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Process-induced Toxicants in Food June 3, 2014 Chi-Tang Ho.

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Presentation on theme: "Process-induced Toxicants in Food June 3, 2014 Chi-Tang Ho."— Presentation transcript:

1 Process-induced Toxicants in Food June 3, 2014 Chi-Tang Ho

2 From Diet to Disease High-fat foods are rich in the lipid phosphatidylcholine (PC) and its metabolite choline (C). Intestinal bacteria convert C to TMA. In the liver, the enzyme FMO3 processes TMA to TMAO — a metabolite that makes its way into the blood. Wang et al.1 show that circulating TMAO may contribute to greater plaque development in the arteries, and so to heart disease.

3 Structure of PC (Phosphatidylcholine) Active Methyl Donor

4 Definition of a Process Toxicant Processing toxicants are defined as those substances present in food as a result of food processing/preparation that are considered to exert adverse physiological (toxicological) effects in humans, i.e., substances that create a potential of real risk to human health.

5 Trans Fatty Acids

6 Trans fats, unsaturated fatty acids with at least one double bond in the trans configuration Formed during the partial hydrogenation of vegetable oils The average consumption of industrially produced trans fatty acids in the US is 2-3% of total calories consumed

7 Trans Fat regulation In April 2004, the FDA Food Advisory Committee voted in favor of recommending that trans fatty acid intake level be reduced to "less than 1% of energy (2g per day of a 2000 kcal diet)“ The FDA ruled that, effective January 1, 2006, the nutrition labels for all conventional foods and supplements must indicate the content of trans fatty acids The New York City has asked 20,000 restaurants and 14,000 food suppliers to eliminate partially hydrogenated oils from kitchens

8 Typical trans fatty acid contents of foods produced by partially hydrogenated vegetable oils Foodg/serving% of daily energy intake for 2000-kcal diet French fries: 4.7-6.12.1-2.7 Fish burger5.62.5 Chicken nuggets5.02.3 Pizza1.10.5 Popcorn1.20.5 Doughnuts2.71.2

9 Intake of trans fat and diseases Cardiovascular disease: 2% increase in energy intake from trans fatty acids was associated with a 23% increase in the incidence of coronary heart disease  Raise levels of low-density lipoprotein cholesterol  Reduce levels of high-density lipoprotein cholesterol  Increase the ratio of total cholesterol to HDL cholesterol

10 Intake of trans fat and diseases Increase the risk of sudden death from cardiac causes. May increase the risk of diabetes Trans fats promote inflammation Trans fats may cause endothelial dysfunction

11 Produced during oxidation of poly-unsaturated fatty acids Acrolein, malonaldehyde, and 4-hydroxy-2- nonenal React with protein and DNA and as a result are toxic and mutagenic. AcroleinMalonaldehyde4-hydroxy2-nonenal (HNE) Lipid-derived Bioactive Carbonyls Species

12 Formation Pathway of Malonaldehyde Pryor et al, 1976 Linolenic acid ← How is its formation mechanism ?

13 Acrolein Strongest electrophile among α,β-unsaturated aldehydes  react with thiol and amino groups of protein causing alteration of the structure and function of matrix protein  React with DNA at guanine residues to form 8-hydroxy- propanodeoxyguanosine (OHPdG) Generated in biological systems under oxidative stress Environmental and industrial pollutant, automobile exhaust, wood smoke, cigarette smoke

14 Reaction of acrolein with proteins

15 Acrolein Acrelein will produce abundantly through autoxidation of ω-3 polyunsaturated fatty acids, such as fish oil ω-3 eicosapentaenoic acid (EPA) (20:5 ) ω-3 docosahexaenoic acid (DHA) (22:6)

16 Proposed formation pathway for undesirable acrolein

17 Reactive Carbonyl Species (RCS) from Maillard Reaction Deoxyosone, methylglyoxal (MGO) and glyoxal (GO) Produce through Maillard reaction Strong electrophiles, react with proteins and DNA

18 RCS Generation in Vitro Maillard Reaction

19 Methylglyoxal Generation in Vivo Fatty acid Acetone Acetyl-CoA Fats Glycerol Dihydroxyacetone phosphateGlyceraldehyde-3-phosphate Methylglyoxal Glycerol-3-phosphate Fructose-1,6-bisphosphate Fructose-6-phosphate Glucose-6-phosphate GlucoseProtein Gly, Thr Aminoacetone Aldose reductase NADPH D-Lactate Advanced glycation end products 1,2-propanediol Glyoxalase I Glyoxalase II GSH

