Empirical analysis of lead neurotoxicity mode of action and its application in health risk assessment.

The mode of action (MOA) framework is proposed to inform a biological link between chemical exposures and adverse health effects. Despite a significant increase in knowledge and awareness, the application of MOA in human health risk assessment (RA) remains limited. This study aims to discuss the adoption of MOA for health RA within a regulatory context, taking our previously proposed but not yet validated MOA for lead neurotoxicity as an example. We first conducted a quantitative weight of evidence (qWOE) assessment, which revealed that the MOA has a moderate confidence. Then, targeted bioassays were performed within an in vitro blood-brain barrier (BBB) model to quantitatively validate the scientific validity of key events (KEs) in terms of essentiality and concordance of empirical support (dose/temporal concordance), which increases confidence in utilizing the MOA for RA. Building upon the quantitative validation data, we further conducted benchmark dose (BMD) analysis to map dose-response relationships for the critical toxicity pathways, and the lower limit of BMD at a 5% response (BMDL5) was identified as the point of departure (POD) value for adverse health effects. Notably, perturbation of the Aryl Hydrocarbon Receptor (AHR) signaling pathway exhibited the lowest POD value, measured at 0.0062 µM. Considering bioavailability, we further calculated a provisional health-based guidance value (HBGV) for children's lead intake, determining it to be 2.56 µg/day. Finally, the health risk associated with the HBGV was assessed using the hazard quotient (HQ) approach, which indicated that the HBGV established in this study is a relative safe reference value for lead intake. In summary, our study described the procedure for utilizing MOA in health RA and set an example for MOA-based human health risk regulation.

Health risk assessment of cadmium exposure by integration of an in silico physiologically based toxicokinetic model and in vitro tests.

Cadmium (Cd) is a common environmental pollutant that can damage multiple organs, including the kidney. To prevent renal effects, international authorities have set health-based guidance values of Cd from epidemiological studies. To explore the health risk of Cd exposure and whether human equivalent doses (HEDs) derived from in vitro tests match the current guidance values, we integrated renal tubular epithelial cell-based assays with a physiologically based toxicokinetic model combined with the Monte Carlo method. For females, the HEDs (µg/kg/week) derived from KE2 (DNA damage), KE3 (cell cycle arrest), and KE4 (apoptosis) were 0.20 (2.5th-97.5th percentiles: 0.09-0.48), 0.52 (0.24-1.26), and 2.73 (1.27-6.57), respectively; for males the respective HEDs were 0.23 (0.10-0.49), 0.60 (0.27-1.30), and 3.11 (1.39-6.78). Among them, HEDKE4 (female) was close to the tolerable weekly intake (2.5 µg/kg/week) set by the European Food Safety Authority. The margin of exposure (MOE) derived from HEDKE4 (female) indicated that risks of renal toxicity for populations living in cadmium-contaminated regions should be of concern. This study provided a new approach methodology (NAM) for environmental chemical risk assessment using in silico and in vitro methods.

Assessment of health risk and dose-effect of DNA oxidative damage for the thirty chemicals mixture of parabens, triclosan, benzophenones, and phthalate esters.

Humans are constantly exposed to parabens (PBs), triclosan (TCS), benzophenones (BPs), and phthalate esters (PAEs) due to the widespread existence of these chemicals in personal care products (PCPs), and the high frequency of usage for humans. Previous studies indicated each class of the above-mentioned chemicals can exhibit potential adverse effects on humans, in particular DNA oxidative damage. However, the health risk assessment of combined exposures to multiple PCPs is limited, especially the overall dose-effect of mixtures of these chemicals on DNA oxidative damage. In this study, we measured the urinary levels of 6 PBs, TCS, 8 BPs, 15 metabolites of PAEs (mono-PAEs), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) from 299 adults simultaneously. PBs, TCS, BPs, and mono-PAEs were frequently detected in urinary samples with median concentrations of 52.888, 0.737, 1.305, and 141.381 ng/ml, suggesting a broad, low-level exposure among participants. Risk assessments indicated approximately 22% and 15% of participants suffered health risks (Hazard index >1) from exposure to TCS and PAEs. The relationship between 8-OHdG levels and chemical exposure was estimated by Bayesian kernel machine regression (BKMR) models. It indicated an overall positive correlation between the mixture of these chemicals and 8-OHdG, with methylparaben and mono-benzyl phthalate contributing the most to this association. Of note, sex-related differences were observed, in which exposure to PCPs led to higher health risks and more pronounced dose-effect on DNA damage in the female population. Our novel findings reveal the health risks of exposure to low-level PCPs mixtures and further point out the overall dose-response relationship between DNA oxidative damage and PCP mixtures.

Risk assessment and dose-effect of co-exposure to benzene, toluene, ethylbenzene, xylene, and styrene (BTEXS) on pulmonary function: A cross-sectional study.

