The Key Events Dose-Response Framework: A Foundation for Examining Variability in Elicitation Thresholds for Food Allergens

Food allergies are caused by immunological reactions in individuals sensitized to normal protein components of foods. For any given sensitized individual, the severity of a reaction is generally assumed to be proportional to the dose of allergenic protein. There is substantial clinical evidence that “threshold” doses exist for the elicitation of an allergic reaction; however, the threshold (i.e., lowest dose that elicits a reaction) varies substantially across the sensitized population. Current approaches to protecting sensitized individuals from exposure to food allergens are highly qualitative (i.e., they rely on food avoidance). The Key Events Dose-Response Framework is an analytical approach for refining understanding of the biological basis of the dose-response. Application of this approach to food allergy provides a foundation for a more rigorous quantitative understanding of variability in allergic response. This study reviews the allergic disease process and the current approaches to identifying thresholds for food allergens. The pathway of key biological events occurring between food intake and allergic response is considered, along with factors that may determine the nature and severity of response to food allergens. Data needs, as well as implications for identifying thresholds, and for characterizing variability in thresholds, are also discussed

Updated full range of Eliciting Dose values for Cow’s milk for use in food allergen risk assessment

Access to Eliciting Doses (ED) for allergens enables advanced food allergen risk assessment. Previously, the full ED range for 14 allergenic foods, including milk, and recommendations for their use were provided (Houben et al., 2020). Additional food challenge studies with cow’s milk-allergic patients added 247 data points to the original dataset. Using the Stacked Model Averaging statistical method for interval-censored data on the 697 individual NOAELs and LOAELs for milk generated an updated full ED distribution. The ED01 and ED05, the doses at which 1% and 5% of the milk-allergic population would be predicted to experience any objective allergic reaction, were 0.3 and 3.2 mg milk protein for the discrete and 0.4 mg and 4.3 mg milk protein for the cumulative dose distribution, respectively. These values are slightly higher but remain within the 95% confidence interval of previously published EDs. We recommend using the updated EDs for future characterization of risks of exposure of milk-allergic individuals to milk protein. This paper contributes to the discussion on the Reference Dose for milk in the recent Ad hoc Joint FAO/WHO Expert Consultation on Risk Assessment of Food Allergens. It will also benefit harmonization of food allergen risk assessment and risk management globally

The role of hazard- and risk-based approaches in ensuring food safety

AbstractBackgroundFood legislation in the European Union and elsewhere includes both hazard- and risk-based approaches for ensuring safety. In hazard-based approaches, simply the presence of a potentially harmful agent at a detectable level in food is used as a basis for legislation and/or risk management action. Risk-based approaches allow consideration of exposure in assessing whether there may be unacceptable risks to health.Scope and approachThe advantages and disadvantages of hazard- and risk-based approaches for ensuring the safety of food chemicals, allergens, ingredients and microorganisms were explored at an ILSI Europe workshop.Key findings and conclusionsIt was concluded that both types of approach have their place, depending on the context. However, problems can arise when both types of approach are used in regulation by separate agencies that address different aspects of the same agent/substance present in food. This separation of decision-making can result in hazard-based restrictions on marketing and use, whereas risk-based assessments for those exposed show there is reasonable certainty no harm will result. This in turn can lead to contradictory, confusing and ultimately unnecessary actions. Use of hazard-based approaches for foods also means that comparisons with benefits for nutrition and food security cannot be undertaken. This has the potential to lead to bias in the overall conclusions of regulators and risk managers, who may not have been presented with the benefits of particular foods. The value of risk-based approaches is becoming increasingly recognised

