28/09/2015. (3) Food Toxicology

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1 Introduction to toxicology and risk assessment (3) Food Toxicology Ivonne M.C.M. Rietjens Compounds of concern in food toxicology additives indirect additives (from packaging material) animal drugs pesticide residues unavoidable contaminants natural toxins novel food ingredients food supplements substances from cooking/processing Compounds of concern in food toxicology additives indirect additives (from packaging material) animal drugs pesticide residues unavoidable contaminants natural toxins novel food ingredients food supplements substances from cooking/processing 1

2 Non genotoxic ADI = Acceptable daily intake for avoidable contaminants like additives, pesticides TDI = Tolerable daily intake for unavoidable contaminants like dioxins, mycotoxins, heavy metals = NOAEL or BMDL x 1/10 x 1/10 x other UFs interspecies intraspecies quality of data type of exposure Pesticide residues in food Percentage of samples with measurable residues above the MRL % (64,810 samples) of the surveillance samples analysed (national and EU-coordinated multi-annual programme) were below or at the legal MRLs In 2.6% (1,740 samples) of the samples the legal limits were exceeded for one or more pesticides Risk assessment pesticide residues Acute exposure of the European population to carbendazim residues in table grapes, expressed as percent of the ARfD set for carbendazim Acute exposure of the European population to carbendazim residues in peppers, expressed as percent of the ARfD set for carbendazim. 2

3 Pesticides EFSA concluded: - long-term exposure of consumers did not raise health concerns - short-term exposure: for 77 food samples analysed the acute reference dose (ARfD) might have been exceeded if the pertinent food was consumed in high amounts Compounds of concern in food toxicology additives indirect additives (from packaging material) animal drugs pesticide residues nonfunctional/ unavoidable contaminants natural toxins novel food ingredients food supplements substances from cooking/ processing Natural toxins mycotoxins (from fungi) phytotoxins (from plants) phycotoxins (from marine algae) animal toxins bacterial toxins 3

4 Mycotoxins: food safety risk in a variety of cereal, fruit, nut and milk-based products Mycotoxins of present concern 1) from Aspergillus and Penicillium spp aflatoxins (B,G,M), ochratoxin 2) from Fusarium spp trichothecenes, fumonisines Aspergillus and Penicillium Mycotoxins of major concern and their adverse effects upon chronic exposure aflatoxins carcinogenicity (liver) sterigmatocystin carcinogenicity (liver) ochratoxin A carcinogenicity (kidney)(ben) citrinin carcinogenicity (liver, kidney) patulin carcinogenicity (liver, kidney) 4

5 Fusarium Mycotoxins of major concern and their adverse effects upon chronic exposure: trichothecenes fumonisins zearalenone immunotoxicity growth retardation oesophagal cancer cancer reproductive organs Example: aflatoxine B1 Aspergillus flavus In nuts, beer, wheat mutation hotspots P53 tumor suppressor gene liver cancer International Agency for research on Cancer (IARC) classification Group 1: Group 2A: Group 2B: Group 3: Group 4: carcinogenic to man; should be forbidden probably carcinogenic to man; should be forbidden possibly carcinogenic for man compound cannot be classified because of lack of sufficient data proven to be non-carcinogenic for man based on scientific arguments and conservative 5

6 Epidemiology aflatoxin: high incidence of liver tumors in India, Thailand, Mozambique, Swaziland, Transkei, Kenya related to aflatoxin exposure Estimated daily intake US 18 ng AFB1 /person/day 44 ng AFM1/person/day Zimbabwe 1 mg AFB1 /person/day Epidemiology aflatoxin: Relation between aflatoxin and cancer in Kenya (major source: maize ao cereals) Intake Cancer incidence ng/kg bw/day per 10 6 /year Epidemiology aflatoxin: high incidence of liver tumors in Qidong China related to aflatoxin exposure 6

