findings of the report on mycotoxin control in low- and middle-income countries

For our children

J. David MillerDepartment of Chemistry

Carleton UniversityCanada

• Focus on the health of children

• Where corn is a staple crop, exposure is usually to both fumonisin & aflatoxin: the combination increases hazard.

• Public health lens applied to available data on interventions toreduce exposure.

• Research on gender and mycotoxin management needed to ensure equitable access to information by both men and women.

1. Epidemiology of stunting and wasting and interventions for prevention or treatment

2. Prevalence, regulatory status for mycotoxin control and mycotoxinexposure

3. Human studies of acute (aflatoxicosis) and chronic disease

4. Studies in children and impact of aflatoxin/fumonisin on growthand development

5. Aflatoxin-related immune modulation

6. Experimental studies of acute and chronic toxicity

7. In utero exposure to fumonisins and child health

Cameroon

Analytica Chimica Acta 741:58

↓ ↓

In 2011, JECFA concluded that co-exposure to aflatoxin and fumonisinresults in additive effects beyond exposures to the individual toxins.

ACameroon

Cote d’IvoireGuineaUganda

50:50

IBeninGhanaKenya

MozambiqueTanzania

Zimbabwe

70:30

JDR Congo

CongoGambiaNigeria

20:80

maize:groundnuts

Focus on biomonitoring

• Population exposure assessments are straightforward in fully developed market economies. There is no immediate prospect of enabling uniform information collection in many developing countries.

• Increasing the availability of mycotoxinbiomonitoring including an improved biomarker for fumonisin exposure seems to be the sensible course.

• Availability of reagents, analytical costs and absence of high throughput technology remains a restriction.

Proc Nutrition Soc 2000 59:149

“It may be that the enteropathy arises and is maintained by frequent exposure to a combination of faecally-derived organisms. Other possible initiation factors include food toxins, e.g. aflatoxin, which can be a problem in The Gambia (Wild et al. 1992), or much less likely, a so far unidentified nutrient deficiency.”

Proc Nutrition Soc 2000 59:149Am J Trop Med Hygiene 86:756

An estimated 162 million children aged less than 5 years worldwide were stunted. Poor quality diets and high rates of infection, both in pregnancy and in the first years of life, are known to result in poor child growth.

While the relative contribution of these factors to stunting are unknown, provision of all of these established nutrition-specific interventions in the most affected regions had reduced stunting by less than 20%.

Environ Health Perspect 112:1334

Environ Health Perspect 111:217

Child growth

• Six studies were deemed to be of high quality, with well-defined sample sizes, exposure or dose assessments, outcome measures, and appropriate multivariate analyses.

• Taken together, these studies suggest that mycotoxin exposure contributes to child growth impairment, independent of and together with other risk factors that may cause stunting.

• What is the attributable risk?

Possible mechanisms

• Enteropathy may be partly attributable to aflatoxin related toxic damage on the intestine epithelium, resulting in poor uptake of nutrients;

• aflatoxin associated immune suppression could increase children’s susceptibility to infections such as diarrhea;

• liver toxicity of aflatoxin may damage the production of insulin like growth factor pathway proteins in the liver and an adverse impact on child growth.

A recent study of aflatoxin adducts was conducted in populations participating in randomized community trials of antenatal micronutrient supplementation in southern Nepal and northwestern Bangladesh.

Findings from the Nepal samples demonstrated exposure to aflatoxin, with 94% detectable samples ranging from 0.45 to 2939.30 pg aflatoxin B1-lysine/mg albumin during pregnancy. In the Bangladesh samples the range was 1.56 to 63.22 pg aflatoxin B1-lysine/mg albumin in the first trimester, 3.37 to 72.8 pgaflatoxin B1-lysine/mg albumin in the third trimester, 4.62 to 76.69 pg aflatoxin B1-lysine/mg albumin at birth and 3.88 to 81.44 pg aflatoxin B1-lysine/mg albumin at age two years

Food Chem Toxicol 74:184

1. Epidemiology of stunting and wasting and interventions for prevention or treatment

2. Prevalence, regulatory status for mycotoxin control and mycotoxinexposure globally

3. Human studies of acute (aflatoxicosis) and chronic disease

4. Studies in children and impact of aflatoxin/fumonisin on growthand development

5. Aflatoxin-related immune modulation

6. Experimental studies of acute and chronic toxicity

7. In utero exposure to fumonisins and child health

“It thus becomes the plain duty of health officers, as a body, to determine the actual and relative importance [of interventions]….and to use their efforts to build up the more useful and employ along the lines of greatest public benefit those facilities placed at their disposal.”

