The electrophilic reactivity of Michael acceptors is an important determinant of their toxicity. For a set of 35 α,β-unsaturated aldehydes, ketones and esters with experimental rate constants of their reaction with glutathione (GSH), k_GSH, quantum chemical transition-state calculations of the corresponding Michael addition of the model nucleophile methane thiol (CH₃SH) have been performed at the B3LYP/6-31G** level, focusing on the 1,2-olefin addition pathway without and with initial protonation. Inclusion of Boltzmann-weighting of conformational flexibility yields intrinsic reaction barriers ΔE^‡ that for the case of initial protonation correctly reflect the structural variation of k_GSH across all three compound classes, except that they fail to account for a systematic (essentially incremental) decrease in reactivity upon α-substitution. By contrast, the reduction in k_GSH through β-substitution is well captured by ΔE^‡. Empirical correction for the α-substitution effect yields a high squared correlation coefficient (r² = 0.96) for the quantum chemical prediction of log k_GSH, thus enabling an in silico screening of the toxicity-relevant electrophilicity of α,β-unsaturated carbonyls. The latter is demonstrated through application of the calculation scheme for a larger set of 46 Michael-acceptor aldehydes, ketones and esters with experimental values for their toxicity toward the ciliates Tetrahymena pyriformis in terms of 50% growth inhibition values after 48 h exposure (EC₅₀). The developed approach may add in the predictive hazard evaluation of α,β-unsaturated carbonyls such as for the European REACH (Registration, Evaluation, Authorization and Restriction of Chemicals) Directive, enabling in particular an early identification of toxicity-relevant Michael-acceptor reactivity.