1. Mycotoxins as factors in Africa's Health, Trade and Development J H Williams, PE Jolly, TD Phillips, J-S Wang University of Georgia, University of Alabama Birmingham Texas AMU

2. Contacts J H Tim Williams jhtimwil@uga.edu 237 Redding Building 1109 Experiment St Griffin Ga 30223

3. Linking Trade, Health and Development Trade is a vehicle for development in that surplus production can increase incomes for primary producers and for players along the supply chain. Trade should be a positive for development. Good health is a positive for development in that energy and resources can be applied to productive efforts rather than to care and medicines for the ill. Premature death is negative to the economy. DALYS as a measure of health costs: o Death v Morbidity

4. Trade Considerations Trade pressures result in segregation of clean and contaminated product with unintended consequences to producers and populations. Because Food insecurity and poverty ensures that all will be eaten regardless of safety Price incentives both in the export market and local markets cause clean product to be exported and traded and the concentrated contamination to be consumed at home

5. Present Trade Losses Groundnut losses for Africa estimated at $700 M but cost of infrastructure to improve standards this is high. This is less than $1 per person per year. With Aflatoxin Standards West Africa Exports of Groundnut effectively ended, but production has continued so export trade has been replaced by local consumption of a normally nutrient dense product. Maize is presently not impacted because trade is regional and enforcement is weak and easily corrupted.

6. Trade Risks The big risk of using trade as a development instrument is that the overall food quality is not addressed. Cherry picking the best quality for trade is the easiest approach (at both the individual producer and the national scale) but this clearly introduces the risk of concentrating the toxins and deteriorating public health.

7. Health Considerations Reflecting Developed Country exposure levels environmental health has focused on aflatoxin as a carcinogen (chronic sub-symptomatic, low level intoxication) and a hepatotoxin (acute high level intoxication). Reflecting higher allowable levels of contamination and direct use by producers veterinary medicine has focused on immuno-toxicity and nutritional impairment. From a toxicological perspective humans foods in developing countries equate to animal foods in developed countries.

8. WHO Risk Assessment The Top Seven Risks Nutrition and Immunity o Underweight children – nutrition and immunity o Risky sex or HIV/AIDS - immunity o Unsafe water - immunity o Smoke from open fires- immunity o Iron deficiency- nutrition o Zinc deficiency- nutrition/immunity o Vitamin A deficiency- nutrition/immunity 31% of burden of disease is/ 43% may be modulated by aflatoxin (* evidence exists) 27% of burden of disease may be modulated by fumonisin (#evidence exists) * # *

9. Mycotoxins of Africa Many mycotoxins are possible but two dominate Aflatoxin o Maize. Groundnut. Rice. Dried Cassava. o Broad toxicities and consequences Genetic. Carcinogenic. Nutritional. Immunological. Cytological. Synergistic with HBV o Liver cancer is diagnostic of exposure Fumonisin o Maize o Broad toxicities Carcinogenic. Teratogenic leading to birth defects. Nutritional. Membrane effects. Neurotoxic (particularly horses) Synergistic with AF o Esophageal cancer is diagnostic of exposure

10. Developing Country Exposure Gambia, Benin, Guinea, China, Ghana & Kenya o > 90% chronic exposure Breast milk samples in Africa show 30-40 % of mothers had dietary AF in the last 24 hours. Market samples o 30-40% of staple grain samples in Nigeria, Uganda could not be sold in the USA. World scale - 4.5 billion consume unmanaged foods

11. Aflatoxin Disease Connections Cross sectional studies in Ghana confirm that immunity is modified. Diseases driven by immuno-toxicity o Occurs in Africa with natural levels of exposure from a maize based diet o Cellular and Humoral immunity modified See Jiang 2005 Malaria ~ 10% higher active malaria TB in HIV+s increased 3 fold HIV - progression

12. Progression and Aflatoxin Only cross sectional studies have been done to date.

13. Opportunistic infections in HIV+ patients and AF Evidence is limited to a single observation that HIV+ people have 3x higher risk of TB with high AF. HIV+ people are more exposed to AF o Liver function is decreased by HIV so detoxification is likely reduced o HIV increases financial stress so people may eat lower quality foods

14. Non-communicable diseases Nutritional deficiencies Vitamins A, C, E proven in humans Essential minerals – o Se – deficiencies connected to higher HIV infectivity o Fe – anemia and adverse pregnancy outcomes increased o Zn – maternal effects relating to infant deficiencies documented in pigs. Associated diarrheal susceptibility In utero exposure impacts on infant o Stunting o Immune system teratogenic effects o Longevity ?

