Michael K. Robinson

Understanding fragrance allergy using an exposure‐based risk assessment approach

Conducting a sound skin sensitization risk assessment prior to the introduction of new ingredients and products into the market place is essential. The process by which low‐molecular‐weight chemicals induce and elicit skin sensitization is dependent on many factors, including the ability of the chemical to penetrate the skin, react with protein, and trigger a cell‐mediated immune response. Based on our chemical, cellular and molecular understanding of allergic contact dermatitis, it is possible to carry out a quantitative risk assessment. Specifically, by estimating the exposure to the allergen and its allergenic potency, it is feasible to assess quantitatively the sensitization risk of an ingredient in a particular product type. This paper focuses on applying exposure‐based risk assessment tools to understanding fragrance allergy for 2 hypothetical products containing the fragrance allergen cinnamic aldehyde. The risk assessment process predicts that an eau de toilette leave‐on product containing 1000 ppm or more cinnamic aldehyde would pose an unacceptable risk of induction of skin sensitization, while a shampoo, containing the same level of cinnamic aldehyde, would pose an acceptable risk of induction of skin sensitization, based on limited exposure to the ingredient from a rinse‐off product application.

The importance of exposure estimation in the assessment of skin sensitization risk.

The development of new ingredients and products for the consumer market requires a thorough assessment of their potential for skin sensitization and the possible clinical manifestation of allergic contact dermatitis. The process by which low molecular weight chemicals induce and elicit skin sensitization reactions is complex and dependent on many factors relevant to the ability of the chemical to penetrate the skin, react with protein, and trigger the cell‐mediated immune response. These major factors include inherent potency, chemical dose, duration and frequency of exposure, vehicle or product matrix, and occlusion. The fact that a chemical is a contact allergen does not mean that it cannot be formulated into a consumer product at levels well tolerated by most individuals. Many common ingredients (e.g., fragrances, preservatives) are known skin allergens. However, all allergens show dose‐response and threshold characteristics. Therefore, one should be able to incorporate these chemicals into products at levels that produce acceptably low incidences of skin sensitization under foreseeable conditions of exposure. The critical exposure determinant for evaluating skin sensitization risk is dose per unit area of skin exposed. Use of this parameter allows for comparative assessments from different types of skin sensitization tests (including cross‐species comparisons), and, at least for known potent allergens, there is remarkable similarity in threshold dose/unit area determinations across species. The dose/unit area calculation enables a judgment of the sensitization risk for different product types. This is illustrated using the chemical preservative methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) as a case study.

Population differences in acute skin irritation responses: Race, sex, age, sensitive skin and repeat subject comparisons

The variability in human skin irritation responses has been well documented and can confound our ability to accurately assess differences in skin reactivity between human subpopulations. In the current analysis, results were compiled from nine acute irritation patch test studies, conducted at three test facilities over a 5‐year period. Four irritant test chemicals, 20% sodium dodecyl sulphate, 100% decanol, 100% octanoic acid and 10% acetic acid, were tested in sufficient numbers of test subjects to enable the stratification of results for different human subpopulations. An increased reactivity was noted for Asian versus Caucasian subjects for each of three test chemicals, in contrast to the previously described individual study results from which these data were drawn. Male subjects were directionally or significantly more reactive to each of the test chemicals than female subjects. The oldest age cluster of subjects (56–74 years of age) was directionally or significantly less reactive than younger age clusters. There was virtually identical reactivity between self‐assessed ‘sensitive’ and normal skin groups. Lastly, there was little correlation between the results from individual subjects tested in two or more studies with the same chemicals. These results add to our general understanding of population differences in skin reactivity and the potential implications for ingredient and product skin safety testing and risk assessment.

Anti-e-selectin is ineffective in the treatment of psoriasis: A randomized trial

Summary Background Skin‐homing, memory T lymphocytes play an important role in the pathogenesis of psoriasis by interacting with the vascular addressin, E‐selectin and trafficking into lesional skin. Thus an attractive option for targeted therapy of the disease would be blockade of skin‐homing T cells with an antibody directed at E‐selectin.

A review of the scientific basis for uncertainty factors for use in quantitative risk assessment for the induction of allergic contact dermatitis.

