AcrylamideToxicityResearchtoAddressKeyDataGaps.pptVIP

Acrylamide Toxicity:Research to Address Key Data Gaps Presented by Dr. Stephen S. Olin ILSI Risk Science Institute JIFSAN/NCFST Workshop on Acrylamide in Food October 28-30, 2002 – Chicago Mechanisms of Formation of Acrylamide in Food Analytical Methods Exposure and Biomarkers Toxicology and Metabolic Consequences Risk Communication Toxicity Focus Areas Kinetics and Metabolism Genetic Toxicity Reproductive and Developmental Toxicity Carcinogenicity Neurotoxicity Epidemiology Acrylamide Toxicology Research Themes Assess the significance of adverse effects observed at high doses for low-level human exposures in foods Assess the significance for humans of effects observed in vitro or in vivo in rodents Kinetics, Metabolism Modes of Action:Research Needs Critical events and dose metrics related to modes of action (MoA) for key acrylamide toxicities Metabolic fate and kinetics in humans Physiologically-based pharmacokinetic models Kinetics, Metabolism Modes of Action:Ongoing/Planned Research Critical events/dose metrics/MoA – FDA/NCTR – Linked to NTP bioassay NIEHS – CYP 2E1 null mouse studies Metabolism/kinetics in humans – Several groups – RTI, CDC/NHANES, Stockholm U., Kaiserslautern U., others PBPK models – Kirman et al. (2003) – Rat model; others? Genetic Toxicity:Research Needs Identification and characterization of adducts of acrylamide and/or glycidamide with DNA and significant nuclear proteins Biological relevance Species and dose dependence, in vitro and in vivo Investigation of mechanisms of specific effects (e.g., chromosomal effects, cell transformation) Genetic Toxicity:Ongoing/Planned Research DNA and protein adducts – FDA/NCTR – DNA and protein adducts (including dose response) Industry – DNA adducts in vitro and in vivo Genetic toxicity mechanisms – FDA/NCTR - In vivo mutagenicity in Big Blue and tk+/- mice Industry - Interaction with kinesin-related proteins Reproductive and Developmental Toxicity: Research Needs Dose-response data for g