5
Adverse Impacts of Food on Human Health

This chapter focuses on the range of health hazards, both documented (e.g., microbial) and perceived (e.g., due to the inadvertent mixture of various grains or to the consumption of deoxyribonucleic acid [DNA]), that can be associated with food, whether or not produced by biotechnology. It starts with an overview of food safety issues in general and then describes the context in which new genetically engineered (GE) foods are entering the market. This is followed by a description of the array of potential hazards that should be considered by efforts designed to anticipate or evaluate unintended adverse health effects. It is important to emphasize that the hazards presented below can occur with foods regardless of the method of production or processing and are not specific to the process of genetic engineering.

INTRODUCTION

Predicting and assessing potential adverse human health impacts arising from compositional changes in foods modified by a number of methods, including the genetic engineering of foods, are challenging. Adverse consequences could be narrow in occurrence or diverse and widespread and, because they are unintended, will be unexpected. Foods that could be modified in composition as a result of agricultural biotechnology, as defined in Chapter 1 and described in Chapters 2 and 3, are of interest because of the growing awareness that commonly consumed food constituents and complex mixtures can be beneficial or harmful to health.

Estimates based on population-based research indicate that approximately one-third of preventable morbidity and mortality is of dietary origin and/or a consequence of low levels of physical activity. In contrast to such long-term con-



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Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects 5 Adverse Impacts of Food on Human Health This chapter focuses on the range of health hazards, both documented (e.g., microbial) and perceived (e.g., due to the inadvertent mixture of various grains or to the consumption of deoxyribonucleic acid [DNA]), that can be associated with food, whether or not produced by biotechnology. It starts with an overview of food safety issues in general and then describes the context in which new genetically engineered (GE) foods are entering the market. This is followed by a description of the array of potential hazards that should be considered by efforts designed to anticipate or evaluate unintended adverse health effects. It is important to emphasize that the hazards presented below can occur with foods regardless of the method of production or processing and are not specific to the process of genetic engineering. INTRODUCTION Predicting and assessing potential adverse human health impacts arising from compositional changes in foods modified by a number of methods, including the genetic engineering of foods, are challenging. Adverse consequences could be narrow in occurrence or diverse and widespread and, because they are unintended, will be unexpected. Foods that could be modified in composition as a result of agricultural biotechnology, as defined in Chapter 1 and described in Chapters 2 and 3, are of interest because of the growing awareness that commonly consumed food constituents and complex mixtures can be beneficial or harmful to health. Estimates based on population-based research indicate that approximately one-third of preventable morbidity and mortality is of dietary origin and/or a consequence of low levels of physical activity. In contrast to such long-term con-

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Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects sequences, acute toxicities of dietary origin appear to pose a relatively small population health burden. Acute food toxicities may be very severe, but they generally affect much smaller numbers of people and can be associated rapidly with the food source, so that they usually can be controlled relatively easily. FOOD SAFETY HAZARDS IN FOOD PRODUCTS General Hazards from Foods A variety of safety hazards are associated with foods produced by any method. These can be categorized from greatest to least hazardous by their probability to cause an adverse health effect as: pathogenic microorganisms, nutrient imbalances, naturally occurring toxicants, environmental and industrial chemicals, including pesticides, food and feed additives, food alterations associated with genetic modification. This categorization was first proposed by Wodicka (1982). Pathogens Types of Pathogenic Microorganisms Pathogenic microorganisms in food include: viruses, bacteria, toxin-producers, and parasites. Food-borne pathogens are often particularly risky for children, the elderly, and the immune-suppressed. There are millions of people stricken by food-borne illness every year in the United States and an estimated 76 million illnesses, 325,000 hospitalizations, and 5,000 deaths per year, mostly among the elderly and the very young (CDC, 2003). In the United States, the Norovirus is the most commonly found cause of food-borne illness; other viruses (rotavirus and astrovirus), as well as parasites (Giardia) and bacteria (Campylobacter), play a major role. Three pathogens, Salmonella, Listeria monocytogenes, and Toxoplasma gondii, are responsible for 1,500 deaths each year; other pathogens that also contribute to morbidity and mortality due to food-borne pathogens include Norovirus, Campylobacter, and Escherichia coli O157:H7. It is estimated that unknown pathogenic agents account for 81 percent of illnesses and hospitalizations and 64 percent of deaths due to food-borne illness (Mead et al., 1999). These numbers are far lower than in the past; in the United

