Acrylamide Toxicity: Research to Address Key Data Gaps

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Acrylamide ToxicityResearch to Address Key Data
Gaps

• Presented by
• Dr. Stephen S. Olin
• ILSI Risk Science Institute

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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

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Toxicity Focus Areas

• Kinetics and Metabolism
• Genetic Toxicity
• Reproductive and Developmental Toxicity
• Carcinogenicity
• Neurotoxicity
• Epidemiology

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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

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Kinetics, Metabolism Modes of ActionResearch
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

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Kinetics, Metabolism Modes of
ActionOngoing/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?

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Genetic ToxicityResearch 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)

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Genetic ToxicityOngoing/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

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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

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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

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CarcinogenicityResearch 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

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CarcinogenicityOngoing/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

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NeurotoxicityResearch 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

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NeurotoxicityOngoing/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

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EpidemiologyResearch 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

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EpidemiologyOngoing/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

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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.