Superfund Research Program
PAHs in Humans at Environmental Levels: Pharmacokinetics, Metabolism and Susceptible Individuals
Project Leader: David E. Williams
Grant Number: P42ES016465
Funding Period: 2013-2020
Benzo[a]pyrene (BaP), an International Agency for Research on Cancer class one known human carcinogen, also exhibits cardiovascular, developmental, behavioral, neurocognitive, immunological, and reproductive toxicity. Polycyclic Aromatic Hydrocarbons (PAHs), from combustion of carbon (coal, diesel, tobacco, etc.), comprise three of the top ten chemicals of concern (Agency for Toxic Substances and Disease Registry) at priority pollutant sites and are main drivers of remediation. The EPA cancer risk slope factor is one (mg/kg-day). BaP is the EPA reference compound for cancer risk assessment with PAH mixtures (Relative Potency Factor, BaP=1) and drives remediation goals. Risk estimates are from predominantly mouse models. The remarkable sensitivity (zepto-attomole 14C in biological samples) of accelerator mass spectrometry (AMS) makes possible, with de minimus risk, pharmacokinetic (PK) analysis following [14C]-BaP micro-dosing of humans. A 46 ng (5 nCi) dose was given three to five volunteers with minimum two weeks between dosing and plasma collected over 72 hours. [14C]-BaPeq PK analysis gave plasma T-max and C-max values of 1.25 h and 29-82 fg/mL, respectively. PK parameters were assessed by non- compartment and compartment models. The RPF approach was tested by co-administration of a complex PAH mixture from smoked salmon and the impact of genotype on metabolic profile (Hummel et al., 2018). Major findings were that there is little intra-individual variation, and rapid absorption with extensive metabolism with distinct individual metabolite profiles (Madeen et al., 2019). Finally, there were no detectable BaP-DNA adducts in PBMCs (LOD 0.5 x 10^11 adducts/nucleotide) after 48-72 hours. These results can be incorporated into risk assessment models to set remediation targets driven by human data.