Jump to main content
US EPA
United States Environmental Protection Agency
Search
Search
Main menu
Environmental Topics
Laws & Regulations
About EPA
Health & Environmental Research Online (HERO)
Contact Us
Print
Feedback
Export to File
Search:
This record has one attached file:
Add More Files
Attach File(s):
Display Name for File*:
Save
Citation
Tags
HERO ID
195866
Reference Type
Journal Article
Title
Population distribution of aldehyde dehydrogenase-2 genetic polymorphism: Implications for risk assessment
Author(s)
Ginsberg, G; Smolenski, S; Hattis, D; Sonawane, B
Year
2002
Is Peer Reviewed?
1
Journal
Regulatory Toxicology and Pharmacology
ISSN:
0273-2300
EISSN:
1096-0295
Volume
36
Issue
3
Page Numbers
297-309
Language
English
PMID
12473414
DOI
10.1006/rtph.2002.1591
Web of Science Id
WOS:000179627100008
URL
https://www.scopus.com/inward/record.uri?eid=2-s2.0-0036929328&doi=10.1006%2frtph.2002.1591&partnerID=40&md5=ea3b921159cbd748aacece5f3666e254
Exit
Abstract
The role of genetic polymorphisms in modulating xenobiotic metabolism and susceptibility to cancer and other health effects has been suggested in numerous studies. However, risk assessments have generally not used this information to characterize population variability or adjust risks for susceptible subgroups. This paper focuses upon the aldehyde dehydrogenase-2 (ALDH2) system because it exemplifies the pivotal role genetic polymorphisms can play in determining enzyme function and susceptibility. Allelic variants in ALDH2 cause decreased ability to clear acetaldehyde and other aldehyde substrates, with homozygous variants (ALDH2*2/2) having no activity and heterozygotes (ALDH2*1/2) having intermediate activity relative to the predominant wild type (ALDH2*1/1). These polymorphisms are associated with increased buildup of acetaldehyde following ethanol ingestion and increased immediate symptoms (flushing syndrome) and long-term cancer risks. We have used Monte Carlo simulation to characterize the population distribution of ALDH2 allelic variants and inter-individual variability in aldehyde internal dose. The nonfunctional allele is rare in most populations, but is common in Asians such that 40% are heterozygotes and 5% are homozygote variants. The ratio of the 95th or 99th percentiles of the Asian population compared to the median of the U.S. population is 14- to 26-fold, a variability factor that is larger than the default pharmacokinetic uncertainty factor (3.2-fold) commonly used in risk assessment. Approaches are described for using ALDH2 population distributions in physiologically based pharmacokinetic?Monte Carlo refinements of risk assessments for xenobiotics which are metabolized to aldehyde intermediates (e.g., ethanol, toluene, ethylene glycol monomethyl ether).
Keywords
Acetaldehyde; adverse effects; Aldehyde Dehydrogenase; Asia; Ethanol; genetics; Genetics,Population; Homozygote; Humans; metabolism; Models,Theoretical; Monte Carlo Method; pharmacology; Polymorphism,Genetic; Risk; Risk Assessment; Uncertainty; Xenobiotics; pdf; NRC 2006 document; obtained; Aldehyde Dehydrogenase/genetics/pharmacology; Genetics, Population; Models, Theoretical; Polymorphism, Genetic; Xenobiotics/adverse effects/pharmacology; 0 (Xenobiotics); EC 1.2.1.3 (ALDH2 protein, human); EC 1.2.1.3 (Aldehyde Dehydrogenase)
Tags
•
n-Butanol
Additional Strategies
Source – January 2013 (private)
Additional strategies - 1/2013
Merged reference set - 1/2013
Supporting Studies
Toxicokinetics
•
Formaldehyde
Retroactive RIS import
Pre2013
Formaldehyde IRIS 2011
Old references
•
Trichloroethylene (TCE) (Final, 2011)
•
Trimethylbenzenes (TMB)
Home
Learn about HERO
Using HERO
Search HERO
Projects in HERO
Risk Assessment
Transparency & Integrity