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Citation
Tags
HERO ID
380808
Reference Type
Journal Article
Title
Evaluation of two different metabolic hypotheses for dichloromethane toxicity using physiologically based pharmacokinetic modeling for in vivo inhalation gas uptake data exposure in female B6C3F1 mice
Author(s)
Evans, MV; Caldwell, JC
Year
2010
Is Peer Reviewed?
1
Journal
Toxicology and Applied Pharmacology
ISSN:
0041-008X
EISSN:
1096-0333
Volume
244
Issue
3
Page Numbers
280-290
Language
English
PMID
20153349
DOI
10.1016/j.taap.2010.01.018
Abstract
Dichloromethane (DCM, methylene chloride) is a lipophilic volatile compound readily absorbed and then metabolized to several metabolites that may lead to chronic toxicity in different target organs. Physiologically based pharmacokinetic (PBPK) models are useful tools for calculation of internal and target organ doses of parent compound and metabolites. PBPK models, coupled with in vivo inhalation gas-uptake data, can be useful to estimate total metabolism. Previously, such an approach was used to make predictions regarding the metabolism and to make subsequent inferences of DCM's mode of action for toxicity. However, current evidence warrants re-examination of this approach. The goal of this work was to examine two different hypotheses for DCM metabolism in mice. One hypothesis describes two metabolic pathways: one involving cytochrome P450 2E1 (CYP2E1) and a second glutathione (GSH). The second metabolic hypothesis describes only one pathway mediated by CYP2E1 that includes multiple binding sites. The results of our analysis show that the in vivo gas-uptake data fit both hypotheses well and the traditional analysis of the chamber concentration data is not sufficient to distinguish between them. Gas-uptake data were re-analyzed by construction of a velocity plot as a function of increasing DCM initial concentration. The velocity (slope) analysis revealed that there are two substantially different phases in velocity, one rate for lower exposures and a different rate for higher exposures. The concept of a "metabolic switch," namely that due to conformational changes in the enzyme after one site is occupied - a different metabolic rate is seen - is also consistent with the experimental data. Our analyses raise questions concerning the importance of GSH metabolism for DCM. Recent research results also question the importance of this pathway in the toxicity of DCM. GSH-related DNA adducts were not formed after in vivo DCM exposure in mice and DCM-induced DNA damage has been detected in human lung cultures without GSH metabolism. In summary, a revised/updated metabolic hypothesis for DCM has been examined using in vivo inhalation data in mice combined with PBPK modeling that is consistent with up-to-date models of the active site for CYP2E1 and suggests that this pathway is the major metabolizing pathway for DCM metabolism.
Tags
IRIS
•
DCM (Dichloromethane) (Final, 2011)
OPPT REs
•
OPPT_Methylene Chloride_F. Human Health
Total – title/abstract screening
On topic
Peer review
Primary source
Cited in IRIS document or IRIS HERO page
On topic - additional tags for titles/abstracts
ADME
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