toxicology component of fda’s action plan for acrylamide richard canady, phd dabt us food and drug...
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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 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