Am J Public Health (N Y) 1912 2:7

Public health evidence

• The “best quality” evidence (i.e. indicating that an intervention is ready for implementation) is for an approach that has reached a mature stage of development, results in significant intervention effects, and addresses the needs of important stakeholders.

1.Sufficient evidence for implementation as evidencedwith multiple studies with health metrics and/or biomarker data.

2. needs more field evaluation

3. needs formative research

4. no evidence/ineffective

As currently envisaged, the recommendations would be relevant for investment of public, nongovernmental organization, and private funds at the scale of the subsistence farmer, the smallholder, and through to a more advanced value chain.

Table 7.1. Summary of the Working Group’s evaluation of interventions associated with the reduction of aflatoxin and/or fumonisin exposure

InterventionCategory

of evidencea

Context Gap (research/translation) Combination/issues/comments

Dietary diversity —b Dose effect reduction of HCC

• Investment in appropriate crops for the target region both suitable for the climate and culturally acceptable

Difficult in food-insecure situations or in food-, arable land-, or water-insecure countries.

Genetic resistance Contamination

Aflatoxin in maize 3• Movement of resistance in agronomic lines

• Identification of resistance genes

Combination: Biocontrol; agronomic and post-harvest practices Issues: Small research community; large environmental effect on phenotype expression; resistance is polygenic

Fumonisin in maize 2Combination: Agronomic and post-harvest practices Issues: Small research community; large environmental effect on phenotype expression; resistance is polygenic

Aflatoxin in peanuts 4• Identification of sources of resistance

• Movement into agronomic lines

Combination: Biocontrol; agronomic and post-harvest practices Issues: Large environmental effect on phenotype expression limits resistance expression over large areas; small research community; resistance is polygenic; resistance is not well described



of evidencea


Biological control Contamination

Atoxigenic strains 2

• Frequency and outcomes of genetic recombination

• Consistency of efficacy evaluated across geography and users

Combination: Agronomic and post-harvest practices Comment: Ongoing translational research in the USA and Africa



of evidencea


Primary prevention Dose effect

Dioctahedral smectite clay

2• Dose and duration on efficacy and safety

• Effects on infants, children, and pregnant women

Combination: Clay amended with chlorophyllin and other trapping agents Issue: Formulation strategiesComments: Possible enhanced efficacy during outbreaks; potential to mitigate aflatoxins and fumonisins

Chlorophyllin 2

Lactobacillus 3

Yeast glucan 4

Chemoprevention Dose effect

Broccoli sprout extract

2

• To date, phase II clinical trials for efficacy; need for scaling to longer-term interventions

• Translation to local, culturally acceptable foods with these enzyme inducers

• Biomarker studies to date; no health end-point studies yet

Comment: Opportunity for use in acute-exposure situations; native plants; dietary diversification

Intervention Category of evidence Context Gap (research/translation) Combination/issues/comments

PostharvestDose effect/ contamination

Package 1

• Knowledge translation is cultural

• Modules need to be developed in partnership with farmers, area agricultural extension workers, traditional leaders, church groups, health workers, and civil society

Comments: Ready to be implemented; use in chronic-exposure situation as an ongoing intervention package; needs to be applied as a multifactorial intervention package

Sorting 1

• Done in all cultures for all crops; however, best practices need to be formally taught at the village level Comment: Important for complementary food

Issue: Fate of the rejected food

Nixtamalization 1• Requires adequate water for washing

• Has not been adapted in Africa or Asia

Ready for implementation

• Increasing dietary diversity• Package of storage practices and

sorting • Sorting• Nixtamalization (in Latin America)

IIn 1630, Dr. Thuillier observed that the intensity of the malady was in proportion to the amount of ergoty grain consumed and that those with more diverse diets suffered less or not at all. He fed sclerotia to chickens, geese and pigs & they all died. More than a century later, L'Abbé Tessier proposed cultivation of potatoes instead of rye, improved drainage and the enforced cleaning of grains.