Safety evaluations for chemicals which possess the ability to cause sensitization by skin contact have traditionally been done using an ad hoc comparative risk assessment technique. Recently, several papers have been published supporting the use of an alternative, and potentially better, quantitative risk assessment approach. While they represent a relatively new approach to risk assessment for sensitizers, quantitative methods have been used for decades to support risk assessments for systemic toxicity. Historically, these methods have involved the extrapolation of toxicity data − generally from studies in laboratory animals at relatively high doses to human exposures at lower doses. For toxicity endpoints with a threshold, this process has traditionally involved the use of uncertainty factors. For example, uncertainty factors are commonly used to extrapolate from laboratory animals to humans, and from ‘average’ humans to sensitive subpopulations. In the absence of data to support a different value, a default factor of 10 is widely accepted for each of these areas. Recent papers have advocated the use of a similar approach to characterize the risk of the induction of skin sensitization by allergens of varying potency and potential for skin contact. As with other forms of toxicity, a quantitative assessment of risk for allergic skin reactions can be approached by identifying a NOAEL (no observed adverse effect level) and applying appropriate uncertainty factors. Three major areas of data extrapolation have been identified: inter‐individual susceptibility, the influence of vehicle or product matrix, and exposure considerations. This paper provides an overview of each of these areas with an evaluation of the available scientific database to support an uncertainty factor in the range of 1–10 for each area.

A noninvasive method to assess skin irritation and compromised skin conditions using simple tape adsorption of molecular markers of inflammation.

Background/aims: We have developed a simple noninvasive method to assess inflammatory changes in human skin, even in the absence of visible clinical irritation. Our approach is based on a simple tape (Sebutape®) adsorption method to recover molecular mediators of skin inflammation (e.g., cytokines). This procedure has been used to investigate baseline cytokine levels on skin, to assess normal skin condition and to evaluate changes due to chemical insult, existing dermatitis, or sun exposure.

Xenobiotic metabolism gene expression in the EpiDerm™ in vitro 3D human epidermis model compared to human skin

There is an urgent need to validate in vitro human skin models for use in safety testing. An important component of validation is characterizing the metabolizing capacity of these models. We report comparison of the expression of 139 genes encoding xenobiotic metabolizing enzymes in the EpiDerm model and human skin. In microarray analysis, the expression of 87% of the genes was consistent between the EpiDerm model and human skin indicating the presence of similar metabolic pathways suggesting commonality in function. Analysis of EpiDerm models constructed from four donors showed highly comparable expression of xenobiotic metabolizing genes demonstrating reproducibility of the model. Overall, the expression of Phase II enzymes appeared to be more pronounced in human skin and the EpiDerm model than that of Phase I enzymes, consistent with the role of skin in detoxification of xenobiotics. Though the basal expression of CYPs in particular was low in EpiDerm, significant induction of CYP1A1/1B1 activity was observed following treatment with 3-methylcholanthrene. These results indicate that the xenobiotic metabolizing capacity of the EpiDerm model appears to be representative of human skin. Models such as EpiDerm provide a valuable in vitro approach for evaluation of metabolism and toxicity of cutaneous exposures to xenobiotics.

Population differences in skin structure and physiology and the susceptibility to irritant and allergic contact dermatitis: implications for skin safety testing and risk assessment

Skin safety testing and risk assessment utilize a comparative toxicological approach whereby the inherent toxicity (irritation or sensitization) is related to exposure to determine the potential risk to a consumer population. However, consumers cover a broad spectrum of individual characteristics in terms of skin types and functions, as well as their basic habits and practices in use of consumer products. Thus, we try to use very conservative estimates for both inherent susceptibility to the toxic effect as well as the potential worst‐case exposures. While the inherent variation can be considerable even within a country, it is magnified even further when products are marketed globally. Questions have arisen, therefore, as to whether a skin safety testing approach conducted locally or regionally can adequately predict for adverse effects for the global consumer. A good deal of speculation exists that population differences are real and should mandate population‐specific safety testing prior to marketing products in certain regions of the world. In an attempt to address this question, this review has summarized extensive literature covering basic skin biology and function and susceptibility to irritant and allergic skin responses. Throughout this literature, there are individual studies demonstrating population differences in skin properties or in the responsiveness to chemical insult. Some of the research on this topic has pointed fairly convincingly to a demonstrable population difference. The best example of this is the tendency for blacks to have a lesser skin reactivity than Caucasians, likely due to a more impenetrable barrier. In contrast, the comparative data for Caucasians and Asians, for males and females, and for different age clusters are far less compelling. In terms of tendencies, there are little data to support any real difference in skin barrier function or in skin irritation responsiveness between Caucasians and Asians or between males and females. Comparing different age profiles, there does appear to be a slight decline in reactivity to irritants among the elderly (> 65 years). Susceptibility to skin sensitization tends to be more related to exposure than any inherent susceptibility, though some data exist to suggest a slightly increased sensitivity in females versus males. On the basis of these data, standard procedures for skin safety testing and risk assessment can be considered relatively conservative. Most clinical skin safety studies are conducted in test populations that are comprised primarily of female Caucasians between the ages of 18 and 65 years. If anything, the skin reactivity “character” of this population cohort tends to skew toward the more reactive. This is not to say that population‐specific safety testing should not be done. There may be important reasons to pursue a population‐specific testing strategy in certain situations, perhaps due to regional, sex‐specific, or age‐specific marketing or to satisfy a regulatory or external relations need. However, there is yet no scientific justification to mandate such a strategy, based on our current knowledge of skin responsiveness and how it compares across diverse populations. There are clearly gaps in our understanding of population differences, particularly in regard to skin irritation that should guide future clinical research efforts. Side‐by‐side population testing for both acute and chronic skin irritation, more comparative testing of Asian subpopulations, testing for neurosensory irritation, and testing objective skin responses among hyperreactive subpopulations of multiple races are all areas in which additional research is needed. While current testing strategies have provided an excellent track record of success in providing safe and effective products to the worlds consumers, results of such research will, in the future, help us to refine and further improve our skin testing and risk assessment capabilities.

