Response to “letter concerning: Clewell (2019) incorporation of <i>in vitro</i> metabolism data and physiologically based pharmacokinetic modeling in a risk assessment for chloroprene.” (UIHT-2020-0053)

Clewell, Harvey J.; Campbell, Jerry L.; Landingham, Cynthia Van; Franzen, Allison; Yoon, Miyoung; Dodd, Darol E.; Andersen, Melvin E.; Gentry, P. Robinan

doi:10.1080/08958378.2020.1817199

Cited by 1 publication

(3 citation statements)

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“…A physiologically-based pharmacokinetic (PBPK) model was previously developed for chloroprene (CP; 2-chloro-1,3-butadiene) to estimate lung dose metrics and correlate these dose metrics with toxicity and carcinogenicity in the mouse (Clewell et al, 2019;2020). The dose metric calculated with this PBPK model was total amount of CP metabolized per gram of lung.…”

Section: Introductionmentioning

confidence: 99%

“…Extending the CP PBPK model (Clewell et al, 2019;Clewell et al, 2020) to include the production of various reactive intermediates requires detailed information on rates of in vitro metabolism and identification of various metabolites of CP formed by microsomal metabolism (Cottrell et al, 2001;Munter et al, 2003;Himmelstein et al, 2004;Munter et al, 2007). In a study to speciate metabolites (Munter et al, 2003), the main metabolites identified were the diol produced by epoxide hydrolase mediated hydration of 1-CEO and pathways to a variety of reactive aldehydes and ketones formed from 2-CEO were noted by identification of conjugates that were found both in the presence and absence of glutathione transferase.…”

Section: Introductionmentioning

confidence: 99%

“…Relying on the results from these two papers (Munter et al, 2003;Himmelstein et al, 2004) for describing metabolism and amounts of metabolites available for reaction with GSH, and merging the CP PBPK model from Clewell et al (2019) and PBPK models for glutathione production, turnover and reactivity with reactive products Clewell et al, 2001), allows refinement and extension of the earlier PBPK model for CP (Clewell et al, 2019;2020) to develop model descriptions of reactive metabolite production, reaction of these metabolites with glutathione and conditions under which GSH depletion is expected to lead to disproportionate increases in adduction of reactive metabolites with tissue nucleophiles other than GSH.…”

Section: Introductionmentioning

confidence: 99%

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Using available in vitro metabolite identification and time course kinetics for β-chloroprene and its metabolite, (1-chloroethenyl) oxirane, to include reactive oxidative metabolites and glutathione depletion in a PBPK model for β-chloroprene

Campbell,

Clewell,

Van Landingham

et al. 2023

Front. Pharmacol.

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Introduction: ß-chloroprene (2-chloro-1,3-butadiene; CP) causes lung tumors after inhalation exposures in rats and mice. Mice develop these tumors at lower exposures than rats. In rats CP exposures cause depletion of lung glutathione (GSH).Methods: PBPK models developed to relate the appearance of mouse lung tumors with rates of CP metabolism to reactive metabolites or total amounts metabolized during exposures have been expanded to include production of reactive metabolites from CP. The extended PBPK model describes both the unstable oxirane metabolite, 2-CEO, and metabolism of the more stable oxirane, 1-CEO, to reactive metabolites via microsomal oxidation to a diepoxide, and linked production of these metabolites to a PK model predicting GSH depletion with increasing CP exposure. Key information required to develop the model were available from literature studies identifying: 1) microsomal metabolites of CP, and 2) in vitro rates of clearance of CP and 1-CEO from active microsomal preparations from mice, rats, hamsters and humans.Results: Model simulation of concentration dependence of disproportionate increases in reactive metabolite concentrations as exposures increases and decreases in tissue GSH are consistent with the dose-dependence of tumor formation. At the middle bioassay concentrations with a lung tumor incidence, the predicted tissue GSH is less than 50% background. These simulations of reduction in GSH are also consistent with the gene expression results showing the most sensitive pathways are Nrf2-regulation of oxidative stress and GSH metabolism.Discussion: The PBPK model is used to correlate predicted tissue exposure to reactive metabolites with toxicity and carcinogenicity of CP.

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Section: Introductionmentioning

confidence: 99%