Mycotoxins as factors Mycotoxins as factors in Africa's Health, in Africa's Health,

Trade and DevelopmentTrade and DevelopmentJ H Williams, PE Jolly, TD Phillips, J-S

WangUniversity of Georgia,

University of Alabama BirminghamTexas AMU

ContactsContacts

• J H “Tim” Williams• jhtimwil@uga.edu

• 237 Redding Building• 1109 Experiment St• Griffin Ga 30223

Linking Trade, Health Linking Trade, Health and Developmentand 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

Trade ConsiderationsTrade 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

Present Trade LossesPresent 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Standards West Africa Exports of Groundnut effectively ended, but production has continued so export trade has been replaced by local consumption of a normally nutrient dense product.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.

Trade RisksTrade 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.

Health ConsiderationsHealth 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.

WHO Risk AssessmentWHO Risk AssessmentThe Top Seven RisksThe Top Seven Risks

• Nutrition and Immunity

o Underweight children – nutrition and immunity o Risky sex or HIV/AIDS - immunityo Unsafe water - immunityo Smoke from open fires - immunityo Iron deficiency - nutritiono Zinc deficiency - nutrition/immunityo 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)

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Mycotoxins of AfricaMycotoxins of Africa• Many mycotoxins are possible but two dominate

• Aflatoxino 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 AFo Esophageal cancer is diagnostic of exposure

Developing Country Developing Country ExposureExposure

• Gambia, Benin, Guinea, China, Ghana & Kenyao > 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

Aflatoxin Disease Aflatoxin Disease ConnectionsConnections

• Cross sectional studies in Ghana confirm that immunity is modified.

• Diseases driven by immuno-toxicityo Occurs in Africa with natural levels of exposure from a maize based

dieto Cellular and Humoral immunity modified See Jiang 2005

• Malaria ~ 10% higher active malaria• TB in HIV+s increased 3 fold• HIV - progression

Progression and Progression and AflatoxinAflatoxin

• Only cross sectional studies have been done to date.

Opportunistic Opportunistic infections in HIV+ infections in HIV+

patients and AFpatients 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 reducedo HIV increases financial stress so people may eat lower quality foods

Non-communicable Non-communicable diseasesdiseases

• Nutritional deficiencies• Vitamins A, C, E proven in humans• Essential minerals –

o Se – deficiencies connected to higher HIV infectivityo Fe – anemia and adverse pregnancy outcomes increasedo Zn – maternal effects relating to infant deficiencies documented in

pigs. Associated diarrheal susceptibility• In utero exposure impacts on infant

o Stuntingo Immune system teratogenic effectso Longevity ?

Focus on HIV Focus on HIV transmissiontransmission

Components of the Components of the HIV epidemicHIV epidemic

• From the toxicology perspective the HIV epidemic is best considered as three components:

o Transmission (infectivity and susceptibility)o Progressiono Opportunistic infections

The Initial QuestionThe 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 consumedo Other driving forces for infectious diseases can be quantified and

controlled for statistically

The Epidemiological The Epidemiological QuestionQuestion

• 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.

HIV Epidemiological Scales HIV Epidemiological Scales and Research Attentionand Research Attention

• Large scale – differences between nationso Largely Ignored

• Local scale – o extensively researched

• Factors established to influence HIV transmissiono Male Circumcisiono Promiscuity

• Sex factors – commercial providers and partner concurrency• Transport corridors• Wealth

o Other STDs• T-Cell Activation• Epithelial integrity

o Education and condom usage

HIV epidemiology at the HIV epidemiology at the continental scale – explaining continental scale – explaining

national differencesnational 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 factorso Conflicto Diet based differences in exposure to mycotoxins with:

• immunotoxicity • impact on membrane barrier properties• Nutrition based changes in infectivity

DataData• 1994 and 2005 FAO data on per capital

consumption (11 year offset infection to death)o Maizeo Groundnuto Rice o Cassava

• 2005 WHO data on deaths rates from HIV, infectious diseases, and cancers (available for all diseases)

• Socio- economic datao Religion as a proxy for male circumcisiono Per capita income

The interval between HIV The interval between HIV infection and deathinfection 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

Differences in HIV death rates Differences in HIV death rates in 2005 across Sub-Saharan in 2005 across Sub-Saharan

NationsNations

Deaths in 2005 reflect infections in 1994

The Mycotoxicological The Mycotoxicological EnvironmentEnvironment

•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 Maizeo Groundnuto Riceo Dried Cassavao Sorghum & Millet

o Aflatoxin, Fumonisin, et alo Aflatoxino Aflatoxino Aflatoxino Aflatoxin, fumonisin, et al

