Closing Remarks by z5tr6438

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




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


ILSI Risk Science Institute
                 Toxicity Focus Areas
 Kinetics and Metabolism
 Genetic Toxicity
 Reproductive and Developmental
  Toxicity
 Carcinogenicity
 Neurotoxicity
 Epidemiology
ILSI Risk Science Institute
                 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


ILSI Risk Science Institute
        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



ILSI Risk Science Institute
         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?

ILSI Risk Science Institute
                      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)
ILSI Risk Science Institute
                      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

ILSI Risk Science Institute
          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




ILSI Risk Science Institute
          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




ILSI Risk Science Institute
                      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

ILSI Risk Science Institute
                      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

ILSI Risk Science Institute
                        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

ILSI Risk Science Institute
                        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

ILSI Risk Science Institute
                        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

ILSI Risk Science Institute
                        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


ILSI Risk Science Institute
                          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.

ILSI Risk Science Institute

								
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