Using Information on Exposure to Characterizing Risks to Human Health from Concurrent Exposures to Multiple Chemicals

This thesis explores the concept of using exposure information to understand, organize, and manage the risks associated with cumulative exposures to chemicals (exposures to multiple chemicals from multiple sources). The issue of cumulative exposures was identified in more than 30 years ago, but in 2012 only a small portion of cumulative exposures from a limited number of sources are evaluated on a systematic basis. One of the reasons for this lack of progress is the sheer size of the number of mixtures that could occur that precludes an evaluation of every mixture. Clearly society requires tools for identifying when and where cumulative risks will pose unacceptable risks. The concepts and approaches outlined in this thesis are an attempt to move the issue of assessing cumulative effects of chemical exposures forward. Chapters 2 and 3 of the thesis present a modelling framework for addressing interindividual variation in cumulative exposures. Chapter 4 investigates the issue of synergy and presents arguments that support the current use of additive models as conservative screens for assessing the risk of effects from cumulative exposures. Chapters 5 and 6 demonstrate how the Cramer class portion of the Threshold for Toxicological Concern can be used to fill data gaps in mixture risk assessment by providing conservative estimates of compounds with missing toxicity data. Chapter 7 presents the concept of the Maximum Cumulative Ratio (MCR). This tool has been shown to be a simple but powerful tool in demonstrating the importance of performing a cumulative exposure. Two ideas have emerged from the body of work. First, it is critical to determine if the thresholds of interaction for chemicals in a cumulative assessment are always higher than the lowest threshold for an individual component of a mixture. If this is true then the current approach of using additive models as a screen will be protective because additive models will keep all doses below the threshold of interaction. Future work is needed to assess if this is always the case. Second, it is critical to determine if the preliminary findings that MCR values in individuals’ cumulative exposures decrease as the cumulative toxicity increases consistently occurs for all cumulative exposures. If the pattern does hold then chemical by chemical approaches will be an efficient means of managing risks. Future work will need to determine if cumulative exposures to other sources of exposure (e.g., dietary, indoor air, or dermal contact to consumer products) confirm if the pattern is a universal phenomenon and when or if there are exceptions. It is hope of the author that the tools and approaches proposed in this thesis will be used by researchers in the future. Too often in the past, chemical regulations have tended to shoot first and aim second. Using the MCR and the other approaches, researchers can identify those sources and chemicals that drive cumulative risks and those individuals most in need of protection. Such information can help guide both industry’s and government’s management of risks from cumulative exposures