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Aflatoxin Risk Assessment Red Book Model Exercise Charles Yoe, Ph.D. College of Notre Dame of Maryland.

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Presentation on theme: "Aflatoxin Risk Assessment Red Book Model Exercise Charles Yoe, Ph.D. College of Notre Dame of Maryland."— Presentation transcript:

1 Aflatoxin Risk Assessment Red Book Model Exercise Charles Yoe, Ph.D. College of Notre Dame of Maryland

2 Risk Analysis Risk Assessment Risk Management Risk Communication

3 Risk Assessment What can go wrong? How can it happen? How likely is it? What is the magnitude of the effect?

4 What are the steps? CODEX –Hazard identification –Hazard characterization –Exposure assessment –Risk characterization NAS –Hazard identification –Dose-response assessment –Exposure assessment –Risk characterization

5 Risk Assessment CODEX Hazard Identification –The identification of known or potential health effects associated with a particular agent. Hazard Characterization –The qualitative and/or quantitative evaluation of the nature of the adverse effects associated with biological, chemical, and physical agents which may be present in food. Dose-response assessments should be performed if the data are available.

6 Risk Assessment CODEX Exposure Assessment –The qualitative and/or quantitative evaluation of the degree of intake likely to occur. Risk Characterization –Integration of hazard identification, hazard characterization and exposure assessment into an estimation of the adverse effects likely to occur in a given population, including attendant uncertainties.

7 Risk Assessment NAS Hazard Identification –Determine if exposure to an agent causes an increased incidence of an adverse health effect. Dose-Response Assessment –Characterize the relationship between exposure (at different levels or doses) and the incidence of the adverse health effect.

8 Risk Assessment NAS Exposure Assessment –Measure or estimate the intensity, frequency, and duration of actual or hypothetical exposures of humans to the identified agent Risk Characterization –estimate the probability of specific harm to an exposed individual or population based on information from dose-response and exposure assessments.

9 Turkey X Disease 1960 1000s turkey poults died in England Major investigation Turkeys poisoned by agent in peanut meal component of their feed Agent found in peanuts contaminated with certain mold Mold, Aspergillus flavus, not responsible for poisoning

10 Turkey X Disease 1965 MIT team solved mystery of turkey X Aflatoxin discovered

11 Mycotoxins No awareness of mold-related disease before 1960s Imported peanut meal killed 1000s of turkeys in England 1960s The mold Aspergillus flavus produced toxins that fluoresced under analysis –aflatoxin blue (AFB) –aflatoxin green (AFG) Over 100 mycotoxins identified since aflatoxin

12 Molds and Mycotoxins Considerable worldwide significance –Public health –Agriculture –Economics Aflatoxin cost $20M to US peanut crop 1989 Foods that are ground present particular problems

13 What do we know about aflatoxin?

14 Aflatoxin Mixture of 4 closely related chemicals Two emit blue fluorescence: B1 & B2 Two emit green fluorescence: G1 & G2 Research showed them regularly –peanuts & some peanut products –corn –nuts Fed to animals can show up in derived food products

15 Aflatoxin Experimental studies showed –potent liver poison –malignant tumors in rats, ferrets, guinea pigs, mice, monkeys, sheep, ducks, trout Results reported 1961-1976 Low level but not infrequent contaminant of some human foods

16 Some Questions About Aflatoxin What is to be done? Are aflatoxins a threat to public health? How many cancers can be attributed to them? Why is there no clear link to human cancers? If a menace, how can we control it? How much of our resources is this worth?

17 Aflatoxicosis Poisoning from mold-produced metabolites Affects all tested species and humans Occurs when food supplies are limited and people ate moldy grains Flabby heart, edema, abdominal pain, liver necrosis, palpable liver Chronic ingestion--liver tumors

18 FDA and Aflatoxin Decided limits were in order, based on what could be detected 1968 >30 ppb in peanut products unfit Lowered to 20 ppb soon after No completely safe level can be established for cancer causing chemicals Does this mean as science gets better food becomes less safe?

