Masinja, H (2022) Evaluation of Alternative Non-Animal Approaches for the Prediction of Skin Sensitisation Potential of Agrochemicals. Doctoral thesis, Liverpool John Moores University.

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Abstract

Skin sensitisation in humans is an important toxicological effect to be determined should there be frequent and prolonged exposure. Current approaches to assessing skin sensitisation mostly utilise in vivo testing, although there is a move to alternatives such as in silico, in chemico and in vitro approaches. The aim of this thesis was to investigate whether these alternative approaches could be utilised for agrochemical active ingredients (AIs) and formulations. Agrochemicals represent a unique problem for risk assessment due to the high level of regulatory compliance required in addition to the intrinsic issues of assessing formulations. Using the in vivo experimental results as a benchmark, the overall sensitivity and specificity of the Classification Labelling and Packaging (CLP) threshold calculation method, regardless of agrochemical formulation type, were determined to be 58% and 82% respectively. Thus, for the plant production products (PPPs) assessed, the threshold method had a high probability of accurately predicting non-sensitisers. To supplement the information, the in vitro triple pack (Direct Peptide Reactivity Assay, KeratinoSensTM and h-CLAT) was applied using established Integrated Testing Strategies and Defined Approaches. Overall, the triple pack performed poorly for the assessment of AIs and formulations alike. The Genomic Allergen Rapid Detection (GARD) assay for the ten AIs showed a high sensitivity but a low total accuracy; the sensitivity was 0% with the in vivo non-sensitisers being predicted as sensitisers in the GARD assay. Eight of the ten PPPs tested in the SENS-IS assay produced results that were in good agreement with the vertebrate study outcomes. Findings from investigations into the Two Dimensional (2D) in vitro test methods demonstrated that testing of complex mixtures in those models could not be conducted accurately with current methods. Use of the SENS-IS method allowed for direct application of the PPP to the Reconstructed Human Epidermis (RhE) test system so that good comparison to the products intended and anticipated use can be made. It is envisaged that the work conducted in this thesis will add to the toxicology research conducted on skin sensitisation thus far and be of use primarily for decision making in hazard assessment of agrochemicals.

Item Type:	Thesis (Doctoral)
Uncontrolled Keywords:	Skin sensitisation; New approach methodologies; in vitro; in silico; Agrochemical; SENS-IS; Genomic Allergen Rapid Detection Assay; Defined Approaches
Subjects:	R Medicine > RM Therapeutics. Pharmacology
Divisions:	Pharmacy & Biomolecular Sciences
Date Deposited:	16 Nov 2021 11:32
Last Modified:	30 Aug 2022 15:22
DOI or ID number:	10.24377/LJMU.t.00015788
Supervisors:	Cronin, M, Enoch, S and Currie, R
URI:	https://researchonline.ljmu.ac.uk/id/eprint/15788

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