Gerrit Schüürmann

Interspecies differences in triphenyl phosphate (TPhP) biotransformation are critical for extrapolating toxicological outcomes but remain poorly characterized. This study compared TPhP biotransformation (0.1–10 μmol·L–1) in rat, human, and trout liver S9 fractions to determine kinetic parameters and metabolic pathways. Human S9 exhibited the highest intrinsic clearance, driven by strong substrate affinity, whereas rat S9 showed lower clearance despite higher catalytic capacity. In contrast, rainbow trout displayed markedly limited biotransformation, characterized by only 39.11% depletion at 2.5 μmol·L–1 and apparent zero-order kinetics with very low reaction velocity, indicating a pronounced metabolic bottleneck. Nontarget analysis revealed both conserved and species-specific biotransformation pathways. Hydrolysis, monohydroxylation, and glucuronidation of monohydroxylated metabolites were conserved across all species. Aromatic dihydroxylation and subsequent glucuronidation were restricted to mammalian models, consistent with higher cytochrome P450 activity measured in these species. Notably, a dihydrodiol metabolite was detected in all species, indicating a conserved bioactivation pathway likely involving arene oxide intermediates. Detoxification of this intermediate was species-dependent, with glutathione conjugation occurring in rat- and trout-S9 incubations while being absent in human-S9. Collectively, these results demonstrate species-specific metabolic biotransformation of TPhP and highlight the importance of integrating toxicokinetics and metabolomics to improve the risk assessment of emerging contaminants.

Anaerobic bacteria transform aromatic halides through reductive dehalogenation. This dehalorespiration is catalyzed by the supernucleophilic coenzyme vitamin B₁₂, cob(I)alamin, in reductive dehalogenases. So far, the underlying inner-sphere electron transfer (ET) mechanism has been discussed controversially. In the present study, all 36 chloro-, bromo-, and fluorobenzenes and full-size cobalamin are analyzed at the quantum chemical density functional theory level with respect to a wide range of theoretically possible inner-sphere ET mechanisms. The calculated reaction free energies within the framework of Co^I···X (X = F, Cl, and Br) attack rule out most of the inner-sphere pathways. The only route with feasible energetics is a proton-coupled two-ET mechanism that involves a B₁₂ side-chain tyrosine (modeled by phenol) as a proton donor. For 12 chlorobenzenes and 9 bromobenzenes with experimental data from Dehalococcoides mccartyi strain CBDB1, the newly proposed PC-TET mechanism successfully discriminates 16 of 17 active from 4 inactive substrates and correctly predicts the observed regiospecificity to 100%. Moreover, fluorobenzenes are predicted to be recalcitrant in agreement with experimental findings. Conceptually, based on the Bell-Evans-Polanyi principle, the computational approach provides novel mechanistic insights and may serve as a tool for predicting the energetic feasibility of reductive aromatic dehalogenation.

Aromatic aldehydes are ubiquitous in humans' everyday life. As aldehydes, they can form imines (Schiff bases) with amino groups of skin proteins, leading to immune response-triggered allergic contact dermatitis. Many known aromatic aldehydes are considered as weak or nonsensitizers, but others like atranol and chloratranol, two components of the fragrance oak moss absolute, show strong sensitization potency. This large discrepancy in potency and, in particular, the underlying reaction mechanisms are only little understood so far. To reduce this knowledge gap, our chemoassay employing glycine-para-nitroanilide (Gly-pNA) as an amino model nucleophile was applied to 23 aromatic aldehydes. The determined Gly-pNA second-order rate constants for imine formation (k₁ ≤ 2.85 L·mol^-1·min^-1) and the imine stability constant (K ≤ 333 L·mol^-1) are on the lower end of the known amino reactivity scale for aldehydes, confirming many aromatic aldehydes as less potent sensitizers in line with animal and human data. The substantially higher sensitization potency of atranol and chloratranol, in turn, is reflected by their unique reaction chemistry profiles, inter alia, identifying them as cross-linkers able to form thermodynamically more stable epitopes with skin proteins (despite low formation kinetics, k₁). The discussion further includes a comparison of experimentally determined k₁ values with computed reactivity data (Taft σ*), the impact of the substitution pattern of the aryl ring on the reactivity with Gly-pNA, and analytically determined adduct patterns. Overall, this work provides new insights into the reaction of aromatic aldehydes with amino groups under aqueous conditions and fosters a better understanding of the chemistry underlying skin sensitization.

