New approach methodologies (NAMs): identifying and overcoming hurdles to accelerated adoption.

New approach methodologies (NAMs) can deliver improved chemical safety assessment through the provision of more protective and/or relevant models that have a reduced reliance on animals. Despite the widely acknowledged benefits offered by NAMs, there continue to be barriers that prevent or limit their application for decision-making in chemical safety assessment. These include barriers related to real and perceived scientific, technical, legislative and economic issues, as well as cultural and societal obstacles that may relate to inertia, familiarity, and comfort with established methods, and around regulatory expectations and acceptance.

Identification and semi-quantification of protein allergens in complex mixtures using proteomic and AllerCatPro 2.0 bioinformatic analyses: a proof-of-concept investigation.

The demand for botanicals and natural substances in consumer products has increased in recent years. These substances usually contain proteins and these, in turn, can pose a risk for immunoglobulin E (IgE)-mediated sensitization and allergy. However, no method has yet been accepted or validated for assessment of potential allergenic hazards in such materials.

Identification of true chemical respiratory allergens: Current status, limitations and recommendations.

Asthma in the workplace is an important occupational health issue. It comprises various subtypes: occupational asthma (OA; both allergic asthma and irritant-induced asthma) and work-exacerbated asthma (WEA). Current regulatory paradigms for the management of OA are not fit for purpose.

Application of AllerCatPro 2.0 for protein safety assessments of consumer products.

Foreign proteins are potentially immunogenic, and a proportion of these are able to induce immune responses that result in allergic sensitization. Subsequent exposure of sensitized subjects to the inducing protein can provoke a variety of allergic reactions that may be severe, or even fatal. It has therefore been recognized for some time that it is important to determine whether a given protein has the potential to induce allergic responses in exposed subjects.

Specificity of the local lymph node assay (LLNA) for skin sensitisation.

The local lymph node assay (LLNA) has provided a large dataset against which performance of non-animal approaches for prediction of skin sensitisation potential and potency can be assessed. However, a recent comparison of LLNA results with human data has argued that LLNA specificity is low, with many human non-sensitisers, particularly hydrophobic chemicals, being false positives. It has been suggested that such putative false positives result from hydrophobic chemicals causing cytotoxicity, which induces irritancy, in turn driving non-specific lymphocyte proliferation.

Challenges in the classification of chemical respiratory allergens based on human data: Case studies of 2-hydroxyethylmethacrylate (HEMA) and 2-hydroxypropylmethacrylate (HPMA).

Occupational asthma resulting from workplace exposure to chemical respiratory allergens is an important disease. No widely accepted or formally validated tests for the identification of chemical respiratory sensitizers. Consequently, there is a heavy reliance on human data from clinical examinations.

Propylene glycol, skin sensitisation and allergic contact dermatitis: A scientific and regulatory conundrum.

Propylene glycol (PG) has widespread use in pharmaceuticals, cosmetics, fragrances and personal care products. PG is not classified as hazardous under the Globally Harmonised System of Classification and Labelling of Chemicals (GHS) but poses an intriguing scientific and regulatory conundrum with respect to allergic contact dermatitis (ACD), the uncertainty being whether and to what extent PG has the potential to induce skin sensitisation. In this article we review the results of predictive tests for skin sensitisation with PG, and clinical evidence for ACD.

Bisphenol A, T17 cells, and allergy: a commentary.

There is a continuing interest in whether Bisphenol A (BPA) is able to cause adverse health effects through interaction with elements of the immune system. That interest has been fuelled further by the recent publication of a draft opinion on BPA prepared by the European Food Safety Authority (EFSA) Panel on Food Contact Materials, Enzymes and Processing Aids (CEP). This draft opinion judged effects on the immune system to be the most sensitive health outcome, and identified BPA-induced changes in the frequency of T-helper (T)-17 cells in the spleens of mice as being the critical effect based on an association of these cells with inflammation.

Reference Chemical Potency List (RCPL): A new tool for evaluating the accuracy of skin sensitisation potency measurements by New Approach Methodologies (NAMs).

Considerable progress has been made in the design of New Approach Methodologies (NAMs) for the hazard identification of skin sensitising chemicals. However, effective risk assessment requires accurate measurement of sensitising potency, and this has proven more difficult to achieve without recourse to animal tests. One important requirement for the development and adoption of novel approaches for this purpose is the availability of reliable databases for determining the accuracy with which sensitising potency can be predicted.

Effects of Exercise and Sleep Deprivation on Reaction Severity During Oral Peanut Challenge: A Randomized Controlled Trial.

Background: The severity of allergic reactions to foods can vary markedly. Little is known of variations in reaction severity within or between individuals or the effects of cofactors.

Objective: We examined the effects of sleep deprivation and exercise and repeat challenges on the severity and patterns of allergic reactions to peanut.

Methyl methacrylate and respiratory sensitisation: a comprehensive review.

Methyl methacrylate (MMA) is classified under GHS as a weak skin sensitiser and a skin and respiratory irritant. It has recently been proposed that MMA be classified as a respiratory sensitiser (a designation that in a regulatory context embraces both true respiratory allergens, as well as chemicals that cause asthma through non-immunological mechanisms). This proposal was based primarily upon the interpretation of human data.

Adaptation of an ELISA assay for detection of IgG responses against therapeutic monoclonal antibodies in a mouse immunization model.

