Toxicology component of fda s action plan for acrylamide
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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 Meeting December 4 and 5, 2002. Goal of the toxicity component of FDA’s action plan.

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Toxicology Component of FDA’s Action Plan for Acrylamide

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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 Meeting

December 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

  • Toxicokinetics

  • Animal carcinogen

  • Human neurotoxicant

  • Reproductive/developmental effects

  • 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


3. Plans for neurotoxicity study

  • FDA – plans are being developed for

    • Inclusion of neurotoxicity endpoints in NTP study

    • Study of neurodevelopment

  • Ongoing academic research into mechanism of neurotoxicity


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


4. Plans for Reproductive/ developmental effects study

  • 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)


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.


Safety/risk assessment - Effective dose, Exposure, ADI

  • Lowest neurotoxic dose in rats

    • 1000 mcg per kg body weight

    • No effect seen at200 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


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