Physiologically Based Toxicokinetic Modeling of 1,3-Butadiene Lung Metabolism in Mice Becomes More Important at Low Doses

Evelo, Chris T.; Oostendorp, Johanna G. M.; Berge, W.F. ten; Borm, Paul

doi:10.2307/3431586

Cited by 3 publications

(1 citation statement)

References 20 publications

(47 reference statements)

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“…Butadiene also induces cytochrome P450 metabolism in liver and lung microsomes of rats and mice (470,471). Various physiologically based pharmacokinetic (PBPK) models have been developed for butadiene (472)(473)(474)(475)(476)(477). Some models describe the disposition of butadiene as well as its epoxide metabolites.…”

Section: Pharmacokinetics Metabolismmentioning

confidence: 99%

Aliphatic Hydrocarbons

Carreón¹,

Herrick²

2012

Patty's Toxicology

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Aliphatic hydrocarbons are open‐chain compounds that may be saturated or unsaturated. The saturated compounds, known as paraffin hydrocarbons or alkanes , include methane and its homologs having the empirical formula C n H 2 n +2 . The unsaturated compounds fall into a number of homologous series: ( 1 ) those containing one double bond (ethylene and its homologs) and having the formula C n H 2 n are known as olefins or alkenes ; ( 2 ) those containing one triple bond (acetylene and its homologs) are called acetylenes or alkynes and have the formula C n H 2 n −2 ; ( 3 ) those having two double bonds (allene, 1,3‐butadiene and 1,4‐pentadiene represent three types) are diolefins or alkadienes and also have the formula C n H 2 n −2 ; ( 4 ) those having a large number of double or triple bonds or both double and triple bonds are named in analogous fashion as alkatrienes , alkatetraenes , alkadiynes , alkenynes , and alkadienynes . Aliphatic hydrocarbons are asphyxiants and central nervous system ( CNS ) depressants. Serious toxic effects of aliphatic hydrocarbons include asphyxia and chemical pneumonitis for many paraffins, axonal neuropathy for n ‐hexane, and cancer for 1,3‐butadiene.

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Section: Pharmacokinetics Metabolismmentioning

confidence: 99%

Aliphatic Hydrocarbons

Carreón¹,

Herrick²

2012

Patty's Toxicology

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Extrahepatic Metabolism by CYP2E1 in PBPK Modeling of Lipophilic Volatile Organic Chemicals: Impacts on Metabolic Parameter Estimation and Prediction of Dose Metrics

Yoon

Madden

Barton

2007

Journal of Toxicology and Environmental Health, Part A

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Physiologically based pharmacokinetic (PBPK) models are increasingly available for environmental chemicals and applied in risk assessments. Volatile organic compounds (VOCs) are important pollutants in air, soil, and water. CYP2E1 metabolically activates many VOCs in animals and humans. Despite its presence in extrahepatic tissues, the metabolism by CYP2E1 is often described as restricted to the liver in PBPK models, unless target tissue dose metrics in extrahepatic tissues are needed for the model application, including risk assessment. The impact of accounting for extrahepatic metabolism by CYP2E1 on the estimation of metabolic parameters and the prediction of dose metrics was evaluated for three lipophilic VOCs: vinyl chloride, trichloroethylene, and carbon tetrachloride. Metabolic parameters estimated from fitting gas uptake data with and without extrahepatic metabolism were similar. The impact of extrahepatic metabolism on PBPK predictions was evaluated using inhalation exposure scenarios relevant for animal toxicity studies and human risk assessment. Although small, the relative role of extrahepatic metabolism and the differences in the predicted dose metrics were greater at low exposure concentrations. The impact was species dependent and influenced by Km for CYP2E1. The current study indicates that inhalation modeling for several representative VOCs that are CYP2E1 substrates is not affected by the inclusion of extrahepatic metabolism, implying that liver-only metabolism may be a reasonable simplification for PBPK modeling of lipophilic VOCs. The PBPK predictions using this assumption can be applied confidently for risk assessment, but this conclusion should not necessarily be applied to VOCs that are metabolized by other enzymes.

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Potential New Approaches for Children's Inhalation Risk Assessment

Firestone

Sonawane

Barone

et al. 2007

Journal of Toxicology and Environmental Health, Part A

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The U.S. Environmental Protection Agency (EPA) practice of risk assessment is moving toward more thoroughly considering children's unique susceptibilities and exposure potential. Childhood is assessed as a sequence of life stages that reflects the fact that as humans develop, windows of susceptibility may appear that lead to enhanced sensitivity to exposure of environmental agents, while changes in behavior and physiology may increase exposure and dose. The U.S. EPA developed guidance in the past few years that addresses some aspects of increased susceptibility and exposure and dose. However, when it comes to considering inhalation exposure, dose, and risk, current U.S. EPA practice does not explicitly address children. The purpose here is to begin studying the adequacy of practice for children's health and to explore possible next steps in developing new methods to more accurately assess life-stage-specific differences. The existing guidelines and policies used to address potentially unique susceptibilities of children for inhaled environmental chemicals were considered, as well as what may be learned from examples of approaches that have been applied by state agencies (such as the California Environmental Protection Agency) or in the literature, to incorporate potentially unique susceptibilities and exposures to children. Finally, there is a discussion of possible approaches for considering inhalation exposure and susceptibility in U.S. EPA risk assessments.

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Physiologically Based Toxicokinetic Modeling of 1,3-Butadiene Lung Metabolism in Mice Becomes More Important at Low Doses

Cited by 3 publications

References 20 publications

Aliphatic Hydrocarbons

Aliphatic Hydrocarbons

Extrahepatic Metabolism by CYP2E1 in PBPK Modeling of Lipophilic Volatile Organic Chemicals: Impacts on Metabolic Parameter Estimation and Prediction of Dose Metrics

Potential New Approaches for Children's Inhalation Risk Assessment

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