Microbial reductive dechlorination provides a green and highly desirable approach to address the pollution raised by the substantial legacies of polychlorinated biphenyls (PCBs) in soil, sediment, and underground water. It has been shown that the reaction event is catalyzed by supernucleophilic cob(I)alamin housed in reductive dehalogenases (RDases). However, the mechanism still remains elusive. Herein, we unravel the mechanism via quantum chemical calculations, considering a general model of RDase and the dechlorination regioselectivity of two representative PCB congeners, 234-236-CB and 2345-236-CB. The B₁₂-catalzyed reductive dechlorination of PCBs starts with the formation of a reactant complex, followed by a proton-coupled two-electron transfer (PC-TET) and a subsequent single-electron transfer (SET). The PC-TET yields a cob(III)alamin-featured intermediate, which is quickly reduced by the latter SET fueled by significant energetic benefits (∼100 kcal mol⁻¹). It rationalizes the exclusive detection and characterization of cob(I/II)alamins in RDase-mediated dehalogenation experiments. The determined mechanism successfully reproduces the experimental dechlorination regioselectivity and reactivity, as observed with Dehalococcoides mccartyi strain CG1.

Recent innovative adsorption technologies for water purification rely on micrometer-sized activated carbon (AC) for ultrafast adsorption or in situ remediation. In this study, the bottom-up synthesis of tailored activated carbon spheres (aCS) from sucrose as renewable feedstock is demonstrated. The synthesis is based on a hydrothermal carbonization step followed by a targeted thermal activation of the raw material. This preserves its excellent colloid properties, i.e., narrow particle size distribution around 1 µm, ideal spherical shape and excellent aqueous dispersibility. We investigated the ageing of the freshly synthesized, highly de-functionalized AC surface in air and aqueous media under conditions relevant to the practice. A slow but significant ageing due to hydrolysis and oxidation reactions was observed for all carbon samples, leading to an increase of the oxygen contents with storage time. In this study, a tailored aCS product was generated within a single pyrolysis step with 3 vol.-% H₂O in N₂ in order to obtain the desired pore diameters and surface properties. Adsorption characteristics, including sorption isotherms and kinetics, were investigated with monochlorobenzene (MCB) and perfluorooctanoic acid (PFOA) as adsorbates. The product showed high sorption affinities up to log (K_D/[L/kg]) of 7.3 ± 0.1 for MCB and 6.2 ± 0.1 for PFOA, respectively.

The nematode Caenorhabditis elegans has been widely used as a model organism for assessing chemical toxicity. So far, however, a respective baseline narcosis reference has been lacking to predict narcosis-level toxicity and to identify excess-toxic compounds and associated mechanisms of action. Employing 22 organic narcotics that cover 7.2 units of their log K_ow (octanol/water partition coefficient) from -1.20 to 6.03, a baseline narcosis model has been derived for a glass-vial 96-h growth inhibition test with C. elegans, both without and with correction for compound loss through volatilization and sorption. The resultant effective concentrations yielding 50% growth inhibition, EC₅₀, vary by 6.4 log units from 5.04 · 10^-1 to 1.90 · 10^-7 mol/L (exposure-corrected). Application of the new model is illustrated through sensing the toxicity enhancement (T_e) of four Michael-acceptor carbonyls driven by their reactive mode of action. Moreover, narcosis-level predicted vs experimental EC₅₀ of two α,β-unsaturated alcohols demonstrate the biotransformation capability of C. elegans regarding ADH (alcohol dehydrogenase). The discussion includes narcosis-level and excess-toxicity doses (critical body burdens) as well as chemical activities A₅₀ (at the EC₅₀) as compared to fish, daphnids, ciliates, bacteria, zebrafish embryo, and cell lines. Overall, the presently introduced model for predicting C. elegans baseline narcosis enables generating respective pre-test expectations, enriches experimental results by mechanistic information, and may complement 3Rs (reduce, refine, replace) test batteries through its ADH metabolic capacity.

