Jia Sheng Wang and Timothy D Phillips

Abstract

Cost-effective interventions that reduce human diseases and death from aflatoxin exposure are high priorities particularly for developing nations. A calcium montmorillonite clay, NovaSil™, when mixed at low inclusion rates with animal feeds can act as a selective enterosor-bent for aflatoxins. NovaSil™ sequesters aflatoxins in the gastrointestinal tract and neutralizes their toxic effects by reducing the bioavailability of the toxins in the blood and other organs. These findings are especially significant for developing countries since clay-based strategies for managing aflatoxicosis would be practical, culturally acceptable, sustainable and unique in reducing external exposure and risk. When included in the diet of animals at levels up to 2.0% (w/w), NovaSil™ clay did not interfere with vitamin or micronutrient utilization. These results also support the hypothesis that NovaSil™ clay interventions in developing countries could have a major impact on health and well-being of susceptible humans who are highly and frequently exposed to these dietary toxins without compromising their nutritional status. Recent work has confirmed the relative safety of NovaSil™ in a long-term rodent study at and in a Phase I Adverse Events trial. No significant NovaSil™-related effects were observed in either study, and the conclusions were that NovaSil™ should be tested in a Phase II human trial in Ghana. A study population in Ghana has been identified that is exposed to high levels of dietary aflatoxins based on biomarkers in their blood and urine samples. This study will evaluate the consequences of NovaSil™ treatment on aflatoxin exposure over a 3-month period. In summary, enterosorption strategies, based on dietary NovaSil™ clay, hold great promise for the management of aflatoxins in high-risk human populations especially in developing countries. The remedy is novel, inexpensive and easily disseminated.

Introduction

Aflatoxins are a group of carcinogenic mycotoxins produced primarily by the fungi Aspergillus flavus and Aspergillus parasiticus. These toxins occur frequently in agricultural commodi ties including cereal grains, cottonseed, peanuts and tree nuts (CAST, 2003). These compounds are heat stable and can survive a variety of food processing procedures; thus, aflatox-ins can occur as "unavoidable" contaminants in many foods and feeds, particularly those derived from maize and peanuts. Of the four naturally occurring aflatoxins (Bi, B2, Gi, and G2), aflatoxin Bi is the most toxic and has been shown to interact with genes involved in carcinogenesis (McMahon et al., 1986; 1987; Smela et al., 2001) and tumor suppression (Aguilar et al., 1993). Several studies also suggest that aflatoxins impair the cellular and humoral immune system, and that chronic low level exposure to these food contaminants may result in suppression of the immune system and increased susceptibility to disease (Rodricks and Stoloff, 1977; Miller et al., 1978; Richards et al., 1978; Pestka and Bondy, 1994; Hinton et al., 2003; Turner et al., 2003). In addition, dietary aflatoxins also reduce significantly hepatic vitamin A in chickens (Pimpukdee et al., 2004). In the United States, the action level of aflatoxins in foods intended for human use is 20 ng/g. Although many countries have regulatory limits for aflatoxin in foods/feeds, outbreaks of poisoning still occur. For instance, Kenya (with an aflatoxin regulatory level of 20 ng/g) recently experienced an outbreak of aflatoxin poisoning in humans with a case-fatality rate of 39%, which was reportedly linked to consumption of maize containing aflatoxin levels as high as 8,000 ng/g (CDC, 2004).

Intervention strategies for the aflatoxin problem

Due to the significantly negative impact of aflatoxins on human and animal health, particularly in developing countries, intervention strategies that are effective yet economically feasible are needed. Several intervention strategies are available, including diverse physical, chemical, and biological methods, for managing aflatoxins in agricultural commodities, the simplest of which requires isolation and destruction of the contaminated source. This approach, however, often is not practical since alternative food supplies may not be available, or replacement supplies may not be affordable. Thus, the use of detoxification and decontamination procedures has become a viable option for remediating aflatoxin-contaminated foodstuffs. Optimally, remediation procedures should: (i) remove, inactivate or effectively destroy the mycotoxin from the commodity; (ii) not result in the deposition of toxic substances, metabolites, or by-products in the commodity; (iii) retain nutritional value and food/feed acceptability of the commodity; (iv) not cause significant alterations in the physical properties of the commodity; and (v) destroy fungal spores, if possible (Park et al., 1988). Importantly, detoxification or decontamination procedures should be readily available, easily utilized and cost-effective (CAST, 2003).

