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Human plasma concentrations of herbicidal carbamate molinate extrapolated from the pharmacokinetics established in in vivo experiments with chimeric mice with humanized liver and physiologically based pharmacokinetic modeling.
MedLine Citation:
PMID:  25016177     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
To predict concentrations in humans of the herbicidal carbamate molinate, used exclusively in rice cultivation, a forward dosimetry approach was carried out using data from lowest-observed-adverse-effect-level doses orally administered to rats, wild type mice, and chimeric mice with humanized liver and from in vitro human and rodent experiments. Human liver microsomes preferentially mediated hydroxylation of molinate, but rat livers additionally produced molinate sulfoxide and an unidentified metabolite. Adjusted animal biomonitoring equivalents for molinate and its primary sulfoxide from animal studies were scaled to human biomonitoring equivalents using known species allometric scaling factors and human metabolic data with a simple physiologically based pharmacokinetic (PBPK) model. The slower disposition of molinate and accumulation of molinate sulfoxide in humans were estimated by modeling after single and multiple doses compared with elimination in rodents. The results from simplified PBPK modeling in combination with chimeric mice with humanized liver suggest that ratios of estimated parameters of molinate sulfoxide exposure in humans to those in rats were three times as many as general safety factor of 10 for species difference in toxicokinetics. Thus, careful regulatory decision is needed when evaluating the human risk resulting from exposure to low doses of molinate and related carbamates based on data obtained from rats.
Authors:
Masanao Yamashita; Hiroshi Suemizu; Norie Murayama; Sayako Nishiyama; Makiko Shimizu; Hiroshi Yamazaki
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-7-9
Journal Detail:
Title:  Regulatory toxicology and pharmacology : RTP     Volume:  -     ISSN:  1096-0295     ISO Abbreviation:  Regul. Toxicol. Pharmacol.     Publication Date:  2014 Jul 
Date Detail:
Created Date:  2014-7-12     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8214983     Medline TA:  Regul Toxicol Pharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2014 Elsevier Inc. All rights reserved.
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