BIOLOGY-BASED DOSE-RESPONSE MODELS FOR HEALTH RISK ASSESSMENT OF CHEMICAL MIXTURES

摘要

Currently risk assessment tackles chemicals as single substances affecting individual health endpoints while, in reality, man is exposed to mixtures of chemicals present in the environment and consumer products. This may result in lower or greater toxicity of mixtures than what would be expected by summing the toxicity of individual chemicals. The extent of the change in tissue dose depends on the concentrations of all components and the mechanism(s) of biochemical interaction among them. Physiologically based pharmacokinetic models (PBPK) are mathematical descriptions of absorption, distribution, metabolism and elimination of chemicals in the body, which can be particularly useful in addressing environmental mixture toxicity. In this work we present a pharmacokinetic/pharmacodynamic (PBPK/PD) model for benzene, toluene, ethylbenzene and all xylenes that accounts for the interactions among these chemicals at the sites of metabolism. The PBPK/PD model was coupled to a model of the metabolic chain of benzene to estimate the biologically effective dose of benzene metabolites, the main culprits for benzene toxicity. This was linked to a pathology model to associate the probability of leukemia risk to the total concentration of benzene metabolites in urine. This model was applied to exposure scenarios based on environmental concentrations of the four VOCs measured in Thessaloniki, Greece. Our results show that combined exposure modifies health risk estimates even at low doses, after lifelong exposure to VOCs. The current WHO methodology for ambient air guidelines, based primarily on epidemiological evidence, should be enriched to take into account the toxicity pathways and mechanisms of environmental mixtures.