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Aflatoxin Risk Assessment “Red Book” Model Exercise

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Presentation on theme: "Aflatoxin Risk Assessment “Red Book” Model Exercise"— Presentation transcript:

1 Aflatoxin Risk Assessment “Red Book” Model Exercise
Charles Yoe, Ph.D. College of Notre Dame of Maryland This exercise was adapted from an exercise prepared as part of an International Life Sciences Institute (ILSI) meeting for the Association of Southeast Asian Nations (ASEAN) members in the winter of 1999 held in Kuala Lumpur. It is reproduced here to provide an introduction to some of the techniques of food safety risk analysis. In particular it demonstrates how the so-called Red Book paradigm has been adapted to food safety usages. The “Red Book” is the National Academy of Sciences 1983 risk assessment paradigm that consists of: Hazard Characterization, Dose-Response, Exposure, and Risk Characterization. The exercise begins with an overview of risk analysis. For more information on these topics you may reference the links and materials on this Food Safety Risk Analysis Clearinghouse web site. It then introduces some of the language of the National Academy of sciences (red Book) and CODEX. From that point on it transitions into a discussion of aflatoxin which is subsequently used as an example of a food safety risk assessment. This example is offered for heuristic purposes only. Nothing in this example should be construed as a factual statement on the risk of aflatoxin anywhere in the world.

2 Risk Analysis Risk Risk Management Assessment Risk Communication
Risk analysis is the overarching or umbrella concept. It is the big picture, the term we use for the whole process. Risk analysis it comprises three parts. There is overlap among these parts and their boundaries are not always clear. Risk analysis provides us with a way of thinking about things. This exercise concentrates primarily on the risk assessment task. Risk Communication

3 Risk Assessment What can go wrong? How can it happen?
How likely is it? What is the magnitude of the effect? Here is an intuitive definition of risk assessment. Risk assessment is the work required to adequately answer these questions. It can be qualitative, quantitative or something in between.

4 What are the steps? CODEX NAS Hazard identification
Hazard characterization Exposure assessment Risk characterization NAS Hazard identification Dose-response assessment Exposure assessment Risk characterization There are many risk assessment models in the professional literature. Some are general purpose models, others have been developed for the assessment of specific risks. Two well known risk assessment models being applied to food safety are the CODEX and National Academy of Sciences models. CODEX is the international standard setting body. NAS is a United States organization. These models provide a way to think about risk assessment. They are not theorems or requirements. Actual assessments that rely on these models get done in different ways and their steps are not always clearly identified. You will not find these four steps clearly delineated in every risk assessment or even most of them. But some version of each of the steps can usually be found in assessments that use these models. Models provide a simplified description of how things work in the world. Building models we gain insight into what outcomes can be expected under certain conditions and we can simulate what happens if we change assumptions and parameters. This exercise provides an example that uses these basic models.

5 Risk Assessment CODEX Hazard Identification Hazard Characterization
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. Here are the definitions of the steps in a CODEX risk assessment. Notice despite their formality that these steps echo the intuitive definition offered earlier.

6 Risk Assessment CODEX Exposure Assessment Risk Characterization
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. These are the last two tasks in a CODEX risk assessment. Risk characterization does not specify what the integration looks like or how it gets done. Many risk assessments characterize their risk with probabilities. In the example that follows we use an increased number of expected cancer deaths to characterize the risk.

7 Risk Assessment NAS Hazard Identification Dose-Response Assessment
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. The words differ for the National Academy of Science model but not by much. The approach is essentially the same as the CODEX approach. These models provide a systematic approach to answering the risk assessment questions posed earlier.

8 Risk Assessment NAS Exposure Assessment Risk Characterization
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. Note that risk characterization is explicitly described as a probability here. That is common but certainly not necessary.

9 Turkey X Disease 1960 1000’s 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 Here are a few facts to introduce aflatoxin, the focus of this risk assessment exercise. These facts and those that follow were taken from the following source materials: Joint FAO/WHO Expert Committee on Food Additives, 49th meeting, Rome June 1997, Annex 1 Aflatoxins. U.S. FDA Aflatoxin Update, Aflatoxin in Corn not Reaching Consumers April 13, 1989. Aflatoxins U.S. FDA Bad Bug Book (see link from Clearinghouse)

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

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 These facts were obtained primarily from the book Food Safety by Julie Miller Jones, Eagan Press, St. Paul, 1992.

