Phthalate metabolites: Characterization, toxicities, global distribution, and exposure assessment

Phthalates are plasticizers in various products and regarded as endocrine disruptors due to their anti-androgen effects. Environmental occurrence and toxicities of parent phthalates have been widely reported, while the current state of knowledge on their metabolites is rarely summarized. Based on the available literature, the present review mainly aims to 1) characterize the potential metabolites of phthalates (mPAEs) using the pharmacokinetics evidences acquired via animal or human models; 2) examine the molecular and cellular mechanism involved in toxicity for mPAEs; 3) investigate the exposure levels of mPAEs in different human specimens (e.g., urine, blood, seminal fluid, breast milk, amniotic fluid and others) across the globe; 4) discuss the models and related parameters for phthalate exposure assessment. We suggest there is subtle difference in toxic mechanisms for mPAEs compared to their parent phthalates due to their alternative chemical structures. Human monitoring studies performed in Asia, America and Europe have provided the population exposure baseline levels for typical phthalates in different regions. Urine is the preferred matrix than other specimens for phthalate exposure study. Among ten urinary mPAEs, the largest proportions of di-(2-ethylhexyl) phthalate (DEHP) metabolites (40%), monoethyl phthalate (mEP) (43%) and DEHP metabolites/mEP (both 29%) were observed in Asia, America and Europe respectively, and mono-5-carboxy-2-ethypentyl phthalate was the most abundant compounds among DEHP metabolites. Daily intakes of phthalates can be accurately calculated via urinary mPAEs if the proper exposure parameters were determined. Further work should focus on combining epidemiological and biological evidences to establish links between phthalates exposure and biological phenotypes. More accurate molar fractions (F_UE) of the urinary excreted monoester related to the ingested diesters should be collected in epidemiological or pharmacokinetic studies for different population.