Low dose aflatoxin B1 toxicokinetics and intervention in human volunteers: a pilot study

1665 We have previously shown that chlorophyll (Chl) and its derivative chlorophyllin (CHL) reduce carcinogen bioavailability, biomarker damage, and tumorigenicity in trout and rats. These findings have been partially extended to humans, where CHL was found to reduce urinary excretion of aflatoxin B1 (AFB1)-DNA repair products in rural Chinese unavoidably exposed to dietary AFB1. However, no AFB1 pharmacokinetic data were gathered by that study, and Chl was not included. To address this a small un-blinded crossover study is under way to establish AFB1 toxicokinetic parameters in human volunteers, and the effects of CHL or Chl co-treatment on those parameters. For protocol 1, fasted subjects received an IRB-approved dose of 14C-AFB1 (31.2 ng, 5 nCi) by gelatin capsule with 100 ml water, followed by normal eating and drinking after hr 2. Blood and total urine samples were collected at specified intervals over 72 hr, and 14C-AFB1 equivalents were determined by accelerator mass spectrometry. The protocol was repeated 3 times for each volunteer. Plasma sample analysis revealed a rapid absorption phase, reaching a Cmax of 0.567 ± 0.095 fg/ml at 1 hr (Tmax) (volunteer 1) and 0.534 ± 0.083 fg/ml at 0.92 ± 0.52 hr (volunteer 2). A two compartment model with first-order input and elimination was fitted to each plasma data set, yielding absorption rate constants for volunteers 1 and 2 of 7.22 ± 4.34 hr-1 and 12.46 ± 7.92 hr-1, mean plasma distribution half-lifes (t1/2 α) of 2.02 ± 0.35 hrs and 4.41 ± 2.79 hrs, terminal half-lifes (t1/2 β) of 68.52 ± 49.27 and 92.04 ± 31.18, and AUC(0-24) of 7.26 ± 2.27 pg hr/L and 7.40 ± 0.46 pg hr/L, resp. Urine eliminated over 0-24 hr contained 28.0 ± 2.2% and 35.0 ± 7.9% of the administered dose for volunteers 1 and 2, resp. Protocols 2 and 3 were similar except capsules also contained 150 mg of Chl purified from spinach, or CHL, resp. Though still in progress, single-trial results suggest CHL delayed AFB1 absorption and reduced Cmax and AUC., whereas Chla reduced absorption, Cmax and AUC. These initial results are providing AFB1 toxicokinetic parameters previously unavailable for humans, and suggest that Chl and CHL may limit the bioavailability of aflatoxin in humans as in animals. (Partially supported by NIH grants ES00210, ES03850, CA90890. The AMS work was performed under the auspices of the U.S. D. O.E. by University of California, Lawrence Livermore National Laboratory under Contract No. W-7405-Eng-48.)