Abstract
Alternative methods for accurate in vitro assessment of skin and respiratory sensitizers are urgently needed. Sensitization is a complex biological process that cannot be evaluated accurately using single events or biomarkers, since the information content is too restricted in these measurements. On the contrary, if the tremendous information content harbored in DNA/mRNA could be mined, most complex biological processes could be elucidated. Genomic technologies available today, including transcriptional profiling and next generation sequencing, have the power to decipher sensitization, when used in the right context. Thus, a genomic test platform has been developed, denoted the Genomic Allergen Rapid Detection (GARD) assay. Due to the high informational content of the GARD test, accurate predictions of both the skin and respiratory sensitizing capacity of chemicals, have been demonstrated. Based on a matured dendritic cell line, acting as a human-like reporter system, information about potency has also been acquired. Consequently, multiparametric diagnostic technologies are disruptive test principles that can change the way in which the next generation of alternative methods are designed.
Highlights
For more than a decade, regulatory organizations have promoted the development of alternative in vitro methods for assessing chemicals and their effect on humans
Of note, when designing multiparametric genomic test systems based on large biomarker signatures, there are inherent risks in data analysis relating to overfitting and model instability, potentially resulting in an overestimation of test accuracy [20]
Independent test cohorts must be used for validation, and the prediction model should be based on appropriate multivariate prediction models, such as support vector machine (SVM), Random Forest, or a multivariate regression [13,14]
Summary
For more than a decade, regulatory organizations have promoted the development of alternative in vitro methods for assessing chemicals and their effect on humans. The need to fulfill these requirements has urged the larger cosmetic and chemical companies to start refining existing conventional test systems, as well as developing additional approaches. No stand-alone assay replacing, e.g., the LLNA (Local Lymph Node Assay), has been achieved. In relation to these single mechanistic tests, the OECD (Organisation for Economic Co-operation and Development) has described the skin sensitization as an adverse outcome pathway and the key events that a reliable test must comprise. This proposal is strongly influenced by the availability of test methods, rather than regarding sensitization as a biological event that should be scientifically analyzed in the most predictive manner [1]. The resulting question is whether this strategy is good enough for fulfilling the needs of an alternative approach?
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