7 EFSA (2004) In consideration of the carcinogenic properties of aflatoxin B1, human exposure should be reduced to levels as low as reasonable achievable (ALARA) maximum levels for aflatoxin M1 have been set for consumable milk at 0.05 μg/kg, and μg/kg for infant formulae, respectively, aiming to reduce human exposure to the lowest achievable level Risk assessment: Margin of Exposure (MOE) for compounds that are both genotoxic and carcinogenic MOE = BMDL 10 EDI (human) BMR BMDL BMD MOE > : low concern BMR = benchmark response (pe 10% effect above background) BMD = Bench Mark Dose; dose causing the BMR BMDL = lower confidence limit of the BMD EFSA (2007) MOE assessment AFB1 Data on liver tumors in rats: BMDL 10 of 0.17 μg/kg bw per day Estimated daily intake: ng/kg bw per day MOE: The margins of exposure (MOEs) for all estimated intakes indicated a potential concern for human health. 7

8 Best approach to reduce aflatoxin exposure worldwide prevention based on good agricultural practice possible decontamination education of producer and consumer combined with regulatory limits and monitoring programs Example vomitoxin = DON = deoxynivalenol O O O C 2 O O O trichothecene from Fusarium spp on wheat in bread, and other wheat products Immunotoxicity, growth retardation DON: infection wheat unavoidable - GR: undesired effect = growth retardation TDI: 0.5 mg/kg bw/day (requires MRL 100 mg/kg wheat = detection limit and % of NL wheat abbandonned) - JECFA suggested TDI of 1 mg/kg bw/day (growth retardation - GR: adverse effects nausea & immunotoxicity TDI at 2.5 mg/kg bw/day Netherlands: 1999 children 1-4 jr 50 % 1.3 mg/kg bw/day 5 % > 2.4 mg/kg bw/day 8

9 Risk assessment DON 26,613 analytical results collected by 21 European countries DON was found in almost half the samples, the highest levels being observed in wheat, maize and oat grains and derived products chronic exposure between 0.22 and 1.86 μg/kg b.w. per day. main contributor: bread and rolls exposure of consumers close to or above the TDI of 1 μg/kg b.w. per day is possible Natural toxins mycotoxins (from fungi) phytotoxins (from plants) phycotoxins (from marine algae) animal toxins bacterial toxins Phytotoxins example: Star Anise Anisatin in Japanese not Chinese star anise GABA antagonist October 2001: Netherlands: 8 people ended up in hospital after drinking star mix tea 9

10 Phytotoxins: cyanogenic glycosides CN: Cassave linamarin Konzo: tropical myelopathy spastic paralysis Phytotoxins: aristolochic acids Belgium (1990s) botanical weight loss preparation Instead of patients kidney damage and cancer due to aristolochic acids Aristolochia fangchi instead of Stephania tetrandra (fangji) NL warenwet (2001): ban on aristolochic acids botanicals: no European regulations / legislations Phytotoxins

11 Phytotoxins: EFSA: There is world-wide recognition of potential problems associated with botanicals and botanical products, not only in terms of safety, but also in terms of the claimed amounts and stability of the active ingredients. As the market volume expands, so does the need for a better characterisation of botanicals and botanical preparations, and for harmonising the scientific assessment of risks from exposure of consumers to these products Natural toxins mycotoxins (from fungi) phytotoxins (from plants) phycotoxins (from marine algae) animal toxins bacterial toxins Phycotoxins mostly: dinoflagellata toxins accumulate in food chain (toxic mussels) bloom: red tide or red water 11

12 Phycotoxins paralytic shellfish poison (PSP) diarrhetic shellfish poison (DSP) neurotoxic shellfish poison (NSP) amnesic shellfish poison (ASP) ciguatera fish poison (CFP) alexandrium sp. saxitoxin dinophysis sp. dinophysis toxin gymnodinium sp. brevetoxin Pseudo-nitzschia sp. domoic acid Gambierdiscus sp. ciguatera toxin Natural toxins mycotoxins (from fungi) phytotoxins (from plants) phycotoxins (from marine algae) animal toxins bacterial toxins Example: tetrodotoxin from puffer fish blocks Na + channels neurons O paralysis - 2 N O O N N O O O C 2 O O Japan: 75 deaths/year 12