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 More on molds and the mycotoxins they produce7.

13 What do we know about aflatoxin?
A brief review of some aflatoxin facts follows.

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 These facts are compiled from the Codex and FDA documents.

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

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? These questions or questions like them come up over and over. Policy questions like these arise all the time. We do risk assessment so we can address questions like these in a probabilistic manner rather than in the dichotomous (safe/unsafe) manner of a traditional food safety analysis. We will use risk assessment to address some of these. Others are posed for example purposes only.

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 These are some of the bad things that can happen as a result of aflatoxins!

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? The so-called safe limit has changed over time as our ability to detect the substance has improved. The question posed here is not a trivial one. It seems if we can detect it, it’s too much. This is a no threshold model used for most potential carcinogens—we will return to it later. ppb means parts per billion.

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 It does make sense to regulate aflatoxin at 20 ppb if you believe these things.

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 It does not make sense to regulate at 20 ppb it if you believe these things. Where is the science in this process? We need to see this is science-based decision making. It is not science. That is not a bad thing. It is honest and it is an improvement. The science will get better even as the detection methods have. And along with the science the risk assessment will improve. In the meantime we must manage these risks and they are currently managed in the US based on a 20 ppb action level.

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 The Food and Drug Administration has had some experience with aflatoxin in which economics has become a significant consideration. Risk management is not based entirely on the results of a risk assessment or even on science, for that matter. Other factors and social values, like economics, are considered in a risk management decision.

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 The story of aflatoxin regulation is, in part, a story of detection. Mycotoxins have existed for millennia--ergot poisoning in the Middle Ages in Europe is one example. Mycotoxins have been recognized as a hazard relatively recently. Science is pushing us to deal with problems that we were unaware of in the past.

24 ppb Weight of contaminant divided by weight of food
In kg of peanut butter, 20 ppb is 20 micrograms In case you are not familiar with parts per billion. . .

25 Aflatoxin Occurrence 1989 Occurrence varies by region. Phil. is an abbreviation for the Philippines. This shows the number of shipments in which aflatoxin was detected out of a total number of shipments inspected. Which of these are over the limit of 20 ppb? See last column. These would be rejected if the nation has a 20 ppb action level. In third world countries the choice may be between having food that exceeds the 20 ppb level and not having food. That is not the same choice a developed country might face.

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 How are people exposed to aflatoxin in your country? What are the pathways of concern? They differ regionally, as do other exposure concerns.

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 ppb from peanuts How is aflatoxin regulated now in your country? What would improve the regulation process? Does risk assessment have a role?

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 We have backed off of a no-threshold model in the US because of the economic consequences of our scientific detection capabilities. It is not wise to remain oblivious to economic consequences.

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 These risk management options can be expensive. So, armed with knowledge that the results of a risk assessment could upset some people let us try a risk assessment.

30 Let’s look at a CODEX/NAS risk assessment
Remember this is an example of a specific risk assessment approach. Chemical risk assessment, as is done for food additives, for example, is different. Import risk assessments will often be unique and based on probabilistic risk assessment models. Microbial risk assessment is more different still.

31 Hazard Identification
Evolving understanding Turkey X JECFA 1987 JECFA 1997 Let's walk through the risk assessment steps. We start with Hazard Identification. This is where we ask and answer what can go wrong and how can it happen? We've considered the history and what we know about aflatoxin, now we turn to what Joint Food Agricultural Organization (FAO)/World Health Organization (WHO) Expert Committee on Food Additives ( JECFA) has had to say about it over time.

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 JECFA has evaluated aflatoxin twice.

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 The most recent evaluation was in 1997.

34 JECFA 1997 Hepatitis B virus may increase liver cancer risk
Estimated 50 to 100% of liver cancers are associated with Hepatitis B A significant fact is that Hepatitis B positive people are at greater risk of liver cancer from aflatoxin and other carcinogens. This is part of the how can it happen dimension of risk assessment.