19 FDA and Aflatoxin Meeting 20 ppb not too great a burden on peanut butter industry –discolored peanuts could be eliminated by sorting machines –required substantial new quality control measures Did this make scientific sense? –If aflatoxin can be detected it is unacceptable if it cannot it is acceptable

20 Yes Potent cancer causing agent in animals Do not wait for human data to control it Animal tests are reliable indicators of human risk Risky at any level of intake Eliminate human exposure or reduce it to lowest possible level

21 No Animal cancers occur at levels well above FDA limit Provide some safety to humans but 20 ppb is too low Policy of no safe level is not supported by science Animals not proven reliable indicators of human risk Carcinogenic potency highly variable among species No evidence of cancer in humans

22 FDA and Aflatoxin Easy to detect 5ppb in some labs 1 ppb almost routine in some labs FDA did not call for these lower limits Large fraction of peanut butter would fail 1 ppb standard Economic impact of 1ppb could be very large

23 Detection Analytical chemists can now measure levels toxicologists are unable to evaluate for biological significance 1 ppm is like a second in 11.6 days 1 ppb is a second in 32 years 1 ppt is a second in 3,169 years

24 ppb Weight of contaminant divided by weight of food In kg of peanut butter, 20 ppb is 20 micrograms

25 Aflatoxin Occurrence 1989

26 A Few More Points Corn responsible for most human exposure Peanuts and peanut butter in US Drought and other damage encourage mold Heat not enough to destroy mycotoxin Processing not effective in destroying mycotoxins Preventing formation is crucial

27 Aflatoxin and Peanuts Average concentration in peanuts and peanut butter is 2 ppb FDA defect action level (DAL) to seize peanuts is 20 ppb In practice anything over 15 ppb is rejected Average daily intake estimate is 0.005 ppb from peanuts

28 Science and Economics Just how certain is our science on matters like this? Size of economic consequence should not influence scientific thinking, but it influences scientists and policy makers when there are scientific uncertainties

29 Aflatoxin Management Options Constant testing –more in drought years Seize contaminated crops Destroy contaminated crop residues Agricultural techniques –forced air drying of crops –controlled storage conditions Minimize exposure to moldy foods

30 Lets look at a CODEX/NAS risk assessment

31 Hazard Identification Evolving understanding Turkey X JECFA 1987 JECFA 1997

32 JECFA 1987 Evaluated at 31st meeting of JECFA 1987 Considered potential human carcinogen Insufficient information to set tolerable intake level Urge reduction to lowest practicable level

33 JECFA 1997 One of most potent mutagenic and carcinogenic substances known Liver cancer in most species Some evidence humans are at lower risk than other species Epidemiological studies show no detectable independent risk Ongoing studies--Shanghai, Thailand, Qidong

34 JECFA 1997 Hepatitis B virus may increase liver cancer risk Estimated 50 to 100% of liver cancers are associated with Hepatitis B

35 What is the hazard?

36 Hazard Identification The Committee considered that the weight of scientific evidence, which includes epidemiological data, laboratory animal studies in vivo and in vitro metabolism studies, supports a conclusion that aflatoxins should be treated as carcinogenic food contaminants, the intake of which should be reduced to levels as low as reasonably achievable Source JECFA 1997

37 Hazard Characterization We will use a simple dose-response analysis This makes the two models, CODEX and NAS essentially equivalent

38 Aflatoxin Toxicity B1 (AFB1) most common, most studied, most toxic Toxicity varies by species –LD50.5 mg/kg for duckling –LD50 60 mg/kg for mouse –Binds to nucleic acids in some species –Difficult to assess for humans Death usually from liver damage

39 Dose-Response Analysis Limitations of available aflatoxin data –Confounded by concurrent Hepatitis B –Reliability & precision of aflatoxin exposure in study population are unknown –Shape of dose-response relationship unknown

40 Sources of Information Animal bioassays Human feeding trials Epidemiological data Cell lines (tissue cultures) Animal studies most common for cancers

41 Animal Studies Relatively high dose to relatively few animals Absence of data in low dose region Which mathematical model best approximates dose-response in low dose region Fit data that exists Linear extrapolation to zero from fitted curve or 95% confidence interval

42 Dose Response Linear Interpolation Excess Tumor Rate Dosage Experimental Range Estimated Dose Response Upper Confidence Limit Linear Extrapolation Alternative Extrapolations Actual Data