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Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects States, measures such as drinking water disinfection, sewage treatment, milk sanitation and pasteurization, and shellfish monitoring have been largely successful. Newly emerging food safety hazards, however, are largely attributed to foodborne zoonoses that do not necessarily cause illness in animals and are therefore difficult to detect. Additionally, new vehicles have been identified, for example, Salmonella enteritidis found inside eggs (and not just on shells) and bacterial contaminants in juices, fruits, and vegetables formerly believed safe. Recently, outbreaks of the so-called “bird flu” have occurred, in which an avian virus is transmitted to humans through handling of birds (e.g., chickens in processing them for food) (Abbott and Pearson, 2004). Sources of Contamination Often contaminated water and animal feeds are the source for animals. In many instances these pathogens survive traditional preparation. For example, E. coli O157:H7 can persist in a rare hamburger and Salmonella enteritidis in an omelet or in a raw egg used for salad dressing. Bacteria can be transferred from foods intended to be properly cooked to other foods, such as when salmonella-contaminated chicken juice is on a cutting board that is then used to prepare a salad. Improper food storage can allow the growth of pathogens in food, such as Clostridium botulinum and Staphalococcus aureus. Although commodity corn and other grain products are strictly and regularly monitored at multiple processing stages, including mills, dairy facilities, and by regulators, practically all corn or corn products contain at least tiny amounts of fungal mycotoxins. In a recent report, 363 samples of cereal-based infant food were tested, and 100 percent were found to carry various mycotoxins (Lombaert et al., 2003). Consumer illnesses, however, have not been directly attributed to these small amounts of mycotoxin exposure. Although the potential exists for mycotoxins to reach hazardous levels, the level of monitoring makes it highly unlikely for a contamination event at hazardous levels to occur. Contaminated lots are identified and discarded, obviating the need for a recall. In a recent report for the UK Food Standards Agency, two loads of organic corn meal were prevented from being sold to consumers because of excessive levels of fumonisins, a type of mycotoxin (FSA, 2003). On occasion, a food processing plant is a source of contamination with either a biological (e.g., E. coli) or nonbiological (e.g., mycotoxin) contaminant. These events may be due to the inadvertent introduction of the contaminant or to a breakdown in the usual monitoring and control systems. When recognized, such events either are corrected before consumers are exposed to a potentially hazardous food or recalled by regulatory agencies (the U.S. Department of Agriculture’s Food Safety and Inspection Service and the U.S. Department of Health and Human Services, Food and Drug Administration).

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Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects Introduction of Pathogens into Food Contaminants that are introduced early in the production process are a major problem. Introduction of contaminants can occur via contaminated animal feeds, impure water, and inadequately composted manure, or by “contamination during production and harvest, initial processing and packing, distribution, and final processing” (Tauxe, 1997). Others are introduced or enhanced in the process of food storage and preparation. Reports of incidences of bacterial food-borne illnesses in the United States between 1996 and 2001 have declined: Yersinia (49 percent), Listeria (35 percent), Campylobacter (27 percent), and Salmonella (15 percent) (Pinner et al., 2003). These declines may be due to new food safety measures that were put in place in the 1990s. Infections with E. coli, however, have not shown a similar decline. The number of E. coli contamination events in the United States declined only between 2000 and 2001, suggesting a year-to-year variation rather than a consistent trend (Bender et al., 2004). Overall, reports of trends in meat contamination indicate that the prevalence of E. coli in ground beef may not have changed (FSIS, 2003). Nutrient Deficiencies, Toxicities, and Other Nutrient Imbalances Importantly, concerns regarding nutrient deficiencies and toxicities have been raised because of the acknowledged capability of genetic engineering to markedly change the composition of plant foods. Thus, modifications of food composition must consider the potential impact on nutrient deficiencies, toxicities, interactions, and/or other imbalances. The deletion of essential nutrients from foods or, more likely, their enhancement, has the potential of influencing the risk of nutrient deficiencies or toxicities, respectively, in the general or subsets of the population, depending on exposure patterns. In this context it should be noted that to date most nutrient toxicities are due to the addition of nutrient levels in excess of normal physiologic needs, achieved through fortification or due to the excessive consumption of nutrient supplements. Nutrient Deficiencies and Toxicities The concepts of nutrient deficiencies were developed several decades ago (Youmans, 1941), and have been undergoing significant change since then (Bendich, 2001). One recent conceptualization of deficient intakes is expressed by an Institute of Medicine report, that is, the “level of intake of a nutrient below which almost all healthy people can be expected, over time, to experience deficiency symptoms of a clinical, physical, or functional nature” (IOM, 1994). This concept recognizes that single and multiple nutrient deficiencies may have multiple manifestations that are expressed at diverse levels of intake, determined by gender, age, physiological state (e.g., puberty, postmenopause, preg-