Sorting contaminated grains is the primary tool used to reduce mycotoxin contamination in grains and nuts after harvest. This has proven benefits for healthEur J Obstetrics Gyn & Repro Biol 60:109; Botany, Patronage, and Community at the 17th Parisian Royal Academy of Sciences, 1990

Sorting

Sorting emerged soon after the discovery of aflatoxin in 1961. The need for efficient ways to remove aflatoxin contaminated nuts prompted experiments on the concentrations of aflatoxin in kernels from shells that were not visibly moldy. This revealed that visual sorting was an efficient way to segregate more versus less contaminated kernels in the laboratory.

Whitaker et al. (1998) demonstrated that visual sorting of groundnuts provided a practical first action regulatory method. They found that sound mature kernels and sound half kernels contained ca. 7% of the aflatoxin with the damaged kernels containing the rest.

These strategies work best where there is on-going training. A study in the Philippines found that manual sorting reduced aflatoxin concentration in a lot from 300 ng/g to <15 ng/g. Recent research conducted in Kenya (and Haiti) demonstrated that manual sorting of groundnuts purchased at local markets could reduce lot aflatoxin concentrations by ~98%

In the case of maize in Africa, manual sorting is moderately effective at the village level for segregating kernel lots for decreased concentrations of aflatoxin. Removing visibly mouldy, insect-damaged and broken grains by hand reduced aflatoxin concentrations by 40% based on reports from a study in Benin. Studies in South Africa and Tanzania have demonstrated that hand-sorting of maize kernels by removing the visibly infected/damaged kernels by local farmers reduced fumonisin by 20%.

In South Africa, the effectiveness of hand sorting to reduce fumonisin exposure was documented by biomarkers

A recent study from Malawi found that most people recognized that molds were dangerous to human health but about half thought that the toxins were destroyed during cooking . This might explain why about a third reported that they bought moldy maize. Women were less informed on issues related to molds in foods (Mycotoxin Res 32:27).

We found that the education of women should be considered critical because of their roles as mothers, educators, and businesswomen managing household nutrition, farming, and the selling of smallholder crops. More research on gender and mycotoxin management is needed to properly develop education campaigns and ensure equitable access to information by both men and women. Culturally-sensitive modules need to be developed in partnership with farmers, area agricultural extension workers, traditional leaders, church groups, health workers, and civil society

What would be a productive approach to creating capacity to do this work?



of evidencea


Dietary diversity —b Dose effect reduction of HCC

• Investment in appropriate crops for the target region both suitable for the climate and culturally acceptable

Difficult in food-insecure situations or in food-, arable land-, or water-insecure countries.

Genetic resistance Contamination

Aflatoxin in maize 3• Movement of resistance in agronomic lines

• Identification of resistance genes

Combination: Biocontrol; agronomic and post-harvest practices Issues: Small research community; large environmental effect on phenotype expression; resistance is polygenic

Fumonisin in maize 2Combination: Agronomic and post-harvest practices Issues: Small research community; large environmental effect on phenotype expression; resistance is polygenic

Aflatoxin in peanuts 4• Identification of sources of resistance

• Movement into agronomic lines

Combination: Biocontrol; agronomic and post-harvest practices Issues: Large environmental effect on phenotype expression limits resistance expression over large areas; small research community; resistance is polygenic; resistance is not well described

Proc Natl Acad Sci U S A. 2014 111:4001

Miracle 1966

Proc Natl Acad Sci U S A. 2014 111:4001

For our children

• There are some things that we know reduce exposure to aflatoxin.

• More effort to develop and apply these ‘known knowns’ will have important child health and economic benefits.

• Strategies that make sense for urban and rural areas are likely to be different.

• In all countries, reducing exposures has been a tough challenge requiring engagement from government, civil society and the private sector.

Cost of mycotoxins in Canada and the USA, $ 0.5 to 2 billion/year depending on the year. Cost of testing alone is $200 million. Effect on trade is very large.

For each of the three toxins aflatoxin (1964), dexoynivalenol (1975) and fumonisin (1990), it took upwards of 10years to bring them under control.

Risk Analysis 10:561

In 2001, Dr. Jerry Rice wascontacted by a country in Africa that had a lot of thegroundnut crop was highlycontaminated by aflatoxin.

He was upset that he had no information that would be immediately useful and began work on such a publication in 2003.

The project was restarted in 2008 by Prof. Wild and brought to completion.

Aflatoxin and fumonisin where there are important co-exposures.ca. 100 pages of text accessible to policy makers

findings of the report on mycotoxin control in low- and middle-income countries

Presentations & Public Speaking