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Long-Term Goal 1-14: Research Description
Back to Long-Term Goal 1 (LTG 1):
Research Descriptions and Posters
Title: Constructing a Biologically-based Dose Response (BBDR) Model to Refine Risk Assessment Approaches to Respiratory Effects from Inhaled Reactive Gases: Chlorine
Presenter: Annie M. Jarabek (NHEERL/NCEA)
Contributors: Douglas Crawford-Brown (University of North Carolina); Christopher J. Portier (NIEHS); Douglas C. Wolf, Howard Kehrl, and Jane Ellen Simmons (NHEERL); Julia S. Kimbell, Melvin E. Andersen and Rusty S. Thomas (Hamner Institute for Health Sciences)
Science Questions:
Chlorine, an important commercial gas listed as a Hazardous Air Pollutant (HAP) on the Clean Air Act Amendments (CAAA), is used as an intermediate in many chemical syntheses and in water disinfection. Its ready availability has also increased its potential use in chemical terrorism. Characterization of its toxicity after inhalation exposures for different scenarios is of key interest to the National Homeland Security Research Center (NHSRC). Default regulatory risk assessment relies on a rudimentary description of internal dose and the single, most sensitive effect in the most sensitive test species (typically rodents) as the response measure. Statistical curve-fitting for this singular effect is used to describe the dose-response relationship and estimate the point of departure (POD) for risk assessment. Extrapolation to durations different than those of the study on which the POD is derived is based on application of "Haber's Rule". We will use chlorine as a prototypical irritant to understand the determinants of its dosimetry and characterize biological responses representing epithelial disruption due to oxidative stress as the mode of action (MOA). This information will be used to develop a mechanistic BBDR model intended to supplant reliance on the default extrapolation algorithms. The key science questions to be addressed are the following:
- What are the roles of concentration, duration, and dosimetry (e.g., airflow and airway anatomy) as key determinants of the MOA for chlorine?
- How will integration of diverse endpoints improve the description for the pathogenesis of chlorine?
- Can information from other irritant gases be used to refine the understanding of epithelial disruption due to chlorine?
- Do different biological responses require different duration adjustment to equivalence across exposure scenarios or for extrapolation across species?
The Research:
A relatively rich set of human and laboratory animal toxicological studies exists for chlorine that can be readily enhanced with new endpoints to facilitate integrated, mechanistically-motivated analyses across different studies and species. As with other inhaled reactive gases of interest to NHSRC (e.g., aldehydes or alkylating agents), the sentinel effect of inhaled chlorine in all species is irritant and corrosive damage in the respiratory tract. Due to the differences in airway architecture, ventilation rate, and breathing mode across species, characterization of gas uptake and epithelial responses using anatomically-accurate computational models is necessary for accurate dose, duration, and interspecies extrapolation. Dosimetry models such as hybrid computational fluid dynamics- physiologically-based pharmacokinetic (CFD-PBPK) models afford the flexibility to predict different dose metrics and have been instrumental in analysis for irritants such as ozone, formaldehyde, and hydrogen sulfide. Construction of a hybrid CFD-PBPK model is underway for chlorine (Jarabek et al., in preparation). The CFD structure is optimized against uptake data in the upper respiratory tract of F344 rats obtained at various concentrations and flow rate combinations to characterize extraction efficiency.
Recent studies have established that a key event in the MOA for the epithelial responses induced by inhaled chlorine is oxidative stress mediated by hypochlorous acid (HOCl) which forms in tissues by hydrolysis, with subsequent downstream biological responses. The PBPK portion of the CFD-PBPK model extends the dose description into the tissue phase. Chlorotyrosine in tissue has been used as a relevant biomarker for inflammation and as a dosimeter for chlorine exposures (Sochaski et al., 2008). The tissue reaction rates of hydrolysis and protein oxidation will be obtained from the literature and verified against oxidized amino acid measurements such as 3, and 3,5-dichlorotyrosine in various epithelial tissue samples (Jarabek et al., in preparation).
A set of "C x t" studies (i.e., the concentration times duration product is equivalent across different experimental regimens) is underway in rats to determine the dose-response and time course of various endpoints of oxidative stress, cytotoxicity, and tissue damage. They represent various levels of biological organization (e.g., gene alterations, biochemical changes, and tissue histopathology) and have been evaluated for other irritants. The experimental data will be used to develop a response model component that distinguishes four (4) different tissue states based on the degree of oxidative stress: normal, adaptive, inflammatory, and toxicity. The CFD-PBPK and response components will be coupled as a BBDR model. Similar endpoints are being assessed in a human clinical study. The human data will be used to describe the dose-response of endpoints in the target context and verify interspecies extrapolations based on the BBDR model.
Impact and Outcomes:
- Clarify the role of oxidative stress, cytotoxicity and inflammation in epithelial disruption and pathogenesis of respiratory irritation from inhaled chlorine
- CFD-PBPK model to describe dosimetry of inhaled chlorine across species
- Response model that will differentiate between tissue states based on degree of oxidative stress, and possibly support alternative dose response modeling of adaptation and homeostasis (Zhang et al., 2008)
- BBDR model to improve duration and interspecies adjustments for inhaled chlorine and advance refinements in assessment approaches for reactive gases
Key Products:
Jarabek, A.M. J.D. Schroeter, M. E. Andersen and J.S. Kimbell. (In preparation). A hybrid CFD-PBPK model of chorine gas uptake and tissue dosimetry in the upper respiratory tract (URT) of F344 rats. Presented at the 2007 Annual Meeting of the Society of Toxicology, March, Charlotte, NC. The Toxicologist, Abstract No. 398.
Jarabek, A.M., Roberts, K.C., Sochaski, House, D., M.A., Gross, E.A., James, R.A., Andersen, M.E. and Moss, O.R. (In preparation). Uptake and internal dosimetry of chlorine in the upper respiratory tract (URT) of F344 Rats. Presented at the 2007 Annual Meeting of the Society of Toxicology, March, Charlotte, NC. The Toxicologist, Abstract No. 805.
Sochaski, M.A., Jarabek, A.M., Murphy, J and Andersen, M.E. (2008). 3-chlorotyrosine and 3,5-dichlorotyrosine as biomarkers of respiratory tract exposure to chlorine gas. J. Anal. Toxicol. 32, 1 - 7.
Zhang, Q., Pi, J., Woods, C., Jarabek, A.M., Clewell, H.J., III, and Andersen, M.E. (2008). Hormetic dose response in adaptive cellular control systems. Dose Response 6, 196 - 208.