Biotherapeutic monoclonal antibodies (mAb) play important roles in clinical medicine but their potential to elicit immune responses in patients remains a major issue. In a study designed to investigate the effect of aggregation on immunogenic responses, mice were immunized with two monoclonal antibodies (mAb1 and mAb2). Serum levels of total IgG, IgG, and IgG were measured by ELISA.

Enzymes and sensitization via skin exposure: A critical analysis.

Some proteins, including enzymes, can induce allergic sensitization of various types, including allergic sensitization of the respiratory tract. There is now an increased understanding of the role that the skin plays in the development of IgE-mediated allergy and this prompts the question whether topical exposure to enzymes used widely in consumer cleaning products could result in allergic sensitization. Here, the evidence that proteins can interact with the skin immune system and the way they do so is reviewed, together with a consideration of the experience gained over decades of the use of enzymes in laundry and cleaning products.

Allergic Sensitization to Nickel and Implanted Metal Devices: A Perspective.

There is continuing interest in the interrelationships between allergic sensitization to metal allergens, metal implants, and the development of adverse reactions to implanted devices. Here, we focus on sensitization to nickel (although, in practice, it is commonly not possible to distinguish between events associated with nickel and other potentially allergenic metals used in devices). The purpose of this article was to review whether exposure to nickel resulting from implanted devices is associated with the development of de novo sensitization to nickel and also whether nickel sensitization, either newly acquired or pre-existing, has a causal relationship with adverse health effects.

Perforin, COVID-19 and a possible pathogenic auto-inflammatory feedback loop.

During COVID-19 infection, reduced function of natural killer (NK) cells can lead to both compromised viral clearance and dysregulation of the immune response. Such dysregulation leads to overproduction of cytokines, a raised neutrophil/lymphocyte ratio and monocytosis. This in turn increases IL-6 expression, which promotes scar and thrombus formation.

Rethinking agrochemical safety assessment: A perspective.

Agrochemical safety assessment has traditionally relied on the use of animals for toxicity testing, based on scientific understanding and test guidelines developed in the 1980s. However, since then, there have been significant advances in the toxicological sciences that have improved our understanding of mechanisms underpinning adverse human health effects. The time is ripe to 'rethink' approaches used for human safety assessments of agrochemicals to ensure they reflect current scientific understanding and increasingly embrace new opportunities to improve human relevance and predictivity, and to reduce the reliance on animals.

Identifying key priorities for research to protect the consumer with food hypersensitivity: A UK Food Standards Agency Priority Setting Exercise.

Introduction: Food hypersensitivity (FHS), including food allergy, coeliac disease and food intolerance, is a major public health issue. The Food Standards Agency (FSA), an independent UK Government department working to protect public health and consumers' wider interests in food, sought to identify research priorities in the area of FHS.

Methods: A priority setting exercise was undertaken, using a methodology adapted from the James Lind Alliance-the first such exercise with respect to food hypersensitivity.

Critical Evaluation of Low-Molecular Weight Respiratory Sensitizers and Their Protein Reactivity Potential Toward Lysine Residues.

Interest in the development of methods to evaluate the respiratory sensitization potential of low-molecular weight chemicals continues, but no method has yet been generally accepted or validated. A lack of chemical reference standards, together with uncertainty regarding relevant immunological mechanisms, has hampered method development. The first key event in the development of either skin or respiratory sensitization is the formation of stable adducts of the chemical with host proteins.

Classification of chemicals as respiratory allergens based on human data: Requirements and practical considerations.

Occupational asthma is an important health problem that can include exacerbation of existing asthma, or induce new asthma either through allergic sensitisation, or non-immunological mechanisms. While allergic sensitisation of the respiratory tract can be acquired to proteins, or to low molecular weight chemicals (chemical respiratory allergens) this article is on the latter exclusively. Chemical respiratory allergy resulting in occupational asthma is associated with high levels of morbidity and there is a need, therefore, that chemicals which can cause sensitisation of the respiratory tract are identified accurately.

Skin Sensitization Tests: The LLNA and the RhE IL-18 Potency Assay.

Contact allergy is of considerable importance to the toxicologist, and regulatory authorities worldwide require testing for skin sensitization potential and appropriate hazard labeling to enable management of the risk to human health. Although traditionally the identification of skin-sensitizing chemicals has been carried out using animal models, in Europe legislative changes have promoted, and now require, the use of non-animal methods (i.e.

The activity of methacrylate esters in skin sensitisation test methods II. A review of complementary and additional analyses.

Allergic contact dermatitis is an important occupational health issue, and there is a need to identify accurately those chemicals that have the potential to induce skin sensitisation. Hazard identification was performed initially using animal (guinea pig and mouse) models. More recently, as a result of the drive towards non-animal methods, alternative in vitro and in silico approaches have been developed.

Harnessing co-operative immune augmentation by contact allergens to enhance the efficacy of viral vaccines.

Although the development of successful vaccines against coronaviruses may be achieved, for some individuals the immune response that they stimulate may prove to be insufficient for effective host defence. The principle that a relatively strong contact allergen will have an enhancing effect on sensitization compared with a less potent contact allergen if they are co-administered, may not, at first, appear relevant to this issue. However, this augmentation effect is thought to be due to the sharing of common or complementary pathways.