Consensus on gut feelings in general practice

Contains fulltext : 81134.pdf (publisher's version ) (Open Access)BACKGROUND: General practitioners sometimes base clinical decisions on gut feelings alone, even though there is little evidence of their diagnostic and prognostic value in daily practice. Research to validate the determinants and to assess the test properties of gut feelings requires precise and valid descriptions of gut feelings in general practice which can be used as a reliable measuring instrument. Research question: Can we obtain consensus on descriptions of two types of gut feelings: a sense of alarm and a sense of reassurance? METHODS: Qualitative research including a Delphi consensus procedure with a heterogeneous sample of 27 Dutch and Belgian GPs or ex-GPs involved in academic educational or research programmes. RESULTS: After four rounds, we found 70% or greater agreement on seven of the eleven proposed statements. A "sense of alarm" is defined as an uneasy feeling perceived by a GP as he/she is concerned about a possible adverse outcome, even though specific indications are lacking: There's something wrong here. This activates the diagnostic process by stimulating the GP to formulate and weigh up working hypotheses that might involve a serious outcome. A "sense of alarm" means that, if possible, the GP needs to initiate specific management to prevent serious health problems. A "sense of reassurance" is defined as a secure feeling perceived by a GP about the further management and course of a patient's problem, even though the doctor may not be certain about the diagnosis: Everything fits in. CONCLUSION: The sense of alarm and the sense of reassurance are well-defined concepts. These descriptions enable us to operationalise the concept of gut feelings in further research

Ad hoc Joint FAO/WHO Expert Consultation on Risk Assessment of Food Allergens Part 2: Review and establish threshold levels in foods of the priority allergens

The main purpose of this second meeting was to establish threshold levels in foods of the priority allergens. Based on the defined approach, the Expert Committee discussed and agreed on the safety objective, which could be described as “to minimise, to a point where further refinement does not meaningfully reduce health impact, the probability of any clinically relevant objective allergic response, as defined by dose distribution modelling of minimum eliciting doses (MEDs) and supported by data regarding severity of symptoms in the likely range of envisioned Reference Doses (RfD)”. The Committee further identified several important considerations to guide decision-making. These included a clear definition of criteria to be met by quantitative data on which reference doses (RfD) are based, supporting data on health manifestations (severity) at the proposed RfD, quality, quantity, availability and accessibility of data (for priority allergens), as well as how to deal with priority allergens for which information supporting one or more of those considerations was lacking.El objetivo principal de esta segunda reunión fue establecer niveles umbral en los alimentos de los alérgenos prioritarios. Sobre la base del enfoque definido, el Comité de Expertos discutió y acordó el objetivo de seguridad, que podría describirse como “minimizar, hasta un punto en el que un mayor refinamiento no reduzca significativamente el impacto en la salud, la probabilidad de cualquier respuesta alérgica objetiva clínicamente relevante, como definido por el modelo de distribución de dosis de dosis mínimas provocadoras (MED) y respaldado por datos sobre la gravedad de los síntomas en el rango probable de dosis de referencia previstas (RfD) ”. El Comité identificó además varias consideraciones importantes para orientar la toma de decisiones. Estos incluyeron una definición clara de los criterios que deben cumplir los datos cuantitativos en los que se basan las dosis de referencia (RfD), datos de apoyo sobre manifestaciones de salud (gravedad) en la RfD propuesta, calidad, cantidad, disponibilidad y accesibilidad de los datos (para alérgenos prioritarios). , así como cómo tratar los alérgenos prioritarios para los que faltaba información que respaldara una o más de esas consideraciones.Instituto de Investigación de Tecnología de AlimentosFil: Baumert, Joseph. Universidad de Nebraska-Lincoln. Departamento de Ciencia y Tecnología de Alimentos; Estados UnidosFil: Brooke-Taylor, Simon. Brooke-Taylor & Co. Consultor australiano de regulación alimentaria y análisis de riesgos (Pty Ltd); Australia.Fil: Crevel, René W.R. René Crevel Consulting Limited; Reino Unido.Fil: Houben, Geert F. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Jackson, Lauren. Administración de Alimentos y Medicamentos de los Estados Unidos. División de Ciencia y Tecnología del Procesamiento de Alimentos. Ingeniería de Procesos; Estados UnidosFil: Kyriakidis, Symeon. Laboratorio Estatal de Química General (GCSL).Autoridad Independiente de Ingresos Públicos (IAPR); Grecia.Fil: La Vieille, Sébastien. Universidad Laval. Departamento de Ciencias de los Alimentos; Canadá.Fil: Lee, N Alice. Universidad de Nueva Gales del Sur. Escuela de Química e Ingeniería. Ciencia e ingeniería de los alimentos; Australia.Fil: López, María Cristina. Universidad Nacional de San Martín. Ingeniería de Alimentos; Argentina.Fil: Luccioli, Stefano. Administración de Alimentos y Medicamentos de los Estados Unidos. Centro de Seguridad Alimentaria y Nutrición Aplicada; Estados UnidosFil: O’Mahony, Patrick. Autoridad de Seguridad Alimentaria de Irlanda; Irlanda.Fil: O’Mahony, Patrick. Universidad College Dublin; Irlanda.Fil: Polenta, Gustavo Alberto. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Investigación Tecnología de Alimentos; Argentina.Fil: Polenta, Gustavo Alberto. Instituto de Ciencia y Tecnología de los Sistemas Alimentarios Sustentables (ICyTeSAS) UEDD INTA-CONICET; Argentina.Fil: Pöpping, Bert. Food Consulting Strategically (FOCO); Alemania.Fil: Pöpping, Bert. Comités de Normalización ISO - CEN. Grupo de trabajo CEN Alérgenos Alimentarios (CEN TC 275 WG 12).); Alemania.Fil: Remington, Benjamin C. Remington Consulting Group B.V.; Holanda.Fil: Remington, Benjamin C. Universidad de Nebraska–Lincoln. Programa de Recursos e Investigación de Alergias Alimentarias. Estados UnidosFil: Srikulnath, Sirinrat. Universidad de Kasetsart (UKaset). Instituto de Investigación y Desarrollo de Productos Alimentarios. Centro de Servicio de Aseguramiento de la Calidad de los Alimentos. Unidad de Alérgenos Alimentarios; Tailandia.Fil: Taylor, Stephen L. Universidad de Nebraska-Lincoln. Departamento de Ciencia y Tecnología de Alimentos; Estados UnidosFil: Turner, Paul J. Colegio Imperial de Ciencia, Tecnología y Medicina. Alergia e Inmunología Pediátricas; Inglaterra