A review of the Buehler guinea pig skin sensitization test and its use in a risk assessment process for human skin sensitization.

The Buehler test is a valuable procedure for screening the sensitization potential of chemicals prior to human exposure. Our experience of over 20 years has shown it to be effective in detecting strong, moderate, and most weak sensitizers. The topical exposure inherent in the Buehler test allows it to be utilized to investigate dose responses, cross reactivity between structurally related chemicals, and the sensitization potential of contaminants in raw material mixtures. For safety assessment purposes, Buehler test results provide an initial indication of the sensitization potential of the material in question under relevant, but exaggerated, exposure conditions. These results can be compared to results on benchmark chemicals to assess sensitization risk for subsequent human exposure. Optimizing the sensitivity of the Buehler test requires adherence to the published methodology and proper interpretation of the challenge and rechallenge data obtained. Adjuvant-type test methods are generally considered to be more sensitive than topical methods. However, when done properly, topical test procedures such as the Buehler test or the open epicutaneous test can accurately detect most chemicals with any realistic potential for sensitizing humans by the topical route. Moreover, from a risk assessment perspective, these topical tests avoid the problems of overestimating the weak sensitization potential of many topically applied materials or underestimating the sensitization potential of very strong sensitizers; both are potential concerns with invasive adjuvant-type test methods. The Buehler test or other topical test methods are particularly valuable for comparative sensitization risk assessment since human sensitization data on benchmark materials are all derived from topical exposure. The risk assessment is developed by comparing the guinea pig data on the new material versus relevant benchmark chemicals or formulations and also by evaluating the existing human sensitization data on the benchmark material. These data are then utilized to predict human sensitization risk from topical exposure to the new material. Confirmation of human safety can be derived from human repeat insult patch testing (HRIPT) and other clinical tests such as the product use test and the diagnostic patch test. Utilized in this manner, the Buehler test is an integral component of an overall skin sensitization safety assessment program for a new chemical or product formulation.

A Skin Sensitization Risk Assessment Approach for Evaluation of New Ingredients and Products

Skin sensitization risk assessment of new ingredients or products is critical before their introduction into the marketplace. The risk assessment process described in this article involves evaluation of skin sensitization hazard, consideration of all potential human exposures, comparative ingredient/product benchmarking, and, when appropriate, the management of the risk. In this article, a risk assessment process is reviewed along with a description of the risk assessment tools that are employed for evaluating a new ingredient or product. The basic process we use for evaluating the skin sensitization risk of a new product or ingredient is considered a no effect/safety factor approach. The tools used for conducting a risk assessment include structure activity relationship analysis, exposure assessment, preclinical testing (e.g., local lymph node assay [LNNA]) and clinical testing (e.g., human repeat insult patch testing [HRIPT]). The skin sensitization risk assessment process described in this paper has been used successfully for many years for the safe introduction of new products into the marketplace. This process is dynamic--it can be applied to a diversity of product categories (e.g., shampoo, transdermal drug). In summary, the skin sensitization risk assessment process described in this article allows one to carefully assess the skin sensitization potential of a new ingredient or product so that it can be safely introduced into the marketplace.