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It is postulated that a uniform particle size, dioctahedryl smectite clay (UPSN) will act as a primary intervention strategy for populations at high risk for mycotoxicosis by tightly and preferentially sorbing aflatoxins (AF) and fumonisins (FB) in the gastrointestinal tract. The composition of matter for UPSN is identical to NovaSil (NS) clay, which has already been reported by our laboratory to be safe and efficacious in animals and humans. The uniformity of particle size will have the added value of reducing variability and contaminant levels from batch-to-batch. It is further postulated that UPSN (like NS) will result in significant reduction in the "external dose" and bioavailability of AF and FB in this project, our initial experiments will focus on confirming the molecular mechanisms, mode of action and specificity of UPSN in vitro.
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Following this work, clinical intervention trials (a pilot study in food) and a Phase IIa trial will be run at our study site in the Northern Ashanti Region of Ghana, West Africa. In these trials, UPSN or placebo (medical grade starch) will be used. During this intervention protocols, health status, any adverse events, blood chemistry, serum vitamins and minerals and biomarkers of acute and chronic AF/FB exposure will be carefully monitored to delineate safety and efficacy of UPSN.
<P>In this project, our specific aims are two-fold and are founded on the central hypothesis that effective UPSN intervention therapies can be implemented to significantly diminish exposure (and risk) from AF/FB contaminated foods. The long-term goal of this project is to provide an innovative and culturally acceptable intervention that will improve disease management in "high risk" populations by reducing exposure of humans to aflatoxins and fumonisins.
NON-TECHNICAL SUMMARY: The findings from this research will be of direct relevance to developing countries where the poor are frequently exposed to mycotoxins and the incidence of aflatoxicosis, infectious disease, malnutrition, and primary liver cancer is elevated. Avoiding consumption of AF/FB contaminated foods can significantly reduce risk; however, for many communities a change in diet is not feasible. A simple preventive measure such as mitigating mycotoxin exposure with UPSN clay represents a practical and sustainable approach. This approach is novel in that it decreases the bioavailability of a potent cancer initiator (AF) and a cancer promoter (FB) in the diet by sequestration of both toxins in the GI tract. The preferred delivery of a therapeutic dose of UPSN clay may eventually be through its inclusion in common foods such as peanut butter, corn meal, or salt (like iodine).
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APPROACH: Aim 1 (Year 1). Confirm the high affinity sorption of aflatoxins and fumonisins to UPSN surfaces. Based on previous in vitro and in vivo research, we hypothesize that UPSN will be comparable to NovaSil (NS) and will not tightly sorb lipophilic and water soluble vitamins such as vitamin A and riboflavin. This conclusion is based on the fact that smectite is the "active" ingredient in NovaSil and UPSN is also smective minus contaminants such as quartz and calcium carbonate. Aim 2 (Year 2-3). In this research, 5-6-week-old male and female Sprague-Dawley rats will be fed rations containing 0, 0.25, or 2.0% (w/w) levels of UPSN for 12 weeks. Total feed consumption, cumulative feed consumption, body weight, total body weight gain, feed conversion efficiency, cumulative feed conversion efficiency, and relative organ weights will be recorded. Analysis of hematological parameters, clinical chemistry, and selected vitamin and mineral levels will also be assessed in animals from the different treatment groups. Aim 3 (Year 3-5). Pilot Study: Fifty participants (adults of both sexes) that are exposed to aflatoxins from their normal diet will be recruited and assigned to Placebo or UPSN Treatment Groups (25 per group). An amount of corn meal from the individual households of each of the 50 participants that will be needed for meals over each 5-day period, will be weighed by monitors from the Nutrition Unit of the District Hospital, Ejura and thoroughly mixed with an appropriate amount of either UPSN clay or Placebo (medical grade starch) prior to initiation of the study. The dose of UPSN and Placebo used to treat the meal samples will be no higher than 0.5% w/w, (weight of UPSN or Placebo/weight of dry meal) and will be independently derived for each participant in the study. The treated corn meal will be enough to use for meals (3/day) for a period of 5 days for each participant. On day 6, participants will again provide enough processed corn meal from their kitchens to be weighed by monitors and mixed with an appropriate amount of UPSN clay or placebo. At this time, the Placebo-treated group will be "switched" with the clay-treated group for a remainder of 5 days. In essence, we will confirm efficacy of the clay in both groups of participants. Each participant will get clay and placebo, but at different times. Biomarkers of AF and FB exposure will be assessed each day in urine from all groups before, during and after the trial. Phase IIa Trial: In the second intervention, aflatoxins and fumonisins will be determined in human body fluids (before, during and one month following a 3 month intervention with UPSN or placebo delivered as a slurry in water before each meal (3 times daily). Aflatoxin M1 in urine and aflatoxin albumin adduct in blood will be used as biomarkers of aflatoxin exposure. FB1 in urine will be used as a biomarker for fumonisin exposure.