3
Synthetic Carcinogens in the Diet

This chapter addresses two principal questions. First, do naturally occurring and synthetic chemicals, considered as general classes, differ in their chemical and physical properties, e.g., extent of halogenation, lipophilicity, environmental or biological half-life? Second, can the principles and techniques used to evaluate synthetic chemicals as potential carcinogens be used to evaluate naturally occurring chemicals? It should be emphasized that the purpose of this chapter is comparative. It discusses general principles and does not review in detail the wealth of material available on the universe of synthetic chemicals. Instead, it examines how synthetic chemicals have been addressed by the toxicological and regulatory communities, and considers whether naturally occurring chemicals, as a group, may differ in their potential hazardous properties, as a group, from synthetic chemicals.

The public, the scientific community, and, consequently, the regulatory agencies have been concerned with synthetic chemicals for some time. Although food additives are regulated, many synthetic additives, both intentional and incidental, can be found in the diet. Some of the incidental ones, such as cyclamate, are at the center of current controversies regarding their possible carcinogenicity. In the past, the public has been exposed to other synthetic additives before they were regulated and/or removed from the diet.

It is axiomatic that a specific chemical, whether it is of natural or synthetic origin, is the same in its physical, chemical, and toxicological properties. However, it is uncertain whether naturally occurring chemicals, as a class, differ in some important way from



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--> 3 Synthetic Carcinogens in the Diet This chapter addresses two principal questions. First, do naturally occurring and synthetic chemicals, considered as general classes, differ in their chemical and physical properties, e.g., extent of halogenation, lipophilicity, environmental or biological half-life? Second, can the principles and techniques used to evaluate synthetic chemicals as potential carcinogens be used to evaluate naturally occurring chemicals? It should be emphasized that the purpose of this chapter is comparative. It discusses general principles and does not review in detail the wealth of material available on the universe of synthetic chemicals. Instead, it examines how synthetic chemicals have been addressed by the toxicological and regulatory communities, and considers whether naturally occurring chemicals, as a group, may differ in their potential hazardous properties, as a group, from synthetic chemicals. The public, the scientific community, and, consequently, the regulatory agencies have been concerned with synthetic chemicals for some time. Although food additives are regulated, many synthetic additives, both intentional and incidental, can be found in the diet. Some of the incidental ones, such as cyclamate, are at the center of current controversies regarding their possible carcinogenicity. In the past, the public has been exposed to other synthetic additives before they were regulated and/or removed from the diet. It is axiomatic that a specific chemical, whether it is of natural or synthetic origin, is the same in its physical, chemical, and toxicological properties. However, it is uncertain whether naturally occurring chemicals, as a class, differ in some important way from

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--> chemicals of synthetic origin. Do they, for example, persist in the environment in the same way? Thus, knowledge of synthetic chemicals may be invaluable in assessing the potential carcinogenicity of naturally occurring chemicals. A characteristic of synthetic chemicals often deemed desirable for commercial purposes is chemical stability. This is often achieved by halogenation, particularly chlorination, although other techniques are also available, such as the replacement of ester bonds by ether linkages. Chemical stability usually gives rise to persistence in the environment, to bioaccumulation, and to recalcitrance to metabolism. For example, highly chlorinated chemicals such as PCBs, PBBs, and the pesticides DDT and mirex have been shown to be persistent and hazardous. In addition, TCDD, a byproduct of combustion and other processes, is a stable, environmentally persistent chemical that bioaccumulates and causes severe acute and chronic effects in animals. Naturally occurring chemicals, unlike synthetics, have not been intentionally altered to achieve chemical stability. A number of halogenated compounds are natural products; however, their degree of chlorination and, therefore, their resistance to metabolism, is generally not as great as that of synthetic chemicals. In addition, naturally occurring chemicals usually exist as a single stereoisomer; synthetics, on the other hand, are frequently a mixture of two or more stereoisomers. Further, naturally occurring chemicals are more likely to appear in the diet as conjugates than are synthetic chemicals. Such conjugates include glucuronides, glucosides, methylated compounds, glutathione conjugates, and others. Many of these conjugates will be hydrolyzed, either in the gastrointestinal tract or in mammalian tissues, and the resulting hydrolysis products may be toxic if indeed the chemical in question is toxic. Furthermore, it should be noted that the toxicokinetics following the ingestion of a conjugate may influence the rate of delivery of the toxic moiety to the active site.