15. Focus on HIV transmission

16. Components of the HIV epidemic From the toxicology perspective the HIV epidemic is best considered as three components: o Transmission (infectivity and susceptibility) o Progression o Opportunistic infections

17. The Initial Question If aflatoxin is influencing infectious diseases through immuno-suppression does the amount of toxin prone foods consumed correlate with infectious diseases? Assumptions: o Chronic exposure is a function of quantity consumed o Other driving forces for infectious diseases can be quantified and controlled for statistically

18. The Epidemiological Question Transmission of HIV in Africa is much higher than in Europe or N America as measured by frequency of transmissions per discordant sexual encounter. The reason for higher transmission, after controlling for known differences in environmental factors, is not definitively established.

19. HIV Epidemiological Scales and Research Attention Large scale – differences between nations o Largely Ignored Local scale – o extensively researched Factors established to influence HIV transmission o Male Circumcision o Promiscuity Sex factors – commercial providers and partner concurrency Transport corridors Wealth o Other STDs T-Cell Activation Epithelial integrity o Education and condom usage

20. HIV epidemiology at the continental scale – explaining national differences Possible factors: o HIV serotype (type 2 is less infective) o Prevalence of religious/tribal groups influencing: Male circumcision frequency Duration of sexual partnerships Concurrence o Labor migration and transport factors o Conflict o Diet based differences in exposure to mycotoxins with: immunotoxicity impact on membrane barrier properties Nutrition based changes in infectivity

21. Data 1994 and 2005 FAO data on per capital consumption (11 year offset infection to death) o Maize o Groundnut o Rice o Cassava 2005 WHO data on deaths rates from HIV, infectious diseases, and cancers (available for all diseases) Socio- economic data o Religion as a proxy for male circumcision o Per capita income

22. The interval between HIV infection and death Without ARV therapies studies in Kenya and South Africa show the mean survival time after infection is approximately 11 years. Thus deaths in 2005 reflect transmissions in 1994 making 1994 the most appropriate food environment to HIV transmission epidemiological analysis In North America/EU estimate is 15 years

23. Differences in HIV death rates in 2005 across Sub-Saharan Nations Deaths in 2005 reflect infections in 1994

24. The Mycotoxicological Environment Limited management of food contamination leads to widespread exposure Market and some biomarkers studies confirm continent wide exposure to major toxins Major sources of mycotoxin exposure are: o Maize o Groundnut o Rice o Dried Cassava o Sorghum & Millet o Aflatoxin, Fumonisin, et al o Aflatoxin o Aflatoxin, fumonisin, et al

25. Mycotoxin-prone Food Consumption Patterns

26. Correlations between staple foods and diseases in Africa

27. HIV related to maize consumption Model A: All countries Y = 5.26 * X + 63.0 (n = 36 : R 2 = 0.47) Model B: Excluding outliers Y = 4.98 * X + 42.4 (n = 33 : R 2 = 0.67) Model C: S African outliers Y = 7.47 * X + 550.5 (n = 3 : R 2 = 0.94)

28. Cancer as a diagnostic of mycotoxins? Using cancer as a toxin diagnostic o Aflatoxin associated with Liver cancer o Fumonisin associated with Esophageal cancer

29. Correlations with diagnostic cancers Statistical significance: Maize v HIV p< 0.001 Maize v Esophageal cancer p<0.01 Other variables Circumcision and Circumcision x maize p<0.05 HIV mortality over-rides aflatoxin because people do not live long enough for liver cancer to be manifest ( most occurrence after 50 years)

30. Covariance or Causality Probabilistic v Mechanistic Evidence Bradford Hills criteria o NB lack of evidence does not preclude causality 1 Strength of relationship2 Consistency 4 Temporality 9 Analogy 8 Experiment 7 Coherence 6 Plausibility5 Biological gradient 3 Specificity

31. Interventions for Mycotoxins Protection despite contamination o Food Additives Mineral binders – 40% of animal feeds o Human trials prove safety and efficacy o Other benefits – viral diarrhea in infants (EU) Yeast based binders Improved food quality o Production (varieties, pest control, IPM, CAFT, timely harvest, rapid and complete drying o Storage o HACCP in processing o Standards and enforcement Consequence of unattainable standards Challenges to enforcement o Food security o Infrastructure

32. Interventions against Fumonisin Insect control o Pesticides, Resistant varieties, IPM, GM, In the USA fumonisin levels have dropped in response to bt deployment Milling o Hulling Leaching Food additives – o Bentonite that binds AF also binds FN in acid environments Proven for humans in Ghana Proven for one animal model - rats

33. Suggested Actions Trade promotion must be in the context of a general program to improve food quality in developing countries. Utilize HIV, Malaria and TB funds for research on the toxin/infectious diseases link Consider testing bentonite as an intervention where babies are underweight without food shortages Campaigns to improve public awareness of toxins

34. Thank you