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1、Toxicology Component of FDAs 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 FDAs action plan,Examine the li
2、kelihood 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, mono
3、mer/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 Intera
4、gency 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,Tox
5、icokinetics 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
6、 (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 af
7、fects 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 nuc
8、lear 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 Bioavailabil
9、ity 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 suff
10、icient 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 crite
11、ria 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
12、conduct these studies FDA will participate in all experimental protocol designs to assure regulatory needs are met,2 . FDA carcinogenicity study plans shorter term,Mechanistic studies, including bioavailability and markers of exposure and effect DNA and protein adducts caused by acrylamide Adducts a
13、re 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 exposu
14、res 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
15、 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
16、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 transformat