20  MG Protein Glycation DNA Glycation  AGEs Inflammation Thrombosis Angiogenesis Tissue Injury Protein Cross Linking Cellular Apoptosis Gene Transcription Ramasamy, R., Yan, S. F., and Schmidt, A. M., 2006, Cell 124, 258-260 Glycation of Transcription Modulators Changes Caused by Methylglyoxal (MG)

21 Diabetes  retinopathy  neuropathy and nephropathy Non-diabetic nephropathy Macrovascular disease (atherosclerosis) Alzheimer's disease Cataracts Aging Health Concerns with MG

22 Human plasma MG level in different studies MG ( μg/dL) Quantifying method † Source PatientsControl 15.8  4.6 (n=20)4.7  1.2 (n=15) 2,3-diaminonaphthalene; 3,4- hexanedione; ESI/LC/MS Odani, Hinzato, and Matsumoto, 1999 20.6  3.8 (n*=15)4.9  1.2 (n=15) Methanol; Meso-stilbenediamine; HPLC (358nm) Khuhawar and Kandhro, 2006 † Quantifying method is listed with the sequence of deproteinization agents, derivatization agents, internal standard, and equipment. * This study included both diabetes and ketosis patients. MG in Human Plasma

23 MG in Beverages

24 One can of soda: 300 ml Blood volume in kid: 2.5 L Avg. MG in Soda: 196 μg/dL MG in one can: 196*3 = 588μg MG Con. in kid: 588/25 =23.5 μg/dL MG Con. in diabetes: 20.6 μg/dL Consuming soda may increase MG level in Blood

25 Carbonated Soft Drinks and Carbonyl Stress Burden Thirty minutes after consuming 300 mL of carbonated cola (11.3 g carbohydrate/100 mL; 7.2 μM MG), the blood MG levels of subjects were raised from 113±22 to 136±34 nM, and the blood glucose levels were raised from 94±8 to 113±18 mg/dL. Glucose and MG containing carbonated soft drinks appear to lead to transient increase in plasma MG levels. It is of great interest whether habitual intake of carbonated drinks enhances human carbonyl stress. Nakayama et al., J. Toxicol. Sci. 34(6): 699-702, 2009

26 MG in Commercial Cookies MG levels in commercial cookies range from 3.7 to 81.4 mg/Kg Commercial cookies made from ammonium bicarbonate and fructose showed the highest levels of MG MG was rapidly formed on the upper site of the cookies regardless of shape or thickness of the samples Dietary exposure of Spanish population to MG from cookies was estimated to be 216 μg/person/day Arribas-Lorenzo and Morales, 2010

27 MG: Polyphenolic compound mixed with molar ratio 3:1 Incubation of 1 hour R1R1 R2R2 ECHH ECGGallateH EGCHOH EGCGGallateOH Green Tea Catechins R 1 = R 2 = H ; Theaflavin(TF1) R 1 = G, R 2 = H or R 1 = H, R 2 = G ; Theaflavin monogallate esters(TF2) R 1 = R 2 = G ; Theaflavin digallate ester(TF3) G = Galloyl Black Tea Theaflavins Inhibition by Tea Polyphenols

28 Formation of EGCG-MG Adduct

29 Another Maillard Reaction-derived Toxicants: Heterocyclic Amines (HAs) Heterocyclic amines occur at the ppb range in foods Most of them demonstrated potent mutagenicity and as probably human carcinogens IQ has even demonstrated carcinogenic activity in monkeys Their capability of formation even during ordinary cooking practices implies frequent exposure by the general public

30 AbbreviationZR1R1 R2R2 R3R3 IQCHHH MeIQCMeHH MeIQxNHHMe 4,8-DiMeIQxNMeH Commonly occurred Heterocyclic amines

31 Mechanism for the formation of heterocyclic amines

32 Mechanism for the formation of 4,8-DiMeIQx

33 Formation of PhIP: A Powerful Carcinogen in Processed Foods

34 Postulated Pathways for EGCG’s Inhibitory Activity in PhIP Formation

35 Factors affect formation of HAs Temperature Time Precursors: creatinine, phenylalanine, (reducing sugars, amino acids) Involvement of Lipids Direct involvement of Strecker aldehydes Water content Concentration of polyunsaturated fats Metal ions Antioxidants

36 Acrylamide

37 Acrylamide - toxicology Proven neurotoxic compound in animals and in humans Effects range from drowsiness to incoordination, hallucinations, confusion, abnormal sensation, muscle weakness, incoordination Genotoxic compound with the potential to affect the germinal cells thus leading to hereditary changes Causing cancer in laboratory animals (rats) Studies in humans (e.g. 8000 workers in China) which were positive on neurotoxicity failed to prove relationship with cancer in humans (too small numbers ?)

