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Acrylamide Toxicity: Research to Address Key Data Gaps

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

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Acrylamide Toxicity: Research to Address Key Data Gaps

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  1. Acrylamide Toxicity:Research to Address Key Data Gaps Presented by Dr. Stephen S. Olin ILSI Risk Science Institute

  2. 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

  3. Toxicity Focus Areas • Kinetics and Metabolism • Genetic Toxicity • Reproductive and Developmental Toxicity • Carcinogenicity • Neurotoxicity • Epidemiology

  4. 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

  5. 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

  6. 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?

  7. 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)

  8. 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

  9. Reproductive and Developmental Toxicity: Research Needs • Dose-response data for germ cell toxicity in rodents • Role of acrylamide vs. glycidamide • Further examination of potential for developmental neurotoxicity

  10. Reproductive and Developmental Toxicity: Ongoing/Planned Research • Germ cell toxicity – • NIEHS – CYP 2E1 null mouse dominant lethal study • Developmental neurotoxicity – • FDA/NCTR – TBD • Academic – Mechanistic studies

  11. Carcinogenicity:Research Needs • Confirm and clarify carcinogenicity in standard rodent models • Pathology working group review • Assess effects of perinatal exposure • Develop enhanced data for dose-response assessment • Determine mechanisms of induction of key tumors

  12. Carcinogenicity:Ongoing/Planned Research • Clarify carcinogenicity – • NTP/NCTR – Well-designed 2-year studies of acrylamide in rats and mice • NTP/NCTR – Neonatal mouse studies (acrylamide and glycidamide) • NIEHS – PWG review of previous studies? • Mechanisms – • NTP/NCTR – In conjunction w/2-year studies? • Industry – Thyroid, brain, cell proliferation

  13. Neurotoxicity:Research Needs • Relationships between dose, duration, and effect-levels and onset of neurotoxicity • Determine effects of low-level, long-term dietary exposures • Link damage at cellular/tissue level with functional changes • Mechanisms of neurotoxicity • Role of acrylamide vs. glycidamide vs. ? • Bridge effects in animals and humans

  14. Neurotoxicity:Ongoing/Planned Research • Dose/duration/effect/onset – • FDA/NCTR – Ancillary studies with 2-year rodent bioassays to assess cumulative damage from low-level dietary exposures? • Mechanisms - • Academic – Nerve terminal damage, axonal transport, key proteins, etc. • NIEHS – CYP 2E1 null mouse, antioxidant, Phase II enzyme inhibitor • NIOSH – Markers in exposed workers

  15. Epidemiology:Research Needs • Study new or previously evaluated exposed worker cohorts for specific effects • Link biomarkers of exposure with effects in workers • Assess feasibility and design criteria for study of acrylamide exposure/effects in non-occupationally exposed populations

  16. Epidemiology:Ongoing/Planned Research • Specific effects in workers – • NIOSH – Reproductive and neurobehavioral • Industry – Reassessment of published studies • Biomarkers – • NIOSH – Biomarkers included • Feasibility/design of study of non-occupationally exposed population – • CDC/NHANES, EPIC • See, e.g., Mucci et al., 2003

  17. Conclusions • Ongoing/planned research (including FDA/NCTR work) will address many of the important toxicology research needs. • Key objectives include developing PBPK model for humans and understanding the significance of high-dose carcinogenic and neurotoxic effects for low-level exposures to acrylamide in foods.

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