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Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects nancy, and lactation), genetic variability, health status, activity levels, and diet composition, and often are the result of chronically inadequate intakes rather than acute insufficiency. This conceptualization is, however, very conservative in the sense that many individuals are likely to experience signs and symptoms of deficiency before “almost” all healthy people achieve a deficiency state. Importantly, acute and chronic effects of nutrient intakes are examined in the most recent evaluation of nutrient requirement levels (IOM, 1997, 1998, 2000a, 2000b). Although the diagnoses of specific nutrient states in individuals often are challenging, such diagnoses are relatively straightforward compared with the estimation of minimum intake levels that are required to prevent a deficiency state in an individual. Thus, the amount of a nutrient recommended to individuals to avoid deficiency is set at sufficiently high levels to minimize individual risk (to < 3 percent), that is, the Recommended Dietary Allowance, “the average daily nutrient intake level sufficient to meet the nutrient requirement of nearly all (97 to 98 percent) healthy individuals in a particular life stage and gender group” (IOM, 2001). The concept of nutrient toxicities is relatively new. Upper tolerable levels of intakes have been set only recently by authoritative bodies (IOM, 1997, 1998, 2000a, 2000b, 2001, 2003). Expanding Definitions of Nutrient Deficiencies and Toxicities Other aspects of nutrient deficiencies and toxicities relevant to this discussion are the expanding definitions of nutrients and of their benefits and toxicities and the increased recognition of the roles of genetic variability in determining susceptibility to deficiency and toxicity states. The current awareness of the link between food and health reflects both relatively detailed understanding of relationships between a nutrient and a designated function or disease risk (e.g., enhanced immune function and cardiovascular disease, respectively), and less-specific associations among diet and other disease risks (e.g., cancer). These links significantly expand traditional concepts of nutrient deficiencies and toxicities (IOM, 1997, 1998, 2000a, 2000b, 2001, 2003). Nutrient Imbalances and Interactions Adverse health effects also may occur as a consequence of interactions among nutrients or among essential nutrients and other common food components. The underlying mechanisms are multiple. The most common are influences on uptake or excretion, changes in assimilation, and alterations in metabolism. These have downstream effects on nutrient transport and storage and on nutrient-dependent functions (IOM, 1998). Relationships between calcium and phosphorus, calcium and iron, and iron and ascorbic acid serve as examples that

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Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects illustrate the complex character of problems that merit consideration in evaluations of nutrient-nutrient imbalances or interactions. Calcium and phosphorus form complexes in chyme when the calcium to phosphate ratio falls below 0.375:1. These complexes are expected to decrease calcium bioavailability. Various clinical studies, however, have not detected decreases in calcium absorption at ratios as low as 0.08:1. Thus theory has not been supported by empirical evidence. Others point out that homeostatic compensation may account for a lack of empirical support, but that homeostatic compensation becomes progressively more difficult as calcium intakes fall below requirement levels (IOM, 1997). This is of potential concern because mean calcium intakes among vulnerable age groups in the United States are significantly below estimates of need (Alaimo et al., 1994; Johnson, 2000). Thus one must consider not only relative amounts of nutrients in assessments of interactions, but also the possible influence of the absolute intake of one or, possibly, all interacting nutrients. To further illustrate the challenge, calcium intakes also may interfere with iron, zinc, and magnesium availability. Choosing iron for illustrative purposes, Hallberg and colleagues (1992) demonstrated a dose-response relationship between calcium intake and inhibition of iron absorption. The underlying mechanism for this interference is not clear. No one has demonstrated that iron deficiency in human populations is explained by excessive calcium intakes. On the other hand, demonstrating such relationships may be difficult among populations with low levels of iron deficiency. The external validity of studies assessing such impacts is limited by difficulties in simultaneously controlling multiple factors with adverse or enhancing effects on iron and/or calcium chemical activity or net bioavailability. For example, the availability of non-heme iron is enhanced markedly by the presence of ascorbic acid (vitamin C). Ascorbic acid appears to enhance nonheme iron absorption linearly at ascorbic acid intakes up to 100 mg. Absorption may be improved two-to sixfold or more within this range of ascorbic acid intakes (Allen and Ahluwalia, 1997). Issues related to iron absorption become particularly relevant to populations of European extraction because of their high rates of hemosiderosis. Nutrient interactions also may influence nutrient urinary losses. Using calcium again for illustrative purposes, the acquisition of optimal bone mass in childhood and adolescence is dependent upon several factors, such as genetic endowment, activity, and diet (Bachrach, 2001). Among the dietary factors that influence calcium excretion is sodium (Massey and Whiting, 1996). The effect of sodium on calcium retention is sufficiently large to possibly influence the acquisition of bone mass in childhood or bone loss in adulthood, especially among individuals with low levels of calcium intake. Although the renal tubular mechanism that underlies this interaction is understood incompletely, it is described sufficiently well to suggest that anticipatory reviews of nutrient physiology could arouse concerns of this nature and other analogous ones in early evaluations of new products. Thus exclusive reliance on postmarketing population studies to discover

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Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects such adverse interactions or waiting until their discovery to assess biological plausibility of statistically significant relationships is not necessary. Increased gastrointestinal losses of nutrients also occur, but mostly via interactions with food components other than nutrients. The most functionally relevant losses on a global basis relate to interactions between phytate and iron or zinc. The impact of phytates can be much broader. They also have been implicated in binding to proteins, thereby decreasing their availability as well as to calcium and starches. Binding calcium decreases its bioavailability and also may impair carbohydrate digestion since calcium ions enhance amylase activity. Phytates also bind to carbohydrates and thus may influence their bioavailability more directly (Jenkins et al., 1994). Other antinutrients also are of potential concern (see Box 5-1). Interference with assimilation may occur because of dietary amino acid imbalances that adversely affect the biological value of a protein or of a protein BOX 5-1 Potential Adverse Health Effects of Antinutrients Antinutrients are compounds in food that inhibit the normal uptake or utilization of nutrients. In addition to those discussed in the text of this chapter, other antinutrients are of potential concern to human health. These include: Lectins: Lectins are compounds that typically originate in plants that can bind to epithelial surfaces and damage them through incompletely understood mechanisms. They also appear to have broader bioactivities that are as yet poorly described (Evans et al., 2002; Reynosa-Camacho et al., 2003; Santidrian et al., 2003). Nevertheless, their potential adverse effects remain an area of concern (Jenkins et al., 1994). Saponins: Saponins also are plant-based compounds that typically foam when added to water. They can hinder the absorption of lipid-soluble nutrients by binding bile acids and interfering with micelle formation through this and possibly other mechanisms. Tannins: Tannins are compounds found in nearly every plant throughout the world, and can form complexes with dietary proteins and thus impair their digestibility. Tanins also might reduce trypsin and amylase activity, thus impairing protein and carbohydrate digestion (Jenkins et al., 1994). Other food components with antitryptic and anti-α-amylase action, found in commonly consumed foods (e.g., cereal grains and legumes), potentially can interfere with digestion.