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--> Synthetic Food Additives Tables 3-1 and 3-2 list examples of direct and indirect synthetic food additives, respectively. Direct (intentional) additives include antioxidants, colorants, flavor ingredients, artificial sweeteners, solvents, and humectants. Indirect additives include pesticides, solvents, and packaging-derived chemicals. Table 3-3 lists sources of nonintentional food additives, some natural, some synthetic, that may have toxicologic significance. Depending upon circumstances of processing or packaging, the same chemical can be a direct, indirect, or nonintentional food additive. Direct, or intentional, food additives are chemicals or compounds, natural or synthetic, added deliberately to make some change in the food product, e.g., to add color, to preserve, or to provide a nutritional supplement (see Table 3-1). Indirect additives are chemicals or compounds present but not added deliberately to change a product. Pesticides can be classified based on their use. Table 3-2 lists examples of indirect synthetic food additives, including pesticides, according to their use category. Representative chemical classes are presented. Over the past several decades, pesticides from many of these categories have been banned or otherwise regulated because of a concern for their carcinogenic potential or other risk to human health or the environment. Table 3-2 also provides examples of chemicals derived from packaging materials, including vinyl chloride (a known human carcinogen), acrylonitrile (a known animal and suspected human carcinogen), as well as dyes used for printing. Recent attention has focused on several phthalate esters used as plasticizers since these compounds are known peroxisome proliferators in rodents. Table 3-3 lists sources of nonintentional food additives with possible toxicological significance. These chemicals may enter foods indirectly in trace amounts during production, processing, packaging, and storage from a wide variety of sources, both natural and synthetic.

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--> Table 3-1 Selected Direct Food Additives Appearance modifiers Glazes, waxes, polishes. Clouding and crystallization agents and inhibitors (e.g., methyl glucoside-coconut oil ester, oxystearin), colors and coloring adjuncts (e.g., FD & C Yellow No. 5 (tartrazine, a pyrazolone dye)), FD & C Yellow No. 6 (Sunset Yellow, a monoazophenyl naphthalene dye)), and surface finishing agents (e.g., oxidized polyethylene and polyvinyl-pyrrolidone) Curing and pickling agents Sodium nitrite, salt, sodium tripolyphosphate, and ascorbic acid Nutrient replacements Microemulsified protein (natural) and sucrose polyesters Nutrient supplements All essential nutrients (e.g., vitamin A and other vitamins, iron and other minerals, amino acids, and essential fatty acids) pH control agents Acids (e.g., acetic, tartaric, and hydrochloric), bases (e.g., sodium bicarbonate and sodium hydroxide), and buffering agents (e.g., sodium citrate) Processing aids Fermentation and malting aids (e.g., gibberellic acid and potassium bromate), formulation aids (e.g., starch as a binder), freezing agents (e.g., liquid nitrogen and carbon dioxide), lubricants and release agents (e.g., mineral oil), and washing, peeling, and vegetable-cleaning agents (e.g., sodium hydroxide and sodium n-alkyl benzene sulfonate)

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--> Product stability and safety aids Antioxidants (e.g., BHA), preservatives and antimicrobials (e.g., sodium benzoate and potassium sorbate), sequestrants (e.g., EDTA and sodium metaphosphate), synergists (e.g., citric acid), oxidizing and reducing agents (e.g., hydrogen peroxide), and inert gases (e.g., nitrogen and combustion gas) Solvents, vehicles, bulking agents, dispensing aids Solvents (e.g., alcohol and propylene glycol), bulking agents (e.g., microcrystalline cellulose), and dispensing aids (e.g., nitrogen) Sweeteners Nutritive (e.g., sucrose and glucose (natural)) and reduced calorie (e.g., saccharin, cyclamate, acetsulfam, and aspartame) Taste and flavor modifiers (except sweeteners, salt, and pH control agents) Flavoring ingredients (e.g., vanillin), flavoring adjuncts (e.g., triethyl citrate (solvent and fixative)), flavor enhancers (e.g., msg (natural) and ethyl maltol) Texture and consistency control agents Anticaking agents (e.g., calcium stearate and silica aerogel), dough conditioners and strengtheners (e.g., potassium bromate and acetone peroxide), drying agents (e.g., anhydrous dextrose), emulsifiers (e.g., mono- and diglycerides and polysorbates), firming agents (e.g., calcium salts), flour-treating agents (e.g., benzoyl peroxide), humectants (e.g., sorbitol), leavening agents (e.g., sodium carbonate and sodium acid phosphate), masticatory substances (e.g., paraffin and

