Impact/Purpose:

This project is consistent with the Air Toxics Strategic Principles in that it focuses on a prototypic chemical (chlorine) from the high priority hazardous air pollutant (HAP) class of halides that can be studied directly in human exposures, as well as in experimental animals and in modeling paradigms. Chlorine is highly relevant because it is prototypic for other HAPs that are chemically reactive, including aldehydes (e.g. acrolein), and acids (e.g. hydrogen chloride). Thus, understanding determinants of dosimetry and tissue interactions for chlorine is relevant to these and other respiratory irritant HAPs which cannot be directly studied in humans.

The data to be generated by the NHEERL team members and the CIIT Centers for Health Research will be used by our NCEA collaborator to make a novel application of the value of information (VOI) approach to reduce uncertainties in risk assessment. VOI will be used to determine the magnitude of factors to be applied to interspecies and intrahuman extrapolations. Analysis of the newly generated acute exposure-response data will also provide insights to further improve Acute Reference Exposure methodology. The goal of this project will be to develop linkages between measurements of chemical reactivity of respiratory irritants, and species differences in dosimetry and sensitivity, thereby reducing uncertainties in the risk assessment process. The RfC for chlorine will also be refined in this process.

Description:

This project represents a multidisciplinary collaboration to develop and test methods for more precisely predicting human exposure-dose-response relationships of respiratory tract irritants. These irritants have the unique property of reacting chemically with proteins and lipids at the air-liquid interface of the respiratory tract. In vitro and in vivo laboratory animal and human toxicological studies will be gathered and analyzed using computational biological models to establish linkages that can be used for improving extrapolations and risk assessments. The basic scientific question being addressed in this project is whether toxicology models based on chemistry of the toxicants can be predictive of in vivo effects. If models can be developed and validated, an important scientific goal would be achieved. The EPA goal of simplifying the daunting list of HAP chemicals and mixtures could also be realized. In vitro models might also be developed which are predictive for effects of unknown mixtures, and which do not require the use of laboratory animals. There is a paucity of data available for risk assessments of important HAP's. The goal of this project is to develop such data for chlorine and to develop methods applicable to a broader range of HAP's for reducing the uncertainty in risk assessments. The significance of this project lies in methodologic advances in three distinct areas which when used together result in more scientifically defensible risk assessments. 1) Advances in quantifying delivered dose of respiratory irritant HAP's, including chlorine, and understanding the most important determinants of inter- and intra-species differences in dose. 2) The improved use of indicators of oxidative stress as markers for assessing intra- and inter-species differences in toxicity using both in vitro and in vivo techniques. 3) Development of a VOI approach to decision making that can be applied to extrapolation of animal results to humans. Such an approach makes optimal use of delivered dose and toxicity information to inform risk assessments. These methods are likely to have broad applicability to a variety of reactive HAP's which cause respiratory toxicity.

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