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Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects mixture. These are described well in the literature. These adverse effects result from inefficiencies in amino acid utilization imposed by inadequate levels of one or more indispensable amino acids. Differences in the biological values of proteins (the ratio of retained to absorbed nitrogen) are appreciated easily by contrasting the value of wheat gluten to egg protein at levels of intake that range from 0.1 g/kg body weight to 0.6 g/kg body weight in adults. Wheat gluten’s biological value ranges from 1.06 to 0.37 as intakes rise from 0.1 to 0.6 g/kg body weight and that of egg protein from 1.03 to 0.71 at intakes from 0.2 to 0.5 g/kg body weight (Inoue et al., 1974; Young et al., 1973). The ratio depends primarily on the ability of amino acid patterns of individual proteins or dietary protein mixtures to meet an organism’s indispensable amino acid needs for growth and maintenance. The potential impact of dietary amino acid balance is evident in studies of amino acid supplementation or protein mixtures. For example, the successive supplementation of wheat flour with lysine, tryptophan, methionine, threonine, isoleucine, and valine increases nitrogen retention incrementally to over three times the levels achieved without supplementation (Bressani, 1971). Studies of protein mixtures also reflect these relationships, that is, the net biological value of dietary protein depends on the proportion of protein from various sources. For example, corn and soybean have complementary amino acid patterns in the sense that although corn is relatively deficient in lysine, it supplies a relative surfeit of methionine; the opposite is true for soy. Thus a maximum biological value is attained when corn supplies approximately 40 percent of dietary protein and soy 60 percent. The mixture’s biological value falls as the proportion of either protein source falls or rises in isonitrogenous diets. Furthermore, it is possible to add a protein with an imbalanced amino acid pattern to an otherwise adequate dietary protein intake and observe adverse effects on growth rates, as some amino acids are known to cause other types of toxicities when consumed in excessive amounts, and others to do so only when their intake is excessive relative to that of a structurally similar amino acid (i.e., amino acid antagonisms with excessive intakes of leucine relative to those of isoleucine) (Harper, 1964). Naturally Occurring Toxicants Adverse effects can result from consuming naturally occurring toxicants in foods through several different scenarios (see Box 5-2). Some foods contain naturally occurring toxins that elicit adverse reactions only if the food is eaten in abnormal amounts. An example is the presence of cyanogenic glycosides in lima beans, cassava, and fruit pits, among other foods. Cyanide can be released from these compounds by enzymes present in the plant tissues during the storing and processing of the food or by stomach acid after the food has been ingested. The amount of cyanide present in lima beans varies with the variety, the part

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Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects BOX 5-2 Adverse Health Effects: Naturally Occurring Toxicants in Foods Naturally occurring constituents of food that can cause illness (at levels that are relatively easy to reach by consumers) Toxicants in seafood (improper harvesting) Staphylococcal enterotoxins in various foods (improper storage and handling) Botulinal toxins in various foods (improper preservation) Mycotoxins in various foods (improper storage) Unusual foods that can cause illness (at levels that are relatively easy to reach by consumers) Poisonous mushrooms Poisonous plants such as foxglove and Senecio Poisonous fish such as puffer fish Naturally occurring constituents of food that can cause illness (with unusually high consumption) Cyanogenic glycosides in lima beans, cassava, and fruit pits Phytoestrogens in ginseng Naturally occurring components of foods that can cause illness with usual consumption levels (only in susceptible consumers) Food allergens Lactose intolerance Components leading to celiac disease Naturally occurring constituents of foods that can cause illness with usual consumption levels (only with unusual means of processing or preparation) Lectins in under-processed kidney beans Trypsin inhibitors in under-processed legumes SOURCE: Adapted from Taylor and Hefle (2003).

