Many environmental pollutants have been associated with human diseases. Our current knowledge of chemical induced adverse health effects is mainly limited to the toxicity of the individual chemicals. For the majority of chemicals, its individual toxicity is well documented, examples arsenic and skin, lung and bladder cancers; dioxin and chloracne; lead and neurotoxicity; benzo[a]pyrene and lung cancer. The scientific community increasingly recognizes the adverse effects associated with chemical mixtures are a serious concern. The task of generating data for all the possible combinations of mixtures would be difficult due to various factors, including an infinite number of combinations, difficulty in the selection of the dose range, application
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A flow cytometry based micronucleus test and AhR activation assay were used to assess the effect of PAHs and metals mixtures on genotoxicity and metabolism, respectively. The mixture induced changes in the cell cycle parameters were also assessed. Binary to quaternary mixtures of B[a]P and metals increased the MN formation and AhR activation compared to B[a]P alone, but the mixtures of PAHs decreased the genotoxicity and AhR activation of B[a]P. There was no significant difference in genotoxicity of seven-chemical mixtures compared to either B[a]P or metals. The changes in the cell cycle parameters and AhR activation are correlated with genotoxicity of mixtures. The genotoxicity of PAHs and metal mixtures could be concentration and component dependent; when the concentration of metals decreased in the total mixtures, they did not result in a significant increase in the genotoxicity of B[a]P. So, the concentration of the individual chemicals plays a key role in the outcome of toxicity of mixtures. The possible reasons suggested for metals co-mutagenicity include oxidative stress and associated changes in AhR activity and inhibition of DNA repair mechanism. The competition for binding to metabolic enzymes is could be one of the reasons for the observed reduction of genotoxicity with B[a]P with PAHs …show more content…
The interaction between the mixtures become complex for higher order mixtures (ternary and higher orders) and it is difficult to explain the mixture toxicity based on the mechanism action of chemicals due to complexity of interaction.
7. High throughput in vitro assays are extremely useful to determine mixture effect on toxic pathway and associated outcome of toxicity.
In short, data from this current study suggest that the combined toxicity of PAHs and metals is dose, and mixture type, and biological endpoint dependent. The traditional addition of dose or effect may over- or under-estimate potential risks of these mixtures. A suite of bioaccessibility and toxicity evaluation protocols such as those utilised in this thesis for obtaining site specific data can afford a better informed risk assessment of site contamination of mixtures.
Future directions
1. In this study, the in vitro assays based on human cell lines were used to evaluate the toxicity of several common cellular responses and toxic effects. The toxicity evaluation of mixtures can be extended to other endpoints like apoptosis, p53 mediated DNA damage, metal stress response and other adaptive responses for a more comprehensive understanding of adverse
A flow cytometry based micronucleus test and AhR activation assay were used to assess the effect of PAHs and metals mixtures on genotoxicity and metabolism, respectively. The mixture induced changes in the cell cycle parameters were also assessed. Binary to quaternary mixtures of B[a]P and metals increased the MN formation and AhR activation compared to B[a]P alone, but the mixtures of PAHs decreased the genotoxicity and AhR activation of B[a]P. There was no significant difference in genotoxicity of seven-chemical mixtures compared to either B[a]P or metals. The changes in the cell cycle parameters and AhR activation are correlated with genotoxicity of mixtures. The genotoxicity of PAHs and metal mixtures could be concentration and component dependent; when the concentration of metals decreased in the total mixtures, they did not result in a significant increase in the genotoxicity of B[a]P. So, the concentration of the individual chemicals plays a key role in the outcome of toxicity of mixtures. The possible reasons suggested for metals co-mutagenicity include oxidative stress and associated changes in AhR activity and inhibition of DNA repair mechanism. The competition for binding to metabolic enzymes is could be one of the reasons for the observed reduction of genotoxicity with B[a]P with PAHs …show more content…
The interaction between the mixtures become complex for higher order mixtures (ternary and higher orders) and it is difficult to explain the mixture toxicity based on the mechanism action of chemicals due to complexity of interaction.
7. High throughput in vitro assays are extremely useful to determine mixture effect on toxic pathway and associated outcome of toxicity.
In short, data from this current study suggest that the combined toxicity of PAHs and metals is dose, and mixture type, and biological endpoint dependent. The traditional addition of dose or effect may over- or under-estimate potential risks of these mixtures. A suite of bioaccessibility and toxicity evaluation protocols such as those utilised in this thesis for obtaining site specific data can afford a better informed risk assessment of site contamination of mixtures.
Future directions
1. In this study, the in vitro assays based on human cell lines were used to evaluate the toxicity of several common cellular responses and toxic effects. The toxicity evaluation of mixtures can be extended to other endpoints like apoptosis, p53 mediated DNA damage, metal stress response and other adaptive responses for a more comprehensive understanding of adverse