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--> Texture and consistency control agents (continued) glycerol esters of wood rosin), stabilizers and thickeners (e.g., modified food starches), surface-active agents (e.g., sodium lauryl sulfate and dimethyl polysiloxane), and texturizers (e.g., glycerine and modified food starch)   Sources: Adapted from Hall 1979, Hodgson and Levi 1987, U.S. GPO 1991. Occurrence and Exposure This section discusses chemical additives found in drinking water and the diet, foodstuffs containing the most important additives, and concentrations of additives in representative foodstuffs and drinking water. The large amount of exposure data on synthetic chemicals in the diet precludes detailed enumeration. For the great majority of constitutive chemicals so far identified (see Chapter 2), virtually no data exist on the extent of human exposure. However, among these are approximately 2,000 constitutive chemicals with recognized commercial value, including nutrients, some colors, and many flavoring ingredients, which are either isolated from natural sources or duplicated by synthesis for intentional addition to foods. For these substances there are extensive data on exposure, both from natural and intentional addition (NRC 1973, 1975, 1976, 1978, 1979, 1984, 1989; Stofberg and Kirschman 1985; Stofberg 1987). Drinking Water Whether consumed directly or used in food processing and preparation, drinking water is a source of potential exposure to a large

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--> Table 3-2 Selected Indirect Synthetic Food Additives and Additives Used in Packaginga Use Category Chemical Class or Broad Category Pesticides   Acaricides Organosulfur compounds, formamidines, dinitrophenols, and organochlorines (DDT analogs) Algicides Organotins Fungicides Dicarboximides, chlorinated aromatics, dithiocarbamates, and mercurials Herbicides Amides, acetamides, bipyridyls, carbamates, thiocarbamates, phenoxy compounds, dinitrophenols, dinitroanilines, substituted ureas, and triazines Insecticides Chlorinated hydrocarbons, chlorinated alicyclics, cyclodienes, chlorinated terpenes, organophosphates, carbamates, thiocyanates, dinitrophenols, fluoroacetates, botanicals (nicotinoids, rotenoids, and pyrethroids), juvenile hormone analogs, growth regulators, inorganics (arsenicals and fluorides), and microbials Insecticide synergists Methylenedioxyphenyls, and dicarboximides Molluscicides Chlorinated hydrocarbons Nematocides Halogenated alkanes Rodenticides Anticoagulants, botanicals (alkaloids and glycosides), fluorides, inorganics, and thioureas

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--> Packaging   Adhesives and pressure-sensitive adhesives A wide variety of solvents, resins, polymers, glues, preservatives, and miscellaneous additives Adjuvants (emulsifiers, antistatic agents, lubricants, plasticizers, colorants, filtering aids, etc.) A wide variety of chemical classes Antioxidants and stabilizers Substituted phenols, triazenes, organotin stabilizers, other free-radical acceptors, inorganic compounds, and adjuvants Coatings (for metals, plastics, paperboard, etc. A wide variety of polymers, copolymers, resins, rosins, drying oils, glycerides, fatty acids, catalysts, colorants, solvents, and adjuncts Components of paper and paperboard A wide variety of polymers, copolymers, catalysts, olefins, esters, inorganic compounds, chelating agents, defoaming agents, preservatives, solvents, and adjuncts Substances used as basic components of articles in contact with food (containers, utensils, films, membranes) Polymers, copolymers, resins, fibers, lubricants, colors, and adjuvants

