QSAR Models for Human Carcinogenicity: An Assessment Based on Oral and Inhalation Slope Factors.

Carcinogenicity is a crucial endpoint for the safety assessment of chemicals and products. During the last few decades, the development of quantitative structure-activity relationship ((Q)SAR) models has gained importance for regulatory use, in combination with in vitro testing or expert-based reasoning. Several classification models can now predict both human and rat carcinogenicity, but there are few models to quantitatively assess carcinogenicity in humans. To our knowledge, slope factor (SF), a parameter describing carcinogenicity potential used especially for human risk assessment of contaminated sites, has never been modeled for both inhalation and oral exposures. In this study, we developed classification and regression models for inhalation and oral SFs using data from the Risk Assessment Information System (RAIS) and different machine learning approaches. The models performed well in classification, with accuracies for the external set of 0.76 and 0.74 for oral and inhalation exposure, respectively, and r2 values of 0.57 and 0.65 in the regression models for oral and inhalation SFs in external validation. These models might therefore support regulators in (de)prioritizing substances for regulatory action and in weighing evidence in the context of chemical safety assessments. Moreover, these models are implemented on the VEGA platform and are now freely downloadable online.

Air quality in the Olona Valley and in vitro human health effects.

Air quality is a major point in current health policies in force globally to protect human health and ecosystems. Cardiovascular and lung diseases are the pathologies most commonly associated with air pollution and it has been estimated that exposure to particulate matters and ground-level ozone and nitric oxides caused >500.000 premature deaths in Europe. Although air quality was generally improved in the recent years, further efforts are required to reduce the impact of air pollution on humans. The present study applied a multidisciplinary approach to estimate the adverse effects on the health of the inhabitants of the Olona Valley in the north of Italy. Chemical analyses quantified the air levels of metals, dioxins, PCBs, PAHs and some macropollutants, including total, fine and coarse airborne particles. These results were used as input for the health risk assessment and in vitro bioassays were used to evaluate possible adverse effects on the respiratory tract due to the organic pollutants adsorbed on the airborne particulate matter. Critical alerts were identified from the air characterization and from the chemical-based risk assessment in view of the levels of arsenic, nickel, benzene, fine and coarse particulate matters found in the investigated zone, which can induce severe adverse effects on human health. These findings were confirmed by bioassays with A549 and BEAS-2B cells. We also used the cell transformation assay with BALB/c 3T3 cells to assess the carcinogenicity of the organic extracts of collected particles as an innovative tool to establish the possible chronic effects of inhaled pollutants. No significant changes in morphological transformation were found suggesting that, although the extracts contain compounds with proven carcinogenic potential, in our experimental conditions the levels of these pollutants were too low to induce carcinogenesis as resulted also by the chemical-based risk assessment.

Soil quality in the Lomellina area using in vitro models and ecotoxicological assays.

Soil quality is traditionally evaluated by chemical characterization to determine levels of pollutants. Biological tools are now employed for soil monitoring since they can take account of the global biological effects induced by all xenobiotics. A combined monitoring of soils based on chemical analyses, human-related in vitro models and ecotoxicological assay was applied in the Lomellina, a semirural area of northern Italy. Chemical characterization indicated overall good quality of the soils, with low levels of toxic and carcinogenic pollutants such as heavy metals, PAHs, PCDD/Fs and PCBs. HepG2 cells were used as a model for the human liver and BALB/c 3T3 cells to evaluate carcinogenic potential. Cells were treated with soil extractable organic matter (EOM) and the MTS assay, DNA release and morphological transformation were selected as endpoints for toxicity and carcinogenicity. Soil EOMs induced dose-dependent inhibition of cell growth at low doses and cytotoxicity only at doses of 500 and 1000 mg soil equivalents/ml. Potential issues for human health can be hypothesized after ingestion of soil samples from some sites. No statistically significant inductions of foci were recorded after exposure to EOMs, indicating that the levels of the soil-extracted organic pollutants were too low to induce carcinogenesis in our experimental conditions. An acute phytotoxicity test and studies on Caenorhabditis elegans were used as ecotoxicological assays for plants and small invertebrates. No significant alerts for ecotoxicity were found. In this proposed case study, HepG2 cells detected differences in the toxicity of soil EOMs, indicating that this cell line could be appropriate to assess the potential harm caused by the ingestion of contaminated soil. Additional information on the carcinogenic potential of mixtures was provided by the cell transformation assay, strengthening the combined approach.

Chemical-based risk assessment and in vitro models of human health effects induced by organic pollutants in soils from the Olona Valley.

Risk assessment of soils is usually based on chemical measurements and assuming accidental soil ingestion and evaluating induced toxic and carcinogenic effects. Recently biological tools have been coupled to chemical-based risk assessment since they integrate the biological effects of all xenobiotics in soils. We employed integrated monitoring of soils based on chemical analyses, risk assessment and in vitro models in the highly urbanized semirural area of the Olona Valley in northern Italy. Chemical characterization of the soils indicated low levels of toxic and carcinogenic pollutants such as PAHs, PCDD/Fs, PCBs and HCB and human risk assessment did not give any significant alerts. HepG2 and BALB/c 3T3 cells were used as a model for the human liver and as a tool for the evaluation of carcinogenic potential. Cells were treated with soil extractable organic matters (EOMs) and the MTS assay, LDH release and morphological transformation were selected as endpoints for toxicity and carcinogenicity. Soil EOMs induced dose-dependent inhibition of cell growth at low doses and cytotoxicity after exposure to higher doses. This might be the result of block of cell cycle progression to repair DNA damage caused by oxidative stress; if this DNA damage cannot be repaired, cells die. No significant inductions of foci were recorded after exposure to EOMs. These results indicate that, although the extracts contain compounds with proven carcinogenic potential, the levels of these pollutants in the analyzed soils were too low to induce carcinogenesis in our experimental conditions. In this proposed case study, HepG2 cells were found an appropriate tool to assess the potential harm caused by the ingestion of contaminated soil as they were able to detect differences in the toxicity of soil EOMs. Moreover, the cell transformation assay strengthened the combined approach giving useful information on carcinogenic potential of mixtures.