A practical approach of current interest for the prevention of aflatoxicosis is the incorporation of non-nutritive clay minerals in contaminated food/feed to sorb aflatoxins in the gastrointestinal tract, thus reducing toxin bioavailability and distribution in the blood and other target organs (Phillips et al., 1995; Phillips, 1999). This dietary consumption of clay, i.e., geophagy, has been observed for centuries in both human and animal populations worldwide (Carretero et al., 2002). Potential health benefits of geophagy presumably include enterosorption, i.e., binding the toxic agent in the gastrointestinal tract, which decreases the bioavailability of toxic chemicals and hazardous microbes from both contaminated foods and water.

Animal studies with mycotoxins and calcium montmorillonite clay

In previous enterosorbent studies with aflatoxins, NovaSil™, a processed calcium montmorillonite clay, bound aflatoxin Bi with high affinity and high capacity both in vitro and in vivo. When added to the diet, NovaSil™ significantly protected broiler and Leghorn chicks from the toxic effects of dietary aflatoxin exposure (Phillips et al., 1988). Following these initial findings, the efficacy of NovaSil™ and similar calcium montmorillonite clays for aflatoxins was confirmed in multiple animal species including pregnant rodents (Mayura et al., 1998), chickens (Phillips et al., 1988; Kubena et al., 1990; Pimpukdee et al., 2004), turkeys (Kubena et al., 1991), swine (Lindemann et al., 1993), and lambs (Harvey et al., 1991a). NovaSil™ also decreases the bioavailability of radiolabeled aflatoxins and reduces aflatoxin residues in poultry (Davidson et al., 1987), rats (Sarr et al., 1995), and pigs (Beaver et al., 1990). Afla-toxin M1, an oxidative metabolite of aflatoxin B1, formed in the milk of lactating dairy cattle and goats was reduced significantly when NovaSil™ was incorporated into contaminated diets for the animals (Harvey et al., 1991b; Smith et al., 1994).

NovaSil™ is selective for aflatoxins since, when included in the diet of animals, NovaSil™ did not significantly reduce the toxicity of other common (and structurally diverse) mycotoxins, i.e., zearalenone, deoxynivalenol, T-2 toxin, ochratoxin A, cyclopiazonic acid, ergotamine, and fumonisins. For example, the use of clay in mink fed zearalenone helped to reduce fetotoxicity, but did not alter the hyperestrogenic effects (Bursian et al., 1992). Also, supplementation of swine diets with NovaSil™ clay at 0.5 and 1.0% w/w did not influence the average daily gain of pigs exposed to deoxynivalenol. In poultry studies, the inclusion of NovaSil™ clay in the diet as an enterosorbent did not significantly prevent the adverse effects of T-2 toxin (Kubena et al., 1990), ochratoxin A (Huff et al., 1992), cyclopiazonic acid (Dwyer et al., 1997), and fumonisins (Lemke, 2000).

In these short-term animal studies, no observable adverse effects were reported following ingestion of the dietary NovaSil™ clay. Prior to chronic animal and short-term human studies, NovaSil™ was analyzed for concentrations of various environmental contaminants, including dioxins/furans and heavy metals to insure compliance with federal and international standards. A more recent study in which Sprague-Dawley rats ingested NovaSil™ clay at dietary concentrations as high as 2% throughout pregnancy showed neither maternal nor fetal toxicity, and did not significantly alter trace metal bioavailability in a variety of tissues (Wiles et al., 2004). These findings suggest that NovaSil™ clay may be useful in enterosorbent therapies for the management of aflatoxicosis in high-risk human populations.

Prior to human feasibility and/or intervention trials utilizing NovaSil™, the potential adverse effects of NovaSil™ clay following chronic dietary ingestion need to be established in animals. We used a rodent model to evaluate the relative safety of chronic exposure to NovaSil™ clay via the diet. Male and female Sprague-Dawley rats were fed rations containing 0, 0.25, 0.5, 1.0 and 2.0% NovaSil™ clay ad libitum for 6.5 months. Rats treated with 0.25-2% NovaSil™ clay in the diet had neither dose-dependent nor NovaSil™-related adverse effects on body weight gains, feed conversion ratios, relative organ weights, gross anatomy, histological appearance of major organs, hematology or serum biochemistry parameters. Levels of selected essential nutrients, including Fe, Zn and vitamins A and E, were unaffected (Table 1; Afriyie-Gyawu et al., 2005).

Table 1. Vitamin and mineral concentrations in serum and liver samples from Sprague-Dawley rats following dietary ingestion of 0-2.0% NovaSil™ for 6.5 mo; after Afriyie-Gyawu et al. (2005).

Parameter Treatment Group

Table 1. Vitamin and mineral concentrations in serum and liver samples from Sprague-Dawley rats following dietary ingestion of 0-2.0% NovaSil™ for 6.5 mo; after Afriyie-Gyawu et al. (2005).

Parameter Treatment Group

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