LOAELs rather than NOAELs. De outros. Additional data gaps have been identified by the Threshold Working Group however, the working group concluded that uncertainties associated with these factors were not sufficient to warrant additional uncertainty factors. These other data gaps include the following: (1) it is uncertain what percentage of individuals with celiac disease are sensitive to oat gluten and whether the levels to which they are sensitive are equivalent to those observed for wheat (2) variability in serving sizes and related exposure factors and (3) the incompletely defined effect of food processing on the levels of gluten tolerated by individuals with celiac disease. The uncertainty associated with gluten thresholds arises primarily from the limited amount of clinical data. The critical knowledge gap about individuals with celiac disease is whether chronic, low-level exposure to gluten in a gluten-free diet will cause any harm over a lifetime. We are not aware of any prospective clinical trials that have examined the health of individuals with celiac disease on a gluten-free diet for more than a few months. There is uncertainty as to whether data from these short-term clinical trials will accurately predict reactions following chronic, low-level gluten exposure. Conversely, there appears to be only a small degree of uncertainty as to whether the most sensitive celiac disease populations were included in the available clinical trials since most of the participants had evidence of disease. As discussed in Section III, there may be an oat-sensitive subpopulation. The possible existence of this oat-sensitive subpopulation raises questions related to the definition of quotgluten. quot Because there are limited clinical data on the sensitivity of this subpopulation of individuals with celiac disease, the uncertainty related to the LOAELs or NOAELs for these individuals is high. Nevertheless, it is unlikely that theses individuals are substantially more sensitive to oat gluten than they are to wheat gluten. Table IV-10 presents an example of how an overall uncertainty factor could be derived when estimating a threshold for gluten using the safety assessment-based approach. A standard uncertainty factor of 10 might be applied for intraspecies differences in human responses to gluten. Table IV-10. Example of Uncertainty Factors for the Safety-Assessment-Based Approach. Finding 8 . The safety assessment-based approach is a viable approach to establish a threshold for gluten using currently available LOAEL data for celiac disease. An overall uncertainty factor should be estimated from the data and applied to the LOAEL to establish a threshold for gluten. Any threshold derived from this approach should be reevaluated as new research data become available. Available data are insufficient at the current time to use this approach to establish a threshold for oat gluten for those individuals with celiac disease who may also be sensitive to oats. However, it is likely that a threshold based on wheat gluten would be protective for individuals susceptible to oat gluten. C. Risk Assessment-Based Approach. There are few data from human clinical trials that can be used to develop a dose-response model for gluten and celiac disease. In addition, limited data are available on exposure for example, there are limited data on the actual levels of gluten in the diet of individuals on quotgluten-free dietsquot and on the effects of low-level, chronic gluten exposure in individuals with silent or latent celiac disease. These limitations would lead to a very high level of uncertainty associated with models designed to predict the health effects of gluten in the diet. Therefore, a scientifically defensible hazard characterization and exposure assessment are not possible at the current time. Finding 9 . Use of the quantitative risk assessment-based approach to establish a threshold for gluten does not appear to be feasible at the present time. However, considering the benefits that could be gained from using the risk assessment-based approach, priority should be given to establishing a research program to acquire the knowledge and data needed. D. Statutorily-Derived Approach. The FALCPA does not include requirements or exemptions that could be used to establish a statutorily-derived threshold for gluten. Also, the law does not define the term quotgluten-free. quot Potentially, a threshold could be established using the international standards currently under review by Codex (Codex Alimentarius Commission, 2003. However, the proposed Codex standards do not appear to be based on either a scientific rationale for a distinction between naturally gluten-free foods and foods processed to be free of gluten, or a systematic evaluation of clinical data related to the effect of gluten on acute or chronic celiac disease etiology. The levels being considered by Codex seem to be based on anecdotal evidence and on the levels of gluten that are presumed to be historically present in foods that have been called quotgluten-free. quot Finding 10 . There appear to be no suitable statutory requirements or exemptions that would serve as the rationale for using for a statutorily-derived approach to establish a threshold for gluten. This approach is not viable. Although the FALCPA directs FDA to establish a definition for the term quotgluten-freequot for food labeling, the quantity and quality of the data needed to accomplish this on a scientific basis are severely limited at the current time relative to all three of the potentially viable approaches. This was aptly summarized by the consensus statement published after a conference of experts convened by the National Institutes of Health which noted that quotThe strict definition of a gluten-free diet remains controversial due to the lack of an accurate method to detect gluten in food products and the lack of scientific evidence for what constitutes a safe amount of gluten ingestion quot (NIH, 2004). These experts concluded that additional research is needed to quotDefine the minimum safe exposure threshold of gluten in the diet relative to celiac disease quot (NIH, 2004). In view of the consensus opinion stated in the NIH report, the Threshold Working Group concluded that Finding 6 should be reemphasized. Any approach used to establish a threshold for gluten to protect consumers with, or susceptible to, celiac disease should be used in an iterative manner and reexamined periodically to consider new knowledge, data, and approaches. V. References Abouzied, M. M. Carroll, M. Mozola, M. A. (2004). A Sandwich ELISA test for detection and quantitation of gluten in food products and ingredients. Abstract of presentation at AOAC Annual Meeting, September 19-23, 2004. Akiyama, H. Isuzugawa, K. Harikai, N. Watanabe, H. Iijima, K. Yamakawa, H. Mizuguchi, Y. Yoshikawa, R. Yamamoto, M. Sato, H. Watai, M. Arakawa, F. Ogasawara, T. Nishihara, R. Kato, H. Yamauchi, A. Takahata, Y. Morimatsu, F. Mamegoshi, S. Muraoka, S. Honjoh, T. Watanabe, T. Sakata, K. Imamura, T. Toyoda, M. Matsuda, R. Maitani, T. (2004). 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Introdução: Globalização poderia ser definida como ldquoGrowing interdependência dos países em todo o mundo através do crescente volume e variedade de transações transfronteiriças em bens e serviços e de relações internacionais E também através da difusão mais rápida e difundida da tecnologia (Johnson e Turner, 2003, p. 10). Argumenta-se que a integração negativa de romper o comércio e as barreiras protetoras e as conseqüências da velocidade e do tamanho dos fluxos de capital nos mercados financeiros internacionais que levaram aos custos angustiantes dos países desenvolvidos sob a forma de crise de subprime, Crise financeira global. (Herbert Oberhaumlnsli / Oscar Vera, 2003). Como resultado da crise financeira global os bancos centrais em todo o mundo têm respondido em termos de níveis fiscal e monetário. O Banco de Reserva da Índia também respondeu com certas medidas fiscais e monetárias. Este relatório fala sobre os efeitos da crise financeira global sobre o setor bancário indiano e ...
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