The diagnostic role of gut feelings in general practice A focus group study of the concept and its determinants

Contains fulltext : 81297.pdf (publisher's version ) (Open Access)BACKGROUND: General practitioners sometimes base clinical decisions on gut feelings alone, even though there is little evidence of their diagnostic and prognostic value in daily practice. Research into these aspects and the use of the concept in medical education require a practical and valid description of gut feelings. The goal of our study was therefore to describe the concept of gut feelings in general practice and to identify their main determinants METHODS: Qualitative research including 4 focus group discussions. A heterogeneous sample of 28 GPs. Text analysis of the focus group discussions, using a grounded theory approach. RESULTS: Gut feelings are familiar to most GPs in the Netherlands and play a substantial role in their everyday routine. The participants distinguished two types of gut feelings, a sense of reassurance and a sense of alarm. In the former case, a GP is sure about prognosis and therapy, although they may not always have a clear diagnosis in mind. A sense of alarm means that a GP has the feeling that something is wrong even though objective arguments are lacking. GPs in the focus groups experienced gut feelings as a compass in situations of uncertainty and the majority of GPs trusted this guide. We identified the main determinants of gut feelings: fitting, alerting and interfering factors, sensation, contextual knowledge, medical education, experience and personality. CONCLUSION: The role of gut feelings in general practice has become much clearer, but we need more research into the contributions of individual determinants and into the test properties of gut feelings to make the concept suitable for medical education

Peanut Can Be Used as a Reference Allergen for Hazard Characterization in Food Allergen Risk Management: A Rapid Evidence Assessment and Meta-Analysis

