1. Overview of Food Toxicology 유해물질관리단 위해관리팀 김 광 진

2. Toxicology  Study of Adverse effects of compounds on living organisms.  Key concepts Dose makes the poison Dose-response curves dose-response frequency-response plots cumulative response curves

3. Classification of Toxicology  Descriptive Toxicology - What?  Mechanistic Toxicology - Why?  Analytical Toxicology - How much?

4. Classification of Toxicants  Physical State - Gas, solid  Toxicity - Extremely, slightly  Chemical Composition - Heavy metal, organophosphous pesticides  Mechanism of action - Anticholinergic, inhibitor, carcinogen

5. Toxic responses  Immediate vs. Delay  Local vs. Systemic  Reversible vs. irreversible Reversible-rapidly regenerating tissue ex: liver 와 CNS

6. Phases  Exposure phase  Toxicokinetic phase : the toxicity of a compound depends on the amount of the compound at the site of action - Absorption - Distribution - Metabolism - Excretion  Toxicodynamic phase

7. Exposure  Time and frequency of exposure (Acute/subchronic/chronic….)  Route of administration oral, lung, skin, injection…  Dose  Physical and chemical form of the toxicant  Particle size, solubilization  Host related factors age, health, pre-absorption metabolism

8. Methods in Toxicology

9. Toxicity Testing  Acute  Sub-acute  Chronic  Genotoxicity-mutagenecity  Carcinogenic, reproductive, teratogenic Sensitivity & specificity

10. Tests  LD50-Acute lethality - 24hour test, survivors observed for 7 days - Objectives: * give measure of acute toxicity for comparison with other compounds * identify clinical manifestations of acute toxicity * give dose-ranging guide for future studies AgentLD50, mg/kg Ethyl alcohol10,000 Sodium chloride4,000 Ferrous sulfate1,500 Morphine sulfate900 Phenobarbital sodium 150 nicotine1 Tubocurarine0.5 Hemicholinium-30.2 Tetrodotoxin0.1 Dioxin0.001 Botulinum toxin0.00001 Approximate acute LD50 of some representative chemical agents

11. Tests  Sub-chronic Toxicity Study - 3 months - 2 or more species (20 rats/6 dogs) - 3 doses: * high dose that produces toxicity but not death in >10% * low dose with no observed effect (NOEL or NOAEL) * mid-range dose

12. Tests  Genetic Toxicity Study - 세균을 이용한 복귀돌연변이시험 : TA98, TA100, TA1535, TA1537 또는 TA97 TA102 또는 WP2uvrA : 최소 1 개 균주에서 플레이트 당 1 개 이상 농도 - 포유류 배양세포를 이용한 염색체이상시험 : Chinese hamster(CHL, CHO, V79 등 ) : 사람임파구 - 설치류를 이용하는 소핵시험 : 일반적으로 마우스를 이용

13. Tests  Reproductive and Developmental - 수태능 및 초기배 발생시험 : 생식발생과정 중 착상까지 투여 - 출생전후 발생 및 모체기능시험 : 착상부터 이유기까지 투여 - 배태자발생시험 : 착상부터 경구개가 폐쇄되는 시기까지 투여  Endpoint - 생식세포 형성장애, 수태저해, 임신유지, 분만, 보육등에 대한 영향, 유산, 발육지연, 기형발생

14. Tests  Immunotoxicity Study - 아나필락시스 쇼크 반응시험 : 감작 (induction), 야기 (challenge) - 수동 피부 아나필락시스 반응시험 : 동종 ( 기니픽 - 기니픽 ) 피부 아나필락시스 반응시험 : 이종 ( 마우스 - 랫드 ) 수동 피부 아나필락시스 반응시험 - 피부감작성시험 : Adjuvant and Patch test, Draize Test Maximization Test 등

15. Tests  Chronic - time period depends on expected time of exposure, for food use lifespan - assess cumulative effect - use maximum tolerated dose (MTD) - one or more species, both sexes, 3 dose - assess dose response for: * incidence of tumors vs. controls * time of tumor development * tumors/animal * benign vs. malignant * site of tumor development - monitor wt, food consumption, overall health

16. Carcinogen classification Group 1The agent(mixture) is carcinogenic to human Group 2AThe agent(mixture) is probably carcinogenic to human Group 2BThe agent(mixture) is possibly carcinogenic to human Group 3The agent(mixture or exposure circumstance) is not classifiable as to its carcinogenicity to human Group 4The agent(mixture) is probably not carcinogenic to human International Agency for research on cancer

17. Group AKnown human carcinogenHuman carcinogen Group B1Limited evidence from human Probable human Group B2Sufficient evidence from animals Probable human Group CPossible; limited evidence from animals, and none from human Possible human carcinogen Group Dunknown, no dataNot classifiable as to human carcinogenicity Group ENot carcinogenic; human or animal No evidence of carcinogenicity in human Carcinogen classification Environmental Protection Agency

18. Hazard characterization  국제 공인 독성시험법에 근거한 독성시험자료  국제적으로 공인된 만성독성시험자료 - Rat : 24 개월, Mouse : 18-24 개월  해당물질의 노출경로와 일치하는 자료  해당물질에 대한 독성이 가장 민감한 동물 종의 자료  Female, Male 자료를 개별 고려 - 민감하고 분명한 자료  용량 - 반응이 유의하게 증가하는 자료  상대적으로 저용량에서 실험된 Adverse effect

19. FDA List of Dietary Supplements Associated with Health Problems  Herbals Chaparral comfrey Yohimbe Lobelia Germander Willow bark Wormwood Jin Bu Huan Ephedra Weight-loss products  Amino Acids L-tryptophan Phenylalanine  Vitamins and Minerals Vitamin A Vitamin B6 Niacin Selenium  Germanium

20. Soy Products/Food  Whole grain cereals  Seeds  Nuts  Herbs  Willows  Dates  tea  Clover  Rice  Beans  Carrots  Potatoes  Cherries  Apples  pomegranates In 2000, 27% of US consumers used soy

21. Seafood Toxicities  Scromboid or histamine fish poisoning  Paralytic shellfish poisoning (PSP)  Domoic acid; neurotoxic  Ciguatera poisoning by dinoflagellate algae - ciguatoxin, scaritoxin, maitotoxin, ciguaterin  Puffer fish poisoning : tetrodotoxin

22. Factors affecting formation  Type of food  Cooking method  Temperature  time

23. Toxicants Formed During Processing  Acrylamide  Polycyclic aromatic hydrocarbons  Heterocyclic amines

24. Food Additive

25. Types  Direct Food Additives - Sweeteners - Coloring agents - Preservatives - Flavor enhancers  Indirect Food Additives - those that become part of the food in trace amounts due to its packaging, storage or other handling

26. Pesticides and Food  Intentionally added to food supply  Must establish safety of residues expected at levels of use required for efficacy

27. Food Contaminents Lead Mercury PCBs Mycotoxins

28. Lead Contamination of Food  일반국민에게서 식품을 통한 납의 주요 노출원은 과일 (fruits) 과 곡류 (grains)  식품중에는 다음과 같은 경로를 통해 노출됨 - 공기중 식물의 직접적인 노출 (direct deposit from the air to plants) - 납이 함유된 토양을 먹은 livestock 으로 부터 - 오염된 패류 (contaminated shellfish) - 납 - 함유 glaze 를 가진 식기를 통해 (potentially for dishes with lead-containing glaze)