43 Low Dose Response Threshold/No threshold assumption is significant Many mathematical models possible Determines potency estimate Does not rely on safety factors

44 Dose-Response Potential biases in potency –Only studies with + association were used –Historical levels ignored in favor of current levels of intake –Hepatitis B prevalence systematically underestimated in early studies –Non-primary liver cancers may have been included –Interpolation method

45 Dose-Response Population risks Vary from population to population –Geographically –Culturally--diet –Susceptibility--base health

46 Dose Response Factors Diet also affects toxicity Human response variable –males and children more susceptible Hepatitis B increases cancer risk

47 Potency Values HbsAg+ 0.3 cancers/year per 100,000 population per ng aflatoxin/kg bw per day Uncertainty range 0.05 to 0.5 HBsAg- 0.01 cancers/year per 100,000 population per ng aflatoxin/kg bw per day Uncertainty range 0.002 to 0.03

48 Exposure Assessment Estimating frequency and intensity of exposure to agent Magnitude, duration, schedule and route of exposure Size, nature and class of exposed population Detailing associated uncertainties

49 Aflatoxin Exposure Assessment Contamination levels data appear biased Studies focus on commodity lots thought contaminated Contamination levels must be used with caution for patterns of importance not exact contamination estimates

50 CDF Aflatoxin in US Maize Cumulative density Contamination (µg/kg)

51 Hypothetical Standards Assume 20 µg/kg rejection level –4% maize crop rejected –mean aflatoxin level of 0.91 µg/kg Assume 10 µg/kg rejection level –6.2% maize crop rejected –mean aflatoxin level of 0.58 µg/kg Standards remove most highly contaminated, reducing average

52 Risk Characterization Combine dose-response and exposure assessments Describe risk in meaningful and useful fashion

53 Cancer Incidence Combine –Aflatoxin potency estimates (risk per unit dose) Dose response –Estimates of aflatoxin intake (dose per person) Exposure What are the uncertainties in these analyses?

54 Lets do a simple risk assessment.

55 Sample Data and Assumptions Assume: –Low contamination of food –Small prevalence of hepatitis B (1% carriers) –Potency =.3 with HBSAG+ –Potency =.01 with HBSAG- –European diet intake = 19 ng/person per day –Adult human weighs 60 kg –Population of 30 million

56 Aflatoxin Risk Assessment 1) Calculate estimated population potency –a) What is potency for HBSAG+? –b) What is % of HBSAG+? –c) What is potency for HBSAG-? –d) What is % of HBSAG-? –e) ab + cd = population potency

57 Aflatoxin Risk Assessment 2) Calculate intake per kg bw –a) What is intake per person? –b) What is weight of a person? –c) a/b 3) Calculate increased cancer rate due to aflatoxin –a) 1e x 2c

58 Aflatoxin Risk Assessment 4) Calculate increased number of cancers –a) What is cancer rate? –b) What is population –c) ab 5) Repeat calculations for uncertain range of potency

59 Calculate Cancers per Year 0.01 x 99% + 0.03 x 1% = 0.013 cancers/year per 100,000 population per ng aflatoxin/kg bw per day Range in cancer deaths is 0.002 to 0.035 19 ng/person per day 60 kg bw per person =.317 ng/kg bw per day.317 ng/kg bw per day x 0.013 cancers/year per 100,000 population per ng aflatoxin/kg bw per day = 0.0041 cancers/year per 100,000 people

60 Calculate Cancers per Year 30,000,000 people x 0.0041 cancers/year per 100,000 people = 1.23 cancers/year

61 Risk Assessment Model Which steps were hazard identification? Which steps were dose-response assessment? Which steps were exposure assessment? Which steps were risk characterization?

62 Model Comparison Food safety vs... CODEX/NAS Model Did food safety have four steps? What were major differences? What were similarities? Which was easier? Why? Which do you prefer? Why?

63 Lets see how we can address the uncertainty in a model like this.



66 Whats Next? Once the risk has been assessed –Risk management decides what to do about it –Risk Communication The risk is described to others Management options are explained

67 The End

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