35 What is the hazard? How are you coming along with the concepts of risk assessment. Can you answer this question? Is the hazard. . . cancer? peanuts? aflatoxin? Or is it something else all together? The terminology of risk assessment can be confusing.

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 Based on our evolving understanding of aflatoxin JECFA has made the following statement. Is it any more clear what the hazard is now? If not, you may be normal! The language and concepts of risk analysis, remember we are doing risk assessment now, can be messy.

37 Hazard Characterization
We will use a simple dose-response analysis This makes the two models, CODEX and NAS essentially equivalent If the hazard characterization is done via dose-response analysis, the two risk assessment models are essentially equivalent. This continues the how can it happen and moves into the what are the consequences dimension of risk assessment.

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 Dose-response analysis requires toxicity studies. In this respect this approach is similar to the traditional food safety analysis. It is clear that there is much science focused into the risk assessment process.

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 Dose-response is a different kind of model. It does not rely on a determination of what is safe or unsafe. The information content of the data are limited by many factors. These are a few of the relevant limitations.

40 Sources of Information
Animal bioassays Human feeding trials Epidemiological data Cell lines (tissue cultures) Animal studies most common for cancers What kinds of toxicity studies might be available? That depends. Here are some potential sources of useful dose-response data. Where can you find this kind of information? The Clearinghouse web site you are currently visiting is a good portal to these kinds of data. To see what is available check these URLs which can be found through the Databases linkages in this web site. Through Databases/Residues and Additives/FAO Through Databases/Natural Resources/TOXNET

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 Animal studies have their advantages and disadvantages. The absence of data in the low dose ranges and the need to extrapolate from one species to another are two of the more significant disadvantages. The problems are often addressed by a linear extrapolation, with or without a confidence interval.

42 Dose Response Linear Interpolation
Upper Confidence Limit Actual Data Excess Tumor Rate Alternative Extrapolations Estimated Dose Response Imagine each dot represents the results of a study. The estimated dose-response curve was fitted to these points using statistical techniques. An upper confidence limit on that fitted curve was also calculated using classical statistical techniques. The fitted curve (estimated dose response) goes to zero, implying a threshold is required. By using the upper confidence limit on this fitted curve a no threshold model can be estimated. With these statistical techniques our observed data end at dosages near the left most point on our graph. We have no information about what happens at doses lower than this, but these are often the doses to which humans are exposed. One common way of extrapolating this information is using a linear extrapolation. In this example we extrapolate from the upper confidence limit rather than from the fitted curve itself to the origin. The extrapolations need not be linear (dotted line above). Non-linear relationships may actually describe the response better than a linear one. A few non-linear extrapolations are offered. It is clear that this is not all science. The conservative assumptions built-in to the risk assessment are justified on the basis of the protection of human health and life. Such a decision is really more the function of risk management than risk assessment. Perhaps you recall that the risk analysis model presented at slide 2 showed some overlap and ambiguity in assessment and management? Here is an example. A point on terminology. If zero is taken as a given point we are interpolating. If not we are extrapolating. The literature uses the two interchangeably. Extrapolation was used here. Typically, we would choose a tolerable rate of excess tumors, say 10E-6, and find the dosage corresponding to this rate. That dosage would be considered an acceptable daily dose. Another use of these data and the one we will use here is to calculate the slope of the linear extrapolation to obtain the “unit risk” for cancer. Linear Extrapolation Dosage Experimental Range

43 Low Dose Response “Threshold/No threshold” assumption is significant
Many mathematical models possible Determines potency estimate Does not rely on safety factors What are the potential biases with this extrapolation? Cancer risks could be over- or underestimated. This is not science but it does rely on toxicological data and sophisticated statistical techniques. This approach does not rely on safety factors the way most chemical food safety assessments that use the EDI/ADI ratio does. It is a different way of extrapolating results from animals to humans. This is one of the major differences between the two approaches to food safety. These subjective judgments can bother bench scientists but a decision must be made, remember our questions posed earlier. Something must be done and we cannot wait until the scientists are completely satisfied with their information before a decision is made.