The octanol/air partition coefficient K_oa is important for assessing the bioconcentration of airborne xenobiotics in foliage and in air-breathing organisms. Moreover, K_oa informs about compound partitioning to aerosols and indoor dust, and complements the octanol/water partition coefficient K_ow and the air/water partition coefficient K_aw for multimedia fate modeling. Experimental log K_oa at 25 °C has been collected from literature for 2161 compounds with molecular weights from 16 to 959 Da. The curated data set covers 18.2 log units (from -1.0 to 17.2). A newly developed fragment model for predicting log K_oa from molecular structure outperforms COSMOtherm, EPI-Suite KOAWIN, OPERA, and linear solvation energy relationships (LSERs) regarding the root-mean-squared error (rms) and the maximum negative and positive errors (mne and mpe) (rms: 0.57 vs 0.86 vs 1.09 vs 1.19 vs 1.05-1.53, mne: -2.55 vs -3.95 vs -7.51 vs -7.54 vs (-5.63) - (-7.34), mpe: 2.91 vs 5.97 vs 7.54 vs 4.24 vs 6.89-10.2 log units). The prediction capability, statistical robustness, and sound mechanistic basis are demonstrated through initial separation into a training and prediction set (80:20%), mutual leave-50%-out validation, and target value scrambling in terms of temporarily wrong compound-K_oa allocations. The new general-purpose model is implemented in a fully automatized form in the ChemProp software available to the public. Regarding K_oa indirectly determined through K_ow and K_aw, a new approach is developed to convert from wet to dry octanol, enabling higher consistency in experimental (and thus also predicted) K_oa.

Henry's law constant is important for assessing the environmental fate of organic compounds, including polar accumulation, indoor contamination, and the impact of airborne predominance on persistence. Moreover, it can be used in the context of alternative 3R bioassays to inform about the compound loss through volatilization as a confounding factor. For 2636 compounds, curated experimental log K_aw (air/water partition coefficient) data at 25° covering 23.6 orders of magnitude (from -18.6 to 5.0) have been collected from the literature. Subsequently, a new fragment model for predicting log K_aw from molecular structures has been developed. According to the root-mean-squared error (rms) and the maximum negative and positive errors (mne and mpe), this general-purpose model outperforms COSMOtherm, EPISuite HENRYWIN, OPERA, and LSER with calculated input parameters significantly (rms 0.50 vs 0.92 vs 1.25 vs 1.28 vs 1.38, mne -2.74 vs -6.78 vs -9.11 vs -6.24 vs -6.27, mpe 2.25 vs 6.22 vs 8.27 vs 11.5 vs 7.69 log units). Initial separation into a training and prediction set (80%:20%), mutual leave-50%-out validation, and target value scrambling (temporarily wrong compound-K_aw allocations) demonstrate the prediction capability, statistical robustness, and mechanistically sound basis of the fragment scheme. The new model is available to the public in fully computerized form through the ChemProp software, and can be combined with a separate existing model to extend the log K_aw prediction to temperatures different from 25 °C.

Outer-sphere electron transfer does not underpin microbial B ₁₂ -dependent olefinic reductive dehalogenation.

Chemoassay profiling of organic electrophiles through the direct peptide reactivity assay has become an OECD-accepted nonanimal component in the REACH evaluation of potential skin sensitizers. For aldehydes forming imines (Schiff bases), however, existing chemoassays yielded inconclusive results, indicating issues with their NH₂ sensitivity and the reversibility of the reaction. In the present study, a new kinetic chemoassay employing the N terminus of glycine-para-nitroanilide, Gly-pNA, as a model nucleophile for protein NH₂ groups is introduced and applied to nine aliphatic monoaldehydes and glutardialdehyde (1,5-pentanedial) that have log K_ow (octanol/water partition coefficient) values from 0.63 to 3.99. The Gly-pNA second-order rate constants k₁ range from 8.56 to 150 L·mol^–1·min^–1 for the monoaldehydes. Interestingly, glutardialdehyde with a k₁ of 17 731 L·mol^–1·min^–1 is 170-fold more reactive than its monoaldehyde counterpart pentanal. This can be rationalized by hydration or tautomerization of the dialdehyde to monoaldehydic forms, now facilitating Schiff base formation through an intramolecular H bond. Comparison with murine local lymph node assay data from the literature reveals that adduct stability in terms of reaction thermodynamics (K = k₁/k_–1^pseudo) rather than formation kinetics (k₁) governs the skin sensitization potency of Schiff-base-forming aldehydes. The discussion includes analytically determined adduct patterns, and the impact of α- and β-carbon substitution as well as hydrophobicity on aldehyde reactivity.