TOXIC INTERACTIONS OF POLYCYCLIC AND HALOGENATED AROMATIC HYDROCARBONS

点击翻译按钮获取中文摘要

The Massena Superfund Site is contaminated with both polycyclic aromatic hydrocarbons (PAHs) and halogenated aromatic hydrocarbons (HAHs), which include the polychlorinated biphenyls (PCBs) and the polychlorinated dibenzo-dioxins (PCDDs) and -furans (PCDFs). The long-term carcinogenic potential of the PAHs and the short-term microsomal enzyme inductive and immunosuppressive effects of the HAHs are well-documented. However, the health effects associated with simultaneous exposure to both classes of compounds have not been investigated. It is the objective of this project to determine the extent to which PAHs interact with the toxicity of HAHs, representative of this site, by using two well-established animal model toxic endpoints of each class, microsomal enzyme induction and immunosuppression, both of which are mediated by the cytosolic Ah receptor (AhR). The sensitivity of responsive C57BL/6 (Ahb/b) mice to PAH and HAH toxicity will be compared with that of non-responsive congenic C57BL/6 (Ahd/d) mice (alias B6.D2) to determine role of the AhR in the putative interactive toxicity of PAHs and HAHs. This approach will complement the other projects in this program which are primarily analytical or concentrate on health effects which are not AhR-mediated. This work will further our understanding of the toxicology of complex mixtures of xenobiotics and will substantially improve risk assessment technology at this site and similar sites contaminated by both PAHs and HAHs. Based on the known mechanisms of action of both the PAHs and the HAHs present at the site, we propose that: 1) there is interaction between the two classes of compounds present at this site, 2) the levels of interaction can be investigated using established animal models, 3) the putative interaction significantly alters the toxic equivalency factors for HAHs, which are used in risk assessment, and 4) the extent to which the interaction occurs is dependent on the developmental stage of exposure (prenatal, perinatal, young adult, late adult). Specific Aim 1: Investigate the potential for toxic interaction between representative PAHs and HAHs found at the Massena Superfund site and establish the levels at which PAHs interact with HAH toxicity. The kinetics of exposure will be investigated to determine the significance of the sequence of exposure to PAHs and HAHs to the toxic sequelae. Specific Aim 2: Establish that responsive and non-responsive strains of mice can be used as a model to investigate the interactions of PAHs and HAHs. Specific Aim 3: Determine the toxic equivalency factors (TEFs) of defined mixtures of HAH isomers and congeners, representative of this superfund site, with and without concomitant exposure to PAHs. Specific Aim 4: Establish at which developmental stage the animal is most sensitive to the interactive effects of PAHs and HAHs.