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Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects of the plant, and the growing conditions. Commercial varieties of lima beans, in comparison with certain wild varieties, contain low levels of cyanogenic glycosides. However, ingesting three-fourths of a pound of lima beans may be sufficient to elicit a severe case of cyanosis (Cheeke and Shull, 1996), the result of cyanide poisoning. Other foods contain naturally occurring toxicants that elicit adverse reactions only if the food is prepared in a manner that allows for the retention of a toxicant that is normally destroyed or discarded. For example, the lectins present in kidney beans are typically destroyed by thoroughly cooking kidney beans before eating them. Noah and colleagues (1980) reported that consumers who soaked a quantity of raw kidney beans and ate them with little or no cooking had a prompt onset of abdominal pain and bleeding. In other cases, foods may become contaminated with naturally occurring toxicants. For example, botulism and staphylococcal food poisoning are produced by bacteria, aflatoxin, and other mycotoxins by molds, and paralytic shellfish poisoning and ciguatera fish poisoning arise from aquatic algal microorganisms called dinoflagellates. Consumer illnesses have been attributed to the very occasional presence of cucurbitacins in zucchini (Morgan and Fenwick, 1990). Cucurbitacins are thought to be formed in zucchini as a result of environmental stress, such as drought. Ingestion of these compounds may result in acute gastrointestinal illness. However, consumers often avoid eating them because they cause bitterness in the zucchini. Opines are an example of toxicants that are generated by a bacterial pathogen (crown gall) produced in vegetables that carry the disease (discussed in Chapter 2). Opines are small carbon compounds produced by tumors that are induced by the crown gall bacteria. The opines spread throughout the plant, and therefore may be ingested when the plant is eaten, however, with unidentified effects on humans (McHughen, 2000). Environmental or Industrial Contaminants Toxic substances are classified in general according to their potential to cause adverse effects with acute or longer-term exposure, the organ systems affected, and types and severity of effects that they elicit. A toxin generally is defined as any endogenously produced substance that can induce a harmful response in a biologic system, causing serious injury to a specific function or organ, or producing death. The sixteenth century physician Paracelsus said that “the dose makes the poison,” meaning that any substance is harmful if too much of it is ingested, and that different endpoints are associated with different dosages. Types of Toxicity Toxic substances often are classified according to the organ system where damage occurs, for example, to the brain and nervous system (neurotoxicity), to

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Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects the liver (hepatotoxicity) and so forth. Toxic substances also may be classified by their source, effect (e.g., carcinogenic initiator or promoter), physical state (e.g., gas and liquid), chemical characteristics (e.g., proteins, heavy metals and halogenated hydrocarbons), and/or mechanism of action (e.g., cytochrome oxidase inhibition by cyanide). Toxic effects may be local or systemic, although most often this differentiation is a matter of degree. The affected organ most likely to initiate systemic effects is the brain or, more broadly, the central nervous system. Toxins or toxicants that affect the circulatory system, blood and broader hematopoietic system, visceral organs, and the skin, in that order, also may have systemic effects, and those that affect muscle and bone generally are the least likely to have broader systemic consequences. Toxins and toxicants also may be classified by the type of damage they induce. Various examples are discussed below. Acute Effects Some proteins are known to be toxic (e.g., botulinum toxin, snake venoms, and plant toxins). Generally, known toxic proteins in food act via acute mechanisms at low doses (EPA, 2000; NRC, 2000). Another type of acute effect is teratogenicity. Teratogens are classified as acute toxicants because generally there is only a small window during which they can disrupt embryonic development. Subchronic and Chronic Effects Testing for subchronic and chronic adverse effects of specific compounds in whole foods is not a simple undertaking (see Chapters 4 and 6) and in consequence, we have very little information about the role of proteins (e.g., lectins), and other food constituents that produce such effects. Certain agents are of particular concern because of their ability to disrupt specific types of normal cellular processes and cause birth defects, mutations, and/or cancer. There is a certain amount of overlap among such agents. For example, prenatal exposure to high levels of vitamin A causes teratogenicity but, to date, has not been associated with mutagenicity. The role of diet and cancer also remains of concern, although specific cancer-causing dietary components have not been identified conclusively to date (Doll and Peto, 1981). Regulatory oversight, through acts such as the Delaney Clause, protect consumers from agents known to be carcinogenic by not allowing them to be added to foods. Very few natural compounds in foods have been tested for their potential to produce adverse health effects (NRC, 1996), although there is some evidence for carcinogenicity of some compounds in laboratory animals (NRC, 1996). In 1996 the National Academies suggested that these may confer risks equivalent to those associated with chemical and pesticide residues in food (NRC, 1996). For example, foods naturally contain many potential carcinogens, includ-

