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

ILSI Risk Science Institute

Acrylamide Toxicity:Acrylamide Toxicity:Research to Address Key Research to Address Key

Data GapsData GapsPresented by Presented by

Dr. Stephen S. OlinDr. Stephen S. Olin

ILSI Risk Science InstituteILSI Risk Science Institute


JIFSAN/NCFST Workshop JIFSAN/NCFST Workshop on Acrylamide in Foodon Acrylamide in Food

October 28-30, 2002 – ChicagoOctober 28-30, 2002 – Chicago Mechanisms of Formation of Acrylamide Mechanisms of Formation of Acrylamide

in Foodin Food Analytical MethodsAnalytical Methods Exposure and BiomarkersExposure and Biomarkers Toxicology and Metabolic ConsequencesToxicology and Metabolic Consequences Risk CommunicationRisk Communication


Toxicity Focus AreasToxicity Focus Areas

Kinetics and MetabolismKinetics and Metabolism Genetic ToxicityGenetic Toxicity Reproductive and Developmental Reproductive and Developmental

ToxicityToxicity CarcinogenicityCarcinogenicity NeurotoxicityNeurotoxicity EpidemiologyEpidemiology


Acrylamide ToxicologyAcrylamide Toxicology Research Themes Research Themes

Assess the significance of adverse Assess the significance of adverse effects observed at high doses for effects observed at high doses for low-level human exposures in foodslow-level human exposures in foods

Assess the significance for humans Assess the significance for humans of effects observed of effects observed in vitro in vitro or or in vivoin vivo in rodentsin rodents


Kinetics, Metabolism & Modes of Kinetics, Metabolism & Modes of Action:Action:

Research NeedsResearch Needs Critical events and dose metrics related to Critical events and dose metrics related to

modes of action (MoA) for key acrylamide modes of action (MoA) for key acrylamide toxicitiestoxicities

Metabolic fate and kinetics in humansMetabolic fate and kinetics in humans Physiologically-based pharmacokinetic Physiologically-based pharmacokinetic

modelsmodels


Kinetics, Metabolism & Modes of Kinetics, Metabolism & Modes of Action:Action:

Ongoing/Planned ResearchOngoing/Planned Research Critical events/dose metrics/MoA – Critical events/dose metrics/MoA –

FDA/NCTR – Linked to NTP bioassayFDA/NCTR – Linked to NTP bioassay NIEHS – CYP 2E1 null mouse studiesNIEHS – CYP 2E1 null mouse studies

Metabolism/kinetics in humans – Metabolism/kinetics in humans – Several groups – RTI, CDC/NHANES, Several groups – RTI, CDC/NHANES,

Stockholm U., Kaiserslautern U., othersStockholm U., Kaiserslautern U., others

PBPK models – PBPK models – Kirman et al. (2003) – Rat model; others?Kirman et al. (2003) – Rat model; others?


Genetic Toxicity:Genetic Toxicity:Research NeedsResearch Needs

Identification and characterization of Identification and characterization of adducts of acrylamide and/or glycidamide adducts of acrylamide and/or glycidamide with DNA and significant nuclear proteinswith DNA and significant nuclear proteins Biological relevanceBiological relevance Species and dose dependence, Species and dose dependence, in vitro in vitro and and in in

vivovivo

Investigation of mechanisms of specific Investigation of mechanisms of specific effects (e.g., chromosomal effects, cell effects (e.g., chromosomal effects, cell transformation) transformation)


Genetic Toxicity:Genetic Toxicity:Ongoing/Planned ResearchOngoing/Planned Research

DNA and protein adducts – DNA and protein adducts – FDA/NCTR – DNA and protein adducts FDA/NCTR – DNA and protein adducts

(including dose response)(including dose response) Industry – DNA adducts Industry – DNA adducts in vitroin vitro and and in vivoin vivo

Genetic toxicity mechanisms – Genetic toxicity mechanisms – FDA/NCTR - FDA/NCTR - In vivoIn vivo mutagenicity in Big Blue mutagenicity in Big Blue

and and tk+/-tk+/- mice mice Industry - Interaction with kinesin-related Industry - Interaction with kinesin-related

proteinsproteins


Reproductive and Reproductive and Developmental Toxicity: Developmental Toxicity:

Research NeedsResearch Needs Dose-response data for germ cell toxicity Dose-response data for germ cell toxicity

in rodentsin rodents Role of acrylamide Role of acrylamide vs.vs. glycidamide glycidamide

Further examination of potential for Further examination of potential for developmental neurotoxicitydevelopmental neurotoxicity


Reproductive and Reproductive and Developmental Toxicity: Developmental Toxicity:

Ongoing/Planned ResearchOngoing/Planned Research Germ cell toxicity – Germ cell toxicity –

