Use of guinea pig data to obtain starting points for skin sensitisation risk assessment - A commentary.

The increasing drive to understand the likelihood of skin sensitisation from plant protection products (PPPs) in workers and the general public has resulted in recent initiatives to establish a quantitative risk assessment (QRA) methodology applicable to these products and their exposure scenarios. The effective evaluation of skin sensitising substances requires not only the identification of that toxicological hazard, but also determination of relative sensitising potency. Typically, this has been achieved by interpretation of local lymph node assay (LLNA) dose response data, delivering what is known as the EC3 value.

The inter-laboratory validation study of EpiSensA for predicting skin sensitization potential.

The Epidermal Sensitization Assay (EpiSensA) is a reconstructed human epidermis (RhE)-based gene expression assay for predicting the skin sensitization potential of chemicals. Since the RhE model is covered by a stratified stratum corneum, various kinds of test chemicals, including lipophilic ones and pre-/pro-haptens, can be tested with a route of exposure akin to an in vivo assay and human exposure. This article presents the results of a formally managed validation study of the EpiSensA that was carried out by three participating laboratories.

Quantitative risk assessment of skin sensitising pesticides: Clinical and toxicological considerations.

Like many other consumer and occupational products, pesticide formulations may contain active ingredients or co-formulants which have the potential to cause skin sensitisation. Currently, there is little evidence they do, but that could just reflect lack of clinical investigation. Consequently, it is necessary to carry out a safety evaluation process, quantifying risks so that they can be properly managed.

Assessing the risk of induction of skin sensitization to plant protection products: A quantitative approach.

Exposure to skin sensitizers is common and regulated in many industry sectors. For cosmetics, a risk-based approach has been implemented, focused on preventing the induction of sensitization. First, a No Expected Sensitization Induction Level (NESIL) is derived, then modified by Sensitization Assessment Factors (SAFs) to derive an Acceptable Exposure Level (AEL).

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.

Risk management of skin sensitisers: A commentary.

Historically, allergic contact dermatitis (ACD) to chemicals encouraged hazard identification improvements, more sophisticated risk assessment and implementation of regulatory strategies, including banning of specific sensitising substances. The validation process applied to hazard identification methods demonstrates their accuracy; their use to characterise sensitiser potency facilitates quantitative and transparent risk assessment. Diagnostic patch testing at dermatology clinics worldwide delivers feedback showing where risk assessment/management has been insufficient or did not target the exposure of concern, thereby facilitating improvements.

Plant extracts, polymers and new approach methods: Practical experience with skin sensitization assessment.

Over the last decade, research into methodologies to identify skin sensitization hazards has led to the adoption of several non-animal methods as OECD test guidelines. However, predictive accuracy beyond the chemical domains of the individual validation studies remains largely untested. In the present study, skin sensitization test results from in vitro and in chemico methods for 12 plant extracts and 15 polymeric materials are reported and compared to available in vivo skin sensitization data.

Proteolytic activity accelerates the T17/T22 recall response to an epicutaneous protein allergen-induced T2 response.

Epicutaneous exposure to protein allergens, such as papain, house dust mite (HDM), and ovalbumin (OVA), represents an important mode of sensitization for skin diseases including protein contact dermatitis, immunologic contact urticaria, and atopic dermatitis. These diseases are inducible by re-exposure to an allergen at both original skin sensitization and distant skin sites. In this study, we examined the serum IgE/IgG response, differentiation of T-helper (T) cells, and epicutaneous T recall response in mice pre-sensitized with protein allergens through the back skin and subsequently challenged on the ear skin.

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.

Epicutaneous challenge with protease allergen requires its protease activity to recall T2 and T17/T22 responses in mice pre-sensitized via distant skin.

Epicutaneous exposure to allergenic proteins is an important sensitization route for skin diseases like protein contact dermatitis, immunologic contact urticaria, and atopic dermatitis. Environmental allergen sources such as house dust mites contain proteases, which are frequent allergens themselves. Here, the dependency of T-helper (T) cell recall responses on allergen protease activity in the elicitation phase in mice pre-sensitized via distant skin was investigated.

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.

Fragrance Skin Sensitization Evaluation and Human Testing: 30-Year Experience.

Background: The human repeated insult patch test (HRIPT) has a history of use in the fragrance industry as a component of safety evaluation, exclusively to confirm the absence of skin sensitization at a defined dose.

Objective: The aim of the study was to document the accumulated experience from more than 30 years of conducting HRIPTs.

Methods: A retrospective collation of HRIPT studies carried out to a consistent protocol was undertaken, with each study comprising a minimum of 100 volunteers.

Total dose defines the incidence of percutaneous IgE/IgG1 mediated immediate-type hypersensitivity caused by papain.

Assessment of human health risk requires an understanding of antigen dose metrics associated with toxicity. Whereas assessment of the human health risk for delayed-type hypersensitivity is understood, the metrics remain unclear for percutaneous immediate-type hypersensitivity (ITH) mediated by IgE/IgG1. In this work, we aimed to investigate the dose metric for percutaneous ITH mediated by IgE/IgG1 responses.

Updating exposure assessment for skin sensitization quantitative risk assessment for fragrance materials.

In 2008, a proposal for assessing the risk of induction of skin sensitization to fragrance materials Quantitative Risk Assessment 1 (QRA1) was published. This was implemented for setting maximum limits for fragrance materials in consumer products. However, there was no formal validation or empirical verification after implementation.

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.

Building confidence in skin sensitisation potency assessment using new approach methodologies: report of the 3rd EPAA Partners Forum, Brussels, 28th October 2019.

Skin sensitising substances that induce contact allergy and consequently risk elicitation of allergic contact dermatitis (ACD) remain an important focus regarding the replacement of animal experimentation. Current in vivo methods, notably the local lymph node assay (LLNA) refined and reduced animal usage and led to a marked improvement in hazard identification, characterisation and risk assessment. Since validation, regulatory confidence in the LLNA approach has evolved until it became the first choice assay in most regulated sectors.

Nickel: Intrinsic Skin Sensitization Potency and Relation to Prevalence of Contact Allergy.

Nickel remains the most commonly identified contact allergen. However, it has proven difficult to demonstrate significant skin-sensitizing activity for nickel in toxicology tests, which typically have indicated a weak skin sensitization potential. Information indicates that in vivo assays are not predictive of dermal sensitization hazard or potency for nickel due to a human-specific mechanistic route for nickel sensitization that animals lack.

Skin sensitisation testing in practice: Applying a stacking meta model to cosmetic ingredients.

Recently, several non-animal approaches contributing to the identification of skin sensitisation hazard have been introduced. Their validation and acceptance has largely been directed towards regulatory classification. Considering the driving force for replacement of in vivo tests centred on cosmetics, it is reasonable to ask how well the new approaches perform in this respect.