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Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects In susceptible individuals, B cells produce allergen-specific IgE antibodies in response to the immune system’s exposure to the specific allergen (Taylor and Hefle, 2002). However, IgE-mediated allergic reactions can also be provoked by exposure to allergens in pollens, mold spores, animal dander, and insect venoms. In the sensitization phase of the allergic response, the allergen-specific IgE antibodies bind to the surfaces of mast cells in various tissues and basophils in the blood. While the sensitization phase is symptomless, subsequent exposure to the specific allergen leads to an interaction between the mast cell/basophil-bound IgE antibodies and the allergen. This interaction causes the sensitized cells to degranulate and release physiologically active mediators into the bloodstream and tissues. These mediators, including histamine, leukotrienes, and prostaglandins, are responsible for the symptoms encountered in IgE-mediated food allergies. An IgE-mediated food allergy causes a variety of clinical manifestations (see Table 5-1), including gastrointestinal, cutaneous, and respiratory symptoms (Bock and Sampson, 2003). Oral allergy syndrome is perhaps the most mild manifestation of IgE-mediated food allergies and is associated primarily with symptoms involving the mouth and pharynx, such as oral itching, lip swelling, facial urticaria, and labial angioedema (Ortolani et al., 1988). Oral allergy syndrome is typically associated with consuming certain fresh fruits and vegetables among individuals who have been sensitized to specific environmental pollens; the implicated fruits and vegetables have allergens that cross-react with the specific pollen allergens (Ortolani et al., 1988). The most severe manifestation of an IgE-mediated food allergy is anaphylactic shock, a rapidly developing constellation of symptoms that can be potentially fatal within minutes if not properly treated (Burks and Sampson, 1993). Foodinduced systemic anaphylaxis is reportedly the leading cause of anaphylaxis admissions to emergency departments in the United States (Kemp et al., 1995; Yocum and Khan, 1994). IgE-mediated food allergies are estimated to be responsible for more than 29,000 emergency room visits and 150 to 200 deaths in the United States annually (Bock et al., 2001). The diagnosis of food allergies can be approached in several ways. In vitro tests of food-specific IgE antibodies are available for common food allergens. A food elimination diet also can be used, in which the suspected food is eliminated from the diet for one to two weeks to test whether symptoms improve (Sampson, 1993). Open or single-blind food challenges can then be used to screen for allergic reactions to food upon reintroduction into the diet. However, the doubleblind, placebo-controlled food challenge (Bock et al., 1988; Goldman et al., 1963) is necessary to confirm a food allergy when multiple food allergies are diagnosed and/or when positive responses need confirmation. Skin tests can also be used to evaluate the existence of food-specific IgE antibodies. The choice of foods used in these challenges is based on a combination of clinical history, skin tests, results of elimination diets, and clinical judgment.

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Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects Eight foods or food groups (milk, eggs, fish, shellfish, peanuts, soybeans, tree nuts [e.g., almonds, walnuts], and wheat) are responsible for more than 90 percent of all IgE-mediated food allergies on a worldwide basis (FAO, 1995). Beyond these most common allergenic foods, more than 160 other foods have been documented to cause IgE-mediated food allergies (Hefle et al., 1996). While the list of the eight most common allergenic foods or food groups is relatively consistent on a worldwide basis, other foods can be common causes of IgE-mediated food allergies in certain regions or countries as a result of cultural dietary preferences. These include buckwheat in Southeast Asia and sesame seeds in countries with principally Middle Eastern populations (Taylor et al., 2002). Non-IgE mediated allergic reactions also encompass a variety of clinical syndromes (Table 5-1). They are expressed clinically over a period of several hours to days and are believed to have an immunologic basis. Among the most common of the non-IgE-mediated allergic reactions are various gastrointestinal syndromes occurring most commonly in early infancy and associated with milk or soybeans, common components of infant formulae (Guajardo et al., 2002; Nowak-Wegrzyn, 2003). They are believed to have an immunologic basis primarily involving either gastrointestinal eosinophils or lymphocytes (Guajardo et al., 2002; Nowak-Wegrzyn, 2003). Food-induced enterocolitis most commonly occurs among infants allergic to cow milk or soy-based formulas. It can cause projectile vomiting and chronic diarrhea severe enough to cause dehydration (Powell, 1978). Benign eosinophilic proctocolitis also presents in the first few weeks or months of life, often in association with cow- or soy-based formula (Machida, 1994; Odze, 1995). Food protein-induced enteropathy involves protracted diarrhea, often vomiting, failure to thrive, and malabsorption of carbohydrates. Celiac disease is an extensive inflammatory condition of the mucosa of the small intestine (Hall, 1987; Murray et al., 2003). Also known as gluten-sensitive enteropathy and celiac sprue, celiac disease is associated with sensitivity to the ingestion of the primary protein fractions of wheat, rye, barley, and related grains, the so-called gluten fraction of wheat, and related protein fractions from the other grains (Skerritt et al., 1990). The mechanism involved in celiac disease is incompletely understood, but the absorptive epithelium of the small intestine is damaged as a consequence of immune-cell-mediated inflammation, and serious nutritional deficiencies can result (Murray et al., 2003). Dermatitis herpetiformis is a related skin condition that also is associated with gluten sensitivity (Hall, 1987; Murray et al., 2003). Allergic eosinophilic gastroenteritis (Min and Metcalfe, 1991) may possibly involve food allergy. IgE may play some role in colic and gastroesophageal reflux in infants, but its role remains unclear (Kelly, 1995). Clinical assessment of non-IgE mediated allergic reactions is similar to that for IgE-mediated reactions in terms of taking a history. However, there are no in vitro or skin tests available for the diagnosis of gastrointestinal syndromes associated with milk and soybeans in early infancy, nor is the placebo-controlled,

