This Project aims to compare in depth the mechanisms and dose-response characteristics for two plant-based blocking agents, native chlorophyll (Chla) and its derivative Cu-chlorophyllin (CHL). Our working hypothesis is that these agents act in vivo primarily via strong non-covalent complexation with carcinogens having complementary planar aromatic structure, thereby reducing carcinogen uptake and systemic bioavailability. Though CHL studies have progressed to an initial clinical intervention trial against aflatoxin B1 (AFB1), its mechanisms against this and other carcinogens are not fully defined. We recently showed native Chla to also strongly reduce dibenzo(alpha,1)pyrene (DBP)-DNA adduction in trout, but beyond this promising result, almost nothing is known of Chla chemoprevention in vivo. Finally, since few if any blocking agents are 100% effective, additional strategies are needed to fully abrogate the effects of genotoxins such as AFB1 and DBP. To address these issues we use 5 models: AFB1 hepatic tumors in rats; AFB1 hepatic tumors in trout; the trout multi-organ DBP model; DBP rat mammary tumors; and human 14C-AFB2 exposures. AIMS 1A-C compare CHL and Chla efficacy in four tumor models, including a 10,000 trout dose-dose matrix design to test the molecular dose hypothesis that Chla-mediated reduction in DNA adduct biomarkers quantitatively predicts tumor outcome over all DBP doses. AIM 1D investigates CHL and Chla effects on AFB2 uptake in humans. AIM 2 compares CHL and Chla protective mechanisms, both systemic (complex stoichiometry and stability; degree and specificity of effects on carcinogen pharmacokinetics; predictivity of complex Kd on CHL efficacy) and cellular (P450 inhibition; electrophile destabilization). AIM 3 investigates combined chemoprevention as a strategy to supplement the incomplete blocking effects of chlorophylls. It examines initiator-specificity and basic mechanisms of tumor suppression in trout, and establishes quantitative interactions between CHL as a blocking agent and ellagie acid (EA) or tea catechins as suppressing agents in the trout stomach tumor model. It provides the first dose-dose matrix quantification of tumor suppression ever conducted, and provides a model to establish rigorously if CHL blocking and EA/tea suppression are synergistic in combined chemoprevention.