The skin allergy risk assessment-integrated chemical environment (SARA-ICE) defined approach to derive points of departure for skin sensitization.

Mechanistically based non-animal methods for assessing skin sensitization hazard have been developed, but are not considered sufficient, individually, to conclusively define the skin sensitization potential or potency of a chemical. This resulted in the development of defined approaches (DAs), as documented in OECD TG 497, for combining information sources in a prescriptive manner to provide a determination of risk or potency. However, there are currently no DAs within OECD TG 497 that can derive a point of departure (POD) for risk assessment.

The skin sensitization adverse outcome pathway: exploring the role of mechanistic understanding for higher tier risk assessment.

For over a decade, the skin sensitization Adverse Outcome Pathway (AOP) has served as a useful framework for development of novel and assays for use in skin sensitization hazard and risk assessment. Since its establishment, the AOP framework further fueled the existing efforts in new assay development and stimulated a plethora of activities with particular focus on validation, reproducibility and interpretation of individual assays and combination of assay outputs for use in hazard/risk assessment. In parallel, research efforts have also accelerated in pace, providing new molecular and dynamic insight into key events leading to sensitization.

Applying a next generation risk assessment framework for skin sensitisation to inconsistent new approach methodology information.

Cosmetic products must be safe for their intended use. Regulatory bans on animal testing for new ingredients have resulted in a shift towards the use of new approach methodologies (NAMs) such as in silico predictions and in chemico / in vitro data. Defined approaches (DAs) have been developed to interpret combinations of NAMs to provide information on skin sensitization hazard and potency, three having been adopted within OECD Test Guideline 497.

Decision making in next generation risk assessment for skin allergy: Using historical clinical experience to benchmark risk.

Our aim is to develop and apply next generation approaches to skin allergy risk assessment that do not require new animal test data and better quantify uncertainties. Quantitative risk assessment for skin sensitisation uses safety assessment factors to extrapolate from the point of departure to an acceptable human exposure level. It is currently unclear whether these safety assessment factors are appropriate when using non-animal test data to derive a point-of departure.

Expansion of the Cosmetics Europe skin sensitisation database with new substances and PPRA data.

The assessment of skin sensitisation is a key requirement in all regulated sectors, with the European Union's regulation of cosmetic ingredients being most challenging, since it requires quantitative skin sensitisation assessment based on new approach methodologies (NAMs). To address this challenge, an in-depth and harmonised understanding of NAMs is fundamental to inform the assessment. Therefore, we compiled a database of NAMs, and in vivo (human and local lymph node assay) reference data.

Next generation risk assessment for skin allergy: Decision making using new approach methodologies.

Our aim is to develop and apply next generation approaches to skin allergy risk assessment (SARA) that do not require new animal test data and better quantify uncertainties. Significant progress has been made in the development of New Approach Methodologies (NAMs), non-animal test methods, for assessment of skin sensitisation and there is now focus on their application to derive potency information for use in Next Generation Risk Assessment (NGRA). The SARA model utilises a Bayesian statistical approach to infer a human-relevant metric of sensitiser potency and a measure of risk associated with a given consumer exposure based upon any combination of human repeat insult patch test, local lymph node, direct peptide reactivity assay, KeratinoSens™, h-CLAT or U-SENS™ data.

A hypothetical skin sensitisation next generation risk assessment for coumarin in cosmetic products.

Next generation Risk Assessment (NGRA) is an exposure-led, hypothesis-driven approach which integrates new approach methodologies (NAMs) to assure safety without generating animal data. This hypothetical skin allergy risk assessment of two consumer products - face cream containing 0.1% coumarin and deodorant containing 1% coumarin - demonstrates the application of our skin allergy NGRA framework which incorporates our Skin Allergy Risk Assessment (SARA) Model.

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.

Development of a next generation risk assessment framework for the evaluation of skin sensitisation of cosmetic ingredients.

All cosmetic products placed onto the market must undergo a risk assessment for human health to ensure they are safe for consumers, including an assessment of skin sensitisation risk. Historically, in vivo animal test methods were used to identify and characterise skin sensitisation hazard, however non-animal and other new approach methodologies (NAMs) are now the preferred and mandated choice for use in risk assessment for cosmetic ingredients. The experience gained over the last three decades on how to conduct risk assessments based upon NAMs has allowed us to develop a non-animal, next generation risk assessment (NGRA) framework for the assessment of skin sensitisers.

Skin sensitization: Uncertainties, challenges, and opportunities for improved risk assessment.

At the ESCD congress held in Manchester in 2016, a session was organized to encourage more dialogue between clinicians with expertise in skin sensitization and toxicologists seeking to provide effective risk assessment to prevent human health issues. That session focused on the remaining uncertainties regarding the induction and regulation of skin sensitization in humans, and the opportunities and challenges associated with the refinement and improvement of risk assessment methodologies. This short article, prompted by those discussions, debates what the authors regard as being among the most important and most intriguing uncertainties about skin sensitization and allergic contact dermatitis in humans, and the most significant opportunities for improving risk assessment.

A comparison of TRECs and flow cytometry for naive T cell quantification.

Assessment of thymic output by measurement of naive T cells is carried out routinely in clinical diagnostic laboratories, predominantly using flow cytometry with a suitable panel of antibodies. Naive T cell measurements can also be made using molecular analyses to quantify T cell receptor excision circle (TRECs) levels in sorted cells from peripheral blood. In this study we have compared TRECs levels retrospectively with CD45RA CD27 T cells and also with CD45RA CD31 T cells in 134 patient samples at diagnosis or during follow-up.