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Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects double-blind challenge used. The definitive diagnosis of non-IgE-mediated food allergy is made when objective improvements occur after the suspected offending food is eliminated from the diet. For celiac disease, similar approaches are employed, although serological assays are frequently used (Murray et al., 2003). Food Intolerance In contrast to true food allergies, food intolerances involve one of several mechanisms: anaphylactoid reactions, metabolic food disorders, or idiosyncratic reactions (Taylor and Hefle, 2002). Anaphylactoid reactions are elicited by substances that provoke the release of mediators from mast cells and basophils without the intervention of IgE. Although this mechanism is well-described for certain adverse reactions to pharmaceuticals, evidence for the existence of food-induced anaphylactoid reactions is largely based on individual case reports where the mechanism is not well characterized (Taylor and Hefle, 2002). Examples of metabolic food disorders include lactose intolerance and favism. Favism is an intolerance to the consumption of fava beans or the inhalation of pollen from the Vicia faba plant (Marquardt, 1981). Favism produces acute hemolytic anemia in individuals who express an inherited deficiency of the enzyme erythrocyte glucose-6-phosphate dehydrogenase (G6PDH), which is critical for maintaining levels of reduced glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH). GSH and NADPH help protect the erythrocyte from oxidative damage. Fava beans contain naturally occurring oxidants, vicine and convicine, which are able to damage the erythrocytes of individuals with the G6PDH deficiency. Idiosyncratic reactions refer to those adverse reactions to food experienced by certain individuals. The mechanism underlying these responses are unknown (Taylor and Hefle, 2002). A good example is sulfite-induced asthma (Taylor et al., 2003). Sulfites are common food additives that are known to elicit asthmatic reactions in sensitive individuals, particularly in situations in which exposure to residual sulfite is comparatively high. Sulfite sensitivity reportedly affects less than 4 percent of all asthmatics (Bush et al., 1986). SAFETY HAZARDS IN FOOD PRODUCTS ASSOCIATED WITH GENETIC MODIFICATION Nature of Modification A large number of compositional changes in foods may potentially arise from any method of genetic modification of food. Furthermore, genetic engineering, as previously discussed, has a higher probability of producing unanticipated changes than some genetic modification methods, such as narrow crosses, and a lower probability than others, such as radiation mutagenesis. Therefore, the nature of

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Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects the compositional change merits greater consideration than the method used to achieve the change, for example, the magnitude of additions or deletions of specific constituents and modifications that may result in an unintended adverse effect, such as enhanced allergenic potential. Constituents whose levels are increased could well include some of the “natural” toxins present in food, thereby enhancing the potential for adverse effects to occur with consumption of that food. Examples of deletions of specific constituents that merit consideration are those intended to enhance nutrient bioavailability by reducing barriers to absorption. Modifications intended to enhance uptake of essential nutrients (e.g., reduction of phytic acid to improve iron or zinc bioavailability, and thus decrease the risk of iron or zinc deficiency) are particularly attractive. Paradoxically, the more effective such modifications are, the likelier are unintended effects on the bioavailability of other dietary constituents, that is, changes that increase uptake of essential trace elements also may increase the bioavailability of unwanted contaminants, such as toxic heavy metals. Hazards that may be of concern after this type of general evaluation are toxicities, allergies, nutrient deficiencies and imbalances, risks related to nutrient displacement, and risks related to endocrine activity and diet-related chronic diseases. These categories are not exclusive. For example, although idiopathic (without known origin) reactions also are distinct possibilities, they are not discussed because, by their very nature, they are presently impossible to predict. Since many idiopathic reactions are likely genetically determined, they may be predictable in the future as genetic polymorphisms are better understood. The International Life Sciences Institute has reviewed the safety of DNA in foods (ILSI, 2002b) and has published a monograph on Genetic Modification Technology and Food: Consumer Health and Safety (ILSI, 2002a). Genetic Variability Human genetic variability likely plays an important role in adverse reactions to foods. The human genome project presents unprecedented opportunities to understand risks to diet-related disease and susceptibility to toxicities. Early haplotype (a unique combination of alleles in a specified chromosomal region) maps support the expectation that unraveling polygenic traits that likely account for a substantial portion of diet-related chronic disease risks may not be as difficult as originally projected (Gabriel et al., 2002). The importance of genetic variability is most salient in the dominance of nutrient-related disorders for which newborns are screened routinely in much of the United States. The predominance of nutrient-related genetic screens is unlikely due to chance, and likely reflective of the predominant role that diet plays in genetic selection, a role that is understood incompletely. Nine disorders are included in current newborn screening programs; the treatment of eight of those disorders rely significantly on nutritional management: phenylketonuria, galac-

