Toxicology Component of FDA’s Action Plan for Acrylamide

Richard Canady, PhD DABT

US Food and Drug Administration

Center for Food Safety and Applied Nutrition

www.cfsan.fda.gov

Food Advisory Sub-Committee MeetingDecember 4 and 5, 2002

Goal of the toxicity component of FDA’s action plan

Examine the likelihood that

adverse health effects are

caused by exposure to acrylamide-containing foods.

Context for toxicology research

Ongoing assessment of knowledge base for acrylamide Past assessments for

Food contact materials, cosmetics, water treatment, pesticide inert ingredient, specialized grout, monomer/polymer manufacture, coal mining, cigarette smoke

Knowledge has changed with regard to How we are exposed

Ingestion from food, not just water

The levels to which we are exposed

Data gap evaluations

World Health Organization/ Food and Agriculture Organization (WHO/FAO) consultation in June

Interagency meeting in September Joint Institute for Food Safety and Applied Nutrition

(JIFSAN) workshop in October Expert panel at Emerging Neurotoxicology

Conference in November Workshop for germ cell mutagen risk assessment

Spring 2003

Outline of presentation of what we know, need, and are planning

1. Toxicokinetics

2. Animal carcinogen

3. Human neurotoxicant

4. Reproductive/developmental effects

5. Safety/risk assessment

1. What we know for toxicokinetics

Absorbed orally Degree of absorption from food has not been studied Most toxicity information from drinking water or injections

Wide and uniform distribution (oral exposure, high dose) Metabolism understood for >1000 micrograms per

kilogram of body weight (mcg/kg) doses Saturable (CYP2E1) conversion to glycidamide Glutathione conjugation

Elimination occurs in hours to days But protein binding (-SH) and potential for cumulative damage

Exposure duration affects neurotoxic dose

1. Toxicokinetics data needs

Bioavailability of acrylamide from food Dose-response for toxicity, disposition, and binding

Dose metrics, critical events, mode of action DNA to hemoglobin adduct relationship DNA and protein binding as a marker of toxicity and

risk Significant nuclear protiens

Toxicokinetics of acrylamide in humans Risk factors for susceptibility

1. Plans for Toxicokinetics data development

FDA – National Center for Toxicological Research (NCTR) DNA/protein adduct characterization and their relationship to

effects and relevant external dose levels Bioavailability

CDC – National Center for Environmental Health (NCEH) Biomarker-intake relationship in studies prior to NHANES

Acrylamide monomer industry Human dosing study, PbPk model development

2. What we know for cancer

2-year rat studies show cancer Drinking water exposures, high doses

Epidemiology not sufficient to change conclusions or weight of evidence

2. Carcinogenicity data needs

Cancer epidemiology in populations of known high exposure

Chronic toxicity/carcinogenicity study Acrylamide and glycidamide in rat and mouse

Review histology slides from existing bioassays using updated diagnostic criteria

Investigate the mechanism of thyroid tumor induction as reported in existing bioassays

2. FDA carcinogenicity study plans:intermediate to long term

FDA nominated acrylamide and glycidamide to the National Toxicology Program as priority selections Chronic carcinogenicity and mechanism NCTR will conduct these studies FDA will participate in all experimental protocol designs

to assure regulatory needs are met

2 . FDA carcinogenicity study plansshorter term

Mechanistic studies, including bioavailability and markers of exposure and effect

DNA and protein adducts caused by acrylamide Adducts are reaction products between a chemical and either

DNA or proteins Adducts can tell us

How much exposure occurs and Help us understand the toxicology

Adducts may be particularly useful in relating animal toxicity studies to potential risks for humans from acrylamide

3. Neurotoxicity

High dose exposures in occupational settings causes neurotoxicity in humans

Effect widely studied, multiple species Cumulative dose important Age-related effects

One study showed more rapid onset of neurotoxicity in young vs old animals

Another showed greater response for neurotransmitter effects in younger animals

But very little data overall

3. Neurotoxicity data needs

Further evaluation of interaction between dose and duration

Improve weight-of-evidence for or against neurodevelopmental effects at food-acrylamide doses Establish a NOAEL for relevant endpoints

FDA – plans are being developed for Inclusion of neurotoxicity endpoints in NTP study Study of neurodevelopment

Ongoing academic research into mechanism of neurotoxicity

3. Plans for neurotoxicity study

4. Reproductive/ developmental effects (other than neurotoxicity)

Decreased body weight, but no structural malformations Reduced litter sizes (5000 mcg/kg treatment of males) Germ cell mutagen in animals at high, injected doses Genetic effects in mice (injection >40,000 mcg/kg)

Specific-locus mutations Heritable or reciprocal transformations Unscheduled DNA synthesis in spermatids,chromosomal

aberrations or micronuclei frequency in spermatogenic cells

4. Reproductive/ developmental effects data needs

Epidemiology for germ cell toxicity Expression profiling for genotoxic effects on

somatic and germ cells Define the germ cell mutations generated

Dose-response Low dose and multiple dose exposure effects Compare food and drinking water exposures

Mechanistic Adduct formation with DNA and significant nuclear proteins Dominant lethal study in CYP2E1 knockout mice

FDA Genotoxicity endpoints in NTP study, including initial

subchronic studies (under development) Workshop for germ cell mutagen risk assessment

NIOSH worker studies NIEHS collaboration for reproductive/genotox

NIEHS evaluation of CYP2E1 knockout mice for dominant lethal effect

Expert review panel by National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (CERHR)

4. Plans for Reproductive/ developmental effects study

5. Safety/risk assessmentUSEPA RfD and USFDA ADI

EPA Reference dose and FDA Acceptable Daily Intake based on Burek et al 1980 finding of sciatic nerve degeneration (electron microscopic) 90 day study in rats Lowest observed effect level 1000 mcg/kg No observed effect level 200 mcg/kg

Only 3 animals examined at EM level per dose group Recovery seen at 144 days for LOAEL dose

1000 fold uncertainty factor Routine EPA re-evaluation of RfD underway

5. WHO/FAO Safety/risk assessment

Noncancer effects judged unlikely at doses from food

Cancer No consensus on quantification of risk

Carcinogenic potency characterized as …similar to that of other carcinogens in food

(benzo[a]pyrene and heterocyclic aromatic amines) …”

However,

“… intake levels for acrylamide are likely to be higher.”

WHO/FAO conclusion

“major concern” for acrylamide based on relative cancer potency

and uncertainty regarding

germ cell mutagenicity findings.

5. Safety/risk assessment - Effective dose, Exposure, ADI

Lowest neurotoxic dose in rats 1000 mcg per kg body weight No effect seen at 200 mcg/kg

WHO/FAO – typical dietary intake 0.3-0.8 mcg/kg body weight

FDA Acceptable Daily Intake for food contact decisions 1000 fold uncertainty factor 0.2 mcg/kg body weight

Summary

Acrylamide causes effects in animals and in humans at doses much higher than those we get through food

However, safety/risk assessment indicates the need for further analysis of the risk

There are substantial gaps in our knowledge of whether the acrylamide levels in food are likely to cause health effects

Data gap analyses by leading experts in a variety of venues in the last 7 months indicate what kind of information is needed

We have initiated programs to carry out the needed information gathering and research, and are already seeing results