Regional and national legislation mandates the disclosure of “priority” allergens when present as an ingredient in foods, but this does not extend to the unintended presence of allergens due to shared production facilities. This has resulted in a proliferation of precautionary allergen (“may contain”) labels (PAL) that are frequently ignored by food-allergic consumers. Attempts have been made to improve allergen risk management to better inform the use of PAL, but a lack of consensus has led to variety of regulatory approaches and nonuniformity in the use of PAL by food businesses. One potential solution would be to establish internationally agreed “reference doses,” below which no PAL would be needed. However, if reference doses are to be used to inform the need for PAL, then it is essential to characterize the hazard associated with these low-level exposures. For peanut, there are now published data relating to over 3000 double-blind, placebo-controlled challenges in allergic individuals, but a similar level of evidence is lacking for other priority allergens. We present the results of a rapid evidence assessment and meta-analysis for the risk of anaphylaxis to a low-level allergen exposure for priority allergens. On the basis of this analysis, we propose that peanut can and should be considered an exemplar allergen for the hazard characterization at a low-level allergen exposure. Resumen: La legislación regional y nacional exige la divulgación de alérgenos "prioritarios" cuando están presentes como ingrediente en los alimentos, pero esto no se extiende a la presencia involuntaria de alérgenos debido a instalaciones de producción compartidas. Esto ha dado lugar a una proliferación de etiquetas de precaución para alérgenos ("pueden contener") (PAL) que los consumidores alérgicos a los alimentos suelen ignorar. Se han hecho intentos para mejorar la gestión del riesgo de alérgenos para informar mejor el uso de PAL, pero la falta de consenso ha llevado a una variedad de enfoques regulatorios y a la falta de uniformidad en el uso de PAL por parte de las empresas alimentarias. Una posible solución sería establecer “dosis de referencia” acordadas internacionalmente, por debajo de las cuales no se necesitaría PAL. Sin embargo, si se van a utilizar dosis de referencia para informar la necesidad de PAL, entonces es esencial caracterizar el peligro asociado con estas exposiciones de bajo nivel. Para el maní, ahora hay datos publicados relacionados con más de 3000 desafíos doble ciego controlados por placebo en individuos alérgicos, pero falta un nivel similar de evidencia para otros alérgenos prioritarios. Presentamos los resultados de una evaluación rápida de la evidencia y un metanálisis del riesgo deanafilaxia a una exposición a alérgenos de bajo nivel para alérgenos prioritarios. Sobre la base de este análisis, proponemos que el cacahuete puede y debe considerarse un alérgeno ejemplar para la caracterización del peligro en una exposición a un alérgeno de bajo nivel.Instituto de Investigación de Tecnología de AlimentosFil: Turner, Paul J. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Patel, Nandinee. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Ballmer-Weber, Barbara K. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Ballmer-Weber, Barbara K. Clínica de Dermatología y Alergología. Kantonsspital; Suiza.Fil: Baumert, Joe L. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Blom, W. Marty. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Brooke-Taylor, Simon. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Brough, Helen. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Brough, Helen. King's College London. Departamento de Alergia Pediátrica; Reino Unido.Fil: Campbell, Dianne E. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Campbell, Dianne E. Tecnologías DBV. Montrouge; Francia.Fil: Chen, Hongbing. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Chinthrajah, R. Sharon. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Crevel, René W.R. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Dubois, Anthony E.J. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Ebisawa, Motohiro. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Elizur, Arnon. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Elizur, Arnon. Universidad de Tel Aviv. Facultad de Medicina Sackler. Departamento de Pediatría; Israel.Fil: Gerdts, Jennifer D. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Gowland, M. Hazel. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Houben, Geert F. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Hourihane, Jonathan O.B. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Knulst, André C. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: La Vieille, Sébastien. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: López, María Cristina. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Mills, E.N. Clare. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Polenta, Gustavo Alberto. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Investigación Tecnología de Alimentos; Argentina.Fil: Polenta, Gustavo Alberto. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Purington, Natasha. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Said, María. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Sampson, Hugh A. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Sampson, Hugh A. Escuela de Medicina Icahn. División de Alergia e Inmunología Pediátricasen. Nueva York. Estados Unidos de América.Fil: Schnadt, Sabine. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Södergren, Eva. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Södergren, Eva. ThermoFisher Scientific; Suecia.Fil: Taylor, Stephen L. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Remington, Benjamin C. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Remington, Benjamin C. Grupo BV. Consultoría Remington; Holanda

Can we define a level of protection for allergic consumers that everyone can accept?

Substantial progress has been made in characterising the risk associated with exposure to allergens in food. However, absence of agreement on what risk is tolerable has made it difficult to set quantitative limits to manage that risk and protect allergic consumers effectively. This paper reviews scientific progress in the area and the diverse status of allergen management approaches and lack of common standards across different jurisdictions, including within the EU. This lack of regulation largely explains why allergic consumers find Precautionary Allergen Labelling confusing and cannot rely on it. We reviewed approaches to setting quantitative limits for a broad range of food safety hazards to identify the reasoning leading to their adoption. This revealed a diversity of approaches from pragmatic to risk-based, but we could not find clear evidence of the process leading to the decision on risk acceptability. We propose a framework built around the criteria suggested by Murphy and Gardoni (2008) for approaches to defining tolerable risks. Applying these criteria to food allergy, we concluded that sufficient knowledge exists to implement the framework, including sufficient expertise across the whole range of stakeholders to allow opinions to be heard and respected, and a consensus to be achieved