Categorization of chemicals according to their relative human skin sensitizing potency.

Although adoption of skin sensitization in vivo assays for hazard identification is likely to be successful in the next few years, this does not replace their use in potency prediction. Notably, measurement of potency of skin sensitizers in the local lymph node assay has been important. However, this local lymph node assay potency measure has not been formally assessed against a range of substances of known human sensitizing potential, because the latter is lacking.

Causality methods in cosmetovigilance: comparison of Colipa and PLM versus global introspection.

The European Cosmetics Regulation requires a post-marketing system for detection of undesirable effects on human health of cosmetic products. Colipa, the European Cosmetic, toiletry and perfumery association, provided guidelines for causality assessment of these effects. In addition another causality method originally designed for causality rating in Post Launch Monitoring (PLM) of novel foods has been employed to assess causality of cosmetic products.

Guiding principles for the implementation of non-animal safety assessment approaches for cosmetics: skin sensitisation.

Characterisation of skin sensitisation potential is a key endpoint for the safety assessment of cosmetic ingredients especially when significant dermal exposure to an ingredient is expected. At present the mouse local lymph node assay (LLNA) remains the 'gold standard' test method for this purpose however non-animal test methods are under development that aim to replace the need for new animal test data. COLIPA (the European Cosmetics Association) funds an extensive programme of skin sensitisation research, method development and method evaluation and helped coordinate the early evaluation of the three test methods currently undergoing pre-validation.

Allergic contact dermatitis: a commentary on the relationship between T lymphocytes and skin sensitising potency.

T lymphocytes mediate skin sensitisation and allergic contact dermatitis. Not unexpectedly, therefore, there is considerable interest in the use of T lymphocyte-based assays as alternative strategies for the identification of skin sensitising chemicals. However, in addition to accurate identification of hazards the development of effective risk assessments requires that information is available about the relative skin sensitising potency of contact allergens.

Refinement of the Dermal Sensitisation Threshold (DST) approach using a larger dataset and incorporating mechanistic chemistry domains.

An essential step in ensuring the toxicological safety of ingredients in consumer products is the evaluation of their skin sensitising potential. Where skin exposure is low, it is possible to conduct a risk assessment using the Dermal Sensitisation Threshold (DST), a process similar to that of the Threshold of Toxicological Concern. This paper describes work building on that previously published, whose aim was to produce a more robust tool for assessing the safety of consumer products.

Non-animal approaches for consumer safety risk assessments: Unilever's scientific research programme.

Non-animal based approaches to risk assessment are now routinely used for assuring consumer safety for some endpoints (such as skin irritation) following considerable investment in developing and applying new methods over the past 20 years. Unilever's research programme into non-animal approaches for safety assessment is currently focused on the application of new technologies to risk assessments in the areas of skin allergy, cancer and general toxicity (including inhalation toxicity). In all of these areas, a long-term investment is essential to increase the scientific understanding of the underlying biological and chemical processes that we believe will ultimately form a sound basis for novel risk assessment approaches.

Assuring consumer safety without animal testing: a feasibility case study for skin sensitisation.

Allergic Contact Dermatitis (ACD; chemical-induced skin sensitisation) represents a key consumer safety endpoint for the cosmetics industry. At present, animal tests (predominantly the mouse Local Lymph Node Assay) are used to generate skin sensitisation hazard data for use in consumer safety risk assessments. An animal testing ban on chemicals to be used in cosmetics will come into effect in the European Union (EU) from March 2009.

A general population from Thailand: incidence of common allergens with emphasis on para-phenylenediamine.

Background: Most studies on the prevalence of allergy to the permanent hair dye chemical para-phenylenediamine (PPD) are reported from populations of eczema patients attending patch-test clinics, and are assumed to be much higher than in the normal population. No data exist on incidence of senitization to PPD resulting from the use of commercial hair dye preparations over a defined time period.

Method: A total of 2545 healthy adult volunteers (Bangkok) were screened for PPD allergy through standard patch testing.

p-Phenylenediamine allergy: the role of Bandrowski's base.

p-Phenylenediamine (PPD) is a commonly used hair-dye and a potent skin allergen. The mechanism of sensitization is unknown, as PPD is protein unreactive. We studied Bandrowski's base (BB), a PPD trimer, as well as 1,4-benzoquinone (BQ), a PPD hapten.

The impact of exposure variables on the induction of skin sensitization.

Whereas many investigations of the variables associated with the elicitation of allergic contact dermatitis have been undertaken, to the point where we can begin to predict the likelihood of elicitation occurring in a given situation, the same is not true for the induction of skin sensitization. Studies have demonstrated that increasing dose has an impact; in an experimental setting, a number of variables received attention some decades ago. However, in the work reported here, the relative importance of the frequency and the duration of exposure is highlighted.

Strong irritants masquerading as skin allergens: the case of benzalkonium chloride.

Chemicals may possess a number of hazards to human health including the ability to cause skin irritation and contact allergy. Identification and characterization of these properties should fall within predictive toxicology, but information derived from human exposure, including clinical experience, is also of importance. In this context, it is of interest to review the case of benzalkonium chloride, a cationic surfactant.

Utility of historical vehicle-control data in the interpretation of the local lymph node assay.

The accepted approach to the interpretation of local lymph node assay (LLNA) data requires comparison of responses in the test groups with background activity found in concurrent vehicle-treated controls. However, of established value in the interpretation of toxicity test data is the use of historical control values that provide one criterion against which to judge the integrity of individual experiments. Specifically, the availability of robust and relevant historical control data permits examination of whether, in any individual experiment, control values fall within the expected range.