Mechanistic Applicability Domain Classification of a Local Lymph Node Assay Dataset for Skin Sensitization

Abstract

The goal of eliminating animal testing in the predictive identification of chemicals with the intrinsic ability to cause skin sensitization is an important target, the attainment of which has recently been brought into even sharper relief by the EU Cosmetics Directive and the requirements of the REACH legislation. Development of alternative methods requires that the chemicals used to evaluate and validate novel approaches comprise not only confirmed skin sensitizers and non-sensitizers but also substances that span the full chemical mechanistic spectrum associated with skin sensitization. To this end, a recently published database of more than 200 chemicals tested in the mouse local lymph node assay (LLNA) has been examined in relation to various chemical reaction mechanistic domains known to be associated with sensitization. It is demonstrated here that the dataset does cover the main reaction mechanistic domains. In addition, it is shown that assignment to a reaction mechanistic domain is a critical first step in a strategic approach to understanding, ultimately on a quantitative basis, how chemical properties influence the potency of skin sensitizing chemicals. This understanding is necessary if reliable non-animal approaches, including (quantitative) structure-activity relationships (Q)SARs, read-across, and experimental chemistry based models, are to be developed.

Predicting skin sensitization potential of organic compounds based on toxicity enhancement to Tetrahymena pyriformis, fathead minnow, and Daphnia magna

“…However, if a demethylated methoxy group is present in the meta and para position, hydroxyl can then be oxidized to a carbon-oxygen double bond (Patlewicz et al 2001;Fabjan and Hulzebos 2008) -as illustrated in Figure 3 -enabling a Michael addition. Similarly, 2-nitro-3-pyridinol (Compound 63) shows toxicity enhancement because of biotransformation (Roberts et al 2007). Notably, biotransformation is important for some sensitizers (especially pro-haptens) to exert their effect ; Natsch and Haupt 2013), thus, biotransformation should be considered during sensitization risk assessment.…”

ISOTHIAZOLINONES AS CAUSAL FACTORS OF CONTACT ALLERGY EPIDEMICS IN THE 20th AND 21st CENTURIES

“…Okazało się jednak, że wyniki oceny metodą LLNA sugerują raczej zaliczenie MI do związków o umiarkowanych, a nawet silnych właściwościach uczulających (19,22). Przykładowe uzyskane wartości EC3 wynosiły bowiem dla MI 0,4%, 1,9% i 2,2%, co odpowiada umiarkowanemu (1,9%, 2,2%) lub nawet silnemu (0,4%) potencjałowi uczulającemu, chociaż znacząco słabszemu w porównaniu z MCI (19,23). Ponadto wykazano na modelu zwierzęcym, że nierozcieńczone MCI/MI oraz sam MI działają żrąco na skórę i błony śluzowe (3).…”

Skin Irritation and Sensitization: Mechanisms and New Approaches for Risk Assessment

“…Thus, the process of the induction of skin sensitization can be viewed as a series of barriers that a chemical must overcome in order to cause skin sensitization. These have been the subject of extensive reviews recently [1,[18][19][20] . The main aspects are discussed in more detail below.…”

“…Nevertheless, a recent detailed review suggested that all the available systems were not yet suitable for use as a full replacement for the animal models [37] . A new approach, quantitative mechanistic modeling, holds promise, but awaits more detailed assessment [20] .…”