The purpose of these studies is to evaluate the mechanisms of immunosuppression in mice and humans associated with combined exposures to polycyclic aromatic hydrocarbons (PAHs) and sodium arsenite (As+3). Suppression of the immune system is known to be associated with a decreased ability to fight infections and cancer. Preliminary data is presented that mice demonstrate synergistic immunosuppression when exposed to As+3 and PAHs in vivo through their food and drinking water. We also present preliminary data demonstrating that human peripheral blood mononuclear cells (HPBMC) are immunosuppressed at environmentally relevant levels of sodium As+3 found in drinking water. PAHs were found to increase the amount of As+3 induced immune suppression as well. Therefore, it is important to understand the mechanism(s) of immunosuppression produced by these agents when exposures occur alone or in combination. The central hypothesis to be tested in this application is that PAHs and As+3 produce synergistic immunosuppression through DNA- damaging and repair pathways. It is important to develop animal models to study synergistic immunosuppression and to pursue mechanistic studies of relevance to human exposures. These studies will determine whether co-exposures from As+3 in drinking water and PAHs in the diet (which are present in the air we breathe and the food we eat) in mouse models result in greater suppression than has previously been found for either class of agents on their own. We will determine the biochemical mechanisms potentially responsible for these interactions, and we will determine whether Zn+2 present in drinking water can protect mice from As+3 exposures. Finally, because we found that human blood T lymphocytes are extremely sensitive to low concentrations of As+3 that are present in drinking water in many populations in the U.S. and elsewhere in the world, we will determine the sensitivities of various humans (males and females of different ages and ethnicities) to these exposures. We will obtain peripheral blood cells from these individuals to determine whether their immune response are suppressed by As+3 and PAH given in vitro alone or in combination. The results of these studies will make an important contribution to understanding environmental agents that modulate the human immune system and perhaps provide an approach to intervention for As+3 drinking water exposures.