# Presentation: 406868

## 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 germ cell toxicity in rodents**
**Role of acrylamide *****vs.***** glycidamide**
**Further examination of potential for developmental neurotoxicity**

## 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**

## 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**

## 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**

## 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**

## 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**

## 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**

## 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**

## 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.**