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 The available dose response data used in this aflatoxin assessment had some potential weaknesses.

45 Dose-Response Population risks Vary from population to population
Geographically Culturally--diet Susceptibility--base health Dose-response data do not describe individual risks. They are developed for populations. An example of the second bullet above is clearly evident when we consider the different prevalence of Hepatitis B around the world.

46 Dose Response Factors Diet also affects toxicity
Human response variable males and children more susceptible Hepatitis B increases cancer risk It was found that diet was important and that varies dramatically around the world. Hence, risks can too.

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 to 0.03 Here are some Joint Expert Consultation on Food Additives (JECFA) data for hepatitis B positive and negative individuals. These potency values are slopes of linear interpolations like that shown in the earlier slide. You’ll use these values in a later calculation you can do for practice. It is not possible to identify the potency values with complete certainty. In recognition of this fact JECFA has estimated potency values as an interval as well.

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 We’ve covered two steps in the risk assessment process. Now we consider exposure to aflatoxin. Exposure continues the how can it happen dimension of risk assessment. With foods we are usually after two pieces of information. What is the concentration of the substance of interest in foods. And how much of these foods do people eat.

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 If we ignore uncontaminated lots in our analysis we are using biased data. That is okay and may even be wise, but it must be recognized. We are often more concerned with patterns in our data than we are with specific measurements from our data.

50 CDF Aflatoxin in US Maize
Contamination (µg/kg) This is a little hard to read. We’d like the axes reversed for easier reading. The logarithmic scale also complicates interpretation some. About 90 percent of all lots have 10 μg/kg or less, about 75 percent have 1 μg/kg or less. Thus, most maize is below the FDA actionable level of contamination. This suggests exposure through this pathway is somewhat limited in the US. These data ignore uncontaminated lots raising the average contamination level seen in this graph. CDF means cumulative distribution function. Cumulative density

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 To understand the implications of our possible risk management measures consider what would happen in the US with these hypothetical standards. These results are based on the data used to generate the cdf on the previous slide. Keep in mind this is a heuristic example, not the actual policy of the US.

52 Risk Characterization
Combine dose-response and exposure assessments Describe risk in meaningful and useful fashion What does it mean to characterize a risk? How would you characterize it based on the discussion that has gone on here to this point? What units of measurement are most useful for this hazard? Probability aflatoxin present in food? Average ppb in food? How do we discuss deaths to make them meaningful? Do we use annual deaths, lifetimes deaths, probability of death, or reduction in life expectancy? Risk characterization must involve a meaningful endpoint. Cancer deaths is certainly a meaningful and quantifiable endpoint. This is the part of the risk assessment that tells us how likely the risk is and how bad it can be. It pulls together all the previous parts of the risk assessment.

53 Cancer Incidence Combine What are the uncertainties in these analyses?
Aflatoxin potency estimates (risk per unit dose) Dose response Estimates of aflatoxin intake (dose per person) Exposure What are the uncertainties in these analyses? You are going to use the data presented here to estimate the increased incidence of cancer to characterize the risk associated with aflatoxin. Then we’ll see how uncertainties can be explored with a probabilistic analysis.

54 Let’s do a simple risk assessment.
Finally, your turn to give it a try. Suppose we are trying to answer the question, “How many additional cancers are caused by aflatoxin?” Make sure you know the question your risk assessment is to answer.

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 Some of these data were presented earlier. These are the assumptions and data we’ll use for our risk assessment. Is there any uncertainty in these assumptions? Does that uncertainty matter? Some uncertainty is due to randomness, some to bias, some to other causes. Ng = nanograms HBSAG+ means Hepatitis B positive, HBSAG- is negative

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 The first step is to calculate the potency for the population at large. The letters at item e refer to the preceding items. The values required for this calculation are given on the previous slide. The potency values have been determined from a dose-response analysis. The prevalence of hepatitis B is determined through epidemiological studies. If you would like to understand the steps involved in this type or risk assessment do the calculations before you go to the next slide.