38 How do we know...... whether somebody had been exposed to acrylamide ? Acrylamide binds to haemoglobin! Biomarker: AA-Hb adduct Level of adduct may reflect exposure to acrylamide over last four months

39 Research before 1999 “Clear-cut dose-response associations were found between the Hb-adduct levels and peripheral nervous functions symptoms. Thirty-nine percent of those with Hb-adduct levels exceeding 1 nmol/g globin experienced tingling or numbness in their hands or feet. For 23 workers there was strong evidence of PNS impairment due to occupational exposure to acrylamide. All but two had recovered 18 months after the cessation of exposure.”

40 Sweden: April 2002 “A scientific group at the University of Stockholm... has found that acrylamide is formed during heating of starch-rich foods to high temperatures. The Swedish National Food Administration has developed a new, rapid method for the analysis of acrylamide in foods. Analysis has shown that acrylamide is present in a large number of foods, including many regarded as staple foods. The levels of acrylamide differ widely within each food group analysed.”

41 Mechanism for the formation of acrylamide from asparagine through the early Maillard reaction

42 Chloropropanols A group of chemical contaminants comprising three carbon alcohols and diols with one or two chlorine atoms that are hypothetically derived from glycerol Dichloropropanols and chloropropanediols were identified as contaminants of the savory food ingredient acid-hydrolyzed vegetable protein (acid- HVP) in the 1970s and 1980s. In view of 3-MCPD (3-monochloropropane-1,2-diol) toxicity, the EC has proposed a provisional tolerable daily intake amount of 2 ug/kg body weight/day.

43 Background –Non-genotoxic carcinogen (JECFA, EU SCF)  threshold –Kidney toxicity at chronic exposure –Inhibits male fertility at high doses Occurrence –Hydrolyzed vegetable proteins (HVP) –Low levels in foods (biscuits, bread, cooked/cured fish and meat) –Migration (food contact materials) Human dietary exposure –2  g/person/day from savory foods –140-1100  g/person/day from soy sauce EU Restriction of 3-MCPD in process flavor is 20 ppb (liquid base) and 50 ppb (dry base) 3-MCPD (3-monochloropropane-1,2-diol)

44 3-MCPD esters Potential concern — Occurrence of 3-MCPD esters in a wide range of cooked foods and breast milk (data published 2004 – 2006) — 3-MCPD-esters in the diet may release some free 3-MCPD by action of gut lipases, potentially contributing to the overall dietary exposure to free 3-MCPD

45 Proposed mechanism for the formation of 3-MCPD diesters from DAG. L represents lipid. Published in: Xiaowei Zhang; Boyan Gao; Fang Qin; Haiming Shi; Yuangrong Jiang; Xuebing Xu; Liangli (Lucy) Yu; J. Agric. Food Chem. 2013, 61, 2548-2555. DOI: 10.1021/jf305252q Copyright © 2013 American Chemical Society

46 Other Process-induced Food Toxicants in Question Furan 5-hydroxymethyl-2-furfural

47 Potential concern Foods, especially jarred and canned foods, subject to heat treatment can contain furan (in particular baby foods in jars) - causes liver cancer in animal studies with high potency - genotoxic carcinogen (IARC class 2B ‘possibly carcinogenic to humans’) - no human epidemiological data on cancer Furan Exposure No reliable exposure Estimates (~ 1 µg/kg bw/day ) U.S. Food and Drug Administration (May 7, 2004; updated June 7, 2004) ( Reinhard et al., Mitt. Lebensmit. Hyg. 2004, 95, 532-535.

48 Ascorbic acid is the major furan precursor under thermal conditions E Erythrose TAG Threonine+Alanine+Glucose GA Glycolaldehyde+Alanine GS Glycolaldehyde+Serine ETAGGAGS Maillard type systems LA Linoleic acid (C18:2) T Trilinoleate LnA Linolenic acid (C18:3) Tn Trilinolenate LATLnATn Lipids AA Ascorbic acid DAA Dehydroasc. acid AADAA 0 2x10 3 4x10 3 6x10 3 8x10 3 1x10 4  mol/mol Furan Ascorbic acid (Maerk et al., J. Agric. Food Chem. 2006, 54, 2786-2793)

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