Review: Risk assessment implications of variation in susceptibility to perchloroethylene due to genetic diversity, ethnicity, age, gender, diet and pharmaceuticals

ABSTRACT

Current cancer risk assessments do not adequately consider impacts of human inter-individual variability on susceptibility to environmental pollutants like perchloroethylene (PCE). PCE is metabolized through both oxidative and glutathione (GSH) conjugation pathways. Toxicity criteria derived using both pathways are 23-fold more stringent than those calculated using only oxidative metabolism. While toxicokinetic modeling of PCE metabolism predicted very high variability through the GSH conjugation pathway, it is unclear if the range in estimates is due to human variability or uncertainty. Thus, the variation in the GSH conjugation pathway of PCE metabolism due to genetics, ethnicity, age, gender, diet, and pharmaceutical co-exposures is examined. Genetic polymorphisms were found at several loci including, GSTT1, GSTM1, CCBL1, AGXT2, NAT8, ACY3, MRP2, OAT1/3, FMO3, and CYP3A that code for enzymes/transporters in the GSH conjugation pathway. Genetic diversity in GSTT1, GSTM1, and CCBL1 between ethnic populations, as well as age, gender, diet, and pharmaceutical co-exposures influences toxic and mutagenic metabolites produced through this pathway. Given this diversity, large differences in PCE metabolism through the GSH conjugation pathway are expected. To be health protective for diverse ethnic populations and lifestyles, both the oxidative and GSH conjugation pathways need to be considered in developing PCE toxicity criteria.

KEYWORDS:

• perchloroethylene
• genetic variation
• susceptibility
• risk assessment
• glutathione