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Polycyclic aromatic hydrocarbons (PAHs) and dioxins are potential causes of multiple diseases by activating the aryl hydrocarbon receptor (AhR) pathway. Health risk assessment of chemicals primarily relies on the relative potency factor (RPF), although its accuracy may be limited when solely using EC50 values. The induction of cytochrome P4501A1 (CYP1A1) serves as a biomarker for AhR activation and is an integrator of dioxin-like toxicity. Here, we present a method for evaluating the risks associated with AhR activation using mathematical models of dose- CYP1A1 induction. The dose-effect curves for certain PAHs and dioxins, including Ant, BghiP, 1,2,3,4,7,8-HxCDD, and others, exhibited a non-classical S-shaped form. The toxic equivalent factor (TEF) profiles revealed a broad range of toxic equivalent factor values. The TEFs for PAHs ranged from approximately 0.01 to 6, with higher values being observed when the concentration was less than 10−10 M, with the exceptions of Ace, Phe, and BghiP. Most congeners of dioxins got the lowest TEF value at around 10−10 M, ranging from 0.04 to 1.00. The binding affinity of AhR to ligands did not display a strong correlation with the EC50 of CYP1A1 expression, suggesting that the AhR-mediated effects of PAHs and dioxins are not fixed but instead fluctuate with the dose. Air samples acquired from a parking area were used to compare the proficiency of RPF and our current approach. In the current method, naphthalene and chrysene were the primary contributors of PAHs to AhR-mediated risks in parking lots air samples, respectively. However, the contributions of naphthalene and chrysene could be disregarded in the RPF approach. • BaP and 2,3,7,8-TCDF were the strongest inducers of AhR activation in PAHs and dioxins, respectively. • Toxicity equivalency factor values varied from −0.5–6 and 0–2 for PAHs and dioxins. • Free energy and CYP1A1 expression had strong correlation in PAHs, but not in dioxins. • Nap is the main pollutant for AhR-mediated risk in actual air samples in our approach, whereas a BaP in the RPF approach. [ABSTRACT FROM AUTHOR]

Silica nanoparticles (SiNPs) could induce adverse pulmonary effects, but the mechanism was not clear enough. Metabolomics is a sensitive and high-throughput approach that could investigate the intrinsic causes of adverse health effects caused by SiNPs. The current investigation represented the first in vivo metabolomics study examining the chronic pulmonary toxicity of SiNPs at a low dosage, mimicking real human exposure situation. The recovery process after the cessation of exposure was also taken into consideration. Fisher 344 rats were treated with either saline or SiNPs for 6 months. Half of the animals in each group received an additional six-month period for recovery. The findings indicated that chronic low-level exposure to SiNPs resulted in notable alterations in pulmonary metabolism of amino acids, lipids, carbohydrates, and nucleotides. SiNPs exerted an impact on various metabolites and metabolic pathways which are linked to oxidative stress, inflammation and tumorigenesis. These included but were not limited to L-carnitine, spermidine, taurine, xanthine, and glutathione metabolism. The metabolic alterations caused by SiNPs exhibited a degree of reversibility. However, the interference of SiNPs on two metabolic pathways related to tumorigenesis was observed to persist after a recovery period. The two metabolic pathways are glycerophospholipid metabolism as well as phenylalanine, tyrosine and tryptophan biosynthesis. This study elucidated the metabolic alterations induced by chronic low-level exposure to SiNPs and presented novel evidence of the chronic pulmonary toxicity and carcinogenicity of SiNPs, from a metabolomic perspective. [Display omitted] • SiNPs affected amino acid, lipid, carbohydrate and purines & pyrimidines metabolism. • SiNPs-caused metabolic changes related to oxidative stress, inflammation and tumorigenesis. • The metabolome disturbance caused by SiNPs was reversible to some extent. • Tumorigenesis-related metabolic changes implied the potential of SiNPs-induced lung cancer. [ABSTRACT FROM AUTHOR]