13 Natural toxins mycotoxins (from fungi) phytotoxins (from plants) phycotoxins (from marine algae) animal toxins bacterial toxins bacterial toxins (p.e. botulinum toxin) botulism: Clostridium botulinum Type A : contaminated food (man) Type B : contaminated food (man) Type C : deadly for birds Type D : in cattle Type E : in fish, dangerous for man Type F : dangerous for man Mechanism: botulinum toxin inhibits release of acetylcholine by presynaptic membrane of motor endplate Example botulinum toxin LD mg/kg blocks Ach release 13

14 Compounds of concern in food toxicology additives indirect additives (from packaging material) animal drugs pesticide residues nonfunctional/ unavoidable contaminants natural toxins novel food ingredients food supplements substances from cooking/ processing Functional foods & food supplements caffein improves cognitive performance calcium prevents osteoporosis luteolin improves the eyes PUFA lower cholesterol levels AOX are anti-carcinogenic, prevent artherosclerosis but more of a healthy ingredient does not always improve health Paracelsus ( ) notion of dose Alle Ding sind Gifft allein die Dosis macht dass ein Ding kein Gifft ist 14

15 Example: Beta-carotene epidemiologic studies reveal: carotenoid-rich diets: reduced risk on lung cancer, cardiovascular diseases, cataract carotenoid-deficient diets: increased risk on lung cancer Beta-carotene Randomized intervention studies / smokers, male, years old 20 / 30 mg b-carotene /day, 5-8 years follow-up New Eng J Med 330 (1994) ATBC study New Eng J Med 334 (1996) CARET study Beta-carotene 4-5 times increase in plasma levels causes adverse effect 15

16 Compounds of concern in food toxicology additives indirect additives (from packaging material) animal drugs pesticide residues nonfunctional/ unavoidable contaminants natural toxins novel food ingredients food supplements substances from cooking/ processing substances from cooking/ processing substances produced by cooking/ processing high temperature cooking/frying proteins: CAs: heterocyclic amines (PhIP in hamburgers) acrylamide PAs: Polycyclic Aromatic ydrocarbons like benzo(a)pyrene acrylamide in chips, french fries, bread carcinogenic in animal studies IARC: group 2A probably carcinogenic to humans calculated cancer risk: at estimated daily intake in NL of 0.4 mg/kg bw /day: about 100 persons / year 500 x 10-6 / lifetime : action to be taken 16

17 Acrylamide: actions taken? C C In 2007 some products higher levels Acrylamide: risk assessment AA and GA are genotoxic: no TDI neurotoxicity (periferic neuronopathy in rats) BMDL 10 = 0.43 mg/kg bw per day MOS values compared to EDI across the age groups so > 100: no risk for a thresholded endpoint Carcinogenicity: lowest BMDL 10 = 0.17 mg/kg bw per day MOE values << Of concern! Risk management actions required Future perspective Quantitative Risk assessment DALY s (Disability Adjusted Life Years) Risks expressed in the number of lost healthy life years in the population 17

18 Example DALY s: acrylamide in chips, french fries, bread Caluclated cancer risk: At EDI in NL 0.4 mg/kg bw /day: 100 persons / year Assumption: cancer: 5 year reduction in life expectancy 500 DALY s healthy life years lost / year DALY s other risk factor: DALY s allow comparison of different health risks Chemical risks food safety <1000 DALY s Other health risks: Food infections DALY s coronairy heart diseases DALY s Conclusions food toxicology: many existing but also newly emerging items thanks to good regulation and control health risks are limited: our food has never been safer 18

19 Thank you for your attention! Wageningen UR 19