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Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects tosemia, maple syrup urine disease, homocystinuria, biotinidase deficiency, congenital adrenal hyperplasia, cystic fibrosis, and some hemoglobinopathies (Khoury et al., 2003). The capability to screen for yet another condition of nutritional importance, celiac disease, may soon be available (Maki et al., 2003). Two classic examples relevant to genetic variability and resulting adverse health effects related to food intake help to illustrate this source of potential concern: celiac disease and hemosiderosis. As previously noted, celiac disease is caused by gluten sensitivity. Gluten is found in wheat, barley, and rye. Hemosiderosis, a condition that results in iron overload, is due to the abnormal regulation of iron uptake. Its prevalence also has been related to the presence of pernicious anemia. Both hemosiderosis and pernicious anemia appear to be most prevalent in populations of Northern European ancestry. It is notable that these examples were identified because of the adoption of Northern European dietary practices by other groups or became evident because of recent (in evolutionary terms) changes in European diets. Awareness of the prevalence of these conditions likely reflects the intensity with which European populations have studied themselves rather than an increased vulnerability to this type of genetic variability. The relatively common occurrence of such genetic variants suggests that “food-relevant” genetic polymorphisms are likely to occur in other ethnic groups. This is not surprising given the role that food availability plays in defining survival and fitness. The central role of food constituents is evident in evolution and, more recently, in early studies of genetic control. What is less salient are the selective advantages associated with most traits identified to date. Furthermore, it is unlikely that such traits are limited to common dietary constituents, such as gluten, iron, and lactose. Hereditary fructose intolerance (HFI) illustrates that such traits are not limited to historically overt conditions as those noted above. HFI demonstrates the unmasking of genetic predispositions that accompany marked changes in the food supply. As fructose has become increasingly prevalent in diets throughout the world, HFI is recognized increasingly as a disease of weaning (Cox, 2002). Mutations of the liver enzyme fructaldolase, required for the metabolism of ingested fructose, is the cause of this condition that may result in death if unrecognized. Its phenotype is not expressed until dietary fructose levels exceed thresh-olds that are not well-characterized. Less salient in its acute effects but similar in its dependence on dietary challenges is the role of saturated fats in the etiology of cardiovascular disease and the marked changes in its prevalence when predisposed individuals are exposed to these common dietary fats. The recent unmasking of a genetic predisposition to type II diabetes among the Pima Indians (Kovacs et al., 2003; Lindsay et al., 2003) is a third example. Undoubtedly, the human genome’s definition will lead to the identification of other genetic variants of functional relevance to diet and it is likely that this knowledge will impact on methods to screen for potentially adverse effects and

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Safety of Genetically Engineered Foods: Approaches to Assessing Unintended Health Effects predict their functional significance. Considerations such as these can be daunting because of the likelihood of 10 to 30 million different single nucleotide polymorphisms (SNPs) in the human genome. Most anticipate that monogenic traits will be relatively easy to identify by relating specific SNPs to specific phenotypes. Of greater interest, however, are traits that are multigenic in origin. Fortunately, recent information suggests that deciphering the basis of multigenic traits may not be as daunting as once thought. Haplotype studies in humans strongly suggest that SNPs are not distributed randomly or independently of each other, and that specific SNPs occur in defined blocks within all chromosomes. These studies also suggest that haplotype blocks vary in size, but their average size differs consistently among population groups defined on the basis of biologic, demographic, and other traits expected to influence patterns of genetic inheritance. If this is borne out by ongoing haplotype mapping efforts, assessing links between individual genotypes and diet-related diseases that are multigenic in origin appears promising (Gabriel et al., 2002). Thus the genetic vulnerability of individuals to some compounds in foods is evident from historical and contemporary perspectives (Stover and Garza, 2002). However, the contribution that GE foods may make to this area of potential adverse health effects in unclear. Methods to predict and assess potential unintended health effects from GE foods are addressed in Chapter 6. REFERENCES Abbott A, Pearson H. 2004. Fear of human pandemic grows as bird flu sweeps through Asia. Nature 427:472–473. Alaimo K, McDowell MA, Briefel RR, Bischof AM, Caughman CR, Loria CM, Johnson CL. 1994. Dietary intake of vitamins, minerals, and fiber of persons 2 months and over in the United States: Third National Health and Nutrition Examination Survey, Phase I, 1988–91. Adv Data 258:1-28. Allen LH, Ahluwalia N. 1997. Improving Iron Status through Diet: The Application of Knowledge Concerning Dietary Iron Bioavailability in Human Populations . Online. The MOST Project. Available at http://www.mostproject.org/improving%20iron%20status.pdf. Accessed May 25, 2003. Bachrach LK. 2001. Acquisition of optimal bone mass in childhood and adolescence. Trends Endocrinol Metab 12:22–28. Bender JB, Smith KE, McNees AA, Rabatsky-Ehr TR, Segler SD, Hawkins MA, Spina NL, Keene WE, Kennedy MH, VanGilder TJ, Hedberg CW. 2004. Factors affecting surveillance data on Escherichia coli 0157 infections collected from FoodNet sites, 1996–1999. Clin Infect Dis 38:5157–5164. Bendich A. 2001. Beyond deficiency: New roles for vitamins and other bioactive molecules—A memorial tribute to Lawrence J. Machlin. Nutrition 17:787–788. Bernstein JA, Bernstein IL, Bucchini L, Goldman LR, Hamilton RG, Lehrer S, Rubin C, Sampson HA. 2003. Clinical and laboratory investigation of allergy to genetically modified foods. Environ Health Perspect 111:1114–1121. Bock SA. 1987. Prospective appraisal of complaints of adverse reactions to foods in children during the first 3 years of life. Pediatrics 79:682–688.

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