Mycotoxin-prone Food Mycotoxin-prone Food Consumption PatternsConsumption Patterns

Correlations between staple foods Correlations between staple foods

and diseases in Africaand diseases in AfricaCassava Groundnuts Maize Rice

All Causes 0.05 -0.21 -0.02 0.03Infectious and parasitic diseases -0.09 -0.19 0.44 -0.31HIV/AIDS* -0.22 -0.23 0.69 -0.42Diarrhoeal diseases 0.22 -0.12 -0.41 0.23Childhood-cluster diseases 0.13 0.27 -0.43 0.20Meningitis 0.14 -0.02 -0.42 0.30Hepatitis B (g) -0.03 -0.18 -0.38 0.38Hepatitis C (g) 0.01 -0.28 -0.39 0.40Malaria 0.39 0.11 -0.43 0.29Tropical-cluster diseases 0.58 -0.11 -0.22 -0.03Respiratory infections 0.17 -0.11 -0.41 0.24Nutritional deficiencies 0.11 -0.19 -0.20 0.19Vitamin A deficiency -0.09 -0.20 -0.25 0.43Iron-deficiency anaemia 0.03 0.04 -0.26 0.39Malignant neoplasms -0.07 0.05 -0.22 0.47Oesophagus cancer* -0.33 -0.40 0.52 -0.40Liver cancer* 0.14 0.27 -0.31 0.30

HIV related to maize HIV related to maize consumptionconsumption

Model A: All countries Y = 5.26 * X + 63.0 (n = 36 : R2 = 0.47)Model B: Excluding outliers Y = 4.98 * X + 42.4 (n = 33 : R2 = 0.67)Model C: S African outliers Y = 7.47 * X + 550.5 (n = 3 : R2 = 0.94)

Cancer as a diagnostic Cancer as a diagnostic of mycotoxins?of mycotoxins?

• Using cancer as a toxin diagnostic o Aflatoxin associated with Liver cancero Fumonisin associated with Esophageal cancer

Correlations with Correlations with diagnostic cancersdiagnostic cancers

Cassava Groundnuts Maize Rice All Causes 0.05 -0.21 -0.02 0.03Infectious and parasitic diseases -0.09 -0.19 0.44 -0.31HIV/AIDS* -0.22 -0.23 0.69 -0.42Diarrhoeal diseases 0.22 -0.12 -0.41 0.23Childhood-cluster diseases 0.13 0.27 -0.43 0.20Meningitis 0.14 -0.02 -0.42 0.30Hepatitis B (g) -0.03 -0.18 -0.38 0.38Hepatitis C (g) 0.01 -0.28 -0.39 0.40Malaria 0.39 0.11 -0.43 0.29Tropical-cluster diseases 0.58 -0.11 -0.22 -0.03Respiratory infections 0.17 -0.11 -0.41 0.24Nutritional deficiencies 0.11 -0.19 -0.20 0.19Vitamin A deficiency -0.09 -0.20 -0.25 0.43Iron-deficiency anaemia 0.03 0.04 -0.26 0.39Malignant neoplasms -0.07 0.05 -0.22 0.47Oesophagus cancer* -0.33 -0.40 0.52 -0.40Liver cancer* 0.14 0.27 -0.31 0.30

Statistical significance:Maize v HIV p< 0.001Maize v Esophageal cancer p<0.01Other variablesCircumcision 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)

Covariance or Covariance or CausalityCausality

• Probabilistic v Mechanistic Evidence• Bradford Hill’s ‘criteria’

o NB lack of evidence does not preclude causality

1 Strength of relationship 2 Consistency4 Temporality

9 Analogy8 Experiment7 Coherence

6 Plausibility 5 Biological gradient 3 Specificity

Interventions for Interventions for Mycotoxins Mycotoxins

• Protection despite contaminationo Food Additives

• Mineral binders – 40% of animal feeds o Human trials prove safety and efficacyo Other benefits – viral diarrhea in infants (EU)

• Yeast based binders

• Improved food qualityo Production (varieties, pest control, IPM, CAFT, timely harvest, rapid and

complete dryingo Storageo HACCP in processingo Standards and enforcement

• Consequence of unattainable standards• Challenges to enforcement

o Food securityo Infrastructure

Interventions against Interventions against FumonisinFumonisin

• Insect controlo Pesticides, Resistant varieties, IPM, GM,

• In the USA fumonisin levels have dropped in response to bt deployment

• Millingo 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

Suggested ActionsSuggested 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

Thank youThank you