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 Second, we calculate intake, by dividing item 2a by item 2b. Simply follow the instructions to do the required calculations. Take some time to understand what you are doing. See how the numbers fit together. Intake studies are often the most difficult data to obtain. Toxicological studies, once done, are applicable for all humans. Intake data must be population specific.

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 You are getting to the endpoint now. Increased cancers is calculated here. How do we get from this to cancer deaths? In this oversimplified example we simply assume a cancer results in death. Clearly, a more careful and realistic example would not rely on an assumption like that.

59 Calculate Cancers per Year
0.01 x 99% x 1% = cancers/year per 100,000 population per ng aflatoxin/kg bw per day Range in cancer deaths is to 0.035 19 ng/person per day  60 kg bw per person = ng/kg bw per day .317 ng/kg bw per day x cancers/year per 100,000 population per ng aflatoxin/kg bw per day = cancers/year per 100,000 people The answers appear in this and following slides. Compare it to your own calculations.

60 Calculate Cancers per Year
30,000,000 people x cancers/year per 100,000 people = cancers/year These are population means. If individuals are closer to the 99th or 1st percentile of aflatoxin exposure they may not be well represented by these data.

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? In the calculation you just did, can you separate the parts of the risk assessment? We certainly answered the question about increased cancers, but did we answer the questions we began with at slides 3 and then again at 16? We think we have answered what can go wrong (additional cancers), how can it happen (aflatoxin), and how bad can it be (death). But do we know how likely it is that these deaths will occur? There is enough uncertainty evident in our analysis to suggest that we cannot be certain that 1.23 new cancers will result. We will turn to this question shortly. As for the policy questions in slide 16, the results of our risk assessment are not an answer. But it does provide some very valuable information for making those decisions and answering those questions. We can use our model to explore questions like how much a specific management measure will reduce cancer deaths. For example, how might forced air drying affect the prevalence and concentrations of aflatoxin and, consequently, the intake of aflatoxin? If we change the intake values and redo our endpoint calculations the difference in deaths would be attributable to the risk management option, in this case forced air drying.

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? You have an opportunity to compare this method with a sample exercise for aspartame posted at the Clearinghouse which uses a food safety chemical risk assessment model. If you have looked at that method you might want to answer these questions. If not, just skip them.

63 Let’s see how we can address the uncertainty in a model like this.
Good risk assessment acknowledges the existence of uncertainty, it identifies it, quantifies it, and addresses it. Uncertainty is reduced when possible and treated in other ways when it is not.

64 Once again, recall that this is an example developed to help you understand the technique. It is not an actual risk assessment of aflatoxin cancers and it should not be interpreted that way. This is a hypothetical example. One option is sensitivity analysis. We could repeat the calculation using different values for the key factors. Recall that potency values were given as an interval estimate. Then we would compare the incidences of cancer associated with different potency rates. In this slide we see key inputs like prevalence of Hepatitis B are described by a range of values and a mode (most likely) identified. This is sufficient information to describe a triangular distribution. In this spreadsheet we see a great difference in cancer rates (this model again assumes a cancer case results in death) around the world. Why would this be so? Differences in diets and Hepatitis B prevalence are two major factors. Another option is to use a Monte Carlo simulation to calculate the cancer incidence for thousands of different scenarios. That has been done by using probability distributions to describe the uncertainty evident in the models’ inputs. The Monte Carlo model results are shown in the green cells at the bottom right. The cells in this slide show one of many thousands of possible scenarios.

65 These are results from our hypothetical example.
This graphic compares the potential distributions of cancer deaths for two different regions of the world. The higher (red) curve for the Far East model shows that cancer deaths from aflatoxin are far more likely in the Far East. These cumulative distribution functions were generated using the model shown in the last slide. Now it is possible to say how likely any number of deaths will be. Bear in mind, this is a different model than the one you used with your sample calculation. The green curve (Europe) shows there is a 60 percent chance of 216 or fewer deaths from aflatoxin.

66 What’s 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 If you would like additional information about the Monte Carlo process, see the Clearinghouse on-line slide presentation. The aspartame food safety example available at the Clearinghouse provides an example of an alternative approach to risk assessment.

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