Toxicokinetic analyses of naphthalene, fluorene, phenanthrene, and pyrene in humans after single oral administration

Abstract

Polycyclic aromatic hydrocarbons (PAHs) are generated by incomplete combustion of organic matter. They have health effects in multiple organs and can cause lung, skin, and bladder cancers in humans. Although data regarding their toxicity is available, information on the absorption, distribution, metabolism, and excretion of PAHs in humans is very limited. In the present study, deuterium-labeled naphthalene (Nap), fluorene (Flu), phenanthrene (Phe), and pyrene (Pyr) were orally administered as a single dose (0.02-0.04 mg/kg) to eight healthy adults. Both serum and urine samples were monitored for 72 h after the exposure. Parent compounds and PAH metabolites (monohydroxy-PAHs; OH-PAHs) were measured by headspace-solid phase microextraction coupled with gas chromatography-mass spectrometry and high-performance liquid chromatography-tandem mass spectrometry, respectively. Based on the time-concentration profiles in serum and urine, non-compartmental analysis was performed, and two-compartment models were constructed and validated for each PAH. Subsequently, all of the parent compounds were rapidly absorbed (T_max: 0.25 to 1.50 h) after oral administration and excreted in urine with a biological half-life (T_1/2) of 1.01 to 2.99 h. The fractional urinary excretion (F_ue) of OH-PAHs ranged from 0.07 % to 11.3 %; their T_1/2 values ranged from 3.4 to 11.0 h. The two-compartment models successfully described the toxicokinetic characteristics of each PAH and its metabolites. F_ue and the two-compartment models could be useful tools for exposure simulation or dose-reconstruction of PAHs. The results of this study will provide useful information for interpreting biomonitoring data of PAHs.

Keywords: Absorption-distribution-metabolism-excretion (ADME); Fractional urinary excretion (F(ue)); Oral administration; Polycyclic aromatic hydrocarbons (PAHs); Toxicokinetic model.