Kinetics of di(2-ethylhexyl) phthalate (DEHP) and mono(2-ethylhexyl) phthalate in blood and of DEHP metabolites in urine of male volunteers after single ingestion of ring-deuterated DEHP.
Level 4 - case-series / case-control
Small single-arm human pharmacokinetic study without a control group
PubMed 22963843 · doi:10.1016/j.taap.2012.08.009
What was done
Four male volunteers aged 28 to 61 years ingested a single oral dose of ring-deuterated di(2-ethylhexyl) phthalate (DEHP-D4; 645 ± 20 µg/kg body weight). Concentrations of DEHP-D4, free ring-deuterated mono(2-ethylhexyl) phthalate (MEHP-D4), and total MEHP-D4 (free plus glucuronidated) were measured in blood for up to 24 hours. Urinary excretion of MEHP-D4, ring-deuterated mono(2-ethyl-5-hydroxyhexyl) phthalate, and ring-deuterated mono(2-ethyl-5-oxohexyl) phthalate was quantified for up to 46 hours post-ingestion.
What was found
The 24-hour blood area under the concentration-time curve (AUC) of DEHP-D4 reached 50% of the AUC of free MEHP-D4. Dose- and body-weight-normalized AUC (AUC/D) for free MEHP-D4 in humans was 2.1-fold and 8.1-fold higher than historical values reported in rats and marmosets, respectively; human DEHP-D4 AUC/D was 50-fold and 100-fold higher than in rats and marmosets. Blood and urine concentration time courses exhibited wide oscillations. Terminal elimination half-lives were short, between 4.3 and 6.6 hours. Total DEHP metabolites excreted in 22-hour urine correlated linearly with the blood AUC of free MEHP-D4.
Why it matters
Human internal exposure to unmetabolized DEHP and its biologically active metabolite MEHP after ingestion is considerably higher than predicted by rodent or non-human primate models. The linear correlation between 22-hour urinary metabolite excretion and blood MEHP exposure provides an empirical basis for biomonitoring-based risk assessment.
Limits
The study was restricted to a sample of four adult men receiving a single dose, precluding assessment of inter-individual variability, female-specific kinetics, or chronic exposure effects. Clinical or toxicological endpoints were not evaluated.
Cited by
- supports Phthalates are cleared by the human body within 12 to 24 hours depending on the compound.