Quantitative risk assessment of contact sensitization: clinical data to assess utility of the model.

BACKGROUND: Contact hypersensitivity quantitative risk assessment (QRA) for fragrance ingredients is being used to establish new international standards for all fragrance ingredients that are potential skin sensitizers. OBJECTIVE: The objective was to evaluate the retrospective clinical data on three fragrance ingredients in order to provide a practical assessment of the predictive value of the QRA approach. It is important to have data to assess that the methodology provides a robust approach for primary prevention of contact sensitization induction for fragrance ingredients identified as potential sensitizers. METHODS: This article reviews clinical data for three fragrance ingredients-cinnamic aldehyde, citral, and isoeugenol-to assess the utility of the QRA approach for fragrance ingredients. RESULTS: This assessment suggests that had the QRA approach been available at the time standards were established for these fragrance ingredients, the clinical response might have been noticeably improved. Prospectively, with the establishment of QRA-derived standards, there should be a continued downward trend in patch test-positive rates for cinnamic aldehyde, citral, and isoeugenol over time. CONCLUSION: While it is recognized that the availability of retrospective data is limited, a longitudinal review of these data gives confidence that the QRA approach should be an effective tool for primary prevention. This study also highlights the importance of continued active monitoring of clinical patch-test data for fragrance ingredients.

Axilla surface area for males and females: measured distribution.

With the recent introduction of exposure-based Quantitative Risk Assessment (QRA) as an approach to the evaluation, of materials in finished consumer products that are potential dermal sensitizers, the need for robust exposure data was clearly identified. The objective of this current study is to provide a value for the axilla surface area (SA) that is statistically derived and can be used in dermal sensitization QRA for ingredients of personal care products meant for use on the axilla. The axilla surface area measured for 60 men and 60 women resulted in a median surface area for a single axilla of 64.5 cm(2) for females and 135.5 cm(2) for males. These participants were representative of the United States population in their range of heights and weights. Furthermore, combining these surface area data with measured use data from this and other studies has enabled calculations of consumer exposure to solid APDO products on a dose/unit area/day basis (9.1 mg/cm(2)/d).

A review of critical factors in the conduct and interpretation of the human repeat insult patch test.

This paper reviews key factors that are critical to the conduct and interpretation of Human Repeat Insult Patch Tests (HRIPTs). A methodology for HRIP testing is described and general guidelines for evaluation of responses indicative of induction and elicitation of skin sensitization and skin irritation are detailed. Understanding and applying these key factors is crucial to the design of such studies and reliability of the resulting data when used in the overall risk assessment process.

Dermal sensitization quantitative risk assessment (QRA) for fragrance ingredients.

Based on chemical, cellular, and molecular understanding of dermal sensitization, an exposure-based quantitative risk assessment (QRA) can be conducted to determine safe use levels of fragrance ingredients in different consumer product types. The key steps are: (1) determination of benchmarks (no expected sensitization induction level (NESIL)); (2) application of sensitization assessment factors (SAF); and (3) consumer exposure (CEL) calculation through product use. Using these parameters, an acceptable exposure level (AEL) can be calculated and compared with the CEL. The ratio of AEL to CEL must be favorable to support safe use of the potential skin sensitizer. This ratio must be calculated for the fragrance ingredient in each product type. Based on the Research Institute for Fragrance Materials, Inc. (RIFM) Expert Panel's recommendation, RIFM and the International Fragrance Association (IFRA) have adopted the dermal sensitization QRA approach described in this review for fragrance ingredients identified as potential dermal sensitizers. This now forms the fragrance industry's core strategy for primary prevention of dermal sensitization to these materials in consumer products. This methodology is used to determine global fragrance industry product management practices (IFRA Standards) for fragrance ingredients that are potential dermal sensitizers. This paper describes the principles of the recommended approach, provides detailed review of all the information used in the dermal sensitization QRA approach for fragrance ingredients and presents key conclusions for its use now and refinement in the future.

Dose metrics in the acquisition of skin sensitization: thresholds and importance of dose per unit area.

Allergic contact dermatitis is a common occupational and environmental health problem and many hundreds of chemicals have been implicated as skin sensitizers. Sensitization is acquired following topical exposure to a contact allergen and induction of a cutaneous immune response of an appropriate magnitude. For effective assessment and management of human health risks there is a need to appreciate the dose metrics that drive the induction of skin sensitization. The available evidence suggests that under most normal conditions of exposure it is the dose per unit area of chemical that has over-riding impact on the effectiveness of sensitization. The exception to this rule is when the area of the application site drops below a certain critical level. Here we review in detail the evidence which supports dose per unit area as being the critical exposure metric in the induction of skin sensitization, and the mechanistic bases for this relationship.

An evaluation of dose/unit area and time as key factors influencing the elicitation capacity of methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) in MCI/MI-allergic patients.

Methylchloroisothiazolinone and methylisothiazolinone (MCI/MI) contact allergy affects 1-3% of patch-tested patients in European centres. The aim of the present study was to evaluate the importance of the factors--time and concentration (dose/per unit area)--in the elicitation capacity by means of a repeated open application test (ROAT) experimental design. The study was designed as a double-blind, placebo-controlled, dose-response ROAT preceded by a diagnostic patch testing. 25 subjects with confirmed MCI/MI allergy and 10 healthy, non-MCI/MI allergic control subjects were exposed to 0.025 microg/cm2 (2 p.p.m.) of MCI/MI/unit area of the skin for 4 weeks. After a wash-out period of at least 4 weeks, the subjects were exposed to 0.094 microg/cm2 (7.5 p.p.m.) of MCI/MI/unit area of the skin for 4 weeks. The study showed the importance of both time and exposure in the elicitation process. It demonstrated that the elicitation threshold for MCI/MI is expected to be in the proximity of 0.025 microg/cm2 although it was not possible to establish a definitive elicitation threshold for MCI/MI in this study.