NIEHS – CYP 2E1 null mouse dominant lethal NIEHS – CYP 2E1 null mouse dominant lethal studystudy

Developmental neurotoxicity – Developmental neurotoxicity – FDA/NCTR – TBDFDA/NCTR – TBD Academic – Mechanistic studiesAcademic – Mechanistic studies


Carcinogenicity:Carcinogenicity:Research NeedsResearch Needs

Confirm and clarify carcinogenicity in Confirm and clarify carcinogenicity in standard rodent modelsstandard rodent models Pathology working group reviewPathology working group review Assess effects of perinatal exposureAssess effects of perinatal exposure Develop enhanced data for dose-response Develop enhanced data for dose-response

assessmentassessment

Determine mechanisms of induction of Determine mechanisms of induction of key tumorskey tumors


Carcinogenicity:Carcinogenicity:Ongoing/Planned ResearchOngoing/Planned Research

Clarify carcinogenicity – Clarify carcinogenicity – NTP/NCTR – Well-designed 2-year studies of NTP/NCTR – Well-designed 2-year studies of

acrylamide in rats and miceacrylamide in rats and mice NTP/NCTR – Neonatal mouse studies NTP/NCTR – Neonatal mouse studies

(acrylamide and glycidamide)(acrylamide and glycidamide) NIEHS – PWG review of previous studies?NIEHS – PWG review of previous studies?

Mechanisms – Mechanisms – NTP/NCTR – In conjunction w/2-year studies?NTP/NCTR – In conjunction w/2-year studies? Industry – Thyroid, brain, cell proliferationIndustry – Thyroid, brain, cell proliferation


Neurotoxicity:Neurotoxicity:Research NeedsResearch Needs

Relationships between dose, duration, and Relationships between dose, duration, and effect-levels and onset of neurotoxicityeffect-levels and onset of neurotoxicity Determine effects of low-level, long-term Determine effects of low-level, long-term

dietary exposuresdietary exposures Link damage at cellular/tissue level with Link damage at cellular/tissue level with

functional changesfunctional changes

Mechanisms of neurotoxicityMechanisms of neurotoxicity Role of acrylamide Role of acrylamide vs. vs. glycidamide glycidamide vs. vs. ?? Bridge effects in animals and humansBridge effects in animals and humans


Neurotoxicity:Neurotoxicity:Ongoing/Planned ResearchOngoing/Planned Research

Dose/duration/effect/onset – Dose/duration/effect/onset – FDA/NCTR – Ancillary studies with 2-year FDA/NCTR – Ancillary studies with 2-year

rodent bioassays to assess cumulative rodent bioassays to assess cumulative damage from low-level dietary exposures?damage from low-level dietary exposures?

Mechanisms - Mechanisms - Academic – Nerve terminal damage, axonal Academic – Nerve terminal damage, axonal

transport, key proteins, etc.transport, key proteins, etc. NIEHS – CYP 2E1 null mouse, antioxidant, NIEHS – CYP 2E1 null mouse, antioxidant,

Phase II enzyme inhibitorPhase II enzyme inhibitor NIOSH – Markers in exposed workersNIOSH – Markers in exposed workers


Epidemiology:Epidemiology:Research NeedsResearch Needs

Study new or previously evaluated Study new or previously evaluated exposed worker cohorts for specific exposed worker cohorts for specific effects effects

Link biomarkers of exposure with effects Link biomarkers of exposure with effects in workersin workers

Assess feasibility and design criteria for Assess feasibility and design criteria for study of acrylamide exposure/effects in study of acrylamide exposure/effects in non-occupationally exposed populationsnon-occupationally exposed populations


Epidemiology:Epidemiology:Ongoing/Planned ResearchOngoing/Planned Research

Specific effects in workers – Specific effects in workers – NIOSH – Reproductive and neurobehavioral NIOSH – Reproductive and neurobehavioral Industry – Reassessment of published studiesIndustry – Reassessment of published studies

Biomarkers – Biomarkers – NIOSH – Biomarkers includedNIOSH – Biomarkers included

Feasibility/design of study of non-Feasibility/design of study of non-occupationally exposed population –occupationally exposed population – CDC/NHANES, EPICCDC/NHANES, EPIC See, e.g., Mucci et al., 2003See, e.g., Mucci et al., 2003


ConclusionsConclusions

Ongoing/planned research (including Ongoing/planned research (including FDA/NCTR work) will address many of the FDA/NCTR work) will address many of the important toxicology research needs.important toxicology research needs.

Key objectives include developing PBPK Key objectives include developing PBPK model for humans and understanding the model for humans and understanding the significance of high-dose carcinogenic significance of high-dose carcinogenic and neurotoxic effects for low-level and neurotoxic effects for low-level exposures to acrylamide in foods.exposures to acrylamide in foods.

Documents

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