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--> Substances used to control the growth of microorganisms Hydrogen peroxide and other peroxides, iodine and chlorine compounds, quaternary ammonium compounds, sulfonated detergents, other surface-active agents, and solvents Prior-sanctioned substancesb   GRAS substances (substances generally recognized as safe for use in or on foods)c   Sources: Adapted from Hodgson and Levi 1987, U.S. GPO 1991. a The indirect additive regulations, in general, make no distinction between natural and synthetic ingredients, except that at several points a regulation expressly authorizes the synthetic equivalents of certain naturally occurring substances, such as fatty acids. Furthermore, the distinction between natural and synthetic is often not clear for these substances. The majority are doubtless synthetic. b Nearly all of the regulations covering indirect additives (components and constituents) used in packaging, also permit, as a class, and unless otherwise restricted, all ''prior sanctioned" substances, i.e., those authorized by FDA or USDA for use in food prior to 1958. Those known by the agency to be prior sanctioned are listed in CFR 21, Part 181. c Packaging regulations also consistently permit, unless otherwise restricted, any GRAS substances used in or on food. There is no one listing of GRAS substances. The two major lists are those published by the FDA (CFR 21, Parts 182, 184, and 186, and lists published by the Flavor and Extract Manufacturers' Association (Smith, R.L., and R.A. Ford, 1993). Beyond the published lists, however, the law permits private, unpublished determination of GRAS status, subject to challenge by the FDA. The number of such private GRAS substances is presumably not large but is unknown. Most GRAS substances would not be suitable for use in packaging.

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--> Table 3-3 Sources of Nonintentional Food Additives of Possible Toxicological Significance During Production   Antibiotics and other agents used for prevention and control of disease   Growth-promoting substances   Microorganisms of toxicologic significance   Parasitic organisms   Pesticide residues (insecticides, fungicides, herbicides, etc.)   Toxic metals and metallic compounds   Radioactive compounds During Processing   Microorganisms and their toxic metabolites   Processing residues and miscellaneous foreign objects   Radionuclides During Packaging and Storage   Labeling and stamping materials   Microorganisms and their toxic metabolites   Migrants from packaging materials   Toxic chemicals from external sources number of synthetic chemicals. However, it is difficult to quantify the number of chemicals or the amounts to which a particular individual might be exposed via drinking water. The U.S. Environmental Protection Agency has published two surveys with information for assessing potential exposure, though one must observe the caveats provided by the agency (EPA 1992). One of these sources of information is a database established by the EPA in response to the Safe Drinking Water Amendments of 1986, which mandated that community water systems and nontransient,

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--> noncommunity water systems be monitored for 34 to 51 volatile organic compounds, identified as "unregulated contaminants." The database was designed to assist the agency in estimating the occurrence of these compounds and their seasonal variations. A summary report presenting results as of July 31, 1992, had data from 43 states on systems using ground and surface water sources for drinking water (EPA 1992a). The trihalomethanes (chloroform, bromodichloromethane, dibromochloromethane, and bromoform), which are formed as the result of the chlorination process, were reported as being present most frequently. All other unregulated contaminants occurred in less than 5% of the water samples. Of the 32 states that reported positive data on specific chemicals, over half found that the trihalomethanes, ethylbenzene, toluene, tetrachloroethylene (perchloroethylene), xylene (all isomers combined), cis/trans-1,2-dichloropropene, 1,1-dichloroethane, dichloromethane, and fluorotrichloromethane occurred at least once. However, the agency cautions that no national inferences can be made from these data nor can the actual concentrations to which any individual is exposed be calculated using these data. The second source of information for assessing potential exposure to synthetic chemicals is the National Survey of Pesticides in Drinking Water Wells, the results and interpretation of which were reported in two phases (EPA 1990, 1992b). The data represent measurements on a statistically representative sample of wells. In the study 1,349 samples from community water system wells and rural domestic water wells were analyzed for the presence of 101 pesticides, 25 pesticide degradation products, and nitrate. The samples were collected between 1988 and 1990. Phase I involved the national estimates of frequency and concentrations of the pesticides, while Phase II, entitled Another Look: National Survey of Pesticides in Drinking Water Wells, Phase II Report (EPA 1992b), was concerned with the presence of the pesticides and correlations with local factors such as patterns of use and ground water vulnerability. It should be noted that the survey was restricted to drinking

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