Inhalation is the most frequent route and the lung is the primary damaged organ for human exposure to benzene, toluene, ethylbenzene, xylene, and styrene (BTEXS). However, there is limited information on the risk and dose-effect of the BTEXS mixture on pulmonary function, particularly the overall effect. We conducted a cross-sectional study in a petrochemical plant in southern China. Spirometry and cumulative exposure dose (CED) of BTEXS were used to measure lung function and exposure levels for 635 workers in 2020, respectively. Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were tested and interpreted as percentages to predicted values [FVC or FEV1% predicted], and FEV1 to FVC ratio [FEV1/FVC (%)]. We found the reduction in FVC% predicted and the risk of lung ventilation dysfunction (LVD) and its two subtypes (mixed and restrictive ventilation dysfunction, MVD, and MVD) were significantly associated with BTEXS individuals. In addition, pulmonary function damage associated with BTEXS was modified by the smoking status and age. Generalized weighted quantile sum (gWQS) regressions were used to estimate the overall dose-effect on lung function damage induced by the BTEXS mixture. Our results show wqs, an index of weighted quartiles for BTEXS, was potentially associated with the reduction in FVC and FEV1% predicted with the coefficients [95% confidence intervals (CI)] between -1.136 (-2.202, -0.070) and -1.230 (-2.265, -0.195). Odds ratios (ORs) and 95% CIs for the wqs index of LVD, MVD, and RVD were 1.362 (1.129, 1.594), 1.323 (1.084, 1.562), and 1.394 (1.096, 1.692), respectively. Furthermore, xylene, benzene, and toluene in the BTEXS mixture potentially contribute to the development of lung function impairment. Our novel findings demonstrated the dose-response relationships between pulmonary function impairment and the BTEXS mixture and disclosed the potential key pollutants in the BTEXS mixture.

Assessment of intestinal injury of hexavalent chromium using a modified in vitro gastrointestinal digestion model.

Intestinal injury assessment of hexavalent chromium (Cr-VI) in humans is crucial for quantifying assessment of adverse health risk posed by the intake of Cr (VI)-contaminated water. To overcome the deficiency in simulating human gastric reduction and intestinal absorption, we modified the constituents of simulated gastric fluid in in vitro digestion method by adding reductants glutathione (18 µM) and ascorbic acid (180 µM), which incorporated with human intestinal epithelial model to construct an in vitro gastrointestinal digestion (IVGD) model for intestinal injury assessment. Cr-VI bioaccessibility results from IVGD model showed that weak gastric acidity significantly increased the intestinal accessible Cr-VI dose by 22.41-38.43 folds. The time-course intestinal absorption indicated prolongation of intestinal exposure destroyed the intestinal epithelium, and 24 h after Cr-VI treatment was a good time point to perform intestinal absorption and toxicity assessment. A series of cell-based bioassays provided initial warning of adverse effect, suggesting that epithelial integrity exhibited greatest sensitivity to Cr-VI exposure and might be used as a sensitive marker for the toxicity assessment of oral exposure to Cr-VI. Notably, this study provides a feasible strategy for delineation of Cr-VI biotransformation and intestinal injury following ingestion exposure, which contributes to address the toxicity data gap of low-dose exposure in humans and puts forward a reference for intestinal toxicity assessment of other chemicals.

The development of a cell-based model for the assessment of carcinogenic potential upon long-term PM2.5 exposure.

To assess the carcinogenic potential of PM2.5 exposure, we developed a cell-based experimental protocol to examine the cell transformation activity of PM2.5 samples from different regions in China. The seasonal ambient PM2.5 samples were collected from three megacities, Beijing (BJ), Wuhan (WH), and Guangzhou (GZ), from November 2016 to October 2017. The mean concentrations of PM2.5 were much higher in the winter season (BJ: 109.64 µg/m3, WH: 79.99 µg/m3, GZ: 49.99 µg/m3) than that in summer season (BJ: 42.40 µg/m3, WH: 25.82 µg/m3, GZ: 19.82 µg/m3). The organic extracts (OE) of PM2.5 samples from combined summer (S) (June, July, August) or winter (W) (November, December, January) seasons were subjected to characterization of chemical components. We treated human bronchial epithelial (HBE) cells expressing CYP1A1 (HBE-1A1) with PM2.5 samples at doses ranging from 0 to 100 µg/mL (0, 1.563, 3.125, 6.25, 12.5, 25, 50, 100 µg/mL) and determined the phenotype of malignant cell transformation. A dose-response relationship was analyzed by benchmark dose (BMD) modeling, and the potential were indicated by BMDL10. The order of the carcinogenic risk of seasonal PM2.5 samples from high to low was BJ-W, WH-W, GZ-W, WH-S, BJ-S, and GZ-S. Notably, we found that the alteration in the lung cancer-related biomarkers, KRAS, PTEN, p53, c-Myc, PCNA, pAKT/AKT, and pERK/ERK was congruent with the activity of cell transformation and the content of specific components of polycyclic aromatic hydrocarbon (PAHs) bound to PM2.5. Taken together, we have successfully developed a cell-based alternative model for the evaluation of